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Stanley Jacobson, Elliott M. Marcus, Stanley Pugsley - Neuroanatomy For The Neuroscientist-Springer International Publishing (2018)
Stanley Jacobson, Elliott M. Marcus, Stanley Pugsley - Neuroanatomy For The Neuroscientist-Springer International Publishing (2018)
Elliott M. Marcus
Stanley Pugsley
Neuroanatomy
for the
Neuroscientist
Third Edition
Neuroanatomy for the Neuroscientist
Stanley Jacobson • Elliott M. Marcus
Stanley Pugsley
Neuroanatomy
for the Neuroscientist
Third Edition
Stanley Jacobson Elliott M. Marcus
Boston, MA, USA Jamaica Plain, MA, USA
Stanley Pugsley
South Abington Twp., PA, USA
Elliott M. Marcus, M.D., was a friend and colleague for over 40 years, and he was
the father of neurosciences at the Tufts University School of Medicine, and with his
passing in 2011, we lost a dear friend, colleague, dynamic teacher, and an outstand-
ing neurologist. This textbook is dedicated to his memory.
The purpose of this textbook is to enable a neuroscientist to discuss the structure
and functions of the brain at a level appropriate for students at many levels of study
including undergraduate, graduate, dental, or medical school level. It is truer in
neurology than in any other system of medicine that a firm knowledge of basic sci-
ence material, that is, the anatomy, physiology, and pathology of the nervous sys-
tem, enables one to readily arrive at the diagnosis of where the disease process is
located and to apply their knowledge at solving problems in clinical situations. The
authors have a long experience in teaching neuroscience courses at the first- or
second-year level to medical and dental students and to residents in which clinical
information and clinical problem-solving are integral to the course.
Dr. Jacobson has taught neuroanatomy and gross anatomy for many years to
medical and dental students at the Tufts University School of Medicine and an
upper-level biology course on the central nervous system to undergraduates at Tufts
University in Medford, MA, utilizing many of Dr. Marcus’ cases to engage stu-
dents. He also has used several movies on the brain developed in Hollywood to
further involve students.
Dr. Marcus practiced neurology for 40 years, and he developed a case history of
problem-solving sessions in the recent book Integrated Neurosciences by
E.M. Marcus, S. Jacobson, and T. Sabin (Oxford University Press, 2014), and he
also conducted a problem-solving seminar in which all medical students at the
University of Massachusetts participate during their clinical neurology clerkship
rotation. This provides students an opportunity to refresh their problem-solving
skills and to review and update that basic science material essential for clinical
neurology.
Dr. Pugsley is a senior neurosurgeon with extensive clinical and teaching experi-
ence. He trained in neurosurgery at the Tufts University School of Medicine. He
observed that the inclusion of case history materials reinforces the basic science
vii
viii Preface
subject matter learned by markedly increasing the interest of students in both basic
and clinical science material. He has added many new cases and a neurosurgeon’s
prospective to disease.
In this third edition, decisions had to be made so that the size of the textbook
remained within reasonable limits. Throughout this book, we have utilized clinical
illustration and integrated the anatomical, neurological, and neurosurgery managed
in most of today’s neuroscience courses, and we have responded to many of the very
worthwhile suggestions from our colleagues. The book contains the core topics con-
cerned with the central nervous system and all chapters have been updated. We have
divided this edition into five parts: (I) Introduction to the Central Nervous System
(Chaps. 1–10); (II) The Systems (Chaps. 11–17); (III) Neuropathology, (Chap. 18)
Vascular Diseases and (Chap. 19) Nonvascular Diseases; (IV) The Nonnervous
Elements, (Chap. 20) Meninges, Blood Supply, Ventricular System, (Chap. 21)
General Case Histories, Problem-Solving, and (Chap. 22) Movies on the Brain; and
(V) Descriptive Atlas of the Brain and Spinal Cord (Chap. 23).
We have added in several chapters, in Chap. 19, representative cases of trauma
and infectious diseases within the CNS to aid students in understanding disease
processes with the central nervous system and, in Chap. 20, the meninges, blood
supply, and ventricular system. We have included an atlas at the end of the spinal
cord (Chap. 3), brain stem (Chap. 6), and diencephalon chapters (Chap. 8). We have
maintained the atlas chapter 23 and 24 with Chapter 23 Descriptive Atlas of Gross
Brain and Chapter 24-Descriptive Atlas –Myelin stained sections.
In Chap. 22, Movies on the Brain, we have added in the film on Concussion
which is an important discussion of the effects of contact sports. We have also used
several of these movies as an adjunct to our teaching; (1) Young Frankenstein
directed by Mel Brooks has a wonderful scene introducing the CNS and (2) Little
Shop of Horrors directed by Frank Oz features Steve Martin as a dentist, and this is
a great introduction to the trigeminal nerve). There are many movies in the science
fiction genre that are also useful for discussion, and Star Trek and its many episodes
and its medical manual are at the top of our list!
A number of other topics including cell biology, cell physiology, embryology,
gross anatomy, nerve, and muscle are usually covered in other courses, and the stu-
dent should examine these topics in those courses. The anatomy of the peripheral
nervous system and autonomic nervous system has been touched on briefly here but
should be reviewed in one of the standard gross anatomy texts.
Most of the case histories utilized in the chapters have been drawn from the files
of Drs. Marcus and Pugsley. For a number of the cases, our associates at the
Geisinger Medical Center in Danville, PA, Tufts Medical Center, St. Vincent
Hospital, Fallon Clinic, and the University of Massachusetts School of Medicine
either requested our opinion or brought a given case to our attention and provided
information from their case files. These individual neurologists and neurosurgeons
are identified in the specific case histories. We are also indebted to the many refer-
ring physicians of those institutions. Medical house officers at St Vincent Hospital
presented some of the cases to Dr. Marcus during morning report. In particular, our
thanks are due to our associates in Worcester: Drs. Bernard Stone, Alex Danylevich,
Preface ix
Robin Davidson, Harold Wilkinson, and Gerry McGillicuddy. Drs. Sandra Horowitz,
Tom Mullins, Steve Donhowe, Martha Fehr, and Carl Rosenberg provided clinical
information from their files for some of the case histories. Our associates at the New
England Medical Center Drs. John Sullivan, Sam Brendler, Peter Carney, John
Hills, Huntington Porter, Thomas Sabin, Bertram Selverstone, Thomas Twitchell,
C. W. Watson, and Robert Yuan likewise provided some of the clinical material. Dr.
Milton Weiner at St Vincent Hospital was particularly helpful in providing many of
the modern neuroradiological images. Dr. Sam Wolpert and Dr. Bertram Selverstone
provided this material for the earlier version of the text. Dr. Val Runge from the
Imaging Center at Texas A&M provided the normal MRIs. Dr. Anja Bergman (left-
handed) had the patience to be our normal case, and the images from her brain form
the normal MRIs in basic science chapters and atlas. Dr. Tom Smith and his associ-
ates in pathology provided much of the recent neuropathological material. Drs. John
Hills and Jose Segarra provided access to neuropathological material for the earlier
version of the text. Drs. Sandra Horowitz and David Chad provided critic of particu-
lar chapters.
Dr. Sarah B. Cairo, M.D., M.P.H., while still a medical student at Tufts Medical
School developed the illustrated drawings that were used throughout the second edi-
tion of this book, and they will be used in this edition to illustrate the retina, path-
ways, levels of the spinal cord, levels of the brain stem, and levels of the thalamus.
Dr. Samuel Giles, MD, while a student at Tufts University School of Medicine,
developed the Malaria and HIV/AIDS cases. He has continued to help us while he
is training in Neurology at the University of Florida in Jacksonville.
Dr. Mary Gauthier Delaplane while a medical student at Boston University
School of Medicine provided anatomical drawings illustrating the cranial nerves
and the neuroembryology. Anne Que, Paul Ning, Tiffany Mellott, Elizabeth Haskins,
and Tal Delman aided Dr. Delaplane. Dr. Marc Bard provided drawings for an ear-
lier text, An Introduction to the Neurosciences, 1972, while a student at the Tufts
University School of Medicine, and we have continued to utilize or have modified
some of these illustrations. We have also borrowed with permission from other pub-
lished illustrations. We have attempted to contact these original sources for contin-
ued permissions. We will acknowledge subsequently any sources that have been
inadvertently overlooked. In many of the clinical chapters, various medications are
recorded. Before utilizing these medications, the reader should check dosage and
indications with other sources.
It is with great pleasure we extend our thanks to our publishers and particularly
our editor Simina Calin for all her help. Special thanks to Michael J. Lukus, PA-C;
Steven Toms, M.D.; and Michel Lacroix, M.D., for the advice and support in this
endeavor. Any faults or errors are those of the authors, and we would therefore
appreciate any suggestions or comments from our colleagues.
xi
xii Contents
Part V Atlas
23 Descriptive Atlas�������������������������������������������������������������������������������������� 667
23.1 Gross Brain Sections: Coronal and Horizontal Sections������������������ 667
23.2 Gross Brain: Lateral Surface (Fig. 23.1)������������������������������������������ 668
23.3 Gross Brain: Medial Surface (Fig. 23.2)������������������������������������������ 669
23.4 Gross Brain Slices: Coronal (Figs. 23.3–23.9) �������������������������������� 670
23.5 Gross Brain Slices Horizontal (Fig. 23.10)�������������������������������������� 677
24 Myelin-Stained ���������������������������������������������������������������������������������������� 679
24.1 Myelin-Stained Coronal Brain Sections (Figs. 24.1, 24.2,
24.3, 24.4, 24.5, 24.6, and 24.7) ������������������������������������������������������ 679
24.2 Myelin-Stained Horizontal Sections (Figs. 24.8, 24.9, 24.10,
and 24.11) ���������������������������������������������������������������������������������������� 685
24.3 Myelin-Stained Sagittal Sections (Figs. 24.12 and 24.13)���������������� 689
Part I
Introduction to the Central Nervous
System
Chapter 1
Introduction to the Central Nervous System
Abstract The brain and spinal cord form the central nervous system. The brain is the
part of the central nervous system that is housed in the cranium/skull. It consists of the
brain stem, diencephalon, cerebellum, and cerebrum. At the foramen magnum, the high-
est cervical segment of the spinal cord is continuous with the lowest level of the medulla
of the brain stem. The spinal nerves from the sacral, lumbar, thoracic, and cervical levels
of the spinal cord form the lower part of the peripheral nervous system and record gen-
eral sensations of pain, temperature touch, and pressure. The 12 cranial nerves attached
to the brain form the upper part of the peripheral nervous system and record general
sensations of pain, temperature touch, and pressure, but in addition we now find the
presence of the special senses of smell, vision, hearing, balance, and taste. The blood
supply to the brain originates from the first major arterial branches from the heart insur-
ing that over 20% of the entire supply of oxygenated blood flows directly into the brain.
Homo sapiens evolved into the modern human in southern Africa for millions of
years. About 100,000–60,000 years ago, they struck out and spread initially along
the continental coast throughout Africa, into the Middle East, Europe, the Indian
subcontinent, and the rest of Asia and finally crossed the land bridge from Asia into
North America and then down into South America (the Out of Africa theory). The
evidence for this comes partly from dating bones to specific periods, but also from
genetics. As you move further away from Africa, across Asia, and then the Americas,
the genetic diversity of indigenous populations drops. This implies that the source
of these populations was in Africa and gradually lost diversity as it expanded.
Human beings enter the world naked but equipped with a nervous system that,
with experience, is ready to function in almost any environment.
One word summarizes the function of the nervous system: “reaction.” The central
nervous system (brain and spinal cord) monitors and controls the entire body by its
peripheral divisions, which are distributed to all the muscles, organs, and tissues. The
brain has an advantageous site in the head and above the neck, which can move in about
a 140° arc. Close to the brain are all of the specialized sense organs, which permit us to
see, smell, taste, and hear our world. The central nervous system is protected by fluid-
filled membranes, the meninges, and surrounded by the bony skull and vertebrae.
The basic conducting element in the nervous system is the nerve cell, or neuron
(Fig. 1.1). A neuron has a cell body, dendrite, and axon. The cell body contains
many of the organelles vital to maintain the cell structure and function, including
the nucleus and nucleolus, and is considered the tropic center of the nerve cell. The
dendrites extend from the cell body and increase the receptive surface of the neuron.
The axon leaves the cell body and connects to other cells. Axons are covered by a
lipoproteinaceous membrane called myelin that insulates the axons from the fluids
in the central nervous system. The site of contact between the axon of one nerve cell
and the dendrites and cell body of another neuron is the synapse (see Chap. 2). The
cells in the nervous system are classified based on their shapes: unipolar, bipolar,
and multipolar (Fig. 1.1; Table 1.1). In the central nervous system, the nerve cells
are supported by glia and blood vessels; in the peripheral nervous system, they are
supported by satellite cells, fibroblasts, Schwann cells, and blood vessels.
Fig. 1.1 Types of neurons in the central nervous system. The cells in the nervous system are
classified based on their shapes: unipolar, bipolar, and multipolar. The input (red) reaches the den-
drites of each cell and is then transported (blue) into the axon where it connects to the next neuron
via a synaptic interruption
1.1 The Neuron 5
Nuclei. Throughout the brain and spinal cord, there are groupings of neurons with a
common function; these are the nuclei. They are found throughout the spinal cord
(ventral and dorsal horn), brain stem (cranial nerve nuclei, reticular formation),
diencephalon (nuclei of the thalamus, hypothalamus, subthalamus, and metathalamus),
basal ganglia (caudate, putamen, globus pallidus, substantia nigra), and cerebral
cortex (amygdaloid nuclei).
Lamina. In the cerebral cortex, cerebellar cortex, and superior colliculus, the gray m
atter
is on the surface and organized anatomically into horizontal columns and physiologically
into vertical columns permitting a nearly infinite number of interconnections.
The senses. Aristotle distinguished five senses: hearing, sight, smell, taste, and
touch. Modern neuroscience, however, includes the five special senses (balance,
vision, hearing, taste, and smell) and the four general senses (pain, temperature,
touch, and pressure). Humans have evolved a series of specialized receptors for
each of these different sensory functions (Table 1.2). The special sensory appara-
tuses are found in the head: the eye and its protective coverings and muscles, the
membranous labyrinth in the temporal bone for hearing and balance, the nose with
olfactory receptors, and the tongue with taste buds. The receptors for general sen-
sation (mechanoreceptors, nociceptors, and thermoreceptors) are located primarily
in the body’s largest organ, the skin. Certain areas, e.g., the lips, fingers, feet, and
genitalia, have a proliferation of the tactile mechanoreceptors. Everywhere except
on the soles and palms we have hair, which is an important tactile receptor but is
continually being depleted by our concern for grooming. The pain receptors, or
free nerve endings in the skin, are located throughout the body, but probably more
receptors are in the skin over the face, lips, hands, and feet and then over the rest
of the body. As you review the receptors in Table 1.2, sense on your own body how
the soles are especially good for feeling pressure and placing the body safely in
light or darkness and the fingers and face are sensitive to touch and temperature.
Remember that we have only discussed the skin receptors so far, which respond to
external stimuli. However, there are also similar receptors within the respiratory,
cardiovascular, endocrine, gastrointestinal, and urogenital systems that monitor
our internal milieu.
1.1 The Neuron 7
Fig. 1.2 Hairy skin showing the epidermis, dermis, and hypodermis. The blood vessels, lymph
vessels, sweat glands, hair follicle, Pacinian tactile receptor, and free nerve endings (for pain) are
also demonstrated (from Human free science.org)
Muscles. The 640± muscles in the body form the bulk of the body and consist of three
different functional and histological entities: skeletal, smooth, and cardiac. Skeletal
muscles are found in the head, neck, arms, legs, and trunk and permit us to undertake
voluntary movements. Smooth, or unstriated, muscles are found in the viscera, blood
vessels, and hair follicles. Cardiac muscles form the auricles and ventricles of the heart.
Each muscle group has a specialized nerve ending that permits the impulse car-
ried down to the motor nerve via a peripheral nerve to stimulate the muscle through
release of a specific chemical. Contraction of the three muscle groups in response to
sensory information originates from the central nervous system via the efferent/
motor peripheral nerves.
Sensory receptors. The general and special sensory receptors in the skin (Fig. 1.2)
provide the afferent nerves that carry sensory information to the spinal cord and
brain. The brain analyzes the sensory input before the muscles, which are controlled
8 1 Introduction to the Central Nervous System
by the efferent nerves carrying information from the brain or spinal cord, and makes
a response. These integrative functions of the central nervous system form the bulk
of the discussion in this book.
The nervous system consists of a peripheral and central division (Fig. 1.3). The
central nervous system (brain and spinal cord, Fig. 1.3) is surrounded by fluid-filled
membranes (meninges with CSF), and the brain is further protected in the bony
skull, while the spinal cord is housed in the bony vertebrae. In contrast, the peripheral
nervous system that brings information from and to the central nervous system lacks
a bony covering, but is protected by the fascia, skin, muscles, and organs where it
distributes. Sensory information enters the central nervous system through the affer-
ent divisions of the peripheral nerves.
Peripheral nerves are found everywhere in the body: skin, muscles, organs, and
glands. Peripheral nerves originate from either the spinal cord or the 12 cranial
nerves associated with the brain. The peripheral nervous system is divided into a
somatic and a visceral division. The somatic division innervates the skin and skel-
etal muscles in the body. The visceral, or autonomic division, innervates the cardiac
muscles of the heart and the smooth muscles and receptors in the blood vessels and
gastrointestinal, respiratory, urogenital, and endocrine organs. The details of the
peripheral nervous system are usually taught as part of gross anatomy, so the student
may want to review an anatomy text.
The central nervous system consists of the spinal cord and brain. The spinal cord
has 32 segments, while the brain consists of the brain stem, cerebellum, diencepha-
lons, and cerebrum. In Fig. 1.3, we show an isolated entire human CNS, while in
Fig. 1.4, we demonstrate the CNS in situ. Attached to all of the 32 segments of the
spinal cord and the brain stem are the sensory ganglia that form the first link in the
sensory system and bring the sensory information into the central nervous system.
Motor axons exit from each of the 32 segments of the spinal cord and all levels of
the brain stem and connect the central nervous system to all muscles and organs in
the body. In the spinal cord, much of the brain stem, and diencephalon, the neurons
are organized into nuclei, while in the superior colliculus of the brain stem, cerebel-
lum, and cerebrum, the neurons are organized anatomically into layers and func-
tionally into vertical columns.
The spinal cord, Chap. 4, is that portion of the central nervous system that lies in the
vertebral canal from the upper border of the atlas (first cervical vertebrae) to the
lower border of the first lumbar vertebrae in the adult (or third lumbar vertebrae in
the neonate). The spinal cord has 32 segments divided into five regions – cervical,
thoracic, lumbar, sacral, and coccygeal – and these regions innervate specific regions
10 1 Introduction to the Central Nervous System
Fig. 1.4 Central nervous system. In (a) a human CNS (brain and spinal cord) is shown, while in
(b) the brain and spinal cord are shown in situ in the skull. From an Introduction to Neurosciences,
Curtis, Jacobson, Marcus. Saunders 1974
1.2 The Nervous System 11
in the neck and upper extremity (cervical segments), thorax and abdomen (thoracic
levels), anterior leg and thigh (lumbar segments), and buttock and posterior leg and
thigh (lumbar segments). This ordered relationship between the spinal cord and
body produces a somatotopic organization throughout the central nervous system.
In the spinal cord, the parenchyma is organized simply into columns of gray
(location of neuronal cell bodies) and white matter (location of axons covered with
myelin) with the gray matter centrally placed and surrounded by the white matter.
12 1 Introduction to the Central Nervous System
This organization is not evident as one looks at isolated cross sections, but when
these sections are reconstructed serially, this columnar organization in the gray and
white matter is apparent. The columns of gray matter in the spinal cord appear in the
shape of a butterfly and are called horns and are divided into a dorsal sensory horn,
a ventral motor horn, intermediate zone, and commissural region. The largest neu-
ronal cell bodies are found in the ventral horn (ventral horn cells), whose axons
form the efferent division of the peripheral nervous system and innervate the skel-
etal muscles (Fig. 1.5). The white matter of the spinal cord is divided into three
columns: anterior, posterior, and lateral. The pathways interconnecting the spinal
cord and brain are found in these columns.
The spinal cord has a tubular shape and has two regions of enlargement, the
lower cervical that controls the upper extremity and the lumbosacral enlargement
that controls the lower extremity.
1.2.2.2 Brain
The columnar organization seen in the gray and white matter of the spinal cord is
modified in the brain stem by the development of the ventricular system and the
presence of the cranial nerves.
The brain stem (Figs. 1.6 and 1.7) consists of three regions from inferior to supe-
rior: medulla, pons, and midbrain. The brain stem is often the most difficult region
of the central nervous system for the student to learn, because of the presence of the
cranial nerves and associated nuclei. You may initially feel overwhelmed by its
1.2 The Nervous System 13
Fig. 1.7 Location of the cranial nerve nuclei in the brain stem with the motor nuclei on the left (in
blue) and the sensory cranial nerve nuclei on the right (in red) Cranial nerve I is found on the base
of the frontal lobe, while cranial nerve II originates from the eye and enters the thalamus. Cranial
nerves III–XII are found in the brain stem. Pure motor cranial nerves are III, IV, VI, XI, and XII.
Pure sensory cranial nerves are I, II and VIII. Mixed sensory and motor cranial nerves are V, VII,
IX, and X
With this reorganization on the floor of the fourth ventricle, the ventral horn
equivalent lies medial to the sulcus limitans, while the dorsal horn equivalent lies
lateral to the sulcus limitans.
Ventral horn equivalent contains somatic motor nuclei of cranial nerves X and
XII in the medulla, VI in the pons, and III and IV in the midbrain.
The dorsal horn equivalent, the general somatic sensory of CN V, and the vis-
ceral sensory of CNs VII, IX, and X lie lateral to the motor cranial nerve nuclei and
are separated on the floor of the fourth ventricle by the presence of the sulcus limi-
tans. One also now finds the presence of the special sensory nucleus of cranial nerve
VIII on the lateral most portion of the floor of the ventricle.
The intermediate zone of the spinal cord evolves into the reticular formation
which contains nuclei connecting to the cerebellum (inferior olive of the medulla)
and basal ganglia (red nucleus of the midbrain). In addition, in its center the motor
and sensory cranial nerve nuclei of IX, X, and XI are located, the ambiguous nuclei
innervating the skin and muscles of pharyngeal arch origin.
Within the tegmentum of the brain stem, sensory and motor tracts with the basilar
surface containing the descending corticospinal and corticobulbar pathways are found.
The lateral margin of the brain stem contains the anterolateral system.
Cranial nerves (see Chap. 7, Fig. 1.7). In order to understand the functions of
the brain stem, the student must first appreciate the distribution of the 12 pairs of
cranial nerves with nerve I attached to the olfactory bulbs on the base of the frontal
lobe, nerve II enters the diencephalon, and nerves III–XII originate in the brain stem
and are distributed in the head, trunk, and abdomen. Also the key to identify dys-
function in the brain stem is to know which cranial nerve nucleus lies in each level.
The nerve rootlets of cranial nerves III and V–XII are found on the anterior
surface of the brain stem, while the roots of cranial nerve IV exit on the posterior
surface of the brain stem. Table 1.3 lists the location of the cranial nerve rootlets and
nuclei in the appropriate brain stem level. Figure 1.7 demonstrates the location of
the cranial nerve nuclei in the brain stem.
Chapter 5 discusses the functional localization in the brain stem and also identi-
fies many of the nuclei and tracts of the brain stem in greater detail and includes
many examples of the consequences of disease in the brain stem. Since the
tegmentum where the cranial nerve nuclei are located is an especially important
region for the student to master, we have divided this region bilaterally into five
zones like an apple with the core and the center, being the reticular formation, and
the pulp being the surrounding four zones (Table 4.2).
The cerebellum, similar to the cerebrum, consists of gray matter on the surface and
white matter inside. It attaches to the tegmentum of the medulla, pons, and midbrain
by peduncles. The cerebellum is divided into two lateral hemispheres and the
midline vermis. From the phylogenetic (evolutionary development) standpoint,
there are three regions: archicerebellum, paleocerebellum, and neocerebellum.
The cerebellum functions at an unconscious level to permit voluntary motor
functions to occur smoothly and accurately. Alcohol consumption and many drugs
affect this region and temporarily impair, for example, gait and coordination.
In the white matter of the cerebellum, four deep cerebellar nuclei are found:
fastigius, dentatus, emboliform, and globosus. The cerebellar cortex projects onto
these nuclei, and then these nuclei project to other areas of the brain stem or dien-
cephalon. The anatomy and functions of the cerebellum are detailed in Chap. 13.
This region, identifiable in the gross brain after a sagittal section, separates the cere-
bral hemispheres and lies at the upper end of the brain stem. The third ventricle
separates the right and left diencephalic masses. Their lateral margin is the posterior
limb of the internal capsule, and their superior surface is the body of the lateral
ventricle and the corpus callosum. The diencephalon stands as the great way station
between the brain stem and cerebral cortex as all the major ascending pathways
terminate here. The diencephalon consists of the following divisions: thalamus,
hypothalamus, epithalamus, and subthalamus. The functional organization in the
diencephalon is the basis for much of the function seen in the cerebrum and also
contains the multimodal associations that make the cerebrum of the human such a
potent analyzer (Table 1.4).
The thalamus forms the largest division of the diencephalon, and it is divided
into several groupings of nuclei. All the ascending pathways terminate in thalamic
nuclei, and then their information is projected with some modifications onto a spe-
cific region of the cerebral cortex. A detailed discussion of the thalamus, its nuclei,
and its functions are found in Chap. 8.
16 1 Introduction to the Central Nervous System
The cerebrum, forming the bulk of the brain and thus of the central nervous system,
consists of a left and a right hemisphere containing the cortical gray matter, white
matter, and basal nuclei (Table 1.6). In each hemisphere, we find four lobes: the rostral
frontal lobe, the middle parietal lobe, and the posterior occipital lobe with the
inferiorly located temporal lobe and the insular and cingulate gyri (Figs. 1.8 and 1.9).
The cerebral cortex consists of a gray matter mantle on the outside and white matter
inside. The cortical gray matter which is corrugated and laminated has six layers and
is broken up into numerous gyri, separated by narrow spaces or grooves, the sulci
(Fig. 1.6). The 12–15 billion cortical neurons are found in the gray cortical mantle.
Students handling a preserved brain are often initially struck by the number of
the gyri and sulci in the cerebral hemispheres and surprised by its weight (about
1500 g). If you have a series of brains to observe, note that there is a great variation
in size. Remember that the size of the brain is related to the size of the skeleton,
muscles, and viscera (but not adipose tissue), so a person of small stature has a
1.2 The Nervous System 17
Fig. 1.8 Lateral surface of the right cerebral hemisphere. The motor (precentral) and sensory
(postcentral) and the location of the frontal, parietal, occipital, and temporal lobes are marked. The
somatotopic organization of the motor–sensory strip is labeled: the head, arm, thorax, abdomen,
and foot. The foot region of the motor strip extends onto the medial surface of the hemisphere as
the paracentral lobule
p roportionally smaller brain. Since women tend to be smaller than men, a woman’s
brain is usually smaller, although this in no way reflects intelligence or abilities.
One of the first clues about the different functions in the two cerebral hemispheres
was observed in stroke victims. Since the left cerebral hemisphere is dominant for
language in right-handed people (93% of the population), strokes in that hemisphere
usually affect speech. Besides language, dominant functions include initiation of
movement, emotions, and artistic abilities.
Note that each hemisphere provides motor controls to the opposite side of the
body. This is because the motor pathway from each cerebral cortex crosses in the
transition between the spinal cord and medulla consequently and the sensory fibers
also cross over to the opposite side of the body in over 90% of the human population
movement which initiates from the left hemisphere, making it dominant for initia-
tion of movement.
General features. The cerebral cortex is divided into four lobes, the frontal,
parietal, occipital, and temporal lobes (Fig. 1.7). Two other important regions in the
cerebrum are the deep insula (Fig. 1.9) within the lateral sulcus and the cingulate
gyrus on the medial surface of each hemisphere (Fig. 1.5). Three of the lobes also
have poles: the frontal, temporal, and occipital pole. The frontal lobe occupies 40%
of the brain and is separated from the parietal lobe by the central sulcus and from
the temporal lobe by the lateral sulcus. The other lobes can be identified (Fig. 1.7)
by first drawing a line from the parieto-occipital sulcus on the medial surface of the
hemisphere to the preoccipital notch on the inferior lateral surface of the hemisphere.
18 1 Introduction to the Central Nervous System
A line is then extended posteriorly from the lateral sulcus until it intersects the first
line. The parietal lobe lies above the lateral sulcus and behind the central sulcus,
anterior to the occipital lobe. The temporal lobe lies below the lateral sulcus anterior
to the occipital lobe. The occipital lobe is most posteriorly placed.
Functional Localization
The cerebral cortex includes motor, sensory, auditory, and visual regions. In addi-
tion, broad areas are involved with multimodal integration, which combines sensory
and motor with an emotional content to determine how to respond in any situation.
These emotional or limbic areas occupy much of the temporal (Chap. 16) and fron-
tal lobes (Chap. 11). (The limbic region denotes the cortical and subcortical brain
areas with tracts primarily involved with emotions, including the cingulate gyrus,
hippocampal formation, parahippocampal gyrus, and nuclei in the diencephalon
(see Chap. 8).) Human beings also use language extensively and much of the
frontal–parietal–occipital–temporal regions that abut the lateral sulcus in the left
hemisphere undertake these functions. Similar areas of the right hemisphere are
devoted to visual–spatial integration; you might wonder just how we have such
detailed information on the organization and functions of the human nervous
system. Much of it comes from research on primates or from defects observed in
patients after strokes, traumas, tumors, or degenerative neurological diseases like
Parkinson’s disease or Alzheimer’s.
Cortical White Matter
The axons entering or leaving the cerebral hemispheres form three distinctive
groups of fibers: associational, commissural, and subcortical.
1. Associational fibers. These two types of fibers (short U and long associational)
provide the integrative circuitry for movement, language, memory, and emotions.
Short associational fibers, the U fibers, form the bulk of (e.g., arcuate) local con-
nections within a hemisphere, while the long associational fibers interconnect
diverse areas in a hemisphere providing multimodal (e.g., uncinate associations
essential for cortical and cingulum).
2. Commissural fibers. Commissural fibers interconnect areas in the contralateral
hemispheres and permits learning and memory in one hemisphere to be shared
1.2 The Nervous System 19
with the other. The bulk of the frontal, parietal, occipital, and temporal lobes is
interconnected by the corpus callosum, best seen in the medial surface of the
hemisphere (Fig. 1.6). The corpus callosum consists of a rostrum, genu, body,
and splenium (Fig. 1.6).
The most rostral part of the temporal lobe and the olfactory cortex of the
uncus are interconnected by the anterior commissure. The hippocampus, an
important area for memory and orientation in space, is also connected by a com-
missure associated with the fornix.
3 . Subcortical fibers. This category of fibers includes fiber bundles reaching the cor-
tex from subcortical areas, corticopetal (toward the cortex), and axons leaving the
cortex and connecting to subcortical nuclei, corticofugal (away from the cortex).
Corticopetal fibers are the subcortical afferents to each cerebral hemisphere and
are primarily from the thalamus of the diencephalon.
Corticofugal fibers from the cerebral hemisphere project onto subcortical structures
including the basal nuclei, diencephalon, brain stem, cerebellum, and spinal cord.
The major subcortical fiber tracts leaving the cerebrum are the corticospinal,
corticonuclear, corticopontine, corticomesencephalic, and fornix.
The internal capsule contains the major grouping of corticofugal and corticope-
tal fibers of the cerebral cortex and consists of an anterior limb, genu, and posterior
limb (Figs. 1.10). The anterior limb provides fibers to and from the frontal lobe.
The genu provides fibers to and from the lower part of the frontal and parietal lobes
(corticonuclear). The posterior limb is the largest portion of the internal capsule and
includes the auditory radiations (auditory fibers to the auditory cortex), visual radia-
tions as well as projections from the sensorimotor cortex to the spinal cord, and
brain stem (corticospinal, corticonuclear, and corticopontine fibers).
Functions in the lobes of the cerebrum. Besides all the functions already
mentioned, the cerebral hemispheres also have the memory stores, which are the
foundation for most conscious and unconscious thought, cultural activity, sexual
behavior, and all of the other positive or negative traits which make the human being
so distinctive. Each cortical region has a memory store that permits the function of
that region (Table 1.5).
A detailed discussion of the functions of each cortical region is presented in
Chaps. 10–17.
Fig. 1.10 Coronal section showing basal nuclei and their relationship to the internal capsule and
thalamus. From Jacobson and Marcus, Neuroanatomy for the Neuroscientist, Springer 2011
Up to this point, the diverse functional gray regions in the brain and spinal cord have
been identified. In order for the nervous system to work, an extensive circuitry has
been established to interconnect areas throughout the central nervous system.
1.2 The Nervous System 21
We have just described the intrinsic white matter circuitry within the cerebrum: the
associational, commissural, and subcortical fibers. The subcortical fibers consist of
a multitude of axonal pathways that provide afferents to the cerebrum and efferents
from the cerebrum.
Many names are used for pathways within the central nervous system, including
fasciculus (bundle), lemniscus (ribbon), peduncle (stalk), and tract (trail). Many of
the pathways also have a name that indicates its function (e.g., the optic tract con-
nects the eyes and visual regions, the corticospinal (Fig. 11.8) tract runs from the
cortex to the spinal cord, and the corticonuclear (Fig. 11.9) tract connects the cere-
bral cortex to the cranial nerve nuclei). Unfortunately, the majority of the pathways
have names that give no clue to their function (e.g., the medial longitudinal fascicu-
lus, lateral lemniscus, and cerebral peduncle). The major tracts and their role in the
central nervous system are discussed in Chap. 6. For each pathway, the student
needs to learn the following:
1 . Cells of origin
2. Location of the tract in the brain or spinal cord
3. Site of termination of pathway
4. Function
We are now going to use as an example of function within the central nervous
system a functionally very significant region that provides volitional motor control
to the muscles of the body.
This cortex is found around the central sulcus that separates the frontal from the
parietal lobe, and it has six layers. Figure 1.6, lateral surface of the brain, identifies
the vertically oriented central sulcus which is surrounded by the precentral/motor
strip and postcentral/sensory cortex. This region controls the skeletal muscles in the
body that permit us to undertake so many tasks, and it is organized functionally in a
somatotopic organization with the head above the lateral sulcus and then comes the
neck, upper extremity, thorax, abdomen, and finally the lower extremity on the
medial surface of the hemisphere. The functions associated with the head occupy
one-third of the motor strip, and the functions of the upper extremity and especially
the hand occupy another one-third of the motor strip. The functions of the thorax
and abdomen occupy 10% of the motor/sensory strip, and the many functions
associated with the leg occupy 15% of the motor strip. In order to perform a skilled
motor task, one is dependent on precise sensory input, so we will first describe the
sensory portion of this circuit.
Sensory information from the foot to the sensorimotor cortex. In the sensory
system, three different neuronal groupings are traversed before the sensory informa-
tion reaches the cerebral cortex from the periphery: the primary, secondary, and
tertiary neurons. The sensory information of importance for precise movement orig-
inates from stretch receptors in the muscles, tendons, and joints of the hand and is
encoded as electrical impulses that detail the contraction status of the muscles,
22 1 Introduction to the Central Nervous System
tendons, and joints. The cells of origin, the primary cell bodies, are in the sensory
ganglia attached to the lumbar and sacral segments of the spinal cord. The information
is carried in by the dendrite of the primary sensory cell, and its axon enters the
central nervous system and ascends uncrossed and ipsilaterally in the posterior
column of the cord until the medullospinal junction. In the medullospinal junction,
second-order nerve cells appear in the posterior column, the gracile nucleus.
The axons from the primary neurons synapse on this nucleus. The axons of the
second-order axons cross the midline and ascend contralaterally in one of the major
ascending white matter pathways, the medial lemniscus, into the thalamus of the
diencephalon where they synapse on the third-order neurons in the ventral postero-
lateral nucleus, which then send fibers ipsilaterally onto the foot region on the upper
end and medial surface of the postcentral gyrus.
Motor control of the foot from the motor–sensory cortex. In the motor system,
two distinct neuronal groups are necessary for a movement: one in the motor cortex
of the cerebrum (the upper motor neuron) and the other in the spinal cord or brain
stem (the lower motor neuron). Motor control to the foot is carried centrifugally by
the corticospinal pathway. The corticospinal pathway to the foot originates from
layer 5 on the medial surface of the motor cortex of the precentral gyrus and to a
lesser degree in the postcentral gyrus. The fibers before exiting the gray matter are
covered with myelin and descend on the same side through the internal capsule,
cerebral peduncle, pons, and medullary pyramid. The corticospinal fibers cross
(decussate) to the other side of the brain in the medullospinal junction and enter the
lateral column of the spinal cord. Fibers to the musculature of the leg descend to the
lower lumbar and sacral levels and synapse in either the intermediate region of the
gray matter of the spinal cord or directly on the ventral horn cells. The axons from
the ventral horn cell leave the central nervous system forming the peripheral nerves
that synapse on the motor end plates of the muscles in the leg which produce the
contraction. The actual initiation of the movement is from the prefrontal and premo-
tor region of the frontal lobe (see Chap. 9).
Interruption of the corticospinal pathway or destruction of the motor cortex
produces upper motor neuron paralysis with increased reflex tone and spasticity,
while injury to the spinal cord ventral horn cells produces lower motor neuron
paralysis and atrophy of the muscle and decreased reflex tone (Table 1.6).
In summary, it takes three orders of sensory neurons to provide the information
to the cerebral cortex and two levels of motor neurons to produce a hand movement
in response to the sensory information. Note that the sensory information ascends
and crosses over, while the motor information descends and crosses so that the
Table 1.6 Comparison of upper motor neuron to lower motor neuron lesion
Upper motor neuron reflexes Reflexes: increase +3, +4, lesion in cortex or anywhere in
2+ (normal) corticospinal pathway. Spastic muscles, sign of corticospinal
3+ or 4+ are signs of UMN pathway). Babinski plantar response (Fig 4.17)
Lower motor neuron reflexes Reflexes: decrease to absent. Lesion (ventral horn cells, 0, +1,
2+ (normal) muscles flaccid, and ventral roots, motor cranial, atrophied.
0 > 1+ are signs of LMN Nerve nuclei and roots)
1.2 The Nervous System 23
same side is represented in the cerebral cortex. Of course, the hand movement also
needs a conscious decision to be made, which is what the cerebral cortex working
as a unit does.
The following two case histories Case History 1.1 and 1.2 have functional deficits due
to the presence of a tumor in the dura, a meningioma, on the frontal lobe. Figure 1.11
is the normal appearing midline/sagittal section showing the pituitary gland and other
structures. In Case History 1.1, the tumor is located on the medial surface of the
dominant hemisphere/right cerebral hemisphere which is the leg region of the motor
cortex. In Case History 1.2, the tumor is on the lateral surface of the prefrontal cortex
in the region which is the motor speech area of the frontal lobe.
Please compare and contrast the functional deficits that are produced by each of
these tumors which were both successfully removed.
Please note the normal appearance of an MRI in Fig. 1.11 to an MRI from our
cases in Figs. 1.12 and 1.13.
Case History 1.1 (Fig. 1.12)
This 45-year-old right-handed, married, white female, mother of four children was
referred for evaluation of progressive weakness of the right lower extremity of 2
years’ duration. This weakness was primarily in the right foot that she would stub
her toes and stumble. Because she had experienced some minor nonspecific back
pain for a number of years, the question of a ruptured lumbar disk had been raised
as a possible etiology. The patient labeled her back pain as “sciatica” but denied
any radiation of the back pain into the leg. She had no sensory symptoms and no
24 1 Introduction to the Central Nervous System
bladder symptoms. Six months before the consultation, the patient had transient
mild weakness of the right leg that lasted a week. The patient attributed her symp-
toms to “menopause” and depression, and her depression had improved with
replacement of estrogen.
1.2 The Nervous System 25
Neurological examination revealed the patient’s mental status was normal, and
the cranial nerves were all intact. There was a minimal drift down of the outstretched
right arm, and there was significant weakness in the right lower extremity with
ankle dorsiflexion, and plantar flexion was less than 30% of normal. Inversion at the
ankle was only 10–20% of normal. Toe extension was 50% of normal. And there
was minor weakness present in the flexors and extensors at the knee. In walking,
the patient had a foot drop gait and had to overlift the foot to clear the floor.
Examination of the shoes showed greater wear at the toes of the right shoe with
evidence of scuffing of the toe. The patient’s deep tendon stretch reflexes were
increased at the patellar and Achilles tendons on the right. In addition, reflexes in the
right arm at the biceps, triceps, and radial periosteal were also slightly increased.
The plantar response on the right was extensor (sign of Babinski) and the left was
equivocal. All sensory modalities were intact. Scoliosis was present with local ten-
derness over the lumbar, thoracic, and cervical vertebrae, but no tenderness was
present over the sciatic and femoral nerves.
Clinical diagnosis. With these clinical considerations in mind, an MRI of the
patient’s head was obtained, and the MRI confirmed the clinical impression of a
meningioma in the right cerebral hemisphere.
Comments
It was clear that the symptoms and signs were not related to compression of the lumbar
nerve roots by a ruptured disk. Such a compression (lumbar radiculopathy) would have
produced a lower motor neuron lesion, a depression of deep tendon stretch reflexes,
lumbar radicular pain in the distribution of the sciatic nerve, tenderness over the sciatic
nerve, no increase in reflexes in the upper or lower extremities, and no sign of Babinski.
The fact that reflexes were more active in both upper and lower extremities on the right,
with the sign of Babinski on the right, suggested a process involving the corticospinal
tract. The fact that the weakness was greatest in the foot suggested a meningioma
involving the parasagittal motor cortex where the foot area is represented.
This tumor was successfully removed by the neurosurgeon with an essentially
complete restoration of function.
Meningioma. The previous Case 1.1 dealt with compression of the medial surface
of the cerebral hemisphere resulting in a contralateral movement disorder in the con-
tralateral lower leg. In the following, Case 1.2 notes the effects of a meningioma
compressing the premotor region in the lateral surface of the dominant right hemi-
sphere, Broca’s area, with resultant effects on language functions. In addition in both
cases, the tumor was readily demonstrated by an MRI (Figs. 1.11 and 1.12) and
removed from the dura, and the patients underwent a complete functional recovery.
Case History 1.2 (Fig. 1.13). This 72-year-old female presented with several
months of progressive headaches and word-finding difficulties. She saw her local
physician, who ordered a head CT. The result was abnormal, suggesting a brain
tumor. Subsequent MRI imaging showed a well-circumscribed mass in the left
frontal region with the appearance of a meningioma (Fig. 1.12).
Past medical history: Hypertension, hypothyroid, varicose vein surgery.
Physical examination: General physical examination was unremarkable. Neuro
logic exam: awake and alert. She had word-finding difficulties. She was able to
26 1 Introduction to the Central Nervous System
comprehend well and could read. Repetition was better than spontaneous speech.
She exhibited frustration at this deficit. Cranial nerve exam was normal. Motor
exam revealed a mild right pronator drift but otherwise no focal motor or sensory
deficits. Reflexes were slightly brisker on the right than on the left.
Clinical diagnosis: With these clinical considerations in mind, an MRI of the
patient’s head was obtained, and the MRI confirmed the clinical impression of a
meningioma in the left frontal lobe.
Subsequent course: The patient was admitted to the hospital where she underwent
craniotomy and excision of this benign meningioma. Over several months postop-
eratively, she made a full recovery except for occasional word-finding difficulties
when she was particularly tired.
Comment: This is a typical presentation for a meningioma. These are slow-growing
benign processes, so they tend to evolve symptoms only very gradually. This tumor
is in the region of her expressive speech area, hence resulting in language deficit.
The mild hemiparesis was due to its proximity to the motor strip. Cure is expected if
the entire lesion can be safely removed.
Bibliography
Denny-Brown D. Handbook of neurological examination and case recording. 2nd ed. Cambridge:
Harvard University Press; 1957.
Edelman ER, Warach J. Medical progress—magnetic resonance imaging. N Eng J Med.
1993;328:708, 716, 785–91.
Greenberg JO, editor. Neuroimaging: a companion to Adams and Victor’s principles of neurology.
2nd ed. New York: Mc Graw Hill; 1999. p. 821.
Johanson DC, Wong K. Lucy’s legacy; the quest for human origins. New York: Harmony Books;
2009.
Kandel ER, Schwartz JH, Jessell TM. Principles of neurosciences. 5th ed. New York: McGraw
Hill; 2000.
Marcus EM, Jacobson S, Sabin T. Integrated neuroscience. 2nd ed. Oxford: Oxford University
Press; 2013.
Martin JH, Brust JCM, Hilal S. Imaging the living brain. In: Kandel ER, Schwartz JH, Niedermeyer
E, Lopes Da Silva F, editors. 1991. 1999.
Nolte J. The human brain. St Louis: Mosby; 1990.
Tatersall I. Human origins; out of Africa. Proc Natl Acad Sci. 2009;106:16018–21.
Chapter 2
Neurocytology: Cells of the CNS
Abstract There are two major cell types that form the nervous system: supporting
cells and conducting cells. The supporting cells of the peripheral nervous system
consist of Schwann cells, fibroblasts, and satellite cells, while the supporting cells
in the CNS consist of the glia; the lining cells of the ventricles, the ependymal; the
meningeal coverings of the brain; the circulating blood cells; and the endothelial
lining cells of the blood vessels. The conducting cells, or neurons, form the circuitry
within the brain and spinal cord, and their axons can be as short as a few microns or
as long as 1 m. The supporting cells are constantly being replaced, but the majority
of conducting cells/neurons, once formed, remain throughout our life.
The basic functional unit of the nervous system is the neuron. The neuron doctrine
(postulated by Waldeyer in 1891) described the neuron as having one axon, which
is efferent, and one or more dendrites, which are afferent. It was also noted that
nerve cells are contiguous, not continuous, and all other elements of the nervous
system are there to feed, protect, and support the neurons. Neurons consist of a cell
body, dendrites, and axon that terminate as a synapse. The axon is usually covered
by the insulator myelin (Table 2.1).
Although muscle cells can also conduct electric impulses, only neurons, when
arranged in networks and provided with adequate informational input, can respond
in many ways to a stimulus. Probably the neuron’s most important feature is that
each is unique. If one is damaged or destroyed, no other nerve cell can provide a
precise or complete replacement. Fortunately, the nervous system was designed
with considerable redundancy; consequently, it takes a significant injury to
incapacitate the individual (as in Alzheimer’s or Parkinson’s disease).
2.1.1 Dendrites
The dendritic zone receives input from many different sources (Fig. 2.1). The action
potential originates at the site of origin of the axon and is transmitted down the axon
in an all-or-nothing fashion to the synapse, where the impulse is transmitted to the
dendritic zone of the next neuron on the chain.
Dendrites have numerous processes that increase the neuron’s receptive area.
The majority of synapses on a nerve cell are located on the dendrite surface. With
the electron microscope, the largest dendrites can be identified by the presence of
parallel rows of neurotubules, which provide highways for the transport of the
action potential. The dendrites in many neurons are also studded with small mem-
brane extensions, the dendritic spines.
2.1.2 Soma
The soma (perikaryon or cell body) of the neuron varies greatly in form and size.
Unipolar cells have circular cell bodies; bipolar cells have ovoid cell bodies; multipo-
lar cells have polygonal cell bodies. The soma is the trophic center for each neuron.
Neurons can also be grouped by axon length: Those with long axons are called Golgi
type I (or pyramidal) cells; those with short axons are called Golgi type II (or satel-
lite) cells (Gray 1959). The Golgi type I cell (Fig. 2.2) has an apical and basal den-
drite, each of which has secondary, tertiary, and quaternary branches, with smaller
2.1 The Neuron 29
branches arising from each of these branches that extend into all planes. They form
the basic long circuitry within the central nervous system. The axons of pyramidal
neurons run long distances within the cortex, but they may also exit from the cortex.
Throughout much of the central nervous system, spines are found on the dendrites.
In the early studies on the brain, these dendritic processes were initially thought to
be an artifact of the Golgi silver neuronal stain, but with electron micrographic
analysis of the brains, they have been noted to be a dynamic addition to the surface
area of many neurons, and a modification of their numbers and types has been
shown to produce mental retardation, Alzheimer’s disease, and schizophrenia
(Fig. 2.3). In the cerebral cortex, there are two basic types of neurons and a cell with
a long axon, type I, and a cell with a short axon, type II.
30 2 Neurocytology: Cells of the CNS
Fig. 2.2 Golgi type I cells (neurons with long axons) in the motor cortex of a rat. (a) shows entire
cell soma, axon, and dendrite ×150 and (b) dendritic spines, ×1100 ((a) and (b)—Golgi rapid
stain), (c) and (d) are electron micrographs of dendritic spines with excitatory synapses, ×30,000
Golgi type I cell. In the cerebral cortex, spines are numerous on the Golgi type
I pyramidal neuron (Fig. 2.2, 2.7), a neuron with long axons, and their axons form
many of the long tracts within the CNS. The transmitter in type I cells is
glutamate.
The Golgi type II cell. The Golgi type II cells (Fig. 2.3) have few if any dendritic
spines, and the axon usually extends only a short distance within the cerebral cortex
(0.3–5 mm).
Spines are absent from the initial segment of the apical and basal dendrite of
pyramidal neurons, but they become numerous farther along the dendritic branches.
Dendritic spines are bulbous, with a neck approximately 1–3 μm in diameter
2.1 The Neuron 31
Fig. 2.3 Golgi type II cells (neurons with short axons) in the motor cortex of the rat (Golgi-Cox
stain, × 450).
c onnecting to the dendrite (Fig. 2.2). Many spines are found on dendrites, and these
spines contain a spine apparatus which functions like a capacitor, charging and then
discharging when its current load is exceeded. Immediately behind the postsynaptic
membrane is an elaborate complex of interlinked proteins called the postsynaptic
density (PSD), in which adhesion molecules, receptors, and their associated signal-
ing proteins are highly concentrated (Fig. 2.1).
Dendritic spines are actin-rich protrusions from neuronal dendrites that form the
postsynaptic part of most excitatory synapses. They provide compartments that
locally control the signaling mechanisms at individual synapses. Many axon termi-
nals are located on the spines. Their importance stems from the fact that they greatly
expand the dendrite’s receptive synaptic surface and are major sites of information
processing and storage in the brain. Changes in the shape and size of dendritic
spines are correlated with the strength of excitatory synaptic connections and heav-
ily depend on remodeling of its underlying actin cytoskeleton (Hotulainen and
Hoogenraad 2010). Spine structure is regulated by molecular mechanisms that
include the extrinsic factors (such as perisynaptic astroglia) and the intrinsic factors
(such as organelles) that are required to build and maintain synapses. Specific mech-
anisms of actin regulation are also integral to the formation, maturation, and plastic-
ity of dendritic spines and to learning and memory. Hippocampal spines show
structural plasticity which may form the basis for the physiological changes in syn-
aptic transmission that underlie learning and memory.
Cytoplasm and Organelles (Fig. 2.4)
The basic eukaryotic cell contains the following:
1. Plasma membrane
2. Glycocalyx (components external to the plasma membrane)
3. Cytoplasm (semifluid)
4. Cytoskeleton—microfilaments and microtubules that suspend organelles, give
shape, and allow motion
32 2 Neurocytology: Cells of the CNS
Plasma Membrane
A lipid/protein/carbohydrate complex,
providing a barrier and containing
transport and signaling systems.
Nucleus
Double membrane surrounding the
chromosomes and the nucleolus. Pores
allow specific communication with the
cytoplasm. The nucleolus is a site for
synthesis of RNA making up the ribo-
some.
Mitochondria
Surrounded by a double membrane with
a series of folds called cristae. Functions
in energy production through metabo-
lism. Contains its own DNA, and is be-
lieved to have originated as a captured
bacterium.
-seen in plants Chloroplasts (plastids)
Surrounded by a double membrane,
containing stacked thylakoid mem-
branes. Responsible for photosynthesis,
the trapping of light energy for the syn-
thesis of sugars. Contains DNA, and
like mitochondria is believed to have
originated as a captured bacterium.
Ribosomes
Protein and RNA complex responsible for
protein synthesis.
Golgi apparatus
A series of stacked membranes. Vesicles
(small membrane surrounded bags) carry
materials from the RER to the Golgi
apparatus. Vesicles move between the
stacks while the proteins are "processed" to
a mature form. Vesicles then carry newly
formed membrane and secreted proteins to
their final destinations including secretion
or membrane localization.
Lysosymes
A membrane bound organelle that is
responsible for degrading proteins and
membranes in the cell, and also helps
degrade materials ingested by the cell.
Vacuoles
Membrane surrounded "bags" that contain
water and storage materials in plants.
Peroxisomes or Microbodies
Produce and degrade hydrogen peroxide, a
toxic compound that can be produced
during metabolism.
Cell wall
Plants have a rigid cell wall in addition to
their cell membranes.
Fig. 2.4 (continued)
34 2 Neurocytology: Cells of the CNS
Table 2.2 Rate of axonal transport of cellular structures (data from Graftstein and Forman;
Mcquarrie; Wujek and Lasek)
Transport rate (mm/
day) Cellular structure
Fast 300 ↔ 400 Vesicles, smooth endoplasmic reticulum, and granules
Intermediate 50 ↔ 15 – Mitochondria
– Filament proteins
Slow 3 ↔ 4 – Actin, fodrin, enolase, component CPK, calmodulin, B and clathrin
Slow 0.3 ↔ 1 – Neurofilament protein, component tubulin, and MAPS
These structures are seen in most cells and in all neurons and glial cell types and
permit each neuron to function (Table 2.2). In these eukaryotic cells, the organelles
tend to be compartmentalized and include the nucleus, polyribosomes, rough endo-
plasmic reticulum, smooth endoplasmic reticulum, mitochondria, and inclusions
(Fig. 2.11). Most neuronal cytoplasm is formed in the organelles of the soma and
flows into the other processes. Newly synthesized macromolecules are transported
to other parts of the nerve cell, either in membrane-bound vesicles or as protein
particles. As long as the soma with a majority of its organelles is intact, the nerve
cell can live. Thus, it is the trophic center of the neuron. Separation of a process
from the soma produces death of that process. (Springer Images 2014)
2.1 The Neuron 35
2.1.5 Nucleus
The rough endoplasmic reticulum or Nissl substance, which turns amino acids into
proteins, is the chromodial substance found in light micrographs. It can be demon-
strated by using a light microscope and basic dyes, such as methylene blue, cresyl
violet, and toluidine blue. The appearance and amount vary from cell to cell. With
electron microscopy, cisterns containing parallel rows of interconnecting rough
endoplasmic reticulum are revealed (Fig. 2.14). Ribosomes (clusters of ribosomal
RNA) are attached to the outer surfaces of the membranes and consist of a large and
a small RNA–protein subunit. The Nissl substance is most concentrated in the soma
and adjacent parts of the dendrite (Fig. 2.6). It is, however, also found throughout
the dendrite (Fig. 2.8B) and even in the axon hillock.
These organelles, found throughout the neuron, are the third largest organelles after
the nucleus and endoplasmic reticulum and supply the energy for many activities in
the eukaryotic cell. They are rod shaped and vary from 0.35 to 10 μm in length and
Fig. 2.6 Electron
micrograph showing a
Type I pyramidal neuron
with its adjoining astrocyte
and oligodendrocyte.
×13500
36 2 Neurocytology: Cells of the CNS
Fig. 2.7 Electron micrograph of the cerebral cortex showing the principal cell types in the central
nervous system: neuron, astrocyte (astro), oligodendrocyte (oligo), and a blood vessel (BV) × 13500
Fig. 2.8 Electron micrographs of a pyramidal neuron in the rat cerebral cortex, (a) soma and
nucleus, and (b) dendrite. Note the large amount of Nissl substance in the soma. The dendrites
have less Nissl substance and many microtubules. ×33,000
In the mitochondria is a DNA from one’s mother, and an intriguing study links
this mitochondrial DNA to a common human female ancestor, Lucy (of the species
Australopithecus afarensis, who lived in Southern Africa over 3,000,000 years ago,
Johanson and Wong 2009, Tatersall 2009). In the cytoplasm, enzymes are found that
break down glucose into pyruvic and acetoacetic acid. These substances are taken
into the mitochondrial matrix and participate in the Krebs citric acid cycle, which
allows the mitochondria to metabolize amino acids and fatty acids.
Neurons in the supraoptic and paraventricular nuclei of the hypothalamus form neu-
rosecretory material (Bodian 1963, 1966; Palay 1957; Scharrer 1966). The axons of
these cells form the hypothalamic–hypophyseal tract, which runs through the median
38 2 Neurocytology: Cells of the CNS
eminence, down the infundibular stalk to the neurohypophysis (pars nervosa), where
the axons end in close proximity to the endothelial cells. The secretory granules are
130–150 millimicrons in diameter and are found in the tract (see Fig. 9.4).
In the classic experiment of Weiss and Hiscoe (1948), they placed a ligature on a
peripheral nerve, and this produced a swelling proximal to the tie, demonstrating
that material flows from the soma, or trophic center, into the axon and ultimately to
the axon terminal. The development of techniques that follow this axoplasmic flow
has revolutionized the study of circuitry within the central nervous system. The abil-
ity to map this circuitry accurately has given all neuroscientists a better understand-
ing of the integrative mechanisms in the brain. With the protein-manufacturing
apparatus present only in the soma, and to a lesser degree in the dendrites, a mecha-
nism must exist to transport proteins and other molecules from the soma, down the
axon, and into the presynaptic side.
Axoplasmic transport is an active process responsible for movement of organelles
(mitochondria), lipids, proteins, synaptic vesicles, and other parts of the cell mem-
2.1 The Neuron 39
Fig. 2.9 The Nissl body/rough endoplasmic reticulum in the pyramidal neurons #1 in layer 5 in
the leg region of the motor cortex of a chimpanzee. The larger pyramidal cell is a giant cell of Betz;
note the astrocyte located next to its apical dendrite. The cell stained in #2 is an astrocyte. Thionin
stain, ×205
branes to and from the soma down the axon to the synapses and back up to the soma.
Microtubules provide the structural basis for this transport and axoplasmic flow, and
they contain the protein motors kinesins and dyneins which are the molecular basis
of this transport with the catalyzing of ATP to ADP providing the energy for this
active transport. This mechanism of transport is not diffusion but rather retrograde
axonal transport associated with the microtubule network that exists throughout the
nerve cell. The rate of flow varies depending upon the product being transported and
ranges from more than 300 mm/day to less than 1 mm a day. The main direction of
the flow is anterograde, from the cell body into the axon and synapse. There is also
a very active retrograde flow from the synaptic region back to the cell body that is a
source for recycling many of the substances found at the synaptic ending.
40 2 Neurocytology: Cells of the CNS
The particles that move the fastest as noted in Table 2.2 consist of small vesicles
of the secretory and synaptic vesicles, and the slowest group is the cytoskeletal
components. Mitochondria are transported down from the cell body at an intermedi-
ate rate. The retrograde flow from the synaptic telodendria back into the soma
returns any excess of material for degradation or reprocessing. The retrograde flow
permits any excess proteins or amino acids to be recycled. It also permits products
synthesized or released at the axonal cleft to be absorbed and then transported back
to the cell.
2.1 The Neuron 41
Fig. 2.11 Protein motors kinesin and dyneins. From Springer Images 2015
The axon originates at the hillock and is a slender process that usually arises from a
cone-shaped region on the perikaryon (Fig. 2.12). This region includes filaments,
stacks of tubules, and polyribosomes (Fig. 2.12b). The initial segment of the axon,
arising from the axon hillock, is covered by a dense material that functions as an
insulator membrane at the hillock that is covered by an electron-dense material.
42 2 Neurocytology: Cells of the CNS
Fig. 2.12 Appearance of the axon hillock, axon origin. (a) In a Nissl stain, ×400; (b) in an electron
micrograph, ×15,000; and (c) in a Golgi rapid stain, ×350
The myelin membrane like all membranes contains phospholipid bi-layers (Fig. 2.14).
In the central nervous system, myelin includes the following proteins:
Proteolipid protein (51%)
Myelin basic protein (44%)
Myelin-associated glycoprotein (1%)
3,3-Cyclic nucleotide (4%)
The oligodendrocytic process forms the myelin sheaths by wrapping around the
axon. The space between the axonal plasma membrane and the forming myelin is
reduced until most of the exoplasmic and cytoplasmic space is finally forced out.
The result is a compact stack of membranes. The myelin sheath is from 3 to 100
membranes thick and acts as an insulator by preventing the transfer of ions from the
axonal cytoplasm into the extracellular space.
Myelin sheaths are in contact with the axon. In light microscopy, they appear
as discontinuous tubes 0.5–3 mm in length, interrupted at the node of Ranvier
(Fig. 2.13).
The axon is devoid of myelin at the site of origin (the nodes) and at the axonal
telodendria. At the site of origin, the axon is covered by an electron-dense mem-
brane, and at the site of the synaptic telodendria, the various axonal endings are
2.1 The Neuron 43
Fig. 2.13 Node of Ranvier. Longitudinal section of a peripheral nerve fixed in osmium, demon-
strating nodes of Ranvier (arrows) (×1000)
The process of covering a naked axon with myelin is myelination. An axon starts
with just a covering formed by the plasma membrane of either the Schwann cell or
the oligodendrocyte. More and more layers are added until myelination is com-
plete. The myelin is laid down by the processes of either the Schwan cell in the
PNS or oligodendrocyte in the CNS twisting around the axon (Geren 1956;
Robertson 1955) (Fig. 2.14).
The sequence of myelination has been studied centrally in great detail (Jacobson
1963); it begins in the spinal cord, moves into the brain stem, and finally ends up
with the diencephalon and cerebrum last. A delay in myelination will produce
developmental delays and may be a consequence of many factors, including genetic
and nutritional ones (e.g., alcoholism—fetal alcohol syndrome), and is usually very
harmful to the fetus. Breakdown of the myelin in a disease, e.g., multiple sclerosis,
44 2 Neurocytology: Cells of the CNS
Fig. 2.14 Myelin sheath from the optic nerve of a mouse demonstrating repeated units ohte
myelin sheath consisitng of light an dark lines. The dark line is called the major dense line (MDL)
represents the oppositon of the inner unit membranes. The less dense line called the interperiod
line, IPL, represents the a approximstion of the outer surface of adjacent myelin membranes
(×67,000) (Courtesy of Alan Peters, Department of Anatomy, Boston University School of
Medicine)
produces major functional deficits where they can affect the basic function of the
cell—the signaling process. Fast axonal transport is associated with the microtu-
bules. The slower components including membrane-associated proteins (MAPS)
are transported inside the microtubules, but the mitochondria actually descend in
the axonal cytoplasm (Table 2.3).
2.2 Synapse 45
The axons in the peripheral nervous system are organized into nerves, while in the
central nervous system, the axons run in groups called tracts with each axon
enwrapped in myelin, and groups of axons are bundled together by the processes of
fibrous astrocytes. The axons vary in diameter (5–33 μm) and in length (0.5 mm–1 m),
but these axons cannot be separated into functional categories based on axonal
diameter. These many pathways (e.g., corticospinal, spinothalamic) will be dis-
cussed within each level of the central nervous system.
2.2 Synapse
Synapses can be seen at the light microscopic level (Fig. 2.13); however, to identify
all the components of synapses, the electron microscope must be used. At the elec-
tron microscopic level, the synapse consists of the axonal ending, which forms the
presynaptic side, and the dendritic zone, which forms the postsynaptic side
(Fig. 2.14). Collectively, the pre- and postsynaptic sides and the intervening synap-
tic cleft are called the synapse.
The electron microscope has permitted one to reveal many new details in synaptic
structure (Bodian 1970; Colonnier 1969; Gray 1959; Palay 1967).
At the synapse, the electrical impulse from one cell is transmitted to another.
Synapses vary in size from the large endings on motor neurons (1–3 μm) to smaller
synapses on the granule and stellate cells of the cortex and cerebellum (less than
0.5 μm). Synapses primarily occur between the axon of one cell and the dendrite of
another cell. Synapses are usually located on the dendritic spins but are also seen on
the soma and rarely between axons. At the synapse, the axon arborizes and forms
several synaptic bulbs that are attached to the plasma membrane of the opposing
neuron by intersynaptic filaments (Fig. 2.13).
The synapses can be seen at the light microscopic level (Fig. 2.15), but they are best
seen with the electron micrograph. where one sees two basic types of synapses,
electrical and chemical, and they differ in location and appearance.
46 2 Neurocytology: Cells of the CNS
Fig. 2.15 Silver stain of a 1 micron plastic embedded section demonstrating boutons on neruons
in the reticular formation. ×1400
At certain synaptic sites, the following compounds may also function as modulator
(usually a slower transmitter) form of neurotransmission: adenosine, histamine,
octopamine, B-alanine, ATP, and taurine. Many of the neuropeptides, such as
substance P, vasoactive peptide, peptide Y, and somatostatin, are also active in neu-
rotransmission or neuromodulation. Catecholamines and 5-hydroxytryptamine
are transmitters linked to synaptic transmission in the central nervous system.
Noradrenaline is a transmitter at the preganglionic synapses. Many steroids and
hormones have also been linked to synaptic transmission. It is still uncertain
whether these compounds play a direct role in nervous transmission or if they are
just related by their importance to the ongoing functions of the entire nervous
system (Table 2.3).
The synaptic vesicles differ in size and shape and may be agranular, spherical,
flattened, or round with a dense core. The spheroidal vesicles retain their shape
regardless of any manipulation. The four basic categories of synaptic vesicles are
given in Table 2.4.
Fig. 2.16 (a) Normal appearance of excitatory synapses in the sensory cortex of the rat demon-
strating agranular synaptic vesicles (300–400 Å) in the presynaptic axonal side. Note the electron-
dense synaptic membranes and the intersynaptic filaments in the synaptic cleft. Electron micrograph
(×65,000). (b) Appearance of degenerating excitatory synapses in the sensory cortex of the brain
after removal of the contralateral region demonstrating increased density of presynaptic side with
edematous parenchyma and the clumping of the synaptic vesicle and the fibrillary appearance of
the degenerating axonal endings
2.2 Synapse 49
Excitatory synapses depolarize the membrane potential and make it more positive,
and they appear asymmetrical, having a prominent postsynaptic bush with presyn-
aptic vesicles (Figs. 2.15 and 2.16). This type of synapse is most commonly seen on
dendrites. Glutamate has been identified in excitatory synapses. At the excitatory
synapse, there is a change in permeability that leads to depolarization of the post-
synaptic membrane and which can lead to the generation of an action potential.
Inhibitory synapses hyperpolarize the membrane potential and make it more nega-
tive. They are symmetrical with thickened membranes on the pre- and postsynaptic
side and vesicles only on the presynaptic side. GABA has been identified in the
inhibitory synapses. At an inhibitory synapse, the neurotransmitter binds to the
receptor membrane, which changes the permeability and tends to block the forma-
tion of the action potential. Synapses on the soma are symmetrical, and they are
considered inhibitory.
Dendritic spines. Dendritic spines are small membranous protrusions that contain
the postsynaptic machinery, including the glutamate receptors, the actin cytoskele-
ton, and a wide variety of membrane-bound organelles, such as smooth endoplas-
mic reticulum, mitochondria, and endosomes.
In addition, dendritic spines in the hippocampus can be affected by stress (Yuncai
Chen, Céline M. Dubé, Courtney J. Rice, and Tallie Z. Baram, 2010) with a resul-
tant dendritic regression and loss of dendritic spines in hippocampal neurons that is
50 2 Neurocytology: Cells of the CNS
The central nervous system has billions of neurons, but the number of supporting
cells exceeds them by a factor of 5 or 6. Supporting cells form a structural matrix,
an internal milieu, and play a vital role in transporting gases, water, electrolytes, and
2.3 Supporting Cells of the Central Nervous System 51
Table 2.5 Mechanoreceptor
Modality Receptor
Sound Cochlea in inner ear/petrous portion of temporal bone transforms
mechanical into neural impulses
Light touch and vibration Encapsulated endings—Meissner’s and Pacinian corpuscles
Proprioception: Muscle spindles and Golgi tendon organs in joints Meissner’s
Encapsulated sensory and Pacinian corpuscles, Merkel’s tactile disks
endings
Pain and temperature Free nerve endings, end bulbs of Krausse and Golgi-Mason
metabolites from blood vessels to the neural parenchyma and in removing waste
products from the neuron. In contrast to the neuron, the supporting cells in the adult
central nervous system normally undergo mitotic division.
The supporting cells are divided into macroglia and microglia:
Macroglia include astrocytes, oligodendrocytes, and ependyma and are the sup-
porting cells or neuroglia (nerve glue) of the central nervous system (Fig. 2.7).
Microglia include the mesodermal microglia cells (of Hortega), perivascular
cells, and any white blood cells found within the parenchyma of the central nervous
system.
Schwann cells, satellite cells, and fibroblasts are supporting cells of the peri
pheral nervous system. Functions of the different supporting cells in the nervous
system are summarized in Table 2.6.
Astrocytes are of two types: fibrous (most common in white matter) or protoplas-
mic (most common in gray matter).
Astrocytes are now thought to be involved in almost all aspects of brain function
as they form much of the internal milieu of the brain. Astrocytes generate signals
that are chemical rather than electrical. Astrocytes are star-shaped glia that hold
neurons in place, get nutrients from them, and digest parts of dead neurons. But
because astrocytes cannot generate action potentials, they haven’t received a lot of
attention, until recently. It has been discovered that astrocytes can indeed communi-
cate with neurons and modify the signals they send or receive. That means astro-
cytes are much more involved than we thought in the processing of information and
in the signaling that occurs at the synapse.
Glymphatic channels. The processes of the astrocytes form periarterial chan-
nels for the passage of macromolecules in the brain propelled by the arterial blood
flow. The waste products in the brain are transported into the perivenous channels
which permit the elimination of macromolecules via the perivenous channels into
the subarachnoid space and then into venous sinuses via the arachnoid granulations
(Nedergaard and Goldman, Scientific American, 2016, vol. 314, pp. 46–49).
52 2 Neurocytology: Cells of the CNS
Endothelial cells form the lining of the capillaries in the central nervous system
(Fig. 2.17). They are of mesodermal origin and bound together by tight junctions.
Their tight junctions and pinocytosis provide the basis of the blood–brain barrier
(see below).
Adapted from Volterra and Meldolesi (2005). Astrocytes, from brain glue to communication elements. Nature Review Neuroscience 5: 626–640
2.3 Supporting Cells of the Central Nervous System 55
Dendritic
LTP spine LTD
Head
Neck
Fig. 2.17 Molecular architecture of inhibitory and excitatory synapses. Molecular architecture of
inhibitory and excitatory synapses. Top panels show excitatory and inhibitory synapses. Excitatory
synapses target on mature mushroom-shaped spines containing a prominent postsynaptic density
(PSD), and inhibitory synapses are present along the dendritic shaft lacking postsynaptic thicken-
ing. Various organelles support the synapse; mitochondria provide energy, polyribosomes and
RNA particles allow local protein synthesis, recycling endosomes (REs) transport internalized
synaptic receptors back to the plasma membrane, and the cytoskeleton regulates spine dynamics.
The abundant actin cytoskeleton is connected to the PSD and is the primary determinant of spine
shape and motility. Transient invasion of dynamic microtubule into dendritic spines can regulate the
formation of spine head protrusions and rapid spine growth. Excitatory and inhibitory synapses
contain a unique set of channels, scaffolding proteins, and other postsynaptic molecules. The micro-
anatomy of the inhibitory and excitatory synapses and their organization of proteins and protein–
protein interactions are depicted in the left and right panels, respectively. Major families of
postsynaptic proteins are shown, including scaffolding proteins, adhesion molecules, and receptors.
Lower panel shows major morphologic events occurring in dendritic spines upon long-term poten-
tiation (LTP, left) or long-term depression (LTD, right). In Alzheimer’s disease and mental retarda-
tion, signaling cascades are triggered similar to LTD, leading to thinner, immature spines. In
contrast, cocaine addiction shows similarities to LTP, resulting in bigger, mushroom-shaped, mature
spines. The molecular and morphologic changes in the synapse are hallmarks of the disease pathol-
ogy and are responsible for the cognitive alterations in neuropsychiatric diseases. Abbreviations:
CamKII Ca2+/calmodulin-dependent kinase II, AMPAR amino-3-hydroxy-5-methyl-4-
isoazolepropionate receptor, GABA γ-aminobutyric acid, GABAR GABA receptor, NMDAR
N-methyl-d-aspartate receptor, mGluR metabotropic glutamate receptor, SAPAP synapse-associated
protein 90/PSD-95-associated protein (From Spronsen, Myrrhe; Hoogenraad, Casper, 2010)
56 2 Neurocytology: Cells of the CNS
(c) The major cell for stimulating the immune response (leukocyte dendritic cells)
is not normally present in the disease-free nervous system.
It is now known that immune cells regularly enter the brain through the capillar-
ies and that macrophages infected with human immunodeficiency virus (HIV), for
example, can infect the brain directly, the so-called Trojan Horse phenomenon
(Haase 1986; Price et al. 1988; Orenstein 2007).
Intracerebral vascular system. Recent studies have shown a lymphatic vascular
system in the meninges of the brain (Louveau et al. 2015) and (Aspelund 2015)
which is an alternative way for T-cells to enter the brain and provide immune
responses which have a key role in fighting disease within the brain. In addition,
there is a regular immune surveillance of the central nervous system, which is suf-
ficient to control many viral infections (Sedgwick and Dorries 1991).
Microglial cells. Microglial cells originate from monocytes that enter the brain
(Fig. 2.18; Table 2.9). Neurons, astrocytes, and oligodendrocytes are ectodermal in
origin, but microglial cells are mesodermal in origin. The ovoid microglia cells are
the smallest of the supporting cells and are divided into two categories: (a) perivas-
cular cells and (b) the resting microglial cells in the brain parenchyma.
Pericytes are found in relation to capillaries but external to the endothelial cells
and enwrapped in the basal lamina. In electron micrographs, they are not as electron
dense as oligodendrocytes and lack the neurofilaments of the astrocyte and the
tubules of the oligodendrocyte. The cytoplasm is denser than that of astrocytes and
contains fat droplets and laminar dense bodies. The granular endoplasmic reticulum
consists of long stringy cisterns.
Microglia are considered multipotent cells because with the proper stimulus,
they can become macrophages. The pericyte contains actin, and this cell may well
be important in controlling the channels entering the endothelial cells (Herman and
Jacobson 1988).
The gut microbiome and the brain. There has been much recent interest in the
relationship between the bacteria which live in the human gut, gut microbiota, and
their communication with the brain and how it influences the functions in the brain
and our well-being. This interaction between the CNS and the enteric nervous sys-
tem/the brain in the gut (Chap. 9) is found throughout the GI system and can be
self-functional or is bidirectional. The vagus nerve appears to be the key to the func-
tions in the enteric nervous system and forms the major interface between the CNS
and enteric systems, and also it affects the endocrine and immune system by modu-
lating neurotransmitters (Gershon 1999). In addition, there is great variability in the
types of flora that inhabits our GI system, and it is well known that they can become
unhealthy and that may contribute to metabolic, autoimmune, and brain disorders
including diabetes, seizure disorders, MS, and even Alzheimer’s disease. Ongoing
studies should better elucidate the actual role of our microbiome in relationship to
our neural function and overall health.
Giant cells. Activated microglial cells can also evolve into giant multinucleated
cells by the fusion of reactive cells. They are seen in viral infections and are consid-
2.3 Supporting Cells of the Central Nervous System 57
Fig. 2.18 Wallerian
degeneration in the right
medullary pyramid in a
human several years after
an infarct in the right
motor–sensory strip—note
that the absence of myelin
is on the right side as this
is ipsilateral to the lesion
and above the decussation
of the corticospinal tract.
Left side is normal, Weigert
myelin stain, ×90
ered the hallmark of AIDS dementia. These cells form by fusion of reactive cells,
multinucleated cells associated with viral brain infections and Creutzfeldt–Jakob
disease, hallmark of AIDS dementia. Reactive microglial cell is a fully active mac-
rophage containing class II MHC and phagocytic activity. These cells are very
active during all major disease states in the brain. Also called gitter cells, giant
multinucleated cells are often found in patients with Creutzfeldt–Jakob disease, a
transmissible spongiform degeneration (Fig. 2.19) and a disease caused by protein-
aceous infectious particles or prions (Baker and Ridley 2001; Litzman 2001; Baker
2001). Compare the normal-appearing synapse in this case of Creutzfeldt–Jakob
disease to that of the normal-appearing synapses and degenerating axons seen after
an experimental lesion (Fig. 2.16a, b).
58 2 Neurocytology: Cells of the CNS
Fig. 2.19 Electron micrograph of a biopsy from the cortex of a 65-year-old male patient with
Creutzfeldt–Jakob disease. (a, b) Reactive astrocytes, gitter cell, in the cerebral cortex. Note the
prominent digestion vacuoles (b) at higher power. (c) Note the presence of intact synapse on the
surface of the degenerating neurons in this case of spongiform neuronal degeneration ((a) ×8000;
(b, c), ×35,000)
2.3 Supporting Cells of the Central Nervous System 59
Fig. 2.20 Ependymal lining cell in the third ventricle of a rat. Note the prominent cilia extending
into the ventricle (arrows) in this 1 μm plastic section
Ependymal cells line all parts of the ventricular system (lateral ventricles, third
ventricle, cerebral aqueduct, fourth ventricle, and spinal canal). They are cuboidal,
ciliated, and contain filaments and other organelles. The processes of these cells
extend in the central nervous system and fuse with astrocytic processes to form the
inner limiting glial membrane. Highly modified ependymal cells are found attached
to the blood vessels in the roof of the body of the lateral ventricles, the inferior horn
of the lateral ventricles, and the third and fourth ventricles. There they form the cho-
roid plexus, which secretes much of the cerebrospinal fluid (Fig. 2.21). Ependymal
cells originate from the germinal cells lining the embryonic ventricle, but they soon
stop differentiating and stay at the lumen on the developing ventricles.
Satellite cells. Satellite cells, which are found only in the peripheral nervous system
among sensory and sympathetic ganglia, originate from neural crest cells. Many
satellite cells envelop a ganglion cell. Functionally, they are similar to the astro-
cytes, although they look more like oligodendrocytes.
Schwann cells. Schwann cells are ectodermal in origin (neural crest) in the
peripheral nervous system and function like oligodendrocytes, forming the myelin
and neurilemmal sheath. In addition, the unmyelinated axons are embedded in their
cytoplasm. Schwann cell cytoplasm stops before the nodes of Ranvier (Fig. 2.12),
leaving spaces between the node and Schwann cells. In an injured nerve, Schwann
cells can form tubes that penetrate the scar and permit regeneration of the peripheral
axons. Nerve growth factor is important to the proliferation of the Schwann cells.
60 2 Neurocytology: Cells of the CNS
Fig. 2.21 Ventral horn cells in the human lumbar spinal cord after injury to the femoral nerve. (a)
Normal ventral horn cell. (b) Chromatolytic neurons, showing a peripheral ring of Nissl substance
(peripheral chromatolysis). (c) Chromatolytic neuron with eccentric nucleus and some dissolution
of the cytoplasmic Nissl substance. Thionin Nissl stain, ×400)
2.4.1 Degeneration
Fig. 2.22 Degenerating axons in the medullary pyramidal tract of a rat 15 days after removal of
the motor cortex. (a) Arrows point out some degenerating axons, ×8000. (b) Showing details of
degenerating axons. Note the collapsed axons and dense axoplasm and also the many axons unaf-
fected by the lesion, ×20,000
2.5 Regeneration
Within a few days after section, the proximal part (attached to a functional neuronal
soma) of the nerve starts regrowing. Nerve growth factor is produced after injury to
the axon, and it promotes the axonal sprouting. If the wound is clean, e.g., a stab
sound, sewing the nerve ends together can dramatically increase the rate of recov-
ery in the affected limb. The regenerating nerves may cross the scar within several
weeks. The crossing is helped by the Schwann cells and fibroblasts, which prolifer-
ate from the proximal end of the nerve. The Schwann cells form new basement
membrane and provide tubes through which the regenerating axons can grow.
In certain peripheral nervous system diseases, only segmental degeneration
occurs. One example is diphtheria: The myelin sheath degenerates but the axon
remains intact. Phagocytes break down the myelin, and Schwann cells rapidly
reform myelin. The rate of movement of the slow component of axoplasmic flow
probably accounts for the rate of axonal regrowth, which is limited to about 1 mm a
day. Slow components of the axoplasmic flow (-Scb) carry actin, fodrin, calmodu-
lin, Clathrina, and glycolytic enzymes that form the network of microtubules, inter-
mediate filaments, and the axolemma, which limit the rate of daily axonal
regeneration, although functional recovery may be a little faster (McQuarrie and
Grafstein 1983; Wujek and Lasek 1983; Kandel et al. 2000, 2009).
Motor fiber may also reinnervate the wrong motor end plate, as when a flexor
axon innervates an extensor. In such a case, the patient has to relearn how to use the
muscle. The muscle that is denervated assists the regenerating axons by expressing
molecules that influence the regenerating axons. Some of the molecules are concen-
trated in the synaptic basal lamina of the muscle. Other molecules are upregulated
following denervation and help in attracting and reestablishing the synapse in the
muscle. These upregulated molecules include growth factors (IGF-3 and FGF-5),
acetylcholinesterase (AChE), agrin, laminin, s-laminin, fibronectin, collagen, and
the adhesion molecules N-CAM and N-cadherin (Hall and Sanes 1993; Horner and
Gage 2000, 2016). Successful nerve regeneration also depends on an adequate
blood supply. For example, in a large gunshot wound, nerves attempt to regenerate
but may not succeed.
The following is a summary of the sequence of regeneration in the peripheral
nervous system:
1 . Peripheral nerve is interrupted.
2. The axon dies back to the first unaffected node of Ranvier, with the myelin and
distal axon beginning to degenerate within 3–4 h.
3. At the site of injury, the axon and myelin degenerate to form a scar. Phagocytosis
begins within 48 h.
4. Axons separated from the cell body degenerate. With an adequate blood supply,
the portion of the axon still connected to the intact cell body begins regenerating
by sprouting.
64 2 Neurocytology: Cells of the CNS
5. Within 72 h, Schwann cells begin to proliferate and form basement membranes
and hollow tubes. Nerve growth factor is also formed and released that stimu-
lates sprouting.
6. From each of the severed axons, sprouts attempt to penetrate the scar. After one
sprout successfully grows through the scar, the other sprouts die. Nerves take a
month or more to grow through the scar.
7. Once an axon penetrates the scar, it grows at 1 mm/day; about one-third of the
severed axons actually reinnervate the muscle and skin.
After an injury, axons in the central nervous system regenerate, but there seems to be
no equivalent to the Schwann cell because oligodendrocytes and astrocytes do not
form tubes to penetrate the scar. Instead, they form a scar that is nearly impenetrable.
Even if the axons penetrate the scar, they have no means of reaching the neuron to
which they were originally connected. Horner and Gage (2000) have reviewed the
question of how to regenerate the damaged central nervous system in the brain that is
inherently very plastic. They have noted that it is not the failure of neuronal regenera-
tion, but it is rather a feature of the damaged environment; and it is now possible to
reintroduce the factors present in the developing nervous system that produced this
wonderful organ. The gene responsible for needed growth factors is probably missing
or inactivated in adult tissue. Recently a brain-derived neurotrophic factor has been
identified, which may eventually help in finding a way to guide the axon, and also the
identification of a potent inhibitor of neurite outgrowth associated with myelin,
NoGo-A. Developmentally NoGo is important in migration and neurite growth, while
in the adult, it has negative functions in recovery from injuries. Efforts are focused to
develop agents to counteract its effects (Schwab 2012). Animal studies have shown
that neurons have considerable plasticity. That is, if some axons in a region die off,
bordering unaffected axons will sprout and form new synapses over many months,
filling in where the synapses were and resulting in major functional reorganization.
This reorganization may eventually produce some recovery of function.
Bypassing the scar. To bypass the obstacles produced by the scar, it has been
shown in experiments with rodents that scaffolds made from silk fibroin (Liu 2016)
or carbon nanotubes (Ahn et al. 2015) can be placed between regions in the brain
with resultant successful axonal regeneration into damaged regions. Studies using
scaffolding are currently being undertaken in humans with lesions in the spinal cord.
Functional neurogenesis occurs throughout life in the adult brain in dentate gyrus of
the hippocampus, from the subventricular zone of the lateral ventricle and olfactory
bulbs. Gage and colleagues have shown that these immature neurons can be
2.5 Regeneration 65
The first nerve growth factor was isolated by Levi-Montalcini and Angeletti in Levi-
Montalcini and Angeletti 1968—Nobel Prize in 1986 shared with S Cohen—but
only recently have biotechnology techniques been able to produce these factors in
large quantities. NGF is now being tested to help in many diseases by improving the
nasal delivery method and gene delivery, and recently its role in immune system
regulation has been identified.
Attempts have been made to help regeneration in the central nervous system, for
instance, by physically placing Teflon tubes on Schwann cells through the scarred
portion of the spinal cord in the hope that the nerves would follow these channels.
However, even though nerves do grow down these channels, no functional recovery
occurs.
Many factors that promote neuronal survival and axon outgrowth (e.g., brain-
derived neurotrophic factor, BDNF) have been identified, and the focus is now on
getting these cells to produce axons to grow into the injured areas and then to grow
through into the uninjured area. With the identification of neurotrophic factor
(netrins 1 and 3) that produces axonal growth (Serafini et al. 1994) and with the
studies of programmed cell death, we are beginning to identify genes that may be
responsible for premature neuron death (Oppenheim 1991); we are now entering an
era of brain research that offers great promise to help patients with neurodegenera-
tive diseases: Huntington’s, Parkinson’s, and Alzheimer’s.
Necrosis. In organs with numerous fibroblasts, necrotic areas are soon filled with
proliferating fibroblasts, but in the central nervous system, there are few fibroblasts,
and the astrocytes do not proliferate in sufficient numbers. Within a few days of an
ischemic attack with infarction, neutrophils are seen at the site of injury. Shortly
thereafter, microglial cells and histiocytes are seen in the region of the dying cells.
Since the blood–brain barrier is usually compromised, monocytes may now migrate
into the parenchyma of the central nervous system in greater numbers and assist in
phagocytosis. The time it takes for the complete removal of injured cells depends on
the size of the lesion. Large infarcts may take several years before phagocytosis is
complete. If the lesion is huge, such as a large infarct in the precentral gyrus, a cav-
ity lined by astrocytic scar will form. In small lesions, the neurons are phagocytized
glia proliferate, a process called replacement gliosis.
Endothelial cells form this barrier in the central nervous system. The endothelial
cells line the capillaries, and the choroid plexuses are joined together by tight junc-
tions, zonula occludens. The capillaries are not perforated, and the endothelial cells
show very little pinocytosis or receptor-mediated endocytosis (Brightman 1989;
Pardridge 2006). This endothelial lining is called the blood–brain barrier because it
is very selective to certain large molecules and dyes and limits the entry of other
substances, including amino acids, water, glucose, and electrolytes into the brain
parenchyma. This interface between the brain and blood system can be modulated
and even opened by many inflammatory mediators (bradykinin, histamine, sero-
tonin, arachidonic acid), some of which can affect the tight junctions and also affect
the neuron and adjoining glia, pericytes, smooth muscles, and cells. Factors which
modulate the BBB have also been used to treat disease within the brains including
cancers and infections.
In the peripheral nervous system, the endothelial cells are fenestrated and very
active in pinocytosis. Fluid-phase endocytosis in the peripheral nervous system is
relatively nonspecific; the endothelial cells engulf molecules and then internalize
them by vesicular endocytosis. In receptor-mediated endocytosis, which is found in
the central nervous system, a ligand first binds to a membrane receptor on one side
of the cell. After binding to the ligand, the complex is internalized into a vesicle and
transported across the cell, and the ligand is usually released.
All vascular branches within the central nervous system are surrounded by a thin
covering formed by astrocytic processes (Fig. 2.23). However, the astrocytic pro-
cesses do not fuse with the endothelial lining of the blood vessel or with the
processes of other cells, so they have minimal effect on limiting the entry of solutes
into the brain parenchyma. Thus, the extracellular space can be entered once the
materials pass through the endothelium.
2.6 Blood–Brain Barrier 67
Fig. 2.23 Wallerian degeneration in the left medullary pyramid in a human several years after an
infarct in the left motor–sensory strip—note that the absence of myelin is on the left side and this
is above the decussation of the corticospinal tract. Right side is normal, Weigert myelin stain, ×90
The intravenous perfusion of various dye compounds (trypan blue, Evans blue) or
stress has been shown to open the blood–brain barrier by activating the hypothalamic–
hypophyseal–adrenal axis and release CRH (Esposito et al. 2001). Acute lesions of the
central nervous system including those caused by infections usually increase the per-
meability of the barrier and alter the concentrations of water, electrolytes, and protein.
In some viral diseases, for example, infected leukocytes (macrophages) more easily
penetrate directly into the brain by passing between the normally tight junctions in the
endothelial cells. This is one way HIV enters the brain from the blood. Also, central
nervous system tumors produce growth factors that cause blood vessels to sprout.
These new capillaries have immature tight junctions that are also quite leaky and have
been studied with some success as a way to deliver chemotherapeutic agents specifi-
cally to the tumor.
Between the cells in the central nervous system is the extracellular space, measur-
ing between 30 and 40 nm and filled with cerebrospinal fluid (CSF) and other
solutes. The CSF is formed primarily by the choroid plexus in the lateral ventricle,
68 2 Neurocytology: Cells of the CNS
Basement Membrane
Pericyte
Endothelial Cell
Lumen
Via Carrier-Mediated
Transport
Astrocyte
Foot Process Mitochondria
Tight junction
protein complex
ZO 2/3
ZO 2/3
ZO 1 Catenins
Plasma membrane
bilayer
ZO 1
ZO 2/3
ZO 2/3
Fig. 2.24 Schematic representation of a brain microvasculature. The blood–brain barrier is cre-
ated by the tight apposition of contiguous endothelial cells. Note the endothelial cells lining the
blood vessels are in close contact with a variety of accessory cells such as astrocytes and pericytes
which modulate the expression of BBB characteristics. Tight junctions between contiguous
endothelial cells prevent the passage of large molecules and pathogens between the blood and the
brain. Tight junctions consist of rows of transmembrane proteins (major types are claudins, occlu-
dins, and junctional adhesion molecules) anchored in the membranes of two adjacent endothelial
cells, while the intracellular portion is anchored to cytoskeletal proteins (e.g., actin) through scaf-
fold protein such as ZO-1. From Cucullo, Luca, Book: Mammalian Brain Development
third ventricle, and fourth ventricle (Fig. 2.24). The amount of extracellular space
in the brain is still a matter of controversy. Chemicals (gliotransmitters; see
Table 2.7) can readily pass from the glia cells to the extracellular space and affect
the neurons. Solutes from the blood plasma also readily enter through the endo-
thelial lining into the extracellular space, and the solutes present in this space
(whether deleterious or not) affect the functions of the central nervous system. A
Specific References 69
Specific References
Baker HF, Ridley RM (editors). Humana Press Series: Methods in molecular medicine, vol. 59;
2001, 292p. 97 illus., 1 in color., Humana Press. 336p.
Barr M, Bertram R. A morphological distinction between neurons of the male and female, and
the behavior of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature.
1949;163:676–8.
Bentivoglio MH, Kuypers GJM, Catsman-Berrevoets CE, Loewe H, Dann O. Two new fluo-
rescent retrogradeneuronal tracers which are transported over long distances. Neurosci Lett.
1980;18:25–30.
Bodian D. An electron microscopic characterization of classes of synaptic vesicles by means of
controlled aldehyde fixation. J Cell Biol. 1970;44:115.
Brady ST. A novel brain ATPase with properties expected for the fast axonal transport motor.
Nature (London). 1985;317:73–5.
Brightman J. The anatomic basis of the blood-brain barrier. In: Neuwelt EA, editor. Implications of
the blood-brain barrier and its manipulation, vol. 1. New York: Plenum; 1989. p. 125.
Colonnier M. Synaptic patterns on different cell types in the different laminae of the cat visual
cortex. An electron microscopic study. Brain Res. 1969;33:268–81.
Cowan WM, Gottlieb DI, Hendrickson AE, Price JL, Woolsey TA. The autoradiographic demon-
stration of axonal connections in the central nervous system. Brain Res. 1972;37:21–51.
Darnell J, Lodish H, Baltimore D. Molecular cell biology. 2nd ed. New York: Scientific American
Books; 1990.
Davis EJ, Foster TD, Thomas WE. Cellular forms and functions of brain microglia. Brain Res Bull.
1994;34:73–8.
70 2 Neurocytology: Cells of the CNS
Palay SL. Principles of cellular organization in the nervous system. In: Quarton GC, Melnechuk
T, Schmitt FO, editors. The neurosciences: a study program. New York: Rockefeller University
Press; 1967.
Pardridge WM. Introduction to the blood-brain barrier: methodology, biology and pathology
[paperback] (editor) Cambrdge University Press; 2006.
Price SD, Brew RB, Sidtis J, Rosenblum M, Scheck A, Cleary P. The brain in AIDS: central ner-
vous system HIV-1 infection and AIDS dementia complex. Science. 1988;231:586–92.
Ramón y Cajal S. Histologie du système nerveux de l=homme et des vertèbres. Paris: J. A.
Maloine; 1909.
Ramón y Cajal S. Degeneration and regeneration of the nervous system. Oxford: London; 1928.
Rassmussen GT. Selective silver impregnation of synaptic endings. In: Windle WF, editor. New
research techniques of neuroanatomy. Springfield, IL: Charles C Thomas; 1957.
Reese TS, Karnovsky MJ. Fine structural localization of the blood-brain barrier to exogenous
peroxidase. J Cell Biol. 1968;34:207.
Ridley R. Fatal protein: the story of CJD, BSE and other prion diseases. In: Harry Baker Series:
Methods in molecular medicine, vol. 3; 1996.
del Rio-Hortega P. El Atercer elemento@ de los centros nerviosos. Boletín de la Sociedad española
delbiologica. 1919;9:69–120.
Scharrer E. Endocrines and the central nervous system. Baltimore: Lippincott Williams & Wilkins;
1966.
Schwartz J. 1980. The transport of substances in nerve cells. Sci Am 242:152–171.
Sedgwick JD, Dorries R. The immune system response to viral infection. Neurosciences.
1991;3:93–100.
Serafini T, TE Kennedy, MJ Galko, C Mizrayan, TM Jessel, M Tessler-Lavigne. 1994. The netrins
define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell
78:409–424.
Sladek JR Jr, Gash DM. Neural transplants: development and function. New York: Plenum Press;
1984.
Tatersall I. Human origins; out of Africa. Proc Natl Acad Sci. 2009;106:16018–21.
Vale RD. Intracellular transport using microtubule based molecules. Ann Rev Cell Biol. 1987;
3:347–78.
Vale RD, Reese TS, Sheetz MP. Identification of a novel force-generating protein, kinesin, involved
in microtubule based motility. Cell. 1985;42:39–50.
Vaughn JE, Peters AE. A third neuroglial cell type. J Comp Neurol. 1968;133:269–88.
Volterra, Meldolesi. Astrocytes, from brain glue to communication elements. Nat Rev Neurosci.
2005;5:626–40.
Weiss PA, Hiscoe MB. Experiments on the mechanism of nerve growth. J Exp Zool. 1948;
197:315–96.
Wislocki GB, Leduc EH. Vital staining of the hematoencephalic barrier by silver nitrate and trypan
blue and cytological comparisons of neurohypophysis, pineal body, area postrema, intercolum-
nar tubercle and supraoptic crest. J Comp Neurol. 1952;96:371.
Wujek JR, Lasek RK. Correlation of axonal regeneration and slow component B in two branches
of a single axon. J Neurosci. 1983;3:243–51.
Young JZ. Functional repair of nervous tissue. Physiol Rev. 1942;22:318–74.
Chapter 3
Neuroembryology and Congenital
Malformations
The in utero development of the central nervous system can be divided into three
periods that roughly correspond to the first, the second, and the third trimester of
gestation (Table 3.1).
Newborns, through genetic inheritance, can make about 40 different sounds
and distinguish some sounds as being either safe or dangerous. They can also
perceive certain shapes and usually have enough myelin for an organized grasp
and suckling reflex.
The first evidence of the differentiation of the nervous system appears at the end of
the second week of gestation. At that time a “heaping up” of ectodermal cells can
be noted at the caudal end of the embryonic disk. This accumulation of cells is
known as the primitive streak (Fig. 3.1a). As development continues, surface ecto-
dermal cells involute through the primitive streak and migrate laterally, forming
the intraembryonic mesoderm, interposed between the surface ectoderm and
subjacent endoderm. As the intraembryonic mesoderm forms, another thickening
of ectodermal cells called Hensen’s node occurs at the cephalic end of the primitive
streak (Fig. 3.1a). Cells migrate inward through this zone and extend between the
surface ectoderm and subjacent endoderm, forming the notochord plate.
Hensen’s
Node Neural
Tube
Neural
Fold
Spinal
Somite Cord
Neural
Primitive Groove
Streak Posterior
Neuropore
A. Primitive streak stage B. Neural plate stage C. Beginning of neural tube D. Brain vesicle stage
(16-day presomite embryo) (20-day two somite embryo) (22-day seven somite embryo) (23-day ten somite embryo)
Fig. 3.1 Dorsal view of the human embryo. (a) Primitive streak stage (16-day presomite embryo).
(b) Neural plate stage (20-day two-somite embryo). (c) Beginning of neural tubes (22-day seven-
somite embryo). (d) Brain vesicles stage (23-day ten-somite embryo)
The notochord is the primary “inductor” for the thickening of the ectoderm over-
lying and on either side of the notochord to form the neural plate which is essential
for the formation of the central nervous system. The many factors in the notochord
that underlie the formation of the neural tube and the transformation of embryonic
cells into adult cells are currently being identified. The notochord ultimately degen-
erates as the body of the vertebrae appears, and it persists as the nucleus pulposus of
the intervertebral disk.
On either side of the neural plate is a thin strip of ectoderm known as the neural
crest. As development proceeds, the neural plate sinks inward to form the neural
groove (Figs. 3.1b and 3.2). At the beginning of the fourth week, this midline groove
continues to deepen until the dorsal lips of the groove meet and fuse, forming the
neural tube, neurulation (Figs. 3.1c and 3.2). The central nervous system is derived
from the neural tube.
3.1 Formation of the Central Nervous System 75
Neural fold
Neural crest cells (red)
Spinal cord
Medulla/Pons
Midbrain
Telencephalon
Diencepahalon
The adjacent neural crest (NC) separates from the overlying ectoderm and comes
to lie lateral to the neural tube (Fig. 3.2), and the NC cells migrate to form many
structures (Table 3.2). The remaining ectoderm becomes the epidermis of the
embryo (somatic ectoderm).
Before the formation of the neural tube, the paraxial mesoderm begins to form
the somites. Fusion of the dorsal margins of the neural groove, forming the neural
tube, begins on about the 22nd day in the region of somites 4–6 (Fig. 3.1c). Fusion
continues in both cranial and caudal directions, and by the 25th day, only the cranial
76 3 Neuroembryology and Congenital Malformations
and caudal ends of the neural tube remain open (called the anterior and posterior
neuropores, respectively). The lumen in the neural tube will become the ventricular
system of the central nervous system.
After delineation of the neural and somatic ectoderm, the neural crest cells
appear as an almost continuous column of cells along the dorsal surface of the crest
of the neural tube from the mesencephalic level through all spinal cord levels
(Fig. 3.2). The neural crest cells are the primordium of the sensory ganglia, the
cranial nerves and the spinal ganglia, the neurilemmal cells, satellite cells, the auto-
nomic ganglia, and probably the pia-arachnoid membrane. Shortly after the closure
of the neural tube, processes from the neural crest cells enter the spinal cord or brain
stem and form the sensory roots of the spinal and cranial nerves.
3.2 Histogenesis
The walls of the neural tube throughout the nervous system consist of germinal
epithelial cells that form a pseudostratified epithelium. After closure of the neural
tube, another cell type is found external to the germinal cell layer. This new cell is
the neuroblast (or immature neuron); these cells originate from the mitotic divisions
of the germinal cell and form a new layer, the mantle or intermediate layer, and
external to the mantle layer is seen a cell-free zone, the marginal layer. Subjacent to
the germinal layer, the subventricular region develops.
The glia are instrumental in the final formation of the central nervous system.
They migrate out from the subventricular layer prior to the neuroblasts and form
processes that reach the sub-meningeal surface and remain connected to the ven-
tricular surface. The neurons migrate out into the region formed by the glia.
Initially the neuroblasts are connected to the lumen by an elongate process, a
transient dendrite. As they migrate into the subjacent mantle layer, they lose this
process and become apolar neuroblasts. Shortly thereafter two new processes
appear; one becomes the axon, the other the dendrite. The axonal process elongates
and more dendritic branches appear, forming a multipolar neuroblast.
Some neurons form only a single process, e.g., these are the sensory ganglion
of the spinal cord and cranial nerves and the mesencephalic nucleus of cranial
nerve V. Some neurons remain bipolar, e.g., the olfactory receptor cells, rods, and
cones of the retina, the bipolar cells in the retina, and the receptor cells in the
vestibular and cochlear ganglion.
It should be noted that the germinal cells also form the supporting cells in the
central system (Fig. 3.3). Throughout the central nervous system, neurons migrate
into the intermediate (mantle) zone to become the definitive structures of the spinal
cord, much of the brain stem, and the basal nuclei. Sidman and Miale (1959) using
tritiated thymidine identified this migration. In these regions the cells in the mantle
layer become the gray matter, while their axons form the marginal zone or white
matter. By contrast, the cerebral cortex and cerebellar cortex are formed by the
migration of neuroblasts through the mantle zone into the marginal zone. Table 3.3
lists the fate of the neurons in the neural tube.
3.2 Histogenesis 77
Table 3.3 List of the fate of the layers in the neural tube
Marginal zone At the surface covered by the presumptive pia contains pathways
in the adult spinal cord and neurons in the cerebrum and cerebellum
Intermediate Becomes gray matter of the adult spinal cord, brain stem,
or mantle zone and diencephalon and contains white matter of the cerebrum
and cerebellum
Subventricular Forms the macroglia (astrocytes, oligodendrocytes)
zone (SVZ) and contains immature neurons throughout life
Ventricular lining zone Early on has germinal cells that form neuroblasts;
in mature brain becomes ependymal lining of ventricles
Since immature cells from fetuses are not as easily rejected, it has been proposed to
recover neuroblasts from the brains of aborted human fetuses. These fetal stem cells
from human embryos would be implanted in adults replacing damaged neurons in
patients with Huntington’s chorea and Parkinson’s disease. This line of transplant
research holds great promise not only for the nervous system but also for the pan-
creas, adrenal, and pituitary.
The harvesting of fetal neuronal stem cells seems especially promising, but there
is much public controversy over the use of fetal or aborted material. In addition,
most aborted materials have some genetic abnormalities. Neural stem cells are mul-
tipotential cells that generate many neuronal cell types, and with the addition of
factors, the cells can be even better differentiated. Current studies are underway to
activate this indwelling cell and also to harvest stem cells from other regions in the
body and direct them into regions in the brain that have been damaged. The results
to date are promising.
Principles of Differentiation Within the CNS:
The following are certain rules that can be applied to the differentiation within
the CNS (after Jacobson 1978):
1. Spatial and temporal gradients of proliferation exist in the neuroepithelial
germinal zone.
2. Neighboring regions have separate origins and are different cytoarchitectonically.
78 3 Neuroembryology and Congenital Malformations
Ramon y Cajal, at the turn of the last century, identified the growth cones that form
connections in the developing nervous system. Since that time neurobiologists have
been searching for the mechanisms that permit the formation of these synapses.
Several mechanisms have been proposed including cell adhesion, repulsion, and
chemoattraction. A diffusible factor that promotes outgrowth of axons in vitro has
been found in the floor plate of the embryonic spinal cord (Serafinin et al. 1994;
Kennedy 1994). Two membrane-associated proteins were purified from the embry-
onic chick brain, netrin-1 and netrin-2, and each protein promotes growth cone out-
growth. Cloning cDNA encoding the netrins showed that they were homologous to
UNC-6, a laminin-related protein (found in the extracellular matrix) required for
migration of cells and axons in the nematode Caenorhabditis elegans.
This homology suggests that growth cones in the vertebrate and nematode
respond to a similar molecule. Further studies with UNC-6 and the netrins have
shown that these molecules may be guidance and targeting signals rather than just
attractive versus repulsive molecules (Goodman 1994). We must expect that further
investigations of these molecules will lead to a better understanding of how the
nervous system actually forms and connects. An understanding of how the nervous
system forms connections may ultimately lead to better methods to repair damage
in the brain.
During the development of both the central and peripheral nervous system, the num-
ber of immature neurons formed is actually double that will ultimately survive
(Cowan et al. 1983). This apparent excess in formation of neurons is a mechanism
whereby the size of the neuronal pool is ultimately matched to the amount of tissue
actually innervated (Kane 1995; Lee 1993; Majon and Joris 1995; Elmore 2007). In
contrast to necrosis, which is a form of cell death that results from acute tissue injury
and provokes an inflammatory response, PCD is carried out in a regulated process
that generally confers advantages during an organism’s life cycle. “Programmed cell
death (PCD) is a fundamental biological process, serving many important functions
in animal development and homeostasis, and the pathogenesis of many diseases is
3.2 Histogenesis 79
The blood supply to the developing brain begins with the invasion of solid cords of
mesodermal endothelial cells, called Wilson’s Buds, which over a period of several
days develop a lumen and a basement membrane. These arteries develop in the pha-
ryngeal arches during the fourth week and are derived from the third pair of aortic
arches and dorsal aortae, and by 6 weeks there are well-established internal and
external carotid vessels. These buds of growing endothelial cells are especially
prominent as the marginal layers evolve. The blood intermediate supply evolves in
direct relationship to the maturation of the CNS and as a consequence of the many
factors released into the developing parenchyma of the CNS. As the astrocytes form
within the CNS, some of their end feet surround the basement membrane of the
brain capillaries and begin to form a blood–brain barrier. The actual tight junctions
between the endothelial cells that delineate the definitive blood–brain barrier are not
complete until just before birth.
When the neural folds fuse, a neural tube is formed. At the rostral end of the nervous
system, two lateral dilations appear: the primordia of the cerebral vesicles. These
regions will grow rapidly, extending anteriorly, inferiorly, and posteriorly as they
form the ventricles in the cerebral hemispheres.
Lateral Ventricles. The cavity in each cerebral vesicle is called a lateral ventricle.
As the cerebral hemispheres grow by continued outward migration of nerve cells,
the ventricles take up less and less space in the brain and are modified into a
C-shaped structure with a spur extending occipitally. Each lateral ventricle in its
final form is divided into an anterior horn, body, inferior horn, and posterior horn.
Foramen of Monro. Early in development, the lumen in the paired telencephalic
vesicles is continuous with that of the neural tube. As the telencephalon differenti-
ates into cerebral cortex and basal nuclei, the ventricles take up relatively less space.
A narrow channel, called the interventricular foramen of Monro, persists between
the cerebral ventricles and the third ventricle (Fig. 3.9).
Third Ventricle. The centrally placed cavity in the diencephalon—the third
ventricle—narrows as the parenchyma of the diencephalon forms.
Cerebral Aqueduct. In the midbrain the tectum and tegmentum expand greatly
and constrict the lumen so that only the narrow cerebral aqueduct remains.
Fourth Ventricle. In the metencephalon (cerebellum and pons) and myelencephalon
(medulla), the tegmentum undergoes a series of flexures, expands laterally, and is
overgrown by the cerebellum. As a result, the cavity in the myelencephalon and
metencephalon called the fourth ventricle assumes a rhomboid shape. The fourth
ventricle is continuous with the narrow cerebral aqueduct above and the constricted
spinal canal below.
3.2 Histogenesis 81
Spinal Canal. In the spinal cord, the expanding gray and white matter nearly
obliterates the ventricular cavity so that only the small spinal canal remains.
Peripheral structures are innervated from the nuclei in the brain stem (by the cranial
nerves) and from the nuclei in the spinal cord (by the spinal nerves). The 12 cranial
nerve nuclei innervate the skin, glands, viscera, striated muscles, and special sense
organs (eye and ear) in the head and neck. The spinal nerves innervate skin, glands,
and striated muscles in the upper and lower extremities and in the thorax, abdomen,
and pelvis.
The origin of the spinal cord can be traced to the 20th day. The neural plate then has
two distinct regions: caudally, a single elongate cylindrical region, which will
become the spinal cord, and, cranially, a shorter broader region, which will become
the brain (Fig. 3.1b).
Until the third month, the spinal cord fills the vertebral column. From then on the
cartilage and bone grow faster than the central nervous system, and by birth the coc-
cygeal end of the spinal cord lies at the level of the third lumbar vertebra. In an adult
it is found at the level of the first lumbar vertebra.
At the end of the somite period (days 30–35), mitotic divisions in the spinal cord
region produce thickened walls and a thin roof and floor, with almost complete
obliteration of the central canal (Fig. 3.4). The ventral portion of the lateral walls
develops and expands earlier than the dorsal region. The ventral portion is called
the basal plate and the dorsal portion is called the alar plate. Processes from cells in
the mantle layer enter the external-most region of the cord, which is called the
marginal zone.
Gray matter. Four columns appear in each half of the gray matter of the spinal
cord: two motors and two sensory (Table 3.4). The somatic afferent and efferent
column innervates the skin and muscle related to the somites, while the visceral
afferent and visceral efferent columns innervate the mucosa, glands, and smooth
muscles in the visceral structures. The somatic efferent cells are the motor neurons
in the ventral horn of the spinal cord; the somatic afferent cells are the neurons in
the spinal ganglia. The visceral efferent cells consist of sympathetic and parasym-
pathetic neurons.
Axons of developing motor neurons in the basal plate enter the adjoining
somites, while sensory roots derived from the adjacent neural crest zone enter the
dorsal or alar plate. In the spinal cord (Fig. 3.3), the plate will become the dorsal or
82 3 Neuroembryology and Congenital Malformations
Fig. 3.4 Schematic
representation of the
development of the spinal
cord (After Hamilton,
W.J. Boyd, J.D., and
Mossman, H.W.: Human
Embryology. Cambridge,
England, Heffer and Sons,
1964)
sensory associative horn, and the basal plate will become the ventral or motor horn.
In the medulla (Fig. 3.5), pons (Fig. 3.6), and midbrain (Fig. 3.7), the alar and basal
plates are restricted to the floor of the developing ventricular system. The remain-
ing bulk of these zones consists of nuclei and tracts that are related to the head,
neck, and special senses.
In the spinal cord, the marginal zone also increases in width as axons that form
the ascending and descending tract enter (Fig. 3.4). The formation of the dorsal and
ventral horns delimits the dorsal, ventral, and lateral columns or funiculi in the mar-
ginal zone. An intermediate horn develops dorsal and lateral to the anterior horn in
the thoracic and lumbar levels of the spinal cord. Cells in this horn are the pregan-
glionic sympathetic neurons. The postganglionic visceral neurons are in the
paravertebral sympathetic chain or in ganglia associated with the visceral organs.
The preganglionic parasympathetic innervation originates from the motor neurons
3.2 Histogenesis 83
Fig. 3.5 Schematic
representation of the
development of the medulla
(After Hamilton, W.J. Boyd,
J.D., and Mossman, H.W.:
Human Embryology.
Cambridge, England,
Heffer & Sons, 1964)
Fig. 3.6 Schematic
representation of the
development of the pons
(After Hamilton, W.J.,
Boyd, J.D., and Mossman,
H.W.: Human Embryology.
Cambridge, England,
Heffer and Sons, 1964)
84 3 Neuroembryology and Congenital Malformations
Fig. 3.7 Schematic
representation of the
development of the
midbrain (After Hamilton,
W.J. Boyd, J.D., and
Mossman, H.W.: Human
Embryology. Cambridge,
England, Heffer and Sons,
1964)
in cranial nerves III, VII, IX, and X and the sacral spinal cord and innervates ganglia
that connect the appropriate organ or gland. Again, these ganglia differentiate very
close to the appropriate structure. In the dorsal or sensory horn of the spinal cord,
there are sensory neurons that provide connections throughout the spinal cord or
brain stem.
The segmental arrangement of the central nervous system stops at the spino-
medullary junction, which marks the site of transition from the spinal cord to the
brain stem. The brain stem and cerebrum are suprasegmental with no evidence of
segmentation present. These regions of the central nervous system are specialized
to control structures in the head and neck as well as exerting control over the
entire body.
During development the spinal cord and the somites lie close together, so the
distance the axon must travel to reach its appropriate muscle is very short.
Undoubtedly, chemical factors help direct the axon to the correct muscle. The
sensory fibers also have only a short distance to run from the ganglia into the
skin or muscle and their axon into the central nervous system; again, probably
by chemical mediation, they establish the connection with the correct dorsal
horn cells.
3.3 Brain Differentiation 85
The brain begins development as a broad zone at the upper end of the developing
central nervous system with three distinct vesicles—the prosencephalon (forebrain),
the mesencephalon (midbrain), and the rhombencephalon (hindbrain).
Brain Flexures. These flexures occur concomitantly with the folds in the head
and change the simple-appearing neural tube into the precursor of the brain with its
divisions. The midbrain flexure in the fourth week bends the brain ventrally and
produces the midbrain flexure and the cervical flexures at the junction of the
hindbrain and spinal cord, and there is a later pontine flexure where the cerebellum
differentiates.
3.3.1 R
hombencephalon (Hindbrain) > Pons, Medulla,
and Cerebellum
The cerebellum and deep cerebellar nuclei are formed by the migration of cells
(Fujita et al. 1966). In the cerebellum there are two distinct germinal centers:
1. A region in the roof of the IV ventricle gives origin to the germinal Purkinje
and Golgi II cells and glia which migrate into the mantle layer of the
cerebellum.
2. The external granule zone that forms beneath the pia of the cerebellum. This
region gives origin to the granule cells, stellate, and basket cells and some of
the glia.
The Purkinje cell layer is the first to form. A little later cells migrate inward from
the more external layers to form the granular layer. In the adult the molecular layer
has only a few cells, but the Purkinje layer and granule cell layer have many neurons.
It appears that as the primitive neurons are migrating into their definitive place, they
form many of the connections necessary for their specialized functions.
The genetic factors which control the migration of cells into the cerebellum and
cerebrum and which provide the connections that are necessary for the proper
function of these structures are only now being identified. (These factors produce
some of the following changes—the glia and neurons migrate and elongate at
certain critical times and are supplied with an adequate blood supply that permits
all this to happen).
The mesencephalon (Fig. 3.7) begins as a wide tube with a conspicuous floor
(tegmentum) and a thin roof (tectum). The addition of fibers and nuclei in the mantle
zone of the tegmentum, concomitant with the formation of the superior and inferior
colliculi in the tectal area, produces a narrow cerebral aqueduct with a large tegmen-
tum and tectum.
The tectum consists of neurons that receive input from the cranial nerves that
relay auditory (inferior colliculus) and visual information (superior colliculus). The
cerebral peduncles form the anterior surface or basis of the midbrain, with the teg-
mentum located between the basis and tectum. The cerebral peduncles consist of
fibers descending from the cerebrum to the brain stem and spinal cord.
Three primary vesicles of brain regions are seen as the neural tube begins to close;
prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon
(hindbrain). The prosencephalon (Figs. 3.8 and 3.9) begins to differentiate at about
3.3 Brain Differentiation 87
Fig. 3.8 Differentiation of embryonic brain areas into adult brain regions
30 days as a dilation of the cranial end of the neural tube (Fig. 3.2c, d); this dilation
evolves into a right and left dilation. Early development of the optic vesicle, which
will become the eye, appears as a lateral diverticulum of the anterior portion of the
prosencephalon. In front of and above the optic stalk, a pair of cerebral vesicles
forms. The cerebral vesicles expand superiorly, anteriorly, and posteriorly.
3.3.4 Diencephalon
Fig. 3.9 Schematic representation of the development of the telencephalon and diencephalon
(After Hamilton, W.J., Boyd, J.D., and Mossman, H.W.: Human Embryology. Cambridge, England,
Heffer and Sons, 1964). Pituitary gland: The pituitary gland develops from two regions: (1) ecto-
dermal > adenohypophysis; (2) neuroectodermal from diencephalon > neurohypophysis
The cranial nerves form connections to the muscles, skin, glands, and blood vessels
in the head and neck. A detailed discussion of the individual cranial nerves can be
found in Chap. 7. In this section, the cranial nerves in Table 3.4 and Fig. 3.10 will
be categorized on the basis of the embryonic derived structures they innervate:
3.3 Brain Differentiation 89
Telencephalon Superior
Colliculus
Optic Nerves
Inferior
Colliculus
Cerebellum
Pons
Ophthalmic
Medulla
Div. CN V
Chorda
Maxillary Tymani
Div. CN V
Pharyngeal Br.
Hypoglossal
CN IX
Nerve
Spinal Accessory
Mandibular
Nerve
Div. CN V
Vagus Nerve
Lingual Br. CN IX
Fig. 3.10 (a) Demonstration of origin of nerve components of the cranial nerves from the ven-
tricular tegmentum of the brain stem. General and special somatic afferents and efferents, CN II,
III, IV, V, VI, VIII, and IX–XII, and general and special visceral efferents and afferents, CN I, VII,
IX and X. (b) Lateral surface of 11-week human embryo demonstrating the cranial and upper
spinal nerves (After Patten, B.M.: Human Embryology, New York, McGraw-Hill, 1953)
Nerve III (oculomotor) is a purely motor nerve that innervates the inferior oblique,
medial, superior, and inferior recti muscles and levator palpebrae superior muscles.
The extrinsic eye muscles develop from the mesenchyme in the orbital region.
Nerve IV (trochlear) is a purely motor nerve and innervates the superior oblique
muscle of the eye. This is the only cranial nerve with rootlets that leave the central
nervous system from the posterior surface of the brain.
Nerve VI (abducens) is a purely motor nerve and innervates the lateral rectus
muscle of the eye.
Nerve XII (hypoglossal) is a purely motor nerve and innervates the extrinsic and
intrinsic muscles in the tongue. Occipital myotomes migrate ventrally and form the
tongue musculature that is innervated by nerve XII. The epithelium and general
connective tissue of the tongue arises by the fusion of pharyngeal endoderm and
branchial mesoderm that are innervated by nerves VII, IX, and X.
3.3.5.2 C
ranial Nerves Innervating the Muscles (Skeletal)
and Skin in the Pharyngeal Arches (Table 3.4)
Cranial nerve innervation of the pharyngeal arches is shown in Table 3.4. After
somites begin to form, five ectodermal grooves appear lateral to the embryonic
pharynx and caudal to the somatoderm, or primitive mouth. The grooves are
90 3 Neuroembryology and Congenital Malformations
separated from one another by elevations, which gradually elongate, fuse with the
opposite side, and extend laterally and anteriorly around the pharynx, forming
arches. In lower vertebrates these arches form the gills, while in vertebrates without
gills, they are called pharyngeal arches. Many of the muscles and bones in the face
and neck originate from these arches.
1. First and second arches are named, respectively, the mandibular and hyoid and
the lower four unnamed (the sixth arch is rudimentary).
(a) First arch (mandibular) innervated by the trigeminal nerve—muscles of
mastication form here.
(b) Second arch (hyoid) innervated by the facial nerve—the muscles of facial
expression form here.
(c) Third arch innervated by the glossopharyngeal nerve—the stylopharyngeus
forms in the third.
(d) Fourth arch innervated by the superior laryngeal nerve of the vagus: crico-
thyroid muscles and constrictor muscles of the pharynx.
(e) Fifth arch regresses.
(f) Sixth arch innervated by the recurrent laryngeal nerve-vocal muscles.
2. Cranial nerves associated with the pharyngeal arches—V, VII, IX, and X–Table 3.5.
(a) Nerve V (trigeminal) is a mixed nerve (motor and sensory) that inner-
vates the first or mandibular arch and also contains a portion ( ophthalmic)
that distributes to the skin up to the vertex of the skull. The motor
division of this nerve innervates the muscles of mastication derived from
the first arch. The sensory division innervates the skin on the face and
forehead.
(b) Nerve VII (facial) is a mixed nerve that distributes to the second pharyngeal
or hyoid arch. The motor division of this nerve innervates the muscles of
facial expression. The sensory division innervates the taste buds on the ante-
rior two-thirds of the tongue.
(c) Nerve IX (glossopharyngeal) is a mixed nerve that innervates structures
associated with the third arch. The motor division of this nerve innervates
the stylopharyngeus muscles.
(d) Nerve X (vagus) is a mixed nerve that innervates structures associated with
the fourth and sixth arches (the fifth arch regresses), providing afferent
and efferent components to the heart, lungs, and much of the gastrointes-
tinal system.
(e) Nerve XI (accessory) is purely motor and innervates the sternomastoid
and trapezius muscles, which originate from the somatic and branchial
mesenchyme in the cervical region.
3.3 Brain Differentiation 91
Nerve III innervates the ciliary ganglion; postganglionic fibers then pass to the
sphincter of the iris, which constricts the pupil in bright light.
Nerve VII provides innervation to the submaxillary and lacrimal ganglia
associated with the following glands: submaxillary, sublingual, nasal, and lacrimal.
Nerve IX provides innervation to the parotid gland via the otic ganglion.
Nerve X provides innervation to the heart, lungs, and gastrointestinal system up
to the transverse colon and the axons from the vagus synapse upon ganglia associated
with these organs.
Nerve I (olfactory) cell bodies are located in the nasal placode (ectodermal thickening
in embryo where special sense organs of CN I, II, and VIII will form) in the upper
fifth of each nasal cavity. The neuroblasts in the olfactory epithelium differentiate into
olfactory epithelial cells. The axons of these cells grow toward the cerebral hemi-
sphere, pierce the roof of the nasal cavity, and enter the region of the hemisphere that
will become the olfactory bulb. The primary fibers synapse in the olfactory bulb. The
secondary cell bodies are located in the olfactory bulb and form the olfactory tracts.
92 3 Neuroembryology and Congenital Malformations
Nerve II (optic) originates from tertiary ganglion neurons in the retina. These
axons are really a tract in the central nervous system and do not constitute a periph-
eral nerve. The axons synapse in the lateral geniculate nucleus of the thalamus.
(Students may also want to review the details of the formation of the eye from the
optic vesicle and lens vesicles in a standard embryology test).
Nerve VIII (Vestibulocochlear) primary cell bodies are located in the cochlea
(auditory division) and vestibule (vestibular division) of the inner ear. (Students
may also want to review the details of the formation of the inner ear from the otic
placode in a standard embryology textbook).
Nerves VII, IX, and X provide innervation to the taste buds on the tongue and
pharynx.
3.3.6 Telencephalon
The telencephalon, part of the forebrain, consists of (1) two neuronal regions
(a cortical zone that becomes the cerebral hemispheres and a deeply placed nuclear
region, the corpus striatum, that becomes the caudate, putamen, and globus p allidus)
and (2) a white matter region that interconnects them, the internal capsule.
The telencephalon begins at 10 weeks as paired small smooth telencephalic
vesicles. By birth a large, convoluted cerebral cortex is present. The first prominent
features are seen.
How the Gyrification Occurs. The biomechanical forces that underlie the gyrifica-
tion that is characteristic of the adult human brain has been demonstrated by
Mahadevan et al. (2016). During weeks 14–26, the brain changes from a smooth
structure to a folded structure, and they have shown that the compression of these
massive number of cells in this limited space causes the cortex to collapse and form
the folds, the gyri and sulci, that are characteristic of the definitive human brain.
The first of these sulci, the primary sulci, appear at about 19 weeks; they are initially
the lateral or Sylvian sulcus, on the lateral surface (Fig. 3.11), and the parieto-
occipital sulcus, on the medial surface (Fig. 3.12). By the 24th week, the Sylvian
sulcus is more pronounced on the lateral surface, and the calcarine sulcus is promi-
nent on the medial surface and becomes prominent (Fig. 3.11). Shortly thereafter
the other primary sulci—the central, callosal, and hippocampal—appear.
After about 30 weeks, the primary sulci are formed, and there is a rapid increase
in the secondary sulci and gyri. By term, formation of the gyri and sulci is complete.
After birth the gyri increase in bulk as the neurons continue to differentiate.
The telencephalic vesicle rapidly changes shape as the frontal lobe forms and
pushes anteriorly, the temporal lobe grows inferiorly, and the occipital and parietal
3.3 Brain Differentiation 93
Weeks
Weeks
10
28
12
37
15
30
19
39
32
22
24 34 41
Fig. 3.11 Development of the lateral surface of the brain during fetal life. Numbers represent
gestation age in weeks (From Larroche, J. CI: The Development of the Central Nervous System
During Intrauterine Life. In Falkner, F. (ed.): Human Development, Philadelphia, W.B. Saunders,
1966, p. 258)
regions expand. The olfactory bulb forms at the base of the frontal lobe by an evagi-
nation of cells that quickly obliterates any trace of the ventricle in the olfactory bulb.
The sulci begin as rather shallow depressions. However, as the neurons continue
to migrate from the ventricular surface, more and more cells are added, and the gyri
become larger, and the sulci become deeper. In the term and adult brain, more than
70% of the cortical surface is hidden from view, deep in the banks of the sulci.
Therefore, when we speak of the total surface of the cerebral hemispheres, we must
include not only the superficial cortex but also the hidden sulcal cortex.
94 3 Neuroembryology and Congenital Malformations
Fig. 3.12 Development of the medial surface of the brain during fetal life. Numbers represent
gestation age in weeks (From Larroche, J. CI: The Development of the Central Nervous System
during Intrauterine Life. In Falkner, F. (ed.): Human Development. Philadelphia, W.B. Saunders,
1966, p. 259)
The brain at birth weighs 300–400 g; by 1 year it weighs 1000 g. The brain
c ontinues to grow and, by late childhood, reaches its final weight of approximately
1500 g.
cortex appear to mature prior to the stellate cells (Altman 1966). Radial glial fibers
form connections from the luminal surface to the pial surface that helps the p rimitive
neurons migrating later into the more superficial layers to traverse the increased cell
densities in the deeper layers. The formation of the cerebrum from inside to outside
permits much of the circuitry to form and also permits the columnar arrangement in
the cortex to evolve.
The development of the six-layered cerebral cortex starts with the migration of
neuroblasts into the deepest layer (4–6) first and then the cells into the external
layers (1–3) last—“inside-out.” Tritiated thymidine studies have been used on
rodents and primates for labeling nerve cells in the germinal layer of the ventricle
on their “birth days” and following them into the cerebrum and identifying their
final destination (Sidman and Feder 1959; Sidman and Miale 1959; Rakic, 1972).
Commissures. Fiber bundles, called commissures (Fig. 3.13a–d), interconnect
the two cerebral hemispheres. The anterior commissure interconnects the olfactory
bulbs and anterior parts of the temporal lobe. The huge corpus callosum intercon-
nects the remaining portions of the hemisphere. The hippocampal commissure
interconnects the hippocampus and adjacent portions of the hippocampal gyrus.
These commissures form in the lamina terminalis that marks the site of the closure
of the anterior neuropore. The ventral surface of the hemispheres at this place fuses,
and the fibers can then cross and interconnect the two hemispheres.
Initially, the anterior commissure, corpus callosum, and fornix (which connect
the hippocampus and hypothalamus) are close to one another (Fig. 3.13a), but as the
brain grows, the corpus callosum expands anteriorly, inferiorly, superiorly, and
caudally with only the rostral tip remaining attached to the lamina terminalis.1
Hippocampus Corpus
Callosum
c
a Fornix
Corpus
Anterior Callosum
Commissure Anterior
Commissure
Fornix
Corpus Uncus Olfactory
Callosum Area
Olfactory Fornix
Area Uncus
Hippocampus
Corpus Callosum
Olfactory
Anterior Commissure Fornix Area
d
Olfactory Area Uncus
b Hippocampus Uncus Hippocampus
Fig. 3.13 Development of the fornix and commissures of the cerebral hemispheres. (a) Three-
month fetus. (b) Four-month fetus. (c) Fetus at the beginning of the fifth month. (d) Fetus at the
end of seventh month (After Keibel, F., and Mall, F.P.: Manual of Human Embryology, Philadelphia,
Lippincott, 1910–12)
1
The hippocampus anteriorly is disrupted by the formation of the corpus callosum, and a small
dorsal hippocampus or indusium griseum remains on the dorsal surface of the corpus callosum.
96 3 Neuroembryology and Congenital Malformations
The developing cerebral hemispheres initially show the three regions common to
the neural tube, ventricular, intermediate and marginal zones. Then the subventricu-
lar zone appears. Cells of the intermediate zone migrate into the marginal zone and
form the cortical layers so that the gray matter is on the periphery and the white
matter, medullary center, is located centrally (Figs. 3.14, 3.15, and 3.16).
Fig. 3.14 Neuroepithelial to radial glia transition. “During neurogenesis, neuroepithelial cells
(NEP) progressively convert to radial glial cells that elongate following the thickening of the neu-
ral tube wall. Basal progenitors (red outlined) are generated at early stages by neuroepithelial cells,
and at later stages by radial glia, and accumulate in the subventricular zone (SVZ). Preplate neu-
rons (green) are generated at early stages by basal progenitors. At later stages neurons derive from
both radial glia (blue) and basal precursors (red).CP cortical plate, SVZ subventricular zone, VZ
ventricular zone. At the end of neurulation, the CNS is made up of a pseudostratified epithelium
where radially arranged bipolar cells span the entire thickness of the neural tube. Since the pro-
genitor cells are not synchronized and at any given time there are cells in all possible phases of the
cycle, the epithelium results in being pseudostratified. From this stage, however, an increasing
number of cells start to divide asymmetrically, giving rise to another neuroepithelial cell and either
to a neuron or, alternatively, to a progenitor cell that will undergo mitosis at a significant distance
from the ventricular surface (basal progenitor) and which will generate neurons via a symmetric
division. Shortly after the appearance of the first neurons, neuroepithelial cells undergo a second
change in their characteristics and acquire molecular and cytological features typical of the astro-
glial lineage, as they give rise to the radial glial cells, The radial glial cells undergo interkinetic
nuclear migration, but their somata do not move across the entire thickness of the neural tube;
rather they remain confined to an apical region, which, therefore, is densely packed with cell nuclei
and which is referred to as the ventricular zone (VZ;).These cells now form a layer at the border
between the VZ and the preplate, known as the subventricular zone (SVZ)”. (From Appolloni,
Irene; Calzolari, Filippo Journal: Cell and Tissue Research Vol. 331 Springer Images)
3.4 Prenatal Development of the Cerebral Cortex 97
Fig. 3.15 Diagrams of the kinetics in cellular migration in the cerebral cortex (a) demonstrate
how the leading process is extended using guidance molecules which regulate actin polymerization
and in (b) demonstrate how the nuclear movement is driven by microtubules radiating out from the
centrosome. The dynein motor complex is anchored to the cell cortex in the leading process and
pulls the centrosome forward. Additional forces may push the nucleus from the back (From
Encyclopedia of Neuroscience)
1
2
a MZ
5
CP
PP
SP 6
IZ
White
matter
Preplate stage Early cortical plate stage Late cortical plate stage Adult
Fig. 3.16 Radial migration and neocortical layer formation of a normal cortical development. (a)
In normal development the preplate (PP) is formed by the first wave of postmitotic cells (blue)
differentiated from radial glia (red) in the ventricular zone (VZ). In the early cortical plate (CP)
stage, new neurons migrate radially from the VZ and split the PP into the marginal zone (MZ) and
subplate (SP). Many neurons adopt somal translocation within the process inherited from radial
glia. In the late CP stage, new neurons first move randomly by multipolar migration in the inter-
mediate zone (IZ) and then migrate radially toward the CP by locomotion along the fibers of
other radial glia. Neurons migrate past their predecessors and expand the CP in an inside-out
fashion. The adult stage is marked by the six-layered neocortex. (b) In reeler mice, neurons fail
to migrate beyond earlier neurons and pile up underneath the PP. Cortical layering in the adult
stage is inverted and disorganized (From Neuronal Migration. Kengaku, M, Encyclopedia of
Neuroscience-540-29678-2_3917, 2009)
p rotein and in which there is total disorganization of the usual laminar pattern.)
When the successive waves of migrating neurons encounter the organizing layer,
reelin provides a signal to detach, from the glial guidewires. The initial cells to
detach form the neurons of layer 6. The apical dendrites of these pyramidal cells in
layers 6 and subsequently layer 5 will extend to the pial surface.
3.5 Changes in the Cortical Architecture as a Function of Postnatal Age 99
3.5 C
hanges in the Cortical Architecture as a Function
of Postnatal Age
Myelination within the cerebral hemisphere and within the cerebral cortex occurs
at different rates in different areas paralleling the changes in psychomotor develop-
ment. Flechsig demonstrated that the sequence of myelination in cerebral cortex
followed a logical pattern.
Although myelination of the cerebral cortex begins during the early postnatal
months, it is evident that this process is not completed at this time. The initial
myelination begins in the vertically oriented fibers of the infragranular layers and
then extends into the supragranular layers. The myelination of horizontal plexuses
occurs at a later stage. Myelination continues to increase beyond 15 years of age and
throughout life with a gradual increase in density of the myelinated fibers particu-
larly in the horizontal plexuses. It is important to note that even in the adult not all
cortical areas will reach the same density of myelinated fibers since the underlying
pattern of distribution and density of pyramidal cells and their processes will differ
significantly among different cortical areas.
Neuronal Maturation. In addition to changes in the degree of myelination, more
basic changes in the relationship between nerve cells are occurring. Thus the
neocortex has received its full complement of neurons by the end of the sixth fetal
month. During postnatal development as shown in silver stains, there is a progres-
sive growth of the apical and basilar dendritic arborizations. The studies of Conel
have demonstrated that the more primitive allocortex (e.g., hippocampus) attains its
final structural form at an earlier stage than the neocortex. The process of maturation
however involves more than a progressive growth and elaboration of dendrites and
synapses. In addition, a remodeling of neuronal connections occurs in large part
based on neuronal activity. In the early perinatal period, there may be an excessive
projection of axons to their targets. Maturation in part consists of the elimination of
these aberrant collateral axon branches. In the primate there are estimated to be 3–4
times as many axons within the corpus callosum at birth compared to the adult state.
In this process the NMDA receptor may have a considerable role in both the neocor-
tex and hippocampus, with the same cascade of the events that occur in long-term
potentiation also responsible for the remodeling and synaptic plasticity. Abnormalities
in development or sensory/environmental deprivation may retard the structural and
functional development of these processes.
3.6 Abnormal Development 101
The complexity of development of the nervous system means that there is a great
chance for things to go wrong. In fact, more malformations occur in the nervous
system than in any other organ system. Of the 0.5% of newborn infants with a major
malfunction, roughly 60% affect the nervous system.
Many defects in the brain and spinal cord are evident at birth (Table 3.6). Some
defects may be limited to only the nervous system, but others may include overlying
ectodermal and mesodermal structures (bone, muscle, and connective tissue). Many
of the malformations are due to genetic abnormalities. Other categories of defects
can be acquired from the maternal environment: infections (syphilis, rubella, AIDS),
drugs (including alcohol, cocaine, etc.), ionizing radiation, environmental toxicants,
metabolic disease, and poor nutrition. The most serious defects are fatal, but even
the less severe abnormalities may significantly impair function. The following dis-
cussion covers many of the major groups of malformations of the peripheral and
central nervous system. More complete lists can be found in pathology textbooks.
3.6.1 M
alformations Resulting from Abnormalities
in Growth and Migration with Incomplete
Development of the Brain
the cerebrum, the neurons that form the deeper cortical layers arrive first, and then
cells destined for outer layers appear. In this abnormality the later waves of migra-
tion stop. The axons from the first cells to arrive begin to extend throughout the
brain and actually form a barrier that interferes with the next wave of migration. The
newly arriving neurons, which were destined for the superficial layers, instead now
form a disorganized mass of neurons deep to the cortex (Table 3.7).
1. Type 1 X-linked dominant lissencephaly. Most of the neurons never reach their
expected destination but instead are arrested in the subcortical white matter and
the subventricular proliferative zone. The cortex is smooth, since development
never proceeds to the stage of development of sulci and gyri that is necessary to
accommodate the large numbers of cortical neurons that would otherwise be
present in a normally developed cerebral cortex. In this mutation, the cortex per
se is thin with the lamination pattern consisting of a rudimentary molecular layer
1 and a thin layer 5/6. Since males have only one X chromosome, this type of
lissencephaly occurs in males. Severe psychomotor retardation and seizures are
the result of this process. Since females have two X chromosomes, the effects of
a single mutant X chromosome are less severe. The double cortex (subcortical
band heterotopia, laminar heterotopia, or diffuse cortical dysplasia) syndrome is
the result. There is only a partial migration defect. Some neurons arrest in the
subcortical white matter, but sufficient neurons reach the intended targets so that
a normal six-layered laminar pattern is present. Cognitive function fully devel-
ops but seizures are present.
2. Miller–Dieker syndrome. This different genetic type of lissencephaly occurs
in the autosomal recessive with linkage to locus 17p13.3. Infantile spasms
and mixed seizures are associated with motor and mental retardation and a
characteristic facies.
3.6 Abnormal Development 103
1. Electroencephalogram: normal.
2. MRI: bilateral triangular-shaped foci of heterotopic gray matter were present in
the frontal white matter extending from the superolateral aspect of the frontal
horns to the gray white junction superiorly.
104 3 Neuroembryology and Congenital Malformations
Lissencephaly (Agyria–Pachygyria). The brain has failed to form sulci and gyri
and corresponds to a 12-week embryo. There are usually also dysmorphic facial
features. In some cases, a few gyri do form. Neuronal migration has been arrested
at this stage due to a chromosomal defect, ischemia, or infection. The studies of
Reiner et al. (1993) have identified a specific gene deletion at chromosome 17
region p13.3, the LIS-1 gene.
Micropolygyria (Fig. 3.17). The gyri are more numerous, smaller, and more
poorly developed than normal.
Macrogyria. The gyri are broader and less numerous than in the normal brain.
Micrencephaly. This is another abnormal defect in which development of the
brain is rudimentary, and the individual has a low-grade intelligence.
The Zika virus and microcephaly. The Zika virus is a flavivirus, and most
viruses in this family are carried by arthropods—mosquitoes and ticks. It is trans-
mitted in utero to fetuses by the bites of infected mosquitoes. It also may be trans-
mitted by sexual contact. It produces microcephaly, eye defects, hearing loss, and
impaired growth especially in the head and neck region.
Porencephaly. There are symmetrical cavities in the cortex due to the absence of
cortex and white matter in these sites.
Schizencephaly (Fig. 3.17). There is an incomplete development of the cerebral
hemispheres with the presence of abnormal gyri. The patient is usually retarded.
Agenesis of Corpus Callosum (Fig. 3.18). There is a complete or partial absence
of the corpus callosum and septum.
The following case, Case 3.2, is an example of agenesis of the corpus callosum.
Case 3.2 Agenesis of corpus callosum: Patient of Dr. Sandra Horowitz, Fig 3.2.
This 20-year-old female warehouse employee was referred for reevaluation of
generalized convulsive seizures that had developed at age 3 years. She had been
seizure-free for 5 years. She had mild developmental delays. Full-scale Wechsler
Fig. 3.17 Schizencephaly. (a) 3D reconstruction and (b) coronal view. MRI, T2 (Courtesy of Dr.
Val Runge, University of Kentucky Medical Center)
106 3 Neuroembryology and Congenital Malformations
Adult Intelligence IQ score was 82, with a verbal score of 88 and a performance
score of 77 (all were within low average range). She demonstrated complete agen-
esis of the corpus callosum with associated alterations of gyral and sulcal patterns.
Figure 3.22 Midline sagittal section T1 weighted.
Holoprosencephaly. Only a single forebrain has formed. This deficit is also com-
monly accompanied by a deficit in medial facial development (Fig. 3.21).
This 10-month-old white male had severe spastic diplegia (a form of “cerebral
palsy”) and severe developmental delays. CT scan demonstrated a fusion of the two
lateral ventricles and no frontal horns. A large cystic area extended superiorly and
posteriorly.
3.6 Abnormal Development 107
3.6.3 E
nvironmentally Induced Migration Disorder: Fetal
Alcohol Syndrome
Fetal alcohol syndrome (FAS), mothers drinking alcohol during pregnancy, causes one
of the more common nongenetic causes of mental retardation (one out of 300–2000
live births or up to 2%). There are other environmentally generated disorders, but the
FAS has the clearest etiology. The current recommendation is for pregnant women to
avoid all alcohol, especially during the first trimester, or to cut back to no more than
two drinks per day. Pregnant alcoholics are at high risk for premature delivery.
In FAS, pre- and postnatal growth retardation occurs along with cardiovascular,
limb, and craniofacial abnormalities, such as a short palpebral fissure, thin vermil-
lion border, and smooth philtrum. Children often have impaired fine and gross
movements and developmental deficits. Microcephaly, heterotopias, and lissen-
cephaly have been reported (Diminski and Kalens 1992; Love et al. 2008). Related
to the problem of FAS is the huge rise in “cocaine babies,” which have similar
deficits that require lifetime care (Fig. 3.20).
Fig. 3.20 Holoprosencephaly. (a) View of frontal poles and (b) coronal section. Note the absence
of any differentiation of the hemispheres (Courtesy of Dr. John Hills, New England Medical
Center Hospitals)
108 3 Neuroembryology and Congenital Malformations
3.6.4 M
alformations Resulting from Chromosomal Trisomy
and Translocation
Through advances in molecular biology, more and more genetic defects are being
localized to specific genes. For example, in translocation syndromes like trisomy 21
(Down’s syndrome), one chromosomal segment is transferred to a nonhomologous
chromosome; this is called a Robertsonian translocation and most commonly affects
chromosomes 13, 14, 15, 18, 21, and 22. Other defects, such as trisomy 18 (Edward’s
syndrome) and trisomy 13 (Patau syndrome), have similar neurologic findings.
Most children with Down’s syndrome are moderately mentally retarded and of
short stature. They have hypoplastic faces with short noses, small ears with promi-
nent antihelices, and prominent epicanthal folds (which perhaps suggested the now
outdated term mongolism). Other defects include a protruding lower lip, a fissured
and thickened tongue, and a simian crease on the palm. A predisposition to leuke-
mia and congenital heart defects often proves fatal. Children with Down’s syndrome
constitute about 5% of children in institutions for the mentally retarded.
The brains of these children show little gross abnormality. The frontal and occip-
ital poles are rounder than normal, and the superior temporal gyrus is thinner.
Conventional stains show the brain to be normal histologically, but the Golgi stain,
which specifically impregnates axons and dendrites, shows sparser dendritic arbori-
zations, fewer dendritic spines, and more anomalous spines (Marin-Padilla 1972;
Purpura 1974; Becker et al., 1986, von Bohlen and Halbach 2010).
Patients who reach middle age may develop a degenerative disease of the ner-
vous system called Alzheimer’s disease (see chapter on dementia).
3.6.5 M
alformations Resulting from Defective Fusion
of Dorsal Structures
Spina Bifida. In spina bifida, the most common malformation in this category, the
arches and dorsal spines of the vertebrae are absent. Often the bony deficit alone is
present. The spinal cord, however, may be malformed either at one level or at many
levels. In some instances the spinal cord, nerve root, and meninges have herniated
through the midline defect in the skin and bone—meningomyelocele (Fig. 3.21).
In other instances only the meninges have herniated through the midline defect; the
sac is called a meningocele.
Cranial Bifida. Cranial bifida is less common than spina bifida and usually
occurs only in the suboccipital region. The cranial bones either fail to fuse or do not
form. The abnormality may only be restricted to the underlying portion of the cere-
brum, or it may be accompanied by a herniation of meninges, meningocele, or
meninges and brain tissue, encephalocele. Cranial bifida is commonly associated
with hydrocephalus and extensive brain damage.
3.6 Abnormal Development 109
Fig. 3.21 Meningomyelocele at sacral level of the spinal cord. Arrow refers to sac, meninges,
neural tissue, and overlying skin (Courtesy of Dr. John Hills, New England Medical Center
Hospitals)
3.6.6 M
alformations Characterized by Excessive Growth
of Ectodermal and Mesodermal Tissue Affecting
the Skin, Nervous System, and Other Tissues
3.6.7 C
utaneous Angiomatosis with Associated Malformations
of the Central Nervous System
Various disorders are included in this category, often some type of vascular anomaly
affecting the skin (a vascular nevus), and are associated with a malformation in the
affected areas of the nervous system. Hemangiomas of the spinal cord may be asso-
ciated with a congenital vascular nevus in the corresponding dermatome.
Sturge–Weber Syndrome. Patients with this abnormality have a large, deep port
red wine nevus over much of the forehead corresponding to the distribution of the
ophthalmic branch of the trigeminal nerve. The vascular malformation involves the
meninges overlying the parieto-occipital cortex. In this cortical region, there is cal-
cification of the second and third layers with neuronal degeneration and prolifera-
tion of reactive glial. Atrophy occurs in the cerebrum. The specific genetic basis of
this syndrome is uncertain.
3.6.8 M
alformations Resulting from Abnormalities
in the Ventricular System
Syringomyelia. In this condition the spinal canal is abnormally large. The cavity
may enlarge to destroy parts or all of the gray matter and adjacent white matter
producing a characteristic “cape-like deficit” in pain sensation (Chap. 9).
Syringobulbia. In this condition there are abnormal slit-like cavities extending
from the fourth ventricle into the subjacent tegmentum of the medulla (most com-
mon) and pons disrupting gray and white matter with accompanying cranial nerve
and long tract signs.
Hydrocephalus. Any abnormality in the absorption of cerebrospinal fluid that
produces increased cerebrospinal fluid pressure and dilation of the ventricular
system is called hydrocephalus. Blockage of the flow in the ventricular system is
Bibliography 111
Fig. 3.22 Noncommuni
cating hydrocephalus,
Dandy–Walker syndrome
(Courtesy of Dr. John
Hills, New England
Medical Center Hospitals)
Bibliography
Abstract The spinal cord is tubular in shape and has 32 segments with the gray
matter in the center and white matter on the outside. Each segment has nerve r ootlets
on the dorsal and ventral surface with a sensory ganglion attached to the dorsal
nerve rootlets. These dorsal root ganglia contain the primary cell bodies of the
general sensory systems—pain, temperature, touch, and pressure from the neck,
thorax, abdomen, and extremities.
The gray matter is shaped like a butterfly, and the gray matter in all levels has
three zones: a dorsal horn, a ventral horn, and an intermediate zone. A lateral horn
containing the preganglionic sympathetic neurons is found in levels T1–L2.
The surrounding white matter is divided into three columns, dorsal, ventral, and
anterior. The white matter is organized with the ascending systems on the outside
and the descending systems closer to the gray matter.
Keywords 32 Segments • Central gray • White matter • Dorsal and ventral nerves
• Ascending tracts • Descending tracts
The spinal cord is cylindrical in shape and lies in the vertebral canal with its
cephalic end continuous with the medulla of the brain stem while the caudal end
terminates on the inner border of the second lumbar vertebrae as the conus
medullaris. From the conus the filum terminale which consists of connective tissue
and pia connects to the inner surface of the first coccyx vertebrae surrounded by
the nerves exiting the lumbar and sacral levels of the spinal cord forming the cauda
equina. The spinal cord had two enlargements, the cervical (from vertebrae C3
to T2) and lumbar (T9–T12). The cervical enlargement innervates the upper limb
while the lumbar enlargement innervates the lower limb.
Sulci. The anterior median sulcus and the posterior median sulcus divide the cord
into equal right and left halves. The dorsal lateral sulcus is found at all levels, and it
marks the location of the dorsal/sensory rootlets. The actual gray and white matter
of the spinal cord end at the lower end of L1.
There are 32 segments of the spinal cord: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral,
and several coccygeal spinal cord segments. They are shown in relation to the
vertebral column in Fig. 4.3. There are seven cervical vertebrae; C8 in Fig. 7.2
is the eighth cervical spinal nerve that arises from the anterior and posterior roots
of the eighth cervical spinal cord segment.
The rootlet of the eighth cervical nerve emerges below the seventh cervical
vertebrae and above the first thoracic vertebrae. The spinal nerves are always named
for the spinal cord segment of origin. The intervertebral disk and foramen (Fig. 4.5)
are normally named by the vertebrae above and below, i.e., L4, five disks and, L5,
Sl foramen. During development and growth, particularly intrauterine growth, the
vertebral column grows faster than the spinal cord it contains so that, in the adult,
the spinal cord does not extend the length of the vertebral column (Fig. 4.3). As a
result, the spinal roots run interiorly before they leave the spinal canal. The spinal
cord ends at the first or second lumbar vertebra, and below this level the spinal canal
contains only spinal roots. This mass of roots reminded early anatomists of a horse’s
tail, so it was named cauda equina. The nerve roots run through the subarachnoid
space, which is filled with cerebrospinal fluid. When a needle is inserted through the
space between the fourth and fifth lumbar vertebra (Fig. 4.5), the point penetrates
the dura and pushes aside the spinal roots. If the needle was inserted above L2, there
would be danger of damaging the spinal cord. Samples of cerebrospinal fluid can
be taken through this needle; pressure can be measured, or anesthetic agents or
radio-opaque dyes can be injected (as in Fig. 4.5).
Meninges/coverings of the spinal cord. The spinal cord just as the other regions in
the central nervous system is protected by three of layers of connective tissue cover-
ings, the pia, arachnoid, and dura. The pia mater is adherent to the external surface
of the spinal cord. The arachnoid and pia form a membrane with c erebrospinal fluid
occupying the subarachnoid space between the pia and arachnoid. The arachnoid lies
against the thick, tough dura. The spinal dura forms a protective tube beginning at the
dura of the skull and tapering to a point in the region of the sacral vertebrae. Between
the dura and the vertebrae lies the epidural space, usually filled with fat. The denticu-
late ligaments anchor the spinal cord to the dura. The spinal cord and, more impor-
tantly, the spinal roots are named in relation to the vertebral column. In humans there
are 8 cervical, l2 thoracic, 5 lumbar, 5 sacral, and 2 coccygeal segments.
The anterior and posterior roots join to form a spinal nerve (Fig. 4.1) just before
having the vertebral canal through a recess in the posterior process of each vertebra
as shown in Fig. 4.2. The canal, the intervertebral neural foramina, is only a little
larger than the nerve so that any swelling of the nerve or diminution of the diameter
4.1 Gross Anatomy 115
of the canal will pinch the nerve. It is not uncommon for the intervertebral disk to
rupture posteriorly or laterally and press on a spinal nerve as it exits. The very
intense pain this pressing causes is referred to the area of the skin where the nerve
began. Frequent sites where the nerve roots are pinched are the intervertebral foram-
ina between L2 and S1, which give rise to the sciatic nerve. The pinched nerve gives
the patient the impression that a hot knife is being dragged along the posterior
aspect of his calf.
Posterior root fibers—sensory nerves. Sensory nerve fibers enter the spinal cord
gray matter (Fig. 4.1) and divide into a medial bundle of large, heavily myelinated
fibers and a lateral bundle consisting of thinly myelinated and unmyelinated axons.
The heavily myelinated medial bundles convey information from the large dorsal
Fig. 4.3 (a) The lateral aspect of the spinal cord exposed within the vertebral column. (b) The
spinous process and the laminae of the vertebrae have been removed, and the dura mater has been
opened longitudinally (From Clemente (Ed), Gray’s Anatomy Philadelphia, Lea and Febiger, 1985)
The gray matter is in the center of the spinal cord covered by the white matter that
forms the connections to and from the spinal cord. The relative amounts of white
and gray matter vary with the spinal cord level (Fig. 4.4).
4.1 Gross Anatomy 117
The white matter decreases in bulk as the sections are further from the brain.
Motor tracts from the brain descend into the white matter to enter the gray matter
and synapse with motor neurons. Sensory fibers enter the cord, section by section,
forming the ascending pathways within the white matter. A section of the cervical
cord contains sensory fibers running up to the brain from the thoracic, lumbar, and
sacral sections. It also contains motor fibers running down to innervate motor axons
of the thoracic, lumbar, and sacral sections. The white matter of a section of the
lumbar cord, however, only contains fibers to and from that level and lumbar seg-
ments inferior to it and the sacral segments. The white matter columns have the
shape of pyramids with their bases at the foramen magnum and their tips at the last
sacral section. The situation in the gray matter is quite different. The gray matter is
organized into a dorsal and ventral horn, and in C8–L2 there is an added interme-
diolateral horn that contains the preganglionic sympathetic neurons. Since the gray
matter innervates a segment, the size of the gray matter (the number of cells it con-
tains) is related to the complexity of the segment. The hand, for example, is inner-
vated by cervical segments 6, 7, and 8 (C6, C7, and C8) and the first thoracic
118 4 Spinal Cord
segment (T1). The hand has the highest concentration of sensory receptors of any
region of the body. All of these receptors send their axons into C6 to Tl where they
synapse, thus increasing the girth of the posterior gray matter. The muscles of the
hand can carry out very fine and intricate movements. They are innervated by nerves
having their cell bodies in the gray matter of C6–Tl.
The innervation of the many muscles that constitute either the upper or lower
extremity requires many cell bodies in the dorsal and ventral horn. Consequently,
the cord is enlarged at C6–T1. The situation is much the same in the lumbar region.
Sensory input from and motor output to the leg is complex, and the gray matter is
large. The thoracic and sacral segments, on the other hand, have very small gray
matter areas since they innervate only a few muscles and receive relatively uncom-
plicated sensory messages. Segments can be recognized, then, by the amount of
gray and white matter relative to the whole cross section. In the lower cervical seg-
ments, the section is large and oval, and the white matter and gray matter are nearly
equal. The thoracic segments have much more white matter than gray matter, and
the shape of the gray matter, a thin H, is very characteristic. The lumbar segments
have more gray matter than white matter, and the sacral segments are very small
and have much more gray matter than white matter. The segments can also be
recognized by the shapes of the gray matter. A careful review of Fig. 4.4 provides a
basis for recognizing the segmental levels of spinal cord sections. The area of the
body which sends sensory fibers into a given spinal cord segment is called a derma-
tome. These have varying shapes and sizes. Figure 4.5 demonstrates the differences
seen at these levels.
Laminar Organization. In order to clear up this confusion about the terminology
in the organization of the gray matter of the cord, Rexed (1952) proposed a laminar
organization of the cat spinal cord which has since been extended to all primates.
Fig. 4.5 The technique of Lumbar Puncture to with draw CSF or add dye (modified from House
and Pansky-A Functional Approach to Neuroanatomy, McGraw Hill NY, 1960
4.1 Gross Anatomy 119
Fig. 4.6 Rexed’s lamination pattern of the spinal gray matter on the right and the location of
ventral horn cells on the left, lumbar section. Myelin stain from Marcus EM and S. Jacobson,
Integrated Neuroscience, Kluwer 2003)
The gray matter is divided into nine layers with a thin tenth region surrounding
the central canal, Fig. 4.6.
Lamina 1 forms the cap of the dorsal horn and is penetrated by many fibers.
It includes the nucleus posterior marginalis. Many intersegmental pathways arise
from this layer, and Aβ, nociceptive fibers terminate in lamina I (Figs. 4.7 and 4.8).
Lamina 2 corresponds to the substantia gelatinosa. This nucleus extends the entire
length of the cord and is most prominent in the cervical and lumbar levels. Cells in
this lamina also form intersegmental connections. C pain fibers terminate in lamina 2.
Lamina 3 is the broad zone containing many myelinated axons and receives
many synapses from the dorsal root fibers.
Lamina 4 is the largest zone and consists primarily of the nucleus proprius of the
dorsal horn. This nucleus is conspicuous in all levels. Aα fibers from mechanore-
ceptors terminate in this layer.
Lamina 5 extends across the neck of the dorsal horn and in all, but the thoracic
region is divided into medial and lateral portions. The lateral portion consists of the
reticular nucleus that is most conspicuous in the cervical levels; corticospinal and
posterior root synapses have been identified in this lamina. The C pain fibers and the
Aβ nociceptive fibers also terminate in these layers.
Lamina 6 is a wide zone most prominent in the cervical and lumbar enlarge-
ments. In these levels, it is divided into medial and lateral zones. Terminals from the
posterior roots end in the medial region while descending fiber tracts project to the
lateral zone.
120 4 Spinal Cord
S1
L5
A B
Lamina 7 includes most of the intermediate region of the gray matter in the
s pinal cord. In this lamina, the intermediolateral and intermediomedial nuclei are
found. The nucleus dorsalis or nucleus spinal cerebellar of Clarke is obvious in C8
through L2 levels. The axons arising from this nucleus form the posterior spinocer-
ebellar tract. In the cervical and lumbar enlargements, this lamina includes many of
the internuncials and the cell bodies of gamma efferent neurons.
Axons from posterior roots, cerebral cortex, and other systems end in lamina 7.
Cells in lamina 7 form tracts that project to higher levels including cerebellum and
thalamus. In the thoracic and sacral regions, axons also leave this lamina to form
preganglionic autonomic connections.
4.1 Gross Anatomy 121
Fig. 4.8 Functional localization within the anterior horns (From Bossy: Atlas of Neuroanatomy
WB Saunders, 1970)
Lamina 8 in the cervical and lumbar enlargement is confined to the medial part
of the anterior horn. Many of the axons from these nerve cells form commissural
fibers in the anterior white column. Axons from descending pathways originating in
the brain stem terminate here.
122 4 Spinal Cord
Lamina 9 includes the largest cell bodies in the spinal cord, the ventral horn
cells. The axons of these cells (alpha motor neurons) form much of the ventral
rootlets that supply the extrafusal muscle fibers. The medial group innervates the
muscles of the axial skeleton while the lateral group innervates the muscles of
the appendicular skeleton.
Lamina 10 includes the commissural axons containing the crossing second fibers
of the pain pathway (spinothalamic).
4.2 Interneurons
Only very small portions of the cells of the gray matter of the spinal cord are ventral
motor horn cells or dorsal horn sensory cells; the vast majority are interneurons—small
cells with short dendrites and axons. These cells interconnect incoming sensory axons
and descending spinal cord tracts with each other and with anterior horn cells. One
such interneuron is the Renshaw cell which is inhibitory; it depresses or totally inhibits
firing. This inhibition is usually to opposing muscle groups. The Renshaw cell itself
can be inhibited by a variety of pathways, such as squeezing the ipsilateral toes and
stimulating the muscle nerve on the contralateral side. Note that in each case the
response to the antidromic stimulation is much reduced. Since the Renshaw cell is
inhibitory to anterior horn cells, inhibiting the Renshaw cell will remove inhibition
from the anterior horn cell. The effect of inhibition of an inhibitory cell is called
disinhibition.
Specific neural circuits or neuronal clusters or centers are responsible for the
generation of simple and complex patterns of movement in the absence of affer-
ent input. At each level in the CNS where there is a motor response, one must
assume there is a circuit which permits one to respond very efficiently—a pat-
tern generator. In actuality, such central patterns are modified or modulated by
input from higher centers in the brain stem, cerebellum, diencephalon, and cere-
brum and by afferent input from sensory and autonomic systems, utilizing many
of the reflex components to be discussed below, and are controlled and/or
modified by descending control motor systems from higher centers (see further
discussion in Chap. 11).
Such pattern generators have been best described at the level of the spinal cord
and the brain stem (mesencephalic locomotor system) for more complex behavior
related to locomotion. The latter system is also involved in the motor components of
emotional expression, as well as chewing, licking, sucking behavior, and also for
ejaculation. For the accurate performance of complex patterned movements,
involving the limbs, afferent input and reflex activity are essential.
4.4 Segmental Function 123
The final effector cell of the spinal cord, the anterior horn cell is probably the best
place to begin a discussion of the segmental function of spinal cord segments. The
extensive dendritic tree allows 20–50,000 individual synaptic areas or knobs, while
the large cell body may have another l–2000 synaptic knobs. Incoming axons may
have more than one synaptic connection and hence exert greater control. Each ante-
rior horn cell gives rise to one large (8–l2 μm) axon, called an alpha motor neuron,
which innervates a motor group or unit made up of 10–200 individual extrafusal
muscle fibers. There is only one motor end plate on each muscle. Therefore, for a
motor group to contract, the anterior horn cell on the proximal end of the axon must
fire an action potential. The muscle group is chained to its anterior horn cell. This
anatomical relationship is often called the final common pathway. Activation of a
specific anterior horn cell precedes activity of a motor group. There is also a smaller
anterior horn neuron called the gamma motor neuron that innervates the intrafusal
muscles fibers adjusting the sensitivity of the muscle spindles.
There are many ways to activate this anterior horn cell; many thousand axons
synapse upon it and its extensive dendritic tree.
Neurons in the anterior horn can be divided into medial and lateral groups (Fig. 4.9).
1. The medial nuclear division is divided into posterior medial and anterior
medial groups. The posterior medial nucleus is most prominent in the cervical
and lumbar enlargement. The medial nucleus innervates the muscles of the
axial skeleton.
2. The lateral nuclear division innervates the appendicular musculature. In the
thoracic region, the intercostal and associated muscles are innervated by this
region. In the cervical and lumbar enlargement, these nuclei become especially
prominent and are divided into individual columns of nuclei (Fig. 4.9), and these
nuclei columns include anterior, anterior lateral, accessory lateral, posterior lat-
eral, and retroposterior lateral. These nuclei are represented functionally so that
from medial to lateral one passes from the midline spine to trunk, upper and
lower limb girdle, upper leg and arm, and lower leg and arm to hand and foot.
The most lateral nuclear groups innervate the muscles in the hand and foot.
3. The preganglionic autonomic nuclei lie in the intermediolateral column, a prom-
inent lateral triangle in the gray matter (Fig. 4.6). There are two distinct
groupings.
(a) Sympathetic. The intermediolateral nucleus from C8 to L2 is the origin of
the preganglionic sympathetic neurons which synapse again either in the
sympathetic trunks or in remote ganglia.
(b) Parasympathetic. The sacral nucleus in S2 to S4 is the origin of pregangli-
onic parasympathetic fibers that run to several ganglions in the walls of the
pelvic organs.
All of the sensory axons forming the posterior roots are from bipolar cells having
their cell bodies in the posterior root ganglion. The sensory information reaching
the spinal cord subserves pain, temperature, and tactile discrimination. Axons can
be divided into many classes by the sensory modality they carry. As far as we know,
each axon carries information about only one modality. The intensity of the pain or
other sensation is coded as action potential frequency.
For the present, two modalities will suffice, for examples, muscle stretch and
pain. Pain is carried by very small axons, many of them unmyelinated, which have
high thresholds and slow conduction velocities. The stretching of muscles, on the
other hand, leads to a barrage of action potentials in large, heavily myelinated nerve
fibers. These axons have low thresholds and rapid conduction velocities. Table 4.1
reviews the types and functions of the sensory receptors.
Reflex response to stretch. The classic stretch reflex is the knee jerk, produced by
tapping the patellar tendon. This simple involuntary response is such a familiar part
of the physical examination and has been used so frequently in medical humor that
precise description seems unnecessary. This simple test can give the astute examiner
many clues to the function and dysfunction of the nervous system. The knee jerk is
described quantitatively by Fig. 4.9, which is taken from the early work of the great
English physiologist Sir Charles Sherrington. As the figure indicates, after a brief
stretch, the muscle contracts with a delay of about l0 ms. It can readily be shown
that this is a response mediated by the spinal cord. When the nerve to the muscle is
cut, the response is abolished. When the spinal cord is severed from the rest of the
nervous system, the response remains.
4.4 Segmental Function 125
The pathway of this response is very simple (Fig. 4.9). The axon from the stretch
receptor runs into the posterior horn, and while it branches many times in the gray
matter, it eventually synapses directly on the cell body of the anterior horn cells of
the muscle stretched. The stretch reflex is often referred to as a monosynaptic reflex.
The only muscle which contract is the one stretched. The reflex continues for as
long as the muscle is stretched. There are stretch reflexes in all muscles, but they are
much stronger in the antigravity muscles, particularly the leg extensors. In addition
to the familiar knee jerk from the quadriceps group, brisk stretch reflexes can be
elicited from the ankle (the Achilles tendon), the jaw, and the biceps and triceps
muscles in the arm. Although the reflex loop is completed within a few segments of
spinal cord, the magnitude of the response can be drastically altered by input from
other levels. For example, grasping the hands together and pulling will greatly
enhance the knee-jerk response (reinforcement). As will be discussed later, the mag-
nitude or briskness of the response can give many clues to pathological processes.
Reflexive response to pain. The majority of spinal cord responses have more flexi-
bility than the monosynaptic response, as can be seen in the reflex withdrawal from
pain. This is one of the most important of the protective reflexes of the spinal cord.
The flexors are activated and the injured limb withdrawn. This augmentation of
response is known as facilitation and is one of the most basic integrative responses
of the nervous system.
The muscle spindle. The major dynamic stretch receptor is the muscle spindle.
They are encapsulated sensory receptors bundle of modified muscle fibers that lie
parallel to the rest of the muscle fibers, and they signal changes in the length of the
muscle. Its structure is shown in Fig. 4.10; it is composed basically of 3–5 small
muscle fibers each containing a specialized, nonstriated region in their center.
126 4 Spinal Cord
The striated ends of the muscle fibers can contract and are innervated by small,
gamma motor neurons. These gamma motor neurons have cell bodies in the anterior
horn, just as do the large alpha fibers that innervate the bulk of the muscle.
The small muscle fibers in the spindle are called intrafusal fibers, and the large
muscle fibers that make up the bulk of the muscle are referred to as extrafusal
fibers. The extrafusal fibers are primarily innervated by large (8–l2 μ) axons. The
pattern is not exclusive, and there is some dual innervation, alpha motor fibers to
both intra- and extrafusal fibers.
4.4 Segmental Function 127
There are two sensory nerves which take origin from the unstriated center region
of the muscle spindle. The largest, (l2 μ) classified Ia, comes from the center of the
sensory region. The unmyelinated ends of the nerve wrap around each of the muscle
fibers and are called primary or annulospiral endings. From these endings arise the
action potentials that stimulate the stretch reflexes. This axon gives off many types
of collateral within the gray matter of the cord that then travels up and down the
cord for several segments.
The second ending gives off a smaller nerve, classified IIa, from specialized,
secondary, or flower-spray endings on either side of the annulospiral ending. These
axons rise to the ipsilateral cerebellum, carrying information on “unconscious
position sense.” They apparently play no part in the stretch reflex. The basic f unction
of the stretch receptor is to fire when the muscle is stretched. The response of the
annulospiral ending is of short latency. The frequency of firing is at first high; it then
slows down, but never adapts completely.
The gamma system. The function of the intrafusal muscle fibers is complicated.
The first function is to keep the muscle spindle tight as the extrafusal fibers contract;
at the rest length (A), the spindle is tight. Any further stretch will set up a volley of
action potentials in the Ia sensory nerve that will lead to a stretch reflex, contraction
of the extrafusal fibers. When the extrafusal fibers contract because of firing in the
alpha motor neuron alone, the spindle goes slack and is no longer responsive to
stretch. Indeed, the muscle would have to be pulled out slightly further than the rest
position for the spindle to react. To rectify this situation, the gamma motor neuron
fires, thus contracting the intrafusal fiber, and the spindle is tight again. Through the
mechanism of the gamma motor neurons, the sensitivity of the stretch reflex is
maintained throughout the entire range of the limb movement.
For example, the knee-jerk reflex can be elicited in many positions of the lower
leg. Another function of the intrafusal fibers is to change the sensitivity of the annu-
lospiral ending. Apparently the annulospiral ending reacts to stretch or deformation
whether it is from without, as in stretch, or from within, as in intrafusal muscle fiber
activity. Probably the most important function of the intrafusal fibers is to modulate
contraction of the extrafusal fibers via the stretch reflex.
Let us digress a moment and consider the simplest type of muscle movement—
opposing the thumb to the palm. Cells in the anterior horn are activated by fibers
from the large descending corticospinal tract, a direct pathway, of which more will
be said later. The intensity of stimulation and the number of motor groups acti-
vated are determined by the motor cortex. The motor cortex basically sets the
tension that is to be developed. The distance moved is a function of the resistance
to movement and the duration of the stimulus. The extent of movement is visually
controlled; when the thumb reaches the desired position, the motor cortex stops
stimulating the anterior horn cells.
In contrast to this type of movement, which requires constant attention if the
desired position is to be achieved, many of our movements, such as walking, require
little attention beyond the decision to walk along the sidewalk. Most of us can even
chew gum at the same time! These movements are probably carried out through
mediation of the gamma system, which allows the brain to set a desired position and
128 4 Spinal Cord
then forget about it. Compare a corticospinal system, which produces a force, and a
second system, the gamma system, which produces a new position. The gamma
anterior horn cells are innervated by descending motor tracts other than the cortico-
spinal. This system is controlled by neurons in the brain stem: the reticular forma-
tion, the vestibular nucleus, and the red nucleus.
Golgi tendon organs, Ib. Golgi tendon organs are a second type of stretch receptor
found in the tendinous insertion of muscles. It contains no muscle fiber system. This
receptor is in series with the muscle fibers and signals tension via Ib sensory fibers.
It is much more sensitive to tension generated by the muscle than to stretch of the
muscle. Activation of the sensory fibers from the tendon organ causes an inhibition
of the contraction of the muscle. Among the functions of the tendon organ is to
protect the insertion of the muscle from too great a stress which might tear the inser-
tion from the bone. Tension information from the tendon organ is transmitted to
higher centers via both dorsal and ventral spinocerebellar tracts.
Any stimulus, such as heat, trauma, or pressure, which produces tissue damage or
irritation, is a nociceptive stimulus. Nociceptive stimuli are the afferent arm of many
reflexes; locally, a red wheal develops around a cut; withdrawal of a limb from a hot
pipe is a spinal cord reflex, while tachycardia from an electric shock to the finger is a
brain stem autonomic reflex. Only when this nociceptive information reaches the thal-
amus and cerebral cortex should we talk about pain. Pain perception by these higher
centers triggers affective responses and suffering behaviors. The pain experience var-
ies enormously from person to person, and the circumstances may alter the response.
Contrast the pain of your thumb being hit with a hammer when you are fixing your sail
boat, doing a “chore” around the house or holding the nail for someone else. As a
gross oversimplification, we perceive pain in two ways, as pricking, itching, or sharp
and easily localizable, such as a razor blade cut or a mosquito bite. This type of pain
is usually short lasting, up to a day or so, and is usually tolerated. In contrast, pain may
be described as dull, aching, or burning and is poorly localized. This type of pain is
longer lasting (rheumatoid arthritis) or repetitive (menstrual cramps) and is often
poorly tolerated, frequently coloring the persons entire view of life.
Pain receptors. Tissue damage releases a variety of typical intracellular substances
including K+, H+, bradykinin, as well as specialized compounds such as serotonin
from blood platelets, substance P from nerve terminals, and histamine from mast
cells. All of these substances directly stimulate the free endings of small myelinated
A delta fibers (1–5 μ diameter) and smaller, unmyelinated C fibers (0.25–1.5 μ
diameter). A second group of released substances including prostaglandin precur-
sors and leukotrienes acts as sensitizers. Many of these small fibers have collaterals
ending in regions containing neurotransmitter vesicles that apparently amplify noci-
ceptive stimuli by releasing substance P when the free nerve ending is stimulated.
4.5 Nociception and Pain 129
In addition to these relatively nonspecific receptors, the upper end of the range of
stimuli to temperature and pressure receptors generates nociceptive responses. For
example, heating a patch of skin to 40 °C with a heat lamp gives a comfortable,
warm sensation. Heating to 47 °C generates a painful but tolerable experience.
Higher temperatures are perceived as unbearable pain. Cold is a diverse sensation,
and recently a cold channel has been identified (McKeeney et al. 2002). Cold and
warmth are sensed by thermoreceptor proteins on the free nerve endings of the
somatosensory neurons; one channel, vanilloid receptor subtype 1 (VR1), is acti-
vated by temperatures above 43 °C and by vanilloid compounds including capsaicin
the component of hot chili peppers. The other vanilloid receptor type 1 (VRL-1) is
sensitive to temperatures above 50 °C. The cation channel that is methanol activated
(CMR1-cold methanol type 1) is activated by temperatures of 8–30 °C and is a
member of the transient receptor potential family of ion channels with VR1 and
VRL-1 also members of this family. These nerve fibers carrying nociceptive infor-
mation join peripheral nerves, segregate into spinal nerves, and once inside the spi-
nal dura, join posterior roots. Their cell bodies are in the posterior root ganglia while
the axon continues and enters the spinal cord in the lateral bundle.
Nociceptive information entering on one posterior root projects for two to three
segments up and down the cord in laminae I–III. From centuries old clinical obser-
vation, we know all nociceptive information reaching consciousness, hence causing
pain, crosses the neuro-axis close to the segment of entry and enters the contralat-
eral white column.
Projection fibers. After extensive processing, large diameter, myelinated axons with
cell bodies in lamina I and V cross the neuro-axis near the central canal (Fig. 3.7) to
join the anterior-lateral white matter. These fibers form the spinothalamic tract that
projects to the brainstem, thalamus, and ultimately the cerebral cortex.
Transmission of pain information through the chain of neurons in the posterior root
is influenced by many factors, some of them originating within the segment, some
from higher centers. Most of us, after cutting or bruising ourselves, rub the sur-
rounding area and obtain relief of the pain for as long as we rub. An animal that has
been hurt will lick the wound, presumably to obtain relief of pain. This subjective
phenomenon is frequently spoken of as counter irritation; stimulation of the large,
myelinated touch fibers reduces the magnitude of transmission of pain sensation
through the posterior horn. This modulation takes place in the substantia gelatinosa,
lamina II, within the “gate” proposed by Wall and Melzak.
Several clinical observations point to the importance of large fiber inhibition of
nociceptive transmission, even in the absence of apparent nociceptive stimulation.
Perhaps the most painful of these condition is avulsion, traumatic tearing out, of
posterior roots. Surgical severing of posterior roots, instead of giving pain relief,
often results in intolerable pain. In both cases large fiber input is lost. In contrast,
130 4 Spinal Cord
destruction by a laser beam of the lateral dorsal root entry zone (for small fibers) is
often highly successful in blocking the flow of nociceptive information up the
neuro-axis. The large fiber input is largely spared because they enter in the medial
zone. Severed peripheral nerves often generate itching or burning sensations, cau-
salgia, which can be alleviated by stimulating the large diameter axons central to the
cut. The large diameter axons have low thresholds so can be stimulated without
stimulating the smaller, high threshold nociceptive fibers. Activity in the large fibers
suppresses background nociceptive inflow. TENS, Trans Epithelial Nerve
Stimulation, is often effective in preventing or reducing peripherally generated
nociception from becoming pain, effective in closing the gate. As mentioned earlier,
branches of many incoming large axons enter the posterior column.
Stimulation of the posterior column sends antidromically conducted action
potentials into the posterior horn and often reduces the pain experience. Damaged
small axons are prone to developing alpha2 adrenergic receptors, so the axon
becomes sensitive to norepinephrine liberated by the peripheral sympathetic nerves.
Pharmacological blocking or surgical severing sympathetic outflow often reduces
pain. The major excitatory neurotransmitter in the pain system is substance P that is
found in abundance in the posterior horn, particularly lamina I and II. The mecha-
nism of postsynaptic action is a reduction in potassium permeability leading to
depolarization. The major inhibitory transmitters in the pain pathway are the
encephalin/endorphin series of peptides released from cells entirely within the pos-
terior horn, mostly lamina II. Their action is closely mimicked by the opioid
peptides. At least three modes of action have been shown, although all studies are
complicated by the very small size of the cell bodies in the substantia gelatinosa
(lamina II).
Many studies suggest these compounds also compete with the excitatory trans-
mitters of the region, substance P and glycine, for postsynaptic sites. Other studies
suggest reduction of Ca2+ influx into the presynaptic terminal in response to incom-
ing depolarization and consequent reduction of the amount of excitatory transmitter
released. Other studies implicate presynaptic inhibition (below). Injection of opi-
oids into the lumbar CSF often reduces nociceptive transmission and reduces the
pain experience. The effect is blocked by the universal narcotic blocker, naloxone.
Successful acupuncture increases endorphins in the lumbar CSF. Descending axons
in both the anterolateral and posterior white columns influence transmission across
this chain of synapses.
Supraspinal control of these encephalin/endorphin neurons is from the brain
stem, particularly from the locus ceruleus (norepinephrine) and raphe nuclei (5HT),
both in the medulla. These areas in turn are modulated by the periaqueductal gray
of the midbrain that also contains an inhibitory endorphin/encephalin system.
Stimulation of these structures results in profound anesthesia (electro anesthesia)
while we can suppress the flow of nociceptive information through the posterior
horn by positive thinking, for example, all “pain” studies are bedeviled by a 40%
placebo effect. Yes, the third, postsurgical morphine injection can be replaced with
saline and still “work” half the time.
4.6 White Matter Tracts 131
The white matter of the cord contains axons which run up and down the spinal cord
connecting segment to segment, intersegmental, and the segments to the brain.
(The white matter is divided into three columns that are delimited by the presence
of the dorsal roots that separate the posterior from the lateral funiculi and the ventral
roots that separates the lateral from the anterior funiculi Fig. 4.16.) The posterior
funiculus consists primarily of the posterior columns. The white matter in the lateral
funiculus is organized so that the ascending fibers are on the outside and the
descending fibers closer to the gray.
The only way that the location of individual tracts has been determined in humans
is to observe degeneration caused by discrete lesions. In this section we will provide
an overview of the pathways in the spinal cord. A detailed discussion of the
individual sensory and motor pathways is included in the diencephalic (Chap. 8)
and in the motor system, Chap. 11. The discussion in this section will focus on top-
ics relevant to only the spinal cord.
Basic principal of the descending motor control. There are two levels of orga-
nization in the voluntary motor system: the upper motor neurons and the lower
motor neuron. The command for voluntary movement initiates in the prefrontal
cortex and then drives the neurons in the motor cortex whose axons leave the
cortex forming the corticospinal pathway (or corticobulbar to lower motor neu-
rons in cranial nerves) whose axons descend through the brain stem and terminate
in the contralateral lower motor neurons in the ventral horn of the spinal cord
(Figs. 4.11 and 4.12).
Voluntary control of lower motor neurons, the descending corticospinal
(see figure in Chap. 11) tract. This tract has its origin in layer V of the cerebral
cortex, most prominently from the motor and premotor cortex of the frontal lobe
(see Chap. 9). At the junction between the medulla and the spinal cord (the level of
the foramen magnum), most of the fibers cross the neuro-axis, decussate, and move
laterally and posteriorly to form the lateral corticospinal tract which terminates on
ventral form cells in the spinal cord, the lower motor neurons. The location of this
pathway in the human is determined by analyzing cord sections obtained at autopsy
from cases where cortical destruction has occurred in the motor areas of the pre-
central gyrus or in the internal capsule and axons degenerated following death of
the cell body (Figs. 4.13 and 4.14).
132 4 Spinal Cord
Dorsal root
Fibers mediating ganglion
motion & position
sense Lateral cortico-
spinal tract
Dentate
Fibers mediating Leg ligament
cts
pain & temperature
Tr a
sense Trunk Wax
muscles 4.5 mm.
Sacral
e ll a r
Lateral spino-
eb
Lumbar
er
Pia mater thalamic tract
-c
o
in
Thoracic
Sp
Anterior
nerve root
Anterior white
commissure 4 - 4.5 mm.
Anterior spinal artery
Fig. 4.11 Diagram illustrating a chordotomy. The cross section of the spinal cord shows the lami-
nation of the spinothalamic tract, the position of the pyramidal tract in relation to it, and the pres-
ence of other tracts in the lower quadrant. A piece of bone wax is mounted 4.5 mm from the tip of
the knife as a depth gauge. Heavy curved lines in the ventral quadrant indicate the sweep of the
knife. Note that a desire to spare the lateral corticospinal tract would result in sparing the sacral
dermatomes (From Kahn and Rand: J. Neurosurg. 9:611–619 1952)
Fig. 4.14 Cervical level, C7, in a patient with ALS. Note the lateral corticospinal tract bilaterally
shows degeneration of myelin. On the right side (R), the anterior corticospinal tract (prior to decus-
sating) is also degenerate. The dorsal nerve roots were intact, but the ventral nerve roots were
atrophic. Spinal cord mounted in celloidin, sectioned at 40 μ, and stained with Luxol Fast Blue.
Courtesy of Dr. Jose Segarra, Boston VA
134 4 Spinal Cord
Basic principal. All ascending sensory systems have three levels of neuronal
organization:
1. Primary sensory neuron in dorsal root ganglion attached to each segment of the
spinal cord origin of the sensory system.
2. Second-order neuron in dorsal horn of spinal cord or gracile and cuneate nuclei
of the medulla. The axons of the second-order sensory neuron cross the neuro-
axis and form ascending pathways within the spinal cord and brainstem that ter-
minate on third-order neurons in the contralateral thalamus of the diencephalon.
3. Third-order neurons in the thalamus. Third-order neurons project to the ipsilat-
eral sensory area of the cerebral cortex.
Fibers carrying information on pain and temperature sense from the body all rises
in the contralateral spinothalamic tract (Fig. 4.15). Compression, intrinsic disease,
or deliberate section will result in anesthesia of the contralateral body beginning
two to three segments below the level of disruption.
Pain and temperature. Primary cell bodies—Cutaneous receptors for pain and
temperature (free nerve endings) send axons to small- and medium-sized dorsal root
ganglion cells. These axons enter the spinal cord via the lateral aspects of the dorsal
root entry zone. Most of these fibers enter Lissauer’s tract and branch extensively
(over two or three segments on either side of the segment of entry) before entering
the posterior horn, laminae I, II, and III (Fig. 4.6).
The secondary neurons arise primarily from cell bodies in lamina I and V that
give origin to large axons which cross in the anterior white commissure and ascend
in the contralateral anterior-lateral funiculus. As discussed earlier in the chapter
(“Nociception and Pain”), many factors modulate information transfer across the
posterior horn, between incoming nociceptive fibers and outgoing spinothalamic
fibers. There is a somatotopic arrangement in the spinothalamic tract (Fig. 3.11)
with the most lateral and external fibers representing sacral levels while the most
intermediate and anterior fibers representing cervical levels. Pain fibers are located
anteriorly to the more posteriorly placed temperature fibers. Perhaps as many as
half the fibers in the tract, often called the spinoreticular tract, end in the brainstem,
while many of the rest send collaterals into the brainstem on their way to the thala-
mus (Chap. 5). There are endings in two major nuclei of the thalamus: the ventral
posterior medial nucleus and the intralaminar nuclei (see Chap. 8).
Recordings from individual spinothalamic neurons reveal four major functional
categories, all contralateral.
1. Low threshold units, activated only by gentle stimuli, for example, by stroking
hairs on the arm
4.6 White Matter Tracts 135
Fig. 4.15 The spinothalamic tract/anterolateral system. Incoming fibers that originate in dorsal root
ganglions are activated by tissue damaging stimuli. The axonal endings may rise ipsilaterally from
up to three spinal cord segments (as the fiber enters on the left, the fiber entering on the right syn-
apses at the level of entry; one axon crosses the neuro-axis and rises; the other axon enters the
anterior horn to participate in local reflexes, such as withdrawal from a hot surface) before a synapse
in the dorsal horn on the second-order sensory neuron. The axons from the second-order sensory
neuron cross and enter the contralateral spinothalamic tract. The major projections of the spinotha-
lamic tract are midline medulla, periaqueductal gray of the midbrain, and the thalamus. In the thala-
mus these end in either the ventral posterior lateral (VPL) nucleus or the intralaminar or dorsomedial
thalamic nucleus. The information from VPL projects onto the postcentral gyrus as a result one
knows where in the body the pain is originating. The information that is projected onto the prefron-
tal cortex via the dorsomedial nucleus permits one to decide how to respond to a painful stimulus
2. Wide dynamic range units, activated by many types of stimuli of both high and
low intensity with response graded by intensity
3. High threshold units, activated only by nociceptive stimuli
4. Thermosensitive units, with high action potential frequency signaling nociception
All of these units have small receptive fields peripherally and larger fields
toward the midline. The posterior horn seems to tease apart what stimulus from
what part of the body. Recording from the thalamic endings of these fibers also
shows this separation of function as well as adding a wake up function—ouch!
A unilateral section of this tract for relief of pain produces a complete absence of
pain and temperature from the opposite side of the body lasting for 6–9 months,
136 4 Spinal Cord
but pain sensation slowly returns. Nociceptive information enters Lissauer’s tract
until it is above the cut and then crosses. There are several “pain” responses to
nociceptive stimuli. A direct spinothalamic pathway to the contralateral ventral
posterior medial nucleus of the thalamus with third-order projection to the post-
central gyrus probably mediates tract running from the spinal cord to the mid-
brain. Stimulation of the post central gyrus, however, rarely generates the
sensation of pain. Pain is rarely reported by patients during epileptic (cortical)
seizures. Apparently the thalamus tells us what (pain), and the postcentral gyrus
tells us where. We test this pathway with the light prick of a pin and expect the
patient can tell us or point to the location of the pinprick. The dull throbbing
quality of the pain probably ascends by a multisynaptic pathway via brain stem
synapses to the midbrain and then to interlaminar thalamic nuclei with much
wider cortical p rojection including the limbic system.
Sympathetic and parasympathetic systems. The limbic system (Chap. 15) has
much to do with our outlook upon life. The thalamus alone can signal poorly local-
ized pain to consciousness. In addition to the spinal thalamic and spinal reticular
pathways, there are other pathways that may convey pain and thermal information
to the thalamus.
Cervicothalamic. This pathway originates from the lateral cervical nucleus in the
lateral column at level Cl and C2 and projects to the brain stem and thalamus.
Spinotectal pathway. This system originates in the deep layers in the midbrain.
The visceral brain innervates the preganglionic sympathetic neurons in the inter-
mediolateral column in the thoracic and lumbar levels as well as to the pregangli-
onic parasympathetic neurons in the brain stem (cranial nerves III, VII, IX, and X)
and also neurons in sacral cord.
Dorsal longitudinal fasciculus. The DLF of Schutz is a lightly myelinated path-
way on the floor of the IV ventricle which interconnects the periventricular nucleus
of the hypothalamus with the ventral part of the central gray of the midbrain and
regions in the brain stem and spinal cord. This tract provides ascending and descend-
ing sympathetic and parasympathetic neurons between the hypothalamus and the
cranial nerves, reticular formation, and thoracolumbar cord.
The descending tracts are diffuse and are found in the lateral part of the reticular
formation and in the anterior and lateral funiculi in the spinal cord. Lesions in these
regions may produce sympathetic dysfunctions, i.e., Horner’s syndrome –paralysis
of the sympathetic fibers to the dilator of the pupil resulting in miosis (constricted
pupil) and an absence of sweating with the body being cooler on the affected side.
Spinocerebellar Tracts to Paleocerebellum/Anterior Lobe of Cerebellum
These two different pathways form the posterior roots to the cerebellum. Both path-
ways carry information on position sense at the conscious and unconscious level.
Ventral spinocerebellar tract. The primary cell body is the dorsal root ganglion
of levels L4–S3, and the second-order neurons are in laminae I–III of the spinal cord
at these levels. These fibers from the lower limb carry in information from the Golgi
tendon organs of muscles in levels L4–S3. Most of these fibers cross over to the
contralateral side in the lateral funiculus in the anterior white commissure and ter-
minate in the anterior lobe and the intermediate area of the parafloccular lobe. Some
4.6 White Matter Tracts 137
of these also may cross back within the cerebellum to end on the ipsilateral side. For
this reason, the tract is sometimes termed the “double-crosser.”
The dorsal spinocerebellar tract is an uncrossed pathway. The primary neuron
for this system is the dorsal root ganglion and carries in information from muscle
spindles in spinal cord levels L4–S3. The second neuron is in Clarke’s column in the
dorsal horn in levels C8–L3 of the cord. The secondary axons ascend uncrossed
from Clarke’s nucleus, enter the inferior cerebellar peduncle, and terminate in the
ipsilateral anterior lobe of the cerebellum.
Cuneocerebellar tract. The cuneocerebellar tract brings in proprioceptive infor-
mation from the upper extremities to the anterior lobe of the cerebellum. These
fibers originate from the ipsilateral accessory cuneate nucleus and enter the anterior
and vermal region of the cerebellum in the inferior cerebellar peduncle.
Medial longitudinal fasciculus, MLF. This pathway is present below the ven-
tricular floor in the midbrain, pons, and medulla and in the anterior funiculus of the
spinal cord. Fibers ascend and descend in this tract coordinating eye movements
with input from the vestibular, visual, and postural systems.
Other spinal pathways. In Table 4.2 we have listed the major ascending pathways.
There are also pathways from the spinal cord to reticular formation of the brain stem
to the vestibular nuclei of the medulla and pons, the inferior olive of the medulla and
to nuclei and pons and midbrain. Figure 4.16 identifies the major descending path-
ways in the spinal cord. They carry a mixture of sensory and motor information onto
the ventral horn cells—the common final pathway.
Table 4.2 (continued)
Pathway Origin Termination Function
Spino-spinal All spinal levels All lamina Intersegmental and
intersegmental, two neuron reflex arcs.
and D.roots
Post. spinocerebellar Clarke’s nucleus Ipsilateral ant lobe Unconscious tactile
from Golgi tendon from C2 to L2 and vermis of and proprioceptive
organs, stretch (largest myelinated cerebellum information for
receptors, and afferent fibers—IA movements
muscle spindles and IB)
Ant. spinocerebellar; Laminae 5, 6, and 7 Contralateral vermis Unconscious tactile
contralateral from most levels of cerebellum proprioception
Cuneocerebellar; Accessory cuneate Anterior lobe and Unconscious tactile and
ipsilateral nucleus in low pyramis and uvula proprioception for upper
medulla of cerebellum extremity and neck
Cerebellar peduncles See Chap. 11
—cerebellum
Causes of muscle weakness or paralysis can be grouped functionally into two cate-
gories. If the difficulty is located in the corticospinal or other descending motor
tract, the problem is called an upper motor neuron lesion.
If the problem is in the anterior horn cell, its axon, or its motor group, the prob-
lem is called a lower motor neuron lesion.
4.7 Upper and Lower Motor Neurons Lesions 139
Descending motor tracts normally exert an inhibitory effect on spinal cord reflexes.
Hyperreflexia is a sure sign of decreased corticospinal function. Descending motor
tract normally exerts an inhibitory effect on spinal cord reflexes to move for a short
interval, and then resistance to movement increases rapidly; upon further pressure,
the resistance suddenly gives way. This latter phenomenon is often referred to as a
clasp-knife reflex. In the leg, spasticity is greatest in the extensors, whereas in the
arm the flexors are more affected. Decreased function of the corticospinal tract
also produces effects a curious reflex of the foot, Babinski sign (Fig. 4.17). If a
moderately sharp object such as a key is drawn over the lateral boundary of the
sole of the foot, the toes of an adult flex (curl). When spasticity is present, the joint
is easy to move for a short interval, and then resistance to movement increases
rapidly, and upon further movement, the resistance suddenly gives way—the
clasp-knife reflex.
In very young children and in adults with corticospinal tract destruction, the toes
extend and fan out as shown in Fig. 4.16. Passively moving or rotating the ankle,
knee, hip, shoulder, elbow, or wrist will easily demonstrate the increased tone.
Fig. 4.17 The major ascending (left half) and descending (right half) pathways in teh spinal cord
labeled in this cervical level of the spinal cord
140 4 Spinal Cord
The patient would present with weaknesses, loss of reflexes, extreme muscle wast-
ing, and a flaccid tone, hyporeflexia, to the muscles, which characterize the lower
motor neuron syndrome. The reason for LMN relates to the loss of the anterior horn
cell or the motor axon. The loss of reflexes and the flaccid tone of the muscles relate
to the loss of the motor side of the stretch reflex pathway. Often, it is possible to
observe spontaneous twitching of the muscle, fasciculation.
The lateral corticospinal tract (see Chap. 11; Fig. 11.8) is the major tract for
voluntary control of skeletal muscle. Destruction of this tract leads to upper motor
neuron signs, spasticity of skeletal muscle, and the loss of voluntary movement.
This paralysis is usually totally distal, in the hand, and somewhat less severe in the
trunk musculature.
Hemiplegia is a paralysis of the arm and leg on the same side.
Monoplegia is the paralysis of a single limb.
The patient would present with weaknesses, loss of reflexes, extreme muscle
wasting, and a flaccid tone (hyporeflexia) to the muscles, which characterize the
lower motor neuron syndrome. The reason for the lower motor neuron lesion relates
to the loss of the anterior horn cell or the motor axon. The loss of reflexes and the
flaccid tone of the muscles relate to the loss of the motor side of the stretch reflex
pathway. Often, it is possible to observe spontaneous twitching of the muscle (fas-
ciculation). The following two case histories compare and contrast the effects of
compression of a nerve rootlet to that of actual compression of the spinal cord. Case
History 3.1 demonstrates the effect of a ruptured cervical disk, producing compres-
sion of a cervical nerve root. Figure 3.16 demonstrates the effects of Amyotrophic
lateral sclerosis on the corticospinal tract.
Case History 4.1. A 55-year-old white housewife first noted pain in the thoracic,
right scapular area, 5 months prior to admission. Three months prior to admission,
a progressive weakness in both lower extremities developed. One month prior to
admission, the patient had been able to walk slowly into her local hospital. Over the
next 2 weeks, she became completely bedridden, unable to move her legs or even to
wiggle her toes. During the last 2 weeks prior to her neurological admission, the
patient had noted a progressive pin and needles sensation involving both lower
extremities. At the same time she developed difficulty with the control of bowel
movements and urination.
Past history: At age 40, 15 years prior to this admission, a left radical mastec-
tomy had been performed for an infiltrating carcinoma of the breast with regional
lymph node involvement. A hysterectomy had also been performed at that time.
4.8 Illustrative Spinal Cord Case Histories 141
Neurologic exam: Mental status in cranial nerve exam was normal. Strength was
intact in the legs. Pin and light touch perception were preserved in all dermatomes.
Reflexes were 1+ at the knees and trace at the ankle jerks bilaterally. Her MRI dem-
onstrated severe spinal stenosis at the L3–4 and L4–5 levels.
Clinical diagnosis: Spinal stenosis with claudication.
Impression neurogenic claudication due to spinal stenosis L3–L4 and L4–L5.
Discussion: This is a classic presentation for neurogenic claudication due to
compression of the cauda equina. Exercise-induced cramping and discomfort in
the legs, relieved by resting or sitting is a clinical feature. Not infrequently, if the
patient leads over a chair or shopping cart, this will have relieved the symptoms
transiently. The patient underwent decompressive laminectomies. Within a week,
her claudication had resolved and within a month, her back discomfort from the
surgery had improved. She was functionally back to her previous level of activity
within 2 months.
Case History 4.3 (Fig. 4.19). This 47-year-old right-handed male developed sudden
onset of severe sharp pain in his neck, left arm, and hand after lifting a heavy object.
He also noticed clumsiness in both hands within 24 h of onset of the pain. Over
several further days, he noticed that he was having difficulty walking. His past his-
tory was notable for a lumbar diskectomy and hypertension.
4.8 Illustrative Spinal Cord Case Histories 143
He had no allergies on exam; his general examination was normal aside from
being in evident discomfort. Neurologic exam—mental status was normal; cranial
nerve exam was normal as well. He had four-fifth strength in the left triceps and
wrist extensors. He had normal strength elsewhere. He was spastic in both legs. He
had diminished sensation to both pin in a left C7 distribution and diminished pin
perception in the right trunk and the leg. He had a depressed triceps jerk on the left.
Reflexes in the upper extremities were otherwise 1+. Reflexes in the lower
extremities with 3+. Toes were upgoing bilaterally on plantar stimulation.
MRI demonstrated a large herniated disk on the left at the C6–7 level, causing
encroachment on the spinal cord.
Clinical diagnosis: Brown-Sequard syndrome/radiculopathy due to herniated cervi-
cal disk. This led to an urgent cervical diskectomy because of spinal cord compres-
sion. His radicular pain was gone within a few hours. Within a month, his hand
clumsiness and spasticity were significantly improved with a mild residual stiffness
in the legs.
Comment. This is a classic present patient for Brown-Sequard syndrome with
motor deficit from corticospinal dysfunction on the side ipsilateral to the spinal cord
compression. Because of local compression on the C7 root, there was sensory loss
in the left arm. His contralateral pinprick deficit was related to spinothalamic tract
dysfunction. It is a contralateral deficit because the spinothalamic fibers cross before
ascending contralateral to their side of origin.
Case History 4.4 (Fig. 4.20). The patient 47-year-old male who developed sudden
onset of severe low back pain radiating into his left leg after picking up a heavy
object as a landscaper. This was associated with an intense tingling into the left great
toe. Coughing or straining increased this pain. He had no response to medications
144 4 Spinal Cord
Fig. 4.22 (a) Case History 4.6. CT demonstrating severe fracture/dislocation of the upper thoracic
spine. This 32-year-old female was the unrestrained driver of a vehicle involved in a roll-over
crash. She sustained severe injuries. She was immediately found to be paraplegic at the scene.
Evaluation in the ER found her to have a dense paraplegia with an upper thoracic sensory deficit
level due to being unrestrained by seat belt. (b) Case History 4.6. Fixture of severe fracture/dislo-
cation of the upper thoracic spine. MRI demonstrating screws implanted surgically to stabilize
these fractures, but patient made no recovery from her paraplegia
Case History 4.8. This 39-year-old right-handed male presented with a 6-year
history of progressive intermittent numbness and tingling in both hands, the right
more pronounced than left. This was increased by repetitive hand use. This tingling
spread from the wrists into the thumbs, index, and middle fingers. He was clumsy
with hand movements on the right. He noticed particular difficulties using a screw-
driver/opening jars. This tingling would frequently wake him up at night and would
resolve if he shook out his hands. Splints provided relief but as soon as he took
splints off, his symptoms would recur.
His employment as an engineer required frequent keyboarding—up to 10 h a
day. He notices that his symptoms were more pronounced at the end of a busy day
of keyboarding. Past history was notable for an ankle fracture. He was otherwise
healthy. He took no medicines and had no allergies. Physical exam—general exam
was normal. He had a positive Tinel’s sign at the right wrist. There was mild
opponens/FDS/APB weakness in the right more than left. There was diminished
sensation to pinprick and light touch in the thumb and index fingers bilaterally,
again more pronounced on the right.
Clinical diagnosis. The patient’s primary care physician suspected carpal tunnel syn-
drome and neurodiagnostics confirmed this. Carpal tunnel syndrome.
Because he had not responded to splinting, he opted for surgery and underwent a
right carpal tunnel release with resolution of his symptoms within a few days. He
has minor symptoms on the left side although significantly improved, as post-op, he
could use his dominant right hand more readily and rest his left hand effectively.
Comment. The Tinel sign is a hypersensitivity of the nerve at the site of a com-
pression or other irritation and helps localize the site of compression. His motor
findings localize this problem to the median nerve.
Case History 4.9. This 56-year-old right-handed male works as a mechanic. He
noted a 6-month history of tingling in his right thumb and index finger. This was
increased by hand use. It was improved with rest of that hand. He had a 1-month
history of weakness in the right hand grip. He says local physician who referred him
neurosurgical consultation.
On closer questioning he stated that he regularly used his right wrist to final
tighten bolts into place and to seat filters in automobile engines by pounding the
wrist against a torque wrench. He did this because he had an arthritic condition of
his thumb that caused pain if he used his hand regularly.
148 4 Spinal Cord
Fig. 4.23 Level sacral II. Sacral levels can be identified by the large amount of gray matter in
comparison to white matter. Gray matter. In this section there are two horns: one sensory (dorsal)
and one motor (ventral). In the ventral horn, the retrodorsal, dorsolateral, and ventrolateral nuclei
innervate the lower extremity. White matter. Most of the fibers forming descending tracts have
ended, and the bulk of the white matter consists of ascending axon and intersegmental fibers. The
dorsal columns at this level contain only fibers from region innervated by the sacral cord; these
form the fasciculus gracilis
150 4 Spinal Cord
Fig. 4.24 Level lumbar II. Lumbar levels can be identified by the nearly equal amount of gray.
Gray matter. In this level two horns are present the dorsal sensory and ventral motor. White matter.
The increase in the amount of white mater reflects first the increase in the fibers joining the poste-
rior column to/from the ascending fasciculus gracilis and the presence of a large lateral column
containing the corticospinal tract (crossed) above its innerva tions of the ventral horn to the muscles
in the thigh, leg, and foot
4.10 Carpal Tunnel Syndrome 151
Fig. 4.25 Level: Thoracic 7 gray matter. Thoracic level can always be identified by the small
amount of gray matter and the presence of the intermediolateral cell column containing
preganglionic sympathetic neurons. White matter. The ascending and descending fibers to the
lower limbs, abdomen, trunk, and pelvis provide the bulk of the white matter in the lateral and
posterior column
152 4 Spinal Cord
Fig. 4.26 Level cervical 7. This is a cervical level in the cervical enlargement and can be identified
as they are the largest level in the spinal cord and are ovoid in shape with the gray matter found in
the shape of a butterfly. White matter. The bulk of this section consists of ascending and descend-
ing fibers to the extremities, thorax, abdomen, trunk, and pelvis. Note how the dorsal columns
increase in size as one ascends the spinal cord due to the accumulation of the ascending general
sensory fibers. The lateral columns are still large as some of the corticospinal tract to the hand is
still present. Reexamine the lower sections of the cord, and note the decrease in bulk of the spinal
cord white matter which results from the innervations from the cervical enlargement to the upper
extremity. And note the decrease in bulk of the cord as one descends. Gray matter. In this cervical
level, one finds in the ventral horn the retrodorsal, dorsolateral, and ventrolateral nuclei which
innervate the hand and forearm region of the upper extremity
Bibliography 153
Bibliography
Abel Majuid T, Bowsher D. The gray matter of the dorsal horn of the adult human spinal cord.
J Anat. 1985;142:33–58.
Asanuma H. The pyramidal tract. In: Brooks VB, editor. Handbook of physiology. Section I. The
nervous system. Vol II. Motor control. Bethesda, MD: American Physiological Society; 1981.
p. 703–33.
Becksted R, Morse J, Norgeren R. The nucleus of the solitary tract in the monkey. J Comp Neurol.
1980;198:259–82.
Burton H, Craig A. Distribution of trigeminothalamic neurons in cat and monkey. Brain Res.
161:515–21.
Carpenter, M.B. 1978. Core text of neuroanatomy, 4th. Baltimore, Lippincott Williams &
Wilkins, 1991.
Everts E. Role of motor cortex in voluntary movement in primates. In: Brooks VB, editor.
Handbook of physiology. Section I. The nervous system. Vol II. Motor control. Bethesda, MD:
American Physiological Society. p. 1083–120.
Finger T, Silver W. Neurobiology of taste and smell. New York: Wiley; 1987.
Foote S, Bloom F, Aston-Jones G. Nucleus locus cereuleus. New evidence of anatomical and
physiological specificity. Physiol Rev. 1983;63:844–914.
Hobson J, Brazier M, editors. The reticular formation revisited. Brain Res. 1983;6:1–564.
Moore B, Bloom F. Central catecholamine neuron systems; Anatomy and physiology of the noree-
phinephrine and epinephrine systems. Ann Rev Neurosci. 1978;2:113–68.
Norgren R. Central mechansims of taste. In: Darian-Smith, editor. Handbook of physiology. Section
I. The nervous system. Vol III. Sensory processes. Bethesda, MD: American Physiological
Socienty; 1984. p. 1087–128.
Riley HA. Brain Stem and Spinal Cord. New York: Hafner; 1960.
Sinclair D. Touch in primates. Ann Rev Neurosci. 1982;5:155–94.
Wall P, Melzak R. Textbook of pain. Edinburgh: Churchill Livingston; 1989.
Willis W. Nocioceptive pathways. Anatomy and physiology of nociceptive ascending pathways.
Philos Trans R Soc Lond B Biol Sci. 1985;308:252–68.
Victor M, Ropper AH. Principles of neurology. 7th ed. New York: McGraw Hill; 2001.
Brodal A. The cranial nerves. Anatomy & anatomical clinical correlation. London: Oxford
Blackwell; 1965.
Clemente C. Gray’s anatomy. 30th ed. Philadelphia: Lea & Febiger; 1988.
DeJong RN. The neurologic examination. New York: Hoeber Medical Division, Harper
& Row; 1978.
Herrick CJ. The brain of the tiger salamander. Chicago: University of Chicago Press; 1948.
Chapter 5
Brain Stem: Gross Anatomy
Abstract The brain stem is located in the posterior cranial fossa and consists of
medulla, pons, and midbrain. We have included the diencephalon in this discussion
on the brain stem as the majority of pathways from the brain stem and spinal cord
terminate on nuclei in the diencephalon.
The gray and white matter in each level is intermixed and demonstrates a
columnar organization. The discussion of each level will include the important
functions, nuclei, and tracts found in that level. The constituent parts of the central
nervous system are the spinal cord, brain stem, cerebellum, diencephalon, and
cerebrum. The cerebellum is attached to the pons and medulla but will be discussed
as part of the motor system in Chap. 11.
The medulla, pons, and midbrain are subdivided by their relationship to the
ventricular system into tectum, tegmentum, and basis (Fig. 5.1).
The tectum forms the roof and walls or the posterior surface; the tectum in med-
ullary, pontine, and midbrain levels consists of regions that have highly specialized
functions related to the special senses and movement—cerebellum inferior and
superior colliculus.
The tegmentum forms the floor or anterior surface; the tegmentum contains
cranial nerve nuclei, reticular formation, and tracts that interconnect higher and
lower centers as well as tracts that interconnect the brain stem with other portions of
the central nervous system.
The basis forms the anterior surface of the tegmentum; the basis contains the
descending fibers from the cerebral cortex to the brain stem corticobulbar/cortico-
nuclear, to the cerebellum corticopontine, and to the spinal cord corticospinal.
Table 6.1 lists the general contents of each region of the brain stem.
The segmental arrangement of the spinal cord stops superior to the first cervical
spinal roots where the transition from spinal cord to medulla occurs. This transition
is gradual and consists of a total reorganization of the pattern, seen in the spinal
cord, of internal cell columns (gray matter), and external fiber columns (white mat-
ter). In the brain stem, the columns of cells are organized into distinct nuclei, and
individual tracts are recognizable in contrast to the nearly uniform pattern in the
spinal cord. Finally, the tracts and nuclei are intermingled throughout the substance
of the brain stem. The external sign of the segmental divisions of the spinal cord—
the pairs of spinal nerves—stops at the spinomedullary junction. The rootlets
attached to the brain stem represent the 11 pairs of cranial nerves, which are associ-
ated with the brain stem. The dorsal root ganglion of the spinal cord has an equiva-
lent in the cranial nerve sensory ganglion associated with nerves V, VII, IX, and X.
Site of transition from the spinal cord to the medulla is found by passing a line from
the superior border of the first cervical nerve root to the inferior border of the pyra-
midal decussation on the anterior surface.
Rostral to that line is the medulla.
Site of transition from the medulla to the pons is made by passing a line from the
superior border of the medullary stria on the floor of the fourth ventricle to the infe-
rior most margin of the massive pons itself; superior to this plane is the pons.
5.2 Relationship of Regions in the Brain to the Ventricular System 157
The boundary between pons and midbrain is found by passing a line from the
inferior margin of the inferior colliculus to the superior margin of the pons; the mid-
brain is superior to this plane.
The boundary between midbrain and diencephalon is formed by passing a line
from the superior margin of the posterior commissure to the inferior margin of the
mammillary bodies.
The diencephalon is separated from the telencephalon laterally by the posterior
limb of the internal capsule and superiorly by the lateral ventricles, corpus callo-
sum, and fornix.
5.2 R
elationship of Regions in the Brain to the Ventricular
System: Fig. 5.2
Fig. 5.2 Coronal sections of gross brain at levels of diencephalon, brain stem (medulla, pons,
midbrain) with regions identified in relationship to ventricular system
158 5 Brain Stem: Gross Anatomy
Anterior surface, Fig. 5.3. In the midline on the anterior or ventral surface of the
medulla and pons is found the ventral median fissure which continues from the
spinal cord onto the medulla and stops at the basilar portion of the pons, the bra-
chium pontis. The anterior spinal artery is found in the ventral median fissure. This
fissure divides the two prominent pyramids which form the basilar portion of the
medulla. These tracts provide voluntary control of all the skeletal muscles in the
body. At the border between the spinal cord and medulla, the ventral median fissure
may be obliterated by the decussation of the pyramids. Lateral to the pyramids are
the large inferior olives. In the medulla the rootlets of the hypoglossal nerve (cranial
nerve XII) exit from the substance of the medulla between the olives and the pyra-
mid. (The 12th nerve innervates the intrinsic muscles of the tongue.) These rootlets
identify the site of the usually inconspicuous ventral intermediate sulcus.
Rootlets of cranial nerves IX, X, and XI. Exiting posterior to the inferior olive is
a nearly continuous series of nerve roots from cranial nerves IX X and XI. These
rootlets identify the ventral lateral sulcus which is inconspicuous in the medulla. The
rootlets for the spinal accessory nerve (nerve XI) originate from the upper cervical
levels and the lowest portion of the medulla and usually stop at the inferior border of
the olive. This motor nerve innervates the ipsilateral sternocleidomastoid and trap-
ezoid muscles. The rootlets in a postolivary position come from the vagal (nerve X)
and glossopharyngeal (nerve IX) nuclei. The inferior three-fourths of the rootlets
originate from the nuclei of the vagus; the remaining one-fourth of the r ootlets arise
5.3 Gross Anatomy of Brain Stem and Diencephalon 159
optic nerve
optic tract
tuber cinereum
mammillary body
interpeduncular fossa
N. III
cerebral peduncle
N. IV
N. V (motor)
N. V (sensory)
pons
N. VI
middle cerebellar peduncle
N. VII
N. VII (intermedius)
pyramid N. VIII
N. XII N. IX
olive N. X
N. XI
Fig. 5.3 Anterior (ventral) surface of brain stem and diencephalon demonstrating the location of
many cranial nerve rootlets (diencephalon CN II; midbrain III and IV; pons V–VII: medulla
VIII–XII)
from the glossopharyngeal nuclei. The ninth cranial nerve carries sensations from
the mucous membranes and taste buds in the posterior part of the mouth and phar-
ynx and innervates the parotid gland and pharyngeal muscles. The vagus nerve
(nerve X) provides motor innervation to the larynx and pharynx and preganglionic
parasympathetic innervation to the viscera and conveys information from the
gastrointestinal tract into the medulla.
The anterior surface of the massive pons consists of the middle cerebellar
peduncle (the brachium pontis) and contains the rootlets of cranial nerves V, VI, VII,
and VIII. In addition to the middle cerebellar peduncles, there is also an inferior
cerebellar peduncle, which interconnects the cerebellum and medulla, and a superior
160 5 Brain Stem: Gross Anatomy
cerebellar peduncle, which connects the cerebellum to the midbrain; these tracts
will be seen on the posterior surface of the medulla and pons and will be discussed
in Chap. 11. The nerve rootlets of the abducens (VI) nerve emerge from the sub-
stance of the pons at the pontomedullary junctions, in a line with the hypoglossal
rootlets. This nerve innervates the lateral rectus muscle of the eye.
The facial (VII) nerve and acoustovestibular (VIII) nerves emerge more laterally
in the line with fibers of nerves IX, X, and XI.
The fibers of nerve VIII are lateral to those of nerve VII. The rootlets of nerve
VIII are more numerous than those of nerve VII. The cochlear portion of the rootlet
is larger than the vestibular portion. Cranial nerve VIII is the receptor for hearing
and balance. Cranial nerve VII has a smaller portion, the intermediate nerve, lying
between the larger motor VI. These fibers are afferent and efferent visceral fibers
and parasympathetic and special sensory; they carry sensations from mucous mem-
branes and taste buds of the anterior two-thirds of the tongue and provide motor
innervation to the facial muscles.
The trigeminal (V) nerve emerges from the substance of the pons laterally and
usually consists of a small motor root and a large sensory root. Cranial nerve V
carries sensory innervation for the head and innervates the muscles of mastication.
The most anterior surface of the pontine basis contains a depression, the basilar
sulcus, in which the basilar artery is found.
The ventral or anterior surface of the midbrain is formed by the cerebral peduncles
in which are found the corticospinal, corticobulbar, and corticopontine fibers. The
cerebral peduncles are separated by the deep interpeduncular fossa where the arte-
rial and venous supply enters the midbrain and where the rootlet of nerve III exits
from the brain. Removal of these vessels leaves small perforations in the anterior
surface of the midbrain forming the posterior perforated substance.
The rootlets of nerve III exit from the tegmentum of the midbrain in the interpe-
duncular fossa on the most medial surface of the peduncle and innervate all extrinsic
eye musculature except for the lateral rectus and superior oblique muscles.
5.3.2 P
osterior Surface of Brain Stem
and Diencephalon: Fig. 5.4
5.3.2.1 Medulla and Pons Posterior Surface (Fig. 5.4)
In this view (Fig. 5.4), the cerebellar peduncles, which formed the medullary and
pontine walls of the fourth ventricle, have been transected and the cerebellum
removed, exposing the ventricle. The posterior surface of the medulla undergoes
considerable changes due to the presence of the fourth ventricle. The spinal canal is
5.3 Gross Anatomy of Brain Stem and Diencephalon 161
Fig. 5.4 Posterior (dorsal surface) of brain stem and diencephalon demonstrating in the medulla
the location of gracile, cuneate, and trigeminal funiculi. In the pons the inferior, middle, and supe-
rior cerebellar peduncles are evident. The only cranial nerve evident on this surface is the rootlets
of CN IV which have crossed in the superior medullary velum prior to their appearance on the
posterior surface. The colliculi of the inferior (auditory) and superior colliculi (visual) of the mid-
brain are present. The pineal gland is evident above the lower margin of the slit like III ventricle
between the diencephalic halves. The diencephalic nuclei are present and separated from the lat-
eral caudate nucleus by the stria terminalis. The lenticular nuclei are separated from the caudate by
the internal capsule
162 5 Brain Stem: Gross Anatomy
continuous with the inferior portion of the fourth ventricle which is a narrow channel
in medullary levels. As the fourth ventricle enlarges from a narrow canal to a wide
channel, the dorsal column fibers disappear as the one on nuclei internal to the colt
second-order axons cross the migrate to an anterior position medullary pyramid,
forming lemniscus. The obex marks the place where the posterior neuronal roof
thins out and disappears, and the ventricle opens and is covered only by pia mater
and the choroid plexus, the tela choroidea.
The dorsal median sulcus is seen at the midline on the spinal cord, medulla, and
pons. In lower medullary levels, the funiculus gracilis is in a paramedian location. In the
medulla, the tracts carrying primary somesthetic axons, the funiculus gracilis and the
funiculus cuneatus, become more pronounced because of the presence of cell b odies
which are internal to the fasciculus gracilis and the funiculus cuneatus and are called the
gracile and cuneate nuclei. The enlargement of the funiculus gracilis is called the clava
(“club-shaped”), while the enlargement of the cuneate funiculus is called the cuneate
tubercle. The funiculus gracilis is separated from the funiculus cuneatus by the poste-
rior intermediate sulcus which continues up from the spinal cord.
Lateral to the funiculus cuneatus is the trigeminal funiculus which is usually not
prominent and continues down into the upper cervical level and contains the spinal
tract and nucleus of the trigeminal nerve (nerve V). The primary axons of nerve V
are so numerous that pontine, medullary, and upper cervical levels are required to
provide enough secondary cell bodies for all the axons to terminate.
Lateral and anterior to the trigeminal funiculus is the lateral funiculus, which is
also not usually prominent and is found posterior to the olivary eminence. On the
sure lateral funiculus contains the dorsal and ventral spinocerebellar tracts; inter-
nally it contains the pain and temperature fibers, the lateral spinothalamic tract.
At the upper medullary level, the gracile and cuneate funiculi and nuclei have
disappeared, and the trigeminal funiculus is covered first by the dorsal spinocer-
ebellar tract and then by the restiform eminence which contains the dorsal
spinocerebellar tract and olivoreticular fibers which unite and form the inferior
cerebellar peduncle (restiform body).
In the medullary, pontine, and midbrain levels, the floor of the fourth ventricle
contains cranial nerve nuclei. Throughout the medulla the paramedian hypoglossal
trigone marks the position of the nucleus of nerve XII, which innervates the intrinsic
muscles of the tongue. Lateral to the hypoglossal trigone (nerve XII) lays the vagal
trigone which marks the location of the dorsal motor nucleus of the vagus nerve
(nerve X). In lower medullary levels, the nuclei of nerves X and XII are covered by
the funiculus gracilis and the nucleus gracilis which disappear as the secondary
axons form the medial lemniscus.
In pontine regions, the hypoglossal and vagal trigone are replaced by the median
eminence which at inferior pontine levels has a prominent swelling, the facial c olliculus.
This marks the location of the nucleus of nerve VI and the genu of nerve VlI.
Lateral to the vagal trigone and median eminence is a sulcus of variable con-
stancy but of functional significance the sulcus limitans. This sulcus marks the sepa-
ration between the embryological alar and basal plates. Sensory nuclei develop in
5.3 Gross Anatomy of Brain Stem and Diencephalon 163
the alar plates while the basal plates form motor nuclei. This functional separation
applies only to the nuclei in the floor of the fourth ventricle. In lower medullary
levels, the sensory area on the floor of the fourth ventricle receives both general and
special sensations from the viscera via nerve X, while in upper medullary and lower
pontine levels, this region receives input from the inner ear via cranial nerve
VIII. The ventricular floor in this region also contains the second-order auditory and
vestibular nuclei.
The vestibular fibers synapse in the medially placed vestibular area, while the
primary auditory fibers terminate in the more laterally placed acoustic tubercle
(cochlear nuclei) which appears on the surface of the inferior cerebellar peduncle.
Lateral and anterior to the trigeminal funiculus is the lateral funiculus, which is
also not usually prominent and is found posterior to the olivary eminence. On the
sure lateral funiculus contains the dorsal and ventral spinocerebellar tracts;
internally it contains the pain and temperature fibers, the lateral spinothalamic tract.
At the upper medullary level, the gracile and cuneate funiculi and nuclei have dis-
appeared, and the trigeminal funiculus is covered first by the dorsal spinocerebellar
tract and then by the restiform eminence which contains the dorsal spinocerebellar
tract and olivoreticular fibers which unite and form the inferior cerebellar peduncle
(restiform body).
In the medullary, pontine, and midbrain levels, the floor of the fourth ventricle
contains cranial nerve nuclei. Throughout the medulla the paramedian hypoglossal
trigone marks the position of the nucleus of nerve XII, which innervates the intrinsic
muscles of the tongue. Lateral to the hypoglossal trigone (nerve XII) lays the vagal
trigone which marks the location of the dorsal motor nucleus of the vagus nerve
(nerve X). In lower medullary levels, the nuclei of nerves X and XII are covered by
the funiculus gracilis and the nucleus gracilis which disappear as the secondary
axons form the medial lemniscus.
In pontine regions, the hypoglossal and vagal trigone are replaced by the
median eminence which at inferior pontine levels has a prominent swelling, the
facial colliculus. This marks the location of the nucleus of nerve VI and the genu
of nerve VII.
Lateral to the vagal trigone and median eminence is a sulcus of variable con-
stancy but of functional significance the sulcus limitans. This sulcus marks the
separation between the embryological alar and basal plates. Sensory nuclei develop
in the alar plates while the basal plates form motor nuclei. This functional separa-
tion applies only to the nuclei in the floor of the fourth ventricle. In lower medul-
lary levels, the sensory area on the floor of the fourth ventricle receives both general
and special sensations from the viscera via nerve X, while in upper medullary and
lower pontine levels, this region receives input from the inner ear via cranial nerve
VIII. The ventricular floor in this region also contains the second-order auditory
and vestibular nuclei. The vestibular fibers synapse in the medially placed vestibu-
lar area, while the primary auditory fibers terminate in the more laterally placed
acoustic tubercle (cochlear nuclei) which appears on the surface of the inferior
cerebellar peduncle.
164 5 Brain Stem: Gross Anatomy
The posterior surface (Fig. 5.4) of the midbrain has two pairs of conspicuous
enlargements, the superior and inferior colliculi, which together form the tectum of
the midbrain. The medial geniculate nucleus of the thalamus is attached to the lat-
eral margin of the superior colliculus. A band of fibers, the brachium of the inferior
colliculus, extends from each inferior colliculus along the border of the superior
colliculus geniculate nuclei of the diencephalon. Cranial nerve IV exits from the
brain stem at the caudal margin of the inferior colliculus (Fig. 5.4). This is the only
cranial nerve with rootlets on the posterior surface of the brain. Fibers of the optic
tract may be traced past the lateral geniculate onto the superior colliculus.
The only external features of the diencephalon are noted on the ventral surface of
the brain (Fig. 5.3): the mammillary bodies, the hypophyseal stalk, and the optic
chiasm and tract. Only after the cerebral hemispheres and corpus callosum are
removed, as in Fig. 5.4, can the entire diencephalon be seen. From the posterior
surface, the third ventricle is seen separating the diencephalon into two identical
structures (Fig. 5.2). Commonly, a small mass, the mass intermedia, is seen in the
third ventricle.
The diencephalon consists of four parts: (1) epithalamus, (2) thalamus and meta-
thalamus, (3) hypothalamus, and (4) subthalamus. See discussion in Chap. 8 on thal-
amus, metathalamus, and subthalamus, and in Chap. 7 see discussion on hypothalamus
and epithalamus. The ventral or anterior surface of the midbrain is formed by the
cerebral peduncles in which are found the corticospinal, corticobulbar, and cortico-
pontine fibers. The cerebral peduncles are separated by the deep interpeduncular
fossa where the arterial and venous supply enters the midbrain and where the rootlet
of nerve III exits from the brain. Removal of these vessels leaves small perforations
in the anterior surface of the midbrain forming the posterior perforated substance.
The rootlets of nerve III exit from the tegmentum of the midbrain in the interpedun-
cular fossa on the most medial surface of the peduncle and innervate all extrinsic eye
musculature except for the lateral rectus and superior oblique muscles.
Epithalamus. On the dorsal surface, posteriorly, the epithalamus is visible at the
midline in Fig. 5.4; it consists of pineal gland, habenular trigone, and stria medullaris.
Thalamus and Metathalamus. The thalamus is seen only on the posterior surface
(Fig. 5.4), and it forms the bulk of the diencephalon and appears to be continuous
with the tegmentum of the midbrain. Anteriorly, it has a small prominence, the ante-
rior tubercle, and posteriorly a larger swelling, the pulvinar. The detailed structure
of the thalamus is discussed in Chap. 8. The thalamus is the primary relay center for
all senses except smell. Crude awareness of pain, touch, temperature, and pressure
are found here. All systems which connect with the cerebral hemispheres must
synapse in the thalamus before they are projected onto the cerebral cortex.
5.4 Arterial Blood Supply to the Brain Stem and Diencephalon 165
The metathalamus consists of two nuclei extending onto the lateral surface of the
midbrain: the medial and lateral geniculate nuclei. The medial geniculate nucleus
receives the auditory fibers via the brachium of the inferior colliculus, and the l ateral
geniculate nucleus receives fibers via the optic tract.
Hypothalamus (Fig. 5.3). The hypothalamus is smaller than the thalamus and is
functionally very important because of its relationship to behavior and emotions.
The hypothalamus forms the walls and floor of the third ventricle below the hypo-
thalamic sulcus. The following parts of the hypothalamus are seen on the anterior
surface of the gross brain the infundibulum, the tuber cinereum (blue), and the
mammillary body. Other nuclear masses can be identified in brain sections stained
with the Nissl method. See Chap. 9 for a discussion on the hypothalamus, its nuclei,
and many functions.
Subthalamus. The subthalamus cannot be seen in the gross brain or in a hemi-
sected brain. In an appropriate coronal section (Fig. 8.11), it can be seen medial to
the internal capsule below the thalamus and lateral to the hypothalamus. It consists
of the zona incerta, the subthalamic nucleus, and the tegmental or prerubral field of
Forel and small portions of substantia nigra and red nucleus. It is an important sta-
tion in the extrapyramidal (involuntary) motor system.
5.4 A
rterial Blood Supply to the Brain Stem
and Diencephalon (Fig. 5.5)
The arterial blood supply to the medulla, pons, midbrain, and cerebellum originates
from the posterior circulation (vertebral, basilar, and posterior cerebral arteries).
The arterial blood supply to the diencephalon originates from the anterior circula-
tion (internal carotid, middle, and anterior cerebral arteries) and from the posterior
circulation (posterior cerebral artery). The blood supply to the medulla, pons, and
midbrain is derived from paramedian and circumferential branches of the posterior
circulation.
5.4.1 Medulla
Paramedian branches of the vertebral artery supply the medullary pyramids, the
inferior olive, the medial lemniscus, the tectospinal tract, the medial longitudinal
fasciculus, and the hypoglossal nucleus and root. A circumferential branch of the
vertebral artery (posterior inferior cerebellar artery—PICA) irrigates the following
structures in the tegmentum of the medulla: cranial nuclei of nerve X, ambiguous
nucleus (of nerves X and XII), descending nucleus and root of nerve V, lateral spi-
nothalamic tract, inferior cerebellar peduncles, dorsal and ventral spinocerebellar
tracts, descending and medial vestibular nuclei, and descending sympathetic fibers.
166 5 Brain Stem: Gross Anatomy
Fig. 5.5 View of the ventral surface of the brain showing cerebellum, brain stem, diencephalon,
and cerebrum. The arterial blood supply to the base of the brain from the internal carotid and ver-
tebral arteries are labeled in Red: ACA-anterior cerebral artery, AICA-anterior cerebellar artery
from basilar, B-basilar artery, IC-internal carotid, MCA-middle cerebral artery, PComm-posterior
communicating artery, PICA-posterior inferior cerebellar artery, from vertebral, SCA-superior cer-
ebellar artery from basilar; Cranial nerve rootlets, CN I–XII, are color coded as follows- The
special sensory cranial nerves—I, II, and VIII are marked in orange (CN I—into olfactory bulb on
base of cerebrum; CN II—into base of diencephalon,CNVIII into pons;). The somatic motor cra-
nial nerves are marked in blue—III, IV, VI, and XII. The visceral sensory cranial nerves are marked
in green—VII, IX–XI
5.4.2 Pons
Paramedian branches of the basilar artery supply the medial surface of the pontine
basis and tegmentum, including the nucleus and rootlets of nerve VI. A circumferen-
tial branch of the basilar artery (anterior inferior cerebellar artery—AICA) s upplies
the lateral portion of the pontine basis and the lateral portion of the pontine tegmen-
tum, including the rootlets and nuclei of nerves V and VII; the dorsal and ventral
cochlear nuclei of nerve VIII; the superior, lateral, and rostral portions of the medial
and descending vestibular nuclei; the lateral spinothalamic tract; and the middle and
superior cerebellar peduncles.
Bibliography 167
5.4.3 Midbrain
Paramedian branches of the posterior cerebral artery supply the medial half of the
cerebral peduncle, nucleus, and rootlet of nerve III and much of the red nucleus.
A circumferential branch of the basilar artery (superior cerebellar artery) supplies
the superior cerebellar surface, the rootlet of cranial nerve V, and a portion of the
inferior colliculus, while a circumferential branch of the posterior cerebral artery
(quadrigeminal artery) supplies the superior cerebellar peduncle, the remainder of
the red nucleus, the lateral half of the cerebral peduncle, and the superior and
inferior colliculus.
5.4.4 Diencephalon
The rostral part of the diencephalon is supplied by penetrating branches from the
middle cerebral artery (striatal and thalamostriatal arteries), while the caudal part of
the diencephalon, including the geniculate nuclei, subthalamus, pulvinar, ventral
posterior medial, ventral posterior lateral, and ventral lateral nuclei of the thalamus,
is supplied by penetrating branches from the posterior cerebral artery. The blood
supply to the hypothalamus and hypophysis is discussed in Chap. 19.
Bibliography
Ropper AH, Samuels MA, Klein JP. Adams and Victor’s principles of neurology. 10th ed.
New York: McGraw Hill; 2016.
Netter F. Atlas of human anatomy. 5th ed. Teterboro, NJ: Icon Learning Systems; 2015.
Marcus EM, Jacobson S, Sabin T. Integrated neuroscience. 2nd ed. Oxford: Oxford University
Press; 2014.
Per Brodal A. The central nervous system. 5th ed. London: Oxford Blackwell; 2016.
Riley HA. Brain stem and spinal cord. New York: Hafner; 1960.
Chapter 6
Brain Stem Functional Localization
Abstract The brain stem is the subcortical region that contains all but 2 of the 12
cranial nerves. Associated with the cranial nerves are centers that control the heart,
lung, and GI systems and control the muscles in the head and neck. We speak and
move our eyes and all the muscles in the head due to the cranial nerves.
All major ascending pathways from the spinal cord and cerebellum pass through
the brain stem on their way to the thalamus. Major pathways originate from the
many nuclei in the brain stem and terminate in the thalamus.
Cerebral cortical control of the cranial nerves, corticonuclear fibers, descends
from the cortex to the brain stem, and cortical fibers to the spinal cord, corticospinal,
pass through the stem on their way to provide motor control of the limbs.
This discussion on functional localization in the brain stem will focus on the
tegmentum, floor of the IV ventricle, and aqueduct, which contains cranial nerves
III–XII and the many tracts and functions associated with them. We will start at the
junction between spinal cord and medulla and move our way up through the medulla,
pons, and midbrain ending up with a review of the major functional centers found
in the brain stem.
The tegmentum (floor of the IV ventricle) of the brain stem (medulla, pons, and
midbrain) is continuous with the gray and white matter of the spinal cord below and that
of the diencephalon above (Fig. 6.1), and based on clinical observations, we have
divided the tegmentum into five zones: ventricular, lateral, medial, core/reticular, and
basilar. Each half of the brain stem should thus be considered organized like an apple
with the core being the reticular formation and the flesh/pulp formed by the four
surrounding zones (Tables 6.1 and 6.2).
Although the discussion in this chapter of each level is confined to the coronal
section under examination, it should be noted that most nuclei and all tracts extend
through more than just one level. Therefore, when reading this section, the student
should keep in mind the origin and destination of structures identified in each of
these sections. It is especially important that the students understand the function
and clinical importance of the anatomical structures they are studying. The cranial
nerve nuclei and many pathways (e.g., corticospinal, corticonuclear, and spinotha-
lamic) in the brain stem are clinically important since any functional abnormalities
in these systems help to identify where the disease process is occurring in the CNS.
The interior gray matter and exterior white matter of the spinal cord gradually
change to a mixture of gray and white matter in the brain stem. Table 6.3 identifies
the nuclei and tracts in the spinal cord and lists their functional equivalents in the
172 6 Brain Stem Functional Localization
Table 6.3 Gray and white matter equivalents in spinal and brain stem structures
Spinal cord region Equivalent brain stem region
Dorsal (sensory) horn Ventricular zone, lateral region with
sensory cranial nerves—VII, IX, X; lateral
zone cranial nerve V
Ventral (motor) horn Ventricular zone, medial region with
motor cranial nerves nuclei: III–VI, X–XII
Reticular formation with motor nuclei of
cranial nerves V, VII, IX, and X
Intermediate zone Reticular formation and associated nuclei
Intermediolateral cell column; (Sympathetic) Parasympathetic nuclei with cranial
T1–T12 and L1 and L2; parasympathetic S2–S4 nerves III, VII, IX, and X
Lateral column of white matter: Basilar zone—corticospinal/not crossed
Corticospinal/ Lateral zone—spinothalamic and
crossed, rubrospinal—spinothalamic rubrospinal
Posterior column of white matter = uncrossed Medial lemniscus: crossed tactile
gracile and cuneate fasciculi information
Anterior column of white matter = MLF, Medial zone—MLF, tectospinal, reticular
vestibulospinal, reticulospinal, spinothalamic formation, reticulospinal
Lateral zone: vestibulospinal
brain stem. The student should be aware that the development of the cerebellum,
midbrain, and cerebrum has greatly affected the neural contents of the brain stem
and has led to the formation of many nuclei and tracts (e.g., the following nuclei—
inferior olive of the medulla, pontine gray of the pons, red nucleus and substantia
nigra of the midbrain, and the corticonuclear and corticopontine tracts).
6.3 F
unctional Localization in Brain Stem Coronal Sections
and an Atlas of the Brain Stem
The previous section on the brain stem has discussed the gross anatomy of this
region. In this section, we will discuss the functional anatomy of the brain stem by
examining coronal sections at representative levels through the medulla, pons, and
midbrain.
Each level will contain the following illustrations: A, section stained for
myelin; B, section with the nuclei and tracts labeled in color; and C, an
MRI at a similar level. Please remember that the MRI is from a living patient,
while the brain sections were obtained from a postmortem specimen. The cra-
nial nerve nuclei and many pathways (e.g., corticospinal, corticonuclear, and
spinothalamic) in the brain stem are clinically important since any functional
abnormalities in these systems help to identify where the disease process is
occurring in the CNS.
6.3 Functional Localization in Brain Stem Coronal Sections… 173
6.3.1 Medulla
The first level we have included is at the sensory and motor decussation (Fig. 6.2).
This section has mostly spinal cord elements, the ventral horns, and the three white
matter columns; however, one can also note brain stem elements—the gracile and
cuneate nuclei. This region is the transitional zone and the region is the size and
shape of the spinal cord. As we move up the brain stem, we come to the widened
medulla with the opening of the fourth ventricle. In the brain stem tegmentum, the
gray and white matter appear intermingled; however, there is a basic organization of
the tracts in the brain stem zones, as shown in Table 6.4.
Gross landmarks in the medulla. The tegmentum of the medulla has two distinct
levels, a narrow lower portion which is similar to the spinal cord and a broader
upper portion which includes the landmarks that are hallmark of this level.
Brain stem level one: Medulla at transition between cervical spinal cord and low
medulla. Motor-sensory decussation
Sensory cranial nerve nuclei (Fig. 6.2a). The primary axons convey pain and
temperature from the head and neck and are located in the spinal tract of the fifth
cranial nerve; these fibers have descended from the pons. The second-order axons
originate from the underlying descending nucleus, and their axons cross and then
ascend contralaterally to the ventral posterior medial nucleus of the thalamus. The
nucleus lateral to the pyramidal tract is the inferior reticular nucleus, a portion of the
reticular formation.
White matter (Fig. 6.2a). At this level the tracts are still in the same positions as
in the spinal cord. Tactile discrimination (fine touch, pressure, vibration sensation,
and two-point discrimination) and proprioception from the extremities, thorax,
abdomen, pelvis, and neck are carried via the dorsal columns. The nuclei can now
be seen that are the 2° neurons in this pathway, the gracile and cuneate nuclei. The
gracile and cuneate tracts (fasciculi) have reached their maximum bulk with the
addition of the last of the fibers from the uppermost cervical levels. The somatotopic
arrangement of the tactile fibers in the posterior column is as follows: the most
medial fibers are sacral and then come the lumbar, thoracic, and, most laterally,
cervical fibers which also form much of the cuneocerebellar tract.
Spinothalamic/anterolateral column. Pain and temperature from the extremities,
abdomen, thorax, pelvis, and neck are carried by the lateral spinothalamic tract
located at the lateral surface of the medulla. Light touch from the extremities, tho-
rax, abdomen, pelvis, and neck is carried via the anterior spinothalamic tract, which
is seen on the surface of the medulla just posterior to the corticospinal tract. In the
spinothalamic pathways, sacral fibers are on the outside, while cervical fibers are on
the inside. The dorsal and ventral spinocerebellar tracts are found in the lateral
funiculus. The rubrospinal and tectospinal tracts, which are important in supporting
voluntary motor movements, are found in the lateral funiculus and near the midline
in the medullary and pontine levels.
174 6 Brain Stem Functional Localization
Fig. 6.2 Lower medullary level at transition level between cervical spinal cord and motorsensory
decussation. (a) Myelin stained (b) Labeled section (c) MRI T1
6.3 Functional Localization in Brain Stem Coronal Sections… 175
Motor cranial nerve nuclei (Fig. 6.3a). This section contains the inferior extent of
the hypoglossal nerve (XII) and the dorsal motor nucleus of the vagus nerve (X).
The hypoglossal nucleus innervates the intrinsic and extrinsic musculature of the
tongue, while the dorsal motor nucleus of the vagus nerve provides parasympathetic
preganglionic innervation of the viscera. This level marks the superior extent of the
cranial portion of the eleventh cranial nerve in the ambiguous nucleus.
Sensory cranial nerve nuclei (Fig. 6.3a). Pain and temperature from the head are
conveyed by the descending nucleus and tract of nerve V that is prominent anterior
to the cuneate nucleus. Note that myelinated ipsilateral primary axons are on the
outside of the second-order neurons, while the second-order neurons are leaving the
inner surface of the nucleus, crossing and entering the medial lemniscus, and form-
ing the trigeminothalamic (quintothalamic) tract.
White matter (Fig. 6.3a). Pain and temperature from the extremities, thorax, abdo-
men, pelvis, and neck are carried via the lateral spinothalamic tract. The spinothalam-
ics are in the lateral funiculus throughout the spinal cord and brain stem! The anterior
spinothalamic tract is adjacent to the lateral spinothalamic tract. The tract carrying
unconscious proprioception from the upper extremity originates from the external
cuneate nucleus, and its fibers enter the cerebellum through the posterior spinocerebel-
lar tract. The function of this nucleus is similar to that of Clarke’s c olumn in the spinal
cord. The vestibulospinal tract is found internal to the s pinothalamic tracts. The dorsal
176 6 Brain Stem Functional Localization
Fig. 6.3 Brain stem at lower medullary level. (a) Section stained for myelin, (b) labeled section,
(c) MRI. Coronal B
6.3 Functional Localization in Brain Stem Coronal Sections… 177
and ventral spinocerebellar tracts are seen on the surface of the medulla covering the
spinal tract of nerve V and the spinothalamic tracts. The rubrospinal tract is an impor-
tant afferent relay to the alpha and gamma neurons in the spinal cord. It originates from
the red nucleus in the tegmentum of the midbrain, crosses the midline, and descends.
It is found in the lateral funiculus of the medulla internal to the spinocerebellar tract
and anterior to spinal nerve V throughout the pons and medulla. It is important in pos-
tural reflexes. The tectospinal tract is phylogenetically an old tract, being the equiva-
lent of the corticospinal tract in nonmammalian vertebrates. It originates from the deep
layers of the superior colliculus and to some extent from the inferior colliculus. It is
seen anterior to the medial longitudinal fasciculus throughout the medulla, pons, and
midbrain and is important in coordinating eye movements and body position.
The medial lemniscus is the largest pathway in the medial zone. However, as we
progress superiorly in the brain stem, these fibers migrate laterally to finally enter the
lateral zone in the midbrain. This migration is necessary for the medial lemniscus to
be correctly positioned as it enters the thalamus. Tactile discrimination and proprio-
ception are conveyed from the extremities, thorax, abdomen, pelvis, and neck by the
axons in the fasciculus gracilis and cuneatus. The nucleus gracilis and the nucleus
cuneatus form the second-order neurons in this pathway and are conspicuous in this
section. Internal arcuate fibers are seen leaving the inner surface of the gracile and
cuneate nuclei, curving around the ventricular gray, crossing the midline (sensory
decussation), and accumulating behind the pyramid and beginning the formation of
one of the major ascending highways, the medial lemniscus. The serotonin-contain-
ing raphe nucleus of the reticular formation is found in this zone throughout the brain
stem. The medial longitudinal fasciculus is located in the midline of the tegmentum
just below the hypoglossal nucleus and above the tectospinal and medial lemniscal
pathways. In all levels of the brain stem, it will be in this subventricular position.
The central core of the medulla, pons, and midbrain consists of the reticular forma-
tion, which is important for many vital reflex activities and for the level of
attentiveness.
Brain stem level three: Brain stem at wide-medullary level.
Note that the corticospinal fibers through this region are pyramidal shaped as
noted in the naming of this pathway the pyramidal pathway (Fig. 6.4a, b). One of
the important concepts from this section is that axons that form the volitional motor
pathway, pyramidal system, originate in the cerebral cortex. These tracts are located
in the basis of the brain stem and include the corticospinal and corticonuclear fibers
that run in the medullary pyramid. Motor system fibers that do not run in the medul-
lary pyramid are considered extrapyramidal (e.g., cerebellar peduncles, rubrospinal
178 6 Brain Stem Functional Localization
Fig. 6.4 (a) Basilar zone. (b) Brain stem at wide-medullary level. Coronal, MRI
6.3 Functional Localization in Brain Stem Coronal Sections… 179
Table 6.5 Clinical defects from lesions in the tegmental zones of the brain stem
Ventricular zone: Interruption of motor cranial nerves III, IV, VI, X, and XII produces lower
motor neuron signs. Interruption of sensory nuclei of VIII produces dizziness and deficits in
hearing; injury to the solitary nucleus produces deficits in taste
Lateral zone: Interruption of the spinothalamic tract produces contralateral decrease in pain
and temperature from the body. Injury to the rootlet or chief sensory or descending nucleus of
CN V produces sensory finding of ipsilateral deficits in pain, temperature, and touch from the
head and ipsilateral weakness in chewing
Medial zone: Interruption of the medial lemniscus, depending on the level of the lesion,
produces loss of touch, pain, and temperature from the head or body; injury to the medial
longitudinal fasciculus produces deficits in coordination of eye movements
Central zone: Lesions here produce abnormalities in the functions associated with cranial nerve
nuclei of VII, IX, X, and XI. The descending parasympathetic and sympathetic fibers can also
be interrupted affecting the pupil (Horner’s) and sweat glands (see Chap. 11 on Cranial Nerves).
Basilar zone: Destruction of the corticospinal tract produces an upper motor neuron lesion with
loss of volitional movement in the contralateral body muscles; interruption of the corticonuclear
tract produces weakness of volitional movement of the muscles in the contralateral head and
neck compression with an alteration in mental status.
tectospinal, etc.). The location of the major structures in the tegmentum of the
medulla is listed below in Table 6.5.
Gross features. At this level the medullary tegmentum expands laterally with the
prominent inferior olive located behind the pyramids.
The floor of the fourth ventricle contains the median eminence and the vestibular
and cochlear tubercles. The median eminence consists of aqueductal gray, while the
vestibular tubercle is formed by the medial vestibular nucleus and the descending
root and nucleus of cranial nerve VIII. The dorsal cochlear nucleus forms the cochlear
tubercle. The ventricle at this level is at its widest extent (Fig. 6.8a, b). The sulcus
limitans in the ventricular floor separates the medially placed motor cranial nuclei
from the laterally placed sensory cranial nuclei.
Motor cranial nerve nuclei (Fig. 6.8a). This level marks the superior extent of nerve
XII and the dorsal motor nucleus of nerve X. The ambiguous nucleus in the lateral
margin of the reticular formation contains cell bodies innervating the pharynx and
larynx (nerve X).
(b) Solitary tract and nucleus. Taste and visceral sensations are found in the solitary
nucleus and tract in the tegmental gray below the medial vestibular nucleus. Fibers
from cranial nerves VII, IX, and X ascend and descend in this tract carrying gen-
eral sensations from the viscera (nerve X) and gustatory sensations from the taste
buds in the tongue (nerves VII and IX) and epiglottis (nerve X).
(c) Vestibular. The medial and descending vestibular nuclei are present with first-
order axons (Fig. 6.8b) found in the descending root of cranial nerve VIII, inter-
stitial to the descending nucleus. Fibers may be seen running from the vestibular
nuclei into the medial longitudinal fasciculus.
(d) Auditory. The dorsal and ventral cochlear nuclei are second-order nuclei in the
auditory pathway and receive many terminals from the cochlear portion of
nerve VIII seen within its borders.
Cerebellum. The conspicuous inferior olivary nucleus in the anterior portion of
the medullary tegmentum consists of the large main nucleus and the medial and
dorsal accessory nuclei. The entire complex is important in supplying information
to the cerebellum. Removal of the olive in animals produces contralateral increase
in tone and rigidity in the extremities, with concomitant uncoordinated movements.
The olive connects to the contralateral cerebellar hemispheres via the inferior cere-
bellar peduncle. The climbing fibers found on the dendrites of Purkinje cells in the
cerebellum originate in the inferior olive. The olive also has strong connections with
the red nucleus and receives input from the spinal cord, cerebellum, red nucleus,
intralaminar nuclei, and basal ganglia. The central core of this section, as in other
levels, consists of neurons of the reticular formation.
Medial zone (Fig. 6.5a). The serotonergic raphe nuclei of the reticular formation
are found in this zone. The position of the MLF and tectospinal and medial lemnis-
cus corresponds to that in the previous level.
Gross landmarks. The hallmark of pontine levels is the prominent basis ponti that
is present on the anterior surface. The cerebellum forms the posterior surface.
The tegmentum takes up much less of these levels due to the massive enlarge-
ment of the pontine basis. With the cerebellum removed, the posterior surface of
the tegmentum demonstrates the three cerebellar peduncles (see Fig. 5.4): infe-
rior cerebellar peduncle, middle cerebellar peduncle, and superior cerebellar
peduncle—posterior surface and the fourth ventricle is now opened.
Gross features. The bulk of this section consists of the middle cerebellar peduncle
(brachium pontis) and the superior cerebellar peduncle lateral to the fourth ventricle
cerebellum. In Fig. 6.9 the cerebellum is present. The fourth ventricle narrows as it
nears the cerebral aqueduct. The medullary pyramids are present at the anterior
surface. Note that the inferior olive is no longer present.
Brain stem level four: Pons at facial colliculus (Fig. 6.5)
6.3 Functional Localization in Brain Stem Coronal Sections… 181
Fig. 6.5 Brain stem - Pons at level of Facial Colliculus of cranial nerves VI and VII. Coronal
2. The nucleus of nerve VI innervates the lateral rectus muscle of the eye. The
rootlet leaves the anterior surface of the nucleus and has the longest intracere-
bral path of any nerve root. The fibers finally exit on the anterior surface of the
brain stem near the midline at the pontomedullary junction. The close proximity
of the nucleus of nerve VI to the rootlets of nerve VII demonstrates why any
involvement of the nucleus of nerve VI usually produces a concomitant altera-
tion in function of nerve VII. The nucleus of nerve VI and the internal genu of
the rootlets of nerve VII form the prominent facial colliculus on the floor of the
fourth ventricle.
Brain stem: Lower pons at level of facial nerve and facial colliculus (Fig. 6.5)
Cerebellar pathways (Fig. 6.5b). At this level the middle and inferior cerebellar
peduncles form the lateral walls of the ventricle as well as the bulk of the cerebellar
medullary center. The ventral spinocerebellar tract is seen lateral to the superior
cerebellar peduncle that it enters and then follows back into the cerebellum. The
superior cerebellar peduncle consists primarily of axons carrying impulses from the
dentate nucleus of the cerebellum to the red nucleus and the ventral lateral nucleus
in the thalamus. This tract is also called the dentatorubrothalamic tract. The tractus
uncinatus connects the deep cerebellar nuclei with the vestibular nuclei and reticular
formation bilaterally.
Sensory cranial nerve nuclei (Fig. 6.5b). Pain and temperature are conveyed from
the head. At pontine levels the descending nucleus of nerve V is small, while the
tract is large. The superior vestibular nucleus is seen at the lateral margin of the
ventricle with primary vestibular fibers present in its substance.
Auditory sensation at this level is related to the superior olive that is seen inferior
to the motor nucleus of nerve VII. The superior olive is one of the secondary nuclei
in the auditory pathway. The auditory fibers are seen accumulating inferior to the
superior olive and cutting through the medial lemniscus to form the lateral
lemniscus.
White matter (Fig. 6.5b). At this pontine level, some of the ascending tracts are
starting to move more laterally. The medial lemniscus will shift laterally and
approach the rubrospinal and spinothalamic tracts. Tactile discrimination and pro-
prioception from the limbs, thorax, pelvis, abdomen, and neck are conveyed by
fibers in the medial lemniscus, which is seen posterior to the corticospinal tract.
Pain and temperature from the head are conveyed by the secondary trigeminotha-
lamic tracts, which are found in the medial lemniscus and ascend to the nucleus
ventralis posteromedialis in the thalamus.
Pain and temperature from the extremities, thorax, abdomen, pelvis, and neck are
carried in the lateral spinothalamic tract, which is near the anterior surface of the
pons, close to the medial lemniscus.
The anterior spinothalamic tract that is mixed in with the lateral spinothalamic
tract carries light touch.
6.3 Functional Localization in Brain Stem Coronal Sections… 183
The gustatory fibers from the tongue are found in the solitary tract. The second-
ary fibers ascend bilaterally in the medial lemniscus. Fibers carrying visceral sensa-
tions also synapse in the solitary nucleus.
The raphe or the medial reticular nuclei are present in this level. The medial lemnis-
cus at this level contains secondary fibers from the dorsal columns and the spinotha-
lamic, trigeminothalamic, and solitary tracts. The medial longitudinal fasciculus
and tectospinal tracts are still present near the midline in the floor of the fourth
ventricle with the medial longitudinal fasciculus conspicuous under the floor and
the tectospinal tract below it.
Central zone (Fig. 6.5a, b). In the center of the pontine tegmentum, the main
efferent ascending tract of the reticular system, the central tegmental tract,
occupies the bulk of the reticular formation. Internal to the nucleus of VI is the
parapontine reticular nucleus that coordinates eye movements. Fibers descend
the opposite frontal eye fields, synapse here, and then connect via the MLF to the
nuclei of IV and III.
Basilar zone (Fig. 6.5b). The descending corticospinal and corticonuclear
pathways are nearly obscured by the fibers of the middle cerebellar peduncle and
the pontine gray.
Table 6.6 reviews the contents of the pontine tegmentum.
Brain stem level five: Upper pons at the motor and main sensory nuclei of nerve V
(Fig. 6.6).
Gross landmarks. The bulk of this section consists of the middle cerebellar
peduncle and cerebellar cortex. The fourth ventricle begins to narrow as it nears the
cerebral aqueduct.
Ventricular zone. In this level there are no motor cranial nerve nuclei on the floor
of the ventricle, with the nuclei in the ventricular floor being for visceral functions.
Motor cranial nerve nuclei (Fig. 6.6). The rootlet of CN V and motor nucleus of
nerve V is conspicuous bilaterally in the reticular formation, medial to the sensory
nucleus, and the entrance of the root of nerve V. Each of these nuclei provides
innervation to the ipsilateral muscles of mastication.
Fig. 6.6 Brain stem at pontine level of cranial nerve V. Coronal. (a) myelin stained (b) Labeled
(c) MRI
6.3 Functional Localization in Brain Stem Coronal Sections… 185
Sensory cranial nerve nuclei (Fig. 6.6). Tactile discrimination from the face is
carried by the trigeminal root into the main sensory nucleus of nerve V, seen lateral
to the intrapontine root of nerve V. The secondary fibers originate from this nucleus
and ascend crossed and uncrossed. The crossed fibers run adjacent to the medial
lemniscus (ventral trigeminothalamic), while the uncrossed fibers run in the dorsal
margin of the reticular formation (dorsal trigeminothalamic). Both fiber pathways
terminate in the ventral posterior medial nucleus of the thalamus.
Proprioception from most the muscles in the head is carried in by the mesence-
phalic root and ends in the mesencephalic nucleus of nerve V, located lateral to the
walls of the fourth ventricle in the upper pontine and midbrain levels. Note cranial
nerves V and VII in the MRI 11-8B. These neurons are the only primary cell bodies
(dorsal root ganglion equivalent) in the CNS. These axons synapse on the chief
nucleus of V. The jaw jerk is a monosynaptic stretch reflex. The receptor is the mes-
encephalic nucleus of nerve V and the effector is the motor nucleus of nerve V.
The superior olive is one of the nuclei in the auditory system. Auditory fibers are
seen running through the superior olive or inferior to it cutting through the medial
lemniscus and crossing the midline, forming the trapezoid body. The fibers are then
found lateral to the medial lemniscus and are known as the lateral lemniscus. The
pontine nuclei are conspicuous in the basilar portion of the pons.
White matter (Fig. 6.6). At this level the medial lemniscus has moved from the
midline to a more lateral position, and many of the ascending sensory systems are
now either in the medial lemniscus or adjacent to it.
Medial zone. The raphe nuclei of the reticular formation are evident in this level.
The medial longitudinal fasciculus is larger in this section between the motor nuclei of
cranial nerves III and VI because it contains many vestibular and cerebellar fibers nec-
essary for accurate eye movements. The tectospinal fibers always lie below the MLF.
Central zone. In the reticular formation, the central tegmental tract is conspicuous.
Basilar zone. The corticospinal tract is found in the pontine gray and white matter.
6.3.3 M
idbrain Blood Supply: Basila Arrteraynd Posterio
Crerebral Arteries
6.3.3.1 Gross Anatomy Inferior Colliculus
Gross landmarks. On the anterior surface of the midbrain, we find the principal
landmark of this level, the cerebral peduncles with the third cranial nerve exiting
from the medial surface of the cerebral peduncles in the interpeduncular fossa. On
the posterior surface of the midbrain, we find the corpora quadrigemina and the
superior and inferior colliculi. The fourth cranial nerve exits from the posterior sur-
face of the midbrain and the junction with the pons. In a coronal section through the
midbrain, one finds the red nucleus in the tegmentum of the midbrain (Fig. 6.7b).
Also in the inferior levels in the tegmentum just before the red nucleus, one finds the
crossing of the superior cerebellar peduncle.
186 6 Brain Stem Functional Localization
Fig. 6.7 (a) Brain stem at inferior collicular level. note inferior collicular nuclei, red nuclei, cere-
bral peduncles. MRI coronal (b) Inferior collicular level of Midbrain, labeled Coronal
Inferior colliculus (Fig. 6.7a, b). The gray matter of the inferior colliculus forms the
tectum at this level. The inferior colliculus is divided into three nuclei, a large cen-
tral nucleus, a thin dorsal nucleus the paracentral or cortical nucleus, and an external
nucleus. The central and cortical nucleus functions as a relay center for the cochlea.
The external nucleus functions for the acusticomotor reflexes through the tectospi-
nal pathway. The brachium of the inferior colliculus carries auditory information
onto the medial geniculate nucleus of the diencephalon. The tectospinal pathway
descends from this region and terminates on motor nuclei of the lower cranial nerves
and upper cervical ventral horn cells.
Ventricular zone (Fig. 6.7a, b). The periaqueductal gray is conspicuous in mid-
brain levels. Descending and ascending tracts associated with the visceral brain are
found here. In the midbrain, the lower half of the periaqueductal gray and some
other nuclei in the tegmentum are part of the midbrain limbic area. This zone is
important in our level of attentiveness. Bilateral lesions to the periaqueductal gray
and midbrain tegmentum usually produce comatose patients.
Motor cranial nerve nuclei (Fig. 6.7a). The nucleus of cranial nerve IV is seen
indenting the medial longitudinal fasciculus in lower regions of the midbrain. The
axons of this nucleus pass posteriorly (unique for a cranial nerve) and exit the brain
at the midbrain–pontine junction where the fibers then proceed anteriorly to reach
the superior oblique muscle through the superior orbital fissure.
Sensory cranial nerve nuclei (Fig. 6.7a). Proprioception is conveyed from the
muscles in the head and neck. The mesencephalic nucleus of nerve V is located at
the lateral margin of the periaqueductal gray. Remember these are the only primary
sensory neurons in the CNS; their axons join the medial lemniscus and ascend to the
ventral posterior medial nucleus in the thalamus. This nucleus controls the superior
oblique muscle of the eye.
Hypothalamus. The mammillary bodies and optic tract are present.
Lateral zone (Fig. 6.7a). At this level the medial lemniscus and the other major
ascending tracts are stretched over the lateral surface of the tegmentum of the mid-
brain. The spinothalamic and trigeminothalamic fibers are found lateral to the
medial lemniscus, while the auditory fibers are located above them. Thus, the fol-
lowing sensory modalities for the entire body are located here: tactile discrimina-
tion, proprioception, pain and temperature, and gustatory and visceral sensations.
Auditory fibers (Fig. 6.7a). The lateral lemniscus is seen superior to the medial
lemniscus. These secondary auditory fibers are now entering the inferior colliculus.
Many of these fibers synapse and then continue up into the medial geniculate as the
brachium of the inferior colliculus.
188 6 Brain Stem Functional Localization
Fig. 6.8 Superior colliculus level of midbrain. (a) Myelin stained, (b) Labeled, (c) MRI T1
6.7 Superior Colliculus Tectum 189
Medial zone (Fig. 6.7a). The raphe nuclei of the reticular formation are very con-
spicuous in these levels. The medial longitudinal fasciculus is prominent in the floor
of the ventricle as it nears cranial nerve III; the fibers located within it are important
in coordinating ocular movements.
Central zone (Fig. 6.7a). This zone in the lower tegmentum of the midbrain is
nearly filled with the crossing fibers of the superior cerebellar peduncle. Ultimately,
all these fibers decussate and continue up to the red nucleus where some fibers syn-
apse, but the majorities of these axons bypass the red nucleus and terminate on the
ventral lateral thalamic nuclei.
Basilar zone (Fig. 6.7a). The bulk of this region is taken up by the pontine gray
and descending fibers from the cerebrum to the pontine gray, the corticopontine
system. The corticospinal and corticobulbar fibers are also present here.
Brain stem level seven: Superior colliculus and cerebral peduncle (Fig. 6.8a, b)
Gross landmarks. On the anterior surface of the midbrain, we find the principal
landmark of this level, the cerebral peduncles with the third cranial nerve exiting
from the medial surface of the cerebral peduncles in the interpeduncular fossa. On
the posterior surface of the midbrain, we find the corpora quadrigemina and the
superior and inferior colliculi. The rootlets of the fourth cranial nerve are unique as
they exit from the posterior surface of the midbrain and the junction with the pons.
In a coronal section through the midbrain, one finds the red nucleus in the tegmen-
tum of the midbrain (Fig. 6.7b). Also in the inferior levels in the tegmentum just
before the red nucleus, one finds the crossing of the superior cerebellar peduncle.
Superior colliculus (Fig. 6.8). The superior colliculi form the rostral portion of the
midbrain tectum. The parenchyma of the superior colliculus is organized in layers.
There are four layers containing gray and white matter from inside out: stratum
zonale, stratum cinereum stratum opticum, and stratum lemnisci. The superficial
layers of the superior colliculus receive their input from the retina via the optic tract
and visual cortex with the contralateral upper quadrant medially and the contralat-
eral lower quadrants laterally. In contrast the deeper layers receive their input from
polysensory sources including the cerebellum, inferior colliculus, spinal cord, retic-
ular formation gracile, cuneate, trigeminal nuclei, and visual regions. A portion of
190 6 Brain Stem Functional Localization
the tectospinal pathway originates at this level and descends in the lower brain stem
to terminate on the lower cranial nerves and ventral horn cells of the spinal cord.
Tectopulvinar fibers originate from here and ascend bilaterally lateral to the audi-
tory fibers into the visual nucleus of the pulvinar, the inferior pulvinar nucleus, and
then are projected onto the extrastriate cortex. (Remember the tectospinal and tec-
tobulbar fibers terminate on the same motor nuclei as the corticonuclear and corti-
cospinal pathways). The zone of the tectum just above the superior colliculus, the
pretectal zone, is important in light reflexes.
Gross features. In this section the roof and floor are formed by the midbrain, while
the basilar portion is made up of the cerebral peduncles. The roof is the superior
colliculus, an important station in the visual pathway. The cerebral aqueduct forms
the narrow ventricular lumen. (Fig. 6.8b). The superior colliculus is a laminated
structure important in relating eye movements and body position. The tectospinal
tract originates from its deepest layer and provides connections onto certain cranial
and spinal neurons.
Proprioception is conveyed from the muscles in the head and neck by the mesence-
phalic nucleus of nerve V, located at the lateral margin of the periaqueductal gray in the
superior collicular levels as well as in the upper pontine and inferior collicular levels.
Cranial nerve III is visible in the floor of the cerebral aqueduct, adjacent to the
medial longitudinal fasciculus. This nerve supplies the medial, inferior, and supe-
rior rectus muscles and the inferior oblique and superior levator muscles of the
eyelid. The Edinger–Westphal nucleus of nerve III is also present; it provides pre-
ganglionic parasympathetic innervation to the constrictor muscle of the pupil via
the ciliary ganglion.
White matter (Fig. 6.8a). Medial lemniscus. At this level in close proximity to the
medial lemniscus includes most of the ascending sensory fibers (Table 6.7). This tract
is stretched out over the inferior and lateral surface of the tegmentum, with the fibers
6.8 Superior Colliculus Tegmentum 191
that mediate pain and temperature from the extremities, thorax, abdomen, and pelvis
located at its superior extent. The trigeminal fibers form its middle portion, and the
fibers that mediate tactile, proprioceptive, and visceral sensations are placed medially.
Lateral spinothalamic. Pain and temperature from the limbs, thorax, and pelvis are
found in this pathway.
Anterior spinothalamic. Light touch fibers from the limbs, abdomen, and neck
are seen near the lateral spinothalamic pathway.
Auditory pathway. The fibers from the inferior colliculus (called at this level the
brachium of the inferior colliculus) are seen at the inferior surface of the superior
colliculus. On the left side, they enter the medial geniculate nucleus of the meta-
thalamus at which point they reach their final subcortical center.
The superior cerebellar peduncle continues to cross in the tegmentum of the mid-
brain; just above this level, many of these fibers synapse in the red nucleus, while
others will continue to the ventral lateral nucleus in the thalamus.
Central zone (Fig. 6.8a). The central tegmental tract is conspicuous in the mid-
brain tegmentum in the reticular formation. The red nucleus is found in the medial
edge of the reticular formation. In the human, it consists of a small magnocellular
region and a large parvocellular region. Fibers from all cerebellar nuclei, but espe-
cially the dentate, synapse here.
Corticorubral fibers run bilaterally from the motor cortex synapse and also termi-
nate here in a somatotopic sequence. Fibers from the red nucleus terminate directly
or indirectly in the cerebellum and on many of the motor nuclei in the brain stem and
spinal cord, which also receive input from the corticospinal and corticonuclear path-
ways. The red nucleus has minimal if any projections in the human onto the thala-
mus, although it most likely influences the cerebellar input onto the thalamus.
The substantia nigra is also located in this level just behind the cerebral pedun-
cle. Its functions are discussed in the relationship between the basal ganglia and
movement (see Chap. 11).
Medial zone (Fig. 6.8a). The serotonergic raphe nuclei of the reticular formation are
present in this level. The medial longitudinal fasciculus in the floor of the cerebral
192 6 Brain Stem Functional Localization
aqueduct is conspicuous and connected across the midline. The oculomotor complex
indents the MLF and receives ascending fibers from cranial nerves VI and VIII through
the MLF. The tectospinal fibers at this level are primarily from the superior colliculus.
Basilar zone (Fig. 6.8a, b). Cerebral Peduncles. At this level, the frontopon-
tine fibers, which occupy the most medial part of the cerebral peduncles, enter
the pons. Figure 6.9a is a stained section of the midbrain through the cerebral
peduncles demonstrating the relationship between the peduncles and the cranial
nerve III. The corticospinal fibers and many of the corticobulbar fibers are still
in the peduncle. In Fig. 6.9b, a coronal section through the brain, the relation-
ship of the cerebral peduncle to the medial temporal lobe demonstrates that the
cerebral peduncles are adjacent to the medial temporal lobe. This may be sig-
nificant if herniation of the temporal lobe produces compression of the cerebral
peduncle and cranial nerve III with the accompanying cranial nerve and upper
motor neuron signs. Table 6.7 lists the significant structures in the tegmental
zones of the midbrain.
Fig. 6.9 Taste buds. (a) Circumvallate papillae of a rhesus monkey showing numerous taste buds.
(b) Taste buds, arrow identifies gustatory pore into which the neuroepithelial cilia project. H&E
stain. ×100
6.9 Functional Centers in the Brain Stem 193
Now that the anatomical features of the brain stem have been discussed, it is appro-
priate to identify some important functional centers located in the brain stem and
diencephalon. During this discussion, it will become evident that the cranial nerves
are the pivotal point for many of these activities.
The central core of the medulla, pons, and midbrain tegmentum consists of the
reticular formation. Upon microscopic examination, this region is seen to consist of
groupings of neurons separated by a meshwork of myelinated fibers. With a Golgi
neuronal stain, Golgi Type I neurons, the cells with long axons are shown with their
dendrites extending transversely and the axons bifurcating into ascending and
descending branches forming a network/reticulum which run throughout the sys-
tem. Each neuron receives input from at least 1000 neurons, and each neuron con-
nects to as many as 10,000 neurons in the reticular formation. The reticular formation
of the brain stem blends inferiorly into lamina VII of the cord, and superiorly it is
continuous with the hypothalamus and dorsal thalamus of the diencephalon.
Many nuclei have been identified in the reticular formation. Functionally, the
nuclei can be divided into cerebellar and non-cerebellar nuclei (Table 6.6).
Cerebellar nuclei of the reticular formation include primarily the lateral and
paramedian nuclei of the medulla and the tegmental nucleus of the pons.
Non-cerebellar portion nuclei are divided anatomically into three columns: the
raphe, central, and lateral groupings. Most of the nuclei in the reticular formation
consist of large cells with ascending and descending axons. Functionally, the reticu-
lar formation in the medulla is especially important since the descending reticulo-
spinal fibers and much of the ascending reticular system originate there.
Descending reticulospinal system. The nucleus reticularis gigantocellularis is
found at the rostral medullary levels, dorsal and medial to the inferior olive. This
nucleus gives origin to much of the lateral reticulospinal tract, which is primarily an
ipsilateral tract, running in the lateral funiculus of the spinal cord in all levels and
terminating on internuncial neurons.
The axons from the nucleus reticularis pontis oralis and caudalis form much of
the medial reticulospinal tract, which runs in the anterior funiculus in all levels and
terminates on internuncial neurons.
The lateral reticular nucleus is located in the lateral margin of the reticular for-
mation dorsal to the inferior olive, while the ventral reticular nucleus is found in the
caudal end of the medulla, dorsal to the inferior olive. These two nuclei, in conjunc-
tion with the nuclei in the pons and midbrain, form much of the ascending reticular
fibers in the central tegmental tract distributing to neurons in the thalamus (intrala-
minar and reticular), hypothalamus, and corpus striatum. The paramedian reticular
194 6 Brain Stem Functional Localization
nucleus is found near the midline at mid-olivary levels, dorsal to the inferior olive,
and provides direct input into the anterior lobe of the cerebellar vermis.
Input to reticular formation. The reticular formation receives information via
the ascending spinal tracts (spinotectal, spinoreticular, spinothalamic, and spinocer-
ebellar), from the brain stem itself (olivoreticular, cerebelloreticular, and vestibulo-
spinal), from the cerebral hemispheres (corticoreticular), and from the basal ganglia
and hypothalamus. The cranial nerves are another important source, especially
nerves I, II, V, VII, VIII, and X, for sensory information that appears to project most
heavily onto the central nuclei. The hypothalamus and striatum also project to the
reticular system via the dorsal longitudinal fasciculus on the floor of the cerebral
aqueduct and fourth ventricle and the more diffuse descending fiber systems in the
core of the reticular formation.
Output. The medial lemniscus is a specific point-to-point relay system with few
synapses (a closed system), while the fiber tracts of the reticular system are a mul-
tisynaptic nonspecific system (an open system) (Table 6.7).
The central tegmental tract is the principal fiber tract of the reticular formation.
Its descending portions are in the medial tegmentum, and its ascending portions are
located in the lateral tegmentum. The ascending system projects to the thalamic
intralaminar and reticular nuclei, hypothalamus, basal ganglia, substantia nigra, and
red nucleus. The reticular system is functionally important in controlling our “pos-
ture” by its reflex relationship to the position of our body in space and in controlling
our internal milieu by maintaining the stability of our viscera. The descending sys-
tem synapses via the reticulospinal tract onto interneurons that mediate their effects
through alpha and gamma motor neurons in the spinal cord and via autonomic path-
ways and cranial nerves onto visceral neurons.
Ascending reticular system. This fiber system is the structural and functional
substrate for maintaining consciousness. It also receives proprioceptive, tactile,
thermal, visual, auditory, and nociceptive information via the spinal and cranial.
The sensory information ascends via the central tegmental tract into the limbic mid-
brain area from which information can be more directly passed into the thalamus
and hypothalamus. This midbrain to diencephalons to telencephalon circuit seems
especially important in determining our level of consciousness.
6.9.1.2 N
eurochemically Defined Nuclei in the Reticular Formation
Affecting Consciousness
1. Cholinergic nuclei. Located in the dorsal tegmentum of the pons and midbrain,
in the mesopontine nuclei, and in the basal forebrain region and project diffusely
to the cerebral cortex through the thalamus and have a modulating influence on
cerebral cortical activity and wakefulness.
2. Monoamine nuclei. In the reticular formation, we find cells containing norepi-
nephrine and serotonin.
(a) The norepinephrine-containing cells are found in the locus ceruleus (blue
staining) in the upper pons and midbrain, and they project widely upon
nuclei in the spinal cord, brain stem, thalamus, hypothalamus, and corpus
striatum which are important for maintaining attention and wakefulness.
(b) Serotonergic nuclei. These nuclei are found in the raphe of the medial teg-
mental zone in the medulla, pons, and midbrain. The nuclei in the pons and
medulla project onto the spinal cord and brain stem, while the nuclei in the
upper pons and midbrain project onto to the thalamus, hypothalamus, corpus
striatum, and cerebral cortex. The serotonergic system facilitates sleep.
An area outside of the reticular formation, the histamine-containing area of the pos-
terior hypothalamus, is also important in maintaining wakefulness.
Respiration is under the control of neurons in the respiratory center in the upper
medulla and pons. Sensory fibers from the lungs ascend via cranial nerve X and
enter the solitary tract and proceed onto the neurons in the reticular formation in
the medulla and pons. Specific regions in the medulla control either inspiration or
expiration. The medullary respiratory center itself is responsive to the carbon diox-
ide content in the blood. Increased carbon dioxide produces increased respiration,
and decreased carbon dioxide produces decreased respiration. In the pons the pneu-
motaxic centers are related to the frequency of the respiratory response. These
centers play onto the medullary respiratory center to determine the respiratory out-
put. The axons from cells in the medullary reticular center descend to the appropri-
ate spinal cord levels to innervate the diaphragm and the intercostal and associated
muscles of respiration. The vagus nerve itself provides preganglionic innervation
of the trachea, bronchi, and lungs. The respiratory response is also modified by
cortical and hypothalamic control; i.e., emotionally stimulated individuals breathe
more rapidly because of the hypothalamic influence on the brain stem and spinal
cord. The actual respiration occurs with the intercostal muscles, the accessory mus-
cles, and the lungs expanding and contracting in concert with associated vascular
changes (autonomic nervous system).
196 6 Brain Stem Functional Localization
The carotid body (innervated by sensory fibers of cranial nerve IX) is found distal
to the bifurcation of the common carotid artery, and the aortic body, innervated by
the sensory fibers of nerve X, is found near the origin of the subclavian arteries.
These axons carry information on blood pressure into the solitary tract and then into
the medullary respiratory centers. These sites are sensitive to oxygen–carbon diox-
ide pressure; when oxygen is reduced, ventilation increases; when oxygen increases,
ventilation decreases. Neural control over the tone of the arterioles is exercised
through vasoconstrictor fibers (and sometimes vasodilator fibers). A vasomotor cen-
ter in the medulla extends from the midpontine to the upper medullary levels. In the
lateral reticular formation of the medulla, stimulation elicits an increase in vasocon-
striction and an increase in heart rate—pressor center. In the lower medulla, stimu-
lation of the depressor center produces a decrease in vasoconstriction and a decrease
in heart rate.
The carotid body (cranial nerve IX) detects changes in the composition of
arterial blood flowing through it, mainly the partial pressure of oxygen, but also
of carbon dioxide. Furthermore, it is also sensitive to changes in pH and
temperatures.
The aortic body (cranial nerve X) contains specialized pressure receptors stimu-
lated by an increase in the size of these blood vessels and thus records blood pres-
sure. This information runs via nerve X to the medulla and depresses activity. Most
sensory nerves, cranial and spinal, contain some nerve fibers, which, when stimu-
lated, cause a rise in arterial pressure by exciting the pressor region and inhibiting
the depressor centers. Higher centers also influence respiratory and vascular centers
in the medulla and alter blood flow, depending on the psychic state; i.e., mental
activity decreases peripheral blood (constricts vessels), while emotional states can
produce increased blood flow, blocking vasodilation.
6.9.4 Deglutition
4. At the same time, the tracheal opening is closed by the epiglottis and glottis, as
the larynx, trachea, and pharynx move up. This movement is noted externally as
the bobbing of the thyroid eminence (Adam’s apple).
5. Finally the inferior constrictor muscle contracts, pushing the bolus into the
esophagus where peristaltic waves and gravity carry it through the esophagus.
Cranial nerves V, IX, X, and XII perform the motor part of the activity, while
nerves V, VII, IX, and X form the sensory function.
6.9.5 Vomiting
Vomiting is produced by many stimuli and is usually a reflex activity. The vomitus
is composed of the gastric contents:
1. It is caused commonly by irritation of the oropharynx, gastrointestinal mucosa,
and genitourinary and semicircular canals. Stimulation of the vestibular system
including the semicircular canals and the nerve itself may also produce
vomiting.
2. The afferent nerves travel via the vagus and glossopharyngeal tracts into the soli-
tary tract. After synapsing on the dorsal motor nucleus of cranial nerve X, the
information is conveyed via the vagus nerve to the stomach. Impulses are also
passed down to the cervical and thoracic level onto the ventral horn cells that
control the simultaneous contraction of the intercostal, diaphragmatic, and
abdominal musculature.
3. Nausea and excessive salivation precede the deep inspiration associated with
retching. The glottis is closed and the nasal passages are sealed off. The
descent of the diaphragm and the contraction of the abdominal muscles exert
the pressure that causes the stomach to contract in a direction contrary to nor-
mal peristalsis and forces vomitus through the relaxed cardia of the stomach
and into the esophagus.
The area postrema is found in the caudal end of the fourth ventricle above the obex
of the medulla. It is part of the circumventricular organs – which include the area
postrema, vascular organ of the lamina terminalis, subfornical organ, subcommis-
sural organ,posterior piruitarymedian eminence and pineal gland. These areas are
very vascular and contains many venous sinuses and the blood–brain barrier is lack-
ing in these regions. The vagal, glossopharyngeal, and hypoglossal nuclei are
strongly interconnected with the area postrema, and due to this cranial nerve input
this region is very sensitive to changes in pressure or to drugs whose passage into
this area is not inhibited by a blood–brain barrier.
198 6 Brain Stem Functional Localization
6.9.7 Coughing
Irritation of the lining of the larynx or trachea produces coughing. The stimulus is
picked up by free nerve endings associated with the internal laryngeal branch (pro-
tector of the larynx) of the superior laryngeal nerve of the vagus (cranial nerve X)
which carries it up into the solitary tract, following the same pathway as in vomit-
ing, except that the muscles contract alternately rather than simultaneously with the
intercostal muscle contracting suddenly. The receptors for taste are the taste buds or
gustatory cells located on the tongue, palate, palatoglossal arch, posterior wall of
the pharynx, and posterior wall of the larynx.
6.9.8 Taste
The taste cells just as the receptive neurons in the olfactory system are in a very
hostile environment, and they are constantly being replaced by new cells, and yet
their functions continue unabated.
Lingual taste buds. The tongue is a very mobile muscular organ that is located
in the oral a cavity and pharynx. It is divided into a root, body, apex, dorsal surface,
and inferior surface. The body and apex of the tongue are very mobile. The tongue
has at least three main functions: (1) forming words, (2) moving food from the oral
cavity > pharynx by passing the bolus along the palate, and (3) taste.
Lingual papillae. The mucous membrane that covers the dorsal surface of the
body and apex of the tongue is rough due to the presence of lingual papillae which
are found in four configurations—circumvallate, foliate, fungiform, and filiform.
1. Circumvallate (Fig. 6.9) are large and flat and lie in the terminal sulcus of the
tongue (marks the separation between the oral and pharyngeal parts of the
tongue) and consist of a wall with a deep central depression, the walls containing
taste buds. There are 8–12 circumvallate papillae located on the posterior one-
third of the tongue, and they are primarily innervated by CN IX.
2. Foliate papillae are small lateral folds of the lingual mucosa and contain taste buds.
3. Fungiform papillae are mushroom shaped and pink in color with taste buds
located among the processes.
4. Filiform papillae are long and thin and are the most numerous processes on
the tongue. They contain sensory nerve endings from cranial nerve V3 (ant
two-thirds dorsum and apex of tongue) and CN IX (post one-third of the
tongue); they do not contain taste buds but are very important in recording
general sensations on the tongue.
5. Taste buds sensitive to “sweet” are located at the the tip of the tongue,the “salt
sensitive taste buds” are found at the sides of the front of the tongue,” sour sensi-
tive taste buds” are located on the sides of the tongue, “bitter sensitive taste
buds” are found at the pharyngeal end, and “umami sensitive buds” are found at
the tip and sides. A few taste buds are also found on the oral surface of the soft
6.9 Functional Centers in the Brain Stem 199
palate, posterior wall of the oral pharynx, and the epiglottis. The lung may also
contain taste buds that identify only salt and sweet. All parts of the tongue
respond in some degree to the five kinds of taste.
6. Subjective taste. Aristotle classically identified four groups of subjective taste
qualities each localized to a zone of the tongue: salty, sweet, sour, and bitter.
Ikeda in 1909 identified glutamic acid as another subjective taste called umami
or savory.
7 . Transduction of the taste response. Salty and sour work with ion channels.
Sodium chloride is involved in a Na+ channel in the taste receptor cells with a
resul-tant depolarization.
Acids (sour) produce an increase in H+ that affects the Na+ channel directly or
blocks K+ channel.
Sweet compounds bind to G-protein receptor molecules that decrease K+
elsewhere in the cell.
Bitter compounds are especially protective as they make the individual aware of
toxic substances and use both ligand-gated channels and G-protein couple receptors.
That permits them to be activated by many compounds.
Savory/umami takes its names from Japanese; umami is a pleasant savory
taste imparted by glutamic acid and ribonucleotides including inosinate and
guanylate. They occur naturally in many foods including meat, fish (sardines),
vegetables (mushrooms), and dairy products. Its taste was named umami, a
word derived from the Japanese adjective umai (delicious). “When glutamate
becomes l-glutamate, that’s when things get delicious.” Umami has taken root
as a scientific term internationally. As the taste of umami itself is subtle and
blends well with other tastes to expand and round out flavors, most people don’t
recognize umami when they encounter it, but it plays an important role making
food taste delicious.
Scoville scale. Is a measurement of the hotness of the capsaicin (active compo-
nent of chili peppers) in chili powder or anything derived from chili pepper or hot
sauce and warns one of how “hot” items can be. This scale is named after Wilbur
Scoville who developed it in 1912.
The hottest heat units are from capsaicin itself at 16,000,000, to police pepper
spray at 5,300,000, pimento at 100–500, and sweet bell pepper at 0. A complete list
of the heat from these items is found at (http://www.chilliworld.com/FactFile/
Scoville_Scale.asp).
8. Chorda tympani and taste. The chorda tympani of cranial nerve VII is more
sensitive to sweet or salty, while glossopharyngeal fibers are more sensitive
to sour or bitter. The gustatory nerve endings usually end in many taste buds
with there being one predominate response in each nerve that matches the
function of that region (e.g., sweet from the apex and bitter from the pharyngeal
border).
9. Second-order neurons. The information from the taste buds is brought cen-
trally via cranial nerves VII, IX, and X > nucleus of the solitary tract. This sec-
ond-order neurons also participate in reflexes including swallowing or coughing.
200 6 Brain Stem Functional Localization
The axons of the second-order neurons ascend uncrossed in the central tegmen-
tal tract to the medial part of the ventral posterior medial nucleus of the thala-
mus that then projects onto the gustatory cortex in the insula and parietal
operculum.
Gustatory information projects from VPM onto orbital cortex where there
is an overlap of olfactory, gustatory, and hypothalamic sensations that pro-
duce a strong response to many gustatory stimuli. Gustatory information
also reaches the parabrachial nucleus in the pontine reticular formation and
is then distributed with nociceptive and visceral information onto hypothala-
mus, amygdale, and septum.
1 0. Cortical neurons. As one ascends in the gustatory system, the neurons are
more sensitive to particular chemical sensations. Cells in the brain stem and
thalamus respond to more than one taste. Cells that are analyzed in the cortical
regions show a selectivity that is not seen subcortical. Taste plays a critical role
in determining what an infant eats. In adult humans, this is not necessarily the
case as we are affected by environmental pressure that produces bizarre eating
habits that may lead to extremes such as obesity or anorexia.
6.10 Localiozation
of Dysfunction in the Cranial Nerves
Associated with the Eye (Table 6.8)
At the level of the brain stem, such examples of close correlation occur frequently.
Thus, the combined progressive involvement of the ipsilateral cranial nerve VIII
(auditory and vestibular), nerve VII (facial), and nerve V (trigeminal), manifested
by deafness, tinnitus (a buzzing or ringing sound in the ear), dizziness, peripheral
facial paralysis, and unilateral facial numbness, not only indicates the location of
the pathology (the cerebellar pontine angle) but also suggests the actual nature of
the pathology: vestibular schwannoma (acoustic neuroma), tumor arising from
Schwann cells of the sheath of nerve VIII. While other pathological lesions may
occur at this site, they are much less common.
Guidelines for Localizing Disease in the Brain Stem
1. Mental status is not directly involved (except that lesions involving the tegmen-
tum of the upper brain stem—reticular formation, etc.—may alter level of
consciousness).
2. No muscle atrophy is presented, except that relevant to local involvement of
cranial nerves.
3. Limb weakness if present involves central control and spasticity.
4. Deep tendon reflexes are increased in a bilateral or unilateral manner. A unilat-
eral or bilateral sign of Babinski maybe present.
6.11 Localization of Disease Processes in the Brain Stem 201
Table 6.8 Dysfunction in the eye due to lesions in the brain stem
Dysfunction in eye movements Location of clinical deficits
Role of MLF Moves the eyes in conjugate coordinated
manner as though yoked together
Ascending fibers cross into MLF and ascend Ipsilateral eye will fully adduct but the left
to III in midbrain eye will fail to adduct with med rectus
OK for convergence
Descending fibers-to VIII and reticular Useful in comatose patient to show doll’s
formation for testing functions at pontine level eye phenomena sign of MLF and VIII
Lateral Gaze Center in the Pons Section of rootlet of VI produces lateral
Lateral rectus on one sides move with medial rectus paralysis of gaze
rectus on other side coordination through
ascending MLF
Disturbance of conjugate Gaze-eye move Damage to pretectal area, the Edinger–
together Westphal nucleus in nucleus of CN III in
midbrain
Convergence focusing from far to near Damage to the nucleus of Perla in midline
of CN III nucleus in midbrain
Cranial nerve dysfunction Compression—herniation of temporal lobe
Third cranial nerve to pupillary constrictor onto nerve III with initial sign paralysis of
(parasympathetic), inferior oblique and pupillary constrictor leads to fixed dilated
superior, inferior and medial rectus “blown pupil” as constrictor fibers are most
and levator palpebrae superioris. peripheral fibers
Sixth cranial nerve to ipsilateral, Small paramedian infarction in tegmentum
lateral rectus muscle of pons (facial colliculus) produces—(1)
ipsilateral facial paralysis and (2) lateral
rectus palsy
Pupillary dysfunction, CN III Compression of CN III—pupillary dilation
results in fixed dilated pupil (blown pupil)
6.11.1 E
xercise to Identify the Tracts and Nuclei in the Brain
Stem (Figs. 6.10–6.14)
Fig. 6.12 Pons at level of root of Vestibular Nerve of Cranial Nerve VIII
Fig. 6.13 Pons at level of root of cranial nerves VI and VII, with trapezoid body of the auditory
system clearly demonstrated
204 6 Brain Stem Functional Localization
Fig. 6.14 Midbrain, Inferior Collicular Level. Tectum - the the auditory fibers are seen entering
the inferior collicular nuclei. Tegmentum - the decussation of the superior cerebellar peduncle, the
MLF and medial lemniscus are myelinated. Basis. The corticospinal tract is seen to begin myelina-
ting in the lateral margin of the cerebral peduncle
Bibliography
Ropper AH, Samuels MA, Klein JP. Adams and Victors principles of neurology. 10th ed. New York:
McGraw Hill; 2015.
Marcus EM, Jacobson S, Sabin TD. Integrated neuroscience. Oxford: Oxford University Press; 2014.
Riley HA. Brain stem and spinal cord. New York: Hafner; 1960.
Sinclair D. Touch in primates. Ann Rev Neurosci. 1982;5:155–94.
Chapter 7
The Cranial Nerves
Abstract There are 12 pairs of cranial nerves, and they originate from the brain
and upper spinal cord and innervate the special sense organs in the head (eye, ear,
nose, and taste buds), the skin over the face and neck, and muscles that permit us to
speak, eat, turn our head, and produce facial expressions. These cranial nerves also
provide parasympathetic innervation to the eye (III) and glands in the head and neck
(VII, IX and X) and the X cranial nerve, the vagus innervates the skeletal muscles
in the larynx that produce speech, and also innervate the organs of the cardiovascu-
lar system, pulmonary system, GI system, and urogenital systems.
The cranial nerves are numbered in sequence from superior to inferior based on the
location of their nerve rootlets within the three cranial fossa of the skull—anterior,
middle, or posterior cranial fossa (Fig. 7.1):
1. Anterior cranial fossa: CN I and II. Cranial nerve I is the most rostral nerve and
hence it’s listed as number I. It originates in the nasal mucosa, and it is found on the
base of the frontal lobe and enters the anterior cranial fossa through foramen in the
ethmoid bone, terminating in the olfactory bulb at the base of the frontal lobe.
Cranial nerve II is actually a pathway in the central nervous system, originates
in the retina of the eye, passes into the brain through the optic canal in the lesser
wing of the sphenoid, and terminates in the diencephalon.
Cranial Nerve 0, the terminal nerve, should be discussed in association with
the cranial nerves. and has been considered by some authors as an additional
cranial nerve. It probably originates from autonomic ganglia, is found medial to
the olfactory nerves, leaves the cranial vault through the cribiform plate, and
terminates in the nasal mucosa medial to the olfactory nerve, The terminal nerves
are unmyelinated and are involved in neuromodulation.
Fig. 7.1 Location of cranial nerve rootlets in the foramen and fissures in the cranial cavity with
accompanying major blood vessels identified
2. Middle cranial fossa: CN III, IV, V, and VI. CN III and IV leave the midbrain,
while VI leaves the pons; passes through the medial most portion of the middle
cranial fossa, close to the internal carotid artery; enters the cavernous sinus; exits
the cranial cavity via the superior orbital fissure with the ophthalmic branch of
the trigeminal, V1; and then terminates on muscles in the orbit.
3. Posterior cranial fossa: CN VIII–XII exit the medulla, with VII and VII exiting
through the internal acoustic meatus/internal acoustic canal of the petrous portion
of the temporal bone high in the posterior fossa. Just below the internal acoustic
meatus, one finds the jugular foramen with IX, X, and XI found in the medial part
of the jugular foramen, and finally XII is the most inferior root exiting through the
hypoglossal foramen in the occipital bone just above the foramen magnum.
7.2 Functional Organization of Cranial Nerves 207
In the spinal cord, the neurons are arranged in continuous columns of cells, each of
which is connected to a structure with a specific function; this grouping of neurons
with similar anatomic and physiologic functions is called a nerve component. In the
spinal cord, the neurons innervate general structures such as the skin, skeletal mus-
cles, blood vessels, and viscera. In the brain stem, the cranial nerves innervate not
only general structures, but they innervate the special sense organs, the eye, ear,
nose, or taste buds.
The cranial nerves that innervate these structures are organized in columns in the
tegmentum from the medulla through the midbrain with their cell bodies in either
the floor of the fourth ventricle or in the reticular formation that forms the core of
the brain stem (Table 7.1).
Other useful facts on the cranial nerves:
Cranial nerve I originates from the olfactory mucosa and terminates in the
olfactory bulbs on the base of the frontal lobe.
Cranial II nerve is actually a pathway in the CNS, and it contains the supporting
cells found in the CNS—oligodendrocytes and astrocytes. The optic nerve
o riginates in the retina, and it exits the eye and runs on the base of the diencephalon
on its way to the LGN of the diencephalon. All the other cranial nerves we find
outside the brain have the supporting elements of the peripheral nerve system—
Schwann cells and fibroblasts.
Cranial nerves III, IV, and VI are wired together to provide conjugate movement
of the eyes.
Cranial nerves III and IV originate in the midbrain; V, VI, and VII originate in the
tegmentum of the pons, while VIII–XII are within the medulla.
The trigeminal nerve (V) innervates the skin on the face and in the oral and nasal
cavities, the teeth, sinuses in the cranial bones, muscles of mastication, and much of
the dura.
The facial nerve (VII) controls the muscles of facial expression, taste buds on the
anterior two-thirds of the tongue, and many glands in the head and neck. General
sensation from the tongue for the anterior two-thirds is from the lingual nerve of the
trigeminal while to the posterior one-third of the tongue is from IX.
The glossopharyngeal nerve (IX) innervates the taste buds in the posterior one-
third of the tongue and initiates swallowing by controlling the stylopharyngeus
muscle.
The vagus X is the longest cranial nerve and controls all the types of muscle in
the body: skeletal muscle in the larynx and pharynx, smooth muscle in the viscera
of the thorax and abdomen, and cardiac muscle. It provides sensory innervation
from these same regions including the larynx and pharynx and viscera, and it also
innervates taste buds in the pharynx and larynx.
A portion of cranial nerve XI is found in the upper cervical levels innervating the
trapeziums and sternomastoid muscle.
Hints: When you study the cranial nerves, first learn the functions of the follow-
ing “easy” cranial nerves:
Special sensory: I (smell), II (vision), and VIII hearing and balance
Eye movements: III, IV, and VI (LR6SO4)
Pure motor functions: XI (shrug shoulders and turn neck) and XII (tongue
movements)
Then learn the “difficult ones” = V, VII, IX, and X
Organization of the cranial nerve nuclei. Figure 7.2 demonstrates the columnar
organization of the cranial nerve nuclei in the tegmentum of the medulla under the
fourth ventricle in a human embryo. From the midline the motor nuclei are medial
to the sulcus limitans, while the sensory nuclei are lateral to the sulcus limitans. (The
sulcus limitans divides the embryonic spinal cord and brain stem into the basilar/
motor plate and the lateral alar/sensory plate.) As one moves from the midline sulcus
into the basal/motor plates, first comes the medial somatic motor (CN XII, VI, IV,
III), then the special visceral (VII, V), and last the general visceral efferent (IX, X,
IX) which abuts on the sulcus limitans and then onto the sensory/alar plate to the
general visceral sensory (X, IX), then the general somatic afferent (CN V), and
finally the special somatic afferent (CN VIII) (After Ranson and Clark 1959).
Columnar organization in the adult brain stem. Figure 7.3 demonstrates:
1. The laterally placed sensory nuclei are separated from the medially placed motor
nuclei by the sulcus limitans.
7.2 Functional Organization of Cranial Nerves 209
Fig. 7.2 Diagram of the cranial nerve columns in the medulla oblongata in a human embryo
(Modified from Ranson and Clark, The Anatomy of the Nervous System, W.B. Saunders, 1959)
2. The sensory nuclei columns are organized from lateral to medial into special,
somatic, and visceral.
3. The motor nuclei columns are organized from lateral to medial into visceral,
branchial, and somatic.
4. This columnar organization also explains why medial lesions in the brain stem
affect motor functions while sensory functions are affected by more lateral lesions.
Origins of cranial nerves and associated muscles:
(A) Pharyngeal arches: In the development of the mammalian brain, there are six
branchial arches with a core of mesoderm lined on the outside with ectoderm
and inside by endoderm which begin on day 22 and form in a craniocaudal
sequence.
(a) Cranial nerve to each pharyngeal arch:
Arch 1 (Mandibular)-by Trigeminal Nerve (V) to maleus and incus, (max-
illary and mandibular swelling). To: Muscles of Mastication, mylohy-
oid, ant belly of digastric, tensor tympani and tensor veli palatini
Arch 2 (Hyoid)- by Facial Nerve (VII) to—stapes, styloid process, lesser
horn of hyoid and upper part of body to hyoid. To: muscles of facial
expression, stapedius, stylohyoid and post belly of digastric.
210 7 The Cranial Nerves
Fig. 7.3 Columnar organization of the cranial nerve nuclei in the brain stem. Sensory nuclei on
the left half and motor nuclei on the right half. The sensory nuclei organized functionally from
lateral to medial—special, somatic, and visceral. Then separation by sulcus limitans. The motor
nuclei organized functionally from lateral to medial—somatic, branchial, and visceral
(c) Paraxial mesenchyme condenses near optic cup for recti muscles inner-
vated by mm of III, IV, and VI.
(d) Placodes, origin of special sensory nerves.
Ectodermal condensations forming olfactory (I), optic (II), and vestibulo-
cochlear (VIII).
7.3.1 C
ranial Nerve I, Olfactory (Fig. 7.4),
Special Sensory/Special Visceral Afferent
Originates in the olfactory mucosa in upper ends of nasal cavity, enters the anterior
cranial fossa via 20 foramina in cruciform plate of the ethmoid, and is found at the
base of the frontal lobe in the anterior cranial fossa (Table 7.2).
Clinical Disorders: Defects in Smell – Anosmia
The most frequent causes of unilateral or bilateral anosmia are:
1. Disease of nasal mucosa producing swelling and preventing olfactory stimuli
from reaching the olfactory receptors.
2. Head trauma—resulting in shear effects tearing the filaments of olfactory recep-
tor cells passing through the cribriform plate.
3. A less common cause of unilateral anosmia is an olfactory groove meningioma.
Table 7.2 (continued)
Cranial nerve Location of cell bodies Function
X Vagus Primary superior–inferior Visceral sensations from the
ganglion; dorsal motor pharynx, larynx, aortic body, and
nucleus—preganglionic thorax and abdomen Gustatory
(parasympathetic innervation). sensation from taste buds in the
Nucleus ambiguous in the epiglottis and pharynx. Skeletal
medulla muscles in pharynx and larynx.
Smooth muscles in the heart,
blood vessels, trachea, bronchi,
esophagus, stomach, and
intestine to lower colon
XI Spinal accessory Cranial portion ambiguous Innervation of the sternomastoid
nucleus in the medulla and and trapezius muscle and mm of
spinal portion at levels: C2, the pharynx and larynx, except
C3, and C4 cricothyroids
XII Hypoglossal Hypoglossal nucleus in the Innervation of intrinsic and
medulla extrinsic muscles of the tongue
except palatoglossal MM
7.3.2 C
ranial Nerve II, Optic (Fig. 7.5), Special Somatic
Sensory
The million or so axons which form the optic nerve are enwrapped in myelin formed
by oligodendrocytes and protected by astrocytes, and consequently this nerve is
really a pathway in the central nervous system with all its inherent strength and
weaknesses. The axons in the optic tract originate from third-order ganglion cells in
the retina and enter cranial vault via optic foramen in the sphenoid bone where it is
found lateral to the pituitary, and some fibers in the optic chiasm enter the overlying
suprachiasmatic nucleus (Fig. 9.2). The majority of the optic fibers terminate either
in the LGN of the thalamus forming the geniculocalcarine pathway or a significant
portion of the axons in the optic tract bypass the LGN and join the brachium of the
superior colliculus to heavily innervate the tectum of the superior colliculus of the
midbrain forming the tectopulvinar pathway. Some of the optic fibers also terminate
in the pretectum of the midbrain (Table 7.3).
Some clinical disorders of the optic nerve:
A complete or partial unilateral loss of vision is produced by retinal or optic nerve
disease. Partial lesions produce a scotoma “a hole in the visual field.”
1. Retinal disease.
Vascular:
–– Transient: carotid occlusive disease—central retinal artery thrombosis; sud-
den and persistent—central venous thrombosis
–– Degeneration—retinitis pigmentosa
214 7 The Cranial Nerves
7.3.3 C
ranial Nerve III, Oculomotor (Fig. 7.6), Pure Motor
(Somatic and Parasympathetic, Only III)
Eye movements—CN III, IV, and VI work together to move the eyes that are
controlled from frontal eye fields via the corticomesencephalic pathway.
1. Originates from nucleus of CN III in the tegmentum of superior colliculus of the
midbrain; fibers run in middle cranial fossa and enter orbit via superior orbital
fissure.
2. General somatic efferent to levator palpebrae superioris, medial rectus, inferior
rectus, superior rectus, and inferior oblique.
3. Parasympathetic—light reflex. The general visceral efferent fibers in the third
cranial nerve innervate the pupil and are consensual. In the light the constrictor
of the pupil constricts (myosis). The sensory information for this reflex is carried
in fibers of the optic nerve which bypasses the LGN, enters the peduncle of the
superior colliculus, and terminates in the Edinger–Westphal nucleus. From this
nucleus there is bilateral preganglionic innervation to the ciliary ganglia via
fibers with the third cranial nerve into the orbit and via the short ciliary nerve
provides, postganglionic parasympathetic innervation to the ciliary muscles and
constrictor of pupil.
4. Sympathetic—dark reflex. In the dark the sphincter of the iris dilates (mydria-
sis). This information is carried in by fibers of the optic tract which terminate in
the hypothalamus, and these fibers then descend bilaterally in the tegmentum on
the floor of the fourth ventricle to spinal cord levels T1–T3. In the spinal cord,
they terminate on preganglionic cells whose axons leave the spinal cord, ascend
to terminate in the superior cervical ganglion where postganglionic fibers run via
the long ciliary nerve to reach the dilator of the iris.
Clinical Disorders of CN III
1. Complete paralysis of nerve III produces ptosis of the lid, paralysis of the medial
and upward gaze, weakness in the downward gaze, and dilation of the pupil. The
eyeball deviates laterally and slightly downward: the dilated pupil does not react
to light or accommodation.
Paralysis of the intrinsic muscles (the ciliary sphincter or pupil) is called internal
ophthalmoplegia, while paralysis of the extraocular muscles (recti and obliques) is
called external ophthalmoplegia.
2. Causes of cranial nerve III dysfunction (Table 7.4):
A compression syndrome involves both pupillary and extraocular muscles.
Initially only the pupil may be involved. Aneurysms may form at the posterior
communicating–internal carotid artery junction.
–– Lesions within the cavernous sinus
–– Herniation of the temporal lobe
–– Tumors—meningioma of tuberculum sellae or sphenoid wing non-compression
syndromes
–– Diabetic cranial neuropathy (vascular)—the pupil may be spared at time of
extraocular involvement
–– Ophthalmoplegic migraine
Originates from nucleus of VI in pons. Fibers run in middle cranial fossa via supe-
rior orbital fissure to lateral rectus in orbit.
Clinical disorders (Table 7.4). This nerve has a long intracranial course and is
thus commonly affected by increases in intracranial pressure (may be unilateral or
7.3 The Individual Cranial Nerves 217
Table 7.4 Dysfunction in the Eye Due to Lesions in the Brain Stem
bilateral) and by nasopharyngeal tumors invading the base of the skull in adults.
Pontine gliomas produce similar effects in children. The major nonneoplastic cause
is a diabetic neuropathy (vascular).
7.3.6 C
ranial Nerve V, Trigeminal (Fig. 7.7), Mixed Nerve
(Sensory and Motor but No Parasympathetic)
Cutaneous to side of the nose, nasal septum, lower eyelid, upper lip, and upper
teeth and meninges and mucous membranes in the nasopharynx, maxillary sinus,
soft palate, tonsil, and roof of the mouth.
V3 (mandibular: largest branch) only branch of V with motor functions (mixed
sensory and motor) enters infratemporal fossa through the foramen ovale.
Sensory:
Cutaneous from the lower lip, jaw and lower teeth, external ear and skin over
cheek, and meninges; general sensation at the anterior two-thirds of the tongue via
lingual nerve
Motor—originates from motor nucleus in pons (branchiomeric/special visceral
efferent) to muscles of mastication (temporal, masseter, lateral and medial ptery-
goid, mylohyoid, and anterior belly of digastric) and to tensor tympani and tensor
veli palatini.
Clinical Disorders:
Injury to the trigeminal nerve paralyzes the muscles of mastication, with the jaw
deviating toward the side of the lesion. Injury may also block sensation of light,
touch, pain, and temperature in the face and results in the absence of the corneal and
sneeze reflexes.
Localization of sensory dysfunction of the trigeminal nerve.
Trigeminal neuralgia (tic douloureux) is a disorder characterized by recurrent
paroxysms of stabbing pains along the distribution of the involved branches.
1. Clinical signs of trigeminal neuralgia:
(a) Etiology: “Idiopathic” – with mean age of onset in the 50s.
(b) Trigger points produce the pain on tactile stimulation. The pain is of short
duration—lancinating pain, usually occurring in clusters or paroxysms. Pain
may resolve spontaneously only to recur months later.
7.3 The Individual Cranial Nerves 219
7.3.7 C
ranial Nerve VII, Facial (Fig. 7.8), Mixed Nerve
(Sensory, Motor, Parasympathetic)
Large motor nucleus in pons. Rootlets in posterior cranial fossa (exits via internal
acoustic meatus): peripheral nerve fibers enter internal acoustic meatus and run in
facial canal in petrous temp; ganglia here for sensory exit via stylomastoid foramen,
then give off branches to post belly digastric, stylohyoid and postauricular mm, and
pass into parotid gland (doesn’t innervate) where it divides into plexus with branches
temp, zygomatic, buccal, marginal, mandibular, and cervical (platysma).
220 7 The Cranial Nerves
Fig. 7.8 Facial nerve, cranial nerve VII. Nerve to second pharyngeal arch, the hyoid arch
Motor:
Motor visceral efferent is from nucleus in pons to muscles of facial expression
and platysma, extrinsic and intrinsic ear muscles, post belly digastric, stapedius, and
stylohyoid.
General visceral efferent preganglionic/parasympathetic to—pterygopalatine/
sphenopalatine ganglion (largest ganglion in the head) from superior salivatory
nucleus in pons and submandibular and submaxillary gland and sublingual glands.
The fibers originate in the superior salivatory nucleus in the pons.
The pterygopalatine ganglia innervate nasal and lacrimal glands and mucous
membrane of the nose, soft palate, tonsils, uvula, roof of the mouth, upper lip and
gums, and to the upper part of the pharynx. Exiting with the facial nerve, they pass
to the pterygopalatine ganglion via the greater petrosal nerve (a branch of the facial
nerve) and to the submandibular ganglion by way of the chorda tympani nerve.
The submaxillary ganglia innervate the submaxillary and sublingual glands and
the adjacent mucosa in the oral cavity. The fibers originate in the superior salivatory
nucleus in the pons. The ganglion hangs from the lower border of the lingual nerve
(of the mandibular nerve, CN V3). It receives innervation via fibers in the chorda
tympani nerve which runs in the margins of the lingual nerve.
Sensory:
Intermediate nerve is the smaller root of the facial nerve (lies between main roor
of VII and VIII) and contains parasympathetic and special sensory axons; it joins
the main root at, or merges with, the geniculate ganglion at the geniculum of the
facial nerve; it has branches chorda tympani and greater petrosal nerve which dis-
tributes to lacrimal, nasal, palatine, submandibular and sublingual glands, and ante-
rior two-thirds of the tongue.
7.3 The Individual Cranial Nerves 221
Special visceral afferent to taste buds (chorda tympani) from anterior two-thirds
of the tongue via petrotympanic fissure.
Clinical disorders:
1. Injury in the brain stem. A central injury to the facial nucleus in the pons pro-
duces ipsilateral paralysis of the facial muscles.
Injury to just the nucleus or tractus solitarius, although rare, produces a loss
of taste on half of the tongue because the taste fibers from nerves VII and IX are
found together in the tractus solitarius.
2. Injury to the facial nerve near its origin or in the facial canal produces:
(a) Paralysis of the facial muscles with the following results:
The muscles sag in the lower half of the face and in the fold around the lips
and nose, and there is widening of the palpebral fissure. Voluntary control of
facial and platysmal musculature is absent. The patient is unable to close the
eyelid. When the patient smiles, the lower portion of the face is pulled to the
unaffected side. Saliva and food tend to collect on the affected side.
(b) Excessive secretions. When the injury is distal to the ganglion, an excessive
accumulation of tears occurs because the eyelids do not move but the lacri-
mal glands continue to secrete. There are also abnormal amounts of secre-
tions in the salivary glands.
(c) Taste is lost from the anterior two-thirds of the tongue.
(d) Corneal reflex. The reflex arc for the corneal blink reflex may be interrupted,
which includes the motor component to the orbicularis from nerve VII and
the sensory corneal nerves of VI. The muscles eventually atrophy.
3. Injury to the facial nerve at the stylomastoid foramen produces ipsilateral paraly-
sis of the facial muscles without affecting taste.
4. Injury to the chorda tympani results in the absence of taste in the anterior two-
thirds of the tongue.
5. Tumors and infections caused by mumps virus (Rubulavirus) of the parotid
gland often involve the facial nerve.
6. Repair of injured facial nerve. The following approaches have been used to
repair a nonfunctional facial nerve to improve the functions and appearance of
one’s face:
(a) Facial nerve repair with nerve grafting,
(b) Hypoglossal nerve transfer
(c) Local (regional) muscle transfer: temporalis and masseter muscle transfers
(d) Microvascular functional muscle transplantation
(e) Nerve stimulation to help in the process of regeneration
Central/cerebral innervation of VII. The corticobulbar pathway to the lower half
of the facial nucleus is a crossed unilateral innervation, whereas the upper half of
the facial nucleus receives a bilateral innervation. A unilateral lesion in the appro-
priate part of the precentral gyrus will thus paralyze the lower half on the opposite
side, while a bilateral cortical involvement paralyzes the upper and lower facial
222 7 The Cranial Nerves
7.3.8 C
ranial Nerve VIII, Vestibulocochlear (Fig. 7.9), Pure
Special Somatic Sensory
Receptive organs for hearing and balance are located in the petrous portion of the
temporal bone.
The CN VIII is found in the posterior cranial fossa (exits internal acoustic meatus
in petrous temporal) and terminates in nuclei in pons and medulla—hearing and
balance.
The vestibular portion of the eighth cranial nerve enters the upper medulla and
distributes to the four secondary vestibular nuclei (Fig. 7.10) that form the vestibu-
lar prominence on the floor of the fourth ventricle lateral to the sulcus limitans.
Some primary vestibular fibers also enter the cerebellum via the juxtarestiform body
and distribute ipsilaterally in flocculus, nodulus, and uvula. There are four vestibu-
lar nuclei: lateral (Deiters), medial, superior, and inferior.
Vestibular Nuclei
The lateral vestibular nucleus gives origin to ascending fibers that cross and
enter the MLF and reach CN III and IV. The lateral vestibulospinal tract originates
exclusively from the lateral vestibular nucleus and descends ipsilaterally to exert a
facilitatory influence on the extensor motor neurons.
The superior vestibular nucleus sends fibers ipsilateral in the MLF and ascends
to cranial nerve nuclei of III, IV, and VI.
The medial vestibular nucleus sends fibers bilaterally to the abducens nucleus,
and fibers ascend and descend bilaterally from this nucleus in the MLF reaching
cranial nerves III and IV. Fibers also descend into the spinal cord to reach ventral
horn cells controlling muscles in the neck and shoulder.
The inferior and medial vestibular nuclei project ipsilaterally into the cerebel-
lum via the juxtarestiform body, and the fibers then distribute bilaterally in the floc-
cular nodular lobe and uvula and onto the fastigial nucleus.
Cerebellovestibular fibers distribute from the anterior lobe and vermis and termi-
nate in the dorsal portions of the lateral and inferior vestibular nucleus. The fastigial
nucleus of the cerebellum sends fibers into the lateral vestibular nucleus.
Cortical projection. The vestibular nuclei project to the cortex of the temporal
lobe (probably from all of the nuclei) via vestibular fibers joining the medial lem-
niscus/proprioceptive pathway and terminate in VPL and MGN of the thalamus and
then to postcentral gyrus and are no doubt responsible for one’s conscious sensa-
tions of vertigo and dizziness.
7.4 Auditory Pathway 223
Fig. 7.9 Cranial Nerve VIII. Vestibuloacoustic nerve. Special somatic sensory-Auditory and ves-
tibular Divisions. (a) Auditory Division. (b) Location of secondary\vestibular nuclei in brain stem.
(c) vestibular branch of VIII
The nerves from the hair cells are bipolar and have their nuclei in the spiral ganglia
close to their origins (Fig. 7.11). Their axons form the acoustic portion of nerve
VIII. Recordings from a single auditory nerve fiber are shown to respond to a wide
range of frequencies; the greater the sound intensity, the greater the range. Other
224 7 The Cranial Nerves
III
Superior
Cbllr
Ped
M
L
VESTIBULAR F
VI
NUCLEI
Mid
Superior
Cbllr
Ped
Medial
Inferior
VIII
Lateral
Inferior
Cerebellar
Peduncle
Fig. 7.10 The four vestibular nuclei and their major connections are shown just below the floor of
the fourth ventricle on this posterior view of the brain stem
ORGAN OF
COCHLEAR CORTI BASILAR
DUCT MEMBRANE
VESTIBULAR TYMPANIC
CANAL CANAL
COCHLEA
AUDITORY
EXTERNAL MIDDLE INTERNAL HELICOTREMA NERVE
EAR EAR EAR OVAL WINDOW
SPIRAL
LABYRINTH
GANGLIA
PINNA
COCHLEA
REISSNER’S
EUSTACHIAN OR ROUND MEMBRANE
AUDITORY TYBE WINDOW
TYMPANIC
EXTERNAL ACOUSTIC MEMBRANE
MEATUS
Fig. 7.11 The major structures of the auditory receptor. The external, middle, and inner ear are
shown in the left, and the cochlea is shown on the right. While not shown in this figure, the chorda
tympani nerve crosses the middle ear just behind the malleus
7.4 Auditory Pathway 225
fibers have different frequency responses. This is consistent with the hair cell
responding to movements of the basilar membrane since a greater length of the
membrane will oscillate at greater sound intensities. The peak sensitivity of most
nerve cells is considerably greater than could be expected on the basis of basilar
membrane displacement.
When the middle ear is infected, transmission of taste impulses from the anterior
two-thirds of the tongue may be blocked here on their way to cranial nerve VII and
the tractus solitarius of the medulla (from Curtis Jacobson and Marcus, An
Introductions to the Neurosciences, W.B. Saunders, 1972).
Cochlear nuclei. The first set of synapses in the auditory pathway is in the dorsal
and ventral cochlear nuclei of the pons. Within the cochlear nucleus, there is a very
definite tonotopic organization. Each of these cells still responds to a range of fre-
quencies, but the frequency range is narrower than in the auditory nerve.
The larger cochlear division of cranial nerve VIII enters the brain stem inferior to
the vestibular branch. The cochlear fibers enter the cochlear nuclei and bifurcate and
distribute to the dorsal and ventral cochlear nuclei on the lateral surface of the infe-
rior cerebellar peduncle.
The dorsal cochlear nucleus forms the eminence of the acoustic tubercle on the
lateral margins of the floor of the fourth ventricle. The dorsal cochlear nucleus is
laminated into three distinct regions with distinct nuclei.
The ventral cochlear nucleus is not laminated. The fibers of the auditory system
are organized tonotopically. Fibers from the apical cochlea (low tones) are found in
the ventral portions of the dorsal cochlear nucleus and in the ventral nucleus, while
fibers from the basilar portion of the cochlea (high tones) terminate only in the dor-
sal portion of the dorsal nucleus.
Secondary auditory pathways arise from the secondary cochlear nuclei and form
three acoustic striae. These pathways carry information bilaterally onto the mid-
brain, thalamus, and auditory cortex. The ventral stria (from ventral nucleus) is the
largest and forms the trapezoid body in the pontine tegmentum. These fibers cross
the midline either by passing under or through the medial lemniscus and then form
a discrete bundle, the lateral lemniscus. Fibers also terminate in the ipsilateral and
contralateral superior olive and nucleus of the trapezoid body.
The dorsal stria arises from the dorsal cochlear nucleus, while the intermediate
stria arises from the dorsal part of the ventral cochlear nucleus. The dorsal stria
passes medially, crosses the midline ventral to the MLF, and joins the contralateral
lateral lemniscus.
Fibers from the intermediate stria pass through the reticular formation and join
the contralateral lateral lemniscus.
In the passage of the auditory fibers from the upper medulla to the midbrain and
diencephalon, several prominent nuclei are found—trapezoid nucleus, superior
olive, and nucleus of the lateral lemniscus. Fibers from these nuclei join the fibers
ascending in the lateral lemniscus. Most of the fibers in the lateral lemniscus termi-
nate in the nucleus of the inferior colliculus either ipsilaterally or contralaterally by
crossing in the commissure (of Probst) of the inferior colliculus. Fibers from the
inferior colliculus and probably a few from the lateral lemniscus continue onto the
226 7 The Cranial Nerves
medial geniculate forming the brachium of the inferior colliculus. The fibers from
the medial geniculate project onto the auditory cortex in the transverse temporal
gyri (of Heschl) area 41. Some projections from the medial geniculate also reach
auditory association area 42. The low tones (apex of the cochlea) are found in the
lateral part of the auditory cortex in the planum temporale, while high tones (base
of the cochlea) are found medially.
Auditory cortex is deep in the lateral sulcus where the superior temporal lobe is
hidden by the overlying parietal operculum (Fig. 1.7). This region can be visualized
by making a deep section with a brain knife that follows the lateral sulcus. This sec-
tion is in the planum temporale and demonstrates that the area posterior to the audi-
tory cortex in the left hemisphere is larger than in the right hemisphere. This
asymmetry was noted by Geschwind and Levitsky (1969) and is directly related to
the presence of Wernicke’s speech area (for understanding spoken language) in the
temporal lobe (Fig. 17.1).
Auditory reflexes. The auditory nerve contains an efferent bundle, the olivoco-
chlear bundle (of Rasmussen), or the efferent cochlear bundle. This bundle origi-
nates from the superior olive or the medial accessory superior olivary nucleus, exits
via the eighth nerve, and distributes in the spiral ganglion on hair cells in the cochlea.
Presumably these fibers modulate synaptic transmission, possibly as early as the
Transverse tem.
poral gyrus
Auditory radiation
Medial geniculate body
Inferior colliculus
Fig. 7.12 The auditory pathway. Note that there are many, non-synchronous synapses. For clarity,
the diagram shows most of the fibers crossing the neuraxis; about half of the fibers do; the other
half ascend on the same side (From B.A. Curtis, S. Jacobson and E.M. Marcus, An Introduction to
the Neurosciences, W.B. Saunders, 1972)
7.4 Auditory Pathway 227
hair cell, many of which have efferent nerve endings. Two muscles influence sound
transmission across the middle ear: the tensor tympani and the stapedius. The tensor
tympani are innervated by cranial nerve V. By tensing the tympanic membrane, it
dampens the vibration. Fibers from the accessory superior olive project bilaterally
to the motor nucleus of the fifth cranial nerve to support reflexive dampening of
loud sounds. The stapedius muscle is innervated by cranial nerve VII and, by pulling
the stapes laterally and away from the oval window, tends to counteract force placed
on the stapes from the tympanic membrane. The reflex is via fibers from the acces-
sory superior olive projecting bilaterally to the motor nucleus of the seventh cranial
nerve. When loud noises or tones are heard or anticipated, these muscles contract
and reduce the percentage of the sound energy impinging on the oval window.
Clinical Disorders of Auditory System
Auditory—Symptoms and signs
Deafness: Classification
Conductive: External and middle ear disease (loss of low-frequency sounds)
Sensory neural (nerve deafness—loss of high-frequency sounds)
1. Disease of the cochlea—often bilateral, hereditary, or related to loud sound
exposure
Antibiotic use—aminoglycosides, dihydrostreptomycin, and vancomycin
If sudden and unilateral, consider vascular etiology: occlusion of the internal
auditory artery.
2. Disease of the eighth nerve: Small tumors (acoustic neuroma) of the eighth nerve
within the bony canal may produce limited CN VIII symptoms. Large tumors,
such as acoustic neuromas, meningiomas, etc., at the cerebellar pontine angle
produce involvement of a cluster of cranial nerves (VIII, VII, ±V, ±IX, X).
Note that these “acoustic neuromas” arise from the Schwann cells of the ves-
tibular divisions of the nerve. A more correct term is vestibular schwannoma.
Tinnitus—various forms of ringing in the ear
Etiology—middle or inner ear or eighth nerve usually associated with hearing
loss
Central lesions of cochlear pathway. Note that beyond the cochlear nuclei,
central connections of the auditory system are both crossed and uncrossed.
Therefore, a unilateral lesion is unlikely to produce a unilateral hearing defect.
Massive intrinsic lesions are required to produce “brain stem deafness.”
Clinical Disorders: Vestibular
Symptoms:
1. Vertigo – a sensation of movement (usually rotation) of the environment or of the
body and head:
(a) When due to involvement of the horizontal (lateral) canals, the sense of
movement is usually rotation in the horizontal plane.
(b) When due to involvement of the posterior or vertical canals, the sense of
movement may be in the vertical or diagonal planes with a sense of the floor
rising up or receding.
228 7 The Cranial Nerves
(c) Vertigo must be distinguished from the more general symptom of dizziness
or light-headedness, which has many causes. Simple light-headedness as a
symptom of pre-syncope (the sensation that one is about to faint) may accom-
pany any process which produces a general reduction in cerebral blood flow
(cardiac arrhythmia, decreased cardiac output, peripheral dilatation of ves-
sels, decreased blood pressure, or hyperventilation). Hypoglycemia and vari-
ous drugs also produce dizziness. Some patients cannot make the distinction,
and a series of operational tests may be necessary to reproduce symptoms.
(d) Rotation, hyperventilation, and orthostatic changes in blood pressure.
Additionally, caloric testing, cardiac auscultation, EKG, and Holter monitor maybe
necessary in selected cases.
2. Nausea and vomiting – vertigo of vestibular origin is accompanied by these
symptoms, because of the connections of the vestibular system to the emetic
center of the medulla.
3. Nystagmus – a jerk of the eyes; slow component alternating with a fast compo-
nent is associated with stimulation or disease of the vestibular system. Nystagmus
is named from the fast component, and the direction of movement is specified:
rotatory, horizontal, or vertical.
4. Unsteadiness – severe or mild.
Etiology: Multiple labyrinthine disease is the most common.
(a) Meniere’s disease: Paroxysmal attacks of vertigo, ± vomiting, and ataxia are
associated with tinnitus and deafness. The etiology relates to endolymphatic
hydrops—increase in volume and distention of the endolymphatic system of the
semicircular canals.
Vestibular Nerve: Vestibular neuropathy acute, self-limited syndrome, which fol-
lows a viral infection. Symptoms are vestibular without cochlear involvement.
There is unilateral vestibular paresis.
Tumors: arising from or compressing vestibular nerve, “acoustic neuroma.” Note
that this tumor actually arises from the Schwann cells of the vestibular nerve.
Brain stem: Infarcts involving the vestibular nuclei will produce vertigo and/or
nystagmus. Almost always other brain stem signs are present.
Cerebral cortex: Stimulation of the temporal lobe in patients with seizures of the
temporal lobe origin that produces dizziness.
7.4.1 C
ranial Nerve IX, Glossopharyngeal (Fig. 7.13), Mixed
(Sensory, Motor, Parasympathetic): Nerve to Third
Pharyngeal Arch
The nerve in posterior cranial fossa exits via jugular foramen. The fibers originate
in the inferior salivatory nucleus in the medulla. These fibers leave the medulla via
the tympanic nerve branch of glossopharyngeal nerve (CN IX) and travel through
the tympanic plexus in the middle ear and then via the lesser petrosal nerve to the
7.4 Auditory Pathway 229
otic ganglion associated with the parotid gland. After synapsing in the otic ganglion,
the postganglionic/postsynaptic fibers travel in the auriculotemporal nerve (a branch
of the mandibular nerve of the trigeminal to the parotid gland).
Motor:
Parasympathetic/general visceral efferent from inferior salivatory nucleus in pons to
parotid gland via otic ganglia
Special visceral efferent from ambiguous nucleus in the medulla to the stylopha-
ryngeus mm that initiates swallowing
Sensory:
General visceral afferent visceral sensations from posterior one-third of the tongue
and carotid body and sinus terminate in solitary nucleus in
the medulla
Special visceral afferent to taste buds on the posterior one-third of the tongue
Terminates in solitary nucleus in the medulla
Reflexes:
Gag reflex. Forms sensory portion; X the motor portion
Carotid body monitors O2<>CO2 via baroreceptors in the sinus which are inner-
vated by the sinus nerve of Hering of IX
Carotid sinus nerve > carotid sinus monitors BP and feeds back to X
7.4.2 C
ranial Nerve X, Vagus (Fig. 7.14), Mixed (Sensory,
Motor, Parasympathetic), and Longest Cranial Nerve
Nerve to fourth and sixth pharyngeal arch. Nerve exits posterior cranial fossa via
jugular foramen with CN IX and XI.
230 7 The Cranial Nerves
1. Motor:
(a) Parasympathetic—general visceral efferent to smooth muscles in the heart,
blood vessels, trachea, bronchi, esophagus, stomach, and small intestine to
lower half of large intestine from dorsal motor nucleus of X in the medulla
(b) Special visceral efferent to muscles in the pharynx and larynx for phonation
and glutination from ambiguous nucleus of X in the medulla
2. Sensory:
(a) General visceral afferent carries visceral sensation from the pharynx, larynx,
aortic body, thorax, and abdomen to solitary nucleus of the medulla.
(b) Special visceral afferent – gustatory sensation from taste buds on the epi-
glottis and pharynx to solitary nucleus of the medulla.
3. Clinical considerations of vagal nerve:
(a) Vagus nerve stimulation to treat severe depression. In 2005, the Food and
Drug Administration (FDA) approved a type of brain stimulation called
vagus nerve stimulation for certain types of depression. This new procedure
7.4 Auditory Pathway 231
uses brain stimulation to improve symptoms, but long-term effects aren’t yet
known. Depression is usually a very treatable condition. Often, standard
treatment with antidepressant medications, psychotherapy, or electroconvul-
sive therapy can help improve even severe cases of depression. If standard
depression treatment doesn’t work, this relatively new type of treatment
involving brain stimulation may be an option.
1. Complications from this procedure include:
(a) For one thing, you may have complications from the surgery to implant the
device. In addition, the device and the stimulation may cause unwanted or
harmful side effects. However, the frequencies and currents of the electrical
impulses can be adjusted to help minimize these effects.
(b) Common side effects and adverse health problems associated with vagus
nerve stimulation include:
–– Voice changes, hoarseness, cough, neck pain, breathing problems (espe-
cially during exercise)
–– Difficulty swallowing and sore throat and tingling or prickling of the skin
–– Also a small risk that the pulse generator may malfunction or move about
within your body. You may then require additional surgery to fix or
remove device.
–– If necessary, you can deactivate the pulse generator temporarily. You may
want to do this if you have intolerable side effects or you want to engage
in heavy exercise. To deactivate it, you hold a magnet over the area of
your chest where it’s implanted.
(c) On the other hand, vagus nerve stimulation doesn’t have the side effects that
are typical of antidepressants. For instance, it’s not associated with weight
gain, sexual problems, memory problems, food or medication interactions,
or sleep disturbances.
(d) The vagus nerve and the relaxation response. Frank Benson in 1974 demon-
strated the effectiveness of meditation on controlling the BP and also anxi-
ety. Benson’s book—The Relaxation Response, 1975—is a bestseller. His
method, the “relaxation response,” teaches us all how to use the vagus and its
control of the heart, lungs, and GI system to help one deal with the stresses
of life—try it and see if it works for you?
7.4.3 C
ranial Nerve XI, Spinal Accessory (Fig. 7.15), Pure
Motor: Somatic and Visceral
7.4.4 C
ranial Nerve XII, Hypoglossal (Fig. 7.16): Pure Motor
Nerve
The muscles it innervates in the tongue form the occipital somites. These somites
form intrinsic and extrinsic mm of the tongue. It originates in hypoglossal nucleus
in the medulla, and the nerve exits in the posterior cranial fossa (exits via hypoglos-
sal foramen). It is general somatic motor from the medulla to intrinsic and extrinsic
muscles of the tongue except palatoglossal which is innervated by cranial nerve X.
Obstructive sleep apnea. Obstructive sleep apnea is a potentially serious sleep
disorder in which breathing repeatedly stops and starts during sleep. Several types
of sleep apnea exist, but the most common type is obstructive sleep apnea, which
occurs when your throat muscles intermittently relax and block your airway during
sleep. The most noticeable sign of obstructive sleep apnea is snoring, although not
everyone who has obstructive sleep apnea snores. The hypoglossal is important in
keeping the airway open so there is no compromise of the airway. After diagnosis at
a sleep center, to relieve this major problem, one may either be placed on a positive
7.5 Cranial Nerve Dysfunction 233
Fig. 7.17 Cranial nerves: origins and distributions of the cranial nerves. Each of the cranial nerve rootlets seen on the base of the brain is connected to a dia-
7 The Cranial Nerves
(b) The nuclei of the somatic motor cranial nerves (III, IV, VI, and XII) are
located close to the midline. These nuclei tend to be involved, then, by
paramedian lesions rather than by lateral lesions. Intrinsic lesions in a para-
median location tend to produce, early in their course, a bilateral involve-
ment of these nuclei. These nuclei are also all located in a relatively dorsal
position. These nuclei would be involved early by a lesion in a dorsal or
tegmental location. Except for cranial nerve IV, the fibers of these cranial
nerves all exit in a relatively paramedian ventral location.
2. Effects of a lesion to a Sensory Cranial Nerve
Cranial nerve V lesions:
(c) In the main sensory root of the trigeminal nerve, in its course within or exter-
nal to the mid-pons, it will produce ipsilateral deficits in pain, temperature,
and touch over the face.
(d) In the descending spinal tract of the trigeminal nerve or of its associated
nucleus, it will produce ipsilateral deficit in pain and temperature sensation
over the face with sparing of facial touch sensation. These structures are situ-
ated close to the lateral spinothalamic tract; the combination of contralateral
pain and temperature deficit over the body and extremities with ipsilateral
pain and temperature deficit over the face is frequently found as a conse-
quence of lesions which involve the dorsal lateral tegmental portion of the
medulla, e.g., infarction of the territory of the posterior inferior cerebellar
artery which supplies this sector. A similar combination may be found in the
infarction of the dorsolateral tegmentum of the caudal pons: the territory of
the anterior inferior cerebellar artery.
(e) The descending spinal tract (analogous to and, in a sense, the direct continu-
ation of Lissauer’s tract) and associated nucleus (analogous to the substantia
gelatinosa) descend into the upper cervical spinal cord. Although there is
considerable overlap, the primary trigeminal fibers synapse on the nucleus of
the descending spinal nucleus at the following levels:
–– Mandibular division fibers at a lower pontine—upper medullary level
–– Maxillary division at a medullary level
–– Ophthalmic division fibers at a lower medullary and upper cervical cord level
There is overlap at the upper cervical cord level between the upper cervical
segment pain fibers and the ophthalmic division pain fibers. It is not surpris-
ing, then, that pain originating in the C2 and C3 roots or segments of the spi-
nal cord may sometimes be referred to the ophthalmic division of the face
(orbit and forehead), and, e.g., the pain of cervical 2 and 3—occipital neural-
gia—is often referred to the orbit.
(f) The secondary pain fibers decussate and join the ventral secondary trigemi-
nal tract (also labeled trigeminothalamic or quintothalamic tract) which, at a
medullary level, is located just lateral to the medial lemniscus. At a pontine
and midbrain location, the secondary trigeminal tract is just lateral to and
essentially continuous with the medial lemniscus and adjacent to the lateral
spinothalamic path. A lesion that involves this tract would then usually
236 7 The Cranial Nerves
Cranial nerve Case History 7.1. This 50-year-old right-handed, male’s factory
foramen was referred for evaluation of ptosis and diplopia involving the left eye.
Approximately 2 weeks prior to admission, the patient developed a bifrontal head-
ache; during the week prior to his evaluation, the headache had become a left-sided
aching pain. It increased in intensity during the 2 days prior to admission and was
present as a constant pain interfering with sleep. If the patient were to cough, he had
additional pain in the left eye. On the day of admission, the headache became much
more severe; it was now the “worst headache he had ever experienced.” In retro-
spect, the patient reported that lights had been brighter in the left eye for approxi-
mately 1 week.
At 3 pm on the day of admission, the patient noted the sudden onset of diplopia,
which was more marked on horizontal gaze to the right and much less marked on
horizontal gaze to the left. At approximately the same time, he noted the rapid onset
of ptosis involving the left lid.
General physical examination: There was moderate resistance to flexion of the neck.
Neurological examination:
1. The left pupil was fully dilated (blown) to approximately 7 mm. There was no
response to light or accommodation.
2. Total ptosis of the left eyelid was present.
3. No medial movement of the left eye was present; there was no upward move-
ment of the left eye possible. The patient had minimal downward gaze of the left
eye. He had full lateral movement of the left eye. Movements of the right eye
were full.
Clinical diagnosis: Subarachnoid hemorrhage secondary to an aneurysm at the
junction of the posterior communicating and internal carotid arteries.
The occurrence on the day of admission of the worst headache ever experienced
by the patient suggested the possibility of a subarachnoid hemorrhage. Most patients
with an acute subarachnoid hemorrhage have an underlying saccular aneurysm.
There are three major locations for single intracranial aneurysms: (1) The junc-
tion of the posterior communicating and the internal carotid arteries, (2) the junction
of the anterior communicating and anterior cerebral arteries, and (3) the bifurcation
of the middle cerebral artery in the Sylvian fissure. The posterior communicating
artery is adjacent and runs parallel to the third cranial nerve. With hemorrhage,
compression of (or bleeding into) the nerve symptoms will develop relevant to cra-
nial nerve III. Thus in patients with prodromal symptoms, a third nerve syndrome
allows the prediction of this specific location of the aneurysm. Because of the
7.6 Cranial Nerve Case Histories 237
arrangement of the fibers within this nerve, the initial symptoms of compression
often involve the pupillary fibers. In retrospect, the early symptoms of lights being
brighter in the left eye 1 week before the ptosis and diplopia developed would be
consistent with a pupil that was unable to constrict in response to light.
Cranial nerve Case History 7.2. This 72-year-old female developed sudden onset
of a sharp “lightning bolt” of pain in the left jaw and maxilla lasting a few seconds
and then resolving. This would occur episodically over the day, up to several dozen
times each day. This could be precipitated by chewing or by talking. Dental and oral
surgical evaluation failed to reveal a cause. This was not associated with other neu-
rologic symptoms or general medical complaints. Brain CT and subsequent MRI
were normal. She was referred for an opinion. Her past history was notable for
hypothyroidism, mild hypertension, and elevated cholesterol.
Medications included Lipitor and lisinopril, and she had an allergy to sulfa drugs.
General examination was notable for being very protective of the left side of her
face and for caution on opening her mouth to speak. She had no obvious oral or
dental triggers. She outlined her pain area as affecting the left maxilla and jaw
region. Cranial nerve exam revealed no abnormalities with detailed assessment of
trigeminal nerve function. Her neurologic exam was otherwise entirely normal.
Clinical diagnosis: trigeminal neuralgia
Discussion: This is a classic case of trigeminal neuralgia with paroxysmal episodes of
a sharp pain in a V2/V3 distribution. Female sex, older age intention, and a classic
trigeminal distribution are hallmarks of this. The deposited etiology of most cases of
trigeminal neuralgia is vascular compression of the trigeminal nerve exiting the brain
stem. Multiple sclerosis, local tumors, or infection for herpes viral infections can
occasionally cause facial pain. She made a good response to Tegretol and, at last fol-
low-up after a year, had mild breakthrough episodes of pain once or twice a month.
Cranial nerve Case History 7.3. This 20-year-old male awakened with drooping
of the right side of his face. There was no trigger or pre-existing known illness. He
noticed that sounds seem to be louder in his right ear (hyperacusis) than his left ear.
This has been present for several days before seeing his primary care physician.
A CT of the brain did not show any abnormalities. He had no significant past
surgical or medical history, took no medicines, and had no allergies. His general
exam was normal. On neurologic exam, he had a significant peripheral right facial
weakness with the forehead and lower face involved equally. On testing of hearing,
he had hyperacusis on the right but otherwise had a normal exam.
Clinical diagnosis: Bell’s palsy
Comment: Sudden onset of a significant motor deficit like this in older person would
prompt consideration of a stroke. In a younger person, this would be less common.
In addition, strokes usually present with a central type facial weakness in which the
lower half of the face is effective but not the forehead. In this person’s case, the
entire face including the forehead was affected. His pupillary reflexes were still
normal so his cornea wouldn’t dry out, and we didn’t need to give him an eye patch
for protection. This directs the examiner to a peripheral cause for the event.
238 7 The Cranial Nerves
Lyme disease is not an infrequent cause of Bell’s palsy and generally responds
well to antibiotic administration. He lived in an area which had many deer ticks with
the bacterium Borrelia burgdorferi. Lyme testing was positive and doxycycline/
prednisone was instituted. His deficits improve significantly but not fully over
approximately 2 months.
Cranial nerve Case History 7.4, Fig. 7.18. This 52-year-old female presented
with a several-year history of progressive hearing loss in the left ear as well as tin-
nitus in that same ear. There were no similar issues on the right side. On evaluation
by her primary care physician, she was noted to have decreased auditory acuity in
the left ear.
Past history was notable for cholecystitis, acid reflux, and hypertension; she had
a history of a cholecystectomy and a cesarean section. She had no allergies. There
was no family history of similar issues. General exam was normal; neurologic
exam—mental status was normal.
Cranial nerves. Upper cranial nerve examination was normal. Seventh nerve
examination revealed very mild facial weakness on the left peripheral in nature, as
well as diminished auditory acuity. Gag, swallowing, and tongue function were all
normal. This hearing loss was subsequently documented on otology evaluation.
Motor exam was normal. Sensory exam was intact to both pin and touch. Reflexes
were 1+ and symmetrical. Finger to nose was symmetrical. Gait was unremarkable.
Impression was a left acoustic neuroma with diminished hearing and a mild left
facial weakness. This led to an MRI which demonstrated an intracanalicular tumor
on the left most consistent with an acoustic neuroma.
Fig. 7.18 Acoustic
neuroma (arrow) on left
CN VIII
7.6 Cranial Nerve Case Histories 239
Bibliography
Per Brodal A. The central nervous system. 5th ed. London: Oxford Blackwell; 2016.
Marcus EM, Jacobson S, Sabin TD. Integrated neuroscience. 2nd ed. Oxford: Oxford University
Press; 2014.
Riley HA. Brain stem and spinal cord. New York: Hafner; 1960.
Ropper AH, Samuels MA, Klein JP. Adams and Victor’s principles of neurology. 10th ed.
New York: McGraw Hill.
Chapter 8
Diencephalon
Abstract The diencephalon appears at the upper end of the brain stem between the
brain stem and cerebrum. All the ascending fiber pathways from the spinal cord and
brain stem terminate upon nuclei in the diencephalon, and this is the basis for crude
awareness of many of these senses at this level. All the diencephalic subdivisions include
the term thalamus, and they include dorsal thalamus/thalamus epithalamus, hypothala-
mus, metathalamus, and subthalamus. Each of these regions has many subnuclei.
The thalamus/dorsal thalamus is the largest zone, and it is the primary provider of
information from the spinal cord and brain stem onto the cerebral cortex permitting
the cerebral cortex to do its many functions. The thalamus is the final processing
station for systems that project to the cerebral cortex; thus it serves an important
integrative function. Many sensations are first crudely appreciated at thalamic levels,
including pain, touch, taste, and vibration. The discriminative processes associated
with these sensations, as well as tactile discrimination, vision, audition, and taste, are
elevated to consciousness in the cerebral hemisphere. Glutamate is the principal
transmitter in the thalamus.
8.1 Overview
This chapter will concentrate on the dorsal thalamus, metathalamus and epithalamus.
The hypothalmus will be reviewed in chapter 9 and the sub thalamus in Chapter 12.
The relationship of the thalamus and cortex is so intimate that when a region in the
cerebral cortex dies the thalamic nuclei which connect to it atrophy-. As can be seen
from the terminology associated with the diencephalon, all structures are described by
their spatial relationship to the thalamus, being above, below, or behind them (epithala-
mus, hypothalamus, metathalamus subthalamus, and thalamus) (Figs. 8.1 and 8.2).
(A) The thalamus has several major roles:
1 . To receive input from the brain stem, cerebellum, and corpus striatum
2. To project this information, after some processing, onto the cerebrum
3. To receive reciprocal projections from the same cerebral area
Due to the convergences of all major ascending somatic sensory, motor, and
reticular systems, consciousness for general sensations is first realized at this level.
In addition, the ascending motor information from the cerebellum mixes with the
striatal and cortical motor fibers in the dorsal thalamus producing a motor thalamic
region. Finally there is a region in the diencephalon that receives input from the
hypothalamus and ascending reticular systems that projects emotional tone (from
autonomic nervous system) onto the cerebral cortex.
All nuclear structures superior to the sulcus are included in the dorsal thalamus,
and all nuclei below it are included in the hypothalamus (Fig. 8.3). These structures
basically surround the third ventricle and comprise the lateral wall and floor of this
ventricle. The hypothalamus will be discussed in Chap. 9 and in the limbic system
(Chap. 16). The subthalamus (including the subthalamic nucleus and zona incerta)
will be discussed with the basal ganglia in Chap. 12.
(B) Thalamus from a phylogenetic perspective.
1. Archithalamus, earliest region, forms thalamic activating system
Archithalamic nuclei – reticular and intralaminar with internal medullary
lamina
2. Paleothalamus, preliminary processing of sensory information and strong
connections to limbic, motor, and sensory thalamus
Paleothalamic nuclei – Ant, VL, VPL, MD, MG, and LG with strong
cerebellar and basal ganglia input and cortical projections through internal
capsule
3. Neothalamus nuclei, newest region and largest of regions. Projects and
interconnects to associational areas in cortex
NeoNuclei – MD, LP, LD, pulvinar, ventrobasal
(C) Functional divisions of thalamic nuclei.
There are three basic types of thalamic nuclei: (1) relay nuclei, (2) associa-
tion nuclei, and (3) nonspecific nuclei.
1. Relay nuclei receive very well-defined inputs and project this signal to func-
tionally distinct areas of the cerebral cortex. These include nuclei that relay
general sensations (the ventral posterolateral, VPL; ventral posteromedial,
VPM) and also the nuclei involved in feedback of cerebellar signals (ventral
lateral, VL) and feedback of basal ganglia output (part of the VL and the ven-
tral anterior nucleus, VA) and finally the special sensory nuclei medial and
lateral geniculate.
2. Association nuclei that include the pulvinar complex receive their input from
the cerebral cortex and project back to the cerebral cortex in the association
areas where they appear to regulate multimodal input onto the cerebral
cortex.
3. Nonspecific nuclei include the intralaminar and midline thalamic nuclei that
project quite broadly through the cerebral cortex and may be involved in g eneral
functions such as alerting.
244 8 Diencephalon
Fig. 8.3 Midthalamic level. (a) Schematic coronal section showing nuclei of diencephalon: thala-
mus, epithalamus, hypothalamus, and subthalamus, and internal capsule and basal ganglia. (b)
Location of thalmus in a Coronal, MRI, T2 weighted.
8.2 Functional Organization of Thalamic Nuclei 245
8.2.1 S
ensory and Motor Relay Nuclei: The Ventrobasal
Complex and Lateral Nucleus
These nuclei (Fig. 8.4) are part of the somatic brain as they receive direct input from
the ascending sensory and motor systems (from the cerebellum) and relay that
information onto the cortex with only minimal modifications. The lateral nuclear
mass is divided into three parts: lateral dorsal, lateral posterior, and pulvinar.
It occupies the upper half of the lateral nuclear grouping throughout the thalamus.
It is bounded medially by the internal medullary lamina of the thalamus and later-
ally by the external medullary lamina of the thalamus. In a stained preparation, its
ventral border with the ventral nuclear mass is distinct.
The lateral nuclear mass starts near the anterior end of the thalamus and runs the
length of the thalamus with its posterior portion, the pulvinar, overhanging the
geniculate bodies and the midbrain. The lateral posterior part of the lateral nuclear
mass projects to the superior parietal lobule and receives input from specific tha-
lamic nuclei. The lateral dorsal part projects onto the posterior cingulated gyrus and
is included in the discussion of the limbic nuclei.
The ventral basal nuclear complex consists of three distinct regions: ventral
anterior, ventral lateral, and ventral posterior.
246 8 Diencephalon
VA. The ventral anterior nucleus (VA) is the smallest and most rostral nucleus of
this group. It can be identified by the presence of numerous myelinated bundles.
The magnocellular portion of this nucleus receives fibers from the globus pallidus,
substantia nigra, and cerebellum via the lenticular and thalamic fasciculi and from the
intralaminar nuclei and has some projections to areas 4 and 6. The parvocellular sub-
division also receives input from these same regions but to a lesser degree. Stimulation
of this nucleus produces the same effects as stimulation of the intralaminar nuclei.
8.2 Functional Organization of Thalamic Nuclei 247
Fig. 8.4 Gross brain. Horizontal section through the brain demonstrating relationship of thalamus
to III ventricle and posterior limb of internal capsule
VL. The ventral lateral nucleus (VL, somatic motor thalamus) occupies the m iddle
portion of the ventral nuclear mass. It is a specific relay nucleus in that it receives
fibers from the contralateral deep cerebellar nuclei (via the superior cerebellar pedun-
cle/dentatorubrothalamic tract) and the ipsilateral red nucleus. This nucleus also
receives fibers from the globus pallidus and from the intralaminar nuclei. This nucleus
projects to area 4 and to area 6 and has a topographic projection to the motor cortex.
The ventral lateral and ventral posterior nuclei contain cell bodies that project onto
the motor and sensory cortex. In these nuclei there is a somatotopic organization with
the head found medial and posterior and the leg anterior and lateral. This nucleus is
important in integrative somatic motor functions because of the interplay between the
cerebellum, basal ganglia, and cerebrum in this nucleus.
Ventral posterior nuclear complex. The ventral posterior nucleus occupies the
posterior half of the ventral nuclear mass and consists of two parts: the ventral pos-
terior lateral nucleus and the ventral posterior medial nucleus. Both of these nuclei
receive input from the specific ascending sensory systems.
VPL. The ventral posterior lateral (VPL) nucleus receives fibers from the poste-
rior columns and the direct spinothalamic tracts with the bulk of the input originating
in the upper extremity. The VPL nucleus projects to the body and neck regions on
the postcentral gyrus (areas 3, 1, 2).
VPM. The ventral posterior medial nucleus (VPM, the arcuate, or semilunar,
nucleus) is located lateral to the intralaminar centromedian nucleus and medial to
the ventral posterior lateral nucleus. The secondary fibers of the trigeminal and
gustatory pathways terminate in this nucleus; thus this nucleus is concerned primar-
ily with taste and with general sensation from the head and face.
Taste and the VPM. The basal region of the ventroposterior medial nucleus
receives the taste fibers and probably some of the vagal input. General sensation
from the face, including pain, temperature, touch, pressure, and proprioception,
248 8 Diencephalon
terminates in other portions of this nucleus. This nucleus projects information from
the face, ears, and head, and tongue regions onto the inferior part of the postcentral
gyrus, areas 3, 1, and 2.
LP. The lateral posterior nucleus projects onto superior parietal lobule and pro-
vides sensory input used in recognition of the parts of the body.
8.2.2 L
imbic Nuclei: The Anterior, Medial, Lateral Dorsal,
Midline, and Intralaminar Nuclei (Fig. 8.4)
The limbic nuclei may also be called the nuclei of the emotional brain; they were
named by their location on the limb or medial surface of the hemisphere.
The anterior nuclei (Fig. 8.4) are at the most rostral part of the thalamus and
form the prominent anterior tubercle in the floor of the lateral ventricle. The tubercle
includes a large main nucleus (anteroventral) and small accessory nuclei (anterodor-
sal and anteromedial). The internal medullary lamina of the thalamus surrounds the
anterior nuclei. The mammillothalamic fibers form the bulk of the fibers in the inter-
nal medullary lamina. This zone is an important relay station in the limbic brain and
receives input from the subiculum, presubiculum, and mammillary body via the
mammillothalamic tract and in turn project onto cingulate cortex. These nuclei are
important in learning and memory.
Lesions in anterior thalamus. Patients with isolated destruction of the anterior
nuclei were evaluated with CT and MRI and behavior testing. These 12 patients
without involvement of the mammillothalamic tract, the anterior part of the internal
medullary lamina, and the dorsomedial and ventrolateral nuclei showed an acute
behavioral syndrome of anterior thalamic infarction dominated by perseverative
behavior with increased sensitivity to interference. All patients had anterograde
memory impairment, with a delayed recall deficit, primarily verbal in left-sided
infarcts and visuospatial in right-sided infarcts with dysarthria and hypophonia and
apathy. The long-term significant persisting abnormalities were in memory and apa-
thy (Ghika-Schmid and Bogousslavsky 2000).
Papez circuit. The anterior nuclear complex is part of the Papez circuit (hippo-
campal formation → fornix → mammillary body → mammillothalamic
tract → anterior thalamic nucleus → anterior thalamic radiation → cingulate cor-
tex → cingulum → perforant pathway → hippocampus). The fornix originates from
neurons in subiculum, and presubiculum and also perirhinal cortex and entorhinal
cortex. This nucleus projects via the fornix to the anterior cingulate gyrus (areas 23,
24, 32) and receives input from the hypothalamus, habenula, and cingulate cortex.
Stimulation or lesions of this nuclear complex alters blood pressure and may
influence memory. The lateral dorsal nucleus, like the anterior nucleus, is sur-
rounded by the rostral portion of the internal medullary lamina of the thalamus and
should be considered a caudal continuation of the anterior nuclear group. This
nucleus projects to the rostral cingulate cortex and onto the parahippocampal gyrus.
The hippocampus is important in memory and spatial orientation (Chap. 16).
The medial nuclear complex or the dorsomedial nucleus consists of both a
large-celled and a small-celled division. This medial region is found between the
8.2 Functional Organization of Thalamic Nuclei 249
internal medullary laminae and the midline nuclei lining the third ventricle (Fig. 8.4).
The magnocellular portion of the dorsomedial nucleus is interconnected with the
hypothalamus, amygdala, and midline nuclei and connects to the orbital cortex; the
large parvicellular division is interconnected with the temporal, orbitofrontal, and
prefrontal cortices (areas 9, 10, 11, 12; see Chap. 15).
The medial nuclear complex is an important relay station between the hypothala-
mus, amygdale, and the prefrontal cortex and is concerned with the multimodal associa-
tions between the limbic (visceral) and somatic impulses that contribute to the emotional
makeup of the individual. In humans, ablation of the medial nucleus or a prefrontal
lobotomy has been used as a therapeutic procedure to relieve emotional distress.
8.2.3 S
pecific Associational: Polymodal/Somatic Nuclei,
the Pulvinar Nuclei (Fig. 8.5)
The pulvinar nuclei. The pulvinar (Fig. 8.5) forms the largest nucleus in the thala-
mus and is continuous with the posterior part of the lateral division. All the major
ascending sensory and motor pathways have some terminations in the medial and
lateral nuclei. The pulvinar therefore is the major multimodal association nucleus of
the thalamus integrating sensory, motor, visual, and limbic information.
The pulvinar is divided into three major nuclei: the medial pulvinar nucleus, the
lateral pulvinar nucleus, and the inferior pulvinar nucleus.
The medial pulvinar nucleus projects onto the prefrontal and anterior temporal
limbic cortex.
Fig. 8.5 3D reconstruction of the thalamic nuclei with the upper portion showing the three major
nuclear masses and the lower portion showing individual nuclei. The coronal section demonstrates
the location of the medial nuclear mass and the lateral nuclear mass separated by the internal med-
ullary lamina with its nuclei. Modified from Carpenter Core Text. Williams & Wilkins 1992
250 8 Diencephalon
The lateral pulvinar nucleus projects onto supramarginal, angular, and posterior
temporal lobe. This extensive projection is onto the cortex surrounding the posterior
end of the lateral sulcus; consequently, lesions here can produce disturbances in
language – including Wernicke’s sensory aphasia.
The inferior pulvinar nucleus receives visual information via the tectum of the
superior colliculus and projections onto the visual association cortex, areas 18/V2
and 19/V3, and MT/V3.
Pulvinar and the dorsal visual stream. Primates including humans possess
two distinct visual systems (Milner and Goodale 2008): a ventral stream > LGN
which is then projected onto the visual striate cortex the striate cortex, area 17, and
a dorsal stream which bypasses the thalamus and terminates directly in the tectum
of the superior colliculus from which the tectopulvinar fibers project onto the visual
pulvinar nucleus and the inferior pulvinar nucleus and which then projects to peris-
triate cortex.
1. The ventral stream, geniculocalcarine, is for object identification, “what path-
way,” which goes directly from retina via the optic nerve to LGN and then pro-
jected onto visual cortical area 17-V1 and enters area MT in the temporal lobe
and is involved with object identification and recognition.
2. The dorsal stream, tectopulvinar, is considered the “where pathway” as it goes
directly from the retina via the optic nerve, bypasses the LGN, and synapses in
the tectum of the superior colliculus. From the tectum of the superior colliculus,
the very extensive tectopulvinar tract terminates in the inferior pulvinar nucleus/
visual pulvinar nucleus. From the inferior pulvinar nucleus, there is a projection
onto extrastriate areas 18 and 19-V2 and V3 and terminates in the parietal lobe.
This dorsal stream is involved with processing the object’s spatial location
(Ungerleider and Mishkin 1982).
Blind Sight: Awareness Without Sight
When the striate cortex is removed or blocked in monkeys, the animals can still carry
out visual discriminations, although their capacity changes in certain ways. What they
can still do so is perhaps not surprising because the output from the eye also reaches a
number of other brain targets lying in the midbrain and thalamus that remain intact even
when V1 is entirely removed (cf. review by Cowey and Stoerig 1991). In recent years it
has become evident that monkeys without primary visual cortex, area V1, can discrimi-
nate shapes, demonstrate contrast sensitivity, and have measurable acuity, although
reduced from normal.
Human subjects with lesions in V1 are phenomenally blind, and they do have some
residual function (Weiskrantz, Cowey, and LeMare 1998). Patient GY has a lesion in
left V1 (De Gelder, Pourtois, and Weiskrantz 2002). He reports being blind to objects
in the right visual field, yet he can correctly point to and grasp them. Functional mag-
netic resonance imaging (fMRI) scans of patient GY show activity in extrastriate
visual areas (areas 18 and 19) when stimuli were presented in the “blind” region.
Without V1, these signals probably go through the dorsal pathway. So damage to V1
can lead to sight without awareness, blind sight. But damage to the (usually right)
parietal lobe can lead to the opposite problem, called anosognosia. These patients can
be blind, but they insist that they can see. They will often confabulate stories or
excuses to prevent them from demonstrating their disability.
8.2 Functional Organization of Thalamic Nuclei 251
8.2.4 S
pecial Somatic Sensory Nuclei: Vision and Audition,
the Lateral Geniculate and Medial Geniculate Nuclei
of the Metathalamus (Fig. 8.5): The Special Somatic
Sensory Cranial Nerves Are Cranial Nerves II and VIII
Audition. The medial geniculate nucleus (MGN) is located on the most caudal por-
tion of the thalamus (metathalamus) and receives the ascending auditory fibers
originating from the following nuclei: cochlear, trapezoid, superior olive, lateral
lemniscal, and inferior colliculus. The auditory fibers end on the medial geniculate
pars parvocellulares. This nucleus projects to area 41 in the temporal lobe, the
transverse temporal gyrus of Heschl. The ventral nucleus of the medial geniculate
receives input from the inferior colliculus. Vestibular fibers end in the magnocellu-
lar portion of the medial geniculate and are projected onto postcentral gyrus.
252 8 Diencephalon
Vision (also, see Chap. 15). The lateral geniculate nucleus (LGN) is a horseshoe-
shaped six-layered nucleus in the posterior margin of the thalamus with its hilus on
its ventromedial surface.
The visual stream of information is divided into two streams, a ventral stream
and a dorsal stream.
1. The ventral stream is for object identification, “what pathway,” which goes
directly from retina via the optic nerve to LGN and then projected onto visual
cortical area 17-V1 and also enters area MT in the temporal lobe and is involved
with object identification and recognition.
2. The dorsal stream for visually guided actions, the “how pathway.” This dorsal
stream goes to extrastriate cortex from the retina via the optic nerve, bypasses the
LGN, and synapses in the tectum of the superior colliculus. From the tectum of
the superior colliculus, the very extensive tectopulvinar tract terminates in the
inferior pulvinar nucleus/visual pulvinar nucleus. From the inferior pulvinar
nucleus, there is a projection onto extrastriate areas 18 and 19-V2 and V3 and
also terminates in the parietal lobe. This dorsal stream is involved with process-
ing the object’s spatial location (Ungerleider and Mishkin 1982). Figure 8.5
demonstrates the visual radiation onto the calcarine cortex of the occipital lobe.
This nucleus contains the six neuronal layers separated by bands of myelinated
axons. The four outer layers contain small- to medium-sized cells that project onto
layer IV of the striate cortex with the two innermost layers that contain large cells
(magnocellular) projecting onto layer I and deep portion of layer IV.
Crossed fibers of the optic tract terminate in laminae 1, 4, and 6, while uncrossed
fibers end in laminae 2, 3, and 5. This nucleus also connects with the inferior pulvi-
nar, ventral, and lateral thalamic nuclei. Some optic fibers proceed directly to the
pretectal area and the superior colliculus with or without synapsing in the lateral
geniculate nucleus. There they partake in the light reflex and accommodation reflex
(see Chap. 15).
Reticular nucleus of the thalamus. The thalamic reticular nucleus forms a cap
around the thalamus, medial to the internal capsule. All fiber systems leaving the
thalamus and projecting onto the cerebral cortex and the fibers coming back from
these same cortical areas pass through this nuclear complex with many specific
systems terminating in this nucleus. This nucleus contains GABA-ergic neurons
and has a modulating effect on thalamic neurons.
Midline nuclei. The midline thalamic nuclei (Fig. 8.4) are located in the
periventricular gray above the hypothalamic sulcus. They are small and difficult to
delimit in human beings, but these nuclei are intimately connected to the hypothala-
mus and the intralaminar nuclei, and their function must be interrelated.
Intralaminar nuclei. The intralaminar nuclei (Figs. 8.3 and 8.4) are found in the
internal medullary laminae of the thalamus. The most prominent intralaminar
8.2 Functional Organization of Thalamic Nuclei 253
Internal capsule (Figs. 8.5 and 8.6). At the lateral margin of the diencephalon is the
internal capsule, a major white matter bundle that contains fibers that connects the
diencephalon and the cerebrum. The internal capsule is a large myelinated region that
254 8 Diencephalon
marks the border between the diencephalon and telencephalon. The internal capsule,
consisting of the anterior limb, genu, and posterior limb, is best visualized in a hori-
zontal section, where it forms an obtuse angle. Note the putamen and globus pallidus
of the corpus striatum are external to the internal capsule (MRI, T2 weighted).
All fibers projecting from the thalamus onto the cerebral hemispheres must pass
through the internal capsule, while all fibers leaving the cerebral cortex and going
either to the diencephalon, basal nuclei, brain stem, or spinal cord must also pass
through its parts. In the following diagrammatic horizontal section, the three major
parts of the internal capsule are identified and their constituent fiber systems dis-
cussed: the anterior limb, genu, and posterior limb.
Anterior limb of the internal capsule (Figs. 8.5 and 8.6). The anterior limb lies
between the caudate nucleus and putamen, and this portion of the capsule contains
the anterior thalamic radiation and the frontopontine fibers.
Genu of the internal capsule. This region is found at the rostral end of the dien-
cephalon on the lateral wall of the lateral ventricle and is the point at which the fibers
are displaced laterally by the increasing bulk of the diencephalon. The corticobulbar
fibers are found in the genu.
Posterior limb of the internal capsule. The posterior limb of the internal capsule
consists of three subdivisions: thalamolentiform, sublenticular, and retrolenticular:
1. The thalamolenticular portion (between the thalamus and lenticular nuclei;
putamen and globus pallidus) contains the corticospinal, corticorubral, cortico-
thalamic, thalamoparietal, and superior thalamic radiations.
Fig. 8.6 Horizontal section through the thalamus, caudate, internal capsule, and lenticular nuclei
(globus pallidus parts I and I; putamen) with the major tracts and radiation in the right internal
capsule labeled. Note the relationship between the lenticular nuclei (globus pallidus and putamen)
and caudate to the internal capsule. Modified after Carpenter Core Text, Williams & Wilkins 1992
8.4 Relationship Between the Thalamus and the Cerebral Cortex 255
2. The sublentiform portion (passing inferiorly and posterior) includes the posterior
thalamic radiations that include optic radiation (Fig. 8.6), acoustic radiation and
corticotectal and temporal pontine fibers.
3. The retrolenticular portion (passing posterior into the temporal and occipital
lobes) contains the posterior thalamic radiation to the occipital and temporal
lobes and the parieto-occipital fasciculus. Many other myelinated fiber bundles
can be seen in the intrinsic thalamic nuclei (Table 8.3).
8.4 R
elationship Between the Thalamus and the Cerebral
Cortex (Figs. 8.7 and 8.8)
The relationship between many thalamic nuclei and cortical areas is so intimate that
when a cortical region is destroyed the neurons in a particular thalamic nucleus
atrophy (Walker 1938). This degeneration is a consequence of the thalamic projec-
tion and its reciprocal from the cortex, being restricted to only a single specific
cortical region and is seen in portions of the following nuclei: anterior, ventral lat-
eral, ventral posterior, lateral geniculate, medial geniculate, and magnocellular por-
tion of the medial dorsal and pulvinar. The intralaminar, midline, posterior, portions
of the pulvinar, and medial nuclei are unaffected by cortical lesions.
Thalamic input onto the cortical layers. The most important sensory input the
cerebral cortex receives is from the thalamus. The densest input from the specific
relay projectional nuclei (e.g., VPL, VPM) is to layer 4, but as indicated above,
pyramidal cells in layers 3 and 5 may also receive direct or indirect inputs. There is
256 8 Diencephalon
Fig. 8.7 Demonstrates the cortical projections from the individual thalamic nuclei. The upper
panel in blue demonstrates the thalamocortical projections onto the cerebral cortex. The lower
panel in red shows the cortical input onto each of the major thalamic nuclei
The zona incerta lies between the thalamus and lenticular fasciculus. The adjacent
substantia nigra also projects onto the subthalamus. The medial portion of the globus
pallidus provides the principal input to the subthalamus via the subthalamic fascicu-
lus, which runs through the internal capsule. The motor and premotor cortex also
project to this region. The subthalamus projects back to both segments of the globus
pallidus, and substantia nigra via the subthalamic fasciculus, and projects to the
thalamus and contralateral subthalamus. The glutaminergic cells in the subthalamus
form the main excitatory projection from the basal ganglia.
In the human, a lesion in the subthalamus, usually vascular in origin, produces hemi-
ballismus: purposeless, involuntary, violent, flinging movements of the contralateral
extremity. These movements persist during wakefulness but disappear during sleep.
This lesion represents underactivity in the indirect pathway (striatal neurons receive
inhibitory dopaminergic input (D2) and pass to the lateral/external) sector of the globus
pallidus mediated by the inhibitory transmitter GABA. Encephalin is also involved as a
transmitter or modulator in this pathway. The neurons of the lateral globus pallidus give
rise to inhibitory fibers again utilizing GABA which connect to the subthalamic nucleus.
In contrast to overactivity that produces Parkinsonism (see Chap. 12).
The thalamic terminations of the major ascending pathways are listed in Table 8.4
below.
Table 8.4 Thalamic terminations of major ascending pathways of the spinal cord brain stem and
cerebellum
Pathway and thalamic terminations Function
Anterolateral/spinothalamics > VPL and DM Pain and temperature
Trigeminothalamics > VPM and DM from the body, head, and
neck
Solitary tract > VPM Taste and general
sensation from the viscera
Cerebellar peduncles: Unconscious sensory and
Superior (cerebellum > VA and VL > cerebrum) motor
Middle (cerebrum > pons to contralateral cerebellum)
Inferior (cerebellum > brain stem and spinal cord and CN VIII)
Optic pathway (special sense) – (1) from retina via lateral Vision and light reflexes
geniculate to striate cortex (Chap. 13); (2) retina to optic of
midbrain tectum > inf. pulvinar > extrastriate cortex
Auditory pathway (special sense) – cochlear nuclei via lateral Audition
lemniscus auditory to inferior colliculus, brachium of inferior
colliculus to medial geniculate and to auditory cortex
Vestibular pathway (special sense-part of proprioceptive Balance (from inner ear)
pathway) – proprioceptive lateral vestibular nucleus to VPL and and proprioception
MGN then to postcentral gyrus
Gustatory pathway, special visceral from taste buds (cranial nerves Taste
VII, IX, and X) in the tongue, pharynx, and larynx to VPM in
thalamus > cortical areas in parietal operculum
Tectopulvinar pathway, inferior pulvinar nucleus Visual tracking
Reticular ascending portion > intralaminar, DM Emotions, consciousness
Monoamine containing >hypothalamus, intralaminar, DM, midline Set tone in motor system
Norepinephrine, dopaminergic, serotonergic and effect limbic system
Ascending sympathetic and parasympathetic to limbic Autonomic functions
thalamus > anterior, DM
8.6 Thalamic Atlas 261
The sections that follow include three levels of the thalamus and describe the
thalamic nuclei we have just identified in situ. In these levels note their location
within the thalamus and discuss their functions. At each level there will a myelin-
stained section with labeled diagrammatic section.
Fig. 8.11 Midthalamus
Gross Features. This level is near the caudal end of the thalamus with elements from
the midbrain and diencephalon present.
Diencephalon occupies the bulk of this section, with the corpus callosum, fornix,
and lateral ventricles forming its superior surface, and the third ventricle its medial
surface. The lateral wall of the diencephalon is formed by the posterior limb of the
internal capsule. The cerebral peduncles are prominent on the inferior surface; adjacent
to them are the substantia nigra and more medially the red nucleus. The laminate lateral
geniculate nucleus is prominent on the left side lateral to the cerebral peduncle.
Epithalamus. This nuclear grouping with its associated tracts is functionally part
of the visceral brain. The habenular nuclei and stria medullaris are present on the
medial surface protruding in the third ventricle. The habenulopeduncular tract is
seen on the left side connecting the medial habenular nucleus to the interpeduncular
8.7 Level: Midbrain, Diencephalic Junction 263
nucleus. At more posterior levels, the pineal gland is seen above the habenular
nuclei and commissure.
Thalamus. The bulk of the thalamus at this level consists of the pulvinar nuclei.
Which connects to the sensory associative cortex in the superior and inferior
parietal lobule? A large ovoid nucleus is present about one-third of the way in from
the third ventricle. This is the central median nucleus of the intralaminar group.
The ascending tract of the reticular system ends here and makes this nucleus impor-
tant in determining our level of consciousness. Lateral to this nucleus is the ventral
posterior medial nucleus. It receives the second-order gustatory and trigeminal
264 8 Diencephalon
fibers carried up to the thalamus in the medial lemniscus. This nucleus projects to
the inferior one-third of the postcentral gyrus, areas 3, 1, and 2 (see Chap. 20). Thus,
we have reached the final subcortical center for gustatory and trigeminal impulses.
Optic Thalamus. On the left side, the laminate lateral geniculate nucleus is pres-
ent. It receives the third-order fibers which stem from the ganglionic cell layer of the
retina via the optic nerve, chiasm, and tract. This thalamic nucleus projects to the
striate cortex on the medial surface of the occipital lobe.
Red Nucleus. This nucleus is conspicuous near the wall of the third ventricle and
receives input from the cerebellum via the superior cerebellar peduncles. It connects
to the ventral lateral nucleus of the thalamus and also to the alpha and gamma motor
neurons in the spinal cord via the rubrospinal tract.
Substantia Nigra. This large pigmented nucleus is an important part of the extra-
pyramidal system. It connects with the globus pallidus, hypothalamus, and midbrain
tegmentum and probably also the caudate–putamen.
Deep Telencephalic Gray. Although the caudate nucleus is a part of the telen-
cephalon, its tail is found in diencephalic levels on the most lateral wall of the
lateral ventricles separated from the thalamus by the external laminae of the thala-
mus. The stria terminalis is found on its medial surface; it is unrelated to the cau-
date nucleus and interconnects the amygdaloid nuclei. The caudate nucleus is an
important part of the extrapyramidal system having to do with supporting volitional
motor functions.
Cranial Nerve Nuclei. Cranial nerves are found only in the medulla, pons, and
midbrain. They are absent from diencephalic levels.
Fornix. This tract is an important part of the limbic or visceral brain. The fornix
originates from the hippocampus located in the medial surface of the temporal lobe.
It takes a circuitous pathway, following the inferior horn and body of the lateral ven-
tricle—through or around the internal capsule to reach the aforementioned nuclei.
Fornix. This tract connects the hippocampus with the septum, habenula, lateral
hypothalamic nucleus, and mammillary bodies. The fornix originates from the hip-
pocampus in the medial portion of the temporal lobe. It is suspended from the
undersurface of the corpus callosum up to the most anterior portion of the thalamus
where it enters the hypothalamus and passes to the mammillary body. In this cross
section, it is seen under the corpus callosum and in the substance of the hypothala-
mus. The hippocampus is an important part of the visceral brain and participates in
recent memory.
Gross Features. The diencephalon occupies the bulk of this section with the corpus
callosum, fornix, and lateral ventricles forming its superior surface, the third ven-
tricle, its medial surface, and the posterior limb of the internal capsule, its lateral
surface. The optic tract is prominent inferiorly, and it is below the lateral geniculate
8.8 Level: Midthalamus 265
nucleus where it will terminate. Lateral to the internal capsule are found the deep
telencephalic nuclei, the globus pallidus, and the putamen.
Epithalamus. The stria medullaris is seen on the superior margin of the third ven-
tricle. This tract connects habenula with the septum, amygdala, and hippocampus.
Thalamus. The thalamus at this level consists of two prominent divisions the medial
and lateral nuclei separated by the internal medullary laminar of the thalamus.
The medial portion, the medial nucleus, connects to the prefrontal and orbital
cortices and receives reciprocal innervation from these same regions as well as the
hypothalamus. It is an important subcortical nucleus in the visceral brain.
The lateral, more heavily myelinated portion consists of dorsal and ventral
regions. Posteriorly the pulvinar is the continuation of this dorsal group. The ven-
tral half consists of the nuclei which receive the specific ascending tracts from
lower levels of the CNS. The ventral posterior medial nucleus receives the ascend-
ing gustatory and cutaneous and proprioceptive fibers from the head. Present also
is the ventral posterior lateral nucleus, which receives the cutaneous (spinotha-
lamic and dorsal columns), proprioceptive (dorsal columns), and visceral informa-
tion via the media! Lemniscus projects to the upper two-thirds of the postcentral
gyrus. The ventral lateral nucleus receives the superior cerebellar peduncle and
projects to the motor and premotor cortices, areas four and six (see Chap. 9).
Consequently, in this section, we have reached the final subcortical center for the
dorsal columns, the spinothalamic and dentatorubrothalamic tracts.
Awareness of pain and temperature and crude touch are located in the ventral
posterior lateral nucleus. More specialized sensory awareness is found in the post-
central gyrus, i.e., the position of digits in space and tactile discrimination.
Hypothalamus. The hypothalamic sulcus, at the midpoint of the third ventricle,
marks the separation between the thalamus above and the hypothalamus below. At
this level a cell stain would show several hypothalamic nuclei at or near the ventricu-
lar surface. On the right side, even in this fiber stain, the mammillary body is con-
spicuous with the mamillothalamic and mammillotegmental fibers forming a capsule
on its medial surface. On the left side, the fornix is seen anterior to the mammillary
body. Near the ventricular surface is a prominent pathway, the mammillothalamic
tract, which connects the mammillary body with the anterior thalamic nuclei.
Subthalamus. This zone lies medial to the cerebral peduncle, below the medul-
lary laminae of the thalamus, and lateral to the hypothalamus. It has three principal
nuclei: (1) subthalamic, touching the cerebral peduncle; (2) zone incerta, below the
external medullary lamina; and (3) the tegmental nucleus of Forel (or prerubral
nucleus), lateral to the mammillothalamic tract. The lenticular fasciculus separates
the zona incerta above from the subthalamic nucleus below. This region is an impor-
tant region for relay in the extrapyramidal system because of its connections with
the globus pallidus, thalamus, and hypothalamus. Fibers reach the subthalamic zone
from the globus pallidus by going through the internal capsule.
Temporal Lobe. This lobe of the cerebrum forms the inferior region of the cere-
brum and contains the hippocampus.
266 8 Diencephalon
Fornix. This tract connects the hippocampus with the septum, habenula, lateral
hypothalamic nucleus, and mammillary bodies. The fornix originates from the hip-
pocampus in the medial portion of the temporal lobe. It is suspended from the
undersurface of the corpus callosum up to the most anterior portion of the thalamus
where it enters the hypothalamus and passes to the mammillary body. In this cross
section, on the dorsal surface of the hippocampus, the fimbria of the fornix is seen.
We next find it under the corpus callosum and the column of the fornix; it enters the
substance of the hypothalamus. The hippocampus is an important part of the vis-
ceral brain and participates in recent memory.
Deep Telencephalic Gray. The caudate (tail) nucleus, the putamen, and the glo-
bus pallidus are present in this section. The caudate nucleus is seen near the superior
surface of the thalamus. The globus pallidus and putamen are found lateral to the
posterior limb of the internal capsule. The globus pallidus is the heavily myelinated
nucleus just lateral to the internal capsule. It receives input from the caudate nucleus
and putamen while it provides the only efferents from the basal ganglia to the sub-
thalamus, the ventral anterior and the ventral lateral nuclei in the thalamus, hypo-
thalamus, the substantia nigra, and the midbrain tegmentum. The fibers leave the
globus pallidus and cut through or around the internal capsule to reach the afore-
mentioned nuclei.
Ventricular System. In this section, we find the following parts of the ventricular
system-inferior horn of the ventricle medial to the hippocampus: the body of the
ventricle above the thalamus and the third ventricle between the diencephalic halves.
Gross Features. This section is near the rostral end of the thalamus. The optic chi-
asm is prominent on the base of the third ventricle.
The diencephalon is much smaller than in the previous levels, while the deep
telencephalic nuclei, the globus pallidus, and the putamen are much larger than in
the previous section. The boundaries of the diencephalon are laterally, the posterior
limb of the internal capsule; medially, the third ventricle; and superiorly, the lateral
ventricle and corpus callosum.
Epithalamus. The stria medullaris is conspicuous on the medial surface of the
thalamus.
Thalamus. The thalamic nuclei at this level consist of two prominent divisions, the
anterior nuclei and the ventral anterior, separated by the internal medullary. The ante-
rior nuclei are important subcortical nuclei in the visceral brain because of their con-
nections to the cingulate cortex and the mammillary bodies. The internal medullary
laminae which separate the anterior nucleus from the ventral anterior nucleus consist
primarily of mammillothalamic fibers, while the external medullary lamina, which
touches the superior surface of the anterior nucleus, contains fibers interconnecting
the anterior nuclei and the cingulate cortex. The ventral anterior nucleus receives
fibers from the intralaminar nuclei, the ventral anterior nucleus, and globus pallidus
and projects to areas four and six (see Chap. 10), the motor and premotor cortices.
Bibliography 267
Hypothalamus. In this cross section, the fornix has just entered the hypothala-
mus. The optic chiasm forms the floor of the third ventricle. Note that a portion of
the fornix is also seen under the corpus callosum.
Subthalamus. This is absent from this cross section. The subthalamus is seen in
mid- and posterior thalamic sections (see preceding levels).
Deep Telencephalic Gray. The globus pallidus and putamen are conspicuous lat-
eral to the posterior limb of the internal capsule. Fibers can be seen leaving the
globus pallidus and sweeping around the internal capsule, as the ansa lenticularis, or
cutting through the internal capsule, the pallidothalamic fibers.
Anterior Commissure. The anterior commissure is seen on the inferior border of
the globus pallidus and putamen. This level is just caudal to the actual decussation
of the anterior commissure. The anterior commissure interconnects portions of the
rostral temporal lobe, olfactory bulb, and olfactory cortex, as well as the amygda-
loid nuclei (see Fig. 8.4).
Telencephalic Cortex. In this section the uncus containing the amygdala with
olfactory cortex forms the medial surface of the temporal lobe.
Bibliography
Abstract The hypothalamus is a very small nuclear mass found at the base of the
third ventricle in the diencephalon. Its functional potency is related to its control of
the hypophysis and its descending autonomic fibers, which affect preganglionic
parasympathetic and sympathetic nuclei in the brain stem and the thoracic, lumbar,
and sacral spinal cord. In addition, this diencephalic region with its important tracts
forms part of the Papez circuit and must be included in any discussion of the limbic
(or emotional) brain in Chap. 22.
9.1 Hypothalamus
The hypothalamus bilaterally forms the medial inferior part of the floor of the dien-
cephalon and is located on the wall of the third ventricle, extending from the ante-
rior margin of the optic chiasm to the posterior margin of the mammillary bodies. It
is bounded dorsally by the dorsal thalamus and laterally by the subthalamus and
internal capsule. It is connected to the hypophysis by the hypothalamic–hypophy-
seal tract and the hypothalamic–hypophyseal portal system. The hypothalamus con-
sists of more than a dozen nuclei with their associated fiber systems. Although the
hypothalamus weighs only 4 g, this small area controls our internal homeostasis and
influences emotional and behavior patterns.
Anatomically the hypothalamus is divided into a medial and a lateral zone (Fig. 9.1).
The medial zone consists of three regions:
1. The anterior zone, including the preoptic, supraoptic, periventricular, anterior,
and suprachiasmatic nuclei (Fig. 9.2)
Fig. 9.1 (a) The location, zones, and nuclei of the hypothalamus. The hypophysis and the nuclei of the
hypothalamus. (b) Location of stained coronal hypothalamic sections used in Figs. 9.2, 9.3, and 9.4
Fig. 9.3 Myelin and cell stain (Kluver–Barrera) of diencephalon at mid-hypothalamus, demon-
strating tuberal nuclei and mammillary bodies (×110)
272 9 Hypothalamus, Neuroendocrine System, and Autonomic Nervous System
Fig. 9.4 Myelin and cell stain (Kluver–Barrera) of diencephalon at posterior hypothalamus
(corpus callosum removed)
9.1 Hypothalamus 273
Fiber tracts and the neurosecretory system mediate the output of the hypothalamus.
The efferent pathways from the hypothalamus are:
1. Mammillothalamic tract, which interconnects the medial mammillary nucleus
with the anterior thalamic nucleus and, ultimately, with the cingulate cortex
274 9 Hypothalamus, Neuroendocrine System, and Autonomic Nervous System
Fig. 9.7 Information flow between the brain and endocrine system
The hypothalamus, through its relation with the autonomic nervous system and
hypophysis, maintains a more or less stable, controlled, internal environment
regardless of the external environment. It affects body temperature, water balance,
neurosecretion, sexual functions, food intake, sleep, and the parasympathetic and
sympathetic nervous systems.
9.2 N
euroendocrine System, the Hypothalamus, and Its
Relation to the Hypophysis
In addition to the direct control of the autonomic nervous system by central path-
ways, the hypothalamus has a powerful influence on other homeostatic mechanisms
of the human by its direct control of the hypophysis. The discussion that follows is
an overview of this information flow that is the basis of the neuroendocrine system
(Figs. 9.7 and 9.8).
276 9 Hypothalamus, Neuroendocrine System, and Autonomic Nervous System
Fig. 9.8 (a) The hypothalamic–hypophyseal tract (neurosecretory system). This tract provides a
direct connection between the hypothalamus and the neurohypophysis. (b1) Electron micrograph
of the hypothalamic–hypophyseal tract (neurosecretory system) neurohypophysis in a female
albino. Neurosecretory granules are seen in the axons of the hypothalamic–hypophyseal tract
where they are stored ×30,000. (b2). Herring body/neurosecretory body where the terminal ends
of axons from the hypothalamus terminate in the posterior pituitary and the neurosecretory materi-
als are temporarily stored here prior to their release ×8000
The hypophyseal gland or pituitary gland consists of two major divisions the ante-
rior lobe or adenohypophysis and the posterior lobe, the neurohypophysis. There is
also a smaller pars intermedia associated with the anterior lobe. The adenohypophy-
sis is the larger region and contains cords of different cell types closely associated
with capillaries of the hypothalamic–hypophyseal portal system. The neurohypoph-
ysis consists of the infundibular stalk and the bulbous neurohypophysis and includes
neuroglia like pituicytes, blood vessels and some finely myelinated axons.
9.2 Neuroendocrine System, the Hypothalamus, and Its Relation to the Hypophysis 277
Fig. 9.9 The hypothalamic–hypophyseal venous portal system. These venous channels provide
vascular continuity between the hypothalamus and the adenohypophysis with releasing factors
from the hypophysiotrophic area of the hypothalamus drains into the veins of the hypothalamus,
which connect to the capillary bed in the infundibular stalk and median eminence. The factors are
then carried to the adenohypophysis
278 9 Hypothalamus, Neuroendocrine System, and Autonomic Nervous System
Blood Supply. The hypophysis receives its blood supply from two pairs of arter-
ies: the superior hypophyseal arteries and the inferior hypophyseal arteries. The
superior hypophyseal arteries leave the internal carotid and posterior communicat-
ing arteries, and supply the median eminence, infundibular stalk, and adenohypoph-
ysis. In the infundibular stalk and median eminence, the arteries terminate in a
capillary network, which empties into veins that run down the infundibular stalk. In
the anterior lobe these veins form another capillary network, or sinusoid
The inferior hypophyseal arteries leave the internal carotid and distribute to the
posterior lobe, where they form a capillary network that flows into the sinus in the
adenohypophysis.
The hypophyseal veins finally drain into the cavernous sinus. The releasing fac-
tors enter the venous drainage of the hypothalamus, which drains into the median
eminence and hypophyseal stalk. These factors are then carried via the hypophyseal
portal system to the adenohypophysis. The capillary loops in the infundibular stalk
and neural hypophysis drain in close proximity to the corticotrophin neurosecretory
axons of the hypothalamic–hypophyseal tract.
The hypophysiotrophic area is a paramedian zone that extends rostral at the level of
the optic chiasm dorsally from the ventral surface to the paraventricular nuclei.
Caudally this area narrows down to include only the ventral surface of the hypothala-
mus at the level of the mammillary recess of the third ventricle. The hypophysiotrophic
center includes neurons in the following hypothalamic nuclei: paraventricular, ante-
rior, arcuate, ventromedial, and tuberal. Releasing and inhibitory factors, listed in
Table 9.2, are produced in the parvicellular hypophysiotrophic area and stimulate the
adenohypophysis to produce and release hormones into the circulation.
A 25-year-old male auto body mechanic in July developed numbness in the median
nerve distribution of the left hand with pain at the left wrist, shooting into the index,
middle, and ring fingers and aching pain in finger joints. To a lesser degree, similar
symptoms had developed in the right hand. The clinical impression of bilateral car-
pal tunnel syndrome was confirmed by nerve conduction studies. In addition, the
patient presented many of the facial features of acromegaly: coarse lips, large jaw,
and nose. None of his family had similar facial features, and according to his mother,
these features had emerged about age 12.
Growth hormone levels were consistently elevated to 17–20 ng/mL (normal is
less than 5 ng/mL fasting and recumbent). A glucose load produced no suppression.
Prolactin level was moderately increased to 37 ng/mL (normal in men is less than
1–20 ng/mL). MRI demonstrated an enlarged pituitary gland with a hypodense
lesion, consistent with an adenoma. A partial agenesis of the corpus callosum (sple-
nium and posterior one-third of the body) was also present and may have related to
long-standing learning disabilities.
9.2 Neuroendocrine System, the Hypothalamus, and Its Relation to the Hypophysis 283
9.2.6.2 Comments
there was a cystic pituitary mass (Fig. 9.10a demonstrates the normal-appearing
gland and Fig. 9.10b the cystic).
History was notable for hypertension, acid reflux, compression fracture and obesity.
He had a negative review of systems otherwise.
General exam revealed obesity and a very ruddy face with a prominent dorsal
thoracic fat pad. This is a typical cushingoid appearance. Mental status was
normal aside from anxiety. Language function was intact. Cranial nerve evalua-
tion demonstrated normal visual acuity and optic disks. There were full extra-
ocular movements and normal pupillary response. The lower cranial nerve exam
was normal. He had intact strength and tone. Sensory exam to both pin and
touch was normal. Reflexes were physiologic. Finger-to-nose testing was nor-
mal as was gait.
He underwent a transsphenoidal excision of this pituitary mass, confirmed to be a
pituitary adenoma. Cortisol levels were normalized, and hypertension was improved
at 2-month follow-up. He had intact endocrine function otherwise postoperatively.
Comment – The obesity, osteoporosis leading to the compression fractures, and
hypertension are all common features of Cushing’s disease. This is from over-
secretion of adrenal-stimulating hormones in the pituitary. This leads to excess cor-
tisol systemically leading to the above findings.
9.2.7 H
ypothalamus and the Autonomic Nervous System
(Fig. 9.12)
muscles in the tunica media, and the effects on the sweat glands result from the
stimulation of the glands through the cranial or peripheral nerves.
The hypothalamus, through its relation with the autonomic nervous system and
hypophysis, maintains a more or less stable, controlled, internal environment
regardless of the external environment. It affects body temperature, water balance,
neurosecretion, food intake, sleep, and the parasympathetic and sympathetic ner-
vous system.
Food intake. Bilateral lesions restricted to the ventromedial hypothalamic nuclei
produce hyperplasia, resulting in obesity. Stimulation of this center inhibits eating.
Experiments have shown that animals with ventromedial lesions are not motivated
to eat more; they just do not know when to stop eating. For this reason, it is thought
that the satiety center is located here.
Bilateral lesions in the lateral hypothalamic region produce anorexia; the animal
refuses to eat and eventually dies. However, if this region is stimulated but not
destroyed, the animal overeats. Appetite, the stimulus for eating, is dependent on
many factors, including glucose concentration in the blood, stomach distension,
smell, sight, taste, and mood. Lesions in other portions of the limbic system may
also affect appetite. Although obesity in humans usually does not have a neurologi-
cal cause, in rare cases, some overweight individuals have had a ventromedial nuclei
lesion.
Sleep cycle. The hypothalamus helps set our level of alertness with the assis-
tance of input from the reticular system and cerebral cortex (see Chap. 16). The
medial preoptic region can initiate slow wave sleep. The lateral hypothalamus
receives input from the ascending reticular system that produces arousal. The pos-
terior portion, including the mammillary body, is important in controlling the nor-
mal sleep cycle. Lesions in this region may produce an inversion in the sleep cycle,
or hypersomnia. Lesions in the anterior hypothalamus may produce insomnia.
The amount of light is monitored in the hypothalamus by input from the optic
nerve directly to the suprachiasmatic nucleus. The sympathetic innervation to the
pineal monitors the dark levels, and melatonin release from the pineal is part of the
sleep mechanism.
Body temperature. Maintenance of a constant body temperature is vital to a
warm-blooded animal. The hypothalamus acts as a thermostat, establishing a bal-
ance between vasodilation, vasoconstriction, sweating, and shivering. It does this by
means of two opposing thermoregulatory centers: one regulates heat loss, and the
other regulates heat production. Lesions in either of these centers interfere with the
regulation of body temperature.
Control center for heat loss. A destructive lesion in the anterior hypothalamus
at the level of the optic chiasm or in the tuberal region renders an animal incapable
286 9 Hypothalamus, Neuroendocrine System, and Autonomic Nervous System
is passed on to the hypothalamic nuclei, which then control the release of ADH into
the circulation.
Water intake is also controlled by hypothalamic neurons, with the area dorsal to
the paraventricular nuclei being one of the water intake centers.
Hypothalamus and emotions. As noted in Cases 9.1–9.2 and in Chap. 16, the
hypothalamus sets the foundation for emotional responses and controls visceral
functions. It exerts these powerful influences through the multisynaptic descending
autonomic pathways in the lateral margins of the reticular formation and by control-
ling the release of the catecholamine – epinephrine (adrenaline) and norepinephrine
(noradrenaline) – from the adrenal medulla.
Most postganglionic sympathetic fibers release a substance that is 80% epineph-
rine and 20% norepinephrine, which acts on alpha- and beta-adrenergic receptors in
the organs; these are called adrenergic fibers. Small doses of acetylcholine injected
into the bloodstream produce the same effect as stimulation of the cholinergic end-
ings of craniosacral column.
Norepinephrine causes constriction of the peripheral vessels, with resultant
increased blood flow in the large vessels. The blood pressure and pulse rate rise and
blood flow to the coronary muscles increases. Epinephrine increases the heart rate
and the force, amplitude, and frequency of heart contractions. It also dilates the
pupils and the urinary and rectal sphincters, causing voiding and defecation. It
inhibits the motility of the gut and causes the bronchial musculature to relax, thereby
dilating the bronchial passages.
Epinephrine increases oxygen metabolism, and the basic metabolic rate causes
hyperglycemia by increasing phosphorylase activity, which accelerates glycogene-
sis in the muscles and liver. And it increases the rate of synthesis of lactic acid to
glycogen, thereby prolonging the contraction of the skeletal muscle.
9.2.10 H
ypothalamus and Light Levels: Optic Nerve
Terminations in the Hypothalamus
The optic nerve brings direct visual input into the suprachiasmatic nucleus of the
hypothalamus via the retinohypothalamic pathway. In many animals abnormal vari-
ations in light levels alter the sexual cycle and prevent estrus. Light levels also affect
the formation of melanin.
Epithalamus. The epithalamus is a subcortical part of the limbic system and is
located on the dorsal surface of the diencephalon above the thalamus. It consists of
the pineal gland, habenular nuclei, stria medullaris thalami, and the habenulopedun-
cular tract (fasciculus retroflexus of Meynert). Through these tracts the habenular
nuclei have extensive connections to the septum and hypothalamus via the stria
medullaris thalami and to the interpeduncular nuclei and onto somatic and autonomic
nuclei in the brain stem and spinal cord, via the habenulopeduncular tract. Through
these same pathways, neuromodulators (especially the melatonin) produced in the
288 9 Hypothalamus, Neuroendocrine System, and Autonomic Nervous System
pineal have considerable influence on the development of the gonads, the release of
pituitary hormones, and the functions of the autonomic nervous system.
Pineal body (Fig. 9.12). The pineal, or epiphysis cerebri, is a small pinecone-
shaped gland found in the roof of the third ventricle. This richly vascularized gland
contains glial cells and pinealocytes and is innervated by the sympathetic nervous
system from the superior cervical sympathetic ganglion with synapses on the pine-
alocytes. Pinealocytes contain serotonin, melatonin, and norepinephrine. The
pineal makes melatonin from serotonin; the enzyme levels necessary for this trans-
formation are controlled by the suprachiasmatic nucleus. This nucleus sends fibers
via the descending sympathetic pathway into the medial forebrain bundle and via
the descending spinal fibers to the intermediolateral cell column of the upper tho-
racic cord and then onto the superior cervical ganglion. The pinealocytes are related
to the photoreceptor cells seen in this region in fish and amphibians. Pinocyte secre-
tion of serotonin and melatonin is a cyclic response to stimulation from the optic
system. These 24 h circadian rhythms may well be the biological clock.
Water balance and neurosecretion: hypothalamic–hypophyseal tract. Water
balance is regulated by the hypothalamic-hypophyseal tract, which originates in the
supraoptic and paraventricular nuclei and runs through the median eminence and
hypophyseal stalk to terminate in close proximity to blood vessels in the neural
hypophysis. A lesion in the region of the supraoptic nucleus or in the hypothalamic-
hypophyseal system causes diabetes insipidus with polyuria (excessive formation
of urine). The patient drinks copious amounts of water (polydipsia) and may excrete
20 L of urine a day. The symptoms of diabetes insipidus may be relieved by the
administration of vasopressin (Pitressin), an antidiuretic hormone (ADH), or extract
from the hypophysis.
The hypothalamic-hypophyseal tract controls the formation and release of ADH,
which causes water to be reabsorbed from the distal convoluted tubules and collecting
Fig. 9.12 Tumor of the pineal. This is an enlarged nonmalignant cyst arising from the pineal gland
(arrow) (Courtesy of Dr. John Hills and Dr. Jose Segarra). From Marcus and Jacobson, 2003
9.2 Neuroendocrine System, the Hypothalamus, and Its Relation to the Hypophysis 289
duct of the kidneys into the bloodstream, thereby limiting the amount of water lost
in the urine. Ingestion of large amounts of water causes a drop in the ADH level
reduces tubular reabsorption with resultant diuresis. Water deprivation increases the
ADH level and causes increased reabsorption and concentrated urine.
The cells in the supraoptic nuclei form much of the ADH or its precursors. ADH
is formed in the cell body, travels down the axons of the hypothalamic-hypophyseal
tract, and is stored in the posterior lobe of the hypophysis as neurosecretory gran-
ules. The osmoreceptors in the aortic and carotid body and in the hypothalamus,
itself detect the concentration of water in the blood. This information is passed on
to the hypothalamic nuclei, which then control the release of ADH into the circula-
tion. Water intake is also controlled by hypothalamic neurons, with the area dorsal
to the paraventricular nuclei being one of the water intake centers.
The hypothalamus sets the foundation for emotional responses and controls visceral
functions. It exerts these powerful influences through the multisynaptic descending
autonomic pathways in the lateral margins of the reticular formation and by control-
ling the release of the catecholamine—epinephrine (adrenaline) and norepinephrine
(noradrenalin)—from the adrenal medulla.
Most postganglionic sympathetic fibers release a substance that is 80% epineph-
rine and 20% norepinephrine, which acts on alpha- and beta-adrenergic receptors in
the organs; these are called adrenergic fibers. Small doses of acetylcholine injected
into the bloodstream produce the same effect as stimulation of the cholinergic end-
ings of craniosacral column.
Norepinephrine causes constriction of the peripheral vessels, with resultant
increased blood flow in the large vessels. The blood pressure and pulse rate rise and
blood flow to the coronary muscles increases. Epinephrine increases the heart rate
and the force, amplitude, and frequency of heart contractions. It also dilates the
pupils and the urinary and rectal sphincters, causing voiding and defecation. It
inhibits the motility of the gut and causes the bronchial musculature to relax, thereby
dilating the bronchial passages.
Epinephrine increases oxygen metabolism and the basic metabolic rate, causes
hyperglycemia by increasing phosphorylase activity, which accelerates glycogene-
sis in the muscles and liver. And it increases the rate of synthesis of lactic acid to
glycogen, thereby prolonging the contraction of the skeletal muscle.
Light produces dramatic effects that are mediated by the hypothalamus via the
direct input from the optic nerve, retinohypothalamic tract, to the suprachiasmatic
nucleus. In many animals abnormal variations in light levels alter the sexual cycle
and prevent estrus. Light levels also affect the formation of melanin.
290 9 Hypothalamus, Neuroendocrine System, and Autonomic Nervous System
Pineal Body (Fig. 9.12). The pineal, or epiphysis cerebri, is a small pinecone,
shaped gland found in the roof of the third ventricle. This richly vascularized gland
contains glial cells and pinealocytes and is innervated by the sympathetic nervous
system from the superior cervical sympathetic ganglion with synapses on the pine-
alocytes Pinealocytes contain serotonin, melatonin, and norepinephrine. The pineal
makes melatonin from serotonin; the enzyme levels necessary for this transforma-
tion are controlled by the suprachiasmatic nucleus. This nucleus sends fibers via the
descending sympathetic pathway into the medial forebrain bundle, and via the
descending spinal fibers to the intermediolateral cell column of the upper thoracic
cord and then on to the superior cervical ganglion. The pinealocytes are related to
the photoreceptor cells seen in this region in fish and amphibians. Pinocytes secre-
tion of serotonin and melatonin is a cyclic response to stimulation from the optic
system. These 24-h circadian rhythms are the biological clock (Fig. 9.12).
The student should examine in a gross anatomy text the details on the autonomic
nervous system. In this section we have included an overview of the relationship of
the autonomic nervous system to the CNS. Langley’s description of the autonomic
nervous system includes three parts: the sympathetic, parasympathetic, and enteric
nervous systems. The enteric nervous system is recognized as a separate portion of
the autonomic nervous system because peristalsis and other spontaneous move-
ments persist after its isolation from all nervous input (Gershon 2003). Much of the
effectiveness of the hypothalamus is due to its innervation of the nuclei in the cen-
tral nervous system that form the autonomic nervous system. In this section we
identify these neurons in the central and peripheral nervous systems and list the
responses produced by the autonomic nervous system in each organ. Note that nor-
mally an antagonistic balance exists between the functions of the parasympathetic
and sympathetic systems. However, this equilibrium may be modified by environ-
mental stresses or disease processes. The somatic nervous system has its own recep-
tors and effectors, which provide cutaneous and motor innervation to the skin and
muscles in the head, neck, and body. The visceral, or autonomic, nervous system
also has its own receptors and effectors, which provide dual motor and sensory
innervation to the glands, smooth muscles, cardiac muscles, viscera, and blood ves-
sels (review these relationships in a gross anatomy text). These axons run part of the
way with somatic fibers, but they also have separate pathways (Table 9.4).
In the somatic nervous system, the efferent neuron is the ventral horn cell or
motor cranial nerve nucleus. Its axon leaves the central nervous system to innervate
a skeletal muscle.
In the visceral nervous system, two efferent neurons are found:
1. The preganglionic neuron originates within the CNS and the preganglionic trans-
mitter Ach.
9.3 Autonomic Nervous System 291
Fig. 9.13 Autonomic nervous system: (A) - sympathetic-Blue, thoracolumbar); (B) parasympa-
thetic, (red, craniosacral). From Marcus and Jacobson, Integrated Neuroscience 2003
(b) In the parasympathetic division, the preganglionic ganglia are close to the
organ and the preganglionic fibers are long with Ach as the transmitter.
Cranial nerve III. The fibers originate in the Edinger–Westphal nucleus in the mid-
brain and innervate the constrictors of the pupil via the ciliary ganglion.
Cranial nerve VII. The axons originate in the superior salivatory nuclei of the
pons and innervate glands in the nasal cavity and palate and in the lacrimal (ptery-
gopalatine), submandibular, and sublingual (submandibular) glands.
Cranial nerve IX. The fibers originate in the inferior salivatory nucleus in the
medulla. The axons exit with nerve IX and end in the otic ganglion which controls
the parotid gland.
Cranial nerve X. The dorsal motor nucleus of the vagus nerve provides pregan-
glionic parasympathetic innervation to the pharynx, larynx, esophagus, lungs, heart,
stomach, and intestines up to the transverse colon. The postganglionic fibers origi-
nate from ganglia in the respective organs and in the nodes of the submucosal plexus
of Meissner and the myenteric plexus of Auerbach in the enteric nervous system
associated with the alimentary tract.
The parasympathetic sacral plexus originates from sacral segments S2 and S4 and
supplies the genitalia, sigmoid colon, rectum, bladder, and ureter. The ganglia are
located in the organ and are named for the organ.
9.5 Sympathetic System 293
In the alimentary canal (esophagus, stomach, intestines, and rectum), there are
about 100 million neurons (Gershon 2003). One network of neurons, Meissner’s
(submucosal) plexus, lies in the connective tissue between the longitudinal muscle
coat and the circular musculature coat in the alimentary canal. Another, Auerbach’s
(myenteric) plexus, lies in the connective tissue between the circular muscle coat
and the muscularis mucosa. Each plexus consists of multipolar, bipolar, and unipo-
lar neurons. The enteric nervous system includes glia that appears similar to the
astrocytes in the central nervous system. The astrocytes enwrap the neurons and
their processes and also form a barrier between the blood and the enteric nervous
system. There are extensive connections within the enteric nervous system and pro-
jections onto the pancreas, gallbladder, and elsewhere. The unipolar and bipolar
Fig. 9.14 Enteric nervous system-the nervous system for the alimentary canal. Benson, J. Atlas of
Female Pelvic Medicine and Reconstructive Surgery, Volume 1, Chapter 3. 2009
Bibliography 295
neurons appear to function as sensory neurons with the multipolar cells forming
many of the connections. The noradrenergic sympathetic postganglionic fibers proj-
ect onto the submucosal and myenteric plexus, where they are inhibitory to the
cholinergic neurons. (The cholinergic vagal input from the dorsal motor nucleus of
the vagus to the submucosa and mucous membrane is excitatory.)
Bibliography
Becker KL. Principles and practice of endocrinology and metabolism. 3rd ed. Lippincott: Williams
and Wilkins; 2001.
Bodian D. Cytological aspects of neurosecretion in opossum neurohypophysis. Bull Johns Hopk
Hosp. 1963;113:57.
Bodian D. Herring bodies and neuroapocrine secretion in the monkey: an electron microscopic
study of the fate of the neurosecretory product. Bull Johns Hopk Hosp. 1966;118:282.
Brady ST, Siegel GJ, Albers W, Price DL. Basic neurochemistry. Principles of molecular, cellular
and medical neurobiology medical aspects. Amsterdam: Elsevier; 2012.
Brownstein, M.J. 1989. Neuropeptides. In: Siegel, GJ, BW Agranoff, R W Albers, and PB Molinoff
(Eds) Basic neurochemistry. Molecular, cellular and medical aspects New York, Raven Press,
p. 287–309
Dudas B. The human hypothalamus: anatomy, functions and disorders. New York: Nova Science
Publishers; 2015.
Gershon MD. The second brain, enteric nervous system. New York: Harper Collins; 1998.
Green JD. The comparative anatomy of the portal vascular system and of the innervation of
the hypophysis. In: Harris GW, Donovan BT, editors. The pituitary gland, vol. I. Berkeley:
University of California Press; 1966. p. 127.
Haymaker W, Anderson E, Nauta WJH. The hypothalamus. Springfield, IL: Charles C Thomas; 1969.
Karczmar AG, Koketsu K, Nishi S, editors. Autonomic and enteric ganglia. New York: Plenum
Press; 1986.
Martin JB, Reichlin S, Brown GM. Clinical Neuroendocrinology. 2nd ed. Philadelphia: F.A. Davis;
1987.
McGeer PL, McGeer EG. Amino acid neurotransmitters. In: Siegal GJ, Agranoff BW, Albers RW,
Molinoff P, editors. Basic neurochemistry. 4th ed. New York: Raven Press; 1989. p. 311–32.
Muller EE, Nistico G. Brain messengers and the pituitary. New York: Academic Press; 1989.
Palay SL. The fine structure of the neurohypophysis. In: Waelsch H, editor. Progress in neurobiology:
II. Ultrastructure and cellular chemistry of neural tissue. New York: Paul B. Hoeber; 1957. p. 31.
Scharrer E. Endocrines and the central nervous system. Baltimore: Williams and Wilkins; 1966.
Szentagothai J, Flerko B, Mess B, Halasy B. Hypothalamic control of the anterior pituitary.
Budapest: Akademiai Kiado; 1968.
Wislocki GB. The vascular supply of the hypophysis cerebri of the rhesus monkey and man. Proc
Assoc Res Nerv Dis. 1938;17:48.
Chapter 10
Cerebral Cortex Functional Localization
Abstract Gross Anatomy. The cerebrum is the largest part of the brain and con-
sists of the cerebral cortex and basal ganglia. The cerebral cortex consists of four
lobes: the anteriorly placed frontal lobe, the parietal lobe in the middle, and the
occipital lobe posteriorly with the inferiorly placed temporal lobe. The cortical
neurons are found on the surface of the cerebrum covering the cortical white matter.
Deep to the white matter is found the basal ganglia which will be discussed in the
motor system.
Keywords Frontal lobe • Parietal lobe • Occipital lobe • Temporal lobe • Cingulate
gyrus • Thalamic nuclei left hemisphere • Right hemisphere
A firm knowledge of the structure and function of the cerebral cortex and the rela-
tionship of the cerebral cortex to the subcortical centers is of crucial importance for
all who wish to understand the behavior and accomplishments of humans as
opposed to other animal forms. The use of the thumb and fingers for fine manipula-
tions with tools, the use of linguistic and mathematical symbols for communication
in the auditory and visual spheres, and the capacity for postponement of gratifica-
tion all reflect the evolution of the cerebral cortex.
The cerebral cortical gray matter consists of 16 billion nerve cells and is organized
into a laminar arrangement with an almost infinite number of synapses. Colonnier
1966 have estimated that in a cubic millimeter of neocortex, there are 2.78 times
10\8 synapses 84% of which are type I (excitatory) and 16% type II (inhibitory).
The almost infinite number and variety of circuits present not only has provided the
anatomical substrate for the recording of an infinite number of past experiences but
has also allowed for a plasticity of future function projected both in time and in
Fig. 10.1 Diagram of the structure of the cerebral cortex. The results obtained with (a) a Golgi
stain, (b) a Nissl stain or other cellular stain, and (c) a myelin stain are contrasted. 1 = molecular
layer; 2 = external granular layer; 3 = external pyramidal layer; 4 = internal granular layer; 5 = large
or giant pyramidal layer (ganglionic layer); 6 = fusiform layer. The following features should be
noted in the myelin stain: 1a = molecular layer; 3a1 = band of Kaes Bechterew; 4 = outer band of
Baillarger; 5b = inner band of Baillarger (After Brodmann, from Ranson S. W., and Clark, S. L.:
The Anatomy of the Nervous System, Philadelphia, W. B. Saunders, 1959, p. 350)
10.1.2 Cytology
From the standpoint of cytology, the neurons within the cerebral cortex may be clas-
sified into two major categories pyramidal and stellate (Fig. 10.2). The axons of
pyramidal cells (type I cells/neurons with long axons) form the majority of associa-
tional, callosal, and subcortical projections, while the stellate cells (type II/neurons
with short axons) form the local circuits. Neurons may also be classified on the basis
of whether the dendrites have spines or an absence of spines.
From the standpoint of electrophysiology, the neurons may be classified as fast
spiking, regular spiking, or bursting (repetitive discharge).
1. Spiny neurons, neurons whose dendrites have spines, account for the majority
of the neurons in the cerebral cortex, Golgi rapid method (Figs. 10.2 and 10.3).
These are excitatory and are of two types:
(a) Pyramidal cells: constitute two-thirds of all neurons in the neocortex. These
cells are defined by a prominent apical dendrite extending through all layers
of the cortex to layer. Pyramidal neurons have cell bodies of variable
height—small 1–12 μ, medium 20–25 μ, large 45–50 μ, and giant 70–100 μ.
The giant pyramidal cells are characteristic of the motor cortex. The upper
end of the pyramidal cell continues on toward the surface as the apical
dendrite. Numerous spines are found on the dendrite providing a large sur-
face area for synaptic contact. The pyramidal neurons have the largest den-
dritic trees and also contain axons that form associational, callosal, and
projectional connections. In general, the larger the cell body, the larger the
apical dendrite and the wider the spread in terms of ramifications of the
terminal horizontal branches. The wider the spread of the apical dendrite,
the greater the number of possible axodendritic synapses. The larger the cell
300 10 Cerebral Cortex Functional Localization
2. Smooth neurons without spines also referred to as stellate cells. In these neurons,
the prominent apical dendrite is not present. Instead dendrites of almost equal
length radiate out from the cell body. These neurons are found in all layers but
predominantly in layer 4 of the sensory cortex. Their axons project locally within
the area and not to distant sites. The most common type of granule cell is the
basket cell that has axons that form baskets around the soma of the pyramidal
cells. The Retzius–Cajal neurons are horizontally oriented cells found in layer 1.
The Martinotti cell, the double bouquet cell of Cajal, and the chandelier cell have
a vertical orientation.
Physiology: The smooth cells are generally fast-spiking and make type II
inhibitory connections utilizing gamma aminobutyric acid (GABA) as the trans-
mitter. In contrast to pyramidal neurons, the action potentials of these fast-
spiking cells are brief; the repolarization phase is rapid and followed by a
significant undershoot. This has been correlated with very large, fast repolarizing
potassium current. The interrelationship of neurons within the neocortex is dem-
onstrated in Fig. 10.3.
10.2 B
asic Design and Functional Organization of Cerebral
Cortex
The cerebral cortex is characterized by two essential design principles: (1) the neu-
rons have a horizontal laminar arrangement, and (2) connections occur in a vertical
columnar manner; these vertical columns extend from pial surface to white matter.
A specific stimulus or a specific stimulus orientation activates each cylindrical col-
umn. Activation of a specific column also activates inhibition in adjacent columns,
the concept of inhibitory surround. In the primary sensory, each column is con-
cerned with a particular modality of sensation for a representation of the body or
specific sector of a field of stimulation. This columnar organization first was
described by Mountcastle for somatosensory cortex and has been subsequently
found throughout the cortex.
Fig. 10.4 The five fundamental types of cortical structures. Type I = agranular motor cortex; type
II = frontal granular; type III = parietal homotypical; type IV = polar cortex area 18; type V = gran-
ular konicortex (From C. Von Economo, The Cytoarchitectonics of the Human Cerebral Cortex.
London, Oxford University Press, 1929, p. 16)
2. Heterogenetic: This type of cortex does not have six layers at any time during
development or during adult life. This type of cortex is also called allocortex and
has three layers. There is also a transitional zone between the allocortex and the
neocortex: the mesocortex that corresponds to the cingulate gyrus, the parahip-
pocampal gyrus, the piriform area, and the anterior perforated substance
(Fig. 10.4).
10.4 T
he Schema of the Fundamental Six-Layered
Neocortices (Refer to Fig. 10.4)
Layer 2: External granular layer. This layer is a relatively densely packed layer
of small stellate granule cells and small pyramidal cells whose apical dendrites ter-
minate in the molecular layer and whose axons are sent to lower cortical layers.
Layer 3: External pyramidal layer. This layer is composed of medium to large
pyramidal cells whose apical dendrites extend to layer 1. The axons of these cells
function as association, commissural, or intracortical association fibers.
Layer 4: Internal granular layer. This layer is densely packed with granular/stel-
late cells. A dense horizontal plexus of myelinated fibers, the external band of
Baillarger, is also present composed of the branches of the specific thalamocortical
projection system. These fibers synapse with the stellate cells of this layer or the
basilar dendrites of the pyramidal cells of layer 3 or with the apical dendrites of the
pyramidal cells of layers 5 and 6.
Layer 5: Internal or large and giant pyramidal cell layer also called the gangli-
onic layer. This layer serves as the major source of outflow fibers particularly to
motor areas of the basal ganglia, brain stem, and spinal cord and possibly to the
projection nuclei of the thalamus. Although cortico-cortical output arises primarily
from the more superficial pyramidal cells of layer 3, layers 5 and 6 also provide such
an output. Note that there is some overlap of the functions of pyramidal cell of lay-
ers 5 and 6. Collaterals of the axons also function as intracortical association fibers.
In the deeper portion of this layer, a dense horizontal plexus of fibers is present, the
internal band of Baillarger.
Layer 6: Fusiform or spindle cell multiform layer. This layer is composed of a
mixture of spindle-shaped, pyramidal, and stellate cells. Dendrites ascend to various
cortical levels. The axons enter the white matter as short association fibers or ascend
to other cortical layers. However, the corticothalamic outflow usually originates
from pyramidal cells in this layer.
It is evident that in the adult human, not all areas of the neocortex have the same
appearance, and Brodmann found over 52 different areas and termed those areas of
homogenetic neocortex that demonstrated the typical six-layered pattern seen in
Fig. 10.1 as homotypical. There are other types of cortex including the agranular
motor cortex. This has many giant pyramidal cells present in layer 5 but with a
virtual absence of an internal granular layer 4. At the opposite extreme is the gran-
ular primary sensory projection cortex. Layers 2, 3, and 4 appear as an almost
continuous granular layer. Layers of 5 and 6 are thin and few large pyramidal cells
are present.
There have been other authors who have divided the cerebral cortex into areas.
Von Economo (1929) also divided the cerebral cortex into categories, and his labels
using letters (F = frontal, P = parietal, O = occipital, T = temporal) are included in
10.5 Organization of the Neocortex 305
Fig. 10.5 Dorsal view of the gross cerebrum of six mammals commonly studied for cerebral corti-
cal functions. Details: human adult male, 71 years old, 195 lbs; newborn human male, full term,
7 lbs; chimpanzee male, 7 years of age, 85 lbs; albino Sprague-Dawley rat male, 5 months of age,
230 g; NZW rabbit male, 5 months of age, 2500 g. Note the presence of gyri in the primate
brains—the human, the chimpanzee, and the rhesus monkey. Also, note the lunate sulcus two-
thirds of the way back from the frontal pole in the brain of the chimpanzee and rhesus monkey,
which is a major landmark separating the occipital lobe from the parietal in those primates which
is not evident in the human brains. The rat and rabbit have a Lissencephalic (smooth) cerebrum
with only a prominent rhinal sulcus found on the inferior border of the cerebrum
our discussion although in this text we will follow the number classification of
Brodmann: (Fig. 10.6a).
Brains of other mammals. In Fig. 10.5, we have included the brains of six
mammals that are commonly used in the study of cortical functions. Although as
you can see there is a great variation in size from the human in the upper left to the
rat and rabbit in the lower right, there are still many valid comparisons that can be
made from studying these diverse species. We have used as examples of gyrince-
phalic mammals the human, chimpanzee, and rhesus monkey; many other m ammals
do show major gyri including the commonly studied dog and cat. There are cytoar-
chitectonic atlases (Bailey and Von Bonin 1951; Conel 1939, 1968; Scheibel and
Scheibel 1967) available for these mammals and others following the Brodmann
numbers that permit very useful interspecies comparisons (Fig. 10.6).
Fig. 10.6 (a) Cytoarchitectural areas of the cerebral cortex as designated by Brodmann, 1909,
demonstrating 52 different areas with many subregions. (A) Lateral surface. (B) Medial surface
(From Curtis, Jacobson and Marcus. 1972: An Introduction to the Neurosciences: Philadelphia.
BA Saunders). (b) New map of cortical areas based on fMRI brain scan data collected by the
Human Connectome Project. The data revealed 97 new regions with many more still expected.
Matthew F. Glasser, David C. Van Essen, NIH-Human Connectome Project, Washington University
10.6 Correlation of Neocortical Cytoarchitecture and Function 307
Fig. 10.6 (continued)
10.6 C
orrelation of Neocortical Cytoarchitecture
and Function
The frontal lobe is the largest lobe in the cerebrum. The following cortical areas per
Brodmann (Fig. 10.6) are noted in the frontal lobe: primary motor area, 4; premotor,
6 and 8; inferior frontal (Broca’s), 44, 45, 47; frontal eye fields, area 8; prefrontal/
orbital, 46, 9, 10, 11, 12, 13, 14. It is customary to divide the frontal lobe into those
more posterior areas devoted to motor functions and those more anterior areas, pre-
frontal devoted to non-motor functions.
Fig. 10.7 (a) Diagrammatic of monkey cerebral cortex demonstrating the pattern of representa-
tion with the precentral area (MS1) and the main postcentral sensory area (SM1). The supplemen-
tary motor cortex (MSII) is also demonstrated on the medial surface of the cerebral hemisphere. A
second sensory area is demonstrated buried in the lateral fissure. (Note the arrangement of the body
parts in the part in the form of a simunculus rather than the homunculus.) Note the arrangements
of the body parts in the motor cortex with the shoulder representation anterior to the elbow, which
is anterior to the wrist and fingers. Note that the proximal body parts extend onto the premotor
cortex. All these findings are similar to what is seen in the human (From Shaltenbrand, G and CN
Woolsey; Cerebral Cortical Localization and organization. Madison, University of Wisconsin
Press. 1964, p. 18). (b) Cytoarchitecture of the cortical areas in the rhesus monkey (from W Krieg,
Brain Books 1985)
10.6 Correlation of Neocortical Cytoarchitecture and Function 309
Fig. 10.7 (continued)
310 10 Cerebral Cortex Functional Localization
Fig. 10.8 Atlas Fig. 23.1 demonstrates the lobes, gyri, and major sulci visible on the lateral sur-
face of the cerebral hemisphere
Fig. 10.9 Atlas Fig. 23.2 demonstrates the lobes, gyri, and major sulci visible on the medial sur-
face of the cerebral hemisphere
10.6 Correlation of Neocortical Cytoarchitecture and Function 311
Primary motor cortex, area 4 (FA), corresponds in general to the precentral gyrus.
It is continued onto the medial surface as the paracentral lobule (Fig. 10.9).
Stimulation: discrete repetitive focal movements are produced based on the area
stimulated, for example, repetitive jerks of the thumb or of the foot. A march of
focal movements may occur, for example, starting in the thumb and then spreading
to hand, then to arm, then to face and leg, etc. Figures 10.10 and 10.11 demonstrate
localizations seen in the motor sensory strip and motor strip after cortical stimula-
tion in the human.
Lesions: an upper motor neuron-type weakness occurs with a contralateral
monoplegia or hemiparesis.
Premotor cortex, area 6 (FB), is located anterior to area 4 and functions as
motor association or elaboration area (Figs. 10.9 and 10.10). This area also func-
tions to inhibit certain functions of the primary motor cortex. The supplementary
motor cortex represents the continuation of this area onto the medial aspect of the
hemisphere (Fig. 10.10).
Stimulation: Patterns of movement occur, for example, tonic rotation of the head,
eyes, and trunk to the opposite side associated with tonic abduction of the arm at the
shoulder and flexion of the arm at the elbow. Stimulation of the supplementary
motor cortex produces similar complex patterns of tonic movement. In addition
there are bilateral movements of the trunk and lower extremities.
Lesions: Transient release of “primitive” automatic reflexes mediated by the pri-
mary motor cortex such as instinctive grasp, and suck occurs. A more persistent
release of these instinctive reflexes follows the combined ablation of areas 6 and 8
and the supplementary motor cortex. Such lesions also produce a significant gait
apraxia—an impairment of the ability to walk without actual weakness or sensory
deficit. Other deficits in the initiation of patterns of movement in relationship to
somatosensory or visual stimuli may also occur.
Area 8 (FC) (Fig. 10.6) located anterior to area 6 in the middle frontal gyrus in
the human is often grouped with area 6 as premotor cortices. This area functions in
relation to conscious eye turning and is often referred to as the frontal eye field or
frontal center for adversive or contraversive eye movement. This area is involved
when the subject responds to the command “turn your eyes to the left (or right).”
312 10 Cerebral Cortex Functional Localization
The effects are mediated by descending crossed connections to the pontine center
for lateral gaze.
Stimulation: A conscious repetitive conjugate eye movement to the opposite field
occurs. More specific effects can also be achieved by discrete stimulation within
this area, for example, eyelid opening, repetitive eyelid movements, and pupillary
dilatation. Bilateral stimulation will result in conjugate upward eye movements
(Figs. 10.10 and 10.11).
Lesions: Transient paralysis of voluntary conjugate gaze to the contralateral
visual field occurs. In general, in man, this paralysis of voluntary gaze does not
occur in isolation but is associated with those processes such as infarction which
have also produced a severe hemiparesis. The patient then lies in bed with the con-
tralateral limbs in a hemiplegic posture and with the head and eyes deviated toward
the intact arm and leg. This deviation most likely reflects the unbalanced effect of
10.6 Correlation of Neocortical Cytoarchitecture and Function 313
Fig. 10.11 Motor representation as determined by stimulation studies on the human cerebral cor-
tex at surgery. The motor homunculus is arranged over the surface of a coronal section of the
cerebral hemisphere. Note the large area devoted to the thumb and fingers (From Penfield W. and
Rasmussen, T. The Cerebral Cortex of Man, New York, MacMillan, 1955, p. 215)
the adversive eye center of the opposite intact hemisphere. The effect is usually
transient clearing in a matter of days or weeks. A transient neglect syndrome pri-
marily involving the contralateral visual field occurs although contralateral tactile
and auditory stimuli may also be neglected. Bilateral ablations within this area in
the monkey, resulted in animals that had a bilateral neglect of the environment,
remained apathetic and continued to have a “wooden expression.” Similar findings
may occur in the human patient with degenerative disorders involving these frontal
areas (Fig. 10.9).
Areas 44 and 45 (FCB). These areas correspond in general to the inferior frontal
gyrus triangular and opercular portions. In the dominant (usually left) hemisphere,
this constitutes Broca’s motor speech center or the anterior speech center.
Stimulation (Figs. 10.11 and 10.12): arrest of speech occurs. Occasionally, sim-
ple vocalization occurs. A similar arrest of speech may also occur on stimulation of
the other speech centers—posterior and superior.
Lesion: A nonfluent aphasia occurs. The patient is mute. With limited lesions,
considerable language may return. While isolated lesions (e.g., embolic infarcts)
314 10 Cerebral Cortex Functional Localization
Fig. 10.12 Projection Fibers passing through the Internal Capsule-Horizontal Section. The
capsule is divided into an anterior limb, genu, and posterior limb. Ascending thalamocortical fibers
are found adjacent to the thalamus while the Descending corticofugal fibers (corticospinal and
corticobulbar) are more laterally placed adjacent to the lenticular nuclei
involving this area may occur, more often this type of language defect is associated
with a contralateral hemiparesis.
Prefrontal: Non-motor Areas
Areas 9, 10, 11, and 12 (FD), the prefrontal areas, are concerned with executive
functions including emotional control and other aspects of cognitive function
(Fig. 10.9). Areas 13 and 14 (FE, FF, FG, FH) are also often included in this group.
Stimulation: Complex partial seizures with alteration of personality, emotion,
and behavior occur often accompanied by tonic motor components. Note that 25%
of complex partial seizures originate in frontal lobe structures but 75% originate in
temporal lobe.
Lesion: An alteration in personality, affect, and control of emotion may occur,
and/or there may be an alteration in cognitive/executive function.
Postcentral gyrus. Areas 3, 1, and 2 (PA, PB, PC): These areas correspond to the
postcentral gyrus and function as the somatosensory projection areas from the body
and head including eyes and its fine movements (continue into paracentral lobule on
the medial surface of a hemisphere).
10.6 Correlation of Neocortical Cytoarchitecture and Function 315
The temporal lobe is a complex structure that includes six-layered neocortex and
more simple-appearing areas lacking six layers—the allocortex, the mesocortex,
and a subcortical nucleus (the amygdala). At its posterior borders, it merges into the
parietal and occipital lobes. The hippocampal formation and amygdala are in the
temporal lobe and are discussed in Chap. 15, the Limbic System.
Auditory cortex (transverse temporal gyri of Heschl) 41; auditory associational 42
and 22; middle temporal 21; inferior temporal 20; posterior temporal 37; entorhinal
27, 28, and 35. The temporal lobe lies below the lateral sulcus, and its lateral surface
has a sequence of three anterior to posterior arranged gyri: the superior, middle, and
316 10 Cerebral Cortex Functional Localization
inferior temporal gyri. The superior temporal gyrus forms the temporal operculum.
Near its posterior end, two gyri are seen running into the lateral fissure (Table 10.3).
These are the transverse temporal gyri, consisting of the primary receptive auditory
cortex, area 41. The middle temporal gyrus extends into the lateral occipital gyrus.
The inferior temporal gyrus extends onto the ventral surface of the cerebrum.
One of the first conclusive bits of evidence on the significance of anatomic asym-
metry in the cerebrum was noted by Geschwind and Levitsky (1968) in the temporal
lobe. They made a horizontal section through the lateral sulcus and removed the
overlying parietal and occipital cortex. They called this exposed region of the supe-
rior temporal gyrus the planum temporale. They noted a larger planum temporale in
the left temporal area than on the right side in right-handed humans (Wernicke’s
area). In left-handed individuals, the area was the same on both sides. Their obser-
vations on the anatomical basis of cerebral dominance have since been supported by
radiological and other anatomical studies.
Areas 41 and 42 (TC, TB), the transverse gyri of Heschl and primary auditory
cortex, extend into the lateral sulcus.
Stimulation: Episodic tinnitus (a ringing sensation) occurs. Usually such seizures
are not limited to this symptom in isolation, since other aspects of temporal lobe are
involved to produce the more complex phenomena of the temporal lobe seizure.
Lesions: Limited unilateral lesions may produce a disturbance in the ability to
localize sounds. Bilateral lesions of a limited nature would be rare but could pro-
duce “cortical deafness.”
Area 22 (TA) corresponds to the superior temporal gyrus and surrounds areas
41–42. This is an auditory higher association center. In the dominant hemisphere,
the posterior half of this area represents an auditory association area concerned with
the reception and interpretation of spoken language. This is one component of the
posterior speech area. The area is often referred to as Wernicke’s receptive aphasia
center. In the non-dominant hemisphere, this area is more concerned with visual
aspects of space.
Stimulation: Stimulation of the posterior speech (Wernicke’s) area (Fig. 16.2)
produces an arrest of speech. Seizures originating in the superior temporal gyrus are
also characterized by “experiential” phenomena: distortions of auditory and visual
10.6 Correlation of Neocortical Cytoarchitecture and Function 317
perception alterations in the sense of time and in well-formed visual and auditory
hallucinations (psychical seizures). Complex partial seizures may begin with these
phenomena but subsequently proceed to impairment of awareness; amnesia and
automatisms (unconscious stereotyped patterns of movement) reflect involvement
of or spread to the mesial temporal areas of hippocampus and amygdala. Fear that
may also accompany these seizures reflects involvement of the amygdala. Olfactory
hallucinations that may also accompany these seizures reflect involvement of the
mesial temporal structure, the uncus.
Lesions: Damage to Wernicke’s area, a part of the posterior speech area, produces
a deficit in the comprehension of speech, a type of fluent aphasia. Suffice it to say,
that bilateral damage to the hippocampus will produce severe deficits in the ability
to record new memories. Damage to the amygdala will alter emotional control.
The occipital gyri consist of visual receptive cortex/calcarine cortex found on the
medial surface of the hemisphere around the calcarine sulcus, striate cortex, and
visual associative cortex on the lateral surface of the hemisphere.
Most of our understanding of occipital lobe function comes from simian studies.
In nonhuman primates, up to now, at least six visual areas have been identified in the
occipital and temporal lobe:
V1—corresponding to area 17 in humans.
V2 and V3—corresponding to area 18.
V4—corresponding to area 19.
V5/MT—area 19 in the posterior portion of the superior temporal gyrus is active
in smooth pursuit of eye movements.
V6—dorsomedial area of area 19.
Area 17 (OC—nomenclature of von Economo and Koskinas, 1925), the stri-
ate cortex, corresponds to the striate cortex bordering the calcarine sulcus and func-
tions as the primary visual projection area. In modern physiological terms, the
designation V1 is utilized.
Stimulation: Seizures originating in this area produce simple unformed visual
hallucinations such as flashing lights, stars, or jagged lines. The phenomena may be
localized to the contralateral visual field or at times to the contralateral eye.
Lesions: Homonymous visual deficits are produced, for example, a homony-
mous hemianopsia or quadrantanopsia.
Areas 18 and 19 (OB, OA), extrastriate cortex, form surrounding stripes around
area 17. These areas function as visual association areas of varying complexity. The
terms V2–V4 are utilized. These areas are also involved in the fixation and follow-
ing of objects in the contralateral visual field. Note that visual areas V4 and V5
extend into the adjacent temporal–parietal cortex.
Stimulation: Some of the effects are similar to stimulation of area 17. In addition,
conjugate deviation of the eyes to the contralateral field will occur.
Lesions: Selective lesions may produce deficits in some of the more complex
visual activities. In addition, defects in visual fixation and following may occur
(see Chap. 14).
There are fundamentally three types of fiber systems that occupy the subcortical
white matter:
1. Projection fibers
2. Commissural fibers
3. Association fibers
1. Projection fibers consist of the corticopetal/afferent fibers (the thalamocortical
radiations) and the corticofugal efferent fibers (the corticothalamic, corticospi-
nal, corticoreticular, corticopontine, and corticorubral tracts) (Fig. 10.12).
2. Commissural fibers. The major commissural systems are the corpus callosum,
anterior commissure, and hippocampal commissure.
Callosal connections. The corpus callosum is the major commissure for the
neocortical areas (Figs. 10.13 and Atlas level Figs. 23.1–12 for labeled gross
sections and; Figs. 24.1–24.12 for myelin stained sections).
Fig. 10.14 (A) The International Federation Ten-Twenty Electrode Placement System. Frontal
superior and posterior views and a single plane projection of the head demonstrating the standard
positions and the Rolandic and Sylvian fissures. The term ten-twenty is based on the placement of
electrodes at percentages of the distance between nasion and inion. From Jasper, H.H.:
Electroencephalogr Clin Neurophvsiol. 10: 374, 1958 (Elsevier). (B) The normal adult electroen-
cephalogram. The patient is awake but in a resting state, recumbent with eyes closed. F = frontal,
T = temporal, C = central, and 0 = occipital. (Bipolar recordings) These abbreviations will be uti-
lized in subsequent illustrations. (C) Effects of eye opening and closure. Opening is associated
with a blocking or suppression of the alpha rhythm of 10 cps and with the appearance of a low-
voltage fast activity of 20 cps (beta rhythm). With eye closure, there is a return of the alpha rhythm
Anterior commissure (in the Atlas examine sections Figs. 28.3 and 28.11). The
anterior commissure interconnects the rostral portions of the superior, middle, and
inferior temporal gyri, inferior–posterior orbital gyri and paleocortex (parahippo-
campal gyrus).
Hippocampal commissure. The hippocampal commissure interconnects the hip-
pocampal formation and dentate gyri (archicortex) and the surrounding presubicu-
lum, entorhinal, and adjacent inferior temporal gyrus. These fibers are conveyed via
the fimbria of the fornix and cross at the point beneath the splenium of the corpus
callosum, where the posterior pillars of the fornix converge.
3. Associational fibers. Two types of subcortical association fibers may be distin-
guished: (a) short subcortical fibers, U fibers, which interconnect adjacent gyri,
and (b) long fiber bundles which reciprocally interconnect distant cortical areas.
The following long fiber bundles have been identified (Fig 10.13 and Atlas
sections Figs. 13.1–10 gross brain sections and Figs. 14.1–12 myelin stained
sections:
(a) The superior longitudinal fasciculus interconnects the superior and lateral
frontal, parietal, temporal, and occipital areas (Fig. 15.5). The arcuate fas-
ciculus is an extension of this fiber system into the temporal area, passing
through the subcortical white matter of the supramarginal and angular gyri.
This fasciculus has considerable importance because of its role in connect-
ing Wernicke’s receptive language centers of the temporal lobe with Broca’s
expressive motor speech centers of the inferior frontal gyrus. Such a connec-
tion must be made if a sentence that has been heard is to be repeated.
(b) The inferior longitudinal fasciculus interconnects the occipital and inferior
temporal areas.
(c) The inferior frontal–occipital fasciculus interconnects the frontal and occip-
ital areas. It is often difficult to clearly differentiate this fiber system from
the uncinate fasciculus.
(d) The uncinate fasciculus passes deep to the lateral sulcus and interconnects
the orbital, medial, and prefrontal areas and the anterior temporal area.
(e) The cingulum passes within the subcortical white matter on the medial sur-
face of the cerebral hemisphere in the cingulate gyrus; it interconnects the
subcallosal, medial–frontal, and orbital–frontal with the temporal lobe,
occipital areas, and cingulate cortex.
10.8 A
fferent Inputs and Efferent Projections
of the Neocortex
(a) Projections occur in a reciprocal manner with many subcortical areas (thala-
mus, basal ganglia, brain stem, and spinal cord). However, these projections
are estimated to account for only 0.1–1% of all fibers in the white matter.
Instead most fibers are involved in intrahemispheric (associational) and
interhemispheric (callosal) connections.
10.8 Afferent Inputs and Efferent Projections of the Neocortex 321
(b) The thalamus is the major source of afferents to the cortex with glutamate, the
prime transmitter. With the exception of the olfactory system, all sensory infor-
mation passes through the thalamus. The thalamus is composed of a series of
relay nuclei that connect in a reciprocal manner with the cerebral cortex and the
striatum (refer to Chap. 8); these nuclei can be subdivided into specific projection
(or relay) nuclei and nonspecific or diffuse projection nuclei (Figs. 8.7 and 8.8
and thalamic atlas Figs. 8.10–8.12).
The dorsal thalamus, Chapter 8) is by far the largest region in the thalmic region
of the diencephalon. This region is composed of a series of relay nuclei that connect
in a reciprocal away with the cerebral cortex and striatum. These nuclei can be sub-
divided into specific projection or relay nuclei and/or nonspecific or diffuse projec-
tion nuclei.
The specific nuclei have specific afferent inputs and project in a relatively precise
topographic manner to specific areas of the cerebral cortex. Experience, or func-
tional disuse, may modify the precise cortical areas devoted to the topographic rep-
resentation of a given sensory area. Examples of specific nuclei (VL, VPL, VPM,
MGN, LGN) and their cortical projections have been provided in Chap. 8. The
densest input from the specific relay projection nuclei is to layer 4, but as indicated
above, pyramidal cells in layers 3 and 5 may also receive direct or indirect inputs.
There is a modality specific columnar arrangement.
The nonspecific nuclei have a more diffuse input and a more diffuse but not nec-
essarily a generalized cortical interaction. Examples include the following: midline
nuclei, central–medial, intralaminar nuclei, reticular, and medial dorsal (which is
diffuse to frontal areas). The nonspecific nuclei project mainly to layer 1.
The ventral thalamus is a thin shell of nuclei that is external to the external
medullary lamina. It does not project directly to the cerebral cortex but receives
innervation from the cerebral cortex. The subnuclei grouped as the thalamic retic-
ular nucleus have specific reciprocal relationships with projection (relay) nuclei
in the dorsal thalamus. These nuclei in the rodent (but not in the primate) have a
high concentration of GABAergic neurons. The drive on the relay nuclei is there-
fore inhibitory.
The epithalamus includes the pineal body, the stria medullaris, and the habenu-
lar trigone. These structures relate primarily to the hypothalamus and are not rele-
vant to a discussion of thalamocortical connections.
There are multiple other subcortical sources of input including the following.
1. Noradrenergic (norepinephrine) pathway from the locus ceruleus of the mid-
brain projecting in primates predominantly to layer 6 of the motor and somato-
sensory cortex and related frontal and parietal association cortex. This pathway
functions in relationship to arousal responses induced by sensory stimuli, and
activity in this system is altered during the rapid eye movement stage of sleep.
322 10 Cerebral Cortex Functional Localization
2. Serotoninergic pathway from the raphe nuclei in the pons and medulla and the
pontine reticular formation. Although these neurons project to all cortical areas,
the predominant projection in the primate is to layer 4 of area 17, the primary
visual cortex. This system may be involved in the onset of the slow-wave stage
of sleep. During rapid eye movement sleep, there is decreased activity in this
system. Damage to the system produces insomnia.
3. Dopaminergic pathways from ventral tegmental—rostral mesencephalic
nuclear groups. The strongest projection is to the prefrontal cortex and limbic
system. The fibers extend to all cortical layers except for 4. The projection is
primarily inhibitory. This system is probably involved when psychotic behavior
occurs in schizophrenia.
4. Cholinergic pathways from the basal forebrain nucleus (of Meynert) project
widely to the cerebral cortex. In addition, cholinergic neurons in the septum
project to the hippocampus. In addition, cholinergic neurons in the brain stem
tegmentum project to the thalamus. Electrical stimulation of brain stem reticular
formation (resulting in desynchronization/arousal of the EEG) results in an
increase in rate of liberation of acetylcholine from the surface of the cerebral
cortex. This effect may be mediated through the reticular formation projection to
the basal forebrain.
5. GABAergic inhibitory pathways from the basal forebrain, ventral tegmental
area, and zona incerta to the sensory and motor cortex.
6. The claustrum projects to all sensory, limbic, and motor areas with an excit-
atory input.
10.9 M
ethods for the Study of Functional Localization
in the Cerebral Cortex
10.9.1.1 Stimulation
Various disease processes in man involving the cerebral cortex may produce a local
area of excessive discharge, in a sense, a local area of stimulation resulting in focal
seizures. Actually, our first understanding of cortical function was derived from the
systematic study of such cases of focal discharge (termed focal seizures, or focal
convulsions, or focal epilepsy, or epileptiform seizures) by Hughlings Jackson in
10.9 Methods for the Study of Functional Localization in the Cerebral Cortex 323
1863 and 1870. Jackson was able to predict that an area existed in the cerebral cortex
that governed isolated movements of the contralateral extremities. Such focal sei-
zures are also referred to as partial seizures in the International Classification (see
Commission, 1981, 1989). These partial seizures are subdivided into simple partial
(simple motor or sensory or psychic symptoms) as contrasted to complex partial
(complex motor sequences of automatic behavior and/or alterations in mental func-
tion as regards perception, memory, and affect) accompanied by impairment of con-
sciousness, confusion, and amnesia. Partial seizures or partial epilepsy must be
distinguished from those seizures which are nonfocal that is bilateral or generalized
in their onset (generalized or idiopathic epilepsy in the International Classifications).
Other methods of stimulation—electrical stimulation—of the cerebral cortex may
be carried out, in the human patient undergoing operative procedures on the cerebral
cortex to identify specific cortical areas. Transcranial electrical and magnetic stimu-
lation of the cerebral cortex has been developed as a clinical technique.
10.9.1.3 Lesions
In humans many conditions can produce damage to the cerebrum including inter-
ruption of the blood supply, tumors, or trauma. Clinical pathological correlation has
produced considerable information.
324 10 Cerebral Cortex Functional Localization
1. The observed effects may indicate deficits directly related to a failure of a posi-
tive function normally subserved by the area destroyed. For example, after
destruction of parietal somatosensory projection areas, deficits in stereognosis
and position sense occur.
2. The effects may reflect the release of centers in other cortical areas or at other
levels of the neural axis. This presumes that the area ablated usually inhibits
certain functions of these other centers. The end result then is an enhancement of
certain functions. Spasticity several days, weeks, or months after ablation of the
motor cortex is an example.
3. A temporary loss of function of a lower center may follow acute ablation of
higher centers. For example, following acute unilateral ablation of all motor cor-
tex in man, there will be observed a temporary loss or depression of deep tendon
reflexes and of other stretch reflexes in the contralateral extremities. There will
be initially a flaccid paralysis. This state (referred to as the “diaschisis of von
Monakow”) is analogous to spinal shock or pyramidal shock. As recovery from
this state occurs, deep tendon reflexes return and become progressively more
active. The flaccid paralysis is replaced by a spastic paresis. Trans-hemispheric
effects also occur as discussed by Andres (1991).
The initial method was postmortem correlation of lesion location with the specific
symptoms and signs. Initially, data as to the actual location of the disease process
and its nature (old scar from traumatic injury, old area of tissue damage due to isch-
emia, infection, local compression, or invasive brain tumor) were dependent on final
examination of the brain at autopsy. One may then speak of the method of clinical
pathological correlation. With the development of neurosurgery, it became possible
to define and to confirm during life the anatomical boundaries of the disease pro-
cess, often allowing for treatment or cure of the basic disease process. The special-
ized techniques of electroencephalography, arteriography, pneumoencephalography,
and radioactive brain scan were developed during the 1930s, 1940s, and 1950s, to
provide some information about localization prior to surgery. The subsequent devel-
opment of the more precise noninvasive imaging techniques of computerized axial
tomography (CT scan), magnetic resonance imaging (MRI scan), and positron
emission tomography (PET scan) during the 1970s and 1980s now provides the
closest correlation of clinical findings and anatomical location of the lesion in the
living patient, supplanting the earlier radiological techniques of arteriography,
pneumoencephalography, and radioactive brain scans.
fMRI—Human Connectome Project. The fMRI is a functional neuroimaging
producer using MRI technology to measure brain activity by detecting changes asso-
ciated with blood flow. With cerebral blood flow and neuronal activity coupled, it
produces accurate functional localization in the brain and is the basis of the new
maps being generated in the Human Connectome Project which is funded by the
NIH. The Connectome Project already has identified over 100 new functional regions
10.9 Methods for the Study of Functional Localization in the Cerebral Cortex 325
above those initially reported by Brodmann and others from cytoarchitectural studies
(Fig. 10.7).
Concept of representation and rerepresentation of function: In considering func-
tional localization, one must keep in mind that a given function may be represented
and re-represented at the various levels of the neural axis.
Ontogenetic factor. In considering the effects of lesions, one must also consider
the ontogenetic factor. Bilateral ablation of the prefrontal cortex in the adult monkey
produces impairment in the capacity to delay responses. Bilateral prefrontal abla-
tion at 1 week of age in the infant monkey does not have this effect. Such a monkey
when tested at 4 months, the usual age when the capacity to delay response appears,
is able to manifest this capacity. Similar observations may be made with regard to
somatosensory and visual pattern discrimination in the infant cat as compared to
adult cats following the appropriate resection of the somatosensory or visual projec-
tion cortex. Similar observations may be made in the human. Thus, extensive
destruction in most adults of the speech areas in the left hemisphere will result in a
marked and lasting deficit in linguistic expression (so-called Broca’s expressive
aphasia). Destruction of this same area in the infant or young child does not produce
an enduring defect.
10.9.3 N
europhysiology Correlates of Cortical
Cytoarchitecture and the Basis
of the Electroencephalogram
The cerebral cortex of the human and of other mammals is characterized by con-
tinuous rhythmic sinusoidal electrical activity of variable frequency. This electrical
activity may be recorded through the scalp of man in the form of the electroen-
cephalogram (EEG) or directly from the cerebral cortex during surgery in the form
of the electrocorticogram (ECG). The term EEG will be used during the subse-
quent discussion to refer to the activity found in either the EEG or the ECG. The
electroencephalogram provides a physiologic correlate of the various states of
consciousness.
1. Alpha Rhythm
The normal electroencephalogram (EEG) in the awake adult who is recorded
while resting with eyes lightly closed is characterized by a dominant activity in
the posterior (parieto-occipital) recording areas of continuous 8–13 Hz sinusoi-
dal waves of 25–75 μV. Amplitudes recorded directly from the cortex are higher.
This pattern is referred to as the alpha rhythm since this was the first pattern
discovered.
2. Beta Rhythm
The second described pattern, the beta rhythm, is found predominantly in the
frontal recording areas and consists of low amplitude 14–30 Hz activities. Many
326 10 Cerebral Cortex Functional Localization
Bailey P, von Bonin G. The isocortex of man. Urbana, IL: University of Illinois Press; 1951.
Brodal A. Neurological anatomy in relation to clinical medicine. 3rd ed. New York: Oxford
University Press; 1981.
Brodmann, K.. Localization in the cerebral cortex. English translation by Garey LJ. London:
Smith-Gordon; 1994.
Brazier, M.A.B.. The electrical activity of the nervous system. 4th ed. Baltimore: Williams and
Wilkins; 1977. p. 66–74, 175–208, 217–36.
Colonnier ML. The structural design of the neocortex. In: Eccles JC, editor. Brain and conscious
experience. New York: Springer-Verlag; 1966. p. 1–23.
Conel J. The postnatal development of the human cerebral cortex, vol. I–VI. Cambridge, MA:
Harvard University Press; 1939–1968.
Eccles JC, editor. Brain and conscious experience. New York: Springer Verlag; 1966.
Engel J Jr. Seizures and epilepsy. Philadelphia: F.A. Davis; 1989. p. 41–70.
Lorente de No R. Cerebral cortex: architecture, intracortical connections, motor projections. In:
Fulton JF, editor. Physiology of the nervous system. 3rd ed. New York: Oxford University
Press; 1949. p. 288–330.
Peters A, Jones EG, editors. Cerebral cortex I: cellular components of the cerebral cortex.
New York: Plenum; 1984.
Rakic P, Singer W, editors. Neurobiology of neocortex. New York: Wiley; 1988.
Reeves AG, editor. Epilepsy and the corpus callosum. New York: Plenum; 1985.
Von Bonin G, Bailey P. The Neocortex of MacacaMulatta: University of Illinois Press; 1947.
Callosal References
Curtis HH. Inter cortical connections of corpus callosum as indicated by evoked potentials.
J Neurophysiol. 1940;3:407–13.
Dehay C, Kennedy H, Bullier J, et al. Absence of interhemispheric connections of area 17 during
development in the monkey. Nature. 1988;331:348–50.
Duchowny M, Jayakar P, Levin B. Aberrant neural circuits in malformation of cortical develop-
ment and focal epilepsy. Neurology. 2000;55:423–8.
French JD, Gernandt BE, Livingston RB. Regional differences in seizure susceptibility in monkey
cortex. Arch Neurol Psychiatr. 1956;72:260–74.
Jacobson S, Marcus EM. The laminar distribution of fibers of the corpus callosum: a comparative
study in rat, cat, monkey and chimpanzee. Brain Res. 1970;24:517–28.
Jacobson S, Trojanowski JQ. The cells of origin of the corpus callosum in rat, cat and rhesus mon-
key. Brain Res. 1974;74:149–55.
Jones EG. Anatomy, development and physiology of the corpus callosum. In: Reeves AG, editor.
New York: Plenum; 1985.
Killackey HP. The organization of somato-sensory callosal projections: a new interpretation. In:
Reeves AG, editor. Epilepsy and the corpus callosum. New York: Plenum; 1985. p. 41–53.
Killackey HP, Chalupa LM. Ontogenetic changes in the distribution of callosal projection neurons
in the post central gyrus of the fetal rhesus monkey. J Comp Neurol. 1986;244:331–48.
Marcus EM. Generalized seizure models and the corpus callosum. In: Reeves AG, editor. Epilepsy
and the corpus callosum. New York: Plenum; 1985. p. 131–206.
Marcus EM, Watson W, Jacobson S. Role of the corpus callosum in bilateral synchronous dis-
charges induced by intravenous pentylenetetrazol. Neurology. 1969;19:309.
Martin JH. Cortical neurons, the EEG and the mechanisms of epilepsy. In: Kandel ER, Schwartz
JH, editors. Principles of neural science. 2nd ed. New York: Elsevier; 1985. p. 636–47.
328 10 Cerebral Cortex Functional Localization
McCulloch WS. Cortico-cortical connections. In: Bucy PC, editor. The precentral motor cortex.
Urbana, IL: University of Illinois Press; 1944. p. 211–42.
McNamara JC. Excitatory amino acid receptors and epilepsy. Curr Opin Neurol Neurosurg.
1993;6:583–7.
Meyer BU, Roricht S, Grafin von Einsiedel H, et al. Inhibitory and excitatory interhemispheric
transfers between motor cortical areas in normal humans and patients with abnormalities of the
corpus callosum. Brain. 1995;118:429–40.
Morrison RS, Dempsey EW. A study of thalamocortical relations. Am J Physiol. 1942;135:281–92.
Myers RE. General discussion: phylogenetic studies of commissural connections. In: Ettlinger EG,
editor. Functions of the corpus callosum. Boston: Little Brown & Company; 1965. p. 138–42.
Pandya DN, Rosene DL. Some observations on trajectories and topography of commissural fibers.
In: Reeves AG, editor. Epilepsy and the corpus callosum. New York: Plenum Press; 1985.
p. 21–39.
Purpura DP. Relationship of seizure susceptibility to morphologic and physiologic properties of
normal and abnormal immature cortex. In: Kellaway F, Petersen I, editors. Neurological and
electroencephalographic correlative studies in infancy. New York: Grune and Stratton; 1964.
p. 117–57.
Scheibel ME, Scheibel AB. Structural organization of non-specific thalamic nuclei and their pro-
jection toward the cortex. Brain Res. 1967;6:60–94.
Spencer WA, Kandel ER. Cellular and integrative properties of hippocampal pyramidal cells and
the comparative electrophysiology of cortical neurons. Int J Neurol. 1968;6:266–96.
Starzl TE, Whitlock DG. Diffuse thalamic projection system in the monkey. J Neurophysiol.
1952;15:449–68.
Steriade M, Llinas R. The functional states of the thalamus and the associated neuronal interplay.
Physiol Rev. 1988;68:649–742.
Velasco M, Lindsley DB. Role of orbital cortex in regulation of the thalamocortical electrical activ-
ity. Science. 1965;149:1375–7.
Von Economo C. The cytoarchitectonics of the human cerebral cortex. London: Oxford University
Press; 1929.
Walker AE. The patterns of propagation of epileptic discharge. In: Schaltenbrand G, Woolsey CW,
editors. Cerebral localization and organization. Madison: University of Wisconsin Press; 1964.
p. 95–111.
Part II
The Systems
Chapter 11
Motor System, Movement, and Motor
Pathways
Abstract There are three major areas that are responsible for producing the fine
motor movements in the human, the cerebral cortex, basal ganglia, and cerebellum.
Our understanding of localization in the motor system is based on studies following
lesions at various levels of the neuroaxis.
In studying the motor system, we will consider reflex activity, central generators of
patterns of movement, voluntary movement, and learned movements. We will also
consider two interrelated aspects: posture and movement. Under posture we will be
studying static or tonic reactions. In the following discussion, we will examine motor
function at the level of the spinal cord, the brain stem, and cerebral cortex. It is
important to realize that motor functions are represented at successively higher phys-
iological and anatomical levels of the neural axis. As we go higher in the neural axis,
we are utilizing and modifying mechanisms that have been integrated at a lower level
of the neural axis, a concept first expressed in the modern era by Jackson. Thus, pat-
tern generators/centers make use of the motor mechanisms involved in reflexes with-
out the necessity of afferent input. In turn voluntary and learned movements
incorporate or impose a higher level of a more complex cortical control of these
reflex and central pattern mechanisms. In subsequent sections, the role of basal
ganglia and the cerebellum in modulating movement will be considered.
Specific neural circuits or neuronal clusters or centers are responsible for the gen-
eration of simple and complex patterns of movement in the absence of afferent
input. In actuality, such central patterns are modified or modulated by afferent input,
utilize many of the reflex components to be discussed below, and are controlled and/
or modified by descending control motor systems from higher centers. Such pattern
generators have been described at the level of the spinal cord and the brain stem
(mesencephalic locomotor system) for more complex behavior related to locomo-
tion. The latter system is also involved in the motor components of emotional
expression, as well as chewing, licking, sucking behavior, and movement and ejacu-
lation of sperm. For the accurate performance of complex patterned movements,
involving the limbs, afferent input and reflex activity, is essential. In the absence of
such afferent input, the movements while repetitive are not as well coordinated (see
Harris-Warrick and Johnson (1989)).
1. The spinal pattern generator. This is probably composed of bilateral clusters of
interneurons in the intermediate gray matter at the base of the posterior horn.
They are responsible for the locomotor movements from this level. These inter-
neurons are the same interneurons involved in the flexion reflex to be described
below. In the spinal cord, the preparation to be discussed below the effects of
dopaminergic and adrenergic agents in triggering behavior can be demonstrated.
2. The mesencephalic locomotion pattern generator. This center is located in the peri-
ventricular tegmentum at the junction of midbrain and pons. Axons from this region
descend to the medullary medial reticular formation. From this region, axons
descend as the medial reticulospinal tract in the ventrolateral funiculus to the spinal
locomotor system of the lumbar spinal cord. In the decerebrate preparation, gluta-
minergic effects can be demonstrated. Glutamate receptor antagonists will prevent
the locomotion effects that occur on stimulation of the mesencephalic center.
3. Other motor pattern centers. The premotor cortex for visually guided move-
ments, the subthalamic nucleus, the pontine reticular formation, and the cerebel-
lum will be discussed below. In addition, in regions with motor functions in the
for example in the brain stem especially associated with cranial nerves, there is
11.2 Concept of Central Pattern Generators 333
AT BIRTH
TRACTION RESPONSE
Stimulus: Stretch shoulder adductors and flexors
Response: All joints flex
1 month/s 2 3 4
GRASP REFLEX
(INITIAL COMPONENT) (FULLY FORMED)
S. Contact between thumb and intex S. Distally moving contact medial palm
R. Thumb and index adduct alone R. All fingers flex
3 months 4 5 6 7 8 9 10 11
Fig. 11.1 Evolution of the automatic grasping responses of infants. From Twitchell, T. E.
Neuropsychologia, 3: 251, 1965 (Elsevier)
(ulnar) border of the hand or to the palmar surface of the hand or to the
dorsum of the hand. This stimulus leads to a non-tonic orientation of the hand
away from the stimulus. This is a more precise form of the tonic avoiding
response noted in a decorticate preparation. The instinctive tactile avoiding
response does not require the pyramidal system. The integrity of the cingulate
area, area 8, and the supplementary motor cortex is required. The reaction is
released in abnormal degree by damage to the parietal lobe (and adjacent
motor cortex). The instinctive grasp and avoidance responses normally are in
equilibrium from an anatomical and physiological standpoint.
11.2 Concept of Central Pattern Generators 335
Fig. 11.2 Avoiding responses. (a) Elicitation of the avoiding response by contact stimulus to the
ulnar border of hand as a normal response in infant of 4–6 weeks. From Twitchell, T.E.,
Neuropsychologia, 3: 250, 1965 (Elsevier). (b) Avoiding response as a pathological phenomenon.
Overextension and abduction of fingers as hand approaches theobject (child with infantile spastic
hemiparesis). (c) Avoiding response as a pathological phenomenon in another patient with infantile
spastic hemiparesis. Reaction of hand to contact stimulation of the palm. From Twitchell, T. E.:
Neurology, 8: 17, 1958 (Lippincott/Williams and Wilkins)
(f) Other reflexes associated with the cerebral cortex. In addition to the instinc-
tive tactile grasp and avoiding responses, various visual triggered responses
of a similar nature may be seen. One may speak of a visual instinctive grasp
reaction. This requires the integrity of the posterior parietal areas, the visual
mechanisms, and the motor cortex. The CT scan evidence suggested a medial
frontal location of lesion responsible for such release. Another variety of
visually cued reaction is the visual instinctive avoiding reaction. This requires
the integrity of the temporal lobe and visual mechanisms. The response
apparently is independent of the pyramidal system. Again, in the intact indi-
vidual, equilibrium of grasp and avoidance is to be noted. While our discus-
sion has focused on the upper extremity, similar grasp and avoiding reactions
may also be noted in the lower extremities. Lesions of premotor cortex also
affect gait: producing an apraxia in walking termed a frontal lobe gait apraxia.
This will be discussed later in this chapter.
Some reflexes are present at birth and disappear with time: the startle reflex, sucking,
rooting, and the extensor plantar response. A sequence of reflex activities is noted in
the developing human infant as regards the use of hands and fingers. In addition a
sequence of changes occurs as regards sitting, standing, and walking as summarized
in Table 11.2.
336 11 Motor System, Movement, and Motor Pathways
11.4 R
elationship of Primary Motor, Premotor,
and Prefrontal Cortex
1. Primary motor cortex (Figs. 11.3 and 11.5). The large and giant pyramidal cells
in the primary motor cortex discharge producing movements in specific direc-
tions (flexion, extension, abduction, adduction) resulting from the contraction of
muscles at a specific joint. Among other sources of input, the primary motor
cortex receives information from somatosensory cortex of the postcentral gyrus
and the ventral lateral nucleus of the thalamus. This input may allow the response
of motor cortex to peripheral stimuli in what are termed long loop reflexes.
11.4 Relationship of Primary Motor, Premotor, and Prefrontal Cortex 337
Fig. 11.3 Somatic figurines. The primary motor and sensory representation and the effects pro-
duced by supplementary motor and second sensory stimulation are demonstrated (From Penfield,
W. and Jasper, H. Epilepsy and the Functional Anatomy of the Human Brain. Boston, Little Brown
and Company 1954, p 105)
3. Prefrontal areas. The prefrontal areas have functions that relate to the limbic
system and the motor system. While the orbital and mesial regions of the prefron-
tal areas related to the limbic system and will be considered in a later chapter, the
dorsal region of the prefrontal cortex is concerned with the executive functions
involved in the planning, regulation, and sequencing of behavior and movement
over time. In this regard, movement is simply the expression of behavior. This
same area of prefrontal cortex functions as the anterior multimodal association
cortex and receives projection from the posterior multimodal association cortex
located at the intersection of the major sensory association areas. In turn this dor-
sal prefrontal area projects to the premotor cortex. Prefrontal cortex are:
Modern concepts of the plasticity of the primary motor cortex: More recent
s tudies reviewed by Sanes and Donoghue (2000) indicate a considerable dynamic
plasticity in the primate primary motor cortex. Thus, although modules for the head
region, upper extremity, and lower extremity can be distinguished, there is, within
each module, a considerable overlap and plasticity with less of the specific localiza-
tion for each movement suggested by the earlier maps. Instead a mosaic is present.
The area devoted to specific movement representations may be modified by trauma
to peripheral nerves, central nervous system damage, and most importantly by
motor skill learning and cognitive motor actions.
The following case history illustrates the effects of focal disease involving the
motor cortex:
Case history 11.1, Fig. 11.4. Three months prior to admission, this 29-year-old,
right-handed, white female manager developed an intermittent “pulling sensation”
over the anterior aspect of the left thigh, lasting a few minutes which recurred about
twice a week. On the evening of admission, she again had the onset of this same
sensation and then had numbness followed by “jerky movements” in her left foot
which progressed to involve the whole left lower extremity. She was then observed
to have tonic extension and then clonus of all four limbs with loss of consciousness
for a minute or less. She still appeared dazed and slightly confused for the next
5 min and was subsequently amnestic for the secondarily generalized seizure.
Physical examination: Normal except for bite marks on the left lateral aspect of
the tongue.
Neurologic examination: Significant only for a slight asymmetry of deep tendon
reflexes, left > right.
Clinical diagnosis: Focal seizures originating right parasagittal motor cortex
(foot area), with question of parasagittal meningioma.
Laboratory data: Electroencephalogram demonstrated rare focal spikes, right
Rolandic parasagittal consistent with the focal source of the secondarily generalized
seizure.
Arteriograms: Fig. 11.4 demonstrates an enhancing lesion in the right parasagit-
tal region just anterior to the central sulcus. These findings were consistent with a
right parasagittal meningioma.
Subsequent course: The patient did well after removal of a well-circumscribed
right parasagittal meningioma by Doctor Bernard Stone. The patient received diphe-
nylhydantoin (Phenytoin) to prevent additional seizures. Muscles make direct con-
nection to the anterior.
Corticorubrospinal system. In the monkey and cat, if the pyramidal tracts are intact,
destruction of the rubrospinal system produces no definite motor deficit. However, in
monkeys and cats that have already had bilateral section of the pyramidal tract (a sec-
tion which has produced very little qualitative change in limb movement), a complete
loss of distal limb movement may occur after additional bilateral destruction of the
rubrospinal tract. In the intact monkey, complex coordinated movements may be
evoked by stimulation of the red nucleus. Flexor excitation predominates with extensor
inhibition. The studies of Lawrence and Kuypers (1968) suggested that the rubrospinal
tract is mainly concerned with steering movements of the extremities, particularly
11.4 Relationship of Primary Motor, Premotor, and Prefrontal Cortex 341
Fig. 11.4 Parasagittal
meningioma. Case History
11.1. Arteriograms
demonstrate the
characteristic features of a
circumscribed vascular
tumor in the parasagittal
Rolandic area, supplied by
the right anterior cerebral
artery and meningeal
branches of the external
carotid artery. (a) Arterial
phase lateral common
carotid injection. (b)
Arterial phase AP view
common carotid injection.
See text for details
d istal segments. On the other hand, the ventromedial brain stem r eticulospinal tract is
mainly concerned with steering movements and posture of the head or body and
synergistic movements of the extremities (Kuypers 1987).
These are widespread connections of these areas both within and between the hemi-
spheres (see Pandya and Kuypers, 1969, Pandya and Vignolo 1971, Ward et al.
1946). Histologically, area 6 is similar to area 4 but lacks, in general, giant
342 11 Motor System, Movement, and Motor Pathways
Fig. 11.5 The motor cortical fields of the human as determined by Foerster employing cortical
stimulation. Stimulation of the area indicated in black produced discrete movements at low thresh-
old and was designated pyramidal. Lines or cross-hatching indicates other areas producing move-
ments and were designated in a broad sense as extrapyramidal. These movements were more
complex synergistic and adversive movements and included the adversive responses obtained by
stimulation of area 19; areas extending to the midline are continued on to the medial surface.
Modified from Foerster, O.: Brain, 59:137, 1936 (Oxford Univ. Press)
pyramidal cells. Area 8 has some similarity to area 6 but is also transitional to the
granular prefrontal areas. There are considerable variations when the several cyto-
architectural maps are compared as to the primary motor cortex the exact boundar-
ies of area 8 in both man and monkey. Areas 44 and 45 in the inferior frontal
convolution (Broca’s motor speech or expressive aphasia centers) should also be
included within this motor association or intermediate frontal grouping, from both
the functional and cytoarchitectural standpoints. For simplicity of presentation, these
areas will be considered later in relation to language function. Note that clinical
lesions, such as vascular infarcts and tumors, usually do not respect cytoarchitectural
borders. Thus, vascular lesions that involve the lateral premotor aspect of area 6 usu-
ally also involve the primary motor cortex. Tumors such as parasagittal meningiomas
may involve both the lateral premotor and the supplementary motor cortex or may
involve the prefrontal and the several premotor areas. With increasing research, there
has come recognition that there are differential functions for the various sectors of
these premotor areas (Wise et al., 1997, Krakauer & Ghez, 2000).
The premotor sector of area 6 projects primarily to the medial pontomedullary
areas. The spinal projections of this area consist of the ventromedial descending
reticulospinal system and the vestibulospinal tracts. The red nucleus receives inputs
from the rostral (proximal) arm and leg sectors of area 4 and the adjacent premotor
cortex and projects as the rubrospinal system.
1. The supplementary motor area (SMA). SMA is concerned with the sequencing of
movements that are initiated internally without triggering from external sensory
stimuli. SMA is concerned with the performance of learned sequences of movement.
11.4 Relationship of Primary Motor, Premotor, and Prefrontal Cortex 343
The area just anterior to the SMA, the pre SMA, is involved along with other prefron-
tal areas such as area 46 in the actual process of learning the sequences (training of a
motor skill). This same pre SMA area is also involved when the same complex
movement sequence is imagined. Once a sequence has been fully and usually over
learned, control may be centered in primary motor cortex.
The readiness potential (Bereitschaftspotential is a change in the electrical
activity of the brain that occurs before the subject’s conscious decision to move
a muscle). In humans, surface electrodes placed on the scalp in the SMA are able
to record, 1–2 s prior to voluntary movements, a significant surface negative
potential with maximum amplitude over the midline of the frontal area corre-
sponding primarily to the supplementary cortex. The process of initiation of
more complex actions enhances this potential. In contrast, when the same move-
ments were triggered by external stimuli, there was no such readiness potential.
2. The lateral premotor area (PMA). In contrast to the SMA, the lateral PMA is
concerned with the sequencing of movements that are triggered by external
stimuli. In this regard, there is a close relationship of the lateral PMA to the
sensory association cortex of the superior parietal cortex (area 5) and the poste-
rior parietal multimodal sensory areas, which are directly connected with the
extra striate visual cortex. This relationship is complex as demonstrated in
reaching for and grasping precisely an object presented at a particular point in
visual space. The lateral PMA has been divided into two major functional areas:
the dorsal and the ventral.
(a) The dorsal lateral PMA neurons are involved in reaching for that object. This
area is also involved in learning to associate specific stimuli particularly visual
with the motor response of reaching for that stimulus. As opposed to the learn-
ing of a repetitive motor act (pressing a key) involving the supplementary
motor cortex, this is a different type of learning referred to as associative learn-
ing. Multiple bits of information must be integrated for this reaching activity,
visual position of object, position of gaze, position of arm, etc., and this
involves information received from various posterior parietal areas adjacent to
the extrastriate cortex discussed in greater detail by Wise et al. (1997).
(b) The ventral lateral PMA is concerned with grasping. This area also must
receive information from the extrastriate cortex regarding size and shape of
the object as well as other multimodal and sensory association data so that
an effective grasp of the object may occur.
Area 6: Stimulation: stimulation of SMA and PMA: Essentially stimulation of PMA
and SMA results in a pattern of movement characterized by tonic abduction of the
contralateral arm at shoulder with flexion at plus deviation of head and eyes to the
contralateral field. In addition, with SMA stimulation bilateral lower extremity
movements may occur. Lesions of these areas will result in a release of grasp reflex
and an apraxia in limb movements. Bilateral lesions of the SMA may result in an
akinetic mute state.
344 11 Motor System, Movement, and Motor Pathways
11.4.4 D
ysfunction in the Premotor and Supplementary
Motor Cortex
Case 11.2 provides an example of a low-grade glioma involving the premotor and
supplementary motor cortex from the standpoint of focal seizure activity.
Case history 11.2, Fig. 11.6. This 57-year-old right-handed woman at age 47 had
the onset of observed generalized convulsive seizures, which occurred without
warning with sudden loss of consciousness. Shortly after the onset of the grand mal
seizures, the patient began to have focal seizures, which increased in frequency to
one per week. She described these as beginning with the abduction and raising of
the right arm at the side and over her head and then a jerking of the right arm, and
then she would fall to the ground. She would remain fully conscious, but she would
be unable to talk. She would have an awareness that something strange was occur-
ring. She had a sinking sensation. She denied any impairment of memory after the
episode. However, she would be aware that her right arm and leg were tingling and
weak for perhaps 5 min afterward, and she would be unable to speak for 10–30 min
afterward. These focal seizures occurred once a month, but for the last 2 years, they
had been occurring once a week. The patient indicated that over the last 10 years,
she has had problems with her memory. She was reported to have had three “nega-
tive” CT scans over the years and yearly EEGs, which did not reveal focal features
or electrical seizure discharges.
Neurological examination: mental status—Delayed recall without assistance
was 0 out of 5 and with assistance 2 out of 5.
Motor system: Intact except for a decreased swing of the right arm in walking.
Reflexes: Deep tendon reflexes were increased on the right at biceps and patellar.
Plantar response was extensor on the right and equivocally extensor on the left.
Clinical diagnosis: Seizures of focal origin left premotor/supplementary motor
cortex possibly secondary to low grade glioma. A meningioma was less likely due
to the reports of “normal CT scans.”
Laboratory Data
MRI scan (Fig. 11.6) demonstrated extensive involvement of the left premotor
and supplementary areas by tumor and edema.
Subsequent course: Doctor Bernard Stone performed subtotal resection of this
tumor. Histological examination of the tissue confirmed the preoperative impression
of an infiltrating glioma—predominantly oligodendroglioma in type. The patient
received postoperative radiotherapy, 5000 rads to the left hemisphere and an addi-
tional 1000 rads to area of tumor. When last seen in follow-up 4 years after surgery,
the patient was still experiencing infrequent (1–2 per month) short focal seizures of
the same type involving focal movements of the right arm, plus speech arrest. The
neurological examination demonstrated some decrease in spontaneous speech some
blunting of affect. Bilateral extensor plantar responses were present. She had a mod-
erate frontal-type apraxia of gait and required a cane to avoid falls.
11.4 Relationship of Primary Motor, Premotor, and Prefrontal Cortex 345
also appear to neglect objects introduced into the visual field contralateral to the
lesion. The patients also neglect contralateral tactile and auditory stimuli.
Suppressor Areas for Motor Activity (Negative Motor Response) These “suppres-
sor” areas cannot be distinguished on cytoarchitectural grounds from adjacent corti-
cal areas. Similar effects have been elicited from stimulation of the caudate nucleus
and of the bulbar medullary inhibitory center. Note must of course be made of a
nonspecific interference with voluntary. Thus, the patient who is experiencing a
focal motor seizure involving the hand cannot use that hand in the performance of
voluntary skilled movements. Similarly, arrest of speech is frequently produced by
stimulation of the various speech areas of the dominant hemisphere, whereas vocal-
ization is only rarely produced. The areas of cortex included (a) the inferior frontal
gyrus, immediately anterior to primary motor area for face, (b) less often-premotor
cortex just anterior to the frontal eye field or the hand area, and (c) the supplemen-
tary motor cortex. The authors speculate that these effects are produced because the
stimulation interferes with the preparation for movement.
Case history 11.3, Fig. 11.7. History of esophageal cancer with metastases to the
lung. He had achieved clinical control of disease with chemotherapy and radiation
therapy. Imaging revealed metastasis to the brain in the medial surface of the left
hemisphere with resultant progressive weakness of his right leg and vague headache
and nausea. This was treated with radiation therapy. He improved at 4-month fol-
low-up with mild residual deficit.
Case History 11.4, Fig. 11.8. This 11-year-old male was struck by a car. He was
unconscious for several minutes, after which he awakened, thrashing around and
yelling incoherently. He was brought to the emergency room for further evaluation.
He had a laceration over the left parietal region. He was immobilized in a hard col-
lar. He had sustained bruises to the legs. He had no general trauma, but was found
to be confused. He had no focal deficits beyond that.
CT of the head and cervical spine demonstrated a contusion of the right temporal
region. He had no fracture or dislocation of the cervical spine.
His past history was unremarkable. On neurologic exam, he was sleepy although
aroused to a voice. He would then the EL and thrash. He did not speak coherently.
He did not follow commands reliably. Remainder of his neurologic exam was
unremarkable.
Hospital course: The patient was admitted and, over a week, gradually improved,
complaining of headaches but having a normal neurologic exam.
Clinical Diagnosis: Bilateral frontal infarction from RTA. Long-term, he was found
to be distractible, having difficulty concentrating at school and in sports. He was
also found to be irritable with no particular precipitant. After a year, he was some-
what better but not at his prior baseline.
Comment: The cerebral contusion sustained by the blow to the head led his altered
behavior at the beginning of his hospital stay. The subtler long-term consequences
of a cerebral concussion/contusion are illustrated by the patient’s irritability and
distractibility in the academic/athletic spheres of his life.
348 11 Motor System, Movement, and Motor Pathways
Case History 11.5. The patient is a 31-year-old male seen because of impulsive
behavior and lack of ability to complete tasks assigned to him. This had dated back a
number of years. It was nonprogressive. He has a history of boxing for many years dat-
ing back to childhood. He had a number of concussions and knockouts in that sport.
Clinical diagnosis: Traumatic injury to the brain from boxing with damage to the
frontal and prefrontal lobe with resultant poor job performance and poor judgment,
irritability, impulsiveness, and bad general behavior.
He had difficulty holding a job because he could not be counted on to complete
tasks and showed a poor judgment. He was also impulsive in social situations,
frequently saying inappropriate things or getting into fights with minor provocation.
Past history was unremarkable other than the above.
General exam was normal. Neurologic exam found him sarcastic and impulsive
in his answers. He was fluent and would follow one-step but not two-step com-
mands reliably. Neurologic exam beyond that was unremarkable. A head CT dem-
onstrated mild atrophy of the brain but no other significant focal abnormality.
Comment: This is a common and unfortunate manifestation of the consequence of
multiple concussions with the subtle psychological dysfunction leading to difficulty
with personal interactions. There is no specific treatment beyond avoidance of the
trauma leading to the concussions.
11.4.5 P
refrontal Cortex (Areas 9, 10, 11, 12, 13, 14,
and 46, Fig. 11.5)
The term prefrontal refers to those portions of the frontal lobe anterior to the agran-
ular motor and premotor areas. Three surfaces or divisions are usually delineated:
(1) lateral–dorsal convexity, (2) medial, and (3) orbital or ventral.
All three are concerned with executive function and relate to the mediodorsal
thalamic nuclei. In general, the lateral–dorsal relates to motor association executive
function, the orbital–ventral and the medial to the limbic–emotional control execu-
tive system. Recent studies have questioned this simplistic approach. Thus, certain
functions previously considered to be associated with dorsolateral location have
been now localized to a medial location (Stuss et al. 2000). In addition, there is
evidence that dorsal lateral lesions also alter affect and motivation. Moreover, as
most pathological processes involve the functions associated with more than one
division either directly or through pressure effects. Most studies of stimulation or of
lesions involving the prefrontal areas have included, within the general meaning of
the term prefrontal, areas beyond areas 9, 10, 11, and 12. Posterior orbital cortex
(area 13) and the posteromedial orbital cortex (area 14) have been added to the
orbital frontal group (Figs. 11.5 and 11.7). These areas all share a common relation-
ship to the medial dorsal nucleus of the thalamus. Areas 46 and 47, located in man
11.4 Relationship of Primary Motor, Premotor, and Prefrontal Cortex 349
on the lateral surface of the hemisphere, are also included. The anterior cingulate
gyrus (area 24) is also included in the prefrontal area, although it may be considered
part of the limbic system and relates to the anterior thalamic nuclei.
1. Overview of the role of the prefrontal area in motor and cognitive function:
Our concern here is primarily with the dorsal prefrontal subdivision. The ventral/
orbital and medial subdivisions also will be considered here but also in the limbic
system chapter. We are concerned with the sequencing of behavior and the planning
of motor function and with a very short type of memory referred to as working
memory (see Chap. 15 for discussion on changes in personality following lesions in
the prefrontal cortex).
Working memory provides for the temporary storage of information that is needed
for ongoing behavior. In the human, aspects of prefrontal function are tested with a
variety of tests. These include more complex forms of the delayed response and
delayed alternation tests. The Luria motor sequences can be easily utilized in the
office: the patient must reproduce a demonstrated sequence of hand movements
(strike the thigh with the open hand, then with the ulnar aspect of the open hand, and
then with the ulnar aspect of the closed fist). In the Wisconsin Card Sorting test, the
patient must sort 60 cards based on color, or symbol or number of symbols.
By changing the rules once, the patient has developed a pattern set, and it is possible
to also determine how readily set can be changed. Failure to change set is termed
rigidity. Activation of the ventrolateral region (inferior to the inferior frontal sulcus)
has been correlated with the updating and maintenance of information. Activation of
the dorsolateral region (dorsal to the inferior frontal sulcus) has been correlated with
the selection/manipulation/monitoring of that information. Activation of the anterior
prefrontal cortex (anterior to a line drawn vertically from the anterior edge of the
inferior frontal sulcus) has been correlated with the selection of processes/subgoals.
The sequence of events in the human following partial vascular lesions (infarcts) of
the precentral cortex or of the motor pathways in the internal capsule has been
studied by Twitchell (1951) as follows:
1. Flaccid paralysis. Particularly with a large lesion, there is a transient period of
flaccid paralysis of the contralateral arm and leg and the lower half of the face,
with a transient depression of stretch reflexes. The duration of this flaccid state
(reflecting “cortical shock”) is variable; it may be quite fleeting depending on the
extent of the lesion (which is usually less than total). The sign of Babinski is
present with an extensor plantar response on tactile or painful stimulation of the
lateral border of the foot.
2. Return of deep tendon reflexes/stretch reflexes. After a variable period of time,
the deep tendon reflexes in the affected limbs return and become hyperactive.
There is increased resistance on passive motion at the joints (when there are
severe lesions even this stage may not be reached). This does not affect all move-
ments equally but tends to have its greatest effect on the flexors of the upper
extremity. A hemiplegic posture and gait is noted: the upper extremity is flexed
at the elbow, wrist, and fingers, and the leg is extended at the hip, knee, and ankle
and externally rotated at the hip with circumduction in walking. Walking is pos-
sible with the hemiplegic limb as movement of the proximal limb begins to
return. In general, recovery of function in the lower extremity is usually greater
than in the upper extremity. Following the return of stretch reflexes, variation in
the relative degree of spasticity in the flexor and extensor muscles in relation to
tonic neck reflexes may be noted with the return of tonic neck reflexes one will
begin to note proximal limb movements.
3. Return of traction response. Abduction of the arm and shoulder will result in
stretch of the abductors. There will then be an adduction of the arm at the shoul-
der. In addition, synergistic flexion of the arm at the elbow, wrist, and fingers will
occur, and objects may be grasped in this manner. This flexion synergy, however,
results in a whole hand grasp; all of the fingers flex together.
4. Return of selective ability to grasp. This stage of recovery involves a more selec-
tive grasp of the entire hand albeit a tonic grasp. There is some dissociated synergy
so that the hand alone tends to grasp. Finger and thumb opposition begin to return.
11.6 Studies of Recovery of Motor Function in the Human 351
5. Return of the instinctive tactile grasp reaction with the capacity for projectile
movement. This occurs with incomplete lesions. If a massive lesion is present,
the instinctive grasp reflex does not return.
6. Return of distal hand movement. Eventually, depending on the extent of the
lesion, some return of distal hand movement may occur, but such recovery is
usually less than that which occurs for movements at more proximal joints, e.g.,
at the shoulder and hip. From a physiological and anatomical standpoint, the
logic of this pattern of recovery should be evident. One sees in this sequence a
recovery of spinal reflex activities; then of brain stem reflex activities, as noted
in the decerebrate preparation; then those noted in the decorticate preparation;
and finally those reflexes integrated at a cortical level. This is level of recovery.
11.7 C
ortical Control of Eye Movements-Frontal
and Parietal Eye Fields
Fig. 11.9 Functional
subdivision of the frontal
eye fields in the monkey
under relatively light
anesthesia: (a) closure of
eyes, (b) pupillary
dilatation, (c) eyelid
opening (awakening
reaction), (d) conjugate
deviation to the opposite
side, and (e) nystagmus to
the opposite side (From
Smith, W. K., (in) Bucy, P.:
The Precentral Motor
Cortex, Urbana, University
of Illinois Press, 1944)
352 11 Motor System, Movement, and Motor Pathways
s ubstrate for all horizontal saccades is the lateral gaze center of the paramedian
pontine reticular formation, associated with the nucleus of cranial nerve VI.
Several types of neurons are present in this center. Neurons referred to as medium
lead burst cells provide direct excitation to motor neurons in the ipsilateral abdu-
cens nucleus and to the interneurons in that nucleus which give rise to the medial
longitudinal fasciculus. Long lead burst cells drive the medium lead burst cells
and receive excitatory input from the higher centers to be discussed below. The
medium lead burst neurons also excite inhibitory burst neurons which in turn
suppress the discharge of contralateral abducens neurons. In addition, there are
neurons located in the dorsal raphe nucleus of the pontomedullary area, which
cease firing during saccades (omnipause neurons). These neurons if stimulated
during a saccade will stop the saccadic movement. Additional neurons provide
tonic discharges relevant to eye position and maintain the eyes in a position set
by the saccade: the flocculus of the old vestibular portion of the cerebellum, the
vestibular nucleus, and the nucleus prepositus hypoglossi. For vertical saccades,
burst and tonic neurons are found in the rostral interstitial nucleus of the MLF in
the mesencephalic reticular formation.
2 . Central control of saccades: A complex system with redundant features is pres-
ent. Essentially, two major cortical areas are involved:
(a) The contralateral frontal eye field (area 8—frontal eye fields {FEF}; Fig. 11.9)
(b) The contralateral lateral intraparietal area of the posterior parietal area at
the border of the extrastriate cortex. Area 8 provides the motor input for the
response to the command, e.g., “look to the left or right field.” The frontal
eye field has major interconnections in a topographic manner with areas that
participate in the streams of information that flow out of the extra-striate
visual cortex.
The optic nerve is divided into two parts with half of the fibers going to the LGN
and V1 with the other half going to the tectum of the superior colliculus to control
eye movement. The posterior parietal area in contrast is involved with visual atten-
tion, with representations of the location of objects of interest. There is a significant
interconnection with area 8 with an exchange of information.
Superior colliculus. Both areas project to the intermediate and deep cell layers of
the superior colliculus. The superior colliculus in turn projects to the mesencephalic
and pontine reticular formation. The same areas of the superior colliculus also
receive inputs from the prestriate areas of the posterior temporal gyri. The superfi-
cial layers of the superior colliculi receive input from both the striate cortex and the
retina. The frontal eye field (area 8) projects not only to the superior colliculus but
also directly to the pontine and mesencephalic reticular formation. The interaction
of area 8 and the superior colliculus is even more complex. Area 8 projects to the
caudate nucleus. The caudate nucleus inhibits the S. nigra pars reticularis, which in
turn acts to inhibit the superior colliculus. Other cortical areas are also involved in
saccades: the SMA eye field and the dorsolateral frontal cortex. The former area has
neurons that direct movement to part of a target. The latter contains neurons that
discharge when the saccade is made to a remembered target.
11.7 Cortical Control of Eye Movements 353
In the older literature, the motor pathways were divided into pyramidal (corticospi-
nal and corticonuclear) and extrapyramidal (rubrospinal, tectospinal, and so on).
These terms are no longer used, and each pathway is now usually described in terms
of its function.
1. Basic principles of voluntary motor system. The motor system consists of two
portions: an upper and lower motor neuron. Upper motor neurons are found in
layer v of the motor sensory strip of the cerebral cortex (Fig. 11.5). The pathways
from the upper motor neurons, corticospinal or corticonuclear, descend and cross
over to innervate the lower motor neurons in the brain stem or spinal cord. The
axons of the upper motor neurons either synapse on interneurons or end directly
on the lower motor neurons. Lower motor neurons are the ventral horn cells in
the spinal cord and motor cranial neurons in the brain stem. The axons from the
lower motor neurons leave the central nervous system and form the motor divi-
sion of the peripheral nervous system.
Voluntary movements of the muscles associated with cranial nerves V, VII,
and IX, X, XI, and XII are via the corticonuclear/bulbar pathway. Control of the
cranial nerves that move the muscles (III, IV, and VI) of the eyes is through the
corticomesencephalic pathway to the pons, which coordinates movements under
the control of cranial nerves III and VI interconnected by the ascending portion
of the medial longitudinal fasciculus.
2. Corticospinal tracts—voluntary control of the limbs, thorax, and abdomen
(Fig. 11.10a, b). This tract innervates the motor neurons that control the skeletal
muscles in the neck, thorax, abdomen, pelvis, and the extremities. It is essential
for accurate voluntary movements and is the only direct tract from the cortex to
the spinal motor neurons. This system originates from the pyramidal cells and
giant cells of Betz in the upper two-thirds of the precentral gyrus, area 4, and to
a lesser degree from area 6 and parts of the frontal, parietal, temporal, and cingu-
late cortices. The fibers pass through the genu of the internal capsule into the
middle third of the cerebral peduncles and enter the pons, where they are broken
into many fascicles and are covered by pontine gray and white matter. In the
medulla, the fibers are again united and are found on the medial surface of the
brain stem in the medullary pyramids. This diffusion tensor imaging MRI in
Fig. 11.11b beautifully demonstrates much of this pathway in the cerebral cor-
tex, internal capsule, cerebral peduncle, and pons.
About 75–90% of the corticospinal tract fibers cross at the medullospinal junc-
tion and are thereafter found in the lateral funiculus of the spinal cord. (The majority
of fibers from the dominant hemisphere cross at the medullospinal junction.) Some
corticospinal fibers remain uncrossed in the anterior funiculus but will slowly cross
at cervical levels. About 50% of the corticospinal fibers end at the cervical levels—
about 30% goes to the lumbosacral levels and the remainder to the thoracic levels.
Most of the corticospinal fibers end on internuncial neurons in laminae 7 and 8 of
the spinal cord, but in regions in the spinal cord where the digits are represented (in
11.8 Major Voluntary Motor Pathways 355
the cervical and lumbosacral enlargements), the corticospinal fibers sometimes end
directly on the motor horn cells. The internuncial neurons are located in lamina 7 of
the spinal cord. Lesions in the corticospinal tract produce contralateral upper motor
neuron symptoms, while lesions in the spinal motor neurons or rootlets cause lower
motor neuron symptoms.
3. Corticonuclear/corticobulbar system—voluntary control of the muscles con-
trolled by cranial nerves V, VII, and IX to XII (Fig. 11.11). This system distributes
to the motor nuclei of the cranial nerves V, VII, IX, X, XI, and XII and provides
Fig. 11.10 Corticospinal pathway. a) Diagram of Pathway from motor-sensory cortex which pro-
vides Voluntary movement of the muscles in the extremities, thorax, and abdomen. b) Demonstration
of Corticospinal pathway with diffusion tensor MRI. Demonstration of Corticospinal pathway
from motor cortex through internal capsule, cerebral peduncle into the pons, diffusion tensor MRI
356 11 Motor System, Movement, and Motor Pathways
Fig. 11.10 continued
voluntary and involuntary control of the muscles and glands innervated by these
nerves. In the older literature, this pathway was called corticobulbar because the
medulla and pons containing these nuclei are collectively called the bulb. We
prefer the term corticonuclear because it makes the student realize the key role of
the cranial nerve nuclei in movement. These fibers are found anterior to the corti-
cospinal fibers in the genu of the internal capsule and medial to the corticospinal
tract in the cerebral peduncle, pons, and medullary pyramids. The fibers supply-
ing the cranial nerves have the following cortical origin:
(a) Muscles of facial expression (motor nerve VII), mastication (motor nerve
V), and deglutition (ambiguous nuclei of nerves IX and X) originate from
pyramidal cells in the inferior part of the precentral gyrus, area 4.
(b) Muscles in the larynx are controlled from the inferior frontal gyrus and from
the frontal operculum (the posterior part of the pars triangularis, area 44).
It appears that many corticonuclear axons end on interneurons and not
directly on the motor neuron of the cranial nerve.
(c) The cortical innervation of the cranial nerves is bilateral, with the exception
of the lower facial muscles, which are innervated by the contralateral cortex.
Consequently, unilateral lesions in the corticonuclear system produce only
weakness and not paralysis. Paralysis results only from bilateral lesions in
the corticonuclear system.
11.8 Major Voluntary Motor Pathways 357
Fig. 11.11 Corticonuclear system. Voluntary control of the motor cranial nerves- V, VII, IX, X,
XI, and XII from the Head region in the lower half of the motor strip (Fig 11.3) and for the Frontal
Eye Fields from the caudal part of middle frontal gyrus (Fig 11.9)
(d) Lower motor neuron lesions of motor cranial nerves. A lesion of the motor
nucleus or rootlet produces a lower motor neuron syndrome with paralysis,
muscle atrophy, and decreased reflexes. Supranuclear lesions produce
upper motor neuron symptoms. Associated with bilateral lesions of the
corticonuclear system is pseudobulbar palsy with bilateral UMN signs and
358 11 Motor System, Movement, and Motor Pathways
11.8.1 R
ubrospinal and Tectospinal Tracts
(Fig 4.16; Table 4.2)
Tectospinal tract and rubrospinal tract. These tracts in the human function normally
as adjuncts to the direct corticospinal and corticobulbar tracts and only when dis-
ease affects the direct pathways can the functions of these tract be considered.
Tectospinal tract. In lower animals not having a well-organized corticospinal and
corticobulbar system, fibers from the superior colliculus or optic tectum function
similarly to the corticospinal and corticobulbar tracts. This tract crosses over and
descends to the cervical spinal cord to terminate in laminae VI, VII, and VIII of the
spinal cord coordinating head, neck, and eye movements in response to visual stimuli.
Rubrospinal tract. Fibers from the magnocellular nucleus of the red nucleus in
the midbrain also appear important in controlling the cranial and spinal nuclei.
These fibers cross over and descend in the lateral region of the tegmentum and spi-
nal cord adjacent to the corticospinal tract.
References
Alexander GE, Delong MR. Central mechanisms of initiation and control of movements. In:
Asbury AK, et al., editors. Diseases of the nervous system. Philadelphia: WB Saunders; 1992.
p. 285–308.
Carew TJ, Kelley DB. Perspectives in neural systems and behavior. . MBL Lectures in Biology,
vol. 10. New York: Alan Liss; 1989.
References 359
Alan Liss NY, Denny-Brown D. Motor Mechanisms: Introduction, the general principles of motor
integration. Handbook of Physiology, Section 1, Neurophysiology, vol. 2. Washington, D.C.:
American Physiologic Society; 1960. p. 781–96.
Denny-Brown D. The Cerebral Control of Movement. Springfield IL: Charles C. Thomas; 1966.
Desmedt JE, editor. Motor control mechanisms in health and disease. New York: Raven Press; 1983.
Fulton JF. Physiology of the nervous system. Third ed. New York: Oxford University Press; 1951.
Ghez C. Chapter 35: The control of movement. In: Kande IER, Schwartz JH, Jessell TM, editors.
Principles of neural science. 3rd ed. New York: Elsevier; 1991. p. 553–47.
Hitzig E. Hughlings Jackson and the cortical motor centres in light of physiological research.
Brain. 1900;23:545–81.
Humphrey, D.R., and Freund, H.J. 1991. Motor control concepts and issues New York, John Wiley
and Sons
Klemm WR, Vertes RP, editors. Brain stem mechanisms of behavior. New York: Wiley Interscience;
1990.
Jackson JH. On convulsive seizures. Lancet. 1890;1:685–8. 735–738, 785–788
Jackson H. A Yorkshireman’s contributions to epilepsy. Arch Neurol. 1982;45:675–8.
Kertesz A, editor. Localization in neuropsychology. New York: Academic Press; 1983.
Luders HO, Noachtar S, editors. Epileptic seizures: pathophysiology and clinical semiology.
New York: Churchill Livingstone; 2000.
Martin JH, Brust JCM, Hilal S. Imaging the living brain. In: Principles of neural science; 1991.
Lance JW, McLeod JG, editors. A physiological approach to clinical neurology. 3rd ed. London:
Butterworths; 1981. (Chapter 4: spinal reflexes, pp. 73–100, chapter 5: muscle tone and move-
ment, pp. 101–127, chapter 6: disordered muscle tone, pp. 28–152
[Galaburda AM, Mesulam MM. Neuroanatomical aspects of cerebral localization. pp. 21–61].
Penfield W, Jasper H. Epilepsy and the functional anatomy of the human brain. Boston: Little
& Brown; 1954. pp. 41–154, 350–539.
Penfield W, Rasmussen T, editors. The cerebral cortex of man: a clinical study of localization.
New York: MacMillan; 1957. Reynolds, E.H. 1988
Ruch TC. Transection of the spinal cord (Chapter 8). Pontobulbar control of posture and orienta-
tion in space (Chapter 9), pp. 207–214, 215–225 (Chapters 6 and 7 on Spinal Reflexes and
Synaptic Transmission, pp. 153180, 181–206). In: Ruch TC, Patton HD, editors. Physiology
and biophysics. Philadelphia: W.B. Saunders; 1965.
Sherrington C. The integrative action of the nervous system. New Haven: Yale University Press; 1947.
Schomer DL. Partial epilepsy. N Engl J Med. 1983;309:536–59.
Taylor J, editor. Selected writings of John Hughlings Jackson. Reprint New York: Basic Books,
Inc; 1931. 1959, pp. 1–36, 385–405, 406–411, 458–463
Wilkins RH, Brody IA. Jacksonian epilepsy. Arch Neurol. 1970;22:183–8. (see also Taylor above)
Willis WD, Grossman RG. Medical neurobiology; neuroanatomical and neurophysiological prin-
ciples of basic clinical neuroscience. 3rd ed. St. Louis, C. V. Mosby, chapter 8: motor systems;
1981. pp. 347–402.
Wise SP. The primate premotor cortex: past, present and preparatory. Ann Rev Neurosci. 1985;8:1–19.
Yakolev PI, Radic P. Patterns of decussation of bulbar pyramids and distribution of pyramidal
tracts on two sides of the spinal cord. Trans Amer Neurol Assoc. 1966;91:366–7.
Bizzi E, Evarts EV. Translational mechanisms between input and output. Neurosci Res Program
Bull. 1971;9:31–59.
Burke RE. Control systems operating on spinal reflex mechanisms. Neurosci Res Program Bull.
1971;9:60–85.
Delong M. Central patterning of movement. Neurosci Res Program Bull. 1971;9:10–30.
360 11 Motor System, Movement, and Motor Pathways
Grillner S, Wallen P. Control pattern generators for locomotion with special reference to verte-
brates. Ann Rev Neurosci. 1985;8:233–61.
Harris-Warrick PM, Johnson BR. Motor pattern networks: flexible foundations for rhythmic pat-
tern production. In: Carew TJ, Kelley DB, editors. Perspectives in neural systems and behavior.
NY: Alan R Liss; 1989. p. 51–71. (MBL Lectures in Biology-Volume 10).
Stein PSG. Motor systems with specific reference to the control of locomotion. Ann Rev Neurosci.
1978;1:61–81.
Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult hydrocephalus with "normal" cerebro-
spinal fluid pressure: a treatable syndrome. N Engl J Med. 1965;273:117–26.
Fisher CM. Hydrocephalus as a cause of disturbances of gait in the elderly. Neurology. 1982;32:1358–63.
Fishman RA. Normal pressure hydrocephalus and arthritis (editorial). N Engl J Med. 1985;312:1255–6.
Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol. 1987;44:21–3.
Inzitar D, Diaz F, Fox A, et al. Vascular risk factors and leuko-araiosis. Arch Neurol. 1987;44:42–7.
Jacobs L, Conti D, Kinkel WR, Manning EJ. "Normal pressure" hydrocephalus: relation-
ship of clinical and radiographic findings to improvement following shunt surgery. JAMA.
1976;235:510–2.
Masdeu JC, Wolfson L, Lantos G, et al. Brain white matter changes in the elderly prone to falling.
Arch Neurol. 1989;46:1292–6.
Rasker JJ, Jansen ENH, Haan J, Oostrom J. Normal pressure hydrocephalus in rheumatic patients:
a diagnostic pitfall. N Engl J Med. 1985;312:1239–41.
Steingart A, Hackinski VC, Lau C, et al. Cognitive and neurological findings in subjects with diffuse
white matter changes on computed topographic scan (leukoariosis). Arch Neurol. 1987;44:32–4.
Sudarsky L. Current concepts-geriatrics: gait disorders in the elderly. N Engl J Med. 1990;322:1441–6.
Sudarsky L, Ronthal M. Gait disorders among elderly patients: a survey study of 50 patients. Arch
Neurol. 1983;40:740–3.
Thompson PD, Marsden CD. Gait disorder of subcorttical arteriosclerotic encephalopathy:
Binswanger’s disease. Mov Disord. 1987;2:1–8.
Tinetti MD, Speechly M. Current concepts: geriatrics: prevention of falls among the elderly.
N Engl J Med. 1989;320:1055–9.
Tinetti MD, Speechly M, Ginter SF. Risk factors for falls among elderly persons living in the
community. N Engl J Med. 1988;319:1701–7.
Chapter 12
Motor System II: Basal Ganglia
Abstract The term “basal ganglia” originally included the deep telencephalic nuclei:
the caudate, putamen, globus pallidus, claustrum, and nucleus accumbens. The globus
pallidus and putamen are lens shaped and are called lenticular nuclei. Collectively the
putamen and caudate are called the corpus striatum. Additional structures now
included within this group are the substantia nigra, the subthalamic nuclei, the ventral
tegmental area, and the ventral pallidum. One is very familiar with disease of the basal
ganglia due to the widespread presence of Parkinson’s disease with its tremor at rest.
The caudate and putamen have the same structure (Table 12.1) and are continuous
anteriorly. The globus pallidus has two sectors: a medial or inner and a lateral or
outer. The substantia nigra has two components: a ventral pars reticularis which is
identical in structure and function to the medial sector of the globus pallidus and a
dorsal darkly staining component the pars compacta which contains large dopamine
and melanin-containing neurons. The nuclei of the basal ganglia may be categorized
as (1) input nuclei (caudate, putamen, and accumbens), (2) intrinsic nuclei (lateral
segment of the globus pallidus, subthalamic nucleus, pars compacta of the substan-
tia nigra, and the ventral tegmental area), and (3) output nuclei (medial segment of
the globus pallidus, pars reticularis of the substantia nigra, and the ventral pallium).
The consideration of the chemical and pharmacological anatomy of transmitters and
circuits within the system will provide an understanding of function and dysfunc-
tion within this system. It should be noted that the nuclei of the basal ganglia, the
circuits involving the basal ganglia, the cortical areas projecting to the basal ganglia,
the cerebellar nuclei relating to the basal ganglia, and the reticular formation (which
has connections with both the cortex and the basal ganglia) were once grouped
together as an “extrapyramidal system.” The term “extrapyramidal disorders” was
used to refer to the effects of lesions within the basal ganglia system. However, the
term “extrapyramidal” was also utilized to refer to the descending pathways: corti-
corubral spinal and cortical reticulospinal that were alternative descending systems
to the pyramidal system. The term extrapyramidal then becomes very nonspecific
and confusing and had best not be utilized. It is important to note, moreover, that the
Fig. 12.1 Diagram of the connections of the basal ganglia with transmitters and major transmitter
action (+) excitatory or (−) inhibitory. GABA gamma aminobutyric acid (−), GLU glutamate (+),
DA dopamine (+). The action of acetylcholine within the striatum has been omitted. See text for
details
12 Motor System II: Basal Ganglia 363
cortical areas giving rise to this extrapyramidal system are also, in part, the same
areas giving rise to the pyramidal system.
The connections and transmitters within this system are presented in the
diagram of Fig. 12.1 and are summarized below.
The essential pathways are the following: cerebral cortex (+) to striatum (cau-
date/putamen) (−) to globus pallidus (−) to ventrolateral thalamus (+) to cerebral
cortex. Additional circuits involve subthalamus and S. nigra. Adding greater detail
to the outline indicates the following sequence:
The major input into the basal ganglia is from the cerebral cortex to the striatum
(caudate nucleus/putamen/accumbens). This input is excitatory – utilizing the trans-
mitter glutamate – and arises primarily from the supplementary motor, premotor, and
motor cortices (areas 8, 6, and 4). However, the projection from the neocortex occurs
from many other areas. In general, frontal and parietal, lateral temporal, and occipital
areas project to the caudate nucleus; supplementary motor, premotor, and primary
motor cortex and primary somatosensory cortex project to the putamen. The hippo-
campal areas, medial and lateral temporal, project to the nucleus accumbens:
1. Major input onto the basal ganglia (Fig. 12.2) is from the cerebral cortex to the
striatum (caudate nucleus/putamen/accumbens) These are outlined in Table 12.2.
Fig. 12.2 Major connections of the basal ganglia with sites for surgical lesions or implantation of
stimulators in Parkinson’s disease. Lesion I – globus pallidus. Lesion II – ventral lateral nucleus of
the thalamus (the sector of VL involvement is termed VIM = nuc, ventral inferior medial). Lesion
III – subthalamic nucleus (Modified from Lin, F.H., Okumura, S., and Cooper, I.S.: Electroenceph.
Clin. Neurophysiol. 13:633, 1961)
364 12 Motor System II: Basal Ganglia
2. Local circuits within the striatum, which involve the excitatory transmitter
acetylcholine.
3. Striatum also receives a major dopaminergic input from the substantia nigra
compacta. Based on the type of receptor, this input may be either excitatory (D1)
or inhibitory (D2). Dopamine receptors have been classified based on the
dopamine-mediated effects on the enzyme adenylate cyclase (which is involved
in the ATP to cyclic AMP transformation). D2 receptors are involved in the inhi-
bition of the enzyme; D1 receptors are involved in stimulation of the enzyme.
Note that five dopamine receptors have now been identified.
Because of this differential input, two pathways have been identified: the
direct 4 and the indirect 5.
4. The major direct outflow pathway arises from those striatal neurons receiving
excitatory dopaminergic input (D1) and passes to the medial globus pallidus –
mediated by the inhibitory transmitter gamma aminobutyric acid (GABA).
Substance P is also involved as a transmitter or modulator in this pathway.
12 Motor System II: Basal Ganglia 365
The major outflow is to the inner (medial) segment of the globus pallidus. There is
a lesser outflow of fibers from the striatum to the substantia nigra reticularis, which
has the same microscopic structure as the globus pallidus. The outflow of the neurons
of these structures is to the ventral lateral and ventral anterior thalamic nuclei, medi-
ated again by the inhibitory transmitter GABA.
This outflow passes via two fiber systems: the fasciculus lenticularis and the ansa
lenticularis. The fasciculus lenticularis penetrates through the posterior limb of the
internal capsule; the ansa lenticularis loops around the undersurface of the most
inferior part of the internal capsule and then passes upward to join the fasciculus
lenticularis. These two fiber systems join at a point known as the field H2 of Forel
and then curve back toward the thalamus in the field Hl of Forel where they are
known as the thalamic fasciculus. This fasciculus then enters the ventrolateral and
ventral anterior nuclei of the thalamus. The outflow of these thalamic nuclei is excit-
atory to the motor areas of the cerebral cortex predominantly to the premotor and
supplementary motor areas.
5. The major indirect outflow pathway arises from those striatal neurons receiving
inhibitory dopaminergic input (D2) and passes to the lateral (or external) sector
of the globus pallidus mediated by the inhibitory transmitter GABA. Enkephalin
is also involved as a transmitter or modulator in this pathway. The neurons of the
lateral globus pallidus give rise to inhibitory fibers again utilizing GABA which
connect to the subthalamic nucleus. This nucleus gives rise to excitatory fibers
utilizing glutamate which provide additional input to medial (inner) sector of the
globus pallidus and the substantia.
As in the direct pathway, the subsequent connection of these structures is inhibi-
tory to the ventral lateral and ventral anterior nuclei of the thalamus. The subse-
quent step in the sequence as in the direct pathway is excitatory to the motor areas
of the cerebral cortex utilizing the transmitter glutamate. In the case of both the
direct and the indirect pathways, a loop has been completed: cerebral cortex to
striatum to globus pallidus to ventrolateral and ventral anterior thalamus back to
cortical motor areas.
In addition to its major input from the cerebral cortex, the caudate–putamen
also receives a lesser afferent input from the nucleus centrum medianum (CM)
(excitatory transmitter presumed to be glutamate or aspartate). It should be noted
that the CM represents a major interlaminar nucleus of the thalamus and is the
main thalamic extension of the reticular formation the centrum medianum; how-
ever, it also receives fibers from the globus pallidus (inhibitory transmitter, GABA).
This again completes an additional loop, relating the basal ganglia to the reticular
formation. It should also be noted that some fibers leave the ansa lenticularis and,
rather than passing into the thalamus, descend to the pedunculopontine nucleus
within the tegmentum of the mesencephalon. This nucleus then projects back to
the globus pallidus. There is also evidence for a direct excitatory input from motor
and premotor areas to the subthalamic nucleus providing an additional circuit for
modulating motor activity.
366 12 Motor System II: Basal Ganglia
6. In terms of final effect of this system on the thalamus, if one starts the analysis at
the striatum, the effect of the direct system on the thalamus is excitatory.
Inhibition of inhibitory drive is referred to as disinhibition. In contrast following
through the sequences of the indirect system, one finds that the end result is
inhibitory. If one begins at the substantia nigra compacta and follows through the
direct and indirect circuits, it is evident that both have the same end result as
regards the final effect at the thalamic and the cortical level.
7. Less excitation. The eventual thalamic and cortical effects of a decrease in dopa-
minergic input at the level of the striatum and the thalamus and cortex will
receive less excitation. The results are the same whether the direct or indirect
pathway is considered. Movement then will be decreased or slowed down. The
terms akinesia and bradykinesia are employed. On the other hand, if there is
increased dopaminergic activity, the end results at the thalamic or cortical level
will be an increase in motor activity irrespective of whether the direct or indirect
pathway is considered. The terms hyperkinesia and dyskinesia are employed.
The ultimate effect of dopamine then is to facilitate movement (Cote and
Crutcher 1991 and Bergman et al. 1990). The striatum also has GABA-mediated
inhibitory outflow to S. nigra compacta. Specific sites in the striatum project to
the S. nigra compacta (and receive afferent input from the S. nigra compacta).
Microanatomy of the striatum (Table 12.3). From a histochemical and histologi-
cal standpoint, distinct areas may be noted, referred to as patches within the larger
background matrix. The patch areas have a high density of neurons; matrix areas
are less dense. Patch zones contain little acetylcholine esterase; matrix areas are
rich in acetylcholine esterase. Patch areas are associated with bundles of dopamine
fibers early in development. Later in development, there are less dense dopaminer-
gic inputs to the matrix (Graybiel and Ragsdale 1978). Neurons within the striatum
may be additionally categorized on the basis of size and morphology of the dendrite
and size as (a) medium-sized, spiny neurons and (b) large or small aspiny neurons.
The different properties of these regions and neuron types are presented in
Table 12.3. There is considerable evidence that the dopamine-containing terminals
and their related synapses and the cholinergic synapses in the striatum have essen-
tially antagonistic actions. Normally, however, they remain in a particular balance.
We will discuss the problem of an imbalance when we come to discuss Parkinson’s
disease (Duvoisin 1967; Hornykiewicz 1970). As discussed above, both tend to be
found in specific sites in striatum (striosomes). These sites exist in a larger matrix
of the striatum. Several additional loops and circuits must now be considered.
Overview of the dopaminergic systems. In addition to the dopaminergic nigros-
triatal pathways, which are of major concern in our discussion of motor function,
there are other major dopaminergic pathways. These other pathways, however, are
of importance when one begins to utilize L-Dopa (the precursor of dopamine) in
therapy of Parkinson’s disease. In addition, these pathways are of importance when
agents (such as neuroleptics employed in the treatment of psychoses or other psy-
chiatric syndromes) are used to block the dopamine receptor or to prevent the stor-
age of dopamine. In addition, the overall disease state in Parkinson’s disease may
also involve these pathways.
(a) The mesolimbic system – originating in the ventral tegmental area, medial and
superior to the S. nigra, and projecting to the nucleus accumbens (ventral stria-
tum), stria terminalis septal nuclei, amygdala, hippocampus, mesial frontal,
anterior cingulate, and entorhinal cortex. A major role in emotion, memory, and
perception is postulated for this system. Hallucinations are a side effect of a
high dose of L-Dopa in the Parkinsonian patient.
(b) The mesocortical system – originating in the ventral tegmental area and project-
ing to neocortex particularly dorsal prefrontal cortex with a role in motivation,
attention, and organization of behavior.
Overlap with the cerebellar system. It is also important to remember that the
major outflow from the cerebellum (via the superior cerebellar peduncle) termi-
nates in relation to the same ventrolateral and ventral anterior nuclei of the thala-
mus. This thalamic nucleus receives a projection from both the cerebellum
(predominantly the dentate nucleus) and the globus pallidus. However, the infor-
mation from the cerebellum is projected in a more limited manner primarily via
ventrolateral to the motor areas of cerebral cortex, predominantly the premotor and
motor cortices. The basal ganglia differ from the cerebellum in several important
respects. In contrast to the more limited relationship of cerebellum to ventral lateral
nucleus of thalamus (projection to motor areas of cortex and projections from
motor areas of cortex via pontine nuclei to the cerebellum), the basal ganglia have
widespread inputs from the cerebral cortex and via several thalamic nuclei back to
multiple cortical areas. These cortical basal ganglion relationships are not diffuse
or overlapping but instead are organized in parallel systems.
368 12 Motor System II: Basal Ganglia
It should be evident that this lesion in the ventral lateral nucleus of the thalamus
would also be extremely effective in eliminating tremor originating in the cerebel-
lum since such a lesion would prevent a disordered cerebellum from acting on the
circuits passing through this nucleus and this disordered cerebellum would no lon-
ger influence motor activities originating at a cortical level. We must consider the
circuits through the basal ganglia, modulators of cortical function, particularly as
regards movement. For voluntary movement, these circuits clearly provide complex
modulation acting on the supplementary motor cortex. This modulation represents
a focused equilibrium of opposing influences. When one of these influences acts to
a disproportionate degree, dysfunction in the main circuit from the cortical motor
cortex to the anterior horn cells and to the reticular formation will result. In general,
a relative decrease in the action of dopamine produces a decrease in movement. Too
much of dopamine action produces an excess of movement, dyskinesia.
12.2 S
pecific Syndromes, Parkinson’s Disease,
and the Parkinsonian Syndrome (Olanow and Tanner
(1999) and Riley and Lang (2007))
The most common disease involving the basal ganglia is Parkinson’s disease, first
described by James Parkinson in 18,173. Parkinson’s disease after Alzheimer’s dis-
ease is the most common degenerative disorder of the central nervous system affect-
ing approximately one million individuals in the United States. The basic pathology
is the progressive loss of dopamine-producing neurons in the pars compacta of the
substantia nigra. A certain mixture of symptoms then develops, each of which may
vary in severity.
Cardinal signs of Parkinson’s disease. The essential signs and symptoms consist
of tremor, rigidity, akinesia, and defects in postural and righting reflexes. Charcot
essentially described this total picture and he named the disease after Parkinson
(Goetz 1986). The cardinal signs and symptoms are summarized in Table 12.4.
Some cases throughout their course may continue to manifest primarily tremor as
the major symptom, and such cases tend to have a more favorable prognosis. Several
types of Parkinson’s disease and syndromes may be specified. The most common
variety is the idiopathic or primary Parkinson’s disease, a degenerative disease aris-
ing insidiously in the patient of age 40, 50, or 60. In a series of 1644 patients with
Parkinsonism, evaluated by Jankovic (Jankovic 1989a, b) at a movement disorder
clinic, 82% were found to have idiopathic Parkinson’s disease. At times, there is a
family history of the same disease.
1. Pathology of Parkinsonian lesions. The basic pathology involves a progressive
loss 3. As we will discuss below, other disease entities may overlap with many of
the same symptoms and signs, and it is appropriate to refer to the larger group
as the Parkinsonian syndrome. The term Parkinsonism has also been employed
for this larger group of the pigmented neuromelanin-containing neurons of the
370 12 Motor System II: Basal Ganglia
pars compacta of the substantia nigra (Fig.12.3). (The pigmented neurons of the
locus ceruleus are also affected.) (The student will recall that both melanin and
dopamine are steps in the metabolic pathway involving phenylalanine.) A long
preclinical period estimated at 5 years occurs in this progressive disease. Various
estimates suggest that when symptoms first occur, 70–80% of striatal dopamine
is depleted. In terms of neurons in the pars compacta of the substantia nigra, 50%
(compared to age-matched controls) to 70% (compared to young individuals) are
already lost. Normally the rate of cell loss in the nigra during normal aging is 5%
per decade. In patients with Parkinson’s disease, the rate of cell death is subse-
quently 45% per decade. On histologic examination, there is a characteristic,
specific finding of Lewy bodies (Fig. 12.4), round, eosinophilic bodies sur-
rounded by a clear halo within the cytoplasm of surviving neurons of the sub-
stantia nigra. In many cases, these Lewy bodies are found in other neurons, e.g.,
cerebral cortex. Immunocytochemistry has demonstrated that a small protein
alpha-synuclein is a major component of the Lewy body (Fig.12.4). Under nor-
mal circumstances, this protein is located in presynaptic nerve terminals. It is
therefore likely that the Lewy body represents degenerated and aggregated neu-
rofilaments. The Lewy body may also be found diffusely in cerebral.
2 . Etiology of Parkinson’s disease. Why do the neurons degenerate? The majority
of cases with L-Dopa-responsive Parkinson’s disease does not have a clear-cut
genetic basis. However, mutations in the alpha-synuclein gene have been found
in several families of Italian or Greek origin with early-onset autosomal domi-
nant Parkinson’s disease mapping to locus 4Q21–4Q25 (Goerdert et al. 1998 and
Duvoisin 1998). Other families with autosomal recessive juvenile-onset disease
have implicated the parkin gene at locus 6q25.2–27. Other gene loci are discussed
Fig. 12.3 The substantia nigra in Parkinson’s disease. Control substantia nigra demonstrating
strong pigmentation. Substantia nigra from case A66-776, a patient with idiopathic Parkinson’s
disease, demonstrating a marked loss of pigmentation. Courtesy Dr. Thomas Smith. Neuropathology
University of Massachusetts)
12.2 Specific Syndromes, Parkinson’s Disease, and the Parkinsonian Syndrome… 371
Fig. 12.4 Lewy body in a pigmented neuron of the substantia nigra. H&E stain, original at 125×
(Courtesy of DR. Thomas Smith). Fig. 19.5, Lewy body. Slide stained for alpha-synuclein. 100×
(Courtesy of Dr. Thomas Smith)
by Dunnett and Bjorklund (1999). The major etiologic factors have involved a
genetic predisposition and possible toxic exposures.
Neuroleptic agents. The use of neuroleptic agents may unmask an underlying
genetic predisposition to Parkinson’s disease. A significant percentage (15–60%
depending on age) of patients who receive neuroleptic tranquilizers also will develop
symptoms of Parkinsonism. These agents include phenothiazides such as chlor-
promazine and haloperidol and reserpine. Reserpine interferes with the storage of
dopamine within the nerve cells and, thus, depletes the brain of this neurotransmit-
ter. Phenothiazides and related compounds, on the other hand, block the postsynap-
tic receptors at dopaminergic synapses. In general, of the symptoms produced by
these agents, the akinesia, rigidity, and tremor will disappear when the agent has
been cleared from the body. However, in some cases, the Parkinsonian features
appear to remain as a permanent deficit. In such patients, one may find evidence in
the family history of other cases of Parkinson’s disease (Schmidt and Jarcho 1966).
Toxic agents. The major impetus for the study of possible toxic exposure came
from the study of cases of Parkinson’s disease developing in miners exposed to
manganese and more recently in cases exposed to the agent MPTP.
Manganese poisoning. A relatively rare cause of a Parkinsonian syndrome is
manganese poisoning. Manganese apparently accumulates in the melanin-containing
neurons of the substantia nigra and interferes with the enzyme systems involved in
the production of dopamine (Mena et al. 1970).
372 12 Motor System II: Basal Ganglia
MPTP toxicity. Another form of Parkinson’s disease induced by the drug MPTP
has provided major insights into the possible etiology of the degeneration of the
dopamine-containing neurons in the substantia nigra. (MPTP is the abbreviated term
for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.) This agent is a by-product of the
chemical process for the production of a reverse ester of meperidine (Demerol):
1-methyl-4-propionoxypiperidine (MPPP). Meperidine is a controlled narcotic;
MPPP is not controlled, has narcotic action, and can be produced in clandestine labo-
ratories. MPTP had been recognized shortly after its legitimate synthesis in 1947 to
produce a severe rigid, akinetic state in monkeys. However, it was not until the sum-
mer of 1982 when MPPP was produced on a large scale in Northern California, for
illicit mass distribution, that significant numbers of young drug abusers began appear-
ing at emergency rooms with an acute Parkinsonian syndrome. The investigation of
these cases has been presented in a series of papers by Langston et al. (1983, 1992)
and Ballard et al. (1985). Essentially, the compound MPTP has selective toxicity on
the dopaminergic neurons of the pars compacta of the S. nigra, not only in human but
also in subhuman primates, such as the rhesus monkey, the Macaca mulatta, and the
squirrel monkey. Both in the human and the monkey, MPTP reproduces the clinical
disease, the pathological findings, and the effects of pharmacological therapy of
Parkinson’s disease to a relatively complete degree, including in older animals the
presence of Lewy bodies. With such an animal model, experimental medical and
surgical therapy can be studied with a clear-cut correlation with the human disease
(e.g., see Aziz et al. (1991), Langston and Ballard (1984), and Kopin (1988)).
Moreover, since there were many patients exposed to the agent but not all exposed
patients and not all acute cases developed the chronic Parkinsonian state, prospective
studies can be performed as to the natural history and factors influencing the onset of
the disease (Stone 1992). In part because of MPTP, increased attention has been
focused on other environmental exposures that may be involved in producing neuro-
toxic effects culminating in Parkinson’s disease (Tanner and Langston 1990; Olanow
and Tatton 1999).
Other pathological processes. These disorders also will produce some of the
symptoms of Parkinson’s disease without the presence of Lewy bodies (Gibb 1988):
1. Bilateral necrosis of the globus pallidus may produce akinesia. Such a necrosis
could occur in carbon monoxide poisoning, or anoxia, or in relation to infarction.
Rigidity in flexion may also follow bilateral necrosis of the putamen or the glo-
bus pallidus.
2. A tremor at rest may occur with destructive lesions involving the ventromedial
tegmentum of the midbrain. Such lesions, apparently, interrupt the pathway from
the substantia nigra to the striatum. A degeneration of neurons in the substantia
nigra and a decrease in dopamine in the corpus striatum occur.
3. “Arteriosclerotic or vascular (multi-infarct)” variety in which bilateral infarcts
occur in the putamen. Usually this is the accompaniment of a lacunar state in
which multiple small infarcts occur in the basal ganglia and internal capsule. The
resultant syndrome of rigidity and akinesia affects the lower half of the body and
thus can be clearly distinguished from the classical idiopathic L-Dopa-responsive
Parkinson’s disease.
12.2 Specific Syndromes, Parkinson’s Disease, and the Parkinsonian Syndrome… 373
Fig. 12.5 Parkinson’s disease. Case 12.1. See text; Handwriting sample: on May 3, 1983, before
therapy with L-Dopa/carbidopa and May, 10, 1983 – 1 week after starting therapy. In each example,
the larger circles have been drawn by the examiner linkage to chromosome 20P in which prominent
iron deposits and neuronal degeneration in globus pallidus and substantia nigra are associated with
childhood onset of Parkinsonian syndrome, dementia, spasticity, dystonia, and chorea.
Fig. 12.6 Hemichorea.
Case 12.2. See text. MRI
demonstrates a hyperdense
area of the head of the
right caudate, adjacent
putamen, and external
capsule – consistent with a
hemorrhage. Sequential
horizontal sections at
5 mm, intervals –
Tl-weighted D – sagittal
section 12.5 mm to the
right of the midline
12.3 Differential Diagnosis of Parkinson’s Disease 377
b romocriptine (Parlodel). Over the subsequent years, other agents were employed,
but the disease continued to progress with all of the problems in management dis-
cussed above. Eventually, in 1997 he underwent mesencephalic fetal cell transplanta-
tion. Evaluation 3 years after the transplant demonstrated a little improvement but a
marked increase in the dyskinesias. Some improvement in dyskinesias occurred after
dopaminergic medications again were reduced.
1. In considering the akinesia and bradykinesia of Parkinson’s disease, the major dif-
ferential diagnosis in the older population are the syndromes of gait apraxia related
to frontal lobe, as discussed in Chap. 9. These may be outlined as follows:
(a) Normal pressure hydrocephalus.
(b) Other types of hydrocephalus: late decompensation of aqueductal stenosis.
(c) Multiple lacunar infarcts (the lacunar state).
(d) Leukoaraiosis – or Binswanger’s disease – involving the periventricular
white matter and seen in elderly hypertensive patients, e.g., Alzheimer’s dis-
ease: note, however, that Mayeux et al. (1985) found that 34% of patients
with Alzheimer’s disease had some extrapyramidal signs. To confound the
picture, 44% of patients with Parkinson’s disease have dementia, with 29%
found to have Alzheimer’s disease and 10% Lewy body dementia.
(e) Frontal lobe tumors, e.g., subfrontal or parasagittal meningiomas.
(f) Myxedema with hypothyroid state.
(g) General paresis of neurosyphilis, now uncommon but refer to case 30.5. In
general, frontal lobe syndromes do not have a prominent tremor (unless a
coincident essential or senile tremor is present). Rigidity may be present but
this variable rigidity is of the frontal lobe type referred to as gegenhalten.
A cogwheel component (to this frontal lobe rigidity) is usually not present unless
there is a superimposed tremor of other cause. The rigidity and akinesia pre-
dominantly affect the lower extremities.
2. In considering the tremor of Parkinson’s disease – the major differential diagno-
sis is essential (or senile or familial tremor). In general, this is a tremor of the
outstretched hand with some increase as termination of movement or when a
sustained posture is maintained. The tremor is not present at rest and there is no
pill rolling quality. Rigidity is not present, and gait is normal with a good swing
of the arm. The tremor is usually long-standing without major disability. Note
that there is a small group of Parkinson’s disease patients with favorable out-
come who have a resting tremor as a predominant symptom over many years.
They will, however, have to a minor degree, on careful examination, many of the
other cardinal symptoms of Parkinson’s disease.
378 12 Motor System II: Basal Ganglia
Initial clinical and experimental studies correlated these disorders with lesions of
the contralateral subthalamic nucleus. (Many patients with Parkinson’s disease
have some symptoms, usually minor, that suggest some degree of involvement
beyond the S. nigra and beyond the dopaminergic nigrostriatal system, e.g., ortho-
static hypotension which is present in the untreated patient.) Idiopathic Parkinson’s
patients also may have some minor degree of upward gaze impairment.
It was recognized that the underlying lesion could be a small infarct due to poste-
rior cerebral penetrating branch involvement, often on a lacunar basis, in a patient
with hypertension or diabetes mellitus. At times, the adjacent thalamic areas were
involved, as well, e.g., the ventral posterior lateral or ventral lateral nucleus. At times,
the responsible lesion was a small hemorrhage in the subthalamic nucleus (Fig. 12.6)
and, rarely, a small metastatic tumor. As regards the explanation for such contralat-
eral excessive movement, hemichorea, or hemiballismus, one needs only to consult
(Fig. 12.1). Decreasing the excitatory drive from the subthalamic nucleus acting on
the medial globus pallidus and the substantia nigra reticularis would decrease the
inhibitory drive from those structures acting in the thalamus. Therefore, the thalamic/
premotor-SMA circuit would be more active and more movement would result.
Hemichorea: Case history 10.2 presented below provides an example of hemichorea
with MRI (Fig. 12.6) correlation of lesion location in the striatum (caudate/putamen)
following a hemorrhage into those structures.
Case History 12.2, Fig. 12.6: This 88-year-old, right-handed, widowed white female
with a past medical history of profound hearing impairment, adult-onset diabetes,
euthyroid goiter, coronary artery disease, and hypertension, 5 days prior to admission,
developed the insidious onset of involuntary rotary movement in the left foot which
increased in intensity and progressed to involve the left shoulder. The movements were
constantly present, even during sleep and with progression; her ability to ambulate
with a walker was impaired. She also had a dull headache greater on the left side than
on the right during the last few days.
Neurological examination:
Motor system: There was minimal weakness in the left upper extremity (5−/5).
There was a persistent hemichorea: involuntary twisting movements of her left foot
and upward and rotary movements of her left shoulder. The movement was exacer-
bated by motor tasks but did dissipate with sleep. Gait was slightly unsteady due to
hesitant placement of the left foot. She did quite well with minimal assistance.
Reflexes: Deep tendon reflexes were symmetrical and physiologic except for
decreased Achilles secondary to diabetes. The left plantar response was extensor.
Sensation: Symmetrically diminished vibration sense in the toes.
Clinical diagnosis: hemichorea.
Laboratory data: MRI scan 3 days after admission revealed mild cortical atrophy
and a hyperdense area, the right basal ganglia (particularly the head of caudate and puta-
men), and external capsule consistent with subacute hemorrhage (Figs. 12.6 and 12.7).
380 12 Motor System II: Basal Ganglia
Fig. 12.7 Hemiballismus.
Myelin stain of basal
ganglia demonstrating a
discrete hemorrhage into
the right subthalamic
nucleus (arrow points to
the subthalamic nucleus on
the unaffected side – from
Luhan JA, Neurology,
Baltimore, Williams, and
Wilkins, 1968, p. 334)
Hospital course: The patient was begun on haloperidol 0.5 mg by mouth every
morning and advanced to 1 mg by mouth three times per day with improvement in
the hemichorea, particularly in the upper extremity over the next 2 weeks.
Hemiballism: As we have previously indicated, the movements of hemichorea may
evolve or merge into more violent, uncoordinated, rotatory, flinging movements at
the shoulder joint and other proximal joints, termed hemiballistic. The responsible
lesion was located in the subthalamic nucleus (Fig. 12.8) or in the putamen or at the
border of lateral pallidum–putamen, as discussed above.
The following case history illustrates this movement disorder in a patient seen
prior to the era of CT and MRI scans in which the localization is relatively clear.
Case History 12.3: This 79-year-old, right-handed, white housewife had the
abrupt onset in the early morning hours, 2 days prior to admission, of almost con-
stant flinging movements of the right arm over which she had no control. At the
same time, she noted that her right arm felt numb and heavy. Over the next 2 days,
the movements decreased markedly and she regained more control of the arm.
History: The patient had a 9 L-Dopa-induced dyskinesias which is not observed
in intact monkeys and humans who have normal dopaminergic and normal basal
ganglia function. Parkinsonian patients, monkeys with MPTP lesions, and patients
with a predisposition to Huntington’s disease will develop dyskinesias after receiv-
ing L-Dopa (see discussion below and Luquin et al. 1992) known diabetic for 21
years, receiving insulin.
Neurological examination: Motor system. Minimal weakness was present in the
right upper extremity at the elbow, wrist, and fingers. Alternating movements and
finger-to-nose testing in the right hand were markedly impaired. Occasional invol-
untary flinging movements occurred at the right shoulder.
Sensory system: Pain, touch, vibration, and position senses were all absent in the
right upper extremity to the elbow and decreased in this extremity above the elbow.
Clinical diagnosis: hemiballismus due to a lesion of penetrating branches of the
posterior cerebral artery, which involved the subthalamic nucleus and ventral posterior
lateral nucleus of thalamus.
12.5 Hemichorea and Hemiballism 381
Fig. 12.8 Huntington’s
disease. Case 10.4. Marked
atrophy of cerebral cortex
and of caudate nucleus in
this patient with a familial
history of the disorder and
a significant increase in the
CAG trinucleotide repeats
(MRI)
Laboratory data: Chest and skull X-rays, EEG, and cerebrospinal fluid studies
were all normal.
Subsequent course: The flinging movements of the right arm subsided sponta-
neously, shortly after admission. Position sense returned and pain sensation showed
a mild improvement. The ataxia on finger-to-nose testing disappeared.
Generalized chorea: Bilateral generalized chorea may occur under the follow-
ing circumstances:
1. Acute onset with an immunological basis, (a) one aspect of rheumatic fever (plus
or minus carditis and arthritis). (b) In relation to various autoimmune diseases
such as lupus erythematosus.
2. As an acute complication of L-Dopa therapy in patients with compromise of the
dopaminergic system or with disease of the basal ganglia – as discussed above.
3. As an acute or chronic complication of various metabolic disorders: hepatic,
renal, hypocalcemia, etc., rarely occurring in pregnancy.
4. As a chronic progressive disorder – indicating a degenerative disease – affecting
the striatum and other sectors of basal ganglia and cerebral cortex. The most
frequent disease in this category is Huntington’s disease. Huntington’s disease is
of importance beyond its frequency in the population of 5–10/100,000. The dis-
ease was originally described in 1872 by George Huntington, based on clinical
observations made by his grandfather, his father, and himself of an apparent auto-
somal dominant syndrome of high penetrance that occurred in families living on
Long Island in New York State. The syndrome was characterized by the develop-
ment in midlife of a progressive psychological change (depression, paranoia, psy-
choses), dementia, and involuntary choreiform movements. The disease often
affected multiple members of a family over a number of generations. Genetic
studies have confirmed that the pattern of inheritance follows an autosomal domi-
nant pattern with extremely high penetrance. In large series, 50% of offspring will
manifest the disease, that is, all who carry the affected gene will manifest the trait
the maternal line. Modern genetic analysis using recombinant DNA techniques
382 12 Motor System II: Basal Ganglia
and studying families with large numbers of affected individuals or large numbers
at risk have allowed the localization of the gene defect. The expression of the gene
may vary
Mean age of onset in a large sample as defined by choreiform movements was 42
years. However, behavioral changes, including depression and suicide attempts,
may precede the movement disorder by 10 years or more. Earlier onset of disease is
associated with a more rapid course and with the earlier development of features of
rigidity. Such patients, for unknown reasons, are more likely to have inherited the
gene from the father. Late-onset cases (onset between 50 and 70 years of life) have
a much more prolonged course, and choreiform movements are often the predomi-
nant feature (see Sax and Vonsattel (1992)). At times the term senile chorea has been
utilized for these late onset cases, which are more likely to have involved (see Roberts
1990; Wexler et al. 1991). The specific mutation has now been identified as an unsta-
ble trinucleotide repeat in the CAG series coding for polyglutamine tracts at the
4p16.3 locus on this chromosome. Normal individuals have 6–34 repeats; patients
with Huntington’s disease have 36–121 (Zoghi and Orr 2000). The gene product is
huntingtin. Patients with onset at an early age or with a more severe form of the
disease have a greater number of repeats. As we have already discussed in Chap. 9
on the spinal cord, similar mutations involving an excessive number of CAG repeats
have also been found in a number of other neurological disorders including several
of the spinocerebellar degenerations and spinobulbar muscular atrophy. Other dis-
orders such as myotonic dystrophy and Friedreich’s ataxia have an excessive num-
ber of repeats in other trinucleotide sequences. Presymptomatic detection is
possible, but this should be done under circumstances where a full gamut of genetic
counseling is available. The underlying gross pathology has been well established
and is demonstrated in Figs. 12.8 and 12.9 with marked atrophy of caudate nucleus
and putamen are the pathologic and neuroimaging hallmarks. This gross pathologi-
cal feature allows for diagnosis and subsequent monitoring of progression by means
of CT scan and MRI scan (Fig. 12.8). In addition, significant cortical atrophy also
occurs as the disease progresses. The gene product huntingtin is expressed widely
throughout the brain. There are high levels in large striatal interneurons and medium
spiny neurons, as well as cortical pyramidal cells and cerebellar Purkinje cells.
Additional analysis has indicated that not all cells and transmitters in the caudate
and putamen are involved in the process of degeneration. The extensive studies have
been reviewed by Albin et al. (1990), Martin and Gusella (1986), Penney and Young
(1988), Young et al. (1988), and Wexler et al. (1991). The cells affected are classi-
fied as medium-sized, spiny neurons that project to sites outside the striatum and
which constitute approximately 90% of all striatal neurons. All of them contain the
transmitter GABA. However, different subtypes are distinguished based on the spe-
cific associated neuropeptide that they contain, e.g., enkephalin, substance P, and/or
dynorphin, and based on the projection destinations. On the other hand, other cells
with interneuron functions are not affected: (a) the large, spiny acetylcholine-con-
taining interneurons, and (b) the small aspiny interneurons containing the neuropep-
tides somatostatin and substance Y. Refer to Table 12.4. Early in the course of the
12.5 Hemichorea and Hemiballism 383
disease, there is a loss of those spiny neurons which contain the GABA and e nkephalin
transmitters and which project to the lateral globus pallidus. At this point in the dis-
ease, the loss of these striatal inhibitory inputs to the lateral globus pallidus results in
increased activity (inhibitory) of the lateral globus pallidus neurons. Since the lateral
globus pallidus is the main input to the subthalamic nucleus and this input is inhibi-
tory, an increased inhibition of the subthalamic nucleus results. As a result, the excit-
atory output from the subthalamic nucleus to the medial globus pallidus (MGP) and
S. nigra reticularis (SNR) is reduced. The output of neurons in MGP and SNR is
reduced. This output is inhibitory and destined for ventrolateral thalamus. The output
of ventrolateral thalamus is no longer inhibited – and increased activity occurs in the
ventrolateral to supplementary motor cortex circuit. Abnormal excessive movements
due to increased activity of SMA then result as discussed above under hemichorea.
The following case history provides an example of Huntington’s disease.
Case History 12.4: This 54-year-old right-handed female was referred for evalua-
tion of a movement disorder. The patient lived alone and it was difficult to obtain
much of any history from the patient. She denied any neurological or psychiatric
disorders except for a problem with memory during the last year. She did indicate
that she had worked for 10 years as a secretary/computer operator but had been fired
10 years ago, because “she did not work fast enough.” She had a past history of
hypertension but had not been reliable in taking her prescribed medication. The
patient’s son was aware that changes in emotion, personality, speech, gait, and a
movement disorder had been present for at least 3 years.
Family history: The patient denied any neurological family history except for a
maternal uncle who had the “shakes” (actually a maternal aunt with essential tremor);
additional investigation revealed that her father clearly had Huntington’s disease
with onset of choreiform movements at age 30 and of irritability, paranoia, and gait
Fig. 12.9 Huntington’s disease. Marked atrophy of the caudate and putamen with secondary dila-
tation of the lateral ventricles is evident. Cortical atrophy was less prominent in this case (Courtesy
of Doctor Emanuel Ross, Chicago)
384 12 Motor System II: Basal Ganglia
disturbance in his early 50s. The patient’s eldest daughter aged 34 had been depressed
for 5 years and had problems with speech and walking for a number of years.
Neurological examination: Mental status – the patient often avoided eye con-
tact. Affect was usually inappropriate with laughter as the response to many ques-
tions. The overall minimental status score was 27/30. The only deficit related to
delayed recall portion of the test 0/3 objects.
Cranial nerves: The patient had a hyperactive jaw jerk. She had frequent facial
grimacing.
Motor system: The patient had decreased tone at the wrists and elbows. As she
sat she had frequent restless and at times choreiform movements of the hands and
feet. Gait was often “bizarre” in terms of occasional sudden movements of a leg as
she moved down the hall and came to a stop. These same movements occurred, as
she remained standing. In addition, in standing or walking, there were intermittent
dystonic postures of either left or right arm.
Reflexes: Deep tendon stretch reflexes were everywhere hyperactive but plantar
responses were flexor.
Clinical diagnosis: Huntington’s disease.
Laboratory data: MRI scans of the head (Fig. 12.8) – The heads of the caudate
nuclei were very atrophic. Cortical sulci were wide consistent with cortical atrophy.
The lateral and third ventricles were secondarily dilated. PCR testing for the CAG
trinucleotide repeats of the huntingtin gene indicated one allele normal at 17 and the
second excessive at 42 repeats.
Subsequent course: This patient is an example of a patient with Huntington’s
disease followed over a longer period of time. His patient refused any treatment for
the movement disorder. According to the son, the patient’s neurological status wors-
ened to a moderate degree over the subsequent 3 years as regards speech, unsteadi-
ness of gait, and mood swings. Onset occurred at age 32 with definite diagnosis of
the disorder in both the father and paternal grandfather.
Figure 12.9 is a pathological specimen from a different case and shows the
marked gross atrophy of the cortex, caudate, and putamen with secondarily dilation
of the lateral ventricles.
12.6 O
ther Movement Disorders Associated with Diseases
of the Basal Ganglia
athetosis is found in the putamen that may have a marbled or mottled appearance as
a result of the presence of excessive numbers of abnormally situated myelin sheaths.
2. Hepatolenticular degeneration (Wilson’s disease): This is a familial disorder
(recessive inheritance), which affects, to a variable degree, the liver and the cen-
tral nervous system and, in many cases, the kidney and bones. In the central
nervous system, the most severe involvement occurs in the basal ganglia: the
putamen and globus pallidus (cavitation, loss of neurons, and an increased num-
ber of swollen astrocytes). To a lesser extent, the cerebellum and cerebral cortex
are involved. The basic etiology is a deficient plasma level of the circulating
copper-binding globulin, ceruloplasmin. Thus, there is an excessive serum level
of unbound copper. Normally, the binding of copper to ceruloplasmin prevents
the passage of copper out of the serum. In Wilson’s disease, however, the
increased amount of unbound copper results to passage of this metal into the
brain liver and kidney. In some cases, usually of early onset, the symptoms of
liver involvement predominate. Wilson’s disease should always be suspected
when hepatocellular disease develops a child or adolescent. Deposition of cop-
per also occurs in the cornea at the scleral junction. The resultant greenish-brown
pigmentation is referred to as the Kayser–Fleischer ring. This ring is almost
always present when central nervous system involvement is present. Overall,
54% of the cases present with neurological onset, 31% with hepatic dysfunction,
14% with psychiatric symptoms, 2% with eye symptoms, 1–2% with hemolytic
anemia, and 1% with heart disease (see Patten (1988)). The tremor is coarse and
best described as sustained postural. The term “wing beating” is often used. The
copper also produces damage to the renal tubules, resulting in glycosuria and
aminoaciduria. Diagnosis can be based on the clinical findings and ceruloplas-
min levels (normal levels are 200–400 mg/L, serum copper) (normal total levels
are 11–24 μmol/L versus 3 to 10 in Wilson’s disease). The treatment of Wilson’s
disease is dependent on a reduction of copper in the diet or the administration of
an agent that will bind copper. Penicillamine (B.B-dimethyl cysteine) is an effec-
tive chelator of copper. It is well absorbed on oral administration and promotes
the urinary excretion of copper, resulting in a decreased level of copper in the
serum, central nervous system, and liver.
3 . Dystonia: Dystonia is a hyperkinetic disorder dominated by sustained muscle
contractions frequently causing twisting and repetitive movements or abnormal
postures. Dystonia may be focal (43%), segmental (30%), generalized (22%), or
unilateral (5%). The most frequent of the cranial dystonias is blepharospasm in
which there is forced eye closure. Other focal dystonias known as occupational
dystonias involve the more specific muscles of the hand and arm utilized in spe-
cific actions: writers, typists, violinists, and pianists.
4 . Movement Disorders Induced by Dopamine Blocking Agents: (Sethi (2001)
has provided a comprehensive review of this topic). These agents produce fre-
quent acute and chronic complications in psychiatric patients:
(a) Acute dystonic reactions – which occur in 2–5% of patients within hours or days
after onset of therapy. Note that this complication occurs not only in psychiatric
patients but also in patients receiving agents of this class as antiemetics.
386 12 Motor System II: Basal Ganglia
(b) Acute akathisia: Acute restlessness and an inability to sit still occur in 20%
of the patients receiving dopamine-blocking agents.
(c) Acute drug-induced Parkinsonian syndrome discussed above. Although
symptoms may appear in any patient given sufficient amount of dopamine-
blocking agents to block 80% of the receptors, there does appear to be a
predisposition to develop symptoms in patients with a family history of
Parkinsonism.
(d) Tardive dyskinesia and other tardive reactions. In this context, tardive has
been defined as 3 months of exposure to the agent (1 month for patients over
the age of 60 years). Usually these are seen in the older patient involving the
mouth, tongue, lips, and face (oral buccolingual facial masticatory syn-
drome). Symptoms usually develop after 6–24 months of drug therapy, and
in many patients, the symptoms decrease after drug withdrawal. In another
group of patients, symptoms develop only after neuroleptic drugs have been
withdrawn, or dosage has been reduced again after prolonged use. In one
series, withdrawal or dose reduction resulted in tardive dyskinesia in 40% of
patients receiving chronic neuroleptic therapy. The presumed pathophysiol-
ogy is not entirely clear.
5. Tics: Motor tics are sudden, brief involuntary movements resembling jerks or
gestures. The patient may experience a poorly defined sensation of an irresistible
urge to move prior to the movement. These movements may be simple: an eye
blink, a head jerk, or a facial grimace. In some cases, the movement is more com-
plex and patterned, resembling a compulsive act. In some cases (syndrome of
Gilles de la Tourette which has autosomal dominant transmission), multiple tics
occur accompanied by vocalizations. The vocalization may consist of a simple
sound or may involve the use of obscene four-letter words referring to defecation,
genitalia, or sexual acts (coprolalia). Then a flurry of tics may occur after the sup-
pression. Tics may continue to occur in sleep. The usual idiopathic tics are com-
mon in children and may persist into adult life. Lees and Tolosa (1988) indicate
one of ten schoolboys will have idiopathic tics. Males are affected three times
more than females.
Bibliography
Albin D, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends
Neurosci. 1989;12:366–75.
Cooper IS. Involuntary movement disorders. New York: Hoeber Medical Division; 1969a.
Cooper JR, Bloom FE, Roth RH. The biochemical basis of neuropharmacology. New York: Oxford
University Press. (see in particular chapter 10: dopamine); 1991. p. 285–337.
Denny-Brown D. The basal ganglia and their relation to disorder of movement. London: Oxford
University Press; 1962.
Galvez-Jimenez N, editor. Movement disorders. Semin Neurol. 2001;21:1–123.
Hallett M. Classification and treatment of tremor. JAMA. 1991;266:1115–7.
Bibliography 387
Haymaker W, Mehler WF, Schiller F. Extrapyramidal motor disorders. In: Haymaker W, editor.
Bing’s local diagnosis in neurological disease. St Louis: CVMosby; 1969. p. 404–40.
Hurtig HI, Stern MB, editors. Movement disorders. Neurol Clin. 2001;19:523–788.
Jankovic J, Tolosa E, editors. Parkinson’s disease and movement disorders. Baltimore-Munich:
Urban & Schwarzenberg; 1988. 499 pp
Lowe J, Lennox G, Leigh PN. Disorders of movement and system degenerations. In: Graham DI,
Lantos PL, editors. Greenfield’s neuropathology, vol. 2. London: Arnold; 1997. p. 281–366.
Marsden CD, Fahn S, editors. Movement disorders II. London/Boston: Butterworths; 1987. 468 pp
Noback CR, Strominger NL, Demarest RJ. Chapter 24: The human nervous system; introduction
and review. 4th ed. Philadelphia: Lea & Febiger; 1991. p. 375–95.
Oppenheimer DR. Diseases of the basal ganglia, cerebellum and motor neurons. In: Adams JH,
Corsellis JAN, Dicker LW, editors. Greenfield’s neuropathology. Edward Arnold: London;
1984. p. 700–47.
Quinn N. Fortnightly review: Parkinson’s disease: recognition and differential diagnosis. BMJ.
1995;310:447–52.
Rascol O, Lees AJ, editors. Dyskinesias movement disorders. 1999;14 Suppl 1:1–80.
Riley DE, Lang AE. Movement disorders. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD,
editors. Neurology in clinical practice. Boston: Butterworth Heinemann II; 2000. p. 1889–930.
Agid Y, Cervera D, Hirsh E, et al. Biochemistry of Parkinson’s disease 28 years later: a critical
review. Mov Disord. 1989;4(S1):126–44.
Agid Y, Javoy-Agid F, Ruberg M. Biochemistry of neurotransmitters in Parkinson’s disease. In:
Marsden CD, Fahn S, editors. Movement disorders II. London/Boston: Butterworths; 1987.
p. 166–230.
Albin RI, Young AB, Penney JB, et al. Abnormalities of striatal projection neurons and N-methyl
D-aspartate receptors in Presymptomatic Huntington’s disease. N Engl J Med. 1990;322:1293–8.
Alexander GE, De Long MR, Strick PL. Parallel organization of functionally segregated circuits
linking basal ganglia and cortex. Ann Rev Neurosci. 1986;9:375–81.
Alyward EH, Codori AM, Rosenblatt A, et al. Rate of caudate atrophy in pre-symptomatic and
symptomatic stages of Huntington’s disease. Mov Disord. 2000;15:552–60.
Aziz TZ, Peggs D, Sambrook MA, Crossman AR. Lesion of the Subthalamic nucleus for the alle-
viation of l-methyl-4 phenyl 1,2,3,6, Tetrahydropyridine (MPTP) induced parkinsonism in the
primate. Mov Disord. 1991;6:288–92.
Ballard PH, Tetrud JW, Langston JW. Permanent human parkinsonism due to l-methyl-4 phenyl,
1,2,3,6, tetra-Hydropyrine (mptp): seven cases. Neurology. 1985;35:949–56.
Bandmann O, Sweeney MG, Daniel SE, et al. Multiple system atrophy is genetically distinct from
identified inherited causes of spinocerebellar degeneration. Brain. 1997;49:1598–604.
Berciano J. Olivopontocerebellar atrophy. In: Jankovic J, Tolosa E, editors. Parkinson’s disease
and movement disorders. Urban & Schwartzenberg: Baltimore/Munich; 1988. p. 131–51.
Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the
Subthalamic nucleus. Science. 1990;249:1436–8.
Bhatia KP. Familial (idiopathic) paroxysmal dyskinesias: an update. Semin Neurol. 2001;21:69–74.
Bhatia KP, Griggs RC, Ptacek LJ. Episodic movement disorders as channelopathies. Mov Disord.
2000;15:429–3.
Brashear A. The botulinum toxins in the treatment of cervical dystonia. Semin Neurol.
2001;21:85–90.
Brooks DJ. Detection of preclinical Parkinson's disease with PET. Neurology. 1991;41(Suppl
2):24–7.
Cooper IS. Involuntary movement disorders. New York: Paul B Hoeber; 1969b.
388 12 Motor System II: Basal Ganglia
Cote L, Crutcher MD. The basal ganglia. In: Kandel ER, Schwartz JH, Jessell TM, editors.
Principles of neural science. 3rd ed. New York: Elsevier; 1991. p. 647–59.
Cotzias GC, Papavasiliou PS, Gellen R. Modification of parkinsonism – chronic treatment with
L-Dopa. N Engl J Med. 1969;280:337–45.
Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinson-
ism. N Engl J Med. 1967;276:374–9.
Crossman AR. A hypothesis on the pathophysiological mechanisms that underlie Levodopa or
dopamine agonist induced dyskinesia in Parkinson's disease: Implications for the future strate-
gies in treatment. Mov Disord. 1990;5:100–8.
Crossman AR, Mitchell IJ, Sambrook MA, Jackson A. Chorea and myoclonus in the monkey
induced by gamma amino butyric acid antagonism in the lentiform complex the site of drug
action and a hypothesis for the neural mechanism of chorea. Brain. 1988;121:1–33.
Daniel SE, de Bruin VM, Lees AJ. The clinical and pathological spectrum of Steele-Richardson
Olszewski syndrome (progressive supranuclear palsy): a reappraisal. Brain. 1995;118:759–70.
De Bie RMA, Schuurman PR, de Haan PS, et al. Unilateral pallidotomy in advanced Parkinson’s
disease: a retrospective study of 26 patients. Mov Disord. 1999;14:951–7.
Delwaide PJ, Gance M. Pathophysiology of parkinson’s signs. In: Jankovic J, Tolosa E, editors.
Parkinson’s disease and movement disorders. Baltimore/Munich: Urban and Schwarzenberg;
1988. p. 59–73.
Deuschl G. Treatment options for tremor. N Engl J Med. 2000;342:505–7.
Dunnett SB, Bjorklund A. Prospects for new restorative and neuroprotective treatments in
Parkinson’s disease. Nature. 1999;399(6738 Suppl):A32–9.
Duvoisin RC. Familial Parkinson’s disease. Neurosci News. 1998;1:43–6.
Ebersbach G, Sojer M, Valladeoriopla F, et al. Comparative analysis of gait in Parkinson’s disease
cerebellar ataxia and subcortical arteriosclerotic encephalopathy. Brain. 1999;122:1349–55.
Eidelberg D, Sortel A, Joachim C, et al. Adult onset Hallervorden-Spatz disease with neurofibril-
lary pathology a discrete clinical pathological entity. Brain. 1987;110:993–1013.
Fearnley JM, Lees AJ. Striatonigral degeneration. A clinicopathological study. Brain.
1990;113:1823–4.
Forno LS, Alford EC. Pathology of Parkinson’s disease. In: Roller WC, editor. Handbook of
Parkinson’s disease. Marcel-Dekker: NY; 1987. p. 209–36.
Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for
severe Parkinson’s disease. N Engl J Med. 2001;344:710–9. (see also editorial by Fischbach
GD, Mc Khann GM. Cell therapy for Parkinson’s disease. Engl J Med. 2001;344:763–5
Furukawa Y, Kish SJ. Dopa responsive dystonia: recent advances and remaining issues to be
addressed. Mov Disord. 1999;14:709–15.
Gerfan CR, Engbar TM. Molecular neuroanatomic mechanisms of Parkinson’s disease. Neurol
Clin. 1992;10:435–49.
Gibb WRG. The neuropathology of Parkinsonian disorders. In: Jankovic J, Tolosa E, editors.
Parkinson’s disease and movement disorders. Baltimore/Munich: Urban & Schwarzenberg; 1988.
p. 205–23.
Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain. 1989;112:1171–92.
Goerdert M, Jakes R, Spillantini MG. Alpha-Synuclein and the Lewy body. Neurosci News.
1998;1:47–51.
Goetz CG. Charcot on Parkinson's disease. Mov Disord. 1986;1:27–32.
Goldblatt D, Markesbery W, Reeves AG. Recurrent Hemichorea following striatal lesions. Arch
Neurol. 1974;31:51–4.
Graybiel AM, Ragsdale CW. Histochemically distinct compartments in stratum of human, mon-
key and cat demonstrated by Acetylthiocholinesterase staining. Proc Natl Acad Sci U S A.
1978;75:5723–6.
Growdon JH, Hirsh MJ, Wurtman RJ, Wiener W. Oral choline administration to patients with tar-
dive dyskinesia. N Engl J Med. 1977;297:524–7.
Guridi J, Obesco JA. The subthalamic nucleus, hemiballismus and Parkinson’s disease: reappraisal
of a neurosurgical dogma. Brain. 2001;124:5–19.
Bibliography 389
Gusella JF, Wexler NS, Conneally DM, et al. A polymorphic DNA marker genetically linked to
Huntington’s disease. Nature. 1983;306:234–8.
Guttman M. Dopamine receptors in Parkinson’s disease. Neurol Clin. 1992;10:377–86.
Hallett M, Litvan I, et al. Scientific position paper of the movement disorder society evaluation of
surgery for Parkinson’s disease. Mov Disord. 2000;15:436–8.
Hornykiewicz OD. Physiological, biochemical and pathological backgrounds of Levao-Dopa and
possibilities for the future. Neurology. 1970;20:1. (Part 2), 1–13
Hornykiewicz O, Kish S, Beckler LE, et al. Brain neurotransmitters in dystonia musculorum defor-
mans. N Engl J Med. 1986;315:347–531.
Huntington G. On chorea. Med Surg Report. 1872;26:317–21.
Huw RM, Lees AJ, Wood NW. Neurofibrillary tangles Parkinsonian disorders-tau pathology and
Taugenetics. Mov Disord. 1999;14:731–6.
Jankovic J. Parkinsonism plus syndromes. Mov Disord. 1989a;4(Suppl l):S95–119.
Jancovic J. Tourette’s syndrome. N Engl J Med. 2001;345:1184–92.
Jankovic J, Fahn S. The phenomenology of tics. Mov Disord. 1986;1:17–26.
Jankovic J, Fahn S. Dystonic syndromes. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and
movement disorders. Baltimore/Munich: Urban & Schwarzenberg; 1988. p. 283–314.
Jarman PR, Davis MB, Hodgson SV, et al. Paroxysmal dystonic choreoathetosis: genetic linkage
studies in a British family. Brain. 1997;120:2125–30.
Jarman PR, Bhatia KP, Davie C, et al. Paroxysmal dystonic choreoathetosis: clinical features and
investigation of pathophysiology in a large family. Mov Disord. 2000;15:648–57.
Kandel E. Disorders of thought: schizophrenia. In: Kandel ER, Schwartz JH, Jessell TM, editors.
Principles of neural science. 3rd ed. New York: Elsevier; 1991. p. 853–68.
Keenen RE. The Eaton collaborative study of Levo Dopa therapy in parkinsonism. Neurology.
1970;20(Part 2):46–59.
Kertesz A. Corticobasal degeneration. J Neurol Neurosurg Psychiatry. 2000;68:275–6.
Kertesz A, Martinez-Lage P, Davidson W, Munoz DG. The Corticobasal degeneration syndrome
overlaps progressive aphasia and frontotemporal dementia. Neurology. 2000;55:1368–75.
Klawans HL, Moses H, Nausieda DA, et al. Treatment and prognosis of Hemiballismus. N Engl
J Med. 1976;295:1348–50.
Klawans HL, Paulson GW, Ringel SP, Barbeau A. Use of L-Dopa in the detection of Presymptomatic
Huntington's chorea. N Engl J Med. 1972;286:1332–4.
Klawans HL. The pathophysiology of drug-induced movement disorders. In: Jankovic J, Tolosa E,
editors. Parkinson’s disease and movement disorders. Urban and Schwarzenberg: Baltimore/
Munich; 1988. p. 315–26.
Koller WC, editor. Role of the controlled release formulation of Carbidopa-Levodopa in the treat-
ment of Parkinson’s disease. Neurology. 1992a;42(Suppl 1):Sl–60.
Koller WC. Initiating treatment of Parkinson's disease. Neurology. 1992b;42(Suppl 1):29–32.
Kopin IJ. MPTP toxicity: Implications for research in Parkinson’s disease. Ann Rev Neurosci.
1988;11:81–96.
Lamousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced
Parkinson’s disease. N Engl J Med. 1998;339:1105–11.
Lang AE, Lozano AM. Medical progress: Parkinson’s disease. N Engl J Med. 1998;339:1044–53.
11301143
Lang AE, Lozano AM, Duff ME, et al. Posteroventral medial pallidotomy in advanced Parkinson’s
disease. N Engl J Med. 1997;337:1036–42.
Langston JW, Ballard P. Parkinsonism induced by 1-methyl, 4-phenyl-1,2,3,6, tetrahydropyridine
(MPTP): Implications for treatment and pathogenesis of Parkinson’s disease. Can J Neurol Sci.
1984;11:160–5.
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of
Meperidine – analog synthesis. Science. 1983;219:979–80.
Langston JW, Widner H, Goetz CG, et al. Case assessment program for intracerebral transplanta-
tion (CAPIT). Mov Disord. 1992;7:2–13.
390 12 Motor System II: Basal Ganglia
Laplane D, Levasseur M, Pillone B, et al. Obsessive compulsive and other behavioral changes with
bilateral basal ganglia lesions. Brain. 1989;112:699–725.
Lees AJ, Tolosa E. Tics. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement dis-
orders. Baltimore/Munich: Urban and Schwarzenberg; 1988. p. 275–81.
Lees AJ. The Steele-Richardson, Olszewski syndrome (progressive Supranuclear palsy). In: Marsden
CD, Fahn S, editors. Movement Disorders II. London/Boston: Butterworths; 1987. p. 272–87.
Lewin R. Trail of ironies to Parkinson's disease. Science. 1983;224:1083–5.
Lewin R. Brain enzyme is the target of drug toxin. Science. 1984;225:1460–2.
Le Witt DA. Clinical studies with and pharmacokinetic considerations of sustained release
Levodopa. Neurology. 1992;42(Suppl 1):29–31.
Lieberman A. Emerging perspectives in Parkinson’s disease. Neurology. 1992;42(Suppl 4):5–7.
Lindvall O. Cerebral implantation in movement disorders: state of the art. Mov Disord.
1999;14:201–5.
Lindvall O, Brundin P, Widner H, et al. Grafts of fetal dopamine neurons survive and improve
motor function in Parkinson's disease. Science. 1990;247:514–77.
Litwin I. Diagnosis and management of progressive supranuclear palsy. Semin Neurol.
2001;21:41–8.
Litwin I, Campbell G, Mangone CA, et al. Which clinical features differentiate progressive supra-
nuclear palsy (Steele- Richardson- Olszewski syndrome) from related disorders? A clinico-
pathological study. Brain. 1997;120:25–9.
Martin JB, Gusella JF. Huntington's disease: pathogenesis and management. N Engl J Med.
1986;315:1267–76.
Mathuranath PS, Xuereb JH, Bak T, Hodges JR. Corticobasal degeneration and/or frontal tempo-
ral dementia? A report of two overlap cases and review of the literature. J Neurol Neurosurg
Psychiatry. 2000;68:304–12.
Mayeux R, Stern Y, Spanton S. Heterogeneity in dementia of the Alzheimer type: evidence of
subgroups. Neurology. 1985;35:453–61.
Meissen GJ, Myers RH, Mastromauro CA, Koroshetz WJ, Klinger KW, Farrer LA, Watkins PA,
Gusella JF, Bird ED, Martin JB. Predictive testing for Huntington's disease with use of a linked
DNA marker. N Engl J Med. 1988;318(9):535–42.
Mena I, Court J, Fuenzalida S, et al. Chronic Manganeses poisoning: treatment with L-Dopa or
5-OH tryptophan. N Engl J Med. 1970;282:5–10.
Martin JR. Hemichorea (hemiballismus) without lesions in the corpus Luysii. Brain. 1951;80:1–10.
Meyers R, Sweeney DB, Swidde JT. Hemiballismus: etiology and surgical treatment. J Neurol
Neurosurg Psychiatry. 1947;58:672–92.
Mitchell IJ, Jackson A, Sambrook MA, Crossman AR. The role of the subthalamic nucleus in
experimental chorea evidence from 2-Desoxyglucose metabolic mapping and horse radish per-
oxidase tracing studies. Brain. 1989;112:1533–48.
Montastruc JL, Rascol O, Senard JM. Treatment of Parkinson’s disease should begin with a
dopamine agonist. Mov Disord. 1999;14:725–30.
Myers RH, Sax DS, Koroshetz WJ, et al. Factors associated with slow progression in Huntington's
disease. Arch Neurol. 1991;48:800–4.
Myers RH, Vonsattel JP, Stevens TJ, et al. Pathologic assessment of severity in Huntington’s dis-
ease. Neurology. 1988;38:341–7.
Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci.
1999;22:123–44.
Papp MI, Lantos PL. The distribution of oligodendroglia inclusions in multiple system atrophy and
its relevance to clinical symptomatology. Brain. 1994;117:235–43.
Parkinson J. An essay on the shaking palsy. London: Sherwood, Neely & Jones; 1817. Reprinted -
the classics of neurology neurosurgery library, Birmingham, Gryphen editions, 1986
Patten BM. Wilson’s disease. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement
disorders. Baltimore/Munich: Urban & Schwarzenberg; 1988. p. 179–90.
Pauls DL, Leckman JF. The inheritance of Gilles de la Tourette's syndrome and associated
behaviors: evidence for autosomal dominant transmission. N EngI J Med. 1986;315:993–7.
Bibliography 391
Pearce RKB. L- Dopa and dyskinesias in normal monkeys. Mov Disord. 1999;14(Suppl 1):9–12.
Penney JB, Young AB. Huntington’s disease. In: Jankovic J, Tolosa E, editors. Parkinson’s disease.
Baltimore: Urban and Schwarzenberg; 1988. p. 167–78.
Rinne JO, Lee MS, Thompson PD, Marsden CD. Corticobasal degeneration a clinical study of 36
cases. Brain. 1994;117:1183–96.
Roberts L. Huntington’s gene: so near and so far. Science. 1990;247:624–17.
Sarma K, Waltz JM, Riklan M, Koslow M, Cooper IS. Relief of intention tremor by thalamic sur-
gery. J Neurol Neurosurg Psychiat. 1970;33:7–15.
Sax DS, Vonsattel JP. Chorea and progressive dementia in an 88-year-old woman. N Engl J Med.
1992;326:117–24.
Schmidt WR, Jarcho LW. Persistent dyskinesias following phenothiazide therapy. Arch Neurol.
1966;14:369–77.
Schneider JS, Pope A, Simpson K, et al. Recovery from experimental parkinsonism in primates
with GM1 Ganglioside treatment. Science. 1992;256:843–6.
Scheinberg IH, Steinlieb I. Wilson’s disease. Philadelphia: W B Saunders; 1984.
Schuurman PR, Bosch DA, Bossuyt PMM, et al. A comparison of continuous thalamic stimulation
and thalamotomy for suppression of severe tremor. N Engl J Med. 2000;342:461–8.
Schwarz GA, Barrows LJ. Hemiballism without involvement of Luy’s body. Arch Neurol.
1960;2:420–34.
Sethi KP. Movement disorders induced by dopamine blocking agents. Semin Neurol. 2001;21:59–68.
Siemers E, Reddy V. Profile of patients enrolled in a new movement disorders clinic. Mov Disord.
1991;6:336–41.
Singer HS. Current issues in Tourette’s syndrome. Mov Disord. 2000;15:1051–63.
Sladek JR, Redmond BE Jr, Collier TJ, et al. Transplantation advances in Parkinson’s disease. Mov
Disord. 1989;4(Suppl 1):S120–5.
Chapter 13
Motor Systems III: The Cerebellum
Movement and Major Fiber Pathways
of the Cerebellum
Abstract The role of the cerebellum is to integrate the sensory input from the
periphery to provide smooth coordinated voluntary movements. It is a laminated
cortical region with four deep nuclei (dentate, fastifigial, emboliform, and inter-
positus) and is attached to the brain stem by three peduncles- the superior, middle
and inferior cerebellar peduncles. Superior cerebellar peduncle (brachium conjunc-
tivum) is primarily efferent and projects via the dentate, fastigial, and interpositus
nucleus to the red nucleus of the midbrain and onto thalamic motor nuclei which
then project onto cerebrum. The middle cerebellar peduncle (brachium pontis) is
the largest cerebellar peduncle and receives input primarily from the contralateral
cerebrum via deep pontine nuclei whose fibers then project onto the neocerebel-
lum. The inferior cerebellar peduncle provides sensory input via climbing fibers
from the inferior olivary nucleus of the medulla and proprioceptive mossy fibers
from the spinocerebellar tract and lateral cuneate nucleus and projects onto the
paleocerebellum. The juxtarestiform body lies next to the inferior cerebellar pedun-
cle and carries ipsilateral input from the vestibular nuclei onto the flocculonodular
lobe of the archicerebellum and midline vermis which are important in posture and
movements.
A number of schemes for dividing the cerebellum into various lobes and lobules
have been devised. From a functional standpoint, it is perhaps best for the student to
visualize the cerebellum as composed of various longitudinal and transverse divi-
sions. To visualize these subdivisions, it is necessary to unfold and to flatten the
cerebellum as shown in Fig. 13.1.
Fig. 13.1 Major transverse and longitudinal subdivisions of the cerebellum. The surface has been
unfolded and laid out flat. (From Noback, C.R. et al.: 1991. The Human Nervous System. 4th
edition, Philadelphia. Lea & Febiger p. 282)
The major longitudinal divisions are the median (vermal cortex), the paramedian
(paravermal), and lateral (remainder of the cerebellar hemispheres).
The major projections and functional correlations are outlined in Table 13.1. In
general, the median (vermal) region is concerned with the medial descending sys-
tems and with axial control. The lateral and paramedian regions are concerned with
the lateral descending systems and with the appendages (the limbs) (midline to axis,
lateral to appendages).
13.2 Cytoarchitecture of the Cerebellum 395
In contrast to the cerebral cortex, all areas of the cerebellar cortex are relatively thin
and have the same basic three-layered cytoarchitectural pattern (Figs. 13.2 and
13.3), consisting of:
1 . Outer molecular layer
2. Purkinje cell layer
3. Inner granule cell layer
4. Underlying medullary layer of white matter
396 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
Pial
Molecular layer
surface
S
B P
Gl
UBC
White matter
Gr
Mt Ct
N
DC
DCN 5-HT
DA
CF NA
Fig. 13.2 Schematic of the basic cytoarchitecture of the cerebellar cortex represented by a single
cerebellar folium. Three types of inputs, climbing fibers (CF), mossy fibers (MF), and aminergic
fibers (DA, dopaminergic; 5-HT, serotonergic; NA, noradrenergic), are illustrated. Five main types
of neurons are identified – P Purkinje cell, Gr granule cell, B basket cell, S satellite cell, UBC
unipolar brush cell. In addition, the glomerulus (Gl) and output to deep cerebellar nuclei (DCN)
are illustrated. Lugaro cells (and their innervation by 5-HT fibers) are not depicted. The orientation
of the diagram is such that the surface on the left side represents the transverse plane and the right
side of the diagram represents the longitudinal plane of the folia (based in large part on description
and drawing from Ito (1984); Ito from Springer Images 2006. Goodleet, Charles R. Neuroscience
in Medicine, Springer, Chapter 14, 2008)
1
However, the mossy fibers from the pontine and brain stem reticular nuclei apparently do not
serve this collateral excitatory function.
398 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
Fig. 13.4 Cerebellar peduncles shown on the dorsal surface of the brain stem after removal of
cerebellum. Superior cerebellar peduncle crosses from cerebellum to midbrain (red nucleus) and
motor thalamic nuclei VL and VA and afferent ventral spinocerebellar tract. Middle cerebellar
peduncle descends in cerebropontine fibers, crosses in the pons and synapses on pontine nuclei,
and is the major afferent to cerebellum. Inferior cerebellar peduncle consists of ipsilateral fibers
and inter-connects spinal cord and medulla with juxtarestiform body containing fibers from CN
VIII and the flocculonodular lobe
13.3.1 Afferents
13.3.2 Efferents
Fig. 13.5 Topographic localization in cerebellum. (a) Summary of projections from the sensory
area and the motor area in the monkey; (b) Summary of corticocerebellar projections in the mon-
key. Note that there is a unilateral representation on the dorsal surface and a representation within
each paramedian lobule on the ventral surface. At the lateral margin, the division between crus I
and crus II is essentially the border between the dorsal and ventral surface. See Fig. 13.1 for termi-
nology in human cerebellum. From Snider. R.S.: 1950. Arch. Neurol. Psych. 64:204 (AMA)
13.5 Functions of the Cerebellum and Correlations 401
13.4 T
opographic Patterns of Representation in Cerebellar
Cortex
The cerebellum acts as a servomechanism, that is, as a feedback loop that dampens
movements and motor power to prevent overshoot and oscillation (that is, tremor).
In short, it acts to maintain stability of movement and posture. More recently, a role
in higher motor function, such as the initiation of planning, the timing of movement,
and motor learning, has been suggested for the cerebellum (Fig. 13.5).
We have already discussed the functional relation of the longitudinal and transverse
subdivisions of the cerebellum. It is evident that these two classifications overlap
from a functional standpoint, and we may specify the following correlations:
1. Vestibular reflexes and eye movement
(a) Anatomic correlation: flocculonodular lobe
(b) Major input: vestibular labyrinth (semicircular canals and otolith organs)
(c) Major deep nucleus: vestibular nuclei (lateral)
(d) Major connections: medial descending systems, vestibulospinal and medial
longitudinal fasciculus, and extraocular motor nuclei
402 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
(b) Major input: motor and premotor cerebral cortex (areas 4 and 6) and parietal
cortex (areas 1, 2, 3, 5) to pontine nuclei to lateral neocerebellum (after
decussation) via the middle cerebellar peduncle
(c) Deep nucleus: dentate
(d) Major connection – via decussation of superior cerebellar peduncle to:
–– Red nucleus (parvocellular) with subsequent rubro-olivary fibers.
–– Ventral lateral nucleus of thalamus, then projecting to motor and premo-
tor cerebral cortex. From these areas, as already discussed, originate the
lateral descending systems lateral corticospinal and corticorubrospinal
and lateral reticulospinal and the anterior corticospinal systems.
and limbic circuits discussed in Chap. 18. These changes did not occur with lesions
of the anterior lobe. The effects on cognitive and emotional function in patients with
prenatal cerebellar hypoplasia may be even more serious and may include autism
(Courchesne et al. 1994; Allin et al. 2001).
13.8 S
yndrome of the Flocculonodular Lobe and Other
Midline Cerebellar Tumors
The major findings in the human, monkey, cat, and dog are a loss of equilibrium and
an ataxia (unsteadiness) of the trunk, gait, and station. Thus, the patient, when
standing on a narrow base with eyes open, has a tendency to fall forward, backward,
or to one side. The patient may be unable to sit or stand. The patient walks on a
broad base, often reeling from side to side and often falling. Despite the loss of
equilibrium, the patient usually does not complain of a rotational vertigo. When
recumbent in bed, the patient often fails to show any ataxia or tremor of limbs. Thus,
the finger-to-nose and heel-to-shin tests are performed without difficulty. With uni-
lateral disease of the flocculonodular lobe, a head tilt may be present. In addition,
spontaneous horizontal nystagmus may be present as a transitory phenomenon.
In humans, the most common cause of this syndrome is neoplastic. The type of
neoplasm depends on the age of the patient. The most likely cause in an infant or
child2 is a medulloblastoma, a tumor arising in nests of external granular cells in the
nodulus forming the roof of the fourth ventricle. In older children and young adults,
the ependymoma, a tumor arising from ependymal cells in the floor of the fourth
ventricle, may cause this syndrome by pressing upward against the nodulus. In
adults it is more appropriate to speak of midline tumors of the vermis since the
Fig. 13.6 Metastatic
midline cerebellar tumor:
Case 13.2. MRI (TI) (a)
sagittal section
3
Progressive multiple sclerosis may produce in the young or middle-aged adult severe involvement
of white matter in the cerebellum and brain stem, resulting in severe truncal ataxia, in which the
patient is ataxic in both the sitting and standing positions. Such cases almost always also manifest
severe appendicular involvement, that is, the cerebellar syndrome is not selective.
406 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
Fig. 13.7 Alcoholic cerebellar degeneration. The anterior lobe syndrome, there is a loss of
Purkinje cells, atrophy of the cerebellar folia with relatively selective involvement of the anterior
lobe. (a) Schematic representation of the neuronal loss. (b) Atrophy of the anterior lobe superior
vermis in sagittal sections. From Victor et al. 1959;579–600
408 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
Stimulation or ablation of the anterior lobe in the cat or dog may produce significant
changes in muscle tone. Thus, stimulation of the middle anterior lobe results in a
decrease in spindle discharge and inhibits gamma rigidity of the decerebrate prepa-
ration. Stimulation of the intermediate area of the anterior lobe produces an
increased spindle discharge and facilitates gamma rigidity in the decerebrate prepa-
ration. Actual ablation of the anterior lobe in these animals or functional ablation
(cooling) produces an increase in decerebrate rigidity without a change in the
gamma system (alpha rigidity). However, in humans, ablation of the anterior lobe
does not change tone.4 The major symptoms are an ataxia of gait with a marked
side-to-side ataxia of the lower extremities as tested in the heel-to-shin test. The
upper extremities, in contrast, are affected to only a minor degree.
This area corresponds to the representation of the lower extremities and to the
area of projection of the spinocerebellar pathways.
Anterior Lobe and Alcoholic Cerebellar Degeneration. Typical of this syndrome
are cases of alcoholic cerebellar degeneration (Fig. 13.7), where a severe loss of
Purkinje cells occurs in the anterior lobe. Although this degeneration occurs primar-
ily in alcoholics, the basic etiology may be a nutritional deficiency (the specific
factor is most likely thiamine).
The major findings of a broad-based, staggering gait with truncal ataxia and
heel-to-shin ataxia can be related to the anterior lobe of the cerebellum. Since symp-
toms improve or do not progress after the discontinuation of alcohol, and the
administration of multiple B vitamins, a toxic or nutritional factor may be postulated
(the reliability of the history of alcohol intake is always open to question. The
amount stated by the patient is usually assumed to be the minimum amount.). Note
that a similar acute cerebellar syndrome occurs as one aspect of the Wernicke–
Korsakoff syndrome (refer to Chap. 30). At the present time, the diagnosis of cere-
bellar atrophy may be confirmed by MRI (midline sagittal section) or by CT scan.
As a result, evidence of cerebellar atrophy is now found in many patients presenting
with other aspects of chronic alcoholism or other nutritional disease who do not
necessarily present with initial symptoms of ataxia.
In other cases, this syndrome is the result of a chronic degenerative disease with
a genetic basis. As in alcoholic cerebellar degeneration, the predominant histologic
change is the loss of Purkinje cells in the anterior lobe. In contrast to alcoholic cer-
ebellar degeneration, the pathology is usually more widespread and not strictly lim-
ited to the anterior lobe.
In the following case history, the major involvement was primarily of the anterior
lobe. There was definite family history, including evidence of consanguinity.
4
In general chronic lesions of cerebellum in humans do not alter tone or tendon reflexes. Acute
lesions of cerebellum resulting from hemorrhage or surgery may produce transient hypotonia
(Diener and Dichgans 1992).
13.10 Syndrome of the Lateral Cerebellar Hemispheres… 409
Case History 13.3: A 45-year-old single white male carpenter presented with a 4-year
history of progressive unsteadiness in walking, present during the daytime as well as
at night, and a minimal loss of coordinated movements in his hands. He felt that his
greatest deficit was unsteadiness. He had some numbness at the toes and minor diffi-
culty in swallowing. His mother and father were second cousins. Several aunts and
uncles had “trouble with their legs” in later life, resulting in a difficulty in walking.
Neurologic Examination. Cranial nerves: Cranial nerves are intact except for
minimal dysarthria. Horizontal nystagmus was present on lateral gaze, vertical nys-
tagmus on upward gaze. Motor system: The patient walked on a broad base with an
ataxia of trunk, as though intoxicated, reeling from side to side, with marked
unsteadiness on turns. He was unable to walk a tandem gait with eyes open. A mild
intention tremor was present, and there was minimal disorganization of alternating
movements. In contrast a marked ataxia and tremor were evident on heel-to-shin
test. Reflexes: There was a relative decrease in ankle jerks compared to knee jerks.
Sensory system: There was a minimal decrease in vibration sensation at the toes.
Clinical Diagnosis: Hereditary Cerebellar Degeneration Involving Predominantly
Anterior Lobe
Laboratory Data. CT confirmed the significant atrophy of cerebellum. In gen-
eral, chronic lesions of the cerebellum resulting from hemorrhage, or surgery may
produce transient hypertonia.
13.10 S
yndrome of the Lateral Cerebellar Hemispheres
(Neocerebellar or Middle-Posterior Lobe Syndrome)
A number of disease entities may produce symptoms that can be related to the lat-
eral hemisphere. Some of these disease entities are mass lesions such as metastatic
tumors or intrinsic tumors. The diagnostic problem, moreover, is complicated by the
fact that involvement of the cerebellar peduncles may produce many of the same
symptoms that result from direct involvement of the cerebellar hemisphere. The
student will recall that the lateral medullary infarct produces an ipsilateral intention
tremor and an impairment of alternating movements of the ipsilateral upper extrem-
ity. Occlusion of the posterior inferior cerebellar artery may produce an infarct of
the lateral medulla and/or of the posterior inferior cerebellum.
Demyelinating disease, that is, multiple sclerosis, may involve in a specific case
both the brain stem and cerebellum in a multifocal manner. Cases presenting rela-
tively pure focal involvement of the lateral hemisphere are those patients surviving
after gunshot or shrapnel wounds. Such cases have been studied by Holmes (1939);
they are not encountered frequently in civilian practice. Diener and Dichgans (1992)
provide a more detailed physiologic analysis of lateral cerebellar lesions affecting
the limbs.
410 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
The major findings in lateral hemisphere lesions are the following signs and
symptoms:
1. Intention tremor in the ipsilateral upper extremity with intention tremor, disorga-
nization of alternating movements (dysdiadochokinesia), dysmetria, ataxia, and
overshoot on rebound. The intention tremor may be described as a tremor per-
pendicular to the line of motion, often becoming more prominent on slower
movements and as the target is approached. This intention tremor may be noted
in the finger-to-nose test.
2. Intention tremor in lower extremities noted as the patient attempts to raise the
foot off the bed to touch the examiner’s finger or in the heel-to-shin test. As with
the other signs of cerebellar disease, intention tremor is usually ipsilateral to the
hemisphere involved.
3. Tremor. At times, in addition to an intention tremor, a sustained postural “tremor”
may be evident, more particularly if the superior cerebellar peduncle or its midbrain
connections are involved. Brief jerks at the onset of movement (intention myoclo-
nus) may occur when the dentate nucleus or superior cerebellar peduncle is involved.
The intention tremor represents a defect in the ability to dampen oscillations and
to dampen overshoot. In the monkey, cerebellar tremor occurs despite deafferenta-
tion (section of the dorsal roots), a finding consistent with the concept that there is
a central generator of oscillations. (However, other theories reviewed by Diener and
Dichgans (1992) suggest the oscillations arise from dysfunction in long-latency
transcortical reflexes.) Having the patient slap the thigh above the knee with the
hand at particular rhythm tests repetitive movements. One can also test for repetitive
13.11 Other Causes of Cerebellar Atrophy 411
movement in the lower extremities by having the patient tap toes or heel on the floor.
Alternating movements are tested by having the patient slap the hand on the thigh
or on the opposite hand, alternating between the palmar and dorsal surface of the
hand. In disease of the cerebellar hemisphere, a marked disorganization of repetitive
and alternating movement occurs. This is almost always ipsilateral to the hemi-
sphere involved (Fig. 13.9).
4. Dysmetria. These patients are also said to demonstrate dysmetria. This may be
defined as a defect in the ability or impaired ability to know the force and rate of
movement necessary for one to accurately control the range of movement of an
extremity. Intention myoclonus may also occur at the onset of movement and
may merge with hemichorea.
1. The posterior inferior cerebellar artery (PICA), usually originating from the ver-
tebral artery: an initial medial branch of this vessel supplies the lateral tegmental
area of the medulla, and the medial and lateral branches supply the cerebellum.
2. The anterior inferior cerebellar artery (AICA), originating from the lower third
basilar artery: the initial branches of this vessel supply the lateral tegmental area
of the lower pons.
3. The superior cerebellar artery (SCA), originating from the rostral basilar artery:
proximal branches supply the lateral tegmental area of the rostral pons and cau-
dal mesencephalon.
All three vessels have extensive leptomeningeal anastomoses over the surface of
the cerebellum that are similar to the leptomeningeal anastomoses of the arteries
supplying the cortical surface of the cerebral hemispheres. As a consequence, verte-
bral artery occlusion may result in a lateral medullary infarct and syndrome but
infarction of cerebellum may be absent or limited. As in the cerebral hemispheres,
border zone infarctions may occur. On the other hand, embolic occlusion is fre-
quently implicated in cerebellar vascular syndromes.
Essentially, the patient has the acute onset of headaches (usually localized to the
occipital or cervical occipital area), severe vertigo, nausea, vomiting, and ataxia of
gait (often so severe that the patient is unwilling or unable to sit or stand). On exami-
nation, nystagmus and ipsilateral dysmetria on finger-to-nose and heel-to-shin tests
will be present. Cerebellar type dysarthria is frequent (particularly when the supe-
rior cerebellar artery is involved). Coma at the onset or shortly after onset usually
indicates severe edema with probable compromise of the fourth ventricle and/or
aqueduct of Sylvius or brain stem. Evolving extraocular palsies are also usually
indicative of compromise of the brain stem.
MRI scan or CT scan allows the following:
(a) Distinction between infarct and hemorrhage
(b) Determination of whether hydrocephalus is present
(c) Determination of the vascular territory of the cerebellum and brain stem
involved
This acute presentation has long been recognized, although occasional patients
are still initially misdiagnosed as suffering from acute labyrinthine vertigo, as in the
example presented below. The majority (80–90%) of cerebellar infarcts have a more
benign course not requiring surgical therapy. Many are recognized only in retro-
spect when a CT scan or MRI is obtained to analyze another CNS event.
In our own experience, the symptomatic cerebellar infarct is often in the territory
of the posterior inferior cerebellar artery (see case history below and Caplan (1986)
and Chaves et al. (1996)) with brain stem signs as in Case 13.6. The anterior inferior
414 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
cerebellar artery is rarely involved in isolation; the posterior inferior cerebellar ter-
ritory is often also infarcted. It is therefore easy to see that prior to the era of CT/
MRI, the clinical features of the associated brain stem infarction (that included
involvement of the cerebellar peduncles) dominated the picture and obscured the
infarct of the cerebellum. Posterior inferior cerebellar artery infarcts are either
embolic of cardiac source or due to atherosclerotic occlusion of the vertebral or less
often the posterior inferior cerebellar artery.
The following case history, Case 13.6, presents a typical example of posterior
inferior cerebellar artery infarct, the territory most frequently affected selectively.
Case History 13–6, Fig. 13.10. This 64-year-old right-handed married white male
on the morning prior to admission awoke at 3 AM with severe posterior headache
and severe vertigo, which was exacerbated by and head movement, nausea and pro-
jectile vomiting, and slurred speech. Shortly afterward, he noted a left facial pares-
thesias, clumsiness of the left upper extremity, and diplopia. Two weeks previously,
the patient had been seen for a transient episode of difficulty controlling the right
arm, a hissing sensation, and impairment of speech.
Past history was significant for hypertension, coronary artery bypass surgery, and
6-year previous episodes of transient weakness and numbness of the right arm with
transient aphasia for which he had been placed on long-term anticoagulants. At that
time, he had normal aortic arch and carotid angiography, but EEG had demonstrated
focal left frontal/temporal slow wave activity.
13.14 Cerebellar Degenerative Diseases 415
The first step in classification is to separate all of these ataxic disorders into two
main categories.
A. The autosomal recessive cerebellar ataxias are usually of early onset (<20
years of age).
B. The autosomal dominant cerebellar ataxias (ADCA) are usually of late
onset (>20 years).
A. Autosomal recessive disorders: The most common disorder in this category is
Friedreich’s ataxia which accounts for at least 50% of all cases of hereditary
ataxia reported in large series from the United States and Europe. This disorder
which has a prevalence of 1–2 per 100,000 maps to chromosome 9q13. The
mutation involves the trinucleotide repeat GAA. The normal number of repeats
is 7–22, but in patients with Friedreich’s ataxia, there are 100–2000 repeats.
416 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
1. CAG trinucleotide expansion: SCA 1, SCA 2, SCA 3, SCA 6, SCA 7, and SCA
12 all involve an expansion of the CAG trinucleotide repeat as in Huntington’s dis-
ease (chromosome 4p16.3), but the chromosome loci are different (SCA 1 at 6p,
SCA 2 at 12q, SCA 3 at 14q, SCA 6 at 19p, SCA 7 at 3P, SCA 12 at 5). This expan-
sion is translated into proteins with expanded polyglutamine tracts. At the ultrastruc-
tural level, these expanded proteins are found in neuronal intranuclear inclusions.
2. CTG trinucleotide expansion: SCA 8 is a CTG expansion on 13q, the same
type of trinucleotide expansion found in myotonic dystrophy.
3. Channelopathy: In EA 1 there is a point mutation in a potassium channel on
chromosome 12. In EA 2 there is a point mutation in a calcium channel on chro-
mosome 19q.
4. Azorean disease – Machado–Joseph disease: refers to the reviews of Rosenberg
(1992) and Sudarsky et al. (1992).
This autosomal dominant spinocerebellar degeneration is clustered among fami-
lies who originated in the Portuguese Azorean Islands. This is the region of origin
5
*As of April 2016, the number of identified loci has grown to 17. SCA 17 involves a CAG trinu-
cleotide expansion.
13.15 An Overview of Tremors 417
for many families residing in Southeastern Massachusetts and the adjacent area of
Rhode Island, and the initial cases were described in this area in 1972. Subsequently,
other cases have been described in many areas of the world reached by Portuguese
seafarers, explorers, whalers, and fishermen (many of whom were recruited in the
Azores). The manifestations depend in part on the age of onset:
(a) Early onset (childhood or young adult) cases have predominantly pyramidal
and features and basal ganglia dysfunction.
(b) Intermediate age of onset (20–40 years) cases have cerebellar deficits and extraocu-
lar disturbances as well as the pyramidal features and basal ganglia dysfunction.
(c) Later-onset (50–60 years) cases are characterized by cerebellar deficits and
peripheral neuropathy.
(d) Possible late-onset case may have a peripheral neuropathy plus Parkinsonism.
Since the molecular basis of the disorder is now clear, the more specific molecu-
lar diagnosis should be utilized when possible: most families carry the SCA 3
mutation. Occasionally the SCA 1 or the SCA 2 mutations have been found. In con-
trast to OPCA to be discussed below, the cerebellar cortex and the inferior olivary
nucleus are not involved. The ataxia instead correlates with a degeneration of the
afferent and efferent cerebellar systems (spinocerebellar tracts and Clarke’s column
dorsal nucleus), and the lid retraction and other extraocular features reflect involve-
ment of the periaqueductal and third nerve nuclear areas.
Before concluding our discussion of the cerebellum and basal ganglia, we will briefly
outline the various types of tremor. This is necessary because many common postural
tremors (physiologic and essential) are mistakenly attributed to more serious disease of
the basal ganglia or cerebellum. Tremor is defined as an involuntary movement charac-
terized by rhythmic oscillation of a body part (or parts) that develops when there is a
synchronized discharge of many motor units. Many peripheral and central factors enter
into this synchronization. Hallett (1998), Elble (1998), and Hua et al. (1998) discuss
the physiology of tremor and the role of mechanical factors and central oscillators.
Tremor is best classified because of the behavioral situation in which the tremor
is observed (Findley 1988; Hallett 1991; Deuschl 1998):
Classification of Tremors
1. Rest tremor: This is a tremor that occurs in a body part that is not voluntarily
activated and is completely supported against gravity. This tremor, particularly
when a pill rolling component is present, is almost always indicative of
Parkinson’s disease or of related disease of the basal ganglia.
2. Action tremors: This is a tremor that is produced by voluntary contraction of
muscle. Within this category, several subtypes may be specified:
3. Postural tremors: These are by far the most common types of tremor and include:
(a) Physiologic tremor. This tremor is usually fine and rapid (6–12 Hz) and
occurs when attempting to sustain a posture. This tremor is significantly
increased or “enhanced” by anxiety, excessive caffeine intake, exercise, and
fatigue. It is also increased by thyrotoxicosis, hypoglycemia, alcohol with-
drawal, and beta-adrenergic drugs, such as those used in the treatment of
asthma and by drugs commonly employed in psychiatry, such as lithium,
neuroleptic, or tricyclic medications. Beta-adrenergic blockers such as pro-
pranolol are often effective against this tremor if specific etiologic factors
cannot be corrected (use in asthmatics, however, is contraindicated).
(b) Essential tremor: This tremor is also called familial, benign, or senile tremor.
Aside from physiologic tremor, essential tremor is the most common tremor
encountered by the physician. Prevalence studies suggest a high frequency,
particularly in older age groups. In the over 40 age group, 5% of the population
may be affected. When familial, the genetic pattern appears to be autosomal
dominant. Onset of familial cases may occur in childhood, in adolescence, in
midlife, or later in life. The hands are most commonly affected, but in some
patients, the head is primarily involved (side-to-side movement). Some also
have involvement of the voice or lips. The frequency of tremor ranges from 4
to 12 Hz. The tremor may remain stable or may slowly progress. Although in
some patients the tremor is of relatively small amplitude, in other patients it
may become relatively coarse, significantly interfering with fine motor activi-
ties. Orthostatic tremor is a variant in which a tremor of trunk and legs and to
a lesser degree of arms occurs on prolonged standing and is associated with a
high frequency of contractions alternating between antagonist muscles.
13.16 Major Fiber Pathways of the Cerebellum 419
The cerebellum is interconnected to the brain stem by three major fiber bundles, or
brachium: superior cerebellar, middle cerebellar, and inferior cerebellar peduncles
(Fig. 13.4).
1. Superior cerebellar peduncle (brachium conjunctivum). The axon of this
pathway is primarily efferent, and ascending axons originate in the deep cer-
ebellar nuclei – dentate and emboliform. These fibers cross in the tegmentum
of the lower midbrain (decussation of the superior cerebellar peduncle) with
some fibers ending on the red nucleus and oculomotor complex. However,
the majority of the fibers in the superior cerebellar peduncle distribute to the
420 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
motor nuclei of the thalamus – ventral lateral and ventral anterior nuclei.
This cerebellar projection to the motor cortex permits the well-controlled
volitional acts of the corticospinal and corticobulbar systems. The ventral
spinocerebellar fibers enter the cerebellum through the superior cerebellar
peduncle.
2. Middle cerebellar peduncle (brachium pontis) is the largest cerebellar peduncle
and is purely afferent. The largest group of descending fibers from the cerebral
hemispheres is directed upon the pontine gray. These fibers form the bulk of the
cerebral peduncle and descend from all cortical lobes and the cingulate and insu-
lar gyrus, with the largest group of fibers coming from the somatosensory strip
and premotor cortex. These corticopontine fibers synapse upon the pontine gray
and then pass into the contralateral cerebellar hemisphere. Lesions in these fibers
systems do not cause any clinical deficit although these fibers must be important
in all fine movements. The corticopontine fibers end on the pontine nuclei. The
axons from the pontine nuclei are crossed and constitute part of the mossy-fiber
input to the granule cells.
3 . Inferior cerebellar peduncle (restiform body) connects the brain stem and spinal
cord with the cerebellum. The climbing fibers from the inferior olive enter this
peduncle and extend to the Purkinje cells in the deep cerebellar nuclei (Fig. 13.2).
The fibers from the vestibular nuclei, reticular formation, and trigeminal nuclei,
as well as the dorsal spinocerebellar fibers, enter through this peduncle. Many of
these fibers contribute to the mossy-fiber input to the cerebellum. The aminergic
fibers from the raphe and locus ceruleus also enter the cerebellum through the
inferior cerebellar peduncle. There is a major cerebellar projection onto the retic-
ular formation of the pons and medulla and onto the vestibular nuclei from the
fastigial nucleus, as well as a strong cerebellar input onto the vestibular nuclei
from the fl occulonodular lobe.
The cerebellar cortex must have proprioceptive information to insure proper muscle
tone and coordination. Fibers carrying this information run to the cerebellum in the
following pathways: posterior spinocerebellar, anterior spinocerebellar, and
cuneocerebellar.
1. Unconscious proprioception from the lower extremity, thorax, abdomen, and
pelvis. This information is carried up to the cerebellum by the anterior and pos-
terior spinocerebellar tracts. These tracts carry information from proprioceptive
receptors in the body into the cerebellum with the anterior pathway crossed
while the posterior is uncrossed.
Bibliography 421
Fig. 13.11 A) Posterior spinocerebellar tract, uncrossed/ipsilateral. The primary cell bodies are in
the ipsilateral dorsal root ganglion; the secondary neuron is located in Clarke’s column in the dor-
sal horn at levels C8–L3 of the cord. The secondary axons ascend uncrossed/ipsilateral in the lat-
eral funiculus, enter the cerebellum via the inferior cerebellar peduncle, and terminate in the
ipsilateral vermis (midline portion of the cerebellum. (B) Anterior spinocerebellar tract, crossed.
The primary neuron is in the dorsal root ganglion, while the secondary neuron is in cells at the
margin of the dorsal horn that are scat-tered throughout the spinal cord, especially in the lumbar
levels. The secondary axon crosses the midline and ascends anterior to the posterior spinocerebel-
lar tract in the lateral funiculus and medulla; it enters the cerebellum via the superior cerebellar
peduncle and terminates in the same parts of the cerebellar vermis as the posterior spinocerebellar
tract except it is located on the contralateral side. The receptors for both tracts are the neuromus-
cular spindles and Golgi tendon organs
422 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
Unconscious Proprioception from the Upper Extremity and Neck and Head:
Cuneocerebellar Pathway
The primary neurons are found in the dorsal root ganglion at cervical levels and
in the trigeminal proprioceptive fibers. Their axons ascend in the dorsal columns
and end in the external cuneate nuclei (external to the cuneate nucleus) in the lower
medullary levels (Fig. 13.3). The secondary axons ascend bilaterally with the poste-
rior spinocerebellar tract and enter the cerebellum primarily uncrossed.
Bibliography
Allin M, Matsumoto H, Santhouse AM, Nosarti C, et al. Cognitive and motor function and the size
of the cerebellum in adolescents born very preterm. Brain. 2001;124:60–6.
Amarenco P, Chevrie-Muller C, Roullet E, Bousser MG. Paravermal infarct and isolated cerebellar
dysarthria. Ann Neurol. 1991a;30:211–3.
Carrera RME, Mettler FA. Physiologic consequences following extensive removals of cerebellar
cortex and deep cerebellar nuclei and effect of secondary cerebral ablations in the primate.
J Comp Neurol. 1947;87:167–288.
Courchesne E, Townsend J, Saitoh O. The brain in infantile autism: posterior fossa structures are
abnormal. Neurology. 1994;44:214–23.
Diener HC, Dichgans J. Pathophysiology of cerebellar ataxias. Mov Disord. 1992;7:95–109.
Dow RS, Moruzzi G. The physiology and pathology of the cerebellum. Minneapolis: University
of Minnesota Press; 1958.
Drepper J, Timmann D, Kolb FP, Diener HC. Non-motor associative learning inpatients with iso-
lated degenerative cerebellar disease. Brain. 1999;122:87–97.
Fiez JA, Petersen SE, Cheney MK, Raichle ME. Impaired non-motor learning and error detection
associated with cerebellar damage. A single case study. Brain. 1992;115:155–78.
Gilman S. Cerebellum and motor function. In: Asbury AK, McKhann GM, Mc Donald WI, editors.
Diseases of the nervous system clinical neurobiology, vol. 1. Philadelphia: W.B. Saunders;
1986. p. 401–22.
Holmes G. Clinical symptoms of cerebellar disease and their interpretation. The Croonian lectures.
Lancet. 1922;1. 1177–1182, 1231–1237; 2:59–65, 111–115
Holmes G. The cerebellum of man. Brain. 1939;62:1–30.
Ito M. The cerebellum and motor control. New York: Raven Press; 1984.
Lechtenberg R. Ataxia and other cerebellar syndromes. In: Ankovic J, Tolosa E, editors.
Parkinson’s disease and movement disorders. Baltimore/Munich: Urban & Schwarzenberg;
1988. p. 365–76.
Lechtenberg R, Gilman S. Speech disorders in cerebellar disease. Ann Neurol. 1978;3:285–90.
Levinsohn L, Cronin-Golomb A, Schmahmann JD. Neuropsychological consequences of cerebel-
lar tumor resection in children. Brain. 2000;123:1041–50.
Mettler FA, Orioli F. Studies on abnormal movement: cerebellar ataxia. Neurology. 1958;8:953–61.
Noback, C.R. et al.: 1991. The Human Nervous System. 4th ed, Philadelphia. Lea & Febiger
p. 282.
Orioli FL, Mettler FA. Consequences of section of the simian restiform body. J Comp Neurol.
1958;109:195–204.
Raymond JLS, Lisberger G, Mauk MD. The cerebellum: a neuronal learning machine? Science.
1996;272:1126–31.
Bibliography 423
Riva D, Giogi C. The cerebellum contributes to higher functions during development. Brain.
2000;123:10411061.
Sanes JN, Dimitrov B, Hallett M. Motor learning in patients with cerebellar dysfunction. Brain.
1990;113:103–20.
Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121:561–79.
Snider. R.S.: 1950. Arch. Neurol. Psych. 64:204 (AMA).
Thach WT. Cerebellar inputs to motor cortex. In: Ciba foundation symposium 132: motor areas of
the cerebral cortex. Chichester: John Wiley; 1987. p. 201–20.
Thach WT, Goodkin M, Keating JG. The cerebellum: the adaptive coordination of movement. Ann
Rev Neurosci. 1992;15:402–42.
Topka H, Valls-Sole J, Massaquoi SG, Hallett M. Deficit in classical conditioning in patients with
cerebellar degeneration. Brain. 1993;116:961–9.
Wood NW, Harding AE. Cerebellar and spinocerebellar disorders. In: Bradley WG, Daroff RB,
Fenichel GM, Marsden CD, editors. Neurology in clinical practice, vol. II. Boston: Butterworth
Heinemann; 2000b. p. 1931–51.
Baloh RW, Yee RD, Honrubia V. Late cortical cerebellar atrophy: clinical and oculographic fea-
tures. Brain. 1986;109:159–80.
Berciano J. Olivopontocerebellar atrophy. In: Jankovic J, Tolosa E, editors. Parkinson’s disease
and movement disorders. Baltimore/Munich: Urban & Schwarzenberg; 1988. p. 131–51.
Bhatia KP, Griggs RC, Ptacek LJ. Episodic movement disorders as channelopathies. Mov Disord.
2000;15:429–33.
Burk K, Abele M, Fetter M, et al. Autosomal dominant cerebellar ataxia type I clinical features and
MRI in families with SCA 1, SCA 2 and SCA 3. Brain. 1996;119:1497–505.
Fujigasaki H, Verma IC, Camuzat A, et al. SCA 12 is a rare locus for autosomal dominant cerebel-
lar ataxia: a study of an Indian family. Ann Neurol. 2001;49:117–21.
Giunti P, Sabbadini G, . Sweeney G,MG, et al. The role of the SCA 2 trinucleotide repeat expan-
sion in 89 autosomal dominant cerebellar ataxia. Frequency, clinical and genetic correlates.
Brain. 1998;121:459–67.
Giunti P, Sweeney MG, Harding AE. Detection of the Machado-Joseph disease/spinocerebellar
ataxia three trinucleotides repeat expansion in families with autosomal dominant motor disor-
ders including the drew family of walworth. Brain. 1995;118:1077–85.
Greenfield JG. The spinocerebellar degenerations. Springfield, IL: Charles C Thomas; 1954.
Thomas CC, Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an
analysis of early diagnostic criteria and intra-familial clustering of clinical features. Brain.
1981;104:589–620.
Klockgether T, Wullner U, Spauschus A, Evert B. The molecular biology of the autosomal- domi-
nant cerebellar ataxias. Mov Disord. 2000;15:604–12.
Mason WP, Graus F, Lang B, et al. Small cell lung cancer, paraneoplastic cerebellar degeneration
and the Lambert–Eaton myasthenia syndrome. Brain. 1997;120:1279–300.
Rosen FS, Harris NL. A 30-year-old man with ataxia telangiectasia and dysarthria. Case records of
the Massachusetts General Hospital: Case #2–1987. N Engl J Med. 1987;316:91–100.
Rosenberg RN. Machado-Joseph disease: an autosomal dominant motor system degeneration.
Mov Disord. 1992;7:193–203.
Rosenberg RN. DNA-triplet repeats and neurologic disease. N Engl J Med. 1996;335:1222–4.
Smitt PS, Kinoshita A, De Leeuw B, et al. Paraneoplastic cerebellar ataxia due to autoantibodies
against a glutamate receptor. N Engl J Med. 2000;342:21–7.
Sudarsky L, Corwin L, Dawson DM. Machado-Joseph disease in New England: clinical descrip-
tion and distinction from olivopontocerebellar atrophy. Mov Disord. 1992;7:204–8.
424 13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways…
Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by
ataxia-telangiectasia. N Engl J Med. 1991;325:1831–6.
Tolosa E, Berciano J. Choreas, hereditary and other ataxias and other movement disorders. Curr
Opin Neurol Neurosurg. 1993;6:358–68.
Truman JT, Richardson EP Jr, Dvorak HF. Case records of the Massachusetts General Hospital,
case 22-1975 (Ataxia-Telangiectasia). N Engl J Med. 1975;292:1231–7.
Victor M, Adams RD, Collins GH. The Wernicke Korsakoff syndrome and related neurological
disorders due to alcoholism and malnutrition. 2nd ed. F. A. Davis: Philadelphia; 1989.
Victor M, Adams RD, Mancall EL. A restricted form of cerebellar cortical degeneration occurring
in alcoholic patients. Arch Neurol. 1959;1:579–688.
Yount WJ. IgG2 deficiency and ataxia telangiectas (editorial). N Engl J Med. 1981;306:541–3.
Colebatch JG, Britton T, Findley LJ, et al. The cerebellum is activated in essential tremor. Lancet.
1990;2:1028–30.
Deuschl G. Tremor: basic mechanisms and clinical aspects. Mov Disord. 1998;13(Suppl 3):1–149.
Deuschl G, Wenzelburger R, Loffler K, et al. Essential tremor and cerebellar dysfunction. Clinical
and kinematic analysis of intention tremor. Brain. 2000;123:1568–80.
13 Motor Systems III: The Cerebellum Movement and Major Fiber Pathways… 425
Dupuis MJM, Delwaide PJ, Boucguey D, Gonette RE. Homolateral disappearance of essential
tremor after cerebellar stroke. Mov Disord. 1989;4:183–7.
Elble RJ. Animal models of action tremor. Mov Disord. 1998;13(S3):35–9.
Findley LJ. Tremors: differential diagnosis and pharmacology. In: Jankovic J, Tolosa E, editors.
Parkinson’s disease and movement disorders. Baltimore/Munich: Urban & Schwarzenberg;
1988. p. 243–61.
Hallett M. Classification and treatment of tremor. JAMA. 1991;266:1115–7.
Hallett M. Overview of human tremor physiology. Mov Disord. 1998;13(S3):43–8.
Hua S, Reich SG, Zirh AT, et al. The role of the thalamus and basal ganglia in Parkinsonian tremor.
Mov Disord. 1998;13(S3):40–2.
Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult hydrocephalus with “normal” cere-
brospinal fluid pressure: a treatable syndrome. N Engl J Med. 1965;273:117–26.
Fisher CM. Hydrocephalus as a cause of disturbances of gait in the elderly. Neurology. 1982;32:1358–63.
Fishman RA. Normal pressure hydrocephalus and arthritis (editorial). N Engl J Med. 1985;312:1255–6.
Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol. 1987;44:21–3.
Inzitar D, Diaz F, Fox A, et al. Vascular risk factors and leuko-araiosis. Arch Neurol. 1987;44:42–7.
Jacobs L, Conti D, Kinkel WR, Manning EJ. “Normal pressure” hydrocephalus: relation-
ship of clinical and radiographic findings to improvement following shunt surgery. JAMA.
1976;235:510–2.
Masdeu JC, Wolfson L, Lantos G, et al. Brain white matter changes in the elderly prone to falling.
Arch Neurol. 1989;46:1292–6.
Rasker JJ, Jansen ENH, Haan J, Oostrom J. Normal pressure hydrocephalus in rheumatic patients:
a diagnostic pitfall. N Engl J Med. 1985;312:1239–41.
Steingart A, Hackinski VC, Lau C, et al. Cognitive and neurological findings in subjects with diffuse
white matter changes on computed topographic scan (leukoariosis). Arch Neurol. 1987;44:32–4.
Sudarsky L. Current concepts-geriatrics: gait disorders in the elderly. N Engl J Med. 1990;322:1441–6.
Sudarsky L, Ronthal M. Gait disorders among elderly patients: a survey study of 50 patients. Arch
Neurol. 1983;40:740–3.
Thompson PD, Marsden CD. Gait disorder of subcorttical arteriosclerotic encephalopathy:
Binswanger’s disease. Mov Disord. 1987;2:1–8.
Tinetti MD, Speechly M. Current concepts: geriatrics: prevention of falls among the elderly.
N Engl J Med. 1989;320:1055–9.
Tinetti MD, Speechly M, Ginter SF. Risk factors for falls among elderly persons living in the
community. N Engl J Med. 1988;319:1701–7.
Chapter 14
Somatosensory Functions and the Parietal
Lobe
Abstract The parietal lobe is the middle lobe of the cerebrum, is found on the
lateral surface of the hemisphere, and consists of postcentral gyrusa and superior
and inferior parietal lobules. In this region of the cerebrum, one finds major func-
tional differences between the left hemisphere which is dominant for language and
the right hemisphere that is important for body imagery. The pain pathway has been
discussed in Chap. 3, spinal cord; Chap. 4, brain stem; and Chap. 6, diencephalon.
In this chapter, we will cover the pathways subserving tactile information for (1) the
extremities, the thorax and abdomen, and the posterior columns and (2) the trigemi-
nal systems subserving tactile information from the head. The importance of these
pathways is apparent when one walks in the dark, drinks, or eats.
14.1 P
ostcentral Gyrus: Somatic Sensory Cortex
[Primary Sensory S-I]
Within areas 1 and 2, there are additional neurons that do not receive direct
thalamic input. These neurons respond instead to more complex properties of the
stimulus such as the specific direction of movement and have been labeled complex
cells. Studies of cortical potentials evoked by tactile stimulation in the monkey have
suggested that there is a secondary somatic sensory projection area (S-II) in addi-
tion to the classic postcentral contralateral projection area. This second area has a
bilateral representation and is found partially buried in the Sylvian fissure at the
lower end of the central sulcus. A similar second area of representation has been
reported by Penfield and Jasper (1954), and Blume et al. (1992) in those seizure
patients in whom an abdominal sensation (aura) was followed by a sensation of
paresthesias in both sides of the mouth and in both hands. Note also that at times,
stimulation of the precentral gyrus by the neurosurgeon during surgery has at times
produced contralateral tingling or numbness, in addition to the more frequent motor
responses (Penfield and Jasper 1954).
Area 3a and 3b receive the major projection form ventral posterior medial
nucleus (VPM) of the thalamus. Some of the neurons in areas 1 and 2 receive direct
input from the ventral posterior thalamic nuclei while other neurons are dependent
on collaterals from area 3.
Postcentral gyrus stimulation. Stimulation of the postcentral gyrus produces a
sensation over the contralateral side of the face, arm, hand, leg, or trunk described
by the patient as a tingling or numbness and labeled paresthesias. Less often, a sense
of movement is experienced. The patient does not describe the sensation as painful.
These various phenomena, occurring at the onset of a focal seizure, may be described
as a somatic sensory aura. There is in the postcentral gyrus a sequence of sensory
representation which, in general, is similar to that noted in the precentral gyrus for
motor function (Fig. 14.1). The representation of the face occupies the lower 40%;
the representation of the hand, the middle upper 40%; and the representation of the
foot, the paracentral lobule. As in the precentral gyrus, certain areas of the body
have a disproportionate area of representation, i.e., the thumb, fingers, lips, and
tongue. Those areas of the skin surface that are most sensitive to touch have not only
the greatest area of cortical representation but also the greatest number and density
of receptors projecting to the postcentral gyrus. The peripheral field of each of these
receptors is also very small (compared, e.g., to the less sensitive skin areas of the
trunk). In addition, at the lower end of the postcentral gyrus, extending into the
Sylvian fissure (the parietal operculum), there is a representation of the alimentary
tract, including taste. Gustatory hallucinations may arise from seizure foci in this
area (Hausser-Hauw and Bancaud 1987). There is also a representation of the geni-
talia in the paracentral lobule, and a rare patient with seizures beginning in this area
has reported paroxysmal sexual emotions including orgasm and nymphomania.
Microelectrode techniques for recording from single cells in the cerebral cortex of
the monkey and cat have allowed a considerable elaboration of the functional local-
ization within the sensory cortex. The studies of Mountcastle (1957) indicated a
vertical columnar organization from the cortical surface to white matter. While each
column is modality specific, each neuron in a particular column is activated by
that specific sensory modality, e.g., touch, movement of a hair, deep pressure, joint
14.1 Postcentral Gyrus: Somatic Sensory Cortex [Primary Sensory S-I] 429
Fig. 14.1 Sensory representation as determined by stimulation studies on the human cerebral
cortex at surgery: Note the relatively large area devoted to the lips, thumb, and fingers (From
Penfield, W., and Rasmussen, T.: The Cerebral Cortex of Man. New York, Macmillan, 1955,
p. 214; from Marcus, EM and Jacobson S. Integrated Neuroscience, Kluwer, 2003)
p osition. Jones et al. (1982), Kasdon and Jacobson (1978), Jones and Powell,
(1970), and Killackey and Ebner (1973) discuss the thalamocortical relationships.
In the monkey a secondary somatic sensory projection (SII) has been identified.
It has a bilateral representation and is found deep in the lower end of the central
sulcus. In several patients with seizures, bilateral sensations have been reported
from the mouth and hands (Blume et al. 1992).
Postcentral gyrus lesions. Immediately following complete destruction of the
postcentral gyrus, there will often be found an almost total loss of awareness of all
sensory modalities on the contralateral side of the body. Within a short time, there
is usually a return of some appreciation of painful stimuli. The patient will, how-
ever, often continue to note that the quality of the painful stimulus differs from that
on the intact side. An awareness of gross pressure, touch, and temperature also
returns. Vibratory sensation may return to a certain degree. Certain modalities of
sensation, however, never return or return only to a minor degree. (In partial lesions
of the postcentral gyrus, however, these various modalities often return to a variable
430 14 Somatosensory Functions and the Parietal Lobe
degree. These modalities are often referred to as the cortical modalities of sensation
or as discriminative modalities of sensation. In contrast, the sensory modalities of
pain, gross touch, pressure, temperature, and vibration are referred to as primary
modalities of sensation).
Perception of these modalities continues to occur after ablation of the postcentral
gyrus although some alteration in quality of sensation is noted. It has been assumed
that the anatomical substrate for such awareness must exist at the thalamic level. In
terms of more specific localization of specific modalities of cortical sensation, the
studies of Randolph and Semmes (1974) suggest that in the monkey small lesions
restricted to area 3b (hand region) produce deficits in discrimination of texture, size,
and shape. Lesions in area 1 interfere with the ability to discriminate texture only
and lesions in area 2 to size and shape.
The following types of sensory awareness usually included in this category are
summarized in Table 14.1.
The following case histories demonstrate the type of sensory phenomena found
in disease involving the postcentral gyrus.
Case History 14.1, Fig. 14.2. One week prior to evaluation, this 40-year-old right-
handed married white male had the onset of repeated 15–2 min duration episodes of
focal numbness (tingling or paresthesias) involving the left side of the face, head,
ear, and posterior neck and occasionally spreading into the left hand and fingers and
rarely subsequently spreading into the left leg. Biting or eating would trigger the
episodes. There was no associated pain, headache, weakness, or associated focal
motor phenomena.
progress with the development of a left field defect, a left hemiparesis, and a loss of
all modalities of sensation on the left side. Subsequently he developed significant
changes in memory and cognition. CT scan demonstrated progression with extensive
involvement of the right side of the brain and spread to the left hemisphere. Death
occurred 33 months after onset of symptoms. At postmortem examination of the
brain, almost the entire right hemisphere was replaced by necrotic infiltrating tumor.
The tumor now had spread into the corpus callosum and temporal and occipital lobes.
The internal capsule, thalamus, hypothalamus, and basal ganglia were destroyed.
The following case presents a patient with episodic pain from a tumor in the left
postcentral gyrus.
Case History 14.2. This 62-year-old white, right-handed housewife, 6 years prior to
admission, had undergone a left radical mastectomy for carcinoma of the breast.
Five months prior to admission, the patient developed a persistent cough, left pleu-
ritic pain, and a collection of fluid in the left pleural space (pleural effusion). She
now had the onset of daily headaches in the right orbit, occasionally awakening her
from sleep. Four months prior to admission, over a 3- to 4-week period, the patient
developed progressive “weakness” and difficulty in control of the right lower
extremity. Several weeks later, the patient now experienced aching pain in the right
index finger in addition to a progressive deficit in the use of the right hand. This was
more a “stiffness and in coordination” than any actual weakness. One month prior
to admission, the patient noted episodes of pain in the toes of the right foot, and
numbness of right foot occurred, lasting 2–3 days at a time. She subsequently devel-
oped difficulty in memory and some minor language deficit, suggesting a nominal
aphasia, prompting hospital admission.
Mental status. Slowness in naming objects was present although she missed only 1
item of 6. Delayed recall was slightly reduced to 3 out of 5 in 5 min.
Cranial nerves. Early papilledema was noted: absence of venous pulsations,
indistinctness of disk margins, and minimal elevation of vessels as they passed over
the disk margin. A right central facial weakness was present.
Motor system. Mild weakness of the right upper limb was present. A more
marked weakness was present in the lower limb (most marked distally). Spasticity
was present at the right elbow and knee. In walking, the right leg was circumducted;
the right arm was held in a flexed posture.
Reflexes. Deep tendon reflexes were increased on the right. A right Babinski
response was present.
Sensation. An ill-defined alteration in pain perception was present in the right
arm and leg—more of a relative difference in quality of the pain than any actual
deficit. Repeated stimulation of the right lower extremity (pain or touch) produced
dysesthesias (painful sensation). Position sense was markedly defective in the right
fingers with errors in perception of fine and medium amplitude movement in the
14.2 Superior and Inferior Parietal Lobules 433
right toes. Simultaneous stimulation resulted in extinction in the right lower extrem-
ity. Graphesthesia (identification of numbers, e.g., 8, 5, 4 drawn on cutaneous sur-
face) was absent in the right hand and fingers and poor in the right leg. Tactile
localization and two-point discrimination were decreased on the right side.
Clinical diagnosis. Metastatic tumor to the left post central and precentral gyri with
a cortical pain syndrome (pseudo-thalamic pain syndrome).
Laboratory data, chest X-ray. Several metastatic nodules were present in the
left lung.
Imaging studies were consistent with a focal metastatic lesion in the parasagittal
upper left parietal area.
Subsequent course. Because there was evidence in this case that the disease had
spread to multiple organs, radiation and hormonal therapy were, therefore, adminis-
tered rather than any attempt at surgical removal of the left parietal metastatic lesion.
Temporary improvement occurred in motor function in the arm, but the patient
eventually expired 5 months after admission. Autopsy performed by Dr. Humphrey
Lloyd of the Beverly Hospital disclosed extensive metastatic disease in the lungs,
liver, and lymph nodes and a single necrotic metastatic brain lesion in the upper left
parietal area, 1.0 cm below the pial surface and measuring 1.2 × 1.0 × 0.6 cm. The
occurrence of episodic pain in the involved arms and legs along with the production
of an experienced painful sensation on repetitive tactile stimulation (dysesthesias)
in patients with sensory pathway lesions is sometimes referred to as a “thalamic” or
“pseudo thalamic” syndrome.
Comments. In this case, the anatomical locus for the pseudo thalamic syndrome is
apparent. The effects of deficits in cortical sensation on the total sensory motor
function of a limb are apparent in this case. The actual disability and disuse of the
right arm and leg were far out of proportion to any actual weakness. Such an extrem-
ity is often referred to as a “useless limb.” The actual weakness that was present
undoubtedly reflected pressure effects on the precentral gyrus and the descending
motor fibers in the adjacent white matter. Destructive lesions of the postcentral
gyrus during infancy or early childhood often produce a retardation of skeletal
growth on the contralateral side of the body. Such a patient examined as an adoles-
cent or adult will be found to have not only cortical sensory deficits in the contralat-
eral arm and leg but also a relative smallness of these extremities (shorter arm or leg,
smaller hand and glove size, smaller shoe size).
fingers—not explained by any sensory deficit. There was a deficit in the conception
and execution in the spatial and temporal patterns of movement. The end result is an
impairment of purposive movement as discussed above. The response to visual
stimuli in terms of attending to and reaching for objects is impaired (see Baynes
et al. 1986, Nagel-Leiby et al. 1990, Perenin et al. 1988, and Pierrott Deseilligny
et al. 1986). Lesions involving the white matter deep to the inferior parietal lobule
may damage the superior portion of the optic (geniculocalcarine) radiation, produc-
ing a defect in the inferior half of the contralateral visual field, an inferior
quadrantanopsia.
(a) Dysgraphia (a deficit in writing in the presence of intact motor and sensory
function in the upper extremities)
(b) Dyscalculia (deficits in the performance of calculations)
(c) Left-right confusion
(d) Errors in finger recognition, for example, middle finger, index finger, and ring
finger, in the presence of intact sensation (finger agnosia)
(e) In addition, disturbances in the capacity for reading may be present. Some
patients may also manifest problems in performing skilled movements on com-
mand (an apraxia) at a time when strength, sensation, and coordination are
intact. Usually only partial forms of the syndrome are present. The problem of
the dominant parietal lobe in language function will be considered in greater
detail and illustrated in the section on language and aphasia. The reader should
refer to Chap. 15 for an illustrative.
Disturbance in concept of body image (neglect) and denial of illness. Patients with
involvement of the non-dominant parietal lobe, particularly the inferior parietal lob-
ule, often demonstrate additional abnormalities in their concepts of body image, in
their perception of external space, and in their capacity to construct drawings.
436 14 Somatosensory Functions and the Parietal Lobe
Family history. The patient’s mother died of metastatic carcinoma of the breast.
Neurological Examination
Mental status. Intact except for the following features: The patient often wan-
dered in her conversation. She often asked irrelevant questions and was often imper-
sistent in motor activities. There was marked disorganization in the drawing of a
house or of a clock. A similar marked disorganization was noted in attempts at copy-
ing the picture of a railroad engine (Fig. 14.3). There was a marked neglect of the
left side of space and of the left side of the body. The patient failed to read the left
half of a page. When she put her glasses on, she did not put the left bow over the ear.
When getting into bed, she did not move the left leg into bed. She had slipped off her
dress on the right side, but was lying in bed with the dress still covering the left side.
The patient had been reluctant to come for neurological consultation. Although she
complained of headache and nausea, she denied any other deficits. Her relatives
provided information concerning these problems. Much additional persuasion over
a 2-week period was required before the patient would agree to be hospitalized.
Cranial nerves. A dense left homonymous hemianopsia was present. When
reading, the patient left off the left side of a page. She bisected a line markedly off
center. Disk margins were blurred, and venous pulsations were absent, indicating
438 14 Somatosensory Functions and the Parietal Lobe
papilledema. The right pupil was slightly larger than the left. A minimal left central
facial weakness was present.
Motor system. Although strength was intact, there was little spontaneous move-
ment of the left arm and leg. The patient was ataxic on a narrow base with eyes open
with a tendency to fall to the left and was unable to stand with eyes closed even on
a broad base.
Sensation. Although pain, touch, and vibration were intact, there was at times a
decreased awareness of stimuli on the left side. Errors were made in position sense
at toes and fingers on the left. Tactile localization was poor over the left arm and leg.
With double simultaneous stimulation, the patient neglected stimuli on the left face,
arm, and leg.
Clinical diagnosis. Metastatic breast tumor to right non-dominant parietal cortex.
Laboratory data. Chest X-ray indicated a possible metastatic lesion at the right
hilum. EEG was abnormal because of frequent focal 3–4 cps slow waves in the right
temporal and parietal areas, suggesting focal damage in these areas.
Subsequent course. Treatment with steroids (dexamethasone and estrogens)
resulted in temporary improvement. The patient refused surgery. Her condition soon
deteriorated with increasing obtundation of consciousness. She expired 2 months
following her initial neurological consultation.
The following case, Case history 14.4, is another example of neglect and denial
of illness but with a visual neglect syndrome as well.
Case History 14.4, Fig. 14.4. This 75-year-old right-handed male presented with
repeated falls and bumping into objects, especially off to the right side. He was
brought to the local ER and then transferred to the medical center. He was found to
have a neglect of the right visual field and a mild right hemiparesis. CT was normal
but subsequent MRI revealed a left posterior cerebral distribution stroke.
His past history was notable for hypertension, obesity, type 2 diabetes mellitus,
peripheral vascular disease, and a prior right carotid endarterectomy after a transient
ischemic attack several years previously. He was a heavy smoker.
General exam revealed an obese male, very short of breath, and having very poor
circulation in his legs.
Neurologic exam demonstrated normal fluency but a profound right visual
neglect which he was unaware of despite its severity.
Cranial nerve exam was remarkable for a right homonymous hemianopsia and a
left motor/pupillary CN 3 palsy. There were no other cranial nerve deficits. He has a
mild right hemiparesis. There were no other neurologic abnormalities demonstrated.
Clinical diagnosis. Infarct in left occipital and posterior parietal lobe with neglect in
right visual field.
Despite the urging of medical staff and family, he declined further workup, feel-
ing he was fine and had no abnormalities.
Comments. These findings of neglect including saying he was fine and didn’t
need further treatment are common with lesions in the non-dominant superior pari-
etal lobe, but in this case, it was in the region of the dominant parietal lobe which is
also important in body image, and so the patient doesn’t recognize a problem in his
body, so all is okay, and there was no reason to stay, which is consistent with a right
posterior parietal hemisphere lesion.
In many cases, the location of lesion may appear to be predominantly posterior
temporal. Such large posterior temporal lesions would certainly compromise the
cortex and subcortical white matter of the adjacent inferior parietal area. In this
case, marked deficits in perception of the cortical modalities of sensation were pres-
ent. In other cases, as in the case demonstrated in Fig. 14.3, such involvement is
much less marked. In some cases, involvement of the motor cortex is evident with
an actual left hemiparesis accompanied by an increase in deep tendon reflexes and
an extensor plantar response. At times in patients with neglect syndromes, there
may be several indications in the clinical examination and in the laboratory studies
that the involvement of the frontal lobe areas is more prominent than the parietal
involvement. We have already indicated that the neglect components of this syn-
drome may also be noted in lesions of the anterior premotor area (area 8). The pre-
frontal and premotor areas as discussed above and in Chap. 10 receive projection
fibers from the multimodal area of the posterior parietal area. It is possible that in
some cases the posterior temporal–inferior parietal location of the lesion may also
be critical in interrupting these association fibers. For these several reasons, it is
perhaps more appropriate to use the term syndrome of the non-dominant h emisphere,
rather than the more localized designation, non-dominant inferior parietal syn-
drome. Duffner et al. (1990) have presented the concept of a network for directed
attention—with right frontal lesions leading to left hemispatial neglect only for
tasks that emphasize exploratory–motor components of directed attention, whereas
parietal lesions emphasize the perceptual–sensory aspects of neglect. With lesions
of the non-dominant hemisphere, there is a significant alteration of the patient’s
awareness of his environment. The behavior of an individual is in part determined
by his own particular perception of the environment. If that perception is altered or
disorganized, the behavioral responses of the patient may appear inappropriate to
440 14 Somatosensory Functions and the Parietal Lobe
others. Obviously, not all individuals will respond in the same manner to a given
environmental situation; part of the response will be determined by the past experi-
ence and personality of the individual. Thus, given the same lesion, one individual
may be unaware of a hemiparesis, another may deny the hemiparesis but agree an
illness is present, and a third may claim to be healthy and claim that people are
conspiring to keep him in the hospital.
14.3.1 T
actile Sensation from the Body: Medial Lemniscus
(Fig. 14.5)
The ascending sensory fibers from the neck, trunk, and extremities for touch (pos-
terior columns), from the face for touch and pain (trigeminothalamic), and from the
viscera for general and special sensation ascend in the medial lemniscus to the
thalamus.
Posterior Columns. The posterior columns consist of the fasciculus gracilis and the
fasciculus cuneatus which conduct proprioception (position sense), vibration sensa-
tion, tactile discrimination, object recognition, deep touch (pressure) awareness, and
two-point discrimination from the neck, thorax, abdomen, pelvis, and extremities.
Organization of the Posterior Columns of Spinal Cord
1. Tactile sensation from the upper extremity originates from spinal cord level T6
and above and is in the lateral half of the posterior columns with cervical fibers
lateral to the thoracic fibers.
2. Tactile sensation from the lower extremity originates from spinal cord levels T7
and below and is located in the medial half of the fasciculus gracilis with sacral
fibers medial to the lumbar and thoracic fibers.
The sensory receptors for the system are the Golgi tendon organs, muscle spin-
dles, proprioceptors, tactile discs, and Pacinian corpuscles (deep touch, or pressure).
The primary cell body is in the dorsal root ganglion. The well-myelinated fibers of
this system enter the spinal cord as the medial division of the dorsal root and
14.3 Parietal Lobe and Tactile Sensation from the Body 441
Fig. 14.5 Medial Lemnsicus—Tactile sensation from the upper extremity, via the fasciculus cune-
atus, and from the lower extremity via the fasciculus gracilis. These fibers form the posterior col-
umns → medial lemniscus → VPL → postcentral gyrus
bifurcate into ascending and descending portions, which enter the dorsal column. In
the spinal cord, the posterior columns are uncrossed and divided into the medial
gracile fasciculus (lower extremity) and the lateral cuneate fasciculus (upper
extremity).
The fasciculus gracilis contains fibers from the sacral, lumbar, and lower thoracic
levels, while the fasciculus cuneatus contains fibers from the upper thoracic and
cervical levels. Fibers from the sacral levels lie most medial, followed by lumbar,
thoracic, and finally, cervical fibers. Fibers from the upper extremity form 50% of
442 14 Somatosensory Functions and the Parietal Lobe
the posterior columns with the lower extremity 25% and the remainder from the
thorax and abdomen. These primary axons ascend in the dorsal columns of the spi-
nal cord to the secondary cell body of this system located in the nucleus gracilis and
the nucleus cuneatus in the spinomedullary junction.
The secondary fibers cross in the sensory decussation in the spinomedullary
junction, form the bulk of the medial lemniscus along with trigeminal and other
fibers, and ascend in the contralateral medial lemniscus to the ventral posterior lat-
eral nucleus (VPL) in the thalamus. From this thalamic nucleus, these fibers are
projected in a somatotopic organization to the postcentral gyrus (areas 1, 2, and 3).
Fibers also descend in the dorsal columns, but their functional significance is
unknown.
Proprioception. The fibers responsible for proprioception cross in the medial
lemniscus.
Vibration and tactile discrimination. The fibers for vibration sensation and tac-
tile discrimination ascend bilaterally in the medial lemniscus to the ventral posterior
lateral nucleus. Consequently, a unilateral lesion can abolish proprioception, but
tactile discrimination and vibration sensation will not be entirely lost.
Clinical lesions. Injury to the posterior column appears not to affect pressure
sense, but vibration sense, two-point discrimination, and tactile discrimination are
diminished or abolished, depending on the extent of the lesion. Interruption of the
medial fibers (cervical–hand region) affects the ability to recognize differences in
the shape, and weight of objects placed in the hand is impaired. Since the extremi-
ties are more sensitive to these modalities than any other body regions, position
sense is impaired more severely in the extremities than elsewhere, and the person
has trouble identifying small passive movements of the limbs. Consequently, the
performance of voluntary acts is impaired, and movements are clumsy (sensory
ataxia). Lesions in lateral fibers of the posterior column, gracilis, may be devastat-
ing due to the interruption of one of the most important sensory mechanisms, the
ability to detect the sole of the foot. This is a major handicap in walking in dim
lighted or a dark room, in driving a car, etc.
14.3.2 T
actile Sensation from the Head: The Trigeminal Nerve
(Fig. 14.6)
Cranial nerve V is the largest cranial nerve in the brain stem, and it has three sensory
nuclei (chief, spinal, and mesencephalic) and three divisions: ophthalmic (V1),
maxillary (V2), and mandibular (V3). The primary cells of the trigeminal nerve are
located in the trigeminal ganglion in Meckel’s cave in the middle cranial fossa. The
second nuclei are in the brain stem and upper cervical spinal cord.
Each of the three divisions brings in sensation of pain, temperature, touch and
pressure from receptors in the skin, muscles, and sinuses they innervate.
14.3 Parietal Lobe and Tactile Sensation from the Body 443
Fig. 14.6 Trigeminal Lemniscus—tactile sensation from the head: trigeminal lemniscus → medial
lemniscus → VPM → postcentral gyrus
The proprioceptive fibers arise from the muscles in the face including the muscles
of mastication, facial expression, ears, and the muscles of the eye. From this
second-order nucleus, axons enter the brain stem, ascend bilaterally through the
pons, and synapse in the midbrain on the mesencephalic nucleus of V from
which fibers then descend onto the motor nucleus of V in the pons for the “jaw
jerk.” The primary tactile and proprioceptive axons synapse in the chief nucleus,
and from this second-order neuron, the information ascends in the dorsal most
portions of the medial lemniscus, trigeminal lemniscus, and synapse in the ven-
tral posterior medial nucleus of the thalamus. This information is then sent onto
the lower one-third of the postcentral gyrus, the region that contains the somato-
topic representation for the head and neck including the face (Fig. 14.1).
Bibliography
Darian-Smith I, Johnson KO, Goodwin AW. Posterior parietal cortex relations of unit activity to
sensorimotor function. Annu Rev Physiol. 1979;41:141–57.
Hausser-Hauw W, Bancaud J 1987. Gustatory hallucinations in epileptic seizures. Electrophysiological
correlates Electrophysiological correlate. Brain.1987; 110:339–359.
Mountcastle VB. Modality and topographic properties of single neurons of cats somatic sensory
cortex. J Neurophysiol. 1957;20:408–34.
Jones EG, Powell TPS. An anatomic study of converging sensory pathways within the cerebral
cortex of the monkey. Brain. 1970;93:793–820.
Kasdon DL, Jacobson S. The thalamic afferents to the inferior parietal lobule. J Comp Neurol.
1978;177:685–706.
Kass JH, Merzenich MM, Killackey HP. The reorganization of somatosensory cortex following
peripheral nerve damage in adult and developing mammals. Ann Rev Neurosci. 1983;6:325–56.
Kass JH, Nelson RJ, Sur M, et al. Multiple representations of the body within somatosensory cor-
tex of primates. Science. 1979;204:521–3.
Kass JH, Nelson RJ, Sur M, et al. Organization of somatosensory cortex in primates. In: Schmitt
FO, et al., editors. The Organization of the cerebral cortex. Cambridge, MA: MIT Press.1965.
Mesulum M, Emily J. Rogalski, Christina Wieneke, Robert S. Hurley, Changiz Geula, Eileen
Neurology of the language network. Nature Reviews Neurology 2014;10:554–569. Published
online 02 September 2014.
Mountcastle VB. Modality and topographic properteis of single neurons of cats somatic sensory
cortex. J Neurophysiology 1957;20:408–434.
Palmini A, Glood P. The localizing value of auras in partial seizures: a prospective and retro-
spective analysis. Neurology. 1992;42:801–8. [In particular: Kertesz A. Issues in localization.
pp. 1–20]
Penfield, W., and Rasmussen, T. The Cerebral Cortex of Man. New York, Macmillan, 1955. Wise
SP, Boussaoud D, Johnson PB, Caminiti R. Premotor and parietal cortex: corticocortical con-
nectivity and combinatorial computations. Annu Rev Neurosci. 1997;20:25–42.
Chapter 15
Visual System and Occipital Lobe
Abstract The eye is the organ of vision, and it is the only receptor that is actually
part of the central nervous. The optic nerve grows out from the brain and enters the
retina. The muscles that move the eye are attached to the outer surface of the eye.
Of all our senses, vision is the most important: we perceive the world mostly through
our eyes. Even though light intensity varies by a factor of ten million between the
brightest snowy day and a starlit night, our eyes and visual system adapt to these
intensity changes. We can discriminate between thousands of hues and shades of
color. Our eyes are set in our heads in such a way that each eye sees almost the same
visual field, making depth perception possible. In the visual system, the primary,
secondary, and tertiary neurons are in the retina and are all part of the central ner-
vous system. The right field of vision projects to the left cerebral hemisphere; the
left field of vision projects to the right cerebral hemisphere.
The anatomy of the receptor of the organ eye is shown in Fig. 15.1. It has three lay-
ers, or tunics:
1 . The outer fibrous tunic—the cornea and sclera
2. The middle vascular and pigmented tunic—the choroid, ciliary body, iris, and
pupil
3. The inner neural tunic—the retina with pigmented epithelium and neuronal
layers
Outer fibrous tunic. This layer consists of two parts: the anterior transparent cor-
nea and the posterior fibrous white sclera. The recti and oblique muscles that move
the eye are attached to the sclera.
The cornea, the window to the world, allows light rays to enter the eye. Most of
the refraction needed to focus light rays on the retina occurs at the air–cornea junc-
tion. The sclera forms the white of the eye and the rest of the outer covering.
Middle tunic—the choroid, the ciliary body, and the iris. The middle tunic is
richly vascular and provides oxygen and nutrients to the inner, photoreceptor layer
and the retina.
(a) Choroid is vascular and pigmented and forms the posterior portion of this tunic.
Its inner portion is attached to the pigmented layer of the retina.
(b) The ciliary body is found in the anterior portion of the middle tunic and consists
of a vascular tunic and the ciliary muscle. The ciliary body surrounds the lens
and consists of a vascular tunic (the ciliary muscle) and the suspensory liga-
ments (the zonule), which suspend the lens (Fig. 15.1). The ciliary muscles
consist of meridional and circular fibers. The meridional fibers are external to
the circular fibers. The ciliary muscles are the muscles used in accommodation,
focusing on near objects.
(c) Lens. The lens separates the anterior chamber from the vitreous body and com-
pletes the refraction of the entering light. A fibrous network, the zonule, sus-
pends the lens. For distance vision the fibers are taut, and the anterior surface of
the lens is pulled flat. For close vision the ciliary muscle contracts and the dila-
tor pupillae. When the circular muscles and the sphincter pupillae contract, the
iris is drawn together, and the pupil constricts, such as purse strings closing the
mouth of the purse. The second set of muscles, the dilator pupillae, are radial
and draw the iris back toward the sclera. The sphincter pupillae are supplied by
the parasympathetic nervous system via the ciliary nerves, the fibers of which
15.1 Structure of the Eye 447
run together with nerve III. The transmission by this pathway is cholinergic; the
dilator pupillae is supplied by the sympathetic nervous system via the superior
cervical ganglion. Neurotransmission in this pathway is alpha-adrenergic.
( d) Pupillary muscles.
Two sets of muscles in the iris (rainbow) control the size of the pupil: the sphinc-
ter and dilator pupillae.
The sphincter pupillae is supplied by the parasympathetic nervous system via the
ciliary nerves, the fibers of which run together with nerve III. Transmission by this
pathway is cholinergic.
The dilator pupillae are supplied by the sympathetic nervous system via the
superior cervical ganglion. Neurotransmission in this pathway is alpha-adrenergic.
The pars ciliaris and pars iridica are primarily a pigmented region on, respectively,
the ciliary body and iris. The pars optica contains the photoreceptor cells and will
be the focus of our discussion. In looking at distant objects, the pupil dilates, and in
focusing on near objects, the pupil constricts.
(e) Pupillary reflexes.
When light is flashed into either eye, the pupil constricts, and the light reflex.
When the eye focuses on close objects, accommodation occurs, and the pupil con-
stricts. Two sets of muscles in the iris control the size of the pupil and sphincter
(Fig. 15.2).
Fig. 15.2 Horizontal meridional section of the eye (E. Wald, Ellen; I. Brook, G. Mandell, Atlas of
Infectious Diseases, Volume 04, Chapter 01, 2002. From Springer Images)
448 15 Visual System and Occipital Lobe
–– Nerve cells that are internal to photoreceptors and whose axons form the optic
nerve that leaves the retinae through a pigment-free area, the optic disk. Light
must traverse the nerve network to reach the photoreceptors.
Pars optica of the retina consists of the following ten layers (Fig. 15.3):
1. Pigmented epithelium (most external)
2. Receptor cell layer—rods and cones
3. External limiting membrane
4. Outer nuclear layer containing the nuclei of rods and cones
5. Outer plexiform layer—containing the synapses of rods and cones with the
dendrites of bipolar and horizontal cells and the cell bodies of horizontal cells
Fig. 15.3 Schematic diagram of the ultrastructural organization of the retina. Rods and cones are
composed of outer segments (OS) and inner segments (IS), cell bodies, and synaptic bases.
Photopigments are present in laminated discs in the outer segments. The synaptic base of a rod is
called a spherule; the synaptic base of a cone is called a pedicle (Modified from Carpenter, M.B.A
Core Text of Neuroanatomy Baltimore, Williams and Wilkins)
450 15 Visual System and Occipital Lobe
6. Inner nuclear layer—containing the cell bodies of bipolar and amacrine cells
7. Inner plexiform layer—containing the synapses of bipolar and amacrine cells
with ganglion cells
8. Ganglion cell layer
9. Optic nerve layer
10. Internal limiting membrane
There are two types of photoreceptor cells: rods and cones. The rods and cones are not
uniformly distributed in the retina. Most of the six million cone cells are located in an
area 2 mm in diameter, the macula lutea (Fig. 15.3), which can be seen through the
ophthalmoscope. In the center of the macula lutea lies a zone of pure cones, the fovea
(Fig. 15.2). The rest of the macula lutea is composed of both rods and cones, and most
of the peripheral retina contains only rods. There are about 123 million rods.
Rods. Vision in dim light and night vision. The rods are sensitive in dim light
as they contain more of the photosensitive pigment rhodopsin than the cones.
This system has poor resolution; newspaper headlines are the smallest letters that
can be recognized.
The rods permit vision, scotopic (dark vision), in the dark-adapted eye. Rods
contain a single pigment, rhodopsin, which is related to vitamin A1 (retinol).
The spectral sensitivity of night or scotopic vision is identical to the absorption
spectra of rhodopsin (Fig. 15.3). Light that can be absorbed by rhodopsin is seen;
light that cannot be absorbed such as red light is not seen at these low light intensi-
ties. Scotopic vision has quite poor definition; two light sources must be quite far
apart to be distinguished as two sources rather than one. Peripheral vision has pro-
gressively poor definition. Several modern inventions, such as night goggles with
infrared sensors, are designed to compensate for these limitations. The visual pig-
ment, rhodopsin, absorbs photons. Each rhodopsin molecule consists of retinal and
opsin. The retinal absorbs the light, while opsin is the protein in the plasma mem-
brane of the rods. The photon converts retinal from the 11-cis form to the all-trans
form. The all-trans retinal has to be reisomerized to 11-cis retinal to reform rhodop-
sin and to begin the process again. The photons result in hyperpolarization of the
plasma membrane that is the light-dependent part of visual excitation. The photore-
ceptors are depolarized in the dark due to the sodium channels remaining open,
called the dark currents. The dark current is turned off in light. Daylight prevents
the regeneration of rhodopsin in the rods. After 5–10 min in the dark, the scotopic
vision begins to return as the rhodopsin is regenerated and reaches maximal sensi-
tivity after 15–23 min. Since rhodopsin does not absorb red light, using red goggles
can preserve night vision.
Cones. Color vision. The cones are sensitive to color. Color vision requires much
higher. The visual pigment of the cones consists of opsin and retinal. The cones are
divided into three separate groups that contain photopigments primarily sensitive to
a different part of the visible spectrum as follows:
15.2 Photoreceptor Layer: Rods and Cones 451
The approximately one million axons from the ganglion cells traverse the inner
surface of the retina to the optic disk, where they turn and form the optic nerve,
which runs for about 1 in. before entering the optic foramen in the sphenoid bone on
its way toward the diencephalon and midbrain. Electrical recordings from optic
nerve fibers also show the types of data reduction occurring in the retina.
15.3 Visual Pathway 453
1. First, there is convergence; many receptors must fire one bipolar cell in the fovea.
Consequently, the “grain” of the visual image depends on the location on the
retinae.
2. Second, brightness can be detected.
3. Third, there is a center-surround contrast enhancement.
4. Lastly, there is a dynamic or motion detection. A spot of light on the retina will be
coded in terms of its brightness and its edges. As it is turned on and off, the
dynamic receptors fire to alert higher centers. The spot of light will receive much
more attention in the optic nerve bandwidth if it is moved around because each
tiny movement will set off a new set of dynamic or movement receptors and these
receptors make up about half the total optic nerve fibers. For example, the rotating
flashing lights of emergency vehicles attracts more attention than a fixed light.
The blind spot is the point of exit of each optic nerve from the eye which contains
only retinal arteries and veins and no photoreceptors, rods or cones. This area is
noted when visual fields are plotted. When swelling of the papilla occurs due to
increased intracranial pressures—(papilledema)—the blind spot is enlarged.
1. Retina
Each retina is divided into a temporal or nasal half by a vertical line passing through
the fovea centralis. This also serves to divide the retina of each eye into a left and right
half. A horizontal line passing through the fovea would divide each half of the retina
and macula into an upper and lower quadrant. Each area of the retina corresponds to a
particular sector of the visual fields, which are named as viewed by the patient.
2. Visual Fields (Fig. 15.5a)
For each eye tested alone, there is a left and right visual field corresponding to a
nasal and temporal field. Because of the effect of the lens, the patient’s left visual
field projects onto the nasal retina of the left eye and the temporal retina of the right
eye. Similarly, the upper visual quadrants project to the inferior retinal quadrants.
3. Cranial Nerve II
(a) Optic nerve. It originates in the ganglion cell layer in the retina, exits the
orbit, enters the optic foramen, and divides into the optic chiasm where the
temporal half of fibers crossover and enter the optic tract while the nasal half
of fibers remain uncrossed and enter the optic tract.
454 15 Visual System and Occipital Lobe
Fig. 15.4 The image is from a macaque monkey, with cholera toxin B + Alexa 488 (green) in the
left eye and cholera toxin B + Alexa 596 (red) in the right eye. Note the distinct laminar separation
of inputs from the right eye and left eye. The brain was cut in a sagittal plane. The image is a mon-
tage of four separate images. The images were collected with a 4× objective, using an Olympus
FV300 confocal microscope, with the aperture removed. Lasers specific for the wavelengths of the
dyes. “Dark field” produced by the use of polarized light to show unstained myelinated axon
bundles. Courtesy of Dr. Harvey Karten, Department of Neurosciences, University of California,
San Diego
(b) Optic chiasm. At the chiasm, the fibers in the optic nerve from the left nasal
retina cross the midline and join with the fibers from the right temporal ret-
ina to form the right optic tract. Fibers from the inferior nasal retina (the
superior temporal visual field) cross in the inferior portion of the chiasm,
which usually lies just above the dorsum sellae. By this crossing, all the
information from the left visual field is brought to the right lateral geniculate
nucleus and subsequently to the right calcarine cortex. The fibers of the right
nasal retina also cross in the chiasm to join the fibers from the left temporal
retina. Thus, the visual pathway repeats the pattern in other sensory systems;
the right side of the visual field is represented on the left cerebrum. Optic
fibers in the chiasm enter the suprachiasmatic nucleus of the hypothalamus.
(c) Optic tract. The crossed temporal fibers combine with the ipsilateral nasal
fibers to form the optic tract of which over half of the fibers continue into the
six-layered lateral geniculate nucleus in the thalamus where it synapses.
The crossed fibers/temporal fibers terminate in layers 1, 4, and 6, while the
uncrossed/nasal fibers terminate in layers 2, 3, and 5.
About half the axons in the optic tract terminate in the lateral geniculate nucleus
with the remainder of the axons bypassing the lateral geniculate and terminating in the
tectum of the superior colliculus with some of these fibers also involved in light reflexes.
(d) Light reflexes.
The optic fibers for pupillary light reflexes bypass the LGN and descend into the
pretectal region of the midbrain. Others, for coordinating eye and head or neck
movements, descend to the superior colliculus. Also some of the retinal fibers syn-
apse in the suprachiasmatic nucleus of the hypothalamus and then project to the
pineal by way of the sympathetic fibers where they influence circadian rhythms and
endocrine functions.
15.3 Visual Pathway 455
Fig. 15.5 Visual pathway from optic nerve > LGN > occipital lobe. (a) Inset: the projection of the
quadrants of the right visual field on the left. (b) Visual pathway, sagittal view of ventral stream, or
the geniculostriate “what pathway” > optic nerve > LGN > and then projects onto the striate cortex
in the occipital lobe. MRI, OsiriX image system. (c) Visual pathway, ventral stream, or the genicu-
lostriate “what pathway” > optic nerve > LGN > striate cortex. Horizontal view. MRI, OsiriX
456 15 Visual System and Occipital Lobe
Fig. 15.5 (continued)
15.3 Visual Pathway 457
Fibers leave the optic tract, bypass the LGN, and enter the pretectal region: fibers
from the pretectal region relay signals bilaterally to the visceral nuclei (Edinger–
Westphal) of the oculomotor complex in the upper midbrain underlying the superior
colliculus.
(e) Lateral geniculate nucleus of the thalamus.
Cells in the LGN grow rapidly in the first 6–12 months after birth, under the
influence of visual stimuli. Visual sensory deprivation during this period leads to
atrophy and lifelong blindness.
1. Optic nerve termination in dLGN. The optic nerve fibers from the temporal
visual field, the crossed fibers, end in layers 1, 4, and 6 (Fig. 15.4). The fibers
from the temporal retina (the nasal visual field), the uncrossed fibers, end in lay-
ers 2, 3, and 5. Each optic nerve fiber ends in one layer on five or six cells.
The dLGN is primarily a relay station in the direct visual pathway. It is divided
into a large dorsal nucleus and a smaller ventral nucleus with the dorsal subdivision
projecting onto layers 4 and 6 of striate cortex. In the human this is a rare site for a
lesion. The lateral geniculate nucleus is a six-layer horseshoe-shaped structure.
Visual processing begins in the large and small cells in the dLGN. The small cells
are in layers 1 to 4 and the large cells in layers 5 and 6. Each LGN cell receives
direct input from a specific area of the retina, and each area of the LGN is driven
from a specific area of the visual field. Each receptive field has a center that is either
on or off and a surround that has the opposite polarity. Some fibers from the lateral
geniculate nucleus also enter the inferior pulvinar nucleus.
2. Projections of magnocellular and parvocellular retina neurons. Two major streams
of visual information leave the retina to the LGN—magnocellular and parvocel-
lular. The total number of cells and fibers in both systems is roughly equal.
Magnocellular stream starts in the large cells of the retinal ganglion (Y cells)
that project to the magnocellular layers of the LGN which subsequently project to
the striate cortex/area 17 into layer 4 superficial to the parvocellular projection. The
cortical neurons of the magnocellular stream respond to movements, orientation,
and contrast, but they respond poorly to light.
Parvocellular stream begins with small cells of the retinal ganglion layer, and its
cells respond well to small spots of light and to short, narrow bars of light, as well as
to on–off stimuli. The parvocellular stream begins with small cells of the retinal gan-
glion layer (X-cells) that project to parvocellular layer of LGN layers 3 and 6. These
cells respond either to shape and orientation or color red/green and blue/yellow.
(f) Optic pathways. The information from the optic nerve reaches the cerebral cor-
tex via two different streams (Milner and Goodale 2008): ventral stream and
dorsal stream.
1. Ventral stream, the geniculostriate or the “what pathway,” enters the LGN and
then projects onto the striate cortex. These fibers go directly from the retina via
the optic nerve to the LGN, then are projected onto the visual striate cortical area
17-V1, also enter area MT in the temporal lobe, and are involved with object
identification and recognition.
458 15 Visual System and Occipital Lobe
scans of patient GY show activity in extrastriate visual areas (areas 18 and 19)
when the stimuli were presented in the “blind” region. Without V1, these sig-
nals probably go through the dorsal pathway. So damage to V1 can lead to sight
without awareness = blind sight. But damage to the (usually right) parietal lobe
can lead to the opposite problem, called anosognosia. These patients can be
blind, but they insist that they can see. They will often confabulate stories or
excuses to prevent them from demonstrating their disability.
(c) Diffusion MRI, also referred to as diffusion tensor imaging or DTI, has been
applied clinically in the study of neurological disorders, especially for the man-
agement of patients with acute stroke (Oppenheimer et al. 2007; Vargas et al.
2009). It can reveal abnormalities in white matter fiber structure and provide
models of brain connectivity; therefore, it is rapidly becoming a standard for
white matter disorders. The ability to visualize anatomical connections between
different parts of the brain, noninvasively and on an individual basis, has
emerged as a major new focus on neural pathways leading to the Human Brain
Connectome project (NIH, NINCDS). DTI tractography study in humans
reveals connections between the pulvinar and cortical and subcortical areas,
including the superior colliculus and caudate, as also noted in the previous pri-
mate studies. The connections to the superior colliculus and caudate were
observed in DTI tractography, supporting the belief that the pulvinar plays an
important role in human visual information processing and visual spatial atten-
tion just as it does in nonhuman primates and cats.
Most of our understanding of occipital lobe function comes from simian studies.
Nonhuman primates with at least six visual areas have been identified.
V1—corresponding to area 17 in humans
V2 and V3—corresponding to area 18
V4 and V5-MT (middle temporal)—corresponding to area 19
V6 DM of V3
460 15 Visual System and Occipital Lobe
1. Striate cortex area 17 (V1), the striate cortex, the principal visual projection area
in humans is found primarily on the medial surface of the hemisphere, occupying
those portions of the cuneus (above) and lingual gyrus (below) that border the
calcarine sulcus. For this reason, it is often termed the calcarine cortex. Much of
this cortex is located on the walls and in the depths of this sulcus.
2. Extrastriate visual cortex areas 18 and 19. These areas form concentric bands
about area 17 and are found on both the medial and lateral surfaces. Area 19 in
humans extends onto the adjacent middle and inferior temporal gyri.
3. Intracortical associations between striate and nonstriate cortex. Area 17 receives
fibers from and sends fibers to area 18 but does not have any direct callosal or
long-association-fiber connections to other cortical areas. The columnar and
horizontal organization of the primary visual cortex has been discussed previ-
ously in Chap. 17. Area 17 is more mature at birth and has the most precise map.
The other visual areas develop through maturation and experience, although
experience modifies V1 as well. Area 18 has extensive connections with areas 18
and 19 of the ipsilateral and contralateral hemispheres, which were demonstrated
by both the earlier strychnine neuronography studies and the more recent horse-
radish peroxidase studies.
4. Callosal fibers. Callosal fibers enter the opposite hemisphere, and association
fibers communicate with the premotor and inferior temporal areas and area 7 of
the adjacent parietal cortex. As discussed in greater detail below, Zeki and associ-
ates (1992) studied each of these visual areas to create a map of the retina. Parallel
pathways process various aspects of visual information—color (wavelength),
motion, stereopsis, and form (line orientation)—and extend from the retina to the
lateral geniculate nucleus, striate cortex, and, finally, extrastriate cortex.
5. Termination of optic radiation. Area 17—striate cortex—optic radiation. Area 17
is the primary visual area/striate cortex and receives the termination of the genic-
ulocalcarine (or optic) radiation. This projection is arranged in a topographic
manner, with the superior quadrant of the contralateral visual field represented on
the inferior bank of the calcarine fissure and the inferior quadrant of the contra-
lateral visual field represented on the superior bank. The macula has a large area
of representation, which occupies the posterior third of the calcarine cortex and
extends onto the occipital pole. The optic radiation terminates on the cells in the
calcarine cortex which respond like retinal ganglion cells. Their receptive fields
consist of an excitatory region surrounded by an inhibitory region. Fields with the
opposite pattern are also seen in higher mammals. The fibers from the LGN ter-
minate in layer 4 with the fibers from the magnocellular streams terminating
more superficial than that of the parvocellular stream.
6. Ocular dominance columns. Ocular dominance columns are seen in the striate
cortex. They are seen as an alternating series of parallel stripes that represent a
column of neurons in the striate cortex innervated by either the ipsilateral or con-
tralateral eye. Ocular dominance columns extend in alternating bands through all
cortical areas and layers and are absent in only the cortical region representing
the blind spot and the cortical area representing the monocular temporal crescent
of the visual field. The mosaic appearance of these ocular dominance columns is
15.4 Occipital Lobe 461
Fig. 15.6 Types of visual stimuli that excite each of the four types of cells found in the calcarine
cortex. The square represents a box 2 in. by 2 in., 5 ft away from the monkey’s eye. The actual
stimuli are bright bars of light on a dark field (Data from Hubel and Wiesel, 1968, J Physiology.
195: 215)
462 15 Visual System and Occipital Lobe
for one eye or the other. For example, a simple cell may be strongly excited by a
bar seen with the right eye and only weakly stimulated by the same bar seen with
the left eye. This differential sensitivity may form the basis of binocular vision.
(b) Complex cell. A number of simple cells having the same orientation activate a
complex cell. The complex cell has a definite orientational preference, but a
much larger receptive field. Any horizontal line of any length within the out-
lined visual field excites complex cell alpha. Lines with different orientations in
the same visual field will drive other complex cells.
(c) Hypercomplex cell. The final cell type is a hypercomplex cell. It has characteristics
very similar to the complex cell except it discriminates lines of different lengths.
Corners and angles also excite these cells. About half a million optic tract fibers
enter each occipital lobe. It should be clear that there are many more cells process-
ing this information, and, indeed, the banks of the calcarine cortex contain many
millions of cells. The response to a large rectangle of light varies with the type of
cell. Only if the edge falls on the center of a cell’s receptive field will it be excited.
(d) Retinal ganglion cells. These cells are very sensitive to position, contrast, and
dynamics. The cortex is also stimulated if the pattern moves a little on the retina.
A different group of ganglion and simple cells will react, but because of their
larger receptive fields, most of the complex and hypercomplex cells continue to
be stimulated. The nervous system has overcome the problem of stationary
images by continually producing rapid, saccadic eye movements that constantly
shift the image on the retina. Indeed, when the image is stabilized by special
contact lenses, it disappears. In the process of data reduction, the visual system
loses the ability to judge absolute light intensity for the most part. Differences in
intensity within a field can be determined easily but not the overall intensity of
the field; photographers who estimate exposures usually waste a lot of film.
Only the pupillary reflex system retains the ability to measure absolute intensity.
Different calcarine cells within a narrow column perpendicular to the surface
repeat this processing for each of the primary-color receptors to give informa-
tion on form, color, motion, and contrast. Lesions as small as 1 mm result in a
detectable loss of all of these modalities in a small area of the visual field.
Zeki and associates (1992) demonstrated how the four identified perceptual path-
ways (color, form with color, dynamic form, and motion) relate to the specific visual
areas—Fig. 15.7.
1. V1 (area 17) and V2 (area 18) distribute information to these specialized fields.
V1 has column and intercolumnar areas. The columns stain heavily for the
energy-related enzyme cytochrome oxidase. The neurons within the columns are
wavelength sensitive, tend to concentrate in layers 2 and 3, and receive input
primarily from the parvocellular layers of the lateral geniculate nucleus.
Information concerning color is then projected either directly or through thin-
column stripes in areas V2 to V4.
15.5 Perceptual Pathways: Color Vision 463
Fig. 15.7 The locations and arrangements of visual areas in the occipital (left), parietal (top),
temporal (bottom), and frontal (right) lobes. Lateral view of a partially opened macaque monkey
brain illustrating the locations and sizes of 29 visual areas and zones. Cortical areas are color coded
by the lobe, occipital (with yellow), temporal (light gray), superior temporal (orange), parietal
(dark green), and frontal (brown), and by their associated cortical streams and modular organiza-
tions. Occipital areas without clear associations to single cortical streams are coded dark gray. Area
V1 contains color-selective blobs (black) and interblobs (yellow). Area V2 contains color-selective
thin stripes (black), motion-/disparity-selective thick stripes (green), and orientation-selective
interstripes (yellow). Area MT and associated areas are coded light green to reflect their association
with the magnocellular-dominated cortical stream macaque cortex (Felleman 2009). Extrastriate
Visual Cortex by Felleman, Daniel J.: Encyclopedia of Neuroscience, Chapter: 3247 2009
2. Areas V3 and V3A (area 18). The cells of the adjacent areas V3 and V3A are
selective for form (line orientation) but are indifferent to wavelength. By contrast,
form-selective neurons are located in the intercolumnar areas in V1. Form related to
color derives from the parvocellular neuron layers of the lateral geniculate nucleus,
which project first to the intercolumnar areas of V1 and then to V4. The second form
system is independent of color and depends on inputs from the magnocellular layers
of the lateral geniculate nucleus to layer 4B of V1 projecting to V3.
3. Area V4 (area 19). Is important in visual object recognition.
4. Area V5 (area 19). The neurons of area V5 (area 19) are responsive to motion
and directionally selective, but they are nonselective for color. In contrast, the
majority of cells in V4 (area 19) are selective for specific wavelengths of light
(color sensitive), and many are selective for form (line orientation) as well.
Extrastriate areas send projections back to the dorsal lateral geniculate nucleus
and the pulvinar of the thalamus. The motion-sensitive system consists of inputs
from the magnocellular layers of lateral geniculate nucleus to layer 4B of area
V1, which then projects to area V5, either directly or through area V2. Each of
the prestriate areas V5, V4, and V3 sends information back to V1 and V2, as well
as to the parietal and temporal areas. This provides for more integrated visual
perception. Extraoccipital higher-level visual processing then occurs in area 7 of
the parietal lobe, areas 23 and 21 of the temporal lobe, and area 8 of the frontal
lobe (see Pandya and Kuypers 1969).
464 15 Visual System and Occipital Lobe
Direct electrical stimulation of areas 17, 18, and 19 in conscious people produces
visual sensations (Pollen 1975). These images are not elaborate hallucinations (as in
complex partial temporal seizures) but rather are described as flickering lights, stars,
lines, spots, and so forth. Often the images are described as colored or moving around.
The images are usually localized to the contralateral field, at times to the contralateral
eye. At times, the patient cannot determine laterality. In addition, stimulation of areas
18 and 19 (and sometimes 17) produces conjugate deviation of the eyes to the contra-
lateral field and, at times, vertical conjugate movements. Discharge of the occipital
cortex may be followed by transient visual defects similar to the transient postictal
hemiparesis that may follow focal seizures beginning in the motor cortex (see Aldrich
et al. (1989)). More complete discussion of seizures beginning in the occipital cortex
can be found in Salanova et al. (1993) and Williamson et al. (1992).
15.6 Summary
Let us consider the example of a slowly moving colored ball. Visual information is
fractionated into the modalities of form, color, and motion in the calcarine cortex.
That information is reassembled elsewhere to give us a unitary view of the ball.
We are just beginning to understand where and how this parallel processing is done.
If the object is the letter A, then further processing takes place in the dominant (usu-
ally left) lateral occipital cortex (Brodmann’s areas 18 and 19), the visual language
association area. Letters seen in the left visual field and represented in the right calca-
rine cortex must project across the posterior corpus callosum before they can be rec-
ognized in the left visual association cortex. Information needed to reconstruct
complex forms flows through the inferior occipital/temporal region, primarily on the
non-dominant side. Located here are cells that can discriminate between human faces,
for example. Similarly, sheep have cells that respond only to the image of a wolf (not
of a sheep), and monkeys have cells that respond only to a human face but not to a
snake or a banana. Many of these cells are sensitive to gaze, being strongly stimulated
by direct eye contact but only weakly stimulated when the eyes are averted.
continue to occur after selective V1 lesions have been made, due to the activation
of V5 (possibly by subcortical input to V5). Vision is clearly abnormal in this
blind field. V1 to V5 input is the dominant input in intact individuals.
2. Partial lesions in area 17. With partial lesions, a partial defect results. For exam-
ple, if only the superior bank of the calcarine fissure is involved, the visual field
defect is limited to the inferior quadrant of the contralateral field. A bilateral
infarct of either the upper or lower bank of the calcarine fissure may produce a
homonymous altitudinal hemianopsia in which apparent blindness exists in
either the entire lower or upper field of vision (as appropriate). With such
calcarine-cortex lesions, the field defects are usually similar (congruous) in both
eyes. By contrast, incomplete optic-tract lesions may produce somewhat unequal
(noncongruous) homonymous field defects in both eyes.
3. Vascular lesions. In particular occlusion of the posterior cerebral artery often
results in a homonymous hemianopsia with macular sparing, that is, vision in the
macular area of the involved field remains intact. Such preservation of the macular
vision probably occurs because the macular area has a large representation in the
most posterior third of the calcarine cortex and is the area nearest the occipital
pole. This area, then, is best situated to receive leptomeningeal anastomotic blood
supply from the middle cerebral and anterior cerebral arteries. Occasionally, with
occipital infarcts, there may be preservation of vision in a small peripheral unpaired
portion of the visual field, called the temporal crescent (see Benton et al. 1980).
In vascular insufficiency or occlusion of the basilar artery, infarction may occur in
the distribution of both posterior cerebral arteries, producing a bilateral homony-
mous hemianopsia and a syndrome of “cortical blindness.” Such patients lose all
visual sensation, but pupillary constriction in response to light is preserved.
4. Lesions of extrastriate areas 18 and 19. Lesions in areas 18 and 19, often referred
to as the visual association areas, produce deficits in visual association, includ-
ing defects in visual recognition and reading. The problem is that in humans with
a unilateral lesion, one is almost never dealing with disease limited to areas 18
and 19 (however, see discussion below of more recent studies). Rather, one finds
that adjacent portions of either the inferior temporal areas or of the inferior pari-
etal lobule (the angular and supramarginal gyri) are involved or that the lesion
extends into the deeper white matter of the lateral occipital area and involves
association and callosal fibers. Such more-extensive lesions will, of course, pro-
duce the deficits previously noted in the discussion of parietal function.
5. Unilateral lesions limited to areas 18 and 19. A limited unilateral ablation might
produce defects in visual following, as tested by evoking optokinetic nystagmus
(e.g., moving vertical black lines on a white background or looking at telephone
poles from a moving train).
6. Bilateral lesions limited to areas 18 and 19. These lesions occur only rarely in
humans. In humans such a lesion would deprive the speech areas of the dominant
hemispheres of all visual information. The patient would presumably see objects
but be unable to recognize them or to place visual sensations in the context of
previous experience. The patient would be, moreover, unable to relate these
visual stimuli to tactile and auditory stimuli. In monkeys, restricted lesions in the
466 15 Visual System and Occipital Lobe
“visual” areas of the temporal and parietal lobes also interfere with pattern
discrimination (Mishkin 1972). Horton and Hoyt (1991) have reported that uni-
lateral lesions specific to the extrastriate V2/V3 cortex produce quadrantal visual
field defects. As discussed by Zeki (1992), rare patients with restricted lesions in
V4 present with achromatopsia. The patients see the world only in shades of
gray, but perception of form, depth, and motion is intact. Rare patients with
lesions limited to V5 have akinetopia. Stationary objects are perceived, but if
they are in motion, the objects appear to vanish. Plant et al. (1993) have reviewed
such impaired motion perception. Selective deficits in form perception are even
less frequent. Destruction of both form systems and therefore of V3 and V4
(areas 18 and 19) would be required, and, as discussed above, such a lesion
would also destroy V1 (area 17), resulting in total blindness. Case 14.4 illustrates
the effects of a space-occupying lesion in the occipital lobe. One should compare
these findings to those reported earlier in Case 15.1, a lesion in the visual system
anterior to the optic chiasm.
Areas 18 and 19 send fibers to the tectal area of the superior colliculus and receive
projections back from the tectum via the inferior pulvinar (Some of these projections
are bilateral). Such connections are necessary for visual fixation and accurate following
of a moving object. The slow and smooth conjugate eye movements that occur when
the eyes are following a moving visual stimulus (pursuit movements) should be distin-
guished from the independent phenomenon of voluntary (saccadic) conjugate eye
movements. Saccadic movements are rapid and shorter in latency and duration. They
do not require a visual stimulus and do not depend on any connections to area 18.
Rather, they are dependent on area 8 in the premotor cortex, which sends fibers to the
lateral gaze center of the pons. Both areas send some fibers to the superior colliculus,
and ultimately, both the saccadic and pursuit movements involve the pontine gaze cen-
ters. In addition, vestibular and cerebellar influences also determine eye movement.
15.7 V
isual Field Deficits Produced by Lesions in the Optic
Pathway
Fig. 15.8 Overview of localized lesion in the common visual field deficits produced by lesions in
the optic pathway
4. Figure 15.8 #4. Location of Homonymous hemianopsia. Lesions behind the optic
chiasm, in this case right optic tract, produce blindness in one visual field, a
homonymous hemianopsia from injury to the optic tract, the lateral geniculate
body, or the geniculocalcarine radiation; see also Case 15.6.
5. Figure 15.8 #5. Location of Superior quadrantanopsia in right Meyers’ loop in
visual radiation. Partial lesions of the geniculocalcarine radiations produce a
quadrantanopsia.
6. Figure 15.8 #6. Location of Left homonymous inferior quadrantanopsia. Upper
right geniculocalcarine tract. Macular sparing is seen with lesions in the visual cor-
tex following calcarine artery infarcts. The macula is represented close to the occipi-
tal pole, and this area receives anastomotic flow from the middle cerebral artery.
7. Figure 15.8 #7. Location of Homonymous hemianopsia with macular sparing.
Visual cortex.
15.7.1 C
ase Histories: Examples with Lesions in the Visual
System
15.7.1.1 L
esion prechiasmatic. Lesion in the optic nerve (see Fig. 15.8 #2)
before the chiasm—result: monocular blindness
eye. These were sudden onset, not associated with pain, and lasted several minutes
after which they resolved fully. He had no other focal neurologic symptoms.
Past history is notable for hypertension, smoking, and high cholesterol. He has
had prior angina episodes. His family history is notable for coronary disease in his
father. On exam, he had a normal neurologic exam with a left carotid bruit.
Clinical diagnosis. CT of the head was normal, and a subsequent angiogram dem-
onstrated a left carotid stenosis.
Impression: Amaurosis in the left eye related to carotid stenosis.
He underwent left carotid endarterectomy, after which he had no further epi-
sodes. He was neurologically intact at the last exam.
Case History 15.2, Level 15.8 #2-monocular blindness: Fig. 15.9. This 53-year-
old white right-handed housewife had a progressive 23-year history of right-sided
supraorbital headache with decreasing acuity and now almost total blindness in the
right eye. During the 3 years before admission, intermittent tingling paresthesia had
been noted in the left face, arm, or leg. About 1 year before admission, the patient
had a sudden loss of consciousness and was amnestic for the events of the next 48
h. No explanation for the episode was clearly established. The cerebrospinal fluid
protein was reported to be elevated (230 mg/dL). The patient and her family reported
some personality changes over a period of several years, including a loss of sponta-
neity and increasing apathy.
General physical examination: There was a minor degree of proptosis (down-
ward protrusion of the right eye).
Fig. 15.9 Sphenoid-wing
meningioma producing
compression of the right
optic and olfactory nerves.
Case History15.2. Refer to
text. Right carotid
arteriogram, venous phase
demonstrating tumor blush
in the subfrontal area of
the anterior fossa,
extending into the middle
fossa (Courtesy of
Dr. Samuel Wolpert.
New England Medical
Center Hospitals.)
15.7 Visual Field Deficits Produced by Lesions in the Optic Pathway 469
Neurologic examination: mental status. The patient was, in general, alert but at
times would become lethargic. Her affect was flat. At times, she would laugh or joke
in an inappropriate manner.
Cranial nerves: There was anosmia for odors, such as cloves, on the right and a
reduced sensitivity on the left. Marked papilledema (increased intracranial pressure)
with elevation of the optic disk and venous engorgement was present in the left eye.
In contrast, there was pallor of the right optic disk indicating optic atrophy. The patient
had only a small crescent of vision in the temporal field of the right eye; only vague
outlines of objects could be seen. A slight left central facial weakness was present.
Motor system: Movements on the left side were slow. Reflexes: A release of grasp
reflex was present on the left side.
This combination of anosmia and reduced vision is called a Foster–Kennedy
syndrome, and this was confirmed in the imaging studies.
Laboratory data: Imaging studies demonstrated a tumor blush in the right subfron-
tal region extending back to the right optic nerve groove consistent with a meningi-
oma arising from the olfactory groove or inner third sphenoid wing (Fig. 15.9).
Clinical diagnosis: Subfrontal meningioma rising from the inner third sphenoid
wing. Alternative location would be olfactory groove.
Hospital course: A bifrontal craniotomy performed by Dr. Sam Brendler exposed
a well-encapsulated smooth tumor, a meningioma, attached to the inner third of the
sphenoid wing. Approximately 90–95% of the tumor was removed exposing the
right optic nerve. Examination 4 months after surgery indicated right anosmia and
right optic atrophy were present.
Case History 15.3, Figure 15.9, 15.8-bitemporal hemianopsia. This 50-year-old
right-handed, white male factory foramen was referred for evaluation of ptosis and
diplopia involving the left eye. Approximately two weeks prior to admission, the
patient developed a bifrontal headache; during the week prior to his evaluation, the
headache had become a left-sided aching pain. It increased in intensity during the
two days prior to admission and was present as a constant pain interfering with
sleep. If the patient were to cough, he had additional pain in the left eye. On the day
of admission, the headache became much more severe; it was now the “worst head-
ache he had ever experienced.” In retrospect, the patient reported that lights had
been brighter in the left eye for approximately one week.
At 3:00 PM on the day of admission, the patient noted the sudden onset of diplo-
pia, which was more marked on horizontal gaze to the right and much less marked
on horizontal gaze to the left. At approximately the same time, he noted the rapid
onset of ptosis involving the left lid.
General physical examination: There was moderate resistance to flexion of the neck.
1. Neurological Examination
2. The left pupil was fully dilated (blown) to approximately 7 mm. There was no
response to light or accommodation.
3. Total ptosis of the left eyelid was present.
4. No medial movement of the left eye was present; there was no upward movement
of the left eye possible. The patient had minimal downward gaze of the left eye.
He had full lateral movement of the left eye. Movements of the right eye were full.
470 15 Visual System and Occipital Lobe
Fig. 15.11 Case History 15.6. Level 15. 8 # 3 bitempo ral hemianopsia. A large pituitary adenoma
with secondary hemorrhage has extended upward out of the sella to compress the optic chiasm and
optic nerves. This 53-year-old white male 11 months before death experienced difficulty in reading
small print, with greater involvement of the right eye than the left. This progressed to total blind-
ness in the right eye and shortly thereafter a sudden loss of vision in the left eye, an absence of
pupillary responses, and a bilateral anosmia. Vision improved after partial surgical removal and
irradiation, but fatal meningitis developed (Courtesy of Drs. John Hills and Jose Segarra)
472 15 Visual System and Occipital Lobe
Case History 15.4 in Fig. 15.10 is another example of the visual field diagrams
in another case with a bitemporal hemianopsia from a pituitary tumor.
15.7.2 L
esions in Occipital Cortex Result: Congruous
Homonymous Hemianopsia
Fig. 15.13 (a) Case History 15.9, This 57-year-old right-handed female presented with a sudden
onset of a right homonymous hemianopsia. Metastatic tumor in the left occipital lobe. MRI. (b)
Tensor analysis of tumor location in the left occipital lobe. MRI
474 15 Visual System and Occipital Lobe
Neurologic exam found her to have normal fluency but mild confusion. She had
normal reading comprehension.
A right homonymous hemianopsia was detected a finger confrontation. She had
full extraocular movements. The pupils were equal and reactive. The remaining
cranial nerve exam was normal. Strength was normal in the limbs. Muscle bulk and
tone were preserved. Pin and light touch perception were intact.
Fig. 15.14 Case History 15.10. Occlusion of right posterior cerebral artery.Tangent screen exami-
nation of visual fields, 3 months after the acute event. This 75-year-old woman had the acute onset
of headache, bilateral blindness confusion, vomiting, mild ataxia and bilateral Babinski signs. All
findings cleared except a homonymous hemianopia with no evidence of macular sparing
Bibliography 475
Fig. 15.15 Case 15.11: Residual left homonymous hemianopsia without macular sparing. CT scan
of a total infarct, presumably embolic in the right posterior cerebral artery cortical territory (occipi-
tal and posterior temporal lobes) obtained 5 days after the acute onset of confusion and possible
visual hallucinations in an 86-year-old right-handed male. As confusion cleared examination indi-
cated a dense left homonymous hemianopia with no evidence of macular sparing O.S. = left eye;
O.D. = right eye. The patient would look to the right and to the midline but would not follow
objects to the left
Bibliography
Aldrich MS, Vanderzant CW, Alessi AC, et al. Ictal cortical blindness with permanent visual loss.
Epilepsia. 1989;30:116–20.
Anand I, Geller EB. Visual auras. In: Luders HO, Nocachtar S, editors. Epileptic seizures: patho-
physiology and clinical semiology. New York: Churchill Livingstone; 2000. p. 298–303.
Barbur JL, Watson JDG, Frackowiak RSJ, Zeki S. Conscious visual perception without V1. Brain.
1993;116:1293–302.
Benton S, Levy I, Swash M. Vision in the temporal crescent in occipital lobe infarction. Brain.
1980;103:83–97.
Brindley GS, Donaldson PEK, Falconer MA, Rushton DN. The extent of the occipital cortex that
when stimulated gives phosphenes fixed in the visual field. J Physiol (London). 1972;225:57–8.
Brindley GS, Lewin WS. The sensations produced by electrical stimulation of the visual cortex.
J Physiol (London). 1968;196:474–93.
476 15 Visual System and Occipital Lobe
Brookhart JM, editor. The nervous system (handbook of physiology, Section 1, Vol III, Part I,
Vision). Bethesda, MD: American Physiological Society; 1984.
Moses WM. Adler's physiology of the eye: clinical application. St. Louis: Mosby; 1987.
Geller EB, Luders HO, Cheek JC, Comair YG. Electrical stimulation of the visual cortex. In:
Luders HO, Noachtar S, editors. Epileptic seizures: pathophysiology and clinical semiology.
New York: Churchill Livinstone; 2000. p. 219–27.
Gloor P, Avoli M, Kostopoulos G. Thalamocortical relationships in generalized epilepsy with bilat-
eral synchronous spike and wave discharges. In: Avoli M, Gloor P, Kostopoulos G, Naquet
R, editors. Generalized epilepsy: neurobiological approaches. Boston: Birkhauser; 1990.
p. 190–212.
Horton JC, Hoyt WF. Quadrontic visual field defects: a hallmark of lesions in extrastriate V2/V3
cortex. Brain. 1991;114:1703–18.
Hubel DH, Wiesel TN. Ferrier lecture: functional architecture of macaque monkey visual cortex.
Proc R Soc London Biol. 1977;198:1–59.
Humphrey NK, Weiskrantz L. Vision in monkeys after removal of the striate cortex. Nature.
1967;215:595–7.
Kennard C, Rose FC. Physiological aspects of clinical neuro-ophthalmology. Chicago: Year Book
Medical Publishers; 1988.
Livingstone M, Hubel D. Segregation of form, color, movement and depth: anatomy, physiology
and perception. Science. 1988;240:740–9.
Lolley RN, Lee RH. Cyclic GMP and photoreceptor function. FASEB J. 1990;4:3001–8.
Mishkin M. Cortical visual areas and their interactions. In: Karzmar AG, Eccles JC, editors. Brain
and human behavior. Berlin: Springer; 1972. p. 187–208.
Pandya DN, Kuypers H. Cortico-cortical connections in the rhesus monkey brain. Brain Res.
1969;13:13–6.
Penfield W, Jasper H. Epilepsy and the functional anatomy of the human brain. Boston: Little
Brown; 1954. pp. 116–26, 168–73, 401–8
Plant GT, Laxer KD, Barbaro NM. Impaired visual motion perception in the contralateral hemi-
field following unilateral posterior cerebral lesions in humans. Brain. 1993;116:1303–35.
Pollen DA. Some perceptual effects of electrical stimulation of the visual cortex in man. In: Chase
TN, editor. The nervous system, Volume 2: the clinical neurosciences. New York: Raven Press;
1975. p. 519–28.
Poppel E, Held R, Frost D. Residual visual function after brain wounds involving the central visual
pathways in man. Nature. 1973;243:295–6.
Salanova V, Andermann F, Rasmussen FB. Occipital lobe epilepsy. In: Wyllie E, editor. The treat-
ment of epilepsy: principles and practices. Philadelphia: Lea & Febiger; 1993. p. 533–40.
Stryer L. Cyclic GMP cascade in vision. Ann Rev Neurosci. 1986;9:87–119.
Van Essen DC. Visual areas of the mammalian cerebral cortex. Ann Rev Neurosci. 1979;2:227–63.
de Gelder B, Tamietto M, van Boxtel G. Intact navigation skills after bilateral loss of striate cortex.
Curr Biol. 2008;18(24):R1128–9. doi:10.1016/j.cub.2008.11.002.
Weiskrantz L, Warrington EK, Sanders MD, Marshall J. Visual capacity in the hemianopic field
following a restricted occipital ablation. Brain. 1974;97:709–28.
Wiesel TN, Hubel DH. Efforts of visual deprivation on morphology and physiology of cells in the
cat's lateral geniculate lobes. J Neurophysiol. 1963a;26:978–93.
Wiesel TN, Hubel DH. Single cell responses in striate cortex of kittens deprived of vision in one
eye. J Neurophysiol. 1963b;26:1003–7.
Williamson PD, Boon PA, Thadani VM, Darcey RM, Spencer DD, Spencer SS, Novelly RA,
Mattson RH. Occipital lobe epilepsy: clinical characteristics, seizure spread patterns and
results of surgery. Ann Neurol. 1992;31:3–13.
Zeki S. The visual image in mind and brain. Sci Am. 1992;267:69–76.
Chapter 16
The Limbic System, Temporal Lobe,
and Prefrontal Cortex
Abstract The neurologist Paul Broca in the latter half of the nineteenth century
initially designated all of the structures on the medial surface of the cerebral hemi-
sphere the “great limbic lobe.” This region, due to its strong olfactory input, was
also designated the rhinencephalon. The olfactory portion of the brain (rhinenceph-
alon or archipallium) comprises much of the telencephalon in fish, amphibians, and
most mammals. In mammals, the presence of a large olfactory lobe adjacent to the
hippocampus was once considered to be evidence of the important olfactory func-
tions of these regions. However, when a comparative neuroanatomist examined the
brains of sea mammals that had rudimentary olfactory apparatus, e.g., dolphins and
whales, the presence of a large hippocampus suggested other than olfactory func-
tions for this region.
In 1937, Papez proposed that olfactory input was not the prime input for this
region, and the experiments of Kluver and Bucy (Am J Phys 119:352, 1937) and
Bucy (1952, 1958) demonstrated the behavioral deficits seen after lesions in this
zone. In primates, only a small portion of the limbic lobe is purely olfactory: the
olfactory bulb, olfactory tract with medial and lateral roots, olfactory trigone at junc-
tion of the olfactory tract with a cerebral hemisphere and with olfactory tubercle
(behind trigone contains islets of Calleja with GABA interneurons), pyriform cortex
of the uncus, and corticoamygdaloid nuclei (Fig. 16.1). The other portions of the
temporal lobe—hippocampal formation, parahippocampal gyrus, and cingulate
gyrus—are now known to be the cortical regions of the limbic system (Fulton, Yale J
Biol Med 26(2):107–118, 1953; Green, Reticular formation of the brain. Boston:
Little, Brown and Company, 1958; Papez, Reticular formation of the brain. Boston:
Little Brown and Company, 1958; Scheer 1963; Isaaccson, The limbic system. 2nd
ed. New York: Plenum, 1982). The olfactory system due to its strong projections onto
the medial temporal lobe directly, by passing the thalamus, will be briefly discussed
prior to our focus on the limbic system and the temporal lobe.
Gyrus supracallosus
allosum
pus C
Cor lucidum
el
mp
eptu rnix
S Fo
Gyrus subcallosus
ia
Parolfactory area
br
Fim
Olfactory tract
Lateral root Uncus
Anterior perforated substance Band of Giacomini
Fig. 16.1 Olfactory tract and its distribution in the cerebrum. This diagrammatic figure shows the
olfactory tract located under the orbital surface of the frontal lobe dividing into the medial root to
the paraolfactory area, the intermedia root to the septal region and via the anterior commissure
onto the opposite olfactory bulb, and the lateral root to the olfactory cortex on the uncus located on
the medial surface of the temporal lobe. The fimbria and the columns of the fornix, the dentate
gyrus, and its continuation as the supracallosal gyrus of the hippocampus are also illustrated. From
Gray’s Anatomy 1912
16.1 Olfactory System 479
Olfactory Bulb. The olfactory bulb lies on the cribriform plates and upon
microscopic inspection is seen to consist of six layers from outside in as follows:
Fig. 16.2 and Table 16.1.
The accessory olfactory bulb, which is found on the dorsal–posterior region of the
main olfactory bulb, forms a parallel pathway independent from the main olfactory
bulb. It receives axonal input from the vomeronasal organ, at the sensory e pithelium in
the vomer bone from the main olfactory epithelium that detects pheromones, among
other chemical stimuli. Like the main olfactory bulb, axonal input to the accessory
olfactory bulb forms synapses with mitral cells within glomeruli. However, mitral cells
Fig. 16.2 Olfactory system with the location of the sustentacular layers and neuroepithelial cells
shown in the olfactory mucosa of the upper ends of the nasal cavity. The olfactory neuroepithelial
cells are shown in the nasal mucosa, with their supporting sustentacular cells and Bowman’s
glands that produce mucus to moisten the olfactory epithelium and dissolve odor-containing gases.
The olfactory axons are shown passing through the cribriform plate of the ethmoid bone. These
axons are found in layer 1 and then end in the glomerular layer, layer 2, in the olfactory bulb. Layer
1, olfactory nerve layer contains entering nerve rootlets from the nasal mucosa; layer 2, glomerular
layer where olfactory nerves synapse on dendrites of mitral and tufted cells; layer 3, external plexi-
form layer (not labeled); layer 4, mitral cell layer contains cell bodies of mitral cells. The olfactory
tract originates primarily from the mitral cell layer and also from tufted cells. Layer 5, internal
plexiform layer. This narrow layer contains axons from mitral and tufted cells which are forming
the olfactory tract. Layer 6, granule cell layers with axons of olfactory nerve passing through this
layer to terminate into contralateral olfactory bulb, septum, and corticomedial nucleus of amyg-
dala. The granule cells in this layer will form local association connections (From Curtis, Jacobson
and Marcus, An Introduction to the Neurosciences)
480 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Table 16.1 Lamination in the olfactory bulb (Fig. 16.2): there are five distinct layers plus the outer
layers that contains the olfactory nerves
Layer 1. Olfactory nerve layer. The unmyelinated olfactory axons from the olfactory mucosa
carried in by the rootlets from cranial nerve I form the most external layer of the bulb. The
nerve fibers form a plexus in the olfactory mucosa covering the superior nasal conchae. These
unmyelinated fibers gather into about 20 bundles, which pierce the cribriform plate of the
ethmoid bone
Layer 2. Glomerular layer. The olfactory nerves synapse with dendrites of mitral cells and tufted
cells in the subjacent glomerular layer. The axons of 20–30 thousand bipolar olfactory cells
terminate in one glomerulus. In addition, the axons of multiple mitral cells and tufted cells also
converge on a single glomerulus. This summation of olfactory information permits a high
sensitivity to odoriferous substances
Layer 3. External plexiform layer (EPL). Contains dendrites of mitral cells and lateral dendrites
of the multipolar tufted and granule cells
Layer 4. Mitral cell layer. This layer consists of the cell bodies of the mitral (bishop’s cap) cells,
which are the largest neurons in the olfactory bulb. Their dendrites form synapses in the
glomerular layers, and their axons form most of the olfactory stria. (These cells are one of the
magnificent examples of nerve specificity in the central nervous system, as shown by the Golgi
neuronal method)
Layer 5. The internal plexiform layer—a narrow layer of granule cell dendrites passing
through on their way to the EPL. Tufted cells send their axons into the internal plexiform layer,
where they form a dense tract and travel within this layer to the opposite side of the bulb where
they terminate on the apical branches of granule cells. Hence, the activity on one side of the bulb
can influence the activity on the opposite side
Layer 6. Granule cell layer. This deepest layer contains stellate-shaped neurons and the axons
from the mitral and tufted cells which form the olfactory tract
in the accessory olfactory bulb project their axons to targets in the amygdala and
hypothalamus where they may influence aggressive and mating behavior. The out-
put of the accessory olfactory bulb is to the project to the medial preoptic area and
the medial hypothalamus, which are involved in regulating reproduction and aggres-
sion. These pathways are thought to be involved in the perception of chemical stim-
uli of a social nature, stimuli which can induce hormonal changes, affect the success
of pregnancy, alter the course of puberty, modulate female cyclicity and ovulation,
and elicit courtship behavior.
A wide overlap of layers exists because the axon collaterals from the mitral and
tufted cells extend throughout the bulb. Adrian (1950) noted that each mitral cell is
most sensitive to one class of odoriferous substances. Kauer (1991) discovered cod-
ing in the olfactory bulb, with each odor activating a different group of nerve cells.
Inhibitory dendrodendritic synapses in the glomeruli and on the mitral cells help to
regulate the response to specific odors (Reese and Shephard 1972). The evidence
points to discrimination between odors in the bulb itself, with more complex dis-
crimination and recognition found in the olfactory cortex (the pyriform cortex).
Olfactory Stria. As noted in Fig. 16.1, the primary axons in the olfactory system
originate from the olfactory receptor cells in the nasal fossae. The secondary axons
originate from the mitral and tufted cells and pass posteriorly as the olfactory stalk,
enter the base of the hemisphere, and divide into the lateral, medial, and intermedial
olfactory stria (Fig. 16.1). The place where the olfactory tract enters the ventral
16.1 Olfactory System 481
surface of the telencephalon and divides is called the olfactory trigone; posterior to
the trigone is the anterior perforated substance (olfactory tubercle), which is charac-
terized in the gross brain by small perforations resulting from the removal of small
penetrating blood vessels that are part of the anterior cerebral circulation.
Sites of Termination of the Olfactory Stria
1 . Intermediate stria >olfactory tubercle
2. Medial olfactory stria > septal region and via the anterior commissure into the
opposite olfactory bulb
3. Lateral olfactory stria > olfactory cortex on the uncus and corticomedial amyg-
daloid nuclei
Limbic Olfactory Interactions—Olfactory Cortex. The corticomedial amygda-
loid nucleus receives olfactory information directly from the lateral olfactory
stria and interconnects with the contralateral corticomedial nuclei (via anterior
commissure) and ipsilateral basolateral nuclei. The primary efferent pathway of
the corticomedial nucleus is the stria terminalis, which projects to the septum, to
the medial hypothalamus including preoptic nucleus of the hypothalamus, and to
the corticomedial nucleus in the opposite hemisphere.
Olfactory Discrimination. Vertebrates with a well-developed sense of smell are
called macrosmatic, while those with a poorly developed sense of smell are called
microsmatic. Dogs and cats are macrosmatic animals, while humans and all of
the great apes are microsmatic. In the dog and cat about 15% of their brain is
taken up with olfaction while in us it is minute. So it is not surprising that the dog
and cat can smell so much better than we can. Nevertheless, we can still distin-
guish thousands of different odors, and a multibillion dollar industry has devel-
oped to stimulate our olfactory system. In fact, many people have built careers on
their olfactory acuity (wine and coffee sniffers and perfumers). Many blind or
deaf people have such a refined sense of smell that they can detect subtle changes
in their environment.
In all other sensory systems, such as vision and audition, it is possible to
speak in terms of a basic measuring system, but in the olfactory system, the
degree of smell is a subjective matter. So only general rules for smell can be
listed. In order for humans to detect an odor, it must have some degree of volatil-
ity and lipid and water solubility. These qualities are necessary for the odorant to
reach the superior portion of the nasal conchae and penetrate the aqueous mucous
membrane, which contains the odor-receptant cilia. Only certain regions of the
mucosa appear to respond to any olfactory stimuli, and most olfactory cells are
sensitive to many different stimuli.
The following seems to best explain the transduction of the olfactory signal
(Burchell 1991; Dionne 1988; Kauer 1988, 2002; Lazard et al. 1989). The odorant
enters the mucous membrane and contacts the cilia on the neuroepithelial cell,
where it reaches a receptor. The receptor stimulates adenylate cyclase interaction
with Gs proteins specific to olfactory cells and produces cAMP which binds to the
cation channel and generates the neuronal response. In addition, odorants may bind
to an olfactory-binding protein in the mucous membrane, which concentrates the
482 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
odorant and moves it to the neuroepithelial cilia where transduction can then begin.
The odorant is inactivated in the endoplasmic reticulum.
The olfactory-binding protein enables the system to present the stimulus to the
neuroepithelium and then inactivate the stimulus, which is released from the neuro-
epithelial cell into the vasculature or olfactory mucosa. Kauer (1988) demonstrated
in a magnificent series of studies that real-time imaging of neural activity in the
olfactory bulb of the salamander can be demonstrated using voltage-sensitive dye
recordings. These studies demonstrate that each odorant has a different onset latency,
different magnitude, and different activation pattern in cells in the olfactory bulb.
Recent studies with in situ hybridization of five different odorant receptor mRNAs
have shown that axons from neurons responsive to a given receptor converge mostly
on a very few glomeruli in the olfactory bulb in a bilaterally symmetrical way (Vassar
et al. 1994). This data shows that a given odorant will produce a response in only a
restricted number of glomeruli and demonstrates that the olfactory system, just as
other sensory systems, uses spatial segregation to identify the specific stimulus
(Kauer and White (2002). Representation of odor information in the olfactory sys-
tem: from biology to an artificial nose. In: Sensors and Sensing in Biology and
Engineering. Barth, F.G., Humphrey, J.A.C. Secomb, T.W. (eds) Springer, Berlin).
Regeneration of Odorant Receptor Neurons
The olfactory epithelium and gustatory epithelium can be regenerated after injury. As
the cells in the epithelium die, they are normally replaced, and with an injury to the
olfactory nerve, the pace of renewal is accelerated. With the regeneration of the recep-
tor cells and depending on the number of the odorant receptors surviving, the specific
functions of any olfactory receptor neurons may be unaffected (Schwob 2002).
Dysfunction in the Olfactory System
If a person has a head cold, food will taste bland because of the inability to smell.
The loss of smell, anosmia, can also result from trauma or compression of the olfac-
tory nerves, from tumors in the floor of the anterior and middle cranial fossa, or
from tumors involving any portion of the frontal lobe overlying the olfactory sys-
tem. Viral infections may reach the olfactory cortex on the medial surface of the
temporal lobe through the olfactory system and produce viral encephalitis. Other
evidence suggests that one of the early changes in Alzheimer’s senile dementia is a
detectable drop-off in the sensitivity of the olfactory. Tumors or injury to either
uncus produces uncinate fits in which the patient has an olfactory hallucination,
with associated visual hallucinations and altered emotion and behavior. On rare
occasions, this includes violent behavior (see Mark and Ervin 1970).
Olfactory–Limbic Interactions
In these days of air pollution, one sometimes wishes we were free of olfactory
senses. However, the olfactory system is necessary for our survival as individuals
and as a species. For example, the aroma of food stimulates salivation and the desire
to eat; musky pheromones stimulate or enhance sexual arousal; unpleasant aromas
produce nausea, vomiting, and tearing; and the strong odor of smoke produces fear.
Vomeronasal Organ and Pheromones: The Accessory Olfactory System
The vomeronasal organ (of Jacobson) is found in the medial wall of the nasal septum
below the nasopalatine recess and is a blind pouch that connects to the surface through
16.2 Limbic System 483
an orifice. This organ is supplied by branches of the olfactory nerve and ophthalmic
branch of the trigeminal nerve and has an epithelium similar to that found in the
olfactory mucosa. Recent studies have demonstrated that this organ is sensitive to phero-
mones, messenger substances between individuals. These substances act like hormones;
however, they are not secreted into the blood but instead are secreted by one individual
of a species and recognized through chemoreception by another member of the same
species. Whether pheromones have any role in human biology is still controversial, but
the perfume industry believes these scents have a major role. The best-studied phero-
mones have been in the insect community with prime examples being the queen sub-
stance of bees and sexual attraction in butterflies (Wyatt, Tristram D. (2003). Pheromones
and Animal Behaviour: Communication by Smell and Taste. Cambridge: Cambridge
University Press; Savic I, Hedén-Blomqvist E, Berglund H. (2009). Pheromone signal
transduction in humans: What can be learned from olfactory loss. Hum Brain Map.
30(9):3057–3065; Steinberg et al. 1994, Dusenbery, David B. (2009). Living at Micro
Scale. Harvard University Press, Cambridge, MA). How this signaling mechanism is
used by the human species is still a subject of much lively discussion.
Emotional Brain. Since the initial observations of Kluver and Bucy (1937) and
Papez (1937), which localized emotions in the telencephalon, many other investiga-
tors have added information concerning the localization of behavior. We now know
that many cortical and subcortical regions are incorporated in the “emotional brain.”
Different investigators have coined different terms to succinctly describe the limbic
system, particularly the visceral, vital, or emotional brain. The term “visceral brain”
would seem appropriate since much of our emotional response is characterized by
specific responses in the viscera (Fulton 1953). On the other hand, the importance of
the emotional response for the self-preservation of the individual and the perpetua-
tion of the species has led other investigators to call this region the vital brain
(MacLean 1955). We can separate the entire central nervous system into a “somatic
brain,” which controls the external environment through the skeletal muscles, and a
“visceral brain,” which controls the internal environment through the control of car-
diac, smooth muscles, and glands. The term used most commonly by investigators
and the one used in this chapter and throughout the book is limbic lobe (limbus = mar-
gin) because the involved regions are located on the medial margin of the cerebrum
and surrounds the brain stem as it enters the diencephalon.. The regions in the limbic
system are divided into cortical and subcortical zones that are interconnected.
1. Reticular Formation of the Brain Stem and Spinal Cord. The spinal and cranial
nerve roots are the first-order neurons for sensory information to reach the somatic
and visceral brain. These peripheral nerves send much sensory information via
axon collaterals into the reticular formation of the spinal cord, medulla, pons, and
484 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Table 16.2 The subcortical and cortical nuclei of the limbic system
Subcortical regions
1. Reticular formation of the brain stem and spinal cord
Midbrain limbic nuclei (interpeduncular nucleus)
Paramedian nucleus − rostral portion of ventral tegmental area
Ventral half of the periaqueductal gray
2. Hypothalamus (preoptic, lateral, mammillary nuclei, longitudinal stria
3. Thalamic nuclei: midline, intralaminar, anterior, dorsomedial
4. Epithalamus
5. Septum
6. Nucleus accumbens
Cortical regions
1. Temporal lobe: amygdala, hippocampal formation, parahippocampal cortex, occipitotemporal
gyrus, inferior frontal gyrus
2. Frontal lobe: prefrontal association areas, supracallosal gyrus and subcallosal gyrus, orbital
frontal cortex
3. Cingulate gyrus and cingulate isthmus
midbrain. The reticular formation is organized longitudinally, with the lateral area
being the receptor zone and the medial area being the effector. In the medial zone
are the ascending and descending multisynaptic fiber tracts of the reticular forma-
tion: the central tegmental tract. There are important limbic nuclear groupings in
the reticular formation: (1) the mesencephalic portion of the reticular formation
seems to be especially important, since this zone provides a direct reciprocal path-
way to the hypothalamus, thalamus, and septum, and (2) the locus coeruleus of the
upper pons and the raphe of the midbrain provide ascending serotoninergic and
adrenergic systems onto the diencephalon and telencephalon.
2. Interpeduncular Nucleus. The interpeduncular nucleus is in the posterior per-
forated substance on the anterior surface of the midbrain in the interpeduncular
fossa extending from the posterior end of the mammillary body to the anterior
end of the pons. It receives fibers from the habenular nuclei (habenulopeduncular
tract) and has reciprocal connections with the hypothalamus and the midbrain
limbic region. Amygdaloid information reaches this region through connections
via the stria terminalis to the septum and then from the septum to the interpedun-
cular nucleus.
3 . Hypothalamus (Chap. 9). The hypothalamus is the highest subcortical center of
the visceral brain. The basic function of this region is to maintain internal homeo-
stasis (body temperature, appetite, water balance, and pituitary functions) and to
establish emotional content. It is a most potent subcortical center due to its con-
trol of the autonomic nervous system.
4 . Thalamus (Chap. 8). The anterior, dorsomedial, midline, and intralaminar dor-
sal thalamic nuclei receive input from the ascending nociceptive pathways,
hypothalamus, and reticular system (especially the midbrain reticular formation)
and project onto the cingulate and frontal association cortex.
16.2 Limbic System 485
5. Epithalamus (Chap. 9). The habenular nuclei of the epithalamus give origin to
the habenulopeduncular tract, which projects to the midbrain tegmentum and
interpeduncular nucleus.
6. Septum. The septum forms the medial wall of the frontal horn of the lateral
ventricle. The septum consists of two parts: the septum pellucidum containing
the septal nuclei (dorsal, lateral, and medial) and the caudal velum interpositum.
The septum pellucidum is rostral to the interventricular foramen. The septum
pellucidum consists of glial membrane and some pia-arachnoid (velum inter-
positum). This paired glial membrane, along with the fornix, separates the bod-
ies of the lateral ventricles. The lower part of the septum pellucidum (septal area)
consists of many neurons and glia.
The septum receives strong input from the amygdala via the stria terminalis and
hypothalamus. The septum connects with the:
1. Hypothalamus, interpeduncular nucleus, and the midbrain tegmentum via the
medial forebrain bundle
2. Habenula via the stria medullaris
3. Basolateral amygdaloid nuclei through the diagonal band
Destruction of the septum in cats causes docile animals to become fearful or
aggressive but only for a short time. Complete destruction of the septum may pro-
duce coma, probably because it destroys the strong connections between the septum
and hypothalamus.
Nucleus Accumbens (see Chap. 10). This nucleus lies below the caudate and
receives fibers from the amygdala via the ventral amygdalofugal pathway and from
the basal ganglia and thus provides a major link between the limbic and basal nuclei.
This nucleus has a high content of acetylcholine. In Alzheimer’s disease, there is a
significant loss of cholinergic neurons in this nucleus.
1. Temporal lobe
(a) Amygdala
(b) Hippocampal formation
(c) Parahippocampal cortex
(d) Occipitotemporal gyrus
2. Frontal lobe. Prefrontal association areas. Orbitofrontal cortex. Supracallosal
gyrus and subcallosal gyrus
3. Cingulate gyrus and cingulate isthmus
1. Temporal Lobe Functions. (Scoville WB, Milner B 1957)
Henry Gustav Molaison, known to the world as Patient HM, has been called the
most important patient in the history of brain science. He was studied by a team of
486 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
neuroscientists for more than 50 years—from the age of 27 to his death aged 82—yet
he could not remember their names or their experiments. Henry Molaison suffered
from profound amnesia, and his unique condition helped neuroscientists to under-
stand more about how our memory functions.
As a child, Henry suffered from epilepsy, which may have been caused by a head
injury he sustained when he was 7 years old. At first his seizures were minor, but
from the age of 16, they became increasingly severe. By the time Henry was 27, he
was unable to work.
Undergoing Surgery
In 1953 Henry was referred to neurosurgeon Dr. William Beecher Scoville at
Hartford Hospital, Connecticut, USA. Scoville suggested surgery to remove the part
of Henry’s brain that was causing his seizures. Scoville contacted researchers at
McGill University in Montreal, who had reported on two similar cases of amnesia in
patients who had undergone temporal lobe surgery. Dr. Brenda Milner, a psycholo-
gist from McGill, traveled to Hartford to visit Molaison and began her research into
his amnesia, his remaining memory, and his brain. This was major and experimental
surgery, but Henry was so incapacitated by his epilepsy that he agreed to undergo the
procedure. Dr. Scoville performed a bilateral medial temporal lobe resection. This
involved removing a portion of Henry’s temporal lobe, including parts of the hip-
pocampus and amygdala, from both sides of the brain (Fig. 16.6). Resection is still
used today to treat severe epilepsy. It is a highly precise surgical procedure, informed
by advanced brain imaging and a detailed knowledge of the brain. Scoville had none
of these tools at his disposal, and he could not foresee the effects of his surgery.
When Patient HM woke from his surgery, he was suffering from severe amnesia.
Henry could remember much of his childhood: he knew his name and family history
and could remember the stock market crash of 1929. However, he struggled to
remember events from the few years leading up to the surgery and could not remem-
ber some things that had happened up to 11 years before. Henry also had severe
anterograde amnesia. This means that he had lost the ability to form new memories.
Later, he would describe his condition as being “like waking from a dream … every
day is alone in itself.”
Anatomical Correlates. From an anatomical standpoint, compared to other lobes
of the brain, the temporal lobe is a complex structure. It contains four diverse corti-
cal regions:
1. Neocortex—six layers: superior, middle, and inferior temporal gyri (see Chap. 10).
2 . Paleocortex—three layers: the olfactory cortex, hippocampal formation, and
subiculum. (The most primitive cortex is the paleocortex (old) of the olfactory
bulb.) The hippocampus is phylogenetically the older part of the cerebral cortex
termed allocortex (different from six-layered cortex) and consists of three layers:
polymorphic, pyramidal, and molecular.
3. Mesocortex—a transitional type of six-layered cortex (transitional between neo-
cortex and allocortex): entorhinal/parahippocampal gyrus (the large posterior
segment of the pyriform region), presubiculum, and parasubiculum.
4. Cortical nucleus—the amygdala.
16.2 Limbic System 487
(a) Amygdala (Figs. 16.3c uncus and 16.4). The amygdala is uniquely located to
provide the intersection between the primary motivational drives of the hypothalamus
and septum and the associative learning that occurs at the hippocampal and neocorti-
cal levels. The amygdala (Fig. 16.4) consists of three main groupings of nuclei: corti-
comedial, basolateral, and central. In addition to these principal nuclei, there are
extratemporal neurons including the nucleus of the stria terminalis and the sublenticu-
lar substantia innominata. The amygdala receives extensive projections from many
cortical areas and in turn sends projections to these areas. In primates as one expects
in comparison to rodents, there has been a significant increase in the projections from
and to neocortex (isocortex) as opposed to allocortex and mesocortex.
These projections originate from:
( 1) The multimodality sensory areas
(2) Tertiary unimodal sensory association areas
(3) Visual association areas which are particularly prominent in the primates
(4) First- and second-order central sensory neurons of the olfactory system
From the standpoint of the role of the amygdala in emotion and instinctive
behavior, there are important connections with the basal forebrain, medial thalamus
(medial dorsal nucleus), hypothalamus (preoptic, anterior, ventromedial, and lateral
areas), and tegmentum of the midbrain, pons, and medulla (to various nuclei con-
cerned with visceral function such as chewing and licking and the motor compo-
nents of emotional expression). The more specific connections of the amygdaloid
nuclei are listed below:
(1) Limbic Nuclei. The central and basolateral nuclear grouping is associated with
the limbic brain and has connections with the parahippocampal cortex, temporal
pole, frontal lobe, orbital frontal gyri, cingulated lobe, dorsomedial nucleus,
catecholamine containing nuclei of the reticular formation, and substantia nigra.
(2) The ventral amygdalofugal pathway projects from the central nucleus to the brain
stem; to the septum; to the preoptic, lateral, and ventral hypothalamus; and—in
the dorsal thalamus—to the dorsomedial, intralaminar, and midline thalamus.
Stimulation of the Amygdaloid Region. In monkeys, cats, and rats, stimulation
produces aggressive behavior. The stimulated cats have a sympathetic response of
dilated pupils, increased heartbeat, extension of claws, piloerection, and attack
behavior. When the stimulus stops, they become friendly. Animals will even fight
when the amygdala is stimulated and stop fighting if the stimulus is off. Eating,
sniffing, licking, biting, chewing, and gagging may also be stimulated here. In con-
trast studies in the cat indicate that stimulation of the prefrontal areas will prevent
aggressive behavior. In humans, stimulation of the amygdale produces feelings of
fear or anger (Cendes et al. 1994). A role in sexual behavior has also been postu-
lated, although this may be more prominent in the female.
Lesions/Ablation of Amygdala. In the studies of Amaral, selective bilateral lesions
of the amygdala in the adult monkey significantly decreased the fear response to
inanimate objects such as an artificial toy snake. This object was now picked up,
whereas previously, such an object had triggered intense fear responses. The social
Fig. 16.3 (a) Demonstration of the limbic areas on the medial surface of the cerebrum and then
the removing the brains stem 16.3b to demonstrate the basal temporal regions and then in 16.3c
dissecting out the diencephalon. From S. Jacobson, and E M Marcus, Neuroanatomy for the
Neuroscientist, 2nd Ed, Springer 2011. (b) Medial surface with brain stem and cerebellum now
removed demonstrating the basal temporal lobe with uncus and temporal pole. (c) Medial surface
of the cerebrum with the thalamus removed to demonstrate relationship between the fornix and
hippocampus
16.2 Limbic System 489
Many of these findings are also seen in the Kluver–Bucy syndrome with its
removal of the hippocampus and amygdala.
Amygdala and Autism. Brothers has proposed that the amygdala is part of the
circuitry that underlies social cognition. Bauman and Kemper noted neuropatho-
logical findings in the postmortem examination of brains from autistic patients.
Amaral and colleagues have reported in monkeys with damage to the amygdala the
role of the amygdala in the detection of threats and organizing an appropriate behav-
ioral response—fear. And they have postulated that lesions in the amygdala may
produce abnormal fears and increased anxiety rather than abnormal social
behavior.
(b) Hippocampal Formation (Figs. 16.7)
This region includes the hippocampus, dentate gyrus, parahippocampus, and
amygdala.
(2) Hippocampal Sectors. The hippocampus is divided into sectors (referred to
as fields) based on cytoarchitectural differences (Fig. 16.7) CA1–CA4 (or fields of
Rose h1–h5). (Note that an older term for the hippocampus is Ammon’s {the ram}
horn, thus Cornu Ammonis = CA.) CA4, the end folium or end blade merges with
the hilus of the dentate gyrus. CA1, the sector closest to the subiculum, is referred
to as the Sommer’s sector. This sector is most severely affected by cell loss follow-
ing hypoglycemia, anoxia, and status epilepticus (Fig. 16.7). However, this selective
vulnerability may also involve CA3 and CA4 with relative sparing of CA2 and the
dentate granule cells. The subsequent gliosis (mesial sclerosis) of the hippocampus
is the pathology found at surgery or autopsy in 75% of cases of complex partial
seizures arising in the hippocampus. The hippocampal regions are interconnected
by a commissure, the hippocampal commissure. In the primate, the dorsal commis-
sure originates in the entorhinal cortex and presubiculum. The ventral commissure
originates in the CA3 sector and the dentate hilus primarily in their more rostral
areas, e.g., in relation to the uncus.
Fig. 16.7 The sectors or fields of the hippocampus. The dentate gyrus, subiculum, and related
structures are demonstrated. Nissl stain. From E, M, Marcus, S Jacobson, Integrated Neuroscience,
Kluwer Academic Publisher 2003
(3) Polymorphic cell. Also referred to as the hilus, this layer is continuous with
CA4 of hippocampus. The pyramidal and granule cell neurons are excitatory
utilizing glutamine as the transmitter. In addition there are inhibitory interneu-
rons (GABAergic), basket cells, in the polymorphic layer of both the hippocam-
pus and dentate gyrus. There are also mossy cells in the polymorph layer
probably excitatory interneurons. There are also scattered interneurons in the
molecular layers.
(2) Anatomy. The dentate gyrus fits inside the hippocampus and, like the hip-
pocampus, has three layers: molecular, granular, and polymorphic. The fibers of the
dentate gyrus are confined to the hippocampal formation, while the hippocampal
fibers leave the hippocampal formation through the fornix and project either to the
septum or to the mammillary bodies and mesencephalic tegmentum. The cortex
adjacent to the hippocampus changes from three layers to six layers and is classified
as transitional mesocortex and includes the parahippocampal gyrus (medial to the
collateral sulcus), including entorhinal cortex. The pyriform lobe consists of the
lateral olfactory stria, the uncus, and the anterior part of the parahippocampal gyrus.
(e) Entorhinal Region/Parahippocampal (Fig. 16.8): The entorhinal/parahip-
pocampal gyrus forms the large posterior segment of the piriform region. This is
Brodmann’s area 28 and constitutes the bulk of the parahippocampal gyrus. This
area has extensive interconnection with the higher association cortex throughout the
neocortex and also receives olfactory information from the olfactory stria. This is
the major pathway for relating neocortex to the limbic cortex of the hippocampus.
The connections of the hippocampal formation are documented in Fig. 16.8 and
summarized in Table 16.3.
Fig. 16.8 Sagittal section. Temporal lobe with amygdala and hippocampus. Myelin stain (From E,
M, Marcus and S. Jacobson, Integrated Neuroscience, Kluwer Academic Publisher 2003)
494 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Fig. 16.9 (A) The perforant pathway (provides connections from the entorhinal cortex to all fields
of the hippocampus including the dentate gyrus and CA fields including CA (1). Modified from
Carpenter MB Core Text of Neuroanatomy, Baltimore: William and Wilkins. (B) MRI sagittal sec-
tion showing medial surface of the cerebrum demonstrating the limbic structures which surround
the brain stem and are on the medial surface of the cerebrum. Portions of Papez circuit are shown
including—fornix, anterior nuclei, mammillary bodies, and cingulate cortex
16.3 Principal Pathways of the Limbic System 497
A. Fornix (Fig. 16.1). Note that the fornix is the efferent pathway from the
hippocampus and subiculum and is connected to the hypothalamus, septum, and
midbrain. The hippocampal formation, including the subiculum and presubiculum,
together with the entorhinal cortex (area 28) and perirhinal cortex (area 35) contrib-
utes to the fornix in a topographical manner. In contrast, the lateral perirhinal cortex
(area 36) and parahippocampal cortical areas TF and TH only contained a handful
of cells labeled via the fornix.
This tract takes a rather circuitous pathway to reach the hypothalamus. The for-
nix originates from the medial surface of the temporal lobe and runs in the medial
wall of the inferior horn of the lateral ventricle, passing onto the undersurface of the
corpus callosum at the junction of the inferior horn and body of the ventricles and
running in the medial wall of the body of the lateral ventricle suspended from the
corpus callosum. The fornix finally enters the substance of the hypothalamus at the
level of the interventricular foramen.
Origin of Fornix. The fibers in the fornix originate primarily from the entorhinal
cortex as follows:
(1) The medial fibers in the fornix originate from cells in the caudal half of the
subiculum, from the lamina principalis interna of the caudal half of the presu-
biculum, and from the perirhinal cortex (area 35).
(2) The intermediate portion of the fornix (i.e., that part midway between the mid-
line and most lateral parts of the fornix) originates from cells in the rostral half
of the subiculum and presubiculum, the anterior presubiculum (only from the
lamina principalis externa), the caudal presubiculum (primarily from the lamina
principalis interna), the rostral half of CA3, the entorhinal/parahippocampal
cortex (EC, primarily 28I and 28M), and the perirhinal cortex (area 35).
(3) The lateral parts of the fornix arise from the rostral EC (28 L only) and the most
rostral portion of CA3.
Subcortically, the medial septum, nucleus of the diagonal band, supramammil-
lary nucleus, lateral hypothalamus, dorsal raphe nucleus, and thalamic nucleus
reuniens all send projections through the fornix, thus forming a major source of
input to the hippocampus and adjacent parahippocampal region (Saunders RC and
Aggleton JP, Origin and topography of fibers contributing to the fornix in macaque
monkeys. 2007, Hippocampus 2007;17(5):396–411).
Different portions of the fornix have specific names:
(1) Portio fimbria (fringe), found on the medial surface of the hippocampus and
consists of fibers from the fornix and hippocampal commissure.
(2) Portio alveus (canal), fibers covering ventricular surface of the hippocampus.
(3) Portio tenia (flat band), connecting the hippocampus to the corpus callosum.
(4) Portio corpus, located underneath the corpus callosum and enters the hypotha-
lamus.
(5) Portio columnaris, found in the substance of the hypothalamus.
(6) Precommissural portion (in front of the anterior commissure) that enters the
septum (from the hippocampus).
498 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
3. Stria Terminalis. The pathway of the stria terminalis (the efferent fiber tract
of the amygdala) parallels the fornix, but it is found adjacent to the body and
tail of the caudate nucleus on its medial surface (refer to Chaps. 23 and 16)
The stria terminalis interconnects the medial corticoamygdaloid nuclei, as
well as connecting the amygdale to the hypothalamus and septum. There is
also a strong termination in the bed nucleus of the stria terminalis, which is
found above the anterior commissure and lateral to the column of the fornix.
4. Ventral Amygdalofugal Pathway. This fiber pathway originates primarily
from the basolateral amygdaloid nuclei and to a lesser degree from the olfac-
tory cortex, spreads beneath the lentiform nuclei, and enters the lateral hypo-
thalamus and preoptic region, the septum, and the diagonal band nucleus.
Some of these fibers bypass the hypothalamus and terminate on the magnocel-
lular portions of the dorsomedial thalamic nuclei.
5. Cingulum. This fiber bundle is found on the medial surface of the hemisphere
and interconnects primarily the medial cortical limbic areas (cingulate corti-
cal regions), especially the EC/parahippocampal formation.
6. The Intracortical Association Fiber System. The superior and inferior longitu-
dinal fasciculus and uncinate fasciculus. The limbic regions on the lateral surface
of the hemisphere have strong interconnections with polysensory and third-order
sensory cortical regions throughout the cerebral cortex through this system.
7. Limbic System and the Corticospinal and Corticobulbar Pathway. The bulk
of the pyramidal pathway originates in the motor-sensory strip. However, most
movements begin with a “thought” in the frontal association areas. A possible
example of release of the bulbar areas for emotional expression from frontal lobe
control is seen in pseudobulbar palsy. Such patients exhibit inappropriate response
to situations because the interrupted corticonuclear/corticobulbar pathway no
longer dampens the strong descending autonomic/limbic input to the brain stem
cranial nuclei. The resultant inappropriate behavior is termed emotional lability.
A sad story may trigger excessive crying, a funny story excessive laughter.
A. Area 41, Fig. 16.10, is the primary auditory cortex and is located on the more
anterior of the transverse gyri of Heschl.
The auditory cortex is a primary special sensory region and has a pronounced
layer 4 (granular or koniocortex) similar to but considerably thicker than areas 17
and 3. Area 41 receives the main projection from the medial geniculate nucleus..
Our understanding of the tonal organization in this region comes from studies in
the monkey and chimpanzee where the lowest frequencies project to the more
rostral areas. Some investigators limit the term “Heschl’s gyrus” to the more
anterior of the transverse gyri and localize the primary auditory cortex to the
posterior aspects of that gyrus (Liegeois-Chauvel et al. 1991). The remaining
neocortical areas of the t emporal lobe have a well-defined six cortical layers and
are classified as homotypical.
500 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Table 16.4 Correlation between symptoms from temporal lobe seizures and stimulation with
anatomical localization
Symptoms Anatomical region
Autonomic phenomena Amygdala. Less often cingulated phenomena
gyrus or orbital frontal
Fear, less often anger or other emotion Amygdala
Crude auditory sensation, tinnitus Heschl’s transverse gyrus (primary auditory
projection)
Vestibular sensations, dizziness vertigo Superior temporal gyrus dizziness/vertigo
posterior to auditory cortex
Arrest of speech Wernicke’s area and posterior speech area
(posterior temporal/parietal (angular
supramarginal)-dominant hemisphere
Olfactory hallucinations Uncinate epilepsy of Jackson. Olfactory cortex of
the uncus (termination of lateral olfactory stria)
Experimental phenomena: complex Lateral temporal cortex: primarily superior
illusions such as déjà vu, jamais vu. Other temporal gyrus. Controversial. However, ictal
illusions of recognition, visual and auditory illusions are abolished by lesions limited to lateral
hallucinations (often of post experience) temporal
Automatisms repetitive simple or complex Primary or secondary bilateral involvement of
often stereotyped motor acts, most amygdale, hippocampus. Invariably accompanied
commonly involving mouth, lips limbs, etc. by confusion and amnesia for the acts
Speech may be involved
Defects in memory recording followed by Hippocampus
amnesia for the event
Déjà vu = sensation of familiarity or strangeness, jamais vu = perception is dreamlike partial epi-
lepsy with temporal structures. In general, as we have indicated, there is mixed symptomatology
during partial seizures of temporal lobe origin
502 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
(c) Visual Defects. Unilateral lesions of the temporal lobe that involve the
subcortical white matter often produce damage to the geniculocalcarine radi-
ations. Since the most inferior fibers of the radiation that swing forward
around the temporal horn (representing the inferior parts of the retina and
referred to as “Meyer’s loop”) are often the first to be involved, the initial
field defect may be a contralateral superior field quadrantanopsia.
(d) Kluver–Bucy Syndrome. This syndrome results from bilateral ablation of
the temporal pole, amygdaloid nuclei, and hippocampus in the monkey
(Klüver and Bucy 1937). The animals could see and find objects, but they
could not identify objects (visual agnosia). The animal showed marked defi-
cits in visual discrimination, particularly in regard to visual stimuli related to
various motivations. They also had a release of very strong oral automatisms
and compulsively placed objects in their mouths, which, if not edible, were
dropped. They had a tendency to mouth and touch all visible objects and
manifested indiscriminate sexual practice. They willingly ate food not nor-
mally a part of their diet (such as corn beef sandwiches). They showed a lack
of response to aversive stimuli and had no recollection or judgment. The
animals also lost their fear (release phenomenon) and, in the case of wild
monkeys, became tame and docile creatures. They had a marked absence of
the fight-or-flight response and also lost fears of unknown objects or objects
that previously had frightened them. (See amygdale above.) The problems in
visual discrimination may reflect a disconnection of the visual association
areas from the amygdala/hippocampal areas.
(e) Memory. Bilateral damage to the hippocampus produces a marked impair-
ment of the ability to form new associations, an inability to establish new
memories at a time when remote memory is well preserved.
(f) Unilateral Effects on Memory. Patients with resection of the left temporal
lobe may lose the ability to retain verbally related material but gain the abil-
ity to retain visually related material relevant to the right hemisphere. The
reverse is true for right temporal lobectomy patients.
(g) Psychiatric Disturbances. Waxman and Geschwind (1975) have described
an interictal personality disorder characterized by hyposexuality, hyper reli-
giosity, hypergraphia, and a so-called stickiness or viscosity in interper-
sonal relationships. In some patients, a psychosis may be apparent in
periods between seizures (the interictal period) that is often most severe
during periods when the seizure disorder is well under control. In other
patients, a transient psychosis may be related to the actual seizure discharge
or the postictal period. There is controversy regarding this issue.
(h) Aggressive Behavior. Aggressive behavior and episodic dyscontrol may be
related to dysfunction of the amygdala or to damage to prefrontal areas,
which inhibit the amygdala. This remains an area of considerable contro-
versy (Mark and Ervin 1970; Geschwind 1983; Ferguson et al. 1986).
(i) Complex partial seizures as discussed above may follow mesial temporal
sclerosis. The following case history illustrates many of the points just dis-
cussed regarding seizures of temporal lobe origin.
16.4 Role of the Temporal Lobe in Learning and Memory 503
found a necrotic glioblastoma involving the superior temporal gyrus and the deeper
temporal and extending superficially under the Sylvian fissure to involve the adjacent
posterior portion of the inferior frontal gyrus. A temporal lobectomy was performed
(from the anterior temporal pole posteriorly for a distance of 6 cm).
The following case also had seizures emanating from the temporal lobe.
Case History 16.2. This 17-year-old right-handed male, at age 4 years, began to
have “staring spells and bizarre behavior.” Some episodes had been preceded by the
“sound of a musical rhythm.” Seizures were controlled for 10 years and then
recurred occurring several times per day.
Neurological examination: Observed 3-min seizure—The seizure began with
loss of contact and a stare and then automatisms of the hands. He stood up, walked
around the room, went to the physician’s desk, and attempted to pull open a nonex-
istent middle drawer. He answered questions vaguely with one or two word answers.
Confusion was present for 1–2 min after the end of the episode.
Cranial nerves—A left central facial weakness was present.
Clinical diagnosis: The seizures beginning with the musical sound might be classi-
fied as simple partial with secondary complex partial.
Laboratory data: EEG—Intermittent focal spike discharge anterior-middle
temporal area. MRI at the Yale Epilepsy Center was consistent with a tumor in the
right anterior temporal lobe.
Subsequent course: Dr. Dennis Spencer at the Yale Epilepsy Center performed
a temporal lobectomy. This demonstrated a cystic glial tumor. Cerebral cortex also
demonstrated abnormal lamination and dysplastic features. Seizures were fully con-
trolled over the next 3 years.
Case History 16.3, Fig. 16.11. This 47-year-old ambidextrous male experienced his
first seizure 1 month prior to admission. He felt light-headed and warm. Then he
was observed to walk 100 feet down a hallway, appearing “dazed” and not recogniz-
ing people. He fell to the floor, with a loss of consciousness, bit his tongue, and was
confused afterward for several minutes.
Neurological examination: At 2, 16, and 48 h after the episode, a persistent
right Babinski sign and slight right hyperreflexia were present.
Clinical diagnosis: Complex partial seizures. In view of the age of onset and persis-
tent focal signs, a brain tumor should be suspected as the etiology.
Laboratory diagnosis: Sleep-deprived EEG—normal. CT and MRI scans dem-
onstrated an extensive infiltrating tumor of the left temporal lobe most likely a glio-
blastoma (Fig. 16.11).
Subsequent course: Despite anticonvulsant therapy (phenytoin), additional epi-
sodes occurred over the next month—loss of train of thought while talking and sev-
eral minutes of loss of memory. A subtotal resection by Dr. Bernard Stone (St. Vincent
Hospital) demonstrated a grade III–IV astrocytoma (glioblastoma). Despite radio-
therapy and chemotherapy, the disease pursued a relentless course producing early
and severe disability prior to death, approximately 1 year after onset of symptoms.
2. Hippocampal System and Memory
Gatekeeper of information flow into the hippocampus–entorhinal/parahippo-
campal gyrus (Fig. 16.7 and 16.9).
16.4 Role of the Temporal Lobe in Learning and Memory 505
Input arises from close-by regions in the medial temporal lobe [entorhinal cortex
(EC) the “gatekeeper” of information flow to and from the hippocampus]. Sensory
input to the EC projects to the dentate gyrus (DG), the CA3 and CA1 fields of the
hippocampus, and the subiculum (Sub) via the perforant pathway. The dentate gyrus
projects to the CA3 field of the hippocampus via Mossy fibers. CA3 neurons project
to the CA1 field of the hippocampus, which in turn projects back to the subiculum.
The subiculum feeds back to the EC. In the EC, superficial and deep layers are
arranged to produce a recurrent loop for incoming sensory information. Some of
this processed information is transferred to the hippocampus via the perforant path-
ways. In turn, after processing in the, output influences information in the entorhinal
reverberating circuit, which in turn repetitively activates the hippocampal formation
or is transmitted to other regions of the cerebral cortex (pre, presubiculum; para,
parasubiculum; based on Andersen P. The Hippocampus, Oxford; New York:
Oxford University Press 2007, Fig. 3.1 p. 38 and Iijima T, Witter MP, Ichikawa M,
Tominaga T, Kajiwara R, Matsumoto G. Entorhinal–hippocampal interactions
revealed by real-time imaging. Science. 1996 May 24;272(5265):1176–1179-Stages
of Human Memory: Declarative Learning).
There are essentially three stages of memory:
(a) Immediate or short-term working memory. This happens in a matter of <10 s
with a capacity of about 12 items. It is best exemplified in simple digit repetition
or the immediate repetition of three or five objects. Monkeys and infants with
prefrontal lesions are unable to consistently perform the task. The neural sub-
strate involves reception in primary sensory area and relays to the adjacent sen-
sory association areas 18, 22, and 5/7, then relays to prefrontal area for very
short-term storage, and then relays to motor association cortex and then to motor
cortex so one can respond to the questioner.
506 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
(b) Long-term memory, labile stage. This stage is transcription and transduction.
It has a duration of about 20–180 min. RNA and protein synthesis are involved
in this stage. And it occurs in the temporal lobe in the entorhinal, parahippocampal
gyrus, in the hippocampus, and in the thalamus in the anterior and dorsomedial
nuclei.
(c) Long-term memory stage of remote memory. This stage is not discretely
localized rather it represents a diffuse storage throughout the cerebral cortex-
working memory, recognition memory, perceptual memory, and semantic.
Although not discretely localized, it must be remembered that remote memories
can be triggered by stimulation of the lateral temporal lobe.
The studies of Milner (1972) have shown that bilateral removal or damage of the
hippocampus produces great.
Difficulty in learning new information is a condition called anterograde amnesia.
The excitatory amino acids, l-glutamate and l-aspartate, are important in learning
and memory through the mechanism of long-term potentiation. Long-term potentia-
tion is a long-lasting facilitation after repeated activation of excitatory amino acid
pathways and is most pronounced in the hippocampus and may be related to the
initiation of the memory trace The amygdala and its connections are associated with
the conditioning of the emotional response of fear (refer to review of Le Doux 2000).
(i) Long-Term Declarative Memory and Non-declarative Memory or
Procedural Memory
- Long-term declarative memory is sometimes referred to as explicit memory.
Declarative memory refers to remembering personal events, cultural history.
It refers to memories which can be consciously recalled such as facts and
events. Declarative memory can be divided into two categories: episodic
memory which stores specific personal experiences and semantic memory
which stores factual information.
- Non-declarative or procedural memory refers to unconscious memories
such as acquired skills (e.g., learning to hit a ball with a bat).
(e) Overview of Location of Memory Areas in the Cerebral Cortex (Fig. 16.12)
I. Seat of conscious memory is in the hippocampus with the inflow from auditory,
limbic, and visual streams. Conscious memory includes semantic and episodic
memory (and can also be classified according to working and long-term mem-
ory processes). The hippocampus is located close to the amygdala, which mod-
ulates the influence of emotion and fear on episodic memory. The hippocampus
communicates with widespread brain regions in support of episodic memory
function.
II. Working memory function is located to a large extent in the prefrontal cortex.
III. Perceptual memories are formed in regions close to primary sensory cortices
but are unconscious memories.
IV. Episodic memory involves the parietal cortex, where maximal surface-recorded
ERP effects occur during recognition.
Working memory is used to describe the process where one “holds on” to small
bits of recently learned information prefrontal and parietal.
16.4 Role of the Temporal Lobe in Learning and Memory 507
Fig. 16.12 Location of memory areas in the cerebrum (Suppressing the Mind, Anesthetic
Modulation of Memory and Consciousness. Veselis, Robert A, Pryor, Kane O. Chapter 11: Propofol
Amnesia—What is Going on in the Brain? Series: Contemporary Clinical Neuroscience Hudetz,
Anthony; Pearce, Robert (Eds.) 1st Edition, 2010, A Humana Press book (modified from Andersen
P. The Hippocampus book. Oxford; New York: Oxford University Press 2007, Fig. 3.1 p. 38 and
Iijima T, Witter MP, Ichikawa M, Tominaga T, Kajiwara R, Matsumoto G. Entorhinal–hippocampal
interactions revealed by real-time imaging. Science. 1996 May 24;272{5265}:1176–1179)
both to recent and remote events. Examples of episodic memory would be the abil-
ity to recount what you did today and where you were when you heard shocking
news hippocampus and adjacent medial temporal.
Remote memory is a memory of events that occurred in the distant past. After
information has been processed in the hippocampus, it is sent out throughout the
cerebral cortex. Internal workings of the hippocampus (exploded view).
Localization of Regions in the Brain that Subserves Memory (Fig. 16.13)
1. Effects of Lesions in the Thalamus on Memory. Graff-Radford et al. (1990)
concluded that small infarcts strategically located so as to interfere both with the
mammillothalamic tract (hippocampal-related neural structures) and ventral
amygdalofugal pathway (which is adjacent to the mammillothalamic tract) pro-
duced diencephalic amnesia. Damage to the anterior thalamic area, the mammil-
lary bodies, and their connections impairs the neural systems related to the
hippocampus. Damage to the dorsomedial thalamic nuclei and their connections
impairs systems related to the amygdala and frontal systems. Isolated lesions of
one system alone do not result in amnesia; combined lesions are required. In a
recent MRI study by Tatemichi et al. (1992) of paramedian thalamopeduncular
infarction, persistent amnesia was observed only when the dominant anterior
nucleus or mammillothalamic tract was damaged.
2. Effects of Lesions in the Fornix on Memory. Lesions here may also be associ-
ated with significant problems in memory recording. Such damage is likely to
occur with colloid cysts or with the surgical procedure necessary to remove this
potentially life-threatening nonmalignant tumor. The effects are most prominent
if bilateral but may also occur with unilateral left-sided damage. Recall that the
Fig. 16.13 Cortical atrophy as found in presenile and senile dementia of Alzheimer’s type. There
is widening of sulci and narrowing of the gyri particularly in frontal and temporal areas
16.4 Role of the Temporal Lobe in Learning and Memory 509
fornix is the major outflow pathway from the hippocampus. Defects in recent
memory have also been reported in tumors involving the posterior or anterior
portion of the corpus callosum. In some of the anterior corpus callosum tumors,
infiltration of both frontal areas has occurred.
3 . Effects of Lesions in the Cerebrum on Recent Memory: The Amnestic
Confabulatory Syndrome; Wernicke–Korsakoff Encephalopathy
Case History 16.4. Patient of Dr. John Sullivan and Dr. John Hills: This 62-year-
old, white, right-handed male had been a known heavy alcoholic spree drinker for
many years. The patient would drink large quantities of wine for 6–8 weeks at a
time. Two years previously, the patient had been admitted to the Boston City
Hospital because of delirium tremens (tremor and visual hallucinations). Two
months prior to admission shortly following the death of a brother-in-law, the patient
began his most recent drinking spree. He unaccountably found himself in Florida,
not knowing where he was and why he was there. Apparently, he had drifted aim-
lessly for 5 weeks with no definite food intake for a month. The patient was brought
back by his family and hospitalized at his local community hospital with diplopia,
ataxia, and marked impairment of memory. The patient had complaints of numbness
of his fingertips and unsteadiness of gait. The patient was shortly thereafter referred
to the Neurology Service.
General physical examination: The liver was enlarged with the edge palpated
approximately 2–1/2 finger breadths below the costal margin.
Neurological Examination
1. Mental Status: The patient was markedly disoriented for time and place. At times,
the patient thought that he was in New Jersey; at other times, he stated correctly that he
was in Boston. The patient, with suggestion, would recall his apparent travels that day
to various other locations within and outside Boston (he was actually in the hospital).
Confabulation was also evident when it was suggested that he had recently seen various
fictitious persons. The patient was unable to state his age. At times, the patient often
indicated to visitors that his mother and father were still alive, though both parents had
been dead for over 20 years. He appeared to have little insight for his disorientation in
time. He had no insight as to his condition or for the reason for his hospitalization.
The patient could name various objects correctly when these were presented to
him, and yet he was unable to retain any memory of which objects had been pre-
sented to him 5 min previously. The patient was able to provide his birth date cor-
rectly. But he could not give his address or telephone number or select the President
of the United States, on a multiple-choice test. The patient was able to do 2 and 3
figure additions and multiplications without difficulty. He was able to do the initial
subtractions in the serial 7 test but then lost track of the number to be subtracted.
2. Cranial Nerves: There was horizontal diplopia on right lateral gaze. The minor
degree of separation of images, however, did not allow precise identification of the
muscle involved. A minor weakness of the right lateral rectus was suspected.
Horizontal nystagmus was present on lateral gaze, bilaterally, and vertical nystag-
mus on vertical gaze.
3. Motor System: Strength was intact except for a minor degree of weakness in
the distal portions of the lower extremities evident on ankle dorsiflexion and toe
510 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
dorsiflexion. The patient walked on a narrow base with eyes open and showed no
evidence of an ataxia of gait. On a narrow base with eyes closed, the patient had a
positive Romberg test.
4. Reflexes: Patellar and Achilles deep tendon reflexes were absent (0) even with
reinforcement.
5. Sensory System: Pain and touch were decreased in the lower extremities below
the mid-calf. Vibratory sensation was absent at the toes and decreased over the tibia
to a marked degree and to a lesser degree over the knees. There was, to a lesser
extent, a decrease in the upper extremities at the fingertips and wrists. Position sense
was decreased at fingers and toes.
Clinical diagnosis: Wernicke’s encephalopathy plus nutritional polyneuro-pathy.
Laboratory data: EEG was normal.
Hospital course: The patient was treated with thiamine, 50 mgs daily. There was
a significant improvement in extraocular functions. There was no significant change
in his mental condition or peripheral neuropathy. Evaluation 3 months later indi-
cated persistent disorientation for time and place and severe selective deficits in
memory (delayed recall was still grossly defective).
4. Progressive Dementing Process in the Cerebrum: Alzheimer’s Disease
Dementia refers to a progressive impairment of previously intact mental facili-
ties. In general, the most common cause of progressive impairment in the older
population is the degenerative disease known as Alzheimer’s, and there is atrophy
of the cerebral cortex in a diffuse manner the rostral frontal and temporal limbic
regions sparing the cortex, sensory and visual cortex. There is a loss of neurons in
the cerebral cortex and in subcortical regions with a loss of dendritic spines in pyra-
midal neurons in the frontal and medial temporal and hippocampus and the forma-
tion of neurofibrillary tangles in the neocortical regions and the hippocampus. When
the process begins before the age of 65 years, the designation presenile is used;
when the process begins after the age of 65 years, the designation senile is employed.
The prevalence increases with age—0.3% for 60–69 years, 3.2% for 70–79 years,
and 10.8% for 80–89 years (Rocca et al. 1991a). Whichever figures are accepted,
the magnitude of the problem from a societal and fiscal standing is staggering. The
over 75 and over 85 age groups are the fastest growing sector of the population.
Alzheimer’s disease has been called the silent epidemic as millions of patients
will require care—straining the resources of families and institutions. There is much
work currently on diminishing the effects of aging on the brain and body including
maintaining a healthy weight, and normal blood pressure, and maintaining an active
life style including exercising, stopping smoking, and encouraging a diet rich in
organic vegetables and omega oils.
We have included the following example of Alzheimer’s (Fig. 16.11) to compare
to that of the alcohol-induced Wernicke’s encephalopathy in Case 16.5. Compare
and contrast the appearance of the MRI from a normal functioning elderly patient to
that of one with Alzheimer’s (Fig. 16.14a, b).
Case History 16.5 Alzheimer’s Disease. This 64-year-old right-handed white male
was initially evaluated for impairment of recent memory on May 1, 1997. Initially
16.4 Role of the Temporal Lobe in Learning and Memory 511
Fig. 16.14 Hippocampus.
(a) Hippocampus of a
normal patient aged 91. (b)
Hippocampus of a patient
with Alzheimer’s disease.
Note the smaller
hippocampus and larger
ventricles in the patient
with Alzheimer’s. MRI, T2
weighted
the wife indicated this had been progressive over 4 years, but she was subsequently
able to date this back to age 54 years, 10 years previously. A review of his record
indicated that he had been seen by another neurologist of our department on
September 14, 1993 with similar complaints with regard to memory. The neurologi-
cal examination at that time demonstrated no focal features, but his mental status
examination indicated an inability to recall any of four objects. He was oriented for
place and person but made errors on time orientation, his date was off by 1 month,
and the day of the week was incorrectly stated. Serial seven subtractions were well
performed. In the interim, the memory problems had progressed. In addition, there
were now personality changes. He no longer participated in those activities which
had previously been of great interest. He was also having some problems in finding
words. There were no problems in the activities of daily living, and he was not get-
ting lost in his familiar environments.
Family history: There was no history of neurological disease in his siblings.
512 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Neurological examination:
1. Mental status: He had particular problems in time orientation. He was able to do the
immediate recitation of three objects and of a test phrase but could remember none
of these on a delayed recall test. He also had difficulty coping a test figure. The
patient was often tangential in his answers and demonstrated inappropriate joking.
2. Cranial nerves: intact.
3. Motor system was intact as regards strength, gait, and cerebellar functions; how-
ever, premotor/frontal lobe functions were abnormal: (1) He had a release of the
instinctive grasp reflex; (2) He had difficulties performing the Luria three-stage
motor sequences demonstrated by the examiner (slap thigh with palmar surface,
then with ulnar surface of the hand, and then with ulnar surface of closed fist).
Clinical diagnosis: Alzheimer’s disease.
Laboratory data: CT scan demonstrated significant dilatation of the temporal
horns with a change in the size suggesting hippocampal atrophy, in addition to a
general increase in lateral ventricular size. There was also blunting of the angles of
the frontal horns.
SPECT scan showed a slight decrease in perfusion in the left parietal region.
Subsequent course: The patient was begun on treatment with 5 mg per day of
donepezil (Aricept), a centrally acting acetylcholinesterase inhibitor, and high dos-
age of vitamin E (a possible antioxidant). When reevaluated at 1 month, his family
reported improvement in memory. There was particular improvement in the delayed
recall section of the exam. There was however no change in personality. He still
showed inappropriate jocularity when he could not answer a question and at times
was tangential in his answers. In January 1999, the family stopped the donepezil
again because he was becoming more agitated with the rationale that this might be
due to this medication. Although the medication was restarted, behavioral distur-
bances became a major problem. He became aggressive telling his wife to get out of
the house and began to wander at night. In December of 1999, he was placed in a
nursing home at which point he was still able to walk. Telephone follow-up with his
wife in July of 2001 indicated that he is no longer agitated. He talks very little.
He recognizes his own name but shows no other response to questions. He occasion-
ally recognizes close relatives. He is usually in a wheelchair and requires assistance
to walk. He is “stiff and afraid” when requested to walk. He has been incontinent for
the last 2 years and requires diapers.
Comment: This patient presents a typical example of the slowly progressive course
of Alzheimer’s disease. Memory problems had begun insidiously at approximately
age 54. Initially these problems in the older adult may be attributed to a benign age-
related process in which there is minor difficulty in accessing information such as
names although the ability to incorporate new information is still intact (“wait a
minute, the name or word will come to me eventually”). As is often the case this
patient was not evaluated neurologically until several years later at age 60.
Administration of the acetylcholinesterase inhibitor temporarily improved memory
function for approximately 18 months. However, by age 67, behavioral disturbance
and urinary incontinence were becoming major problems, and he could no longer be
managed in his home and day care setting. This resulted in his placement in a
16.4 Role of the Temporal Lobe in Learning and Memory 513
nursing home. At age 69, he is now described as relatively nonfluent and very con-
fused. He is usually restricted to a wheelchair and can walk with assistance. The
“fear of walking “is often seen in patients with premotor/frontal gait apraxias. The
stiffness may be basal ganglia, premotor, or pyramidal in origin.
The student may raise the question as to whether, as in Parkinson’s disease, one
might attempt to replace transmitters. An initial approach centered on the choliner-
gic hypothesis has been attempted with little success.
The following MRIs (Fig. 16.14a, b) compare the appearance of the hippocam-
pus in a normal 91-year-old individual to that of a 76-year-old patient with
Alzheimer’s disease.
Frontotemporal disease, Pick’s disease, is similar to Alzheimer’s disease, but
it usually only affects the frontotemporal regions. Figure 16.15 demonstrates
the gross pathology seen in this neurodegenerative disease.
Fig. 16.15 Frontotemporal
degeneration, Pick’s
disease. (a) The control
brain from an 80-year-old
male. (b) The brain of this
89-year-old male who
demonstrated bilateral
marked atrophy in the
basal temporal and frontal
lobes (arrow) with
dementia and memory
dysfunction which are the
sign of this disease. The
hippocampus was also
atrophic
514 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
16.5 T
he Role of the Prefrontal Granular Areas
and Emotions
of pathology (trauma and mass lesions) with major behavioral syndromes has been
suggested (Stuss and Benson 1986). A syndrome of “frontal retardation” or “pseu-
dodepression” (abulia) manifested by apathy, nonconcern, a lack of motivational
drive, and a lack of emotional reactivity has been associated with lesions involving
the frontal poles and/or the medial aspects of both hemispheres.
The following Case History 16.6 is an example of frontal lobe dysfunction due
to trauma.
Case History 16.6, Fig. 16.16. This 18-year-old male who was an unrestrained pas-
senger (please wear a seat belt) in a car crash at a high rate of speed. He was unrespon-
sive at the crash scene. He also sustained a splenic laceration and an arm fracture.
Initial evaluation found him nonresponsive to voice and poorly responsive to pain.
Clinical diagnosis. The CT demonstrated bifrontal contusions.
He was comatose for several days. As he awakened, he was combative and
entirely uncooperative with his medical care, frequently striking out at staff and
throwing his food. He was transferred to a brain injury rehabilitation unit for an
extended stay. At 6 months after his injury, his family described a marked change in
personality to a highly impulsive, rude, and aggressive behavior pattern not previ-
ously present. He could not be left unattended due to his erratic behavior. Behavior
aside, his neurologic exam was normal.
Comment: One function of the frontal lobes is social behavior regulation. The CT
demonstrates extensive damage to these areas. Frequently, this sort of injury leaves
the patient devastated and unable to live independently, despite an otherwise normal
neurologic exam. A common term for this is traumatic brain injury or TBI.
Prefrontal Lobotomy. Based on the initial reports of Jacobsen regarding the effects
of prefrontal lobotomy on reducing emotional responses of the chimpanzee, Moniz,
a neuropsychiatrist, and Lima, a neurosurgeon, introduced in 1936 the surgical pro-
cedures of prefrontal lobotomy to modify the behavior and affect of psychotic
patients. Subsequently, Moniz introduced the procedure of prefrontal leukotomy:
bilateral disconnection of prefrontal areas from subcortical (thalamic and basal gan-
glia) and others. For over a century, it has been recognized that disease in the ante-
rior part of frontal lobes, the prefrontal cortex, produces changes in intelligence and
personality and affects the highest expression of behavioral control with a less excit-
able, less anxious, more passive, and less creative individuals including inhibition
of behavior. Prefrontal lobotomy has also been performed on patients with intrac-
table pain from carcinoma; the patient still perceives the pain but can ignore it and
is no longer anxious or fearful about it (Fig. 16.17).
A number of lobotomies were performed in the 1940s and early 1950s for psy-
chiatric reasons or to modify the emotional response of patient with chronic pain
problems previously requiring large doses of narcotics. Such studies must be inter-
preted with a certain degree of caution. The lesions are produced in individuals with
preoperative abnormalities of personality function. A recent PBS documentary in
2008, The Lobotomist Dr. Walter Freeman’s Brain Surgery, reviewed the reasons
and results of lobotomies and presented several patients who had undergone this
operation. In its day, it appeared to be a simple solution to a major problem. One can
see that many people who were treated with lobotomies, actually became a victim
of the procedure. One of its long-term effects is that patients lose their memories.
Fig. 16.17 Prefrontal lobotomy. A surgical section has separated the prefrontal connections with
the thalamus. Courtesy of Dr. Thomas Sabin and Dr. Thomas Kemper
16.6 Functional Neurosurgery 517
Today with the aid of effective pharmaceutical agents and therapy, there is no longer
a need for this procedure.
However, it is important that the negative effects of the surgery and its unques-
tioned widespread practice in the past are not forgotten. The long-term suffering of
lobotomy patients is unconscionable, and this fascinating film will prevent us from
forgetting about them.
Interruption of anterior thalamic radiation or destruction of dorsomedial
nucleus. A somewhat similar but less drastic personality change can be produced by
bilateral severance of the anterior thalamic radiation from the dorsomedial nucleus
or by direct destruction of the dorsomedial nuclei or orbital cortex. This less mas-
sive resection of cortex lessens anxiety with fewer personality changes. Destruction
of the anterior cingulate regions also produces this less drastic change.
Cingulotomy. A more recent and more specific approach to problems of severe
anxiety, manic behavior, and chronic pain was the approach of stereotaxic anterior
cingulotomy introduced by Ballantine et al. (1967). The effects are not necessarily
those which the same lesion would produce in otherwise normal individuals.
Functional neurosurgery. Surgery to produce personality change (prefrontal
lobotomy or leucotomy) has since fallen into disuse (Valenstein 1986). Figure 16.16 is
a CT from a patient with bilateral contusions in the prefrontal cortex due to trauma
(unrestrained/no seat belt and the passenger had resultant head trauma/TBI in this very
serious accident) which in this case produced many of the symptoms of a prefrontal
lobotomy. Figure 16.17 demonstrates the postmortem appearance of a prefrontal
lobotomy/leukotomy done to relieve major psychiatric abnormalities. The personality
changes that result from the isolation of the prefrontal lobe from input from the limbic
subcortical structures. A recent article has reviewed current psychosurgical or func-
tional neurosurgical procedures (Diering and Bell 1991). Even though some evidence
exists for the limited use of functional neurosurgery in a few situations, the ethical
stigma associated with it has resulted in the near abandonment of this procedure. There
is, however, a considerable resemblance to the effects produced by trauma (to the pre-
frontal areas) in relatively normal individuals. The early results did suggest that these
procedures did produce an alteration in the emotional response with a reduction of
anxiety generated in conflict and painful situations. Emotional response was often
detached from the pain and conflicts.
However, these effects on emotion can now be produced by the use of the tran-
quilizing drugs which were developed beginning in the middle 1950s. The develop-
ment of these drugs, in addition to the prominence of frequent postoperative
complications including seizures and personality alterations, led to the discontinua-
tion of the procedure.
Following prefrontal lobotomy or leukotomy, these patients often were impul-
sive and distractible. Their emotional responses often were uninhibited with an
apparent lack of concern over the consequences of their actions. A related finding
was an inability to plan ahead for future goals; at times, the patients were unable to
postpone gratification, responding to their motivations of the moment. (In a sense, a
loss of the reality principle had occurred.) Although distractible, a certain persevera-
tion of response was noted with an inability to shift responses to meet a change in
518 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Hospital Course. The patient developed headache and vomiting. She had difficulty
walking unsupported and became increasingly more somnolent but could be roused by
painful stimulation. Deep tendon reflexes were increased bilaterally with bilateral
extensor plantar responses (bilateral Babinski signs). Pupils responded to light but
were sluggish. Lumbar puncture indicated a markedly increased pressure, greater than
400 mm. of H2O. Cerebrospinal fluid protein was elevated to 125 mg/100 mL. The
patient became unresponsive and emergency neurological and neurosurgical consulta-
tions were obtained. The patient was semicomatose with periodic Cheyne–Stokes res-
pirations. Pupils were fixed, the left dilated, the right constricted. The patient moved
all limbs in response to painful stimulation, right more than left. A generalized hyper-
reflexia was present with bilateral ankle clonus. Bilateral Babinski signs were present.
A bilateral grasp reflex was present. Note, however, that in a semicomatose patient,
this has little localizing significance. Pain sensation was intact.
Clinical diagnosis. Imaging studies revealed a large subfrontal butterfly-shaped
mass in the anterior cranial fossa bilaterally. The tumor mass derived blood supply
from the ophthalmic arteries. A bifrontal craniotomy was immediately performed
by Dr. Robert Yuan with total removal of a large bifrontal meningioma arising from
the falx and olfactory groove. Histological examination of the tumor indicated a
benign meningioma (meningotheliomatous type).
Postoperative. The patient showed some immediate improvement at the conclu-
sion of surgery, in the sense that both pupils were equal in size and reacted to light.
By the time of discharge from the hospital, 2 months after surgery, considerable
improvement had occurred. She could recognize the doctor by name but did not
know the place, the season, or the month; she could, however, describe a picture she
had just seen. A bilateral deficit in olfaction was present (anosmia). Assistance was
required in walking. A bilateral grasp reflex was present.
Follow-up evaluation 2 years after surgery indicated continued improvement
although the patient still had complaint relevant to impairment of recent memory and
slight unsteadiness of gait. A bilateral grasp reflex was present, and the patient was slow
in walking and fell occasionally. Urinary incontinence occurred with wetting of the bed.
Comment: In retrospect, the evolution of symptoms in this patient clearly indicates a
tumor initially compression both prefrontal areas and producing alterations in mood
and personality. With continued growth of the tumor, compromise of the premotor
areas with resultant apraxia of gait and release of grasp reflex began to occur, either
as a result of direct compression or secondary to the distortion and compression of
the anterior cerebral arteries. It is not unusual to witness the development of a demen-
tia (deficit in recent memory) in large tumors in a subfrontal midline location. A simi-
lar dementia may occur in large aneurysms of the anterior communicating artery.
The sudden unresponsiveness following the lumbar puncture with the development
of periodic Cheyne–Stokes respirations, pupillary changes, and bilateral corticospinal
tract signs all indicated an additional acute exacerbation of the already compromised
brain stem functions. In retrospect, one might hypothesize that the patient’s complaint
of a loss of taste for her food 9 years ago, might well have indicated some loss of
olfactory sensation as our appreciation of food is dependent on olfaction.
520 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
The emotional brain is organized into a hierarchy of function proceeding from the
reticular formation, including mesencephalic midbrain nuclei to the hypothalamus
and thalamus to the limbic and neocortical regions.
Reticular Formation. The reticular formation is the site where information is
received from the periphery. This system is so organized that only certain stimuli
trigger the system, a gate, to alert the brain. If it were possible for any response to
trigger this system, then the individual’s survival would be threatened. The response,
however, is selective because throughout our lives we have evolved a set of emo-
tional responses that determine whether we will respond to situations calmly or with
rage or fear. What happens is that the reticular system, based on the sensory infor-
mation with probably some subconscious cortical assistance, focuses the attention
by sorting out the relevant information, thus enabling the central nervous system to
continue functioning efficiently throughout a crisis.
Hypothalamus. By the time the data reaches the hypothalamus, there are already
distinct, well-organized emotional responses. The hypothalamus, with some assis-
tance from the thalamus, sets the level of arousal needed for the emotional state and
organizes and mobilizes the cortical and subcortical centers (especially the auto-
nomic nervous system).
Pleasure/Punishment Areas. Throughout the limbic brain are found pleasure or
punishment centers. These were located by implanting electrodes at various subcor-
tical sites in an animal and training it to press a bar that connects the electrode to an
electrical current (Olds 1958). If the electrode is in certain pleasure centers, the
animal will self-stimulate until it is exhausted. In fact, the animal would rather press
the lever than eat. The pleasure centers are located throughout the limbic system,
but especially in the septum and preoptic region of the hypothalamus. Other brain
centers when stimulated produce fear responses: pupil dilation, piloerection, and
sweating. In these “punishment regions,” located in the amygdala, hypothalamus,
thalamus, and midbrain tegmentum, the animal quickly stops pressing the bar. If the
situation is nonthreatening, the normal operations of the viscera continue. In a
mildly stressful situation, such as one involving anger or heavy work, some of the
digestive processes slow down, and the heart rate and blood flow increase. If the
situation is threatening—triggering the reactions of fear, pain, intense hunger or
thirst, or sexual arousal—most of the digestive processes slow down and heart rate.
Temporal Lobe References 521
Limbic Cortical Regions. The limbic cortical regions are strongly influenced by
the emotional patterns set by the hypothalamus and amygdala which are then trans-
mitted with only a very few synaptic interruptions through the dorsomedial thala-
mus and anterior thalamus into the limbic cortex where the emotional pattern is
elaborated and efficiently organized. The neocortex (prefrontal cortex and, to a
lesser degree, the temporal lobe), based on past experience, examines the situation,
sorts out the emotional responses from the intellectual, and inhibits or controls the
situation based on what past experience has proven to be expedient for individual
survival. Consider the following examples: a mother responds to her baby’s crying,
while the father sleeps on; in the middle of the night, a jet airplane thundering over-
head causes no response, while a whiff of smoke or breaking glass quickly arouses
the central nervous system and keeps it focused blood flow, and respiration increase.
Once the threatening situation passes, conditions quickly return to a normal balance
between the sympathetic and parasympathetic nervous systems.
Altman J. Are neurons formed in the brains of adult mammals? Science. 1962;135:1127–8.
Anderson P. Organization of hippocampal neurons and their interconnections. In: Isaccson RL, Pribram
KH, editors. The hippocampus, vol. I. Structure and development. New York: Plenum; 1975.
Adolphs R, Tranel D, Damasio H, Damasio AR. Fear and the human amygdala. J Neurosci.
1995;15:5879–91.
Albert DJ, Walsh ML, Jonik RH. Aggression in humans: what is its biological foundation?
Neurosci Biobehav Rev. 1993;17:405–25.
Adrian ED. Sensory discrimination with some recent evidence from the olfactory organ. Brit Med
Bull. 1950;6:330.
Bancaud J. Semiologie clinique des crises epileptiques d’origine temporale. Rev Neurol (Paris).
1987;143:392–400.
Bancaud J, Brunet-Bourgin F, Chauvel P, Halgren E. Anatomical origin of déjà vu and vivid mem-
ories inhuman temporal lobe epilepsy. Brain. 1994;117:71–90.
Blume WT, Girvin JP, Stenerson P. Temporal neocortical role in ictal experiential phenomena. Ann
Neural. 1993;33:105–7.
Breuer J, Freud S. New York: Basic Books; 1957. (Translated and edited by Stachey J)
Burchell B. Turning on and turning off the sense of smell. Nature. 1991;350:16–8.
Burgerman RS, Sperling MS, French JA, et al. Comparison of mesial versus neocortical onset of
temporal lobe seizures. Epilepsia. 1995;36:662–72.
Cendes F, Andermann F, Gloor P, et al. Relationship between atrophy of the amygdala and ictal
fear intemporal lobe epilepsy. Brain. 1994;117:739–46.
Crichton M. The terminal man. New York: Avon Press; 1982.
Devinsky O, Morrell MJ, Vogt BA. Contribution of anterior cingulate cortex to behavior. Brain.
1995;118:279–306.
Dionne VE. How do you smell? The principle in question. Trends Neurosci. 1988;11:188–9.
Engel J Jr. Seizures and epilepsy. Philadelphia: F.A. Davis; 1989. p. 536.
Ferguson SM, Rayport M, Carrie WS. Brain correlates of aggressive behavior in temporal epi-
lepsy. In: Doane BK, Livingstone KE, editors. The limbic system. New York: Raven Press;
1986. p. 183–93.
522 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Fish DR, Gloor P, Quesney FL, Olivier A. Clinical responses to electrical brain stimulation of the
temporal and frontal lobes in patients with epilepsy. Pathophysiological implications. Brain.
1993;116:397–414.
Fletcher PC, Henson RNA. Frontal lobes and human memory insight from functional neuroimag-
ing. Brain. 2001;124:849–81.
Foong J, Symms MR, Barker GJ, et al. Neuropathological abnormalities in schizophrenia. Brain.
2001a;124:882–92.
Fulton JF. The limbic system: a study of the visceral brain in primates and man. Yale J Biol Med.
1953;26(2):107–18.
Gage FH. Challenging an old dogma; neuronogenesis in the adult hippocampus. J NIH Res.
1994;6:53–6.
Geschwind N. Disconnection syndromes in animals and man. Brain. 1965;88(237–294):585–644.
Geschwind N. Interictal behavior changes in epilepsy. Epilepsia. 1983;24(suppl. 1):523–30.
Gloor P. Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses. Brain.
1990;113:1673–94.
Gloor P. The temporal lobe and limbic system. New York: Oxford University Press; 1997. 865pp
Gloor P, Olivier A, Quesney LF, Andermann F, Horowitz S. The role of the limbic system in expe-
riential phenomena of temporal lobe epilepsy. Ann Neurol. 1982;12:129–44.
Green JD. The rhinencephalon. Aspects of its relation to behavior and the reticular activating
system. In: Jasper HH, editor. Reticular formation of the brain. Boston: Little, Brown and
Company; 1958. p. 607.
Halgren E, Walter RD, Cherlow DG, Crandall PH. Mental phenomena evoked by electrical stimu-
lation of the human hippocampal formation and Amygdala. Brain. 1978;101:83–117.
Honavar M, Meldrum BS. Epilepsy. In: Graham DI, Lantos PL, editors. Greenfield’s neuropathol-
ogy. 6th ed. New York: Oxford University Press; 1997. p. 931–71.
Horel JA, Misantone LG. Partial Kluver Bucy syndrome produced by destroying temporal
Neocortex or Amygdala. Brain Res (Amsterdam). 1975;94:347–59.
Isaacson R. The limbic system. 2nd ed. New York: Plenum; 1982.
Ishibashi T, Hori H, Endo K, Sato T. Hallucinations produced by electrical stimulation of temporal
lobe seizures in schizophrenic patients. Tohoku J Med. 1964;82:124–39.
Jackson JH, Beevor CE. Case of tumor of the right temporo-sphenoidal lobe, bearing on the local-
ization of the sense of smell and on the interpretation of a particular variety of epilepsy. Brain.
1889;12:346–57. [Reprinted in Taylor J.(Ed) 406–411.]
Jackson JH, Colman WS. Case of epilepsy with tasting movements and “dreamy state”-very small
patch of softening in the left uncinate gyrus. Brain. 1898;21:580–90. [Reprinted in: Taylor
J (Ed) selected writings of John Hughlings Jackson: on epilepsy and Epileptiform convulsions.
New York: basic Books, 1958; 458–463.]
Jackson JH, Stewart P. Epileptic attacks with a warning of crude sensation of smell and with the
intellectual Aura (dreamy state) in a patient who had symptoms pointing to gross organic dis-
ease of the right temporo-sphenoidal lobe. Brain. 1899;22:534–49.
Johnston D, Amaral DG. Hippocampus. In: Shepherd GM, editor. The synaptic organization of the
brain. 4th ed. New York: Oxford University Press; 1998. p. 417–58.
Kauer J. Contributions of topography and parallel processing to odor coding in the vertebrates’
olfactory pathway. Trends Neurosci. 1991;14:79–85.
Kluver H. Brain mechanisms and behavior with special reference to the rhinencephalon. J. Lancet
(Minneapolis). 1952;72:567.
Kluver H. The “temporal lobe syndrome” produced by bilateral ablations. In: Wolstenhoime EE,
O’Connor CM, editors. Neurological bases of behavior. Ciba Foundation Symposium. London:
J.A. Churchill; 1958. p. 175.
Kluver H, Bucy PC. Psychic blindness and other symptoms following bilateral temporal lobec-
tomy in rhesus monkeys. Am J Phys. 1937;119:352.
Kluver H, Bucy PC. Preliminary analysis of functions of the temporal lobes of monkeys. Arch
Neurol Psychiatr. 1939;42:979–1000.
Temporal Lobe References 523
Stevens JR. Interictal clinical manifestations of complex partial seizures. Adv Neurol.
1975;11:85–112.
Swanson SJ, Rao SM, Grafman J, et al. The relationship between seizure subtypes and interictal
personality. Results from the Vietnam head injury study. Brain. 1995;118:91–103.
Tatnaka Y, Kamo T, Yoshide M, et al. So-called cortical deafness: clinical, neuropsychological and
radiologic observations. Brain. 1991;114:238–40.
Valenstein ES. Great and desperate cures: the rise and decline of psychosurgery and other radical
treatments for mental illness. New York: Basic Books; 1986.
Veselis RA, Pryor KO. Propofol amnesia—what is going on in the brain? In: Hudetz A, Pearce
R, editors. Suppressing the mind. Anesthetic modulation of memory and consciousness,
Contemporary clinical neuroscience. 1st ed. Totowa: Humana Press; 2010. (Chapter: 11).
Vassar R, Chao SK, Sitcheran R, et al. Topographic organization of sensory projections to the
olfactory bulb. Cell. 1994;79:981–91.
Walczak TS. Neocortical temporal lobe epilepsy. Epilepsia. 1995;36:623–35.
Waxman SG, Geschwind N. The Interictal behavior syndrome of temporal lobe epilepsy. Arch Gen
Psychiatry. 1975;32:1580–6.
Wieser HG. Selective amygdalo-hippocampectomy for temporal lobe epilepsy. Epilepsia.
1988;29(Suppl. 2):100.
Adams RD, Victor M, Ropper AH. Psychiatric disorders. In: Principles of neurology. New York:
McGraw Hill; 1997. p. 1501–62.
Adolph R, Sears L, Piven J. Abnormal processing of social information from faces in autism.
J Cogn Neurosci. 2001;13:232–40.
Adolph R, Tranel D, Damasio AR. The human amygdala in social judgment. Nature.
1998;393:417–8.
Amaral D, LeDoux J. 2001. Fear and social conditioning in the amygdala. Lectures at the Boston
Society of Neurology and Psychiatry. 924th meeting June 14th 2001. Boston, MA.
Anderson AK, Phelps EA. Expression without recognition: contributions of the human amygdala
to motional communication. Psychol Sci. 2000;11:106–11.
Baron-Cohen S, Ring HA, Bullmore ET, et al. The amygdala theory of autism. Neurosci Biobehav
Rev. 2000;24:355–64.
Critchley HD, Daly EM, Bullmore ET. The functional neuroanatomy of social behavior. Brain.
2000;123:2203–12.
Foong J, Symms MR, Barker GJ, et al. Neuropathological abnormalities in schizophrenia. Brain.
2001b;124:882–92.
Friston KJ, Liddle PF, Firth CD, et al. The left medial temporal region and schizophrenia. A PET
study. Brain. 1992a;115:367.
Howard MA, Cowell PE, Boucher J, et al. Convergent neuroanatomical and behavioral evidence
of an amygdala hypothesis of autism. Neuroreport. 2000;11:2931–5.
Kallmann FJ. The genetic theory of schizophrenia. An analysis of 691 twin index families. Am
J Psychiatry. 1946;103:309.
Levine DN, Grek A. The anatomic basis of delusions after right cerebral infarction. Neurology.
1984;34:577.
Temporal Lobe References 525
Brown P, Gajdusek DC, Gibbs CJ Jr, et al. Potential epidemic of Creutzfeldt-Jakob disease from
human growth hormone therapy. N Engl J Med. 1985;313:728–31.
Brown P, Goldfarb LG, Kovanen J, et al. Phenotypic characteristics of familial Creutzfeldt-Jakob
disease associated with the codon 178 Assn PRNP mutation. Ann Neurol. 1992;31:282–5.
Brown P, Gibbs CJ, Amyx HL, et al. Chemical disinfection of Creutzfeldt-Jakob disease virus. N
Engl J Med. 1982;306:1279–82.
Brown P, Cervenáková L, Goldfarb LG, et al. Iatrogenic Creutzfeldt-Jakob disease: an example of
the interplay between ancient genes and modern medicine. Neurology. 1994;44:291–3.
Burkhardt CR, Filiey CM, Meinschmidt-DeMasters BK, et al. Diffuse Lewy body disease and
progressive dementia. Neurology. 1988;38:1520–8.
Calford MB, Tweedale R. Interhemispheric transfer of plasticity in the cerebral cortex. Science.
1990;249:805–7.
Caplan L, Chedru F, Lhermitte F, et al. Transient global amnesia and migraine. Neurology.
1981;31:1167–70.
Caplan LR, Schoene WC. Clinical features of subcortical arteriosclerotic encephalopathy
(Bunswanger disease). Neurology. 1978;28:1206–15.
Carpenter WT Jr, Buchanan RW. Schizophrenia. N Engl J Med. 1994;330:681–90.
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and
the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3.
Desimone R. The physiology of memory: recordings of the past. Science. 1992;258:245–6.
Dollard J, Miller NE. Personality and psychotherapy. New York: McGraw Hill; 1950.
Drachman DA, Leavitt J. Human memory and the cholinergic system—a relationship to aging?
Arch Neurol. 1974;30:113–21.
Drachman DA. New criteria for the diagnosis of vascular dementia: do we know enough yet?
Neurology. 1993;43:243–5.
Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community
population of older adults. JAMA. 1989;262:2551–6.
Friedland RP. Epidemiology, education and the ecology of Alzheimer’s disease. Neurology.
1993;43:246–9.
Friston KJ, Liddle PF, Firth CD, et al. The left medial temporal region and schizophrenia. A PET
study. Brain. 1992b;115:367–82.
Gajdusek DC, Gibbs CJ, Asher DM, et al. Precautions in medical care of, and in handling materi-
als from patients with transmissible virus dementia (Creutzfeldt-Jakob disease). N Engl J Med.
1977;297:1253–8.
Gallassie R, Morreale A, Lorusso S, et al. Epilepsy presenting as memory disturbances. Epilepsia.
1977;29:624–9.
Gilden DH. Slow virus diseases of the CNA: part II Scrapie, Kuru, and Jakob-Creutzfeldt disease.
Postgrad Med. 1983;73:113–8.
Goldenberg G, Podreka I, Phaffel-Meyer N, et al. Thalamic ischemia in transient global amnesia:
a SPEC study. Neurology. 1991;41:1748–52.
Graff-Radford NR, Tranel D, Van Hoesen GW, et al. Diencephalic amnesia. Brain. 1990;113:1–25.
Greenlee JE. Infection control—containment precautions in hospitals for cases of Creutzfeldt-
Jakob disease (editorial). Infect Control. 1982;3:222–3.
Growdon JH. Treatment for Alzheimer’s disease? (Editorial). N Engl J Med. 1992;327:1306–8. see
also David et al. 1992. N. Engl. J. Med. 327: 1253–1259.
Grundman M, Jthal L. Treatment of Alzheimer’s disease. Neurol Clin. 2000;18:807–28.
Hansen L, Salmon D, Galasko D. The Lewy body variant of Alzheimer’s disease: a clinical and
pathologicentity. Neurology. 1990;40:1–8.
Harlow H. Learning to love. New York: James Aronson; 1974.
526 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Heiligenberg W. The neural basis of behavior: a neuroethological view. Ann Rev Neurosci.
1991;14:247–67.
Hellmuth J, editor. Disadvantaged child—vol. 2: head start and early intervention. New York:
Brunner-Mazel; 1963.
Hsiao K, Prusiner SB. Inherited human prion diseases. Neurology. 1990;40:1820–7.
Hubel DH. Eye, brain and vision. New York: Scientific American Library; 1988.
Irle E, Wowra B, Kunert HJ, et al. Memory disturbances following anterior communicating artery
rupture. Ann Neurol. 1992;31:473–80.
Jarvis WR. Precautions for Creutzfeldt-Jakob disease. Infect Control. 1982;3:238–9.
Jenkins WM, Merzenich MM, Ochs M, et al. Functional reorganization of primary somatosen-
sory motor cortex in adult owl monkeys after behaviorally controlled tactile stimulation.
J Neurophysiol. 1990;63:82–104.
Kass JH, Krubitzer LA, Chino YM, et al. Reorganization of retinotopic cortical maps in adult
mammals after lesions of the retina. Science. 1990;248:229–31.
Kass J. Plasticity of sensory and motor maps in adult mammals. Ann Rev Neurosci. 1991;14:137–67.
Kandel, E.R., T. Jessell. 1991. Early experience and the fine tuning of synaptic connections. In:
E.R. Kandel, J.H. Schwartz, T.M. Jessell Principles of neural science, New York, Elsevier,
pp. 945–958.
Kandel ER, O’Dell TJ. Are adult learning mechanisms also used for development? Science.
1992;258:243–95.
Kapur N, Ellison D, Smith MP, et al. Focal retrograde amnesia following bilateral temporal lobe
pathology: a neuropsychological and magnetic resonance study. Brain. 1992;115:73–85.
Katzman R. Education and the prevalence of Alzheimer’s disease. Neurology. 1993;43:13–20.
Kemper TL, Bauman ML. The contribution of neuro-pathological studies to the understanding of
autism. Neurol Clin. 1993;11:175–87.
Lin KN, Liu RS, Yeh TP, et al. Posterior ischemia during an attack of transient global amnesia.
Stroke. 1993;24:1093–5.
Madison DV, Malenka RC, Nicoll RA. Mechanisms underlying long term potentiation of synaptic
transmission. Rev Neurosci. 1991;14:379–97.
Markesbery WR. Alzheimer’s disease. In: McKhann CM, McDonald W, editors. Diseases of the
nervous system: clinical neurobiology. 2nd ed. Philadelphia: W.B. Saunders; 1992. p. 755–803.
Marx J. Human brain disease recreated in mice. Science. 1990;250:1509–10.
Marx J. A new link in brain’s defenses—research news. Science. 1992a;256:1278–80.
Marx J. Alzheimer’s debate boils over—news & comments. Science. 1992b;257:1336–8.
Marx J. Familial Alzheimer’s linked to chromosome 14 gene - neurobiology. Science.
1992c;258:550.
Masters CL, Gajdusek DC, Gibbs CJ. The familial occurrence of Creutzfeldt-Jakob disease and
Alzheimer’s disease. Brain. 1981;104:535–58.
Masters CL, Harris JO, Gajdusek DC, et al. Creutzfeldt-Jakob disease: patterns of world-wide
occurrence and the significance of familial and sporadic clustering. Ann Neurol. 1979;5:177–87.
Mathew NT, Meyer JS. Pathogenesis and natural history of transient global amnesia. Stroke.
1974;5:303–11.
Mayeaux R, Sternspanton S. Heterogenicity in dementia of the Alzheimer type: evidence of sub-
groups. Neurology. 1985;35:453–61.
Mazzucchi A, Moretti G, Caffarra P, et al. Neuropsychological functions in the follow-up of tran-
sient global amnesia. Brain. 1980;103:161–78.
McClelland DC, Atkinson JW. The projective expression of needs. J Psvchol. 1948;25:206.
McKee AC, Kosik KS, Kowall NW. Neuritic pathology and dementia in Alzheimer’s disease. Ann
Neurol. 1991;30:156–65.
McKeith IG. Spectrum of Parkinson’s disease, Parkinson’s dementia and Lewy body dementia.
Neurol Clin. 2000;18:865–84.
McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease. Neurology.
1984;34:939–44.
Melo TP, Ferro JM, Ferro H. Transient global amnesia: a case control study. Brain. 1992;115:261–70.
Temporal Lobe References 527
Merzenich MM. Sources of intraspecies and interspecies cortical map variability in mammals:
conclusions and hypothesis. In: Cohen JJ, Strumwasser F, editors. Comparative neurobiology
modes of communication in the nervous system. New York: Wiley; 1985. p. 105–16.
Mesulam MM. Slowly progressive aphasia without generalized dementia. Ann Neurol. 1982;11:592–8.
Mesulam MM. Schizophrenia and the brain. N Engl J Med. 1990;322:842–4.
Nestor PN, Hodges J. Non Alzheimer’s dementias. Semin Neurol. 2000;20:439–46.
Ojemann GA, Creutzfeldt O, Lettich E, et al. Neuronal activity in human lateral temporal cortex
related to short-term verbal memory, naming and reading. Brain. 1988;111:1383–403.
Ott BR, Saver JL. Unilateral amnesic stroke, six new cases and review of the literature. Stroke.
1993;24:1033–42.
Penfield W, Milner B. Memory deficit produced by bilateral lesions in the hippocampal zone. Arch
Neurol Psychiatr. 1958;79:475–97.
Perl DP. Neuropathology of Alzheimer’s disease and related disorders. Neurol Clin. 2000;18:847–64.
Perry RH, Irving D, Blessed G, et al. Clinically and neuropathologically distinct form of dementia
in the elderly. Lancet. 1989;1:166.
Pollen DA. Hannah’s heirs: the guest for the genetic origin of Alzheimer’s disease. New York:
Oxford University Press; 1993. p. 296.
Pons TP, Garraghty PE, Ommaya AK, et al. Massive cortical reorganization after sensory deaf-
ferentation in adult macaques. Science. 1991;252:1857–60.
Powell-Jackson J, Kennedy P, Whitcomb EM, et al. Creutzfeldt-Jakob disease after administration
of human growth hormone. Lancet. 1985;2:244–6.
Prusiner SB. The molecular biology of prion diseases. Science. 1991;252:1515–22.
Riesen AH. Sensory deprivation in progress. In: Stellar E, Sprague JM, editors. Physiological
psychology, vol. 1. New York: Academic Press; 1966. p. 117–47.
Rocca WA, Hofman A, Brayne C, et al. Frequency and distribution of Alzheimer’s disease in
Europe: a collaborative study of 1980–1990 prevalence findings. Ann Neurol. 1991a;30:381–90.
Rocca WA, Hofman A, Brayne C, et al. The prevalence of vascular dementia in Europe: facts and
fragments from 1980–1990 studies. Ann Neurol. 1991b;30:817–24.
Rogers JD, Brogan D, Miran SS. The nucleus basalis of Meynert in neurological disease: a quan-
titative morphological study. Ann Neurol. 1995;17:163–70.
Roman GC, Tatemich TR, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research
studies: report of the NINDS-AIREN international workshop. Neurology. 1993;43:250–60.
Rosen HJ, Lengenfelder J, Miller B. Frontotemporal dementia. Neurol Clin. 2000;18:979–92.
Rosenzweig MB, Leiman AL. Brain functions. Ann Rev Psychol. 1986;19:55–98.
Russell RW. Biochemical substrates of behavior. In: Russell RW, editor. Frontiers in physiological
psychology. New York: Academic Press; 1966.
Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E. Allele-4 with
late onset and sporadic Alzheimer’s disease. Neurology. 1993;43:1467–72.
Schatz CJ. The developing brain. Sci Am. 1992;267:61–76.
Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol
Neurosurg Psychiat. 1957;20:11–21.
Selkoe DJ. The genetics and molecular pathology of Alzheimer’s disease: roles of amyloid and the
presenilins. Neurol Clin. 2000a;18:903–22.
Selkoe DJ. Presenilins, B amyloid precursors and the molecular basis of Alzheimer’s disease. Clin
Neurosci Res. 2000b;1:91–103.
Shenton ME, Kikinis R, Jolesz FA, et al. Abnormalities of the left temporal lobe and thought
disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med.
1992;327:604–12.
Silva AJ, Stevens CF, Tonegawa S, et al. Deficient hippocampal long term potentiation in B-calcium
calmodulin kinase II mutant mice. Science. 1992;257:201–6.
Silva AJ, Paylor R, Wehner JM, et al. Impaired spatial learning in B-calcium-calmodulin kinase II
mutant mice. Science. 1992;257:206–11.
Skoog I, Nilsson L, Palmertz B, et al. A population-based study on dementia in 85-year-olds. N
Engl J Med. 1993;328:153–8.
528 16 The Limbic System, Temporal Lobe, and Prefrontal Cortex
Sparks DL, Markesbery WR. Altered serotonergic and cholinergic synaptic markers in Pick’s dis-
ease. Arch Neurol. 1991;48:796–9.
Spillantini MG, Goedert M. Tau mutations in familial frontotemporal dementia. Brain. 2000;123:
857–9.
Spitz R. Hospitalism. Psychoanal Study Child. 1945;1:53.
Squire LR, Zola-Morgan S. The medial temporal lobe memory system. Science. 1991;253:
1380–6.
Stillhard G, Landis T, Schisms R, et al. Bitemporal hypoperfusion in transient global amnesia:
99mTC-HM-PAO SPECT and neuropsychological findings during and after an attack. J Neurol
Neurosurg Psychiat. 1990;53:339–42.
Strittmatter WJ, Saunders AM, Schmechal D, et al. Apolipoprotein E. High avidity binding to
B. Amyloid and increased frequency of type 4 allele in late onset familial Alzheimer’s disease.
Proc Natl Acad Sci. 1993;90:1977–81.
Suddath RL, Christison GW, Torrey EF, et al. Anatomical abnormalities in the brains of monozy-
gotic twins discordant for schizophrenia. N Engl J Med. 1990;322:789–94.
Tassinari CA, Ciarmatori C, Alesi C, et al. Transient global amnesia as a postictal state from recur-
rent partial seizures. Epilepsia. 1991;32:882–5.
Teitelbaum JS, Zatorre RJ, Carpenter S, et al. Neurologic sequelae of domoic acid intoxication due
to the ingestion of contaminated mussels. N Engl J Med. 1990;322:1781–7.
Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol
Sci. 1970;11:205–42.
Tulving E, Schacter DL. Priming and human memory systems. Science. 1990;247:301–6.
Victor M, Angevine JB, Mancall EL, et al. Memory loss with lesions of hippocampal formation.
Arch Neurol. 1961;5:244–63.
von Cramon DY, Hebel N, Schuri V. Verbal memory and learning in unilateral posterior cerebral
infarction. A report on 30 cases. Brain. 1988;111:1061–78.
von Cramon DY, Hebel N, Schri V. A contribution to the anatomical basis of thalamic amnesia.
Brain. 1985;108:993–1008.
Whitehouse PJ, Price DL, Dark AW, et al. Alzheimer’s disease: evidence for selective loss of cho-
linergic neurons in the nucleus basalis. Ann Neurol. 1981;10:1226.
Will RG, Matthews WB. Evidence for case-to-case transmission of Creutzfeldt-Jakob disease.
Neuro Neurosurg Psychiatry. 1982;45:235–8.
Williams M, Pennybacker J. Memory disturbances in third ventricle tumors. J Neurol Neurosurg
Psychiat. 1954;17:115–23.
Winker MA. Tacrine for Alzheimer’s disease. Which patient, what dose? JAMA. 1994;271:1023–4.
(see also Knapp et al. 1994. JAMA. 271:985–991; and Watkins et al. 1994. JAMA. 271:992–998.)
Woods BT, McKee AC. Case records of the Massachusetts General Hospital—a 67-year-
old man with aphasia and memory loss followed by progressive dementia. N Engl J Med.
1992;326:397–405.
Yankner BA, Dawes LF, Fisher S, et al. Neuro-toxicity of a fragment of the amyloid precursor
associated with Alzheimer’s disease. Science. 1989;245:117–210.
Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and neurotoxic effects of amyloid B protein:
reversal by tachykinin neuropeptides. Science. 1990;250:279–82.
Yankner BA, Mesulam MM. B-amyloid and the pathogenesis of Alzheimer’s disease. N Engl
J Med. 1991;325:1849–57.
Zola-Morgan S, Squire LR, Amaral DG. Human amnesia and the medial temporal region: endur-
ing memory impairment following a bilateral lesion limited to field CA1 of the hippocampus.
J Neurosci. 1986;6:2950–67.
Zola-Morgan SM, Squire LR. The primate hippocampal formation. Evidence for a time limited
role in memory storage. Science. 1990;250:288–96.
Temporal Lobe References 529
Bookman JM, Kingsbury DT, McKinley MP, et al. Creutzfeldt-Jakob disease prion proteins in
human brains. N Engl J Med. 1985;312:73–8.
Boothe RG, Dobson V, Teller DY. Postnatal development of vision in human and nonhuman pri-
mates. Ann Rev Neurosci. 1985;8:495–545.
Butter NM, Mishkin K, Mirsky AF. Emotional response in monkeys with selective frontal lesions.
Physiol Rev. 1968;3:213–5.
Butter CM, Snyder DR, McDonald J. Effects of orbital frontal lesions on aversive and aggressive
behavior in rhesus monkeys. J Comp Physiol Psychol. 1970;72:832–144.
Butters N, Pandya D. Retention of delayed alternation: effect of selective lesions of sulcus princi-
palis. Science. 1969;165:1271–3.
Calleja J, Carpizo R, Berciano J. Organismic epilepsy. Epilepsia. 1988;29:635–9.
Cauvel P, Delgado-Escueta AV, Halgren E, et al., editors. Frontal lobe seizures and epilepsies.
New York: Raven Press; 1992. (see also Delgado-Escueta et al. 1988. Epilepsia. 29: 204–221
for abstracts)
Damasio AR. The frontal lobes. In: Heilman KM, Valenstein E, editors. Clinical neuropsychology.
2nd ed. New York: Oxford; 1985. p. 339–75.
Damasio AR. Medical progress: aphasia. N Engl J Med. 1992;326:531–9.
Damasio AR, Geschwind N. The neural basis of language. Ann Rev Neurosci. 1984;7:127.
Fulton JF, Jacobsen CF. The functions of the frontal lobes: a comparative study in monkeys, chim-
panzees, and man. Adv Mod Biol (Moscow). 1935;4:113–23.
Jacobsen CF. Functions of the frontal association area in primates. Arch Neurol Psychiatr.
1935;33:558–69.
Jacobsen CF, Nissen HW. Studies of cerebral function in primates: IV. The effects of frontal lobe
lesion on the delayed alteration habit in monkeys. J Comp Phys Psychol. 1937;23:101–12.
Jacobsen S, Trojanowski J. Prefrontal granular cortex of the rhesus monkey: I. Intrahemispheric
cortical afferents II. Interhemispheric cortical afferents. Brain Res. 1977;132(209–233):235–46.
Jones EG, Friedman DP, Hendra SHC. Thalamic basis of place and modality specific columns
in monkey cerebral cortex: a correlative anatomical and physiological study. J Neurophysiol.
1982;48:545–68.
Ledoux J. Emotion circuits in the brain. Ann Rev Neurosci. 2000;23:155–84.
Valenstein E. Clinical neuropsychology. New York: Oxford University Press; 1993. p. 49–73.
Chapter 17
Higher Cortical Functions
It is well to warn the student beginning the study of language function prior to the
development of modern neuroimaging this had been an area of much confusion,
with much disagreement and multiple hypotheses. This discussion will be limited to
the more practical problems of anatomical localization.
Dysarthria. Dysarthria refers to a difficulty in articulation of speech from weakness
or paralysis or from mechanical difficulties, and it is not related to a problem in the
cerebral cortex but to disease in the lower motor neurons that control the production
of speech or to a lesion in the corticobulbar pathway. In this chapter, we will discuss
language dysfunction due to lesions in the cerebral cortex and introduce the follow-
ing terms: aphasia, apraxia, and dyslexia.
There are complex disturbances of verbal expression that occur at a time when the
basic motor and sensory systems for articulation are intact. Similarly, there are com-
plex disturbances in language function, as regards comprehension of written and
spoken symbolic forms, that occur at a time when the basic auditory and visual
receptor apparatus is intact. We refer to these more complex acquired disturbances
Fig. 17.1 Lateral surface of the brain of a right-handed individual showing the longer lateral sul-
cus in the left hemisphere (L) than in the right hemisphere (R) which reflects the asymmetry seen
in the brain due to the development of language areas in the superior temporal lobe in the hemi-
sphere dominant for language – in this patient the left hemisphere (Geschwind and Levitsky 1968;
Kertesz and Geschwind 1971)
(Wada et al. 1975). The studies of LeMay and Culebras (1972), LeMay and
Geschwind (1978), Galaburda et al. (1978), and Chui and Damasio (1980) elabo-
rated on the asymmetries of the Sylvian fissure and occipital lobe demonstrated on
arteriography and CT scan during life. Similar asymmetries were demonstrated in
the brains of the great apes, e.g., chimpanzee, but not in the rhesus monkey (LeMay
and Geschwind 1978). LeMay and Culebras (1972) studied the endocranial casts of
human fossil skulls in which imprints of the major fissure could be noted and dem-
onstrated similar differences in Neanderthal man.
Development Aspects
It is clear that from a functional standpoint, a considerable degree of flexibility exists
in the child as regards dominance for language function. Thus, in a child under the age
of 5 years, destruction of the speech areas of the dominant left hemisphere during pre-
or postnatal life produces only a minor long-term language disturbance (Varqha-
Khademe et al. 1985). If the damage to the speech areas in the dominant hemisphere
occurs between the ages of 5 and 12 years, a more severe aphasia occurs; however,
some limited recovery of language may occur within a year. These cases suggest an
equipotentiality of the two hemispheres for language function during the early years
of development. In these cases, under the age of 5 years, the right hemisphere must
assume a dominant role in mediating those learned associations important in language
534 17 Higher Cortical Functions
In approaching the patient with aphasia, it is well to keep in mind that textbook
discussions of this problem are often artificial, in the sense that such discussions
tend to deal with relatively isolated pure types of language disturbance, which have
relatively specific localization. The actual patient with aphasia more often presents
a mixed disturbance with damage to several areas; some have damage to all major
areas in a global aphasia. This is not unexpected when one realizes that all of the
major speech areas of the dominant hemisphere are within the cortical vascular ter-
ritory of the middle cerebral artery. Other areas involved in related disorders are
supplied by the anterior cerebral artery (the superior speech area) or by the posterior
cerebral artery, (those areas involved in pure dyslexia and agnosia). Willmes and
Poeck (1993) and Kirsher (2000) provide additional reviews.
Cortical areas of the dominant hemisphere of major importance in language
disturbances (Fig. 17.2):
(1) Broca’s motor aphasia or expressive speech center is localized into the opercular
and triangular portions of the inferior frontal convolution (areas 44 and 45).
(2) Wernicke’s receptive aphasia area. The auditory association area is found in the
superior and lateral surface of the posterior-superior temporal gyrus (area 22
and adjacent parts of area 42).
(3) Inferior parietal lobule. The angular and supramarginal gyri (areas 39 and 40)
have at times been associated with Gerstmann’s syndrome of dysgraphia,
dyscalculia, left–right confusion, and finger agnosia.
17.3 Aphasia: Dominant Hemispheric Functions 535
Fig. 17.2 Speech areas of the dominant hemisphere, summary diagram combining the data of
pathological lesions and stimulation studies. Precise sharp borders are not implied. The designa-
tions of Penfield and Roberts (1959) the terms “anterior speech area,” “posterior speech area,” and
“superior speech cortex” (From Marcus and Jacobson, Integrated Neuroscience, Kluwer Academic
Publisher 2003)
(4) Supplemental motor cortex (superior speech area) may also play a role in lan-
guage function. Stimulation studies by Luders et al. (1988) have also identified a
basal temporal speech area. In addition to these cortical areas, the association fiber
systems relating these areas to each other and to other cortical areas are of consid-
erable importance for certain types of language disturbance, as we will indicate
later. From a practical localization standpoint, we can, in a general sense, speak of
patients as presenting a nonfluent/anterior type of aphasia (anterior to the central
sulcus) or fluent type (posterior to the central sulcus) (Fig.17.1; Table 17.2).
lobule. However, since the posterior areas are relatively close to one another, it is not
unusual for a single disease process to involve both areas. The fluent aphasias include
(a) Wernicke’s receptive aphasia, (b) disconnection syndromes, (c) Gerstmann’s
syndrome, (d) dyslexia plus, (e) dyslexia without agraphia, and (f) the agnosias.
17.3 Aphasia: Dominant Hemispheric Functions 537
Now let us consider in greater detail language functions and the postulated anatomi-
cal correlations of these various language centers. In these correlations, it is impor-
tant to make a distinction between acute and chronic effects. It is necessary first to
review those components of language function that are evaluated in the neurological
examination and reviewed in Table 17.2 (adapted from Benson (1985)).
Stimulation of the speech areas. In general, as demonstrated in Fig. 17.3, stim-
ulation of the dominant hemisphere – speech areas – produces arrest of speech:
1. Speech arrest or interference was elicited in five areas:
(a) Primary motor cortex when stimulating the representation of muscles
involved in speech of the dominant hemisphere.
(b) Negative motor areas (suppressor areas), that is, the supplementary motor
areas, and inferior frontal gyrus of the dominant hemisphere.
(c) Broca’s area – dominant hemisphere only.
(d) Wernicke’s area – dominant hemisphere only.
(e) Basal temporal language area – dominant hemisphere only. Dinner and
Luders concluded that any effect of stimulating the superior speech area was
related to inhibition of motor activity. This area did not appear to have speech
function per se. (Lesion-type studies do suggest possible speech functions).
2. In stimulation of Broca’s, Wernicke’s, and the basal temporal areas at high
stimulus intensities, complete speech arrest occurred with a global receptive and
expressive aphasia; however, the patient could still perform nonverbal tasks. At
lower intensities of stimulation, the effects were incomplete: speech was slow
and simple but no complex tasks could be performed (both motor sequences and
calculations). Simple but not complex material could be repeated. A severe
naming defect (anomia) still occurred.
538 17 Higher Cortical Functions
fragmented and passed into the cortical branches supplying Broca’s area. Case 17.1
is an example of Broca’s motor aphasia.
Case History 17.1, Fig. 17.4 A 61-year-old right-handed male with sudden onset
of garbled speech and clumsiness of his right hand. This resolved over several min-
utes. He had noted a similar episode several days prior to evaluation.
Past history was notable for hypertension, coronary disease, and severe obesity.
He also had a history of elevated cholesterol.
Clinical Diagnosis. Angiogram demonstrated a left internal carotid artery stenosis
with an ulcer.
Because of repetitive spells, he underwent a left carotid endarterectomy.
Postoperatively, did well with no further recurrence of symptoms. Neurologically
intact.
Fig. 17.4, Case 17.1. Angiogram demonstrated a left internal carotid artery ste-
nosis with an ulcer (arrow)
Fig. 17.4 (a) Case 17.1. Angiogram demonstrated a left internal carotid artery stensosis with an
ulcer (arrow)
540 17 Higher Cortical Functions
Case History 17.2. This 55-year-old, right-handed white housewife while working
in her garden at 10:00 AM on the day of admission suddenly developed a weakness
of the right side of face and the right arm and was unable to speak. Nine years previ-
ously, the patient had been hospitalized with a 3-year history of progressive conges-
tive heart failure secondary to rheumatic heart disease (mitral stenosis with atrial
fibrillation). An open cardiotomy was performed with a mitral valvuloplasty (the
valve opening was enlarged) and removal of a thrombus found in the left atrial
appendage. Postoperatively, the patient was given an anticoagulant, to prevent addi-
tional emboli since atrial fibrillation continued until the present admission. She had
done well in the interim. However, prothrombin time at the time of admission was
close to normal; that is, the patient was not in a therapeutic range for
anticoagulation.
General physical examination: Blood pressure was moderately elevated to
170/80. Pulse was 110 and irregular (atrial fibrillation). Examination of the heart
revealed the findings of mitral stenosis: a loud first sound, a diastolic rumble, and an
opening snap at the apex as well as the atrial fibrillation.
Neurological examination. Mental status and language function: She had no
spontaneous speech, could not use speech to answer questions, and could not repeat
words. She was able to indicate answers to questions by nodding (yes) or shaking
her head (no), if questions were presented in a multiple-choice format. In this man-
ner, it was possible to determine that she was grossly oriented for time, place, and
person. She was able to carry out spoken commands and simple written commands,
such as “hold up your hand, close your eyes.” However, she had significant diffi-
culty in performing voluntary tongue moments (such as “wiggle your tongue,”
“stick out your tongue”) on command.
Cranial nerves: She tended to neglect stimuli in the right visual field and was
unable to look to the right on command although the head and eyes were not grossly
deviated to the left at rest. A marked right supranuclear (central) type facial weak-
ness was present. The patient had difficulty in tongue protrusion and was unable to
wiggle the tongue. When the tongue was protruded, it deviated to the right.
Motor system: There was a marked weakness without spasticity in the right upper
extremity, most prominent distally, and a minor degree of weakness involving the
right lower extremity.
Reflexes: Deep tendon stretch reflexes were increased on the right in the arm and
leg. Plantar responses were both extensor, more prominent on the right.
Sensory system: Intact within limits of testing.
Clinical diagnosis: Broca’s – anterior aphasia due to embolus from the heart to
the left middle cerebral artery, superior division.
Laboratory data: EEG was normal (48 h after admission).
Electrocardiogram revealed atrial fibrillation. CSF was normal.
Subsequent course: Within 24 h, a significant return of strength in the right hand
had occurred; independent finger movements could be made. Within 48 h after
admission, the patient was able to repeat single words but still had almost no
spontaneous speech. She appeared aware of her speech disability and was frustrated.
17.3 Aphasia: Dominant Hemispheric Functions 541
She was able to carry out two- or three-stage commands although tongue movements
and perseveration remained a problem.
Within 6 days of admission, the patient used words, phrases, and occasional
short sentences spontaneously and was better able to repeat short sentences. At this
time, strength in the right arm had returned to normal, but a right central facial
weakness was still present.
Two weeks after admission, she still had expressive disabilities consisting of
word-finding and apraxic components in tongue placement and alternating tongue
movements. Although complete sentences were used, sentence formulation in spon-
taneous speech was slow and labored with word-finding difficulties. Repetition was
better performed. In reading sentences aloud, substitutions or word omissions were
made. The patient did well in naming common pictures and in matching printed
words to spoken words or printed words to pictures. She could write from dictation
and would often respond preferentially in writing when difficulty in speaking was
encountered. A right central facial weakness was still present.
With the passage of time, this type of patient would continue to show some
degree of improvement (Mohr 1973). Improvement could continue to occur over a
2-year period. Although lesions of Broca’s area may produce the acute onset of a
nonfluent aphasia, rapid amelioration of the deficit occurs even when the acute
lesion involves underlying white matter, as well as the superficial cortex. In order to
produce a more persistent severe nonfluent aphasia with good comprehension but
poor repetition, more extensive lesions are required. In the CT scan correlation
study of Naesar (1983), this larger lesion extended from Broca’s area to the anterior
parietal lobe usually including the deep structures such as caudate, putamen, and/or
internal capsule. Ludlow et al. (1986) compared persistent versus nonpersistent
nonfluent aphasia 15 years after penetrating head injuries of the left hemisphere in
the Vietnam War. Both groups had nonfluent aphasia still present at 6 months after
injury with equal involvement of Broca’s area. The group that failed to recover at
15 years had a more extensive left-hemisphere lesion with posterior extension of the
CT scan lesion into Wernicke’s area and some involvement of the underlying white
matter and basal ganglia.
Those patients with severe nonfluency had more extensive lesions of the subcor-
tical white matter involving (a) the subcallosal fasciculus deep to Broca’s area con-
taining projections from the cingulate and supplementary motor areas to the caudate
nucleus plus (b) the periventricular white matter near the body of the left ventricle
deep to the lower motor-sensory cortical area for the mouth.
Case History 17.3, Fig. 17.5 The patient was a 19-year-old female presenting with
headaches and progressive language dysfunction. This was marked by difficulty
initiating speech but with good comprehension. Her primary physician found her to
have an anterior aphasia as well as a mild right hemiparesis.
Clinical Diagnosis. Imaging revealed a large left frontoparietal mass.
Neurosurgery was consulted. Surgery was anticipated to be in the region of the
motor cortex and the anterior language area. Because of this, diffusion tensor imag-
ing was performed. This study allows one to identify functional pathways of brain
542 17 Higher Cortical Functions
fiber tracts, in this case, motor tracts. In addition, functional MRI was performed
Fig 17.4c. This study allows one to image motor, sensory, and language regions of the
brain preoperatively. This helps in planning safe surgical trajectories. The patient had
her surgery and was diagnosed as a low-grade brain tumor called a ganglioglioma.
Below Fig. 17.4a–c are the images done preoperatively, demonstrating the technolo-
gies discussed above.
Initial MRI.
Case History 17.4, Fig. 17.5a–c This 49-year-old right-handed male presented
with a several-month history of progressive headaches, particularly early in the
morning. There were also progressive troubles with word-finding and slurred speech
per his family. This was attributed to overwork so initially he did not seek medical
attention.
After an episode of unresponsiveness and tonic–clonic shaking, he was brought
to the hospital. A CT demonstrated a left frontal mass. Neurosurgical opinion was
sought. His past history was notable for a cervical radiculopathy. He was a smoker.
Past history was otherwise unremarkable.
General exam revealed a bite on the tongue suggesting a seizure. General exam
was otherwise normal.
Neurologic exam revealed a mild expressive aphasia but no other deficits on
mental status testing. Comprehension was well preserved.
Cranial nerve exam was normal. Strength was intact in all limbs. Pin and light
touch were preserved in all extremities. Reflexes were symmetrical. Finger to nose
was done well. Gait was normal.
Clinical Diagnosis. An MRI was done demonstrating a left frontal mass in proxim-
ity to the speech area. Decadron was given, and this improved his headache and
language disturbance.
Functional MRI (Fig 17.5b) confirmed that this was in proximity to the speech
area with the speech area felt to be one gyrus posterior to the tumor edema. He
underwent an awake craniotomy with brain mapping to excise this lesion. The
pathology demonstrated this to be a glioblastoma. He began chemotherapy and
radiation and at 4 months postop was stable with an intact neurologic exam.
Comment: This is typical age for this type of tumor. It is an aggressive tumor
of the glial tissue of the brain. The presentation with progressive morning head-
aches is a classic story for a tumor. The word-finding difficulties and slurred
speech represent an aphasia. Since this tumor is so close to his anterior (motor)
speech area, it is affecting function of that area. The typical anterior type aphasia
presents as difficulty forming words with relatively good preservation of compre-
hension. Posterior (receptive) aphasias more typically present as a confused
patient with rambling speech and poor comprehension. The episode of shaking
and tongue biting are strongly suggestive of a tonic–clonic seizure, comment with
this type of disease.
17.3 Aphasia: Dominant Hemispheric Functions 543
Fig. 17.5 (a) Case 17.5. MRI demonstrating tumor in the left prefrontal cortex. (b) Case 17.5.
Functional MRI confirmed the tumor was in proximity to the speech area but with the speech area
felt to be one gyrus posterior to the tumor edema. He underwent an awake craniotomy with brain
mapping to excise this lesion. The pathology demonstrated this to be a glioblastoma. He began
chemotherapy and radiation and at 4 months postop was stable with an intact neurologic exam
544 17 Higher Cortical Functions
Neurological Examination
Mental status: He was alert but agitated. Speech was fluent and usually grammatical.
He made use of many paraphasias and neologisms (nonsense words). He often
appeared unaware of his errors. He was unable to name single objects such as pencil,
cup, and spoon though he could recognize and demonstrate their use. He could read
occasional individual words, for example, cat and house. He could not comprehend or
carry out either spoken or written commands. His attempts at spontaneous writing
produced only a few letters. He was unable to write words or phrases from dictation.
He did significantly better when asked to copy a printed sentence or phrase. Repetition
of spoken phrases or sentences was poor. Calculations of even a simple nature were
poorly performed. Reflexes: A minor increase in deep tendon stretch reflexes was
present on the right side. The plantar response on the right was equivocal. The left
was flexor.
Clinical diagnosis: Wernicke’s type of fluent aphasia probably secondary to an
embolus to the inferior division of the middle cerebral artery.
Dysgraphia may also result from disease involving the premotor cortex anterior
to the motor cortex representation of the hand. It is likely that information is con-
veyed from the inferior parietal area to the premotor motor association cortex and
then to the precentral motor cortex. This area of premotor cortex (sometimes termed
the writing center of Exner) must function in a manner analogous to Broca’s area. It
would be reasonable to consider dysgraphia from a lesion in this premotor location
as essentially a motor apraxia due to destruction of an area concerned in the motor
association memories for writing. Pure dyslexia may occur without actual involve-
ment of the angular supramarginal areas. The basic lesion as we will indicate is a
lesion that deprives the inferior parietal cortex of information from the visual asso-
ciation areas. Many lesions in the inferior parietal area extend into the subcortical
white matter involving the long association fiber system, the arcuate fasciculus – as
discussed above (Fig. 17.6). Patients with dominant inferior parietal lobule lesions
often demonstrate problems in drawing (constructional drawing). Whether this
reflects damage to the cortex of the angular and supramarginal gyri or a disconnec-
tion of these areas from the more anterior motor areas because of involvement of
subcortical association fibers is usually uncertain. As we have already discussed,
many patients have involvement of all of the components of the posterior speech
areas, the inferior parietal, the arcuate fasciculus, and Wernicke’s area. The follow-
ing case history, 17.6, demonstrates such a sequence of involvement in a tumor
infiltrating this area with greatest difficulty in repetition as the most prominent ini-
tial feature.
Table 17.3 reviews the fluent aphasias.
The following case is an example of Wernicke’s left posterior temporal aphasia.
Case History 17.6 This 57-year-old female, with a long history of hypertension in
the summer, had a brief episode of difficulty in word-finding and a more prolonged
episode in December with confusion, “visual problems,” “inappropriate speech, and
difficulty finding the appropriate words.” Following an additional episode in March
of the next year, she had persistent problems in reading and apraxia of the right hand.
546 17 Higher Cortical Functions
Fig. 17.6 The arcuate fasciculus: dissection of the long fiber system, the superior longitudinal
fasciculus demonstrating the arcuate fasciculus, passing beneath the cortex of inferior parietal, and
posterior temporal areas. A small bundle of U fibers are also demonstrated incidentally at posterior,
inferior margin of the temporal lobe interconnecting adjacent gyri (From Marcus and Jacobson,
Integrated Neuroscience, Kluwer Academic Publisher 2003)
Neurological examination:
Language function: Spontaneous speech was usually quite fluent. She described
the room, the environment, and her friend. In contrast, capacity for repetition was very
poor both as regards spoken and written speech. Spontaneous writing was very poor
except for name and address. Reading to her aloud was poor with little comprehen-
sion. She was able, however, to follow single one-stage spoken or written commands
but unable to do a sequence of commands. Naming of objects was well performed.
Cranial nerves: Extinction occurred in the right visual field for bilateral simulta-
neous stimuli.
Motor system: No hemiparesis was present.
Reflexes: Right-sided hyperreflexia and a right Babinski sign were present.
Clinical diagnosis: Posterior aphasia, infarction of the left posterior temporal and
parietal areas, due to embolic occlusion of inferior division of the left middle cere-
bral artery.
Angiograms demonstrated occlusion of the left internal carotid artery. The left
anterior and middle cerebral artery and its branches filled from the right carotid. An
artery-to-artery embolus was presumed.
Laboratory data: Infarct of the left posterior temporal and parietal areas, CT.
Dyslexia: This lesion has destroyed the visual cortex of the dominant left hemi-
sphere and at the same time damaged the posterior portion or, at least, the selenium
of the corpus callosum (or the fibers radiating from the splenium). The fibers con-
17.3 Aphasia: Dominant Hemispheric Functions 547
veying visual data from the right hemisphere reach the speech areas of the dominant
hemisphere by passing through the posterior segment of the corpus callosum.
The following Case 17.7 presents a unilateral lesion producing a transient and
partial, but selective type of dyslexia.
Case History 17.7 Seven days prior to admission, following a period of athletic
activity, this 15-year-old, right-handed white male high school student had the onset
of a 48-h period of sharp pain in the left jaw and supraorbital area. The next day the
patient noted blurring of vision and the following day had the onset of vomiting.
548 17 Higher Cortical Functions
Four days prior to admission, the patient noted that he was unable to read and to
translate his Latin lessons. No definite aphasia was apparent. Two days prior to
admission, the patient had the sudden onset of severe left facial pain, accompanied
by tingling paresthesias of the right leg. The patient became stuporous and then
unresponsive for approximately 90 min. An examination of spinal fluid at that time
revealed pressure elevated to 290 mm of water with 250 fresh blood cells.
Neurological examination. Mental status and language function: Intact.
Cranial nerves: Small flame-shaped hemorrhages were present on funduscopic
examination’s slight, right; supranuclear-type (central) facial weakness was present.
Neck: A slight degree of resistance was present on flexion of the neck (nuchal
rigidity) consistent with the presence of blood in the subarachnoid space.
Clinical diagnosis. Subarachnoid hemorrhage of uncertain etiology: In view of age
and the transient dyslexia, and the transient paresthesias of the right leg, an arterio-
venous malformation in the left parasagittal parietal-occipital area might be
suspected.
Laboratory data. Arteriogram: An arteriovenous malformation was present in
the left occipital region. The main arterial supply was the posterior temporal branch
of the left posterior cerebral artery. The malformation drained into the lateral sinus.
The posterior portion of the anterior cerebral artery was shifted across the midline,
indicating a hematoma as well as the malformation.
Subsequent course: On the evening after admission, the patient had the sudden
onset of a bifrontal headache and was unconscious for a 2- to 3-min period with
deviation (repetitive driving) of both eyes to the right and with sweating and slow-
ing of the pulse rate. Over the next 2 days, an increase in blurring of the optic disk
margins was noted (early papilledema). Four days after admission, the patient
suddenly complained of being unable to see from his right eye. He became restless
and agitated. Additional headache and neck pain with numbness of right arm and
leg were reported. Examination now disclosed a dense right visual field defect
(homonymous hemianopsia). The deep tendon reflexes were now slightly more
active on the right. Funduscopic examination suggested that recent additional sub-
arachnoid bleeding had occurred since new retinal hemorrhages were present. The
next day the patient was noted to have a significant reading disability (dyslexia),
although other language functions were intact. Because of the progressive evolution
of neurological findings due to an expanding intracerebral hematoma, Doctor
Robert Yuan performed a craniotomy, which revealed blood present in the subarach-
noid space. The left lateral occipital cortical surface had numerous areas of bluish
discoloration indicating an intracerebral clot. The main arterial vessel was a lateral
and inferior branch of the posterior cerebral artery, bearing no relationship to the
calcarine region. The draining vein was located in the occipital-temporal area, close
to the tentorium. At a depth of 1 cm, a hematoma of 50 cc of clot was found. The
clot extended down to the occipital horn of the lateral ventricle but did not enter the
ventricle. The malformation, hematoma, and related cerebral tissue of the lateral
occipital area were removed. The calcarine area remained intact at the end of the
procedure. Over a period of several days, the visual field deficits disappeared.
17.3 Aphasia: Dominant Hemispheric Functions 549
17.5 R
ole of the Corpus Callosum in the Transfer
of Information
The corpus callosum allows the non-dominant hemisphere access to the special
language centers of the dominant hemisphere. Thus, the intact right-handed indi-
vidual can name an object, such as a key; independent of whether the object is
placed in the left or right hand. Following section of the corpus callosum, the object
can be named when placed in the right hand but not when placed in the left hand. In
a similar manner, the corpus callosum allows the dominant hemisphere access to
those specialized areas of the non-dominant hemisphere concerned with concepts of
visual space. There is also evidence that the corpus callosum is involved in the trans-
fer of information concerned with learned sensory discriminations. Thus, the intact
monkey or human, who has been trained to press a key with the right hand, only
when a particular visual pattern appears in the right visual field, has no difficulty in
performing the same discrimination without additional learning when the left visual
field and left hand are employed. Section of the corpus callosum interferes with
such transfer of learned information. There is evidence, however, that some sensory
information and learned sensory discrimination is transferred between hemispheres
via non-callosal pathways.
General or Historical References 551
Ajamone-Marsan C, Ralston BL. The epileptic seizure: its functional morphology and diagnostic
significance. Springfield: Charles C. Thomas; 1957.
Alexander GE, DeLong MR. Central mechanisms of initiation and control of movement. In: Asbury
AK, McKhann GM, McDonald WI, editors. Diseases of the nervous system: clinical neurobi-
ology. 2nd ed. Philadelphia: W.B. Saunders; 1992. p. 285–308.
Brumback RA, editor. Behavioral neurology. Neurol Clin. 1993;11:1–237.
Chui H, Damasio A. Human cerebral asymmetries evaluated by computed tomography. J Neurol
Neurosurg Psychiatr. 1980;43:873–8.
Cole J. Laterality in the use of eye, hand and foot in monkeys. J Comp Physiol Psychol.
1957;50:296–9.
Commission on Classification and Terminology of the International League against Epilepsy.
Proposal for re-revised clinical and electroencephalographic classification of epileptic seizures.
Epilepsia. 1981;22:489–501.
Commission on Classification and Terminology of the International League against Epilepsy.
Proposal for a revised classification of epilepsies and epileptic syndromes. Epilepsia.
1989;30:389–99.
Corkin S, Milner B, Rasmussen T. Effects of different cortical excisions on sensory thresholds in
man. Trans Amer Neurol Assoc. 1964;89:112–6.
Coslett HB, editor. Behavioral neurology/higher cortical function. Semin Neurol. 2000a;20:
405–515.
Coslett HB. Acquired dyslexia. Semin Neurol. 2000b;20:419–26.
Coslett HB, Saffran EM. Evidence for preserved reading in pure alexia. Brain. 1989;112:327–59.
Coslett HB, Brashear HP, Heilman KM. Pure word deafness after bilateral primary auditory cortex
infarcts. Neurology. 1984;34:347–52.
Cracco RQ, Amassian VE, Maccabee PJ. Comparison of human transcallosal responses
evoked by magnetic coil and electrical stimulation. Electroencephalogr Clin Neurophysiol.
1989;74:417–24.
Damasio AR. The frontal lobes. In: Heilman KM, Valenstein E, editors. Clinical neuropsychology.
2nd ed. New York: Oxford; 1985. p. 339–75.
Damasio AR. Medical progress: aphasia. N Engl J Med. 1992;326:531–9.
Damasio H, Damasio A. The anatomical basis of conduction aphasia. Brain. 1980;103:337–50.
Damasio H, Damasio AR. Lesion analysis in Neuropsychology. New York: Oxford University
Press; 1989.
Damasio AR, Geschwind N. The neural basis of language. Ann Rev Neurosci. 1984;7:127–47.
Damasio H, Grabowski T, Frank R, et al. The return of Phineas gage: clues about the brain from
the skullof a famous patient. Science. 1994;264:1102–5.
De Renzi E. Disorders of visual recognition. Semin Neurol. 2000;20:479–86.
Dellatolas G, Luciani S, Castresana A, et al. Pathologic left-handed: left-handedness correlatives
in adult epileptics. Brain. 1993;116:1565–74.
DeRenzi E, Luchelli F. Ideational apraxia. Brain. 1988;111:1173–85.
Duffner KR, Ahern LL, Weintraub S. Dissociated neglect behavior following sequential strokes in
the right hemisphere. Ann Neurol. 1990;28:97–101.
Duffner KR, Mesulam MM, Scinto LFM, et al. The central role of prefrontal cortex in directing
attentionto novel events. Brain. 2000;123:927–39.
Dusser de Barenne JG, McCulloch WS. Suppression of motor response obtained from area 4 bys-
timulation of area 4S. J Neurophysiol. 1941;4:311–23.
Engel J Jr. Seizures and epilepsy. Philadelphia: F.A. Davis; 1989.
Ettlinger FG, editor. Function of the corpus callosum. Boston: Little, Brown and Company; 1965.
Fangel C, Kaada BR. Behavior “attention” and fear induced by cortical stimulation in the cat.
Electroencephalogr Clin Neurophysiol. 1960;12:575–88.
552 17 Higher Cortical Functions
Feinberg TE, Farah MJ. Agnosias. In: Bradley WG, et al., editors. Neurology in clinical practice.
Boston: Butterworth Heinemann; 2000. p. 131–9.
Ferrier D. Experimental researches in cerebral physiology and pathology. Rep West Riding Lunatic
Asylum. 1873;3:30–96.
Fletcher PC, Henson RNA. Frontal lobes and human memory. Insights from functional neuroimag-
ing Brain. 2001;124:849–81.
Foerster O. The motor cortex in the light of Hughlings Jackson’s doctrines. Brain. 1936;59:135–59.
Freund HJ. Differential effects of cortical lesions in humans. In: Bock G, O’Connor M, Marsh J,
editors. Motor areas of the cerebral cortex: Ciba foundation symposium. No. 132. Chichester:
Wiley; 1987. p. 269–81.
Freund HJ, Hummelshein H. Lesions of the premotor cortex in man. Brain. 1985;108:697–733.
Fried I, Materr C, Ojemann G, et al. Organization of visuospatial functions in human cortex: evi-
dence from electrical stimulation. Brain. 1982;105:349–71.
Friedman RB, Albert ML. Alexia. In: Heilman KM, Valestein E, editors. Clinical neuropsychology.
2nd ed. New York: Oxford University Press; 1985.
Fulton JF. Physiology of the nervous system. 3rd ed. New York: Oxford University Press; 1949.
Galaburda AM, LeMay M, Kemper TL, et al. Right-left asymmetries in the brain. Science.
1978;199:852–6.
Gandevia SC, Burke D, McKeon B. The projection of muscle afferents from the hand to cerebral
cortex in main. Brain. 1984;107:1–13.
Gazzaniga MS, Bogen JE, Sperry RW. Observations on visual perception after disconnections of
the cerebral hemispheres in man. Brain. 1965;88:221–36.
Geier S, Bancaud J, Talairach J, et al. The seizures of frontal lobe epilepsy: a study of clinical
manifestations. Neurology. 1977;27:951–8.
Geschwind N. Disconnection syndromes in animals and man. Brain. 1965;88:237–94. 585–644
Geschwind N. Aphasia. N Engl J Med. 1971;284:654–6.
Geschwind N, Levitsky W. Human brain: left-right asymmetries in temporal speech region.
Science. 1968;161:186–7.
Geschwind N, Quadfasel FA, Segarra J. Isolation of the speech area. Neuropsychologia.
1968;6:327–40.
Goldman-Rakic PS. Motor control function of the prefrontal cortex. In: Bock G, O’Connor M,
Marsh J, editors. Motor areas of the cerebral cortex Ciba foundation symposium. No. 132.
Chichester: Wiley; 1987. p. 187–201.
Grafman J, Vance SC, Weingartner H, et al. The effects of lateralized frontal lesion on mood regu-
lation. Brain. 1986;109:1127–48.
Green JR. Sir Victor Horsley: a centennial recognition of his impact on neuroscience and neuro-
logical surgery. BNI Quart. 1987;3:2–16.
Halsband U, Freund HJ. Premotor cortex and conditional motor learning in man. Brain.
1990;113:207–22.
Halsband U, Ito N, Tanji J, Freund HJ. The role of premotor cortex and the supplementary motor
area in the temporal control of movement in man. Brain. 1993;116:243–66.
Harlow JM. Recovery from the passage of an iron bar through the head. Mass Med Soc Publ.
1868;2:327–46.
Hausser-Hauw C, Bancaud J. Gustatory hallucinations in epileptic seizures: electrophysiological,
clinical and anatomical correlates. Brain. 1987;110:339–60.
Heilman KM, Roth LJG. Apraxia. In: Heilman KM, Valenstein E, editors. Clinical neuropsychol-
ogy. New York: Oxford University Press; 1985. p. 134–50.
Heilman KM, Valenstein ED, editors. Clinical Neuropsychology. 2nd ed. New York: Oxford
University Press; 1985.
Heilman, KM, E. Valenstein and RT Watson. 2000. Neglect and related disorders. Semin Neurol
20: 463–470.
Heilman KM, Watson RT, Valenstein E, et al. Localization of lesions in neglect. In: Kertesz A,
editor. Localization in Neuropsychology. New York: Academic Press; 1983. p. 471–92.
General or Historical References 553
Helmstaedter C, Kurher M, Linke DB, Elger CE. Right hemisphere restution of language and
memory functions in right hemisphere language dominant patients with left temporal lobe
epilepsy. Brain. 1994;117:729–37.
Kennard MA, Ectors L. Forced circling in monkeys following lesions of the frontal lobes.
J Neurophysiol. 1938;1:45–54.
Kertesz A, Geschwind N. Patterns of pyramidal decussation and their relationship to handedness.
Arch Neurol. 1971;4:326–32.
Killackey H, Ebner F. Convergent projection of three separate thalamic nuclei into a single cortical
area. Science. 1973;179:283–5.
Kirsher HS. Aphasia. In: Bradley WG, et al., editors. Boston: Butterworth Heinemann; 2000.
p. 141–159.
Landis T, Regard M, Bliestel A, et al. Prosopagnosia and agnosia for non-canonical views: an
autopsied case. Brain. 1988;111:1287–97.
Legarda S, Jayakar P, Duchowny M, et al. Benign rolandic epilepsy: high central and low central
subgroups. Epilepsia. 1994;35:1125–9.
Lehman R, Andermann F, Olivier A, et al. Seizures with onset in the sensorimotor face area:
clinical patterns and results of surgical treatment in 20 patients. Epilepsia. 1994;35:1117–24.
Leiguarda RS, Marsden CD. Limb apraxias. Higher order disorders of sensori motro integration.
Brain. 2000;123:860–79.
Leiguarda R, Starkstein S, Berthier M. Anterior callosal hemorrhage: a partial interhemispheric
disconnection syndrome. Brain. 1989;112:1019–37.
LeMay M, Culebras A. Human brain morphologic differences in the hemispheres demonstrable
by carotid arteriography. New Eng J Med. 1972;287:168–70. (see also N. Geschwind. 1972.
Editorial. New Eng. J. Med. 187:194-195).
LeMay M, Geschwind N. Asymmetries of the human cerebral hemispheres. In: Caramazza A,
Zurif EB, editors. Language acquisition and breakdown. Baltimore: Johns Hopkins; 1978.
p. 311–28.
LeMay M, Kido DK. Asymmetries of the cerebral hemispheres on computed tomograms. J Comput
Assist Tomogr. 1978;2:471.
Luders H, Lesser RP, Dinner DS, et al. The second sensory area in humans: evoked potential and
electrical stimulation studies. Ann Neurol. 1985;17:177–84.
Luders H, Lesser RP, Dinner DS, et al. Localization of cortical function: new information from
extraoperative monitoring of patients with epilepsy. Epilepsia. 1988;29(Suppl 2):56–65.
Ludlow CL, Rosenberg JR, Fair C, et al. Brain lesions associated with nonfluent aphasia, fifteen
years following penetrating head injury. Brain. 1986;109:55–80.
Lynch JC, Mountcastle VB, Talbot WH, et al. Parietal lobe mechanisms for directed visual atten-
tion. J Neurophysiol. 1977;40:362–89.
Marcus EM, Watson CW, Simon SA. Behavioral correlates of acute bilateral symmetrical epilep-
togenic foci in monkey cerebral cortex. Brain Res. 1968;9:370–3.
Marcus EM, Jacobson S, Watson CW, et al. An experimental model of “petit mal epilepsy” in
the monkey: additional studies of the anterior premotor area. Trans. Amer. Neurol. Assoc.
1970;95:279–81.
Meador KF, Watson RT, Bowers D, et al. Hypometria with hemispatial and limb motor neglect.
Brain. 1986;109:293–305.
Mesulam MM, Hoeser GWV, Pandya DN, et al. Limbic and sensory connections of the inferior
parietal lobule (area PG) in the rhesus monkey. Brain Res. 1977;136:393–414.
Meyer B-U, Roricht S, Gafin von Einsiedel H, et al. Inhibitory and excitatory interhemispheric
transfers between motor cortical areas in normal humans and patients with abnormalities of the
corpus callosum. Brain. 1995;118:429.
Part III
Neuropathology
Chapter 18
Cerebral Vascular Disease
Abstract Definition: Cerebral vascular disease refers to disorders of the blood vessels
supplying the brain and spinal cord, which result in neurological symptoms and signs.
The term stroke or cerebral vascular accident refers to an event characterized
by acute onset of these neurological signs and symptoms. The term ictus is used
synonymously.
Demographics: Cerebrovascular disease is the third leading cause of death in
the United States accounting for 10% of all deaths. Approximately 300,000 new
strokes and 300,000 recurrent strokes occur per year in the United States. Age-
adjusted incidence varies between 100 and 300 per 100,000 population depending
on ethnic background and socioeconomic class. Stroke mortality in the United
States began to decline in the early 1900s, and this decline continued throughout the
1900s. This decrease predated the development of antihypertensive drugs and of
antibiotics, anticoagulants, and antiarrhythmic drugs. The explanation for the ear-
lier years of decline is unclear; this may relate to improved hospital care of stroke
patients, resulting in improved survival. The prevalence of stroke survivors in the
United States is approximately 4,000,000 constituting a significant percentage of
the disabled population.
With cerebral vascular disease being a primary cause of damage in the brain, we have included an
overview of cerebral vascular disease and the major syndromes one will encounter. The term refers
primarily to disease of arteries. At present, disease of cerebral veins and sinuses is not common.
(a) The circle of Willis at the base of the brain: the anterior communicating
artery between the two anterior cerebral arteries, the posterior communicat-
ing arteries between the carotid arteries and the posterior cerebral arteries.
Note that variations in the circle of Willis also account for variation in pat-
terns of infarction.
(b) Leptomeningeal anastomoses over the surface of the cerebral hemi-
spheres between the anterior, middle, and posterior cerebral arteries:
Consequently, for each cerebral artery, there is an area of central supply and
one for peripheral supply. The area of peripheral supply constitutes a border
zone or watershed overlapping with the adjacent arterial territory. Similar
leptomeningeal anastomoses also occur over the surface of the cerebellum
between the circumferential branches of the posterior inferior, anterior infe-
rior, and superior cerebellar arteries.
(c) Anastomoses are present between the external and internal carotid
arteries—for example, between external carotid branches and the ophthal-
mic artery. Anastomotic flow may also occur from the external carotid artery
to the muscular branches of the vertebral artery in the neck.
3. Types of Ischemic–Occlusive Disease: Three major categories may be identified.
(a) Atherosclerosis produces ischemia, at times progressing to infarction sec-
ondary to stenosis/occlusion.
(b) Embolism of cardiac or arterial origin constitutes 60% of all cases. Embolic
occlusion is an acute phenomenon. Emboli tend to occur during the active wak-
ing hours. In addition, the anatomical pattern of involvement often suggests
embolic disease, for example, occlusion of the cortical branches of the middle or
posterior cerebral arteries or of the stem of the middle cerebral artery. In terms of
cardio-embolic infarcts, approximately 40% of patients have atrial fibrillation.
(c) Lacunar infarction secondary to occlusion of small penetrating arteries.
These small infarcts are usually within the distribution of a penetrating
artery which has been occluded by a process of fibrinoid degeneration or
lipohyalinosis occurring on a background of long-standing hypertension or
diabetes mellitus.
1. I nternal carotid artery (ICA). This is the most common artery involved in patients
with infarction secondary to atherosclerosis. Not all patients with occlusion of the
carotid artery will have an actual infarct. When infarction occurs the distributions
of an occlusion, distribution is as follows: combined MCA and ACA territory
37.5%, total MCA territory 13% proximal core cortical and deep territory of MCA
21%, watershed cortical territory 29%, and terminal or deep border zone 5%.
(a) The carotid border zone syndrome. The carotid border zone corresponds to
that area of the motor and sensory cortex representing the upper extremity.
The patient will experience episodes of weakness and paresthesias in the
upper extremity. When an infarct occurs, a persistent weakness and sensory
560 18 Cerebral Vascular Disease
deficit will involve the upper extremity. This area of cortex is dependent on an
overlapping blood supply from both the MCA and ACA. With increasing
stenosis of the carotid artery, there is decreased perfusion within this border
zone/watershed region. The adjacent MCA proximal cortical territory may be
involved if the ischemia involves a larger area of cortex with the presence of
a central facial (upper motor neuron) paralysis plus aphasia, if the dominant
hemisphere is involved. The major differential diagnosis is transient ischemia
in the brachial artery distribution.
(b) The ophthalmic artery: Transient retinal ischemia produces transient mon-
ocular blindness (amaurosis fugax). This is often described as a painless dark
shade or curtain, descending over the vision of the involved eye.
Case History 18.1: MCA infarct due to carotid stenosis. This 85-year-old right-
handed male presented with sudden onset of clumsiness and numbness of his left
face and arm. It was painless. He had had no prior episodes of this sort. Several
hours after onset, he went to the emergency room where he was evaluated. Imaging
included a CT scan and, later, an MRI. A right frontoparietal infarct was demon-
strated. Ultrasonography demonstrated a high-grade right carotid stenosis in the
neck. His past history was notable for hypertension, high cholesterol, and coro-
nary disease. General examination revealed a right carotid bruit in the neck. He
was moderately overweight. Neurologic exam revealed a central left facial weak-
ness as well as mild weakness in the left arm, particularly the hand and forearm.
Carotid stenting or surgery was offered as option although the patient declined
either. He made a slow and incomplete recovery over several weeks.
2. Middle cerebral artery syndromes: The MCA is the major terminal branch
of the internal carotid artery (ICA).
(a) Syndromes of the penetrating lenticulostriate branches. Occlusion of
these branches produces a small deep infarct, a lacunar syndrome involving
the internal capsule. The most common syndrome is the pure motor syn-
drome involving weakness of contralateral face, arm, and leg which resolves
over days or weeks. Involvement of several branches will produce a larger
lesion with a paralysis that is more persistent. Note that a less common cause
of the pure motor syndrome is a lacunar infarct of the upper basilar arterial
distribution of the pons.
(b) C ombined syndrome: total occlusion of the initial segment of the MCA.
The patient will present the acute onset of a dense contralateral paralysis and
hemianesthesia involving the face, arm, and leg, a contralateral homony-
mous hemianopsia, plus deviation of the eyes to the ipsilateral side of the
infarct. When the dominant hemisphere is involved, the patient will be mute
with no understanding of speech (a mixed anterior–posterior global aphasia
will be present). Although initially alert, within 24–72 h, the patient will
often become drowsy due to swelling of the hemisphere secondary to signifi-
cant edema plus or minus a hemorrhagic infarction component. In 30% of
cases, transtentorial herniation will occur with dilatation and paralysis of the
ipsilateral pupil. Progressive brain stem compression will occur resulting in
death within a week of the onset of symptoms.
18.2 Clinical Correlates of Vascular Territories: Syndromes 561
(c) Syndromes of the cortical branches: In general, these syndromes are usu-
ally embolic. Either the main cortical stem or the superior division supplying
the precentral and postcentral gyri or the inferior division supplying the pos-
terior parietal lobules and superior temporal gyri may be involved. Involvement
of the main cortical stem produces a contralateral mixed cortical motor –sen-
sory syndrome involving face and arm.
Case History 18.2: Total middle cerebral artery occlusion. This 61-year-old,
right-handed hypertensive female, 1 week prior to admission, suddenly fell to the
floor while taking a bath and lost consciousness. She was found by her son who
noted that she was unable to move her left arm and leg. Her speech had been
“thick,” but no overt aphasia had been present. No headache had been noted.
Both parents had died of heart disease and hypertension.
Physical examination: Blood pressure was 150/100 and pulse was regular at 84.
Neurological examination:
Mental status: The patient was obtunded and slow to respond but grossly ori-
ented to time, place, and person.
Cranial nerves: Papilledema was present bilaterally particularly in the right
fundus where a recent hemorrhage was present. The head and eyes were deviated
to the right. The eyes did not move to the left on command but did move to the
left on vestibular stimulation. The patient neglected stimuli in the left visual
field. Pain sensation was decreased or neglected on the left side of the face.
A marked left central facial weakness was present.
Motor system: A complete flaccid paralysis of the left arm and leg was present.
Reflexes: Deep tendon reflexes were increased on the left compared to the
right. The left plantar response was extensor.
Sensory system: All modalities of sensation were decreased on the left side.
Clinical diagnosis: Acute occlusion of the stem of the middle cerebral artery, possibly
embolic, although primary occlusions of intracranial arteries may occur in the non-
Caucasian population. Hypertensive intracerebral hemorrhage was also possible.
Laboratory data: The EEG indicated severe focal damage with a relative
absence of electrical activity in the right temporal area and focal 3–5 Hz slow
waves most prominent in the right frontal area.
Right brachial arteriogram revealed a complete occlusion of the right middle
cerebral artery at its origin.
Hospital course: The patient showed no significant improvement during a
4-week hospital course.
Comment: Prognosis for survival during the acute state of the first week
depends on the degree of cerebral edema. In patients with massive middle cere-
bral artery territory infarcts due to MCA occlusion who already had early CT
scan evidence of brain swelling within 24 h of the ictus, the majority of these
patients expired, overwhelmingly of herniation effects. Patients older than
45 years had a poorer prognosis than younger patients. Pneumonia is a serious
complication of large infarcts and a major cause of death after the second week.
If the patient survives, prognosis for recovery is related to the size of infarct.
Infarcts of less than 3 cm are associated with a fair to good recovery, greater than
3 cm with severe disability (Olson 1991).
562 18 Cerebral Vascular Disease
Fig. 18.2 Case History 18.5. Anterior cerebral arteries (ACA): old bilateral infarcts due to severe
bilateral stenosis of ACA (complete occlusion on right). (A) Left hemispheric involvement was
marked with (B) a lesser involvement of the right hemisphere. This 61-year-old, right-handed
female 16 months prior to death developed difficulty in speech, right-sided weakness, and apraxia
of hand movements and progressed 2 days later to an akinetic mute state with urinary incontinence.
(Courtesy of Drs. John Hills and Jose Segarra; Marcus and Jacobson (2003))
(b) Cortical branches. These supply the orbital and medial frontal cortex, the genu
and body of the corpus callosum, and the medial aspects of the premotor, motor,
and sensory cortex (supplementary area and paracentral lobule). The resulting
infarct will produce a weakness and cortical sensory deficit of the contralateral
lower extremity, impairment of bladder control, release of grasp and other pre-
motor frontal reflexes, and possible alteration of personality and of level of
consciousness. Patient may have an abulic or hyperactive restless state.
18.2 Clinical Correlates of Vascular Territories: Syndromes 565
Fig. 18.3 Case History 18.6. Weber’s syndrome. An area of infarction is noted in the right cerebral
peduncle (arrow), so located as to involve the exiting fibers of the right third cranial nerve. This
61-year-old patient with rheumatic heart disease, endocarditis, and auricular fibrillation had the
sudden onset of paralysis of the left face, arm, and leg, plus a partial right third nerve palsy
(Courtesy of Dr. John Hills, and Dr. Jose Segarra; From Marcus and Jacobson (2003))
566 18 Cerebral Vascular Disease
putamen supplied by penetrators from the MCA may also produce a contralateral
hemichorea. Occasionally, small hemorrhages or metastatic lesions may be local-
ized to the subthalamic nucleus.
(c) Thalamic syndrome: Infarcts involving the thalamogeniculate supply to the
ventral posterior lateral and ventral posterior medial nuclei may produce a contra-
lateral loss of sensation and a “thalamic pain syndrome;” See Fig. 8.8.
(d) Bilateral paramedian thalamic infarcts: The patient may present the acute
onset of excessive daytime drowsiness associated with changes in personality and
problems in recognition of familiar individuals and photographs. New learning may be
defective. The syndrome is usually transient, clearing over several weeks. The mem-
ory problems might raise the differential of hippocampal ischemia.
(e) Cortical branch syndromes of posterior cerebral artery—Fig. 18.4.
Overall infarcts involving the cortical territory of this artery account for 5% of all
infarcts. The entire cortical territory or the branches may be involved. In general,
occlusions of the cortical branches are a result of emboli particularly in the Caucasian
population. At times emboli to the top of the basilar artery may produce involve-
ment of both posterior cerebral arteries.
(1) Anterior and posterior temporal branches of the posterior cerebral
artery supply the medial and inferior surfaces of the temporal lobe. Ischemia and
infarction of the dominant mesial temporal area including the hippocampus may
produce a confusional state. Bilateral involvement of the mesial temporal areas will
produce a persistent defect in the ability to record new memories (a persistent antero-
grade amnesia). Infarction of the inferior temporal areas may disconnect the visual
cortex from the memory recording areas and from the speech areas. There may be
problems in visual recognition.
Fig. 18.4 Case History 18.7. (A) Occlusion of right posterior cerebral artery (arrow) MRA. (B)
Resultant Infarct in right occipital area, calcarine artery branch territory with homonymous hemi-
anopsia, embolus to posterior cerebral artery from the heart (MRI). Marcus and Jacobson (2003)
18.2 Clinical Correlates of Vascular Territories: Syndromes 567
(2) Calcarine artery branches of the posterior cerebral artery supply the
visual cortex. Infarction of this territory produces a contralateral homonymous
hemianopsia. The macular area is often spared since this central area of vision is
located near the occipital pole and receives collateral circulation from the leptomen-
ingeal branches of the middle cerebral artery.
Occlusion of the stem of the cortical branches in this syndrome is usually embolic
and is characterized by sudden onset of headache, confusion, and visual impair-
ment, if a unilateral visual field defect is seen if bilateral cortical blindness will be
seen with preservation of papillary responses. As the embolus fragments and col-
lateral circulation reduces the ischemia, the confusion may clear, and vision may
return to some degree.
Combined syndrome: cortical plus penetrating branches. Due to embolus from the
top of the basilar artery which combines midbrain, thalamic, and cortical syndrome
5. Vertebral and basilar artery syndromes of the brain stem.
The two vertebral arteries join to form the basilar artery at the junction of the
pons and medulla.
(a) Arterial supply to the cerebellum—also review in Chap. 13.
(1) Posterior inferior cerebellar artery (PICA), usually originating from the ver-
tebral artery: An initial medial branch of this vessel supplies the lateral tegmental
area of the medulla, and the medial and lateral branches supply the cerebellum.
(2) Anterior inferior cerebellar artery (AICA), originating from the lower third
basilar artery: The initial branches of this vessel supply the lateral tegmental area of
the lower pons.
(3) Superior cerebellar artery (SCA), originating from the rostral basilar artery:
Proximal branches supply the lateral tegmental area of the rostral pons and caudal
mesencephalon and may also pulse against the trigeminal nerve producing trigemi-
nal neuralgia (Chap. 6).
All three vessels supplying the cerebellum have extensive leptomeningeal anas-
tomoses over the surface of the cerebellum that are similar to the leptomeningeal
anastomoses of the arteries supplying the cortical surface of the cerebral hemi-
spheres. As a consequence, vertebral artery occlusion may result in a lateral medul-
lary infarct and syndrome, but infarction of cerebellum may be absent or limited. As
in the cerebral hemispheres, border zone infarctions may occur. On the other hand,
embolic occlusion is frequently implicated in cerebellar vascular syndromes.
The top of the basilar artery gives rise to the posterior cerebral arteries at the junc-
tion of the pons and midbrain. The various ischemic vascular syndromes may be
divided into the paramedian (penetrating) and circumferential branch syndromes.
(b) Paramedian branch syndromes: These syndromes always involve the pyra-
midal tract producing a contralateral hemiparesis. Often the contralateral upper
motor neuron hemiparesis is associated with a lower motor neuron ipsilateral cra-
nial nerve syndrome, e.g., Weber’s syndrome of ipsilateral third nerve and contralat-
eral hemiparesis (Fig. 18.5).
(c) Medullary syndrome: Occlusion of the penetrating branches of the vertebral
artery will produce a syndrome characterized by an ipsilateral paralysis and atrophy
of the tongue combined with a contralateral upper motor neuron hemiparesis of arm
568 18 Cerebral Vascular Disease
and leg. At times there may be a contralateral deficit in position sense and vibratory
sensation and other higher modalities of sensation due to involvement of the medial
lemniscus.
(d) Lower pontine syndrome: If unilateral the syndromes will combine an ipsi-
lateral lower motor neuron involvement of cranial nerves 7 (facial) and 6 (abducens/
lateral rectus) with a contralateral upper motor neuron hemiparesis. If the area of
infarction extends into the tegmentum to involve the area of reticular formation
around the abducent nucleus, an ipsilateral gaze paralysis may be present as well as
an internuclear ophthalmoplegia due to involvement of the medial longitudinal fas-
ciculus. Bilateral infarcts that may result from a basilar artery thrombosis are more
common producing a locked-in syndrome. Vertical eye movement and eyelid move-
ments are preserved since the midbrain has been spared.
(e) Upper pontine syndrome: If unilateral, the resultant syndrome reflects the
unilateral involvement of the corticospinal and corticobulbar tracts producing a con-
tralateral pure upper motor neuron syndrome of the face, arm, and leg. This pure
motor syndrome is more often due to an infarct in the lenticulostriate MCA branches
supplying the posterior limb of the internal capsule. Basilar artery thrombosis more
often produces a bilateral infarct in which attacks of left or right hemiparesis may be
followed by a quadriparesis. If the upper midbrain is spared, the patient may present
a locked-in syndrome. When the area of thrombosis extends to the top of the basilar
artery, the midbrain will also be involved; the patient will no longer have any eye
movements and could be potentially totally “locked in,” that is, awake but unable to
communicate in any way.
(f) Circumferential branch syndromes: These syndromes reflect the involve-
ment of the lateral tegmental territories of the three cerebellar arteries. These arter-
ies are named from that surface of the cerebellum which each supplies. Occlusion
of these arteries may produce an infarct of the lateral tegmentum of the brain stem
18.2 Clinical Correlates of Vascular Territories: Syndromes 569
and/or the cerebellar territory. Prior to the development of modern imaging (CT and
MRI), the actual involvement of the cerebellum in patients with the lateral tegmen-
tal syndrome was often missed since the cerebellar pathways also were involved
within the brain stem.
This syndrome, Fig. 18.6, reflects the infarction of the territory of the posterior
inferior cerebellar artery (PICA) supplying the rostral lateral medulla. The actual
point of occlusion is more often located at the intracranial segment of the vertebral
artery than at the PICA. In the pure or modified form, it is one of the more common
of the classical brain stem syndromes.
The following structures overlap with the lateral medullary syndrome: the ves-
tibular nuclei and the entering vestibular portion of the eighth cranial nerve (sudden
vertigo, nausea, and vomiting plus nystagmus), cerebellar peduncle (ipsilateral cere-
bellar symptoms), descending spinal tract and nucleus of the trigeminal nerve (ipsi-
lateral selective loss of pain and temperature over the face), spinothalamic tract
(contralateral loss of pain and temperature over the body and limbs), and descending
sympathetic pathway (ipsilateral Horner’s syndrome). This syndrome is sometimes
seen as one component of a wider basilar artery syndrome. Included within this ter-
ritory are the following: the inferior cerebellar peduncle (ipsilateral finger-to-nose
and heel-to-shin dysmetria and intention tremor), the vestibular nuclei (vertigo, nau-
sea, and vomiting plus nystagmus), the descending spinal tract and nucleus of the
trigeminal nerve (ipsilateral selective loss of pain over the face), the spinothalamic
tract (contralateral loss of pain and temperature over the body and limbs), the
descending sympathetic pathway (ipsilateral Horner’s syndrome), and the nucleus
ambiguus (dysarthria, hoarseness, ipsilateral vocal cord paralysis, and difficulty in
swallowing with ipsilateral failure in palatal elevation).
Case History 18.9, Fig. 18.9. Lateral medullary syndrome.
This 53-year-old male had the sudden onset of vertigo accompanied by nausea
and vomiting, incoordination of his left arm and leg, and numbness of the left side
of his face. On standing, he leaned and staggered to the left. Several hours later, he
noted progressive difficulty in swallowing, and his family described a minor dysar-
thria. He had a 10-year two-pack-per-day cigarette history.
Physical examination: Elevated blood pressure of 166/90
Neurologic examination. Mental status: Intact
Cranial nerves: The right pupil was 3 mm in diameter; the left was 2 mm in diam-
eter. Both were reactive to light. There was partial ptosis of the left eyelid. Both of
these findings consistent with a Horner’s syndrome. A horizontal nystagmus was
present on left lateral gaze, but extraocular movements were full. Pain and tempera-
ture sensation was decreased over the left side of the face, but touch was intact. Speech
was mildly dysarthric for lingual and pharyngeal consonants. Secretions pooled in the
pharynx. Although the palate and uvula elevated well, the gag reflex was impaired.
Motor system: A dysmetria was present on left finger-to-nose test and heel-to-
shin tests. He tended to drift to the left on sitting and was unsteady on attempting to
stand, falling to the left.
Reflexes: Deep tendon reflexes were physiologic and symmetrical except for
ankle jerks which were absent. Plantar responses were flexor.
Sensory system: Pain and temperature sensations were decreased on the right
arm and leg, but all other modalities were normal.
Clinical diagnosis: (1) Dorsolateral medullary infarct
(2) Decreased ankle jerks due to possible diabetic peripheral neuropathy
Laboratory data. An MRI indicated a significant acute or subacute
infarct involving the posterior inferior cerebellar artery territory of the left dorso-
lateral medulla and left posterior inferior cerebellum. MRA suggested decreased
flow in the left vertebral artery.
Subsequent course: A percutaneous endoscopic gastrostomy (PEG) tube was
placed since he was unable to swallow for the first 6 days. By the time of transfer to
a rehabilitation facility, 12 days after admission, finger-to-nose tests and gait had
improved, and he could walk with a walker. Speech and sensory examination had
returned to normal.
(g) Inferior pontine lateral tegmental syndrome. This syndrome reflects
infarction of the territory supplied by the anterior inferior cerebellar artery that usu-
ally arises from the basilar artery and supplies the cochlear nucleus and the auditory
portion of the entering eighth cranial nerve (sudden ipsilateral deafness) and the
facial nerve (ipsilateral peripheral facial paralysis). Many of the symptoms overlap
the lateral medullary symptoms plus nystagmus, cerebellar peduncle with ipsilateral
cerebellar findings, descending tract of nucleus of V (ipsilateral loss of pain and
temperature over the face), spinothalamic (contralateral loss of pain and tempera-
ture over the body), and descending sympathetic syndrome.
(h) Superior pontine lateral tegmental syndrome: The superior cerebellar
artery supplies this territory. At this level, the following structures are involved: the
medial lemniscus and the lateral spinothalamic pathway (contralateral hemianesthe-
sia and hemianalgesia of body and limbs) and secondary trigeminothalamic fibers
(contralateral deficit in pain and touch sensation over the face and superior cerebellar
peduncle (brachium conjunctivum) below or above its decussation (ipsilateral,
contralateral, or bilateral cerebellar symptoms of intention tremor, etc.).
18.2 Clinical Correlates of Vascular Territories: Syndromes 571
(i) Ischemic occlusive disease involving the cerebellum. Autopsy studies local-
ize 1.5–4.5% of all infarcts to the cerebellum. However, CT scan studies indicate
that cerebellar infarcts account for 15% of all intracranial infarcts; the majorities
(80–90%) is not large and are not fatal.
(j) Ischemic occlusive disease of the spinal cord (the anterior spinal artery
syndrome).
The spinal cord is supplied by a major single anterior spinal artery and two poste-
rior spinal arteries. The major vessel, the anterior spinal artery, has a bilateral origin
from the intracranial vertebral arteries. It is dependent on additional supply from the
radicular arteries that originate from intercostal arteries. The inputs from the middle
thoracic artery at T7 and the artery of the lumbar enlargement (of Adamkiewicz) that
usually arises between T 10 and L2 are of critical importance. There are border zones
of arterial circulation at segments T4 and L1. The lesser arterial supply from the
paired posterior spinal arteries has a similar origin from the vertebral arteries.
When infarcts occur, the territory of the anterior spinal artery is usually involved.
This artery supplies the anterior two-thirds of the spinal cord, essentially all of the spi-
nal cord, except the posterior columns. The usual area of infarction is the middle-lower
thoracic spinal cord. The usual syndrome is characterized by the acute onset of a flaccid
paraplegia with an absence of deep tendon reflexes in the lower extremities due to spi-
nal shock and a bilateral pain sensory level at T7-T8. Position and vibratory sensation
will be preserved. If the area of infarction also involves the lumbar sacral spinal cord,
with destruction of the anterior horn cells at that level, the legs will remain flaccid with
muscle atrophy and a loss of deep tendon reflexes. If only the middle–lower thoracic
cord is infarcted, deep tendon reflexes will recover, and spasticity could develop.
Primary vascular disease of the spinal cord is not common. Actual occlusion of
the anterior spinal artery is rare. The usual cause of the anterior spinal artery syn-
drome relates to atrial fibrillation, disease of the aorta, or surgical procedures involv-
ing the heart, aorta, or related vessels: (1) clamping of the aorta for treatment of an
aortic aneurysm and (2) clamping of intercostal branches particularly during surgi-
cal procedures on the kidney and sympathetic ganglia. Dissecting aneurysms of the
aorta may also occlude the critical intercostal vessels.
by hypertension. However, in the elderly, lobar hemorrhages may also occur secondary
to amyloid degeneration of arteries. This category accounts for 5–17% of all strokes
depending on the era and ethnic group surveyed. The incidence among African-
Americans in the United States is 50 per 100,000 populations, approximately double the
incidence in the Caucasian population. These differences are correlated with differences
in prevalence of hypertension, level of attained education, lack of awareness of primary
prevention, and lack of access to health care. In the United States, hypertension detec-
tion and treatment programs have been able to achieve a 33–46% reduction in the over-
all risk of stroke including intracerebral hemorrhage. In the younger adult population,
the use of amphetamines and of illicit street drugs, such as “crack” cocaine, has been
implicated as a risk factor. Note that cocaine may also induce hypertension and vaso-
constriction producing cerebral infarction. The use of anticoagulants and of fibrinolytic
agents can also be complicated by intracerebral hemorrhage.
(1) Major clinical signs: the sudden onset of the worst possible headache ever
experienced by the patient. This is the classical clinical pattern. The headache
has been described as explosive or as “thunderclap.” Such patients should be
assumed to have a subarachnoid hemorrhage (SAH) until proven otherwise.
Approximately 11% of patients also report in retrospect a severe headache
sometimes referred to as a warning or sentinel headache in the day or weeks
prior to the emergency room presentation. Meningeal irritation with nuchal
rigidity usually takes several hours to develop as the blood must migrate to the
infratentorial and cervical area.
Immediate CT scan: This will be positive for subarachnoid blood in 90–95%
of patients if obtained in the first 24 h after the SAH. In the other 5–10% of sus-
pected cases where the CT scan is normal, a lumbar puncture should be obtained.
The diagnosis of subarachnoid hemorrhage (SAH) is based on the presence of
blood in the subarachnoid space.
(2) C
ause of subarachnoid hemorrhage (SAH). The cause in over 85% is a rupture
of a saccular aneurysm due to a defect in the media and internal elastic mem-
brane. Unless promptly recognized and treated, a large percentage of patients will
die of the initial SAH or of complications. A significant percentage of patients
will die before they reach the hospital (12%) or neurosurgical center (30%).
18.5 C
ommon Sites of Saccular Aneurysms (Fig. 18.7),
Table 18.1
(a) The junction of the posterior communicating and the internal carotid arter-
ies. Approximately 30% of aneurysms.
(b) The bifurcation of the middle cerebral artery in the lateral fissure.
Approximately 20% of all aneurysms. Focal symptoms will be present in the
Fig. 18.7 Common sites of saccular aneurysms in the arterial circulation to the brain. (From
McDowell, F: In Beeson, P.B. and McDermott, W; Textbook of Medicine, 13th Edition, Philadelphia,
W.B. Saunders, 1971, p. 230)
MCA territory, including focal seizures or weakness involving the face and pos-
sibly the hand. If the dominant hemisphere is involved, speech may be affected.
(c) The junction of the anterior communicating and anterior cerebral arteries.
Approximately 30% of all aneurysms with SAH from an aneurysm in this
location usually produce a poorly localized syndrome characterized by coma or
obtundation with bilateral Babinski signs.
(3) Less common locations are the following: Basilar vertebral system. 5–10%
of all aneurysms and multiple aneurysms. 15% of all aneurysms
The carotid artery in the cavernous sinus. This is an uncommon location.
Pulsating exopthalmos and a cavernous sinus syndrome maybe present.
(4) Perimesencephalic hemorrhage: This category accounts for 15–20% of all
cases. The bleeding is usually venous in origin (or possibly from capillary
telectangiectasia) into the cisterns about the midbrain and pons. The clinical
manifestation consists of sudden severe headache. In some cases, a transient
loss of consciousness occurs. The diagnosis is based on the presence of blood
in the perimesencephalic and peripontine cisterns.
(5) Other causes of SAH. These accounts for 5% of case with 2.5% due to vas-
cular malformations, and the remainder are due to complications of bacterial
endocarditis (mycotic aneurysms) or to a vasculitis.
(6) Demographics: This category refers to primary bleeding into the subarach-
noid space. As outlined below in Table 18.1, the major cause in 85% of cases
is the rupture of intracranial aneurysms. These aneurysms have a defect in the
media and internal elastic membrane of the arterial wall. They are located at
critical junction or bifurcation points. In a significant proportion of cases, the
bleeding extends into the parenchyma or the ventricles of the brain. Mortality
is high, particularly if rebleeding occurs.
(7) Risk factors for subarachnoid hemorrhage are:
• Age: The incidence increases with age peaking in the sixth decade.
• Race: Blacks have a 2.1× greater risk than whites, except Finnish ancestry.
Whether this risk is independent of hypertension is unclear.
• Gender: There is a moderate preponderance of female with a 1.6× greater
risk of hypertension: Relative risk of 2.8.
• Smoking: Relative risk of 1.9.
• Daily alcohol intake of >2 units: Relative risk of 4.7
Case History 18.11, Fig. 18.8a, b. This 66-year-old male with sudden onset of
excruciating headache and sudden lapse into coma with left hemiparesis. CT dem-
onstrated a subarachnoid hemorrhage and enlarged cerebral ventricles. He had a
ventriculostomy placed due to acute hydrocephalus. This is a spinal fluid drainage
tube to divert CSF.
The patient was awakened, and the angiogram revealed a right middle cerebral
aneurysm.
Clinical Diagnosis. Right middle cerebral artery aneurysm (Fig. 18.11a).
Surgery and prolonged rehabilitation but ultimately good recovery
18.5 Common Sites of Saccular Aneurysms 575
Fig. 18.8 (a) Case History 18.11. Aneurysm in right temporal lobe. (b) Case History
Reconstruction of Aneurysm in right MCA (arrow) MRA-3D reconstruction
Chapter 19
Neuropathology, Nonvascular: Trauma,
Neoplasms, and Communicable Diseases
Abstract In the era of the automobile, bicycle, and motorcycle, trauma to the head
constitutes one of the most frequent neurological problems presented to emergency
room physicians. Not all head injuries involve the brain. Significant scalp lacera-
tions and simple skull fractures may be present without the development of signifi-
cant neurological deficits. On the other hand, closed head injuries may be present
with significant neurological signs but without major external signs of head trauma
(i.e., the scalp and skull appear intact).
Trauma is the most frequent cause of death and disability in children and young
adults. Injury to the brain and spinal cord constitutes the major reason for prolonged
costly hospitalizations in young adults, since such patients often require prolonged
intensive critical unit and long-term rehabilitative care. The long-term effects of
interruption of what were once expected to be productive careers cannot be calcu-
lated simply in terms of the billions of dollars involved but must also take into
account the personal and family miseries, which are incurred.
Certain types of skull injuries provide serious problems as regards the brain and
require surgical attention. Thus, depressed skull fracture may compress the cerebral
cortex, with bony splinters lacerating the dura and cortex.
Penetrating head injuries (the object causing trauma has penetrated the skin,
bone, and meninges) cause direct brain injury and may introduce contaminated
material into the brain, producing abscess formation and meningitis. Fractures
involving the cribriform plate with laceration of the overlying dura and arachnoid
may result in the loss of olfactory sensation (anosmia) and cerebrospinal rhinorrhea:
the drainage of spinal fluid through the nose. The presence of such a pathway, of
course, allows for the ready entry of bacteria from the nasopharynx into the cerebro-
spinal fluid spaces, producing recurrent episodes of meningitis. Air may also enter
the intracranial cavity through this passageway. Both air and infection may also
enter when skull fractures extend into any of the paranasal sinuses or the middle ear.
In the latter instance, a cerebrospinal fluid otorrhea may occur: drainage of spinal
fluid from the external ear canal. Such basilar skull fractures may extend across the
petrous pyramid or tear the tympanic membrane. The blood may be present in the
external ear canal or behind the tympanic membrane. If the basilar skull fracture
extends into the sigmoid sinus, the tissue over the mastoid may show delayed hema-
toma with discoloration of the skin and subcutaneous tissue (“Battle’s sign”).
19.1.2 Concussions
Fig. 19.1 Brain sections from an individual with chronic traumatic encephalopathy (CTE) from
the CTE Center of the Boston University Alzheimer’s Disease Center (ADC Boston University).
These sections demonstrate neuronal degeneration in the hippocampus, and in other cortical areas,
also showing accumulation of the binding protein TDP-43 which is seen in many patients with AD
and ALS affects the cell ability to use genetic information to make proteins and its clumping is
another sign of the cells malfunctioning
Fig. 19.2 Case History 19.1, old contusion and laceration of the right orbitofrontal area
Of great importance from the neurological standpoint are these two traumatic con-
ditions in which progressive compression of the cerebral hemispheres occurs. These
are conditions where early recognition and treatment can provide excellent recov-
ery. The failure of recognition of these entities will result in progressive deteriora-
tion of neurological status with death as the eventual outcome. The use of CT scan
has revolutionized the diagnostic approach to these problems (Cordobes et al. 1981;
Markwalder 1981; Masters et al. 1987).
1. Extradural (Epidural) Hematoma: Extradural hematoma is a complication of
skull fractures that extend across a groove containing a meningeal artery—usu-
ally the middle meningeal artery. Less often, the skull fracture has torn a large
venous sinus. Since the bleeding is usually arterial and brisk and the extradural
space is small (normally the dura is closely applied to the skull), compression of
the cerebral hemisphere soon results with the rapid development and progression
of neurologic symptoms. The classic description is usually that of a short period
of unconsciousness related to the acute trauma, then a short lucid interval, which
is followed by progressive confusion and coma. A rapidly progressive hemipare-
sis is often noted with the development of a fixed dilated pupil on the side of the
hematoma indicating uncal herniation by the mass that is frequently found later-
ally over the temporal lobe. At other times, as in the following case history, these
lateralized findings may be overshadowed by the rapid progression to a stage of
functional midbrain transection.
582 19 Neuropathology, Nonvascular: Trauma, Neoplasms, and Communicable Diseases
Case History 19.3: This 22-year-old airman, during a winter storm, was involved in
an auto accident in which he struck his head against the windshield. The patient
apparently was dazed, perhaps unconscious, for a matter of seconds to minutes.
He was taken by ambulance to the emergency room of the nearby army hospital
where a brief evaluation found the patient was alert, without definite neurological
findings. Skull X-rays demonstrated a linear fracture over the right temporal area.
The patient was alert upon his arrival on the ward. However, within a few hours, the
patient was reported by the nurses to be agitated and confused.
Neurological examination: (8 a.m.) Mental status—the patient was agitated and
unable to cooperate. He was moving all limbs; sitting up in bed; holding his head,
which was tender to palpation; moaning; and hyperventilating to a marked degree.
He answered only occasional questions and then with a yes or no. Cranial nerves:
pupillary responses were sluggish. The right pupil was slightly larger and slightly
more sluggish than the left. Reflexes: deep tendon reflexes were increased b ilaterally.
Plantar responses were bilaterally equivocal.
Neurological diagnosis: Possible evolving acute bilateral epidural or subdural
hematoma.
19.1 Neuropathology Due to Trauma 583
Subsequent course: Progression occurred. Within a short time, the patient was
deeply comatose with little response to stimulation. The pupils were now bilaterally
fixed and dilated. The four limbs were extended in a decerebrate posture with signifi-
cant spasticity on passive motion. The degree of spasticity in the upper limbs could
be modified by tonic neck maneuvers. The plantar responses were bilaterally exten-
sor. Spontaneous respirations were now irregular and infrequent, and the patient
required the assistance of a mechanical respirator.
Revised neurological diagnosis: Acute tentorial herniation with brain stem
compression secondary to epidural hematoma.
Subsequent course: A general surgeon immediately placed burr holes and evac-
uated an epidural hematoma over the right temporal–parietal area. He coagulated
and ligated a bleeding middle meningeal artery branch. There was a rapid improve-
ment in the patient’s status. The patient returned to active duty but was experiencing
some problems related to changes in recent memory, motivation, and personality.
2. Subdural Hematomas: Subdural hematomas represent the accumulation of
blood within the subdural space overlying the cerebral convexities. Such hemato-
mas may be acute, subacute, or chronic. The acute and subacute types are clearly
associated with trauma. The acute type is usually associated with other significant
injuries of the brain such as cerebral contusion, laceration, and intracerebral hema-
tomas. With tears in the arachnoid, blood from the lacerations passes into the sub-
dural space. Moreover, small bridging veins from the pia arachnoid to the superior
sagittal sinus are also likely to be torn. The clinical picture of the acute subdural
hematoma is often then modified by the clinical manifestations of these associated
injuries. The typical picture of a rapidly progressive supratentorial space-occupying
lesion with progressive obtundation of consciousness and the signs of tentorial her-
niation will develop in acute (24–48 h) relationship to the head injury. The chronic
variety may appear after closed head trauma, often apparently trivial. At times, there
may be no definite history of trauma.
The subacute and chronic subdural hematomas develop after a variable latent
period of days, weeks, or months following the injury. The bleeding is venous from
small bridging veins passing from the pia arachnoid to the superior sagittal sinus.
The resultant accumulation of blood then is relatively slow. Associated injuries to
the brain are usually not present. The blood in the subdural space is not readily
removed and remains adherent to the dura. Fibroblasts and blood vessels grow from
the dura at the edges of the clot, producing a thin membrane that separates the clot
from the arachnoid. At the same time, a thicker layer of connective tissue and blood
vessels is forming a membrane where the clot is adherent to the inner layer of the
dura. The hematoma often continues to increase in size apparently for several rea-
sons: continued venous oozing may occur; moreover, bleeding may occur from the
blood vessels that are growing into the hematoma from the dural surface. Finally, it
has been suggested that as some breakdown occurs within the clot, a fluid with high
protein content is produced. The resultant fluid of high osmotic pressure then
attracts more fluid into the hematoma.
584 19 Neuropathology, Nonvascular: Trauma, Neoplasms, and Communicable Diseases
Case History 19.5 (Fig. 19.4). This 91-year-old female fell, striking the back of
her head sustaining a brief loss of consciousness. She awakened with severe head-
ache, nausea, and vomiting. She was brought to the hospital where a head CT was
done, demonstrating a cerebral contusion, predominantly in the left occipital pole.
She had a right homonymous hemianopsia on the examination of the ER
physician.
Past history—hypertension, osteoarthritis, and systemic lupus erythematosus.
Medications—prednisone, hydrochlorothiazide, and occasional naproxen.
Social history—lived by herself, her family checked in on her several time a week.
General exam—bruises of multiple ages over the extremities, torso, and head.
Remaining general exam was unremarkable.
Neurologic exam—mildly confused and anxious. She was fluent and followed
commands but was easily distractible. Cranial nerve exam revealed a right homony-
mous hemianopsia to finger confrontation. Reading comprehension was intact.
Remaining cranial nerve and motor and sensory exam were normal. Reflexes were
symmetrical. Finger-to-nose cerebellar testing was normal.
Clinical Findings. Brain MRI demonstrated an intracerebral hemorrhage
in the occipital lobe.
The patient was hospitalized for several days. Thereafter, she was in rehabilitation
for several further weeks. She had a slow decrease in headache and mild improve-
ment in her visual field deficit over a month. On last follow-up 3 months later, she had
a mild residual right homonymous hemianopsia without other focal findings.
Comments—falls are common in the elderly. She has numerous bruises of vari-
ous ages, suggesting she had had frequent falls. The visual field deficit localizes the
lesion to the injured parieto–occipital area.
Case History 19.5 (Fig 19.5). This patient is a 73-year-old male presenting with a
several month history of progressive headaches, generalized in nature. He also was
noted to be confused by his family several weeks before admission. There was a 1
19.1 Neuropathology Due to Trauma 585
day of left arm clumsiness. A CT was done by the patient’s primary doctor.
This demonstrated a right much more than left chronic subdural hematoma. He was
on no anticoagulants or antiplatelet medicines. He had a history of head trauma,
having sustained a fall done a flight of stairs about 6 months before presentation. At
that time, he had no specific complaints other than a bruised face.
Past history—hypertension, prostatic hypertrophy, retinal tear, depression, and
elevated cholesterol
Medications—sertraline, metoprolol, HCTZ, and atorvastatin
Allergies—none
Physical exam was unremarkable and neurologic exam revealed him to be mildly
distractible but otherwise awake, alert, and oriented. He had a normal cranial nerve exam.
Clinical Diagnosis. Right-sided subdural hematoma.
Motor testing was notable for a mild left hemiparesis. Pin and light touch percep-
tion were intact. He missed double simultaneous stimuli on the left but not the right.
He underwent evacuation of his right-sided subdural hematoma and over 48 h made
a good recovery of function. He has remained asymptomatic at 3 months follow-up.
Comment—the history of trauma in the remote past is a possible explanation for
this patient’s subdural hematoma. Bridging veins from the brain to the dura can be torn
and ooze slowly over time. His hemiparesis fits with the location of his blood clot.
The dissociation between pin and light touch perception preservation and the double
simultaneous stimulation deficit is best explained as a cortical sensory loss. Primary
sensory modalities such as pin or light touch perception are perceived initially at a
thalamic level. Subtler sensory findings such as double simultaneous stimulation or
graphesthesia are detected more typically at a cortical level. The clinical manifesta-
tions are those of a progressive supratentorial mass lesion. At times, progressive focal
symptoms and signs are present; for example, hemiparesis, aphasia, and focal seizures.
586 19 Neuropathology, Nonvascular: Trauma, Neoplasms, and Communicable Diseases
1. The next case is an example of the consequences of not wearing a seat belt.
Case History 19.8 (Fig. 19.7). A 54-year-old unbelted male driver of a vehicle who
lost control in a heavy rainstorm, crashing into a ditch. He had a brief loss of con-
sciousness and awakened with severe neck pain, “clumsiness” in the hands, and
paraplegia. His neck was stabilized at the scene. He was brought to the emergency
room. There, he was found to be paraplegic. He was hypotensive. An emergency CT
of the cervical spine demonstrated a C7–T1 fracture dislocation. His past history
was notable for depression. He had no allergies and had no prior surgical history.
Physical exam—the patient had an adequate airway. He was in a hard collar.
Head and neck exam revealed bruising around the forehead and scalp. Cardiac exam
revealed no murmur or gallop. Breath sounds were equal 1 chest auscultation. His
abdomen was nontender. He had paradoxical respirations (a finding noted with
Fig. 19.8 Case History 19.9. (a) An odontoid fracture, with central cord lesion, CT. (b)
Diagrammatic illustration of the lamination of the corticospinal tract/PT in the spinal cord demon-
strates that the axons to the arm (c) are more internally placed than those to the leg (l) which
resulted in the fibers to the hand affected by this central lesion, while the fibers to the leg were
spared as noted in this Case, Case History 19.9
lamination of the corticospinal tract/PT in the spinal cord which demonstrates that
the axons to the arm (C) are more internally placed than those to the leg (L) which
resulted in the fibers to the hand affected by this central lesion, while the fibers to
the leg were spared as noted in this Case, Case History 19.9. Therefore, his presen-
tation with clumsy hands without weakness in the legs is a typical finding.
19.1 Neuropathology Due to Trauma 591
Case History 19.10 (Fig. 19.9). This 75-year-old female presented with a headache
and gradually worsening clumsiness of the left side. This had progressed over sev-
eral weeks. She was seen by her primary care physician, who ordered a CT and
subsequent MRI of the brain.
Clinical Diagnosis. The MRI demonstrates a right frontal mass, and there were
also several masses in the lungs and liver on further testing. These locations
were felt to represent metastatic disease. Her past history was notable for ovarian
cancer, diagnosed several years ago. This was treated with radiation and chemo-
therapy. Neuro exam—the patient was awake and alert. She complained of a mild
headache. This was typically worse in the morning. She had normal language func-
tion, comprehension, and ability to follow commands. Cranial nerve exam revealed
a mild central facial weakness on the left. There were no other cranial nerve deficits.
She had a hemiparesis on the left side, arm greater than leg. There was no ataxia.
She opted for radiosurgery to treat this brain lesion.
For additional examples of metastatic lesions to the brain, review Case 11.3
with met to prefrontal lobe, Case 13.2 with met to cerebellum from the breast,
and Case 14.3 with met to parietal lobe.
Case History 19.11 (Fig. 19.10). This 65-year-old female presented with a seizure.
Her family states that she had had several months of progressively confused behavior
which was episodic. This generally lasts several minutes to several hours. This led to
a CT and subsequent MRI.
Clinical Diagnosis. This demonstrated a left medial–temporal mass consistent
with a meningioma. Neurologic exam revealed her to be confused, mildly aphasic
but otherwise having no focal deficits. She was planning to have surgery closer to
her family’s home out of state.
Comments—this is a good example of a meningioma-a tumor growing from the
lining of the brain and external to the brain substance itself. These frequently invagi-
nate into the brain. They are generally benign. Presentation with seizures is not
unusual. Because they are usually slow growing, a large size at presentation is also
common.
For additional examples of meningiomas, review Case 1.1 a meningioma on
medial surface of motor cortex affecting contralateral leg, Case 1.2 meningi-
oma to prefrontal Brocas’ region, Case 11.4 parasagittal meningioma, and
Case 16.7 to medial surface of occipital lobe.
Case History 19.12 (Fig. 19.11), This 39-year-old male presented with stiffness
walking and double vision. Ophthalmological evaluation revealed a sixth nerve
palsy on the left. Subsequent neurologic evaluation revealed mild spasticity in all
limbs, which particularly were noted with gait, and these findings lead to an MRI.
Clinical Diagnosis. These findings led to an MRI which demonstrated a large
infiltrating mass in the brain stem, consistent with a glioma. Subsequent biopsy
confirmed this. The patient had undergone radiation therapy and chemotherapy. He
had experienced slow decline in function over several months at the time of last
examination. This is a typical infiltrating astrocytic tumor, intrinsic to the brain
parenchyma.
For additional examples of the effects of a glioma review Cases 7.4 acoustic
glioma; 11.2 subfrontal glioma; 15.2 subfrontal with Foster–Kennedy syn-
drome and 15.6 in occipital lobe; 16.1 to uncus including amygdala, hippocam-
pus, entorhinal and temporal pole, and 16.3 medial temporal lobe.
Case History 19.13 (Fig. 19.12). This 77-year-old male presented with lack of
energy and frequent urination. An evaluation for diabetes excludes this diagnosis,
but subsequent lab testing suggested diabetes insipidus. He was also hypothyroid
and hypoadrenal. He was also found to have loss of vision in the right eye.
Clinical Diagnosis. CT and subsequent MRI demonstrated a large mass of the
pituitary region. He underwent surgical removal of this mass which was found to be
a nonsecreting pituitary adenoma. After surgery, he had modest improvement in his
vision and improvement in the diabetes insipidus but required hormone replacement.
Comments—the endocrine presentation is a common feature of this type of
tumor. Because this tumor was quite large and grew in proximity to the optic nerves,
visual loss is explained on that basis.
For additional examples of the effects of a pituitary tumor, see Fig. 9.10 a
and b pituitary adenoma and Fig. 15.11 a postmortem image of a large pitu-
itary tumor compressing the optic chiasm.
Figure 9.11 demonstrates the fibrous capsule surrounding a pineal tumor.
Cerebellar Astrocytoma
Case History 19.14. This 8-year-old male presented with progressive headaches
and blurring vision. Pediatric evaluation found papilledema leading to an emer-
gency CT of the head.
There are many communicable diseases (from the WHO statistics) including chol-
era, hemorrhagic fever, malaria, measles, meningitis, TB, and sexually transmitta-
ble diseases of syphilis and HIV/AIDS.
In this section we are only going to focus on demonstrating the effects of two of
these sadly very common communicable diseases, malaria and HIV/AIDS. The fol-
lowing illustrative cases are taken from Brain Degeneration and Dementia in Sub-
Saharan Africa (Springer 2015, S Musisi and S Jacobson eds.). These cases
demonstrate the common clinical and pathological findings seen in these communi-
cable diseases.
Malaria is caused by a bite from an infected female Anopheles mosquito, carry-
ing the protozoan parasites of falciparum plasmodium. It infects over 650,000,000
people each year and causes 10% of the deaths in the lower-income countries per
year. It also is a major cause of poverty and hinders economic growth. There has
been much progress in protecting children by providing mosquito nets, but more
help is needed, and there has been some progress in developing a vaccine. In this
case, the patient demonstrated cortical atrophy, a subdural hematoma, and dilation
of the ventricles, all common finding in malaria. We have developed a video
(Cerebral malaria, www.braindementia.org) from a case of cerebral malaria which
demonstrates cortical atrophy, a subdural hematoma, and dilation of the ventricles,
all common finding in malaria.
1. Cerebral Malaria. Case History 19.15 (Fig. 19.13).
A 32-year-old man presented with a history of fever, chills, and weakness for
2 weeks along with generalized tonic–clonic seizures, occurring 2–3 times per day,
for 5 days. He also had a history of loss of consciousness 2–3 times a day, each
episode lasting for 2–3 min. He complained of weakness in the right arm for 4 days.
He had had 4–5 episodes of severe vomiting during the duration of the illness. CNS
examination revealed that he was conscious and oriented. There was no neck rigid-
ity. Strength in the right arm was 4/5. His sensory and motor system exam was
otherwise normal; there was no cranial nerve deficit. Biochemical and hematologi-
cal investigations were normal, except for a peripheral blood smear demonstrating
malaria parasites.
19.2 Neuropathology Due to Communicable Diseases 597
The patient in this case is recovering from her disease after antiretroviral therapy;
however, the CT images shows major lesions in the right (1) and left (3) rostral
internal capsules and a lesion in the insular cortex on the right (3) all of which were
consistent with HIV infection in the brain. These pathological findings are consis-
tent with other studies that have shown similar infarcts due to HIV-associated toxo-
plasmosis, tuberculosis, and cryptococcosis, whose presence were not tested for in
this patient. Our findings of dementia in this patient were supported by the brain
atrophy which was noted with the widening of the sulci in the young woman. Poor
care of patients with limitations in treatment is not uncommon in lower-income
countries. The cause of HIV is well documented. There is antiretroviral medication
which slows the progress of this disease. There is still no consistent cure yet for
HIV, but safety in sexual relations and avoidance of needle sharing in IV drug users
are essential to minimize exposure to this disease.
Reference
McKee AC, Cairns NJ, Dickson DW, et al. Clinicopathological Evaluation of Chronic Traumatic
Encephalitis (CTE.
Part IV
The Nonnervous Elements
Chapter 20
Non-nervous Elements in the CNS
Abstract In addition to the billions of neurons, and the supporting glia within the
central nervous system there are non-nervous elements that protect the CNS—1 the
skull; 2 coverings of the brain, the meninges; 3 blood supply; and 4 the ventricular
system.
In addition to the billions of neurons, and the supporting glia within the central
nervous system there are non-nervous elements that protect the CNS—1 the skull; 2
coverings of the brain, the meninges; 3 blood supply; and 4 the ventricular system.
20.1 Skull
Figure 20.1 demonstrates the layers of skin over the skull and the inner meningeal
membranes inside the skull between the skull and the central nervous system.
The layers of the scalp above the skull from outside in the skin; connective tissue
dense with nerves and blood vessels; aponeuroses of galli; loose connective tissue;
and pericranium/periosteum.
The skull consists of the neurocranium enclosing the brain and the facial skele-
ton for attachments of the skin, muscles, glands, eyes, ears, tongue, and all other
structures associated with the face.
The neurocranium encloses the brain and consists of eight bones—one frontal,
one ethmoid, one sphenoid, and one occipital bone with a left and right parietal and
temporal bone.
Facial skeleton consists of 14 bones (one mandible and one vomer and a left and
right of the following bones: maxillary, nasal, lacrimal, palatine, zygomatic, and infe-
rior nasal conchae). There are also the three pairs of inner ear bones/ossicles—mal-
leus, incus, and stapes deep in the temporal bone. Finally, and not considered a bone
of the skull, there is the single u-shaped hyoid bone which provides attachment to the
intrinsic tongue musculature and larynx which are functionally very important for
communications and swallowing. For a more in-depth review of the 22 bones in the
skull, one should review the skull in one of the many excellent gross anatomy texts.
The brain is enclosed by three membranes, the meninges which consist of the dura
mater, arachnoid, and pia mater (Fig. 20.2). These protective CSF-filled membranes
are formed by a connective tissue with nerves embedded especially in and on the dura.
Layers of meninges, Fig. 20.2.
( 1) The outer thick dura
(2) The middle thin gossamer-like arachnoid membrane
(3) Internal membrane pia which is adherent to the CNS and together with the
arachnoid forms the subarachnoid membrane which forms the subarachnoid
space which is filled with CSF
1. Dura mater (Fig. 20.3).
The externally located dura mater consists of tough fibrous connective tissue.
In the cranial vault, the dura forms the periosteum on many of the adjacent bones
and then is reflected onto the brain where it forms an inner, or meningeal, portion
that compartmentalizes the cranial fault as follows:
1. Falx cerebri (between the cerebral hemispheres)
2. Tentorium cerebelli (between the cerebellum and cerebrum)
3. Falx cerebelli (between the cerebellar hemispheres under tentorium)
4. Diaphragma sellae (covering over location of the pituitary gland)
5. Meckel’s cave/trigeminal cave (is an arachnoid pouch containing CSF, extends
from the posterior cranial fossa, and contains the trigeminal nerve and ganglion)
The dura attaches at the margin of the foramen magnum to the occipital bone and
also forms the inner surface of the second and third cervical vertebrae with the filum
terminale. It is also continuous with the perineurium on the spinal nerves, covers the
20 Non-nervous Elements in the CNS 603
Fig. 20.2 Diagram demonstrating the relationship between the skull, the meninges, and the brain
Fig. 20.3 Compartments in the cranial vault formed by the dura: 1 falx cerebri, 2 tentorium cere-
bri, 3 diaphragma sella, and 5 Meckel’s cave which contains the trigeminal ganglion. The tento-
rium cerebelli is not shown but it hangs from the undersurface of the tentorium and lies between
the cerebellar hemispheres
604 20 Non-nervous Elements in the CNS
filum terminale, and becomes continuous with the periosteum on the coccyx as the
coccygeal ligaments.
The spinal dura forms a sac surrounding the spinal cord while the vertebrae have
their own periosteum.
2. Arachnoid membrane. This thin gossamer-like membrane (Fig. 20.4) is located
between the dura and pia. The space between the pia and arachnoid, the subarachnoid
Fig. 20.4 Pia–arachnoid and arachnoid granulations. (A, B) Arachnoid Granulations (A) (low
power) and (B) (higher power) of arachnoid granulations on medial surface of the gross cerebral
hemisphere (arrows). (C) The pia-arachnoid membrane over the lateral surface of a gross hemi-
sphere showing the arachnoid covering over the sulci and leaving spaces between the gyri, while
the pia actually dips into the sulci and adheres to the sulcal cortex
20.3 Blood Supply to the Brain 605
Fig. 20.5 Stereogram of layers of the meninges in relations to the parenchyma of the brain
space, is filled with the CSF. The arachnoid bridges the cerebral sulci and extends
from the posterior surface of the medulla to the cerebellum (cisterna magna) and
below the neural ending of the spinal cord (lumbar cistern). All of these spaces con-
tain CSF. The arachnoid is usually separated from the dura by the subdural space.
The arachnoid granulations are enlarged villi of the arachnoid membrane which
project into the lateral margins of the superior sagittal sinus, which provide a means
for the cerebrospinal fluid (CSF) in the subarachnoid space to pass into the venous
circulation.
3. Pia, Fig. 20.5. The pia adheres to the central nervous system and is continuous
with the perineurium of cranial and spinal nerves. It attaches to the blood vessels
entering and leaving the central nervous system and fuses with the dura. The cranial
pia bridges over the sulci and extends deep into the sulci in the cerebrum and cere-
bellum leaving sulcal spaces which are filled with CSF. It also forms the non-neural
roof of the III and IV ventricle.
20.3.1 A
rterial Blood Supply Figs. 20.6, 20.7, 20.8, 20.9, 20.10,
and 20.11
Fig. 20.6 (a) Diagram of arterial blood supply to the head, neck, and brain. (b) MRA of arterial
blood supply to the head, neck, and brain, MRA
Fig. 20.7 MRA showing (a) the distribution of the common and external carotid from the arch of
the aorta, (b) arch of the aorta with the distribution of the common carotids and vertebrals. Note on
the right side that the common carotid usually arises from the brachiocephalic artery while on the
left side it arises directly form the arch of the aorta
20.3 Blood Supply to the Brain 607
Blood flow to the brain is divided into the anterior and posterior circulation.
The anterior circulation (internal carotids, anterior cerebral arteries, middle
cerebral arteries, and the anterior communicating arteries) supplies the basal gan-
glia, the anterior diencephalon, the lateral surface of the cerebral, and the anterior
two-thirds of the cerebrum.
The posterior circulation (vertebrals, basilar and posterior cerebral arteries) sup-
ply the brain stem; the cerebellum and much of the diencephalon, and the inferior
temporal lobe and much of the occipital lobe.
The anterior circulation, Fig. 20.8, supplies about 70% of the blood to the brain
and consists of the internal carotids, carotid siphon, middle cerebral artery (MCA),
anterior cerebral artery (ACA), and anterior communicating artery (ACA).
The posterior circulation, Fig. 20.9b, consists of the vertebrals, basilar artery,
and posterior cerebral arteries. And it supplies about 30% of the brain including
the upper cervical spinal cord, cerebellum, brain stem, most of the diencepha-
lon, and inferior and posterior surfaces of the temporal lobe, the orbital frontal
608 20 Non-nervous Elements in the CNS
Fig. 20.9 The arterial circle of Willis. (a) MRA; 20.9. (b) Diagrammatic presentation of the arter-
ies( from Zimmerman and Jacobson, Anatomy, 1989, Little Brown and Company)
Fig. 20.10 Blood supply to the medulla (a) and pons (b). (a) In the medulla the spinal artery sup-
plies the paramedian region of the medulla while the paired vertebral artery supplies the lateral
region and the posterior inferior cerebellar artery (PICA) named after the region it irrigates in the
posterior cerebellum and on its way supplies much of the lateral posterior substance of the medul-
lary tegmentum. (b) In the pons the arterial branches arising from single, midline basilar artery is
either paramedian or short or long circumferential branches, with the anterior inferior cerebellar
artery (AICA) being one of the major circumferential branches to the anterior inferior surface of
the cerebellum and also supplies the tegmentum of the pons
Fig. 20.11 Arterial supply to the lateral surface of the cerebral hemisphere
610 20 Non-nervous Elements in the CNS
Fig. 20.12 Arterial supply to the medial surface of the cerebral hemisphere
20.4 V
enous Drainage of the Brain, Head, and Neck
(Fig. 20.13)
The cerebral veins have very thin walls, no muscular layer, and no valves. They are
found on the surface of the brain in the subarachnoid space or in the substance of the
central nervous system.
1. Superficial cerebral veins. The superficial cerebral veins lie in the sulci, are
thinner, and are usually external to the arteries. They consist of the superior,
middle, and inferior cerebral veins.
a. Superior cerebral veins. A variable number of superior cerebral veins
drain the superior surface of the cerebral cortex and empty into the superior
sagittal sinus.
b. The middle cerebral veins drain the bulk of the lateral and inferior surface;
these veins are found in the lateral sulcus and empty into the cavernous
sinus.
c. The inferior cerebral veins drain the lateral occipital gyrus and the temporal
lobe; this vessel opens directly into the transverse sinus.
2. Internal cerebral veins. The internal and basal veins are the principal cerebral
veins. They conduct blood from the center of the cerebrum and converge upon
20.4 Venous Drainage of the Brain, Head, and Neck 611
the single great cerebral vein (of Galen), which empties into the straight sinus.
The vein of Galen collects venous blood from the medullary center of the cere-
brum, diencephalon, basal ganglia, and midbrain.
Each of the internal cerebral veins is formed near the interventricular fora-
men of Monro by the union of veins from the lenticular nuclei, caudate, septum,
and choroid plexus. The internal cerebral veins run backward in the velum
interpositum in the roof of the third ventricle.
3. Basal vein (of Rosenthal). The paired basal veins originate near the anterior
perforated substance by the union of the vessels from the corpus callosum,
thalamus, insula, and anterior temporal lobe. Each vein passes posteriorly
around the cerebral peduncle and unites with the internal cerebral veins behind
the splenium of the corpus callosum to form the cerebral vein of Galen.
612 20 Non-nervous Elements in the CNS
4. Superior cerebellar veins. The superior cerebellar veins form on the superior
surface of the cerebellum and some branches join the straight sinus and great
cerebral vein, while others branches run into the transverse and superior petro-
sal sinus.
5. Inferior cerebellar veins. These veins drain the inferior surface of the cerebel-
lum, and some branches end in the inferior petrosal sinus and transverse sinus,
while other branches pass posteriorly into the occipital sinus.
6. Brain stem veins. Some of the branches from the medulla and pons terminate in
the superior and inferior petrosal sinuses.
7. Cranial dural sinuses. The sinuses in the dura mater consist of blood vessels
lined with endothelium and enwrapped between the periosteal and meningeal
layers of the dura. These channels convey blood from the superficial and deep
cerebral veins and from veins in the neck, orbit, meninges, and diploe ulti-
mately back to the superior vena cava. The dural sinuses can be divided into
median unpaired channels (superior sagittal, inferior sagittal, straight sinus)
and lateral paired channels (sigmoid, cavernous, superior and inferior petrosal,
and circular).
(a) Unpaired median sinuses.
• The superior sagittal sinus is found in the attached margin of the falx
cerebri in the inner surface of the cranium from the sagittal groove on the
foramen cecum to the internal occipital protuberance. It is small anteri-
orly and enlarges posteriorly. At the internal occipital protuberance, the
superior sagittal sinus curves downward and joins the transverse sinus at
the confluens sinuum. The superior sagittal sinus communicates with
the superficial temporal veins by means of parietal emissary veins; the
superior cerebral veins empty directly into it.
• The inferior sagittal sinus is found in the free margin of the falx cerebri
at the junction of the falx and the cerebelli tentorium. It joins the great
cerebral vein to form the straight sinus.
• The straight sinus continues into the confluens sinuum and then into the
transverse sinus, which lies horizontally in a groove along the squamous
portion of the occipital bone and the petrous portion of the temporal
bone. It also lies in the attached margin of the cerebellar tentorium.
(b) Paired lateral sinuses.
• The sigmoid sinus lies internal to the occipital and temporal bones. The
sigmoid sinus is the continuation of the transverse sinus, and when it
exits the cranial vault through the jugular foramen, it becomes the inter-
nal jugular vein.
• Cavernous sinuses are formed by numerous venous channels which are
found in the dura around the sella turcica of the sphenoid bone
(Fig. 20.13). Each continues from the medial portion of the superior
orbital fissure to the apex of the petrous portion of the temporal bone.
20.5 Ventricular System 613
Rootlets of the III, IV, VI, and ophthalmic and maxillary branch of the
trigeminal nerve are found herein. The internal carotid artery is found in
the cavernous sinus with the rootlets of nerve VI on its lateral surface.
The cavernous sinus anteriorly receives the ophthalmic vein, middle
cerebral veins, and veins from the hypophyseal (pituitary) plexus.
• Superior and inferior petrosal sinuses drain the cavernous sinus and con-
nect it, respectively, to the transverse sinus and the internal jugular vein.
The superior and inferior petrosal sinuses lie in grooves with the same
name in the petrous portion of the temporal bone. Anteriorly the supe-
rior and inferior ophthalmic veins connect the cavernous sinus to the
anterior facial vein.
• The circular sinus surrounds the hypophyseal gland and connects to the
cavernous sinus, and the basilar plexus connects the cavernous sinus
with the vertebral plexus.
10. There are alternate additional channels by which the venous blood leaves the
cranial cavity. The venous blood leaves the brain principally via the internal
jugular and vertebral veins and plexus.
(a) One of the major alternate pathways is provided by the following emissary
veins: frontal, parietal, occipital, and mastoid.
(b) In addition, the superior and inferior ophthalmic veins provide another
channel by which blood leaves the cavernous sinus and enters the anterior
facial vein.
(c) Also the venous plexus around the internal carotid artery connects the cav-
ernous sinus and the internal jugular vein.
The ventricular system consists of the lateral ventricles, third ventricle, cerebral
aqueduct, fourth ventricle, and spinal canal. The central nervous system is surrounded
by CSF. Externally, the meninges, especially the subarachnoid space, contain CSF.
Internally, the ventricular system and cisterns contain CSF and a specialized struc-
ture, the choroid plexus in the ventricles which excretes CSF. CSF also forms much
of the extracellular space in the brain. In Fig. 20.11 in the gross brain, we have identi-
fied the third ventricle, the cerebral aqueduct, and the fourth ventricle with the inter-
ventricular foramen of Monro which interconnects the third ventricle and the lateral
ventricles, marked by the arrow. In Fig. 20.12 we demonstrate the ventricular system
in a 3D reconstruction.
Parts of the ventricular system.
1. The lateral ventricles are found within the cerebral hemispheres and consist of
the body and the anterior, posterior, and inferior horns.
614 20 Non-nervous Elements in the CNS
Fig. 20.14 Gross brain, medial surface with the pineal gland labeled, and the following parts of
the ventricular system identified III (third ventricle), cerebral aqueduct (CA), and IV (fourth ven-
tricle). An arrow marks the the intraventricular foramen of Monro which interconnects the paired
lateral ventricles to the midline III ventricle
Fig. 20.15 3D Reconstruction of the ventricular system in the brain; Lateral ventricles, (body,
inferior horn and posterior horn), intraventricular foaramen, III ventricle, cerebral aqueduct, Fourth
ventricle
20.6 Cerebrospinal Fluid 615
2. The third ventricle (III) lies in the midline between the left and right diencepha-
lon and is continuous superiorly with the frontal horn of the lateral ventricles and
inferiorly with the cerebral aqueduct. Several recesses associated with the third
ventricle are important radiologic landmarks: the optic recess, hypophyseal
recess, and pineal recess.
3. The cerebral aqueduct (CA) is the narrow ventricular space in the center of the
midbrain connecting the third and fourth ventricles.
4. The fourth ventricle (IV) forms that portion of the ventricle seen in pontine and
medullary levels. The fourth ventricle is continuous inferiorly with the narrow
central canal of the spinal cord. The fourth ventricle is continuous with the sub-
arachnoid space laterally by the foramina of Luschka and medially by the fora-
men of Magendie.
5. The narrow spinal canal is seen in the center of the gray commissure of the spi-
nal cord.
The CSF is formed by the choroid plexus (Fig. 2.12) in the lateral ventricles, third
ventricle, and fourth ventricle, which are supplied by the choroidal arteries. It is a
clear, colorless, and basic fluid that resembles protein-free plasma but with many
significant differences (Table 20.1).
Cerebrospinal fluid circulation.
The ventricular system is lined by ependymal cells (see Fig. 2.22). The total
volume of CSF is usually between 100 and 150 mL. The rate of formation is
20 mL/h or about 500 mL/day. Excess fluid is readily absorbed into the venous
sinuses through the arachnoid granulations because the pressure in the CSF is
higher than in the ventricle, and through the cerebral aqueduct into the lateral ven-
tricles via the foramen of Monro into the third ventricle and onto the fourth ven-
tricle. The fourth ventricle, is continuous with the subarachnoid space at the
foramen of Luschka (lateral) and Magendie (medial). In the subarachnoid space,
the fluid passes into the venous sinuses through the arachnoid granulations. An
excess in CSF produces hydrocephalus, which is frequently a consequence of men-
ingitis or hemorrhage (communicating hydrocephalus) or a blockage in the ven-
tricular system (noncommunicating hydrocephalus) caused by hemorrhage,
tumors, or trauma.
Glymphatic system (Jensen et al. 2015). The immune system in the brain.
For many years the parenchyma of the CNS was considered an immunological
privileged site, but recently lymphatics have been identified in the meninges.
Drainage of CSF. The CSF is formed in the choroid plexus in the lateral ventri-
cles and third and fourth ventricles and fills the spaces in the ventricular system in
the center of the brain and also enters the subarachnoid space via the foramen of
Luschka and Magendie.
616 20 Non-nervous Elements in the CNS
The CSF formed in the ventricular system travels through the periarterial space
formed by the end feet of the astrocytes, the glymphatic system, which surrounds an
artery and enters the brain via the periarterial spaces formed by the astrocytes. This
system was recently identified (Jessen NA, Munk AS, Lundgaard I, Nedergaard M,
2015) The CSF containing waste macromolecules and other products is then trans-
ported into the perivenous spaces which surround the many small veins associated
with the brain and ultimately via the arachnoid granulations into the venous sinuses
, superior and inferior sagittal sinuses and finally then into the internal jugular vein.
In addition, the foramen of Luschka and Magendie are apertures which permit the
CSF to leave the IV ventricle, enter the subarachnoid space, and finally be excreted
into the dural venous sinuses in the cerebral veins.
Alternate pathways.
1. The venous blood leaves the brain principally via the internal jugular, vertebral
veins, and plexus.
2. There are additional channels by which the venous blood leaves the cranial cavity.
(a) One of the major pathways is provided by the following emissary veins:
frontal, parietal, occipital, and mastoid.
(b) In addition, the superior and inferior ophthalmic veins provide another chan-
nel by which blood leaves the cavernous sinus and enters the anterior facial
vein.
(c) The venous plexus around the internal carotid artery connects the cavernous
sinus and the internal jugular vein.
The brain has two glands, the pituitary and the pineal, both of which are attached to
the diencephalon and associated with the hypothalamus.
The pituitary or hypophysis cerebri, Fig. 9.11, is attached to the base of the hypo-
thalamus. Its functions are described in the hypothalamus (Chap. 7).
Reference 617
The other gland, the pineal or epiphysis cerebri (pine cone in shape), Fig. 20.15,
is found in the epithalamus.
The pineal gland is also called the “third eye,” as it produces melatonin, a hor-
mone that affects wake/sleep patterns and seasonal functions. By its location in the
center of the brain above the diencephalon, its functions in relationship to light
levels and diurnal cycles would not be apparent; however direct visual information
reaches the pineal from the optic nerve input into the suprachiasmatic nucleus of the
hypothalamus and then enters the stalk of the pineal.
Reference
Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The Glymphatic system: a Beginner’s guide.
Neurochem Res. 2015;12:2583–99.
Chapter 21
Case History Problem Solving
Abstract These cases are representative of the major types of disease seen in the
brain and spinal cord including many classical cases that are rarely seen today
including neurosyphilis. The questions and comments that are included with each
case illustrate the questions one should ask, and the comments explain the reasons
for the workup.
Case history 21.1: This 53-year-old, right-handed, white housewife (Mrs. S. P.) had
the onset of weakness in the lower extremities approximately 10 months prior to
admission. At the same time, the patient noted twitching of the muscles of the legs,
that is, fasciculations. The weakness progressed so that the patient had difficulty in
walking. Approximately 8 months prior to admission, the patient noted the onset of
weakness and fasciculations in the upper extremities. This was noted most particu-
larly with regard to the hands. The patient had had a progression of symptoms in the
intervening months; approximately a 30-lb. weight loss had been experienced.
Although the patient complained of fatigue and some lethargy, she had noted no
definite change in mental status. She had not experienced any headaches or pains in
the neck. She had had no diplopia or visual disturbances. No sensory symptoms had
been noted; no urinary or bowel symptoms had been noted. Past history and family
history were not remarkable.
Neurological Examination
1. Mental status: intact.
2. Cranial nerves: All were intact except for 12. Ridges of atrophy were noted at
the lateral borders of the tongue; there were marked fasciculations of the tongue.
3. Motor system:
(a) There was marked atrophy of a diffuse nature involving the muscles of the
hands and shoulders and throughout the lower extremities.
(b) There was a diffuse weakness involving all of these muscles.
(c) Widespread fasciculations were present in all muscles of both upper and
lower extremities.
increase the pain. During this period of time, his walking had deteriorated. He had
to look constantly to see where his feet were placed and if it were the least bit dark,
he had much difficulty staggering about because he was unable to control his feet.
The patient did not recognize any difficulty with urinary bladder function, but addi-
tional questioning revealed that frequently he would go 18–20 h without voiding.
For 3 years, this patient had taken large amounts of an opiate (paregoric) in an effort
to relieve his discomfort. More recently, he had added an additional addictive habit,
the use of sodium Maytag 6 times a day to decrease the severity of his symptoms.
Neurological Examination
1. Mental status: Intact.
2. Cranial nerves: The pupils were small and slightly irregular. Neither pupil
reacted to light but did react to accommodation.
3. Motor system:
(a) Strength was intact.
(b) A gross ataxia of stance and gait was present.
This was most marked when eyes were closed, less marked when the eyes
were open, and the patient was watching his legs. There was a significant heel-
to-shin dysmetria with a similar pattern as regards worse with eyes closed,
better when the eyes were open, and the patient observed the movements.
(c) Romberg test was positive.
4. Reflexes:
(a) Deep tendon stretch reflexes were absent in the lower extremities at patella
and Achilles, but well preserved in the upper extremities at 2 +.
(b) There were no responses to plantar stimulation.
5. Sensory system:
(a) There was an area of decreased pain sensation over the tip of the nose and in
relationship to both nipples in a roughly circular area.
(b) Position sense was grossly defective even for large amplitude movements at
toes and ankles.
(c) Vibratory sensation was absent at toes and present but diminished at the
ankles.
Questions
1. What is the anatomical explanation for the ataxia of gait, which was worse when
the eyes were closed?
2. What is the anatomical explanation for loss of position and vibratory sensation
in the lower extremities? Note that pain sensation was intact in the lower extrem-
ities although patchy loss of pain sensation occurred about the nipples and over
the tip of the nose.
3. What is the anatomical explanation for the fleeting shooting pains particularly in
the lower extremities?
4. What is the anatomical explanation for the pupillary findings?
622 21 Case History Problem Solving
involvement of pain and temperature and touch sensation plus the ataxia and positive
Romberg sign all suggested that the heavily myelinated fibers in the posterior col-
umns were also involved. The findings of bilateral Babinski signs indicated that the
corticospinal tracts within the lateral columns were also involved. The administra-
tion of vitamin B12 would be expected to readily reverse the hematological changes.
As regards the neurological disease, at an early stage, some of these symptoms may
represent a dysfunction of myelin and axons without actual structural damage. When
patients are treated early, at a stage when axonal damage has not yet occurred and
damage to myelin is minor, a significant improvement may occur although some
neurological signs may still be present on examination. The objective is always to
prevent progression and disability in this treatable disease. When treatment is
delayed so that severe damage to myelin and subsequently to axons has occurred,
significant disability may remain, although progression should be prevented.
Case history 21.4: This 80-year-old white right-handed male was referred for eval-
uation of increasing weakness about the lower extremities. This patient had had a
prostatectomy, 12 years previously for carcinoma of the prostate. Several months
prior to admission, the patient noted poor bladder control. Approximately 3 weeks
prior to admission, the patient noted that he was becoming unsteady in gait, the left
leg showing greater involvement than the right. The patient described this as being
unable to know where to place the left leg. Shortly thereafter the patient awoke one
morning and noted sudden weakness in both lower extremities.
When admitted to a hospital, days before evaluation, it was noted that he had
insufficient strength to stand unassisted, but he could kick both legs about in bed
and certainly could raise the legs from the bed. Vibration sensation was said to be
absent in both legs as was pain sensation. There was loss of position sense in the left
leg. According to the patient, since his admission to the hospital, he had experienced
increased weakness in both lower extremities. Thus, a steady progression of symp-
toms had occurred.
Past history is of additional significance:
(1) Replacement of the femoral artery by graft was undertaken approximately
10 years prior to admission.
(2) In the preceding 9 years, the patient had been noted to have an essential or
senile tremor.
(3) Two years before evaluation, he had an episode in which he awoke in a con-
fused state and had difficulty in thinking. At that time, he was noted to have
increased reflexes on the right side with a right Babinski response. A diagnosis
of cerebral ischemia was made, and the patient was temporarily treated with
anticoagulants (heparin and then warfarin). This had been discontinued. Five
months before of admission, the patient had several bouts of aphasia.
(4) Three months before admission, the patient had several episodes of syncope.
The patient was admitted to his local hospital at that time. A neurological exam-
ination at that time revealed a coarse tremor of the outstretched hands, also
present on action. His deep tendon reflexes were more active on the right than
on the left, and he had an equivocal right Babinski response.
21 Case History Problem Solving 625
Neurological Examination
1. Mental status: This thin, well-developed white male was moderately disoriented
for time, but oriented for place. The patient was able to provide a coherent his-
tory, but the actual dates were somewhat vague. There was a mild nominal
aphasia.
2. Cranial nerves: There was a suggestion of a right visual field deficit.
3. Motor system:
(a) Strength in the upper extremities was intact. There was a significant weak-
ness in both lower extremities, more marked on the left than on the right.
Dorsiflexion at the left ankle was less than 20% of normal, at the right ankle
less than 30% of normal. The patient had less than 5% normal dorsiflexion
of the great toe on the left, approximately 30% on the right. On the left, the
patient was unable to raise the heel off the bed; on the right the patient was
able to raise the heel off the bed to approximately 30°.
(b) There was a resistance to passive movement at flexion–extension of the
elbows; this had some of the qualities of spasticity and possibly some of the
characteristics of Gegenhalten.
(c) Coordination: there was the tremor of the outstretched hands present also on
action and intention as noted previously.
4. Reflexes:
(a) Deep tendon reflexes: There was a reflex asymmetry in the upper extremities;
right biceps was 3++, left, 3+. Triceps were both 1 to 2+. In the lower extrem-
ities, quadriceps and deep tendon reflexes were 3+; ankle jerks were 2 + .
(b) There were now bilateral Babinski responses.
(c) There was a bilateral release of the instinctive grasp reflex.
5. Sensation:
(a) There was a definite pain level on the anterior surface at the level of the
lower end of the xiphoid process and on the posterior surface at the level of
the T8 spinous process. There was no evidence of sacral sparing.
(b) Position sense was absent at the left toe and ankle. Gross movement only was
perceived at the right ankle. Vibratory sensation could not be adequately tested.
6. On examination of the back, there was local tenderness over the T7, T8 spinous
processes.
7. There was evidence of some fecal and urinary incontinence as noted by soiled
bed clothing.
8. Carotid pulses were present bilaterally; the right was greater than the left.
Questions
1. Elderly patients often have multiple neurological problems. This patient cer-
tainly has several neurological problems. Several of these problems are
longstanding and do not present any immediate threat to neurological function.
626 21 Case History Problem Solving
You should have no problem in dissecting off the findings relevant to these
noncritical problems. However, one problem clearly requires immediate atten-
tion. What is the nature of this problem (location of and type of pathology)?
2. Which diagnostic procedures would you obtain and when?
3. Which therapeutic procedures should you undertake?
Clinical diagnosis (relevant acute diagnosis): Spinal cord compression at vertebral
level T7–T8 most likely due to metastatic disease which has spread into the epidural
space from metastatic involvement of the bone. Additional collapse of vertebrae
may have contributed to the extrinsic compression.
Laboratory data: 1. X-rays of the chest were negative except for possible
destructive lesions at D8–D9.
Comment: In contrast to the previous cases, all of which involved one or more sys-
tems (case 1, motor system; case 2, posterior roots and posterior columns; and case
3, peripheral nerve and posterior and lateral columns); this case presents a trans-
verse lesion with a clear-cut sensory level. There had been the progressive involve-
ment of motor function of both lower extremities with upper motor neuron findings,
a loss of bladder control, and evidence of involvement of both posterior column and
spinothalamic sensory modalities. In addition local tenderness was present over the
T7–T8 vertebrae. This patient requires immediate MRI imaging of the spinal cord
and if possible immediate surgical decompression.
Case history 21.5 (modified from Marcus and Jacobson 2003, 2010): This 60-year-
old white male maintenance worker 5 years prior to admission had the relatively
sudden onset of novocaine-like sensation behind the right ear and transient numb-
ness of the right arm and leg. Three years prior to admission, he began to drop
objects from the right hand and developed decreased sensation in the right arm. On
several occasions, he was unaware that he burned his right arm and hand. The
patient had sustained lumbar trauma at age 20 requiring lumbar spine fusion. A
sister had died of a brain tumor.
Neurological Examination
1. General observations: There were numerous scars over the right hand and arm
and to a lesser degree of the left hand.
2. Mental status: Intact.
3. Cranial nerves: The following abnormalities were present:
(a) A dysconjugate rotary nystagmus was present most marked on gaze to the
right and greatest in the abducting eye. At a later point in time, downbeat
nystagmus was present.
(b) There was decreased pain and temperature over all three divisions of the
right trigeminal nerve with decreased corneal sensation. Touch sensation
was intact.
(c) Head was tilted to the left.
21 Case History Problem Solving 627
Comment: The initial symptom of the tingling behind the right ear plus sensory
symptoms in the right arm and leg suggested that the cervical spinal cord was
involved as high as the C 2–C 3 segments.
The clues to the more specific diagnosis as regards the spinal cord are the follow-
ing findings:
1 . The painless burns and trauma to the right hand greater than left
2. The dissociated sensory loss in a cape-like distribution of pain sensation on the
neurological examination with preservation of other sensory modalities
All suggested involvement of the decussating pain and temperature fibers in the
anterior white commissure.
The selective decrease in pain and temperature sensation over all three divisions
of the trigeminal nerve on the right indicated involvement of the descending spinal
tract of the 5th cranial nerve either at a lateral medullary level or at the level of the
upper cervical spinal cord.
However, the occurrence of nystagmus which was greater in the abducting eye
can only indicate involvement of the medial longitudinal fasciculus (MLF) at a low
pontine level. Nystagmus in the setting of syringomyelia must mean that an associ-
ated syringobulbia is also present, with involvement of the vestibular nuclei and the
MLF. The cerebellar findings in this case may indicate involvement of the inferior
cerebellar peduncle in the lateral medulla. It is to be noted that the usual lesion of
syringobulbia is often a slit-like lesion extending in a diagonal manner from the
floor of the fourth ventricle into the lateral medulla. Therefore, the findings in syrin-
gobulbia are reminiscent of a lateral medullary syndrome. In some cases, the nucleus
ambiguous is also involved.
Down beat nystagmus and cerebellar findings are frequently seen in an Arnold–
Chiari malformation. It is important to realize that syringomyelia and syringobulbia
are progressive diseases as demonstrated in this case. This case suggests that it is not
always possible to demonstrate a continuous appearance of the syrinx. The cavity
particularly at a brain stem level may be a narrow slit which may not be imaged by
the MRI particularly by the earlier generation of MRI scanners (the study was per-
formed in 1987).
Case history 21.6: This 66-year-old, retired, white male 10 days prior to admission
noted at his evening bath that he was unable to detect the temperature of water with
his left foot and ankle. Several hours later, he awoke from sleep to void and found
that his balance was defective; he tended to fall over to the right side. He also had a
strange sensation over his right ear and face.
The following morning, the patient noted numbness of the right side of the face,
dysarthria, headache, nausea, and vomiting.
The patient was admitted to his local community hospital where skull x-rays and
lumbar punctures were essentially normal. His symptoms had begun to clear at the
time of his referral for neurological consultation.
Past history: Approximately 6 weeks prior to his admission, the patient had
developed mild symptoms of congestive heart failure and had begun appropriate
treatment.
21 Case History Problem Solving 629
Neurological Examination
1. Mental status: The patient was alert well oriented with memory intact. Language
functions and ability to do calculations were intact.
2. Cranial nerves:
(a) A partial Horner’s syndrome was present on the right with ptosis of the eye-
lid and a slightly smaller pupil. Extraocular movements were intact.
(b) Nystagmus was present on lateral gaze and at times on forward gaze.
(c) Pain sensation was decreased over the entire right half of the face, and the
corneal reflex was absent on the right half of the face. Touch sensation how-
ever was intact.
(d) The uvula deviated to the left. The gag reflex was slower on the right. The
voice was hoarse.
3. Motor system:
(a) Strength was intact.
(b) The patient was ataxic on a narrow base, tending to fall to the right.
4. Reflexes:
(a) An intention tremor was present in the right upper extremity on finger-to-
nose testing. A side-to-side tremor was apparent in the right lower extremity
on heel-to-shin testing.
(b) Deep tendon reflexes were physiological (2+) and symmetrical.
(c) Plantar responses were flexor.
5. Sensation:
(a) Pain sensation was decreased over the left lower extremity. (Examination
shortly after onset of symptoms at his local hospital had demonstrated a
decrease in pain sensation involving all of the left side of the body below C2).
(b) Position, vibration, and light touch were intact.
Subsequent Course
Reevaluation, 2 weeks after the neurological examination recorded above, indi-
cated that the neurological symptoms and findings had almost completely
disappeared.
Questions
1. The findings in this case, when taken in combination, constitute a classic syn-
drome (decreased pain sensation on the right side of the face and the left side of
the body plus right-sided cerebellar findings plus right-sided Horner’s syndrome
plus hoarseness plus nystagmus). Indicate the location of the lesion and the name
of the syndrome.
2. Indicate the most likely etiology. If vascular, indicate the appropriate vessel.
Clinical diagnosis: Dorsolateral medullary syndrome (syndrome of posterior infe-
rior artery, Wallenberg’s syndrome)
630 21 Case History Problem Solving
Comment: The blood supply to the brain stem originates from the two vertebral
arteries which then merge at the junction of the medulla and pons to form a single
basilar artery. This basilar artery then divides at the junction of the pons and mid-
brain into paired posterior cerebral arteries. From each of these arteries, a series of
branches arise. Those arising close to the midline or paramedian form the parame-
dian branches and enter the ventral surface of the brain stem to supply among other
structures the pyramidal tracts. In contrast, there are a series of three circumferential
branches which supply the lateral tegmental regions of the brain stem and then
extend onto the surface of the cerebellum. There are essentially three surfaces of the
cerebellum: the posterior inferior, the anterior inferior, and the superior. Thus, the
three cerebellar circumferential arteries are so named. The posterior inferior cere-
bellar artery usually arises from the vertebral artery, while the anterior inferior cer-
ebellar and the superior cerebellar arteries in contrast arise from the basilar artery.
The posterior cerebral arteries after providing paramedian branches essentially con-
tinue as circumferentially branches above the tentorium supplying the medial (and
inferior) areas of the occipital lobes and medial and inferior surfaces of the temporal
lobes. The areas supplied by the posterior inferior cerebellar artery, within the dor-
solateral medulla, include the inferior cerebellar peduncle (ataxia of gait and ipsi-
lateral limb dysmetria, ataxia, and tremor), the descending spinal tract and
associated nucleus of the trigeminal nerve (selective loss of pain sensation ipsilat-
eral face), the spinothalamic pathway (contralateral loss of pain sensation over the
body and limbs), the descending sympathetic pathway (ipsilateral Horner’s syn-
drome), the vestibular nuclei (vertigo and nausea and vomiting), and the nucleus
ambiguous (ipsilateral paralysis of vocal cord, and uvula and gag reflex plus
hoarseness/dysarthria). At times the actual arterial lesion is in the vertebral artery
rather than the posterior inferior artery per se. In some cases, the infarct includes not
only the brain stem territory but also the posterior inferior cerebellum. In the era
before modern imaging, the associated cerebellar territory would not have been
detected since the cerebellar symptoms due to involvement of the inferior cerebellar
peduncle would have been in general similar to the actual involvement of the cere-
bellum. In some patients, only the posterior inferior cerebellum may be involved
producing headache, vertigo, vomiting, ataxia of gait, and ipsilateral limb symp-
toms of dysmetria and tremor. Artery-to-artery embolus from the vertebral artery
may occur as the etiology in such cases. That a syndrome is vascular may be deduced
from the acute onset of the initial symptoms. In some cases, as in this patient, addi-
tional symptoms are added in a sputtering pattern which may reflect those effects of
blood pressure variations, which may occur in sudden postural changes or in a diur-
nal manner. In addition, vascular syndromes often improve with time as in this case.
Case history 21.7: This 45-year-old, right-handed male with a past history of ele-
vated blood cholesterol (332 mg/100 mL) awoke, to find “numbness” of the left side
of the face and tongue. Diplopia was present particularly on looking to the left.
When he arose from his bed, he noted objective vertigo (room spinning) and walked
with a staggering gait with a tendency to fall to the left. Examination by the patient’s
physician indicated left lateral rectus weakness and an intention tremor of the left
hand. The patient was admitted to his local community hospital where improvement
21 Case History Problem Solving 631
occurred. The numbness of the face and tongue disappeared over several hours. The
diplopia and ataxia improved over the next 1–2 days. The patient was subsequently
transferred to a neurological center for additional evaluation.
Past history: Precordial pain 5 months previously, with EKG changes of an
acute myocardial infarction. Anticoagulation had been used since that time. Despite
that therapy 2 months before the present admission, the patient had a transient epi-
sode of left facial weakness and difficulty in remembering names.
Neurological Examination
1. General: Blood pressure, 130/90; pulse, regular.
2. Mental status: intact.
3. Cranial nerves:
(a) Extraocular movements: Some observers noted a moderate impairment of
conjugate lateral gaze to the left side. When lateral gaze to the left occurred,
there was a dissociated nystagmus with nystagmus greater in the abducting
eye (the left eye). At times during red glass testing on left lateral gaze, a
diplopia was reported. The pattern suggested possible weakness of right
medial rectus although no actual weakness of right medial rectus was
apparent.
(b) There was flattening of the left nasolabial fold with a lesser deficit in the
forehead wrinkling on the left.
(c) Slight slurring of speech was noted.
4. Motor system:
(a) Strength was intact.
(b) There was a mild intention tremor of left hand with impairment of alternat-
ing movements. Mild heel to shin ataxia was present in the left lower
extremity.
(c) Gait: There was a minimal ataxia on narrow base.
5. Reflexes:
(a) Deep tendon reflexes were symmetrical, except for questionable increase in
left ankle jerk.
(b) Plantar responses were flexor on right, equivocal on left.
6. Sensory System: Intact
Hospital course: Steady improvement occurred over a 2-week period.
Questions
1. Locate and diagram the lesion. Concern yourself with the history and findings of
the present episode with regard to localization. Assume a single lesion.
2. Having decided on the location of the lesion, indicate the probable pathology. In
answering this question, you should be aware, of course, that the information
concerning past history is relevant. If vascular, indicate the specific vascular
territory.
632 21 Case History Problem Solving
admission, she had the onset of 10 min episode of paresthesias of either the left
or right arm or leg. Three days prior to admission, she had a brief episode
(minutes in duration) of right-hand weakness. Nevertheless, she had recovered
well from all of these episodes with no residual neurological findings.
General examination: The patient was obese and anxious with blood pressure
elevated to 160/100.
Neurological Examination
1. Mental status: The patient was alert and oriented. Delayed recall was limited to
2/4 objects (all similar to 18 months previously).
2. Cranial nerves – III, IV, and VI: Ptosis of the right eye lid was present. Pupillary
responses were intact. At rest, the right eye was deviated out to the right and
down. No medial or upward movement of the right eye was now possible. VII: A
mild left central supra nuclear weakness was now present.
3. Motor system: Strength was intact.
4. Reflexes: Deep tendon reflexes: These were now increased in the left lower
extremity. These had been previously symmetrical. Plantar responses: A left
Babinski response was now present.
5. Sensory system: All modalities were intact.
Questions
1. Localize the lesion responsible for the new-onset right-sided extraocular find-
ings and the new-onset left central facial weakness, the increased left deep ten-
don reflexes, and the new left Babinski response.
2. Indicate the appropriate vascular territory involved in the present episode.
3. What eponym is attached to the present episode?
4. Indicate the term used to describe the prior episodes.
5. What would be the best studies to demonstrate the lesion?
Clinical Diagnosis
1. Ischemia/infarction of the penetrating (paramedian) territory of the right poste-
rior cerebral artery supplying the right peduncle and third nerve of the rostral
midbrain (Weber’s syndrome).
2. Basilar–vertebral transient ischemic attacks.
Comment: This patient had a background of hypertension and previous transient
ischemic attacks. The facts that motor and sensory symptoms at times were left or
right sided and included bilateral blurring of vision suggested that the basilar–ver-
tebral system was involved. In the present episode, the combination of right-sided
third nerve findings with left central facial weakness plus increased left-sided deep
tendon reflexes and a left Babinski sign all localized the lesion to the upper midbrain
territory supplied by a penetrating branch of the posterior cerebral artery.
Case history 21.9: This 63-year-old former bartender had the onset of weakness
and fatigue. The patient noted a change in his bowel movements. His stools became
black and he was found to be anemic. He lost weight. When admitted to the hospital,
634 21 Case History Problem Solving
he was found to have a carcinoma arising from the rectosigmoid colon and infiltrating
the bladder neck. A sigmoid colostomy was performed, and the patient received
high-voltage x-irradiation directed to the tumor mass.
The patient did well for 8 months at which time multiple nodules were seen in
the lung film, presumably metastatic disease.
Two years after the onset of symptoms, the patient experienced the first of a
number of 30–60 s episodes of spontaneous twitching of the left corner of the mouth
associated with a tingling sensation in the left thumb and index finger. These began
to occur as often as twice daily and lasted as long as 5–20 min. There was no loss of
consciousness. There was no generalized convulsion. The patient was right handed.
Neurological Examination
1. Mental status: Mental status and language function were intact.
2. Cranial nerves: There was questionable flattening of the left nasolabial fold.
3. Motor system: Strength in the extremities appeared normal.
4. Reflexes: Deep tendon reflexes were slightly increased in the left upper extremity.
5. Sensation: Stereognosis and graphesthesia were impaired in the left hand.
Subsequent Course
Appropriate medication was administered, and the patient received x-irradiation.
Three months later, the patient was reported as having a more pronounced left hemi-
plegia. The patient became increasingly confused and then gradually unresponsive,
and then respiratory arrest occurred.
Questions
1 . Characterize the nature of the episodes involving the left face and hand.
2. Indicate the location of the pathology.
3. Indicate the nature of the pathology.
Clinical diagnosis: Focal seizures originating in the right motor cortex area of facial
representation and spreading to the right sensory cortex. The lesion must be pre-
sumed to be metastatic.
Comment: All seizures and recurrent seizures (epilepsy) may be classified as either
focal (partial) or primary generalized. In this case, the seizures were focal. Having
recognized the episodes as focal seizures, the following rules apply:
1 . Focal seizures always indicate focal cortical pathology.
2. Any focal seizure may secondarily generalize.
3. In general, seizures do not originate in dead tissue but in the discharge of neurons
whose excitability has been altered resulting in excessive neuronal discharge.
This patient at autopsy had a single metastatic lesion in the brain involving the
motor–sensory cortex. In 65% of patients with metastatic brain disease, multiple
metastatic lesions are found to be present in the brain.
Where management of only the brain lesion is at issue, the best treatment of a
single metastatic lesion would be excision followed by radiotherapy.
Case history 21.10: This 49-year-old, white, right-handed, married male had the
onset 7–8 months prior to admission of episodes characterized by a raising sensation
21 Case History Problem Solving 635
2. The function of areas to which the seizure discharge occurs, for example, spread
to other cortical areas in the ipsilateral and contralateral hemisphere and to sub-
cortical centers.
3. The function of the brain when deprived of the function of those areas that are
being discharged or involved by the seizure discharge. Thus, the effect of dis-
charge involving the language centers is an interference with the production of
speech and the reception and interpretation of speech. Discharge of the hippo-
campus results in an inability to record new memories.
Case history 21.11: Three weeks prior to admission, this 69-year-old, right-handed
white male had the onset of clumsiness of his right hand, and this was almost imme-
diately followed by weakness and numbness involving the right hand. He then
noticed that his right leg was weak, and he fell to the floor. The weakness and numb-
ness of the hand and leg cleared in a matter of minutes. The patient, however, con-
tinued to have clumsiness on the right hand. On two subsequent occasions, he had a
recurrence of weakness of the right hand lasting a matter of minutes. The patient’s
history was also of significance in that over a 2-month period, he had had 3 epi-
sodes, each 3 min in duration, of a monocular blindness involving the left eye.
Past History:
( 1) The patient had had diabetes mellitus for approximately 20 years.
(2) Six months prior to admission, the patient had a sudden onset of weakness and
coldness of the right lower extremity. This was due to sudden occlusion of the
right femoral artery; a right femoral endarterectomy had been performed with
bypass. His symptoms in the right lower extremity improved.
(3) The patient had had episodes of chest pain (angina pectoris) for a number of
years. The episodes never lasted longer than 5–10 min.
(4) Family history was significant in that the patient’s mother, father, daughter, and
son all had experienced severe diabetes mellitus.
General Physical Examination:
1 . Blood pressure was 130/80 in both the right and left arms.
2. Light pressure on the left eyeball led to a blackout of vision; similar symptoms
were not produced on the right side.
Neurological Examination:
1. Mental status: The patient was oriented for time, place, and person.
2. Cranial nerves: No significant findings were present.
3. Motor system:
(a) Strength was intact except for a minimal drift downward of the outstretched
right arm when both arms were outstretched.
(b) Cerebellar tests and gait were intact.
4. Reflexes:
(a) Deep tendon reflexes were slightly increased in the right arm compared to
the left. The Achilles’ tendon reflexes were absent bilaterally, presumably
related to the patient’s diabetes.
638 21 Case History Problem Solving
5. Sensory system:
(a) Vibration was decreased bilaterally at the toes, presumably related to the
patient’s diabetes.
(b) Occasional errors were made in letter and number recognition in the right
hand (graphesthesia testing).
Questions:
1. What is the diagnosis? Be specific as to the vessel and vascular territory involved,
if vascular in nature.
2. If vascular, indicate the mechanism involved, for example, perfusion or embolic.
3. Outline your diagnostic approach to this problem.
4. Indicate possible therapeutic measures.
Clinical diagnosis: Transient ischemic attacks (TIAs) and minor ischemic neuro-
logical deficits in the distribution of the left carotid artery. TIAs have involved both
the left cerebral hemisphere and the left retina. The hemispheric deficits involve the
border zone (watershed) of the carotid artery and therefore are perfusion related.
Comment: This patient clearly had vascular disease involving the coronary arteries of
the heart and the femoral artery of the leg. Other questions to be considered in this case
include the following: Did he have symptoms of intermittent claudication with tran-
sient pain in the leg muscles on exercise? He clearly had a familial history of diabetes.
Was this type I: early onset requiring insulin or late onset and not requiring insulin.
Was he a smoker? What were his blood lipids in terms of total cholesterol, HDL,
LDL cholesterol fractions, and triglycerides? Were bruits present over the carotid
and other major arteries signifying stenosis? Note that bruits do not have to be pres-
ent; as a matter of fact, when a previously stenotic vessel totally occludes, a previ-
ously present bruit will usually disappear.
In terms of the vascular territory involved, the combination of hemispheric TIAs
involving the right upper extremity and retinals TIAs involving the left eye, it is clear
that basic problem involves the left carotid artery. In terms of the specific territory of
the hemisphere involved by ischemia, the border zone (watershed) of the carotid
artery may be implicated for the following reason. Ischemia (decreased perfusion)
of the anterior cerebral branch of the left carotid artery would involve the right leg
area. Ischemia (decreased perfusion) of the core cortical territory of the middle cere-
bral artery would involve the face and language function areas of the left dominant
hemisphere. The watershed area must then be the area between these two cortical
territories, that is, the right arm/hand. Since the first area involved when decreased
perfusion of the cortical territory of the carotid artery occurs is the watershed, we
can be certain that TIAs involving the hand indicate a problem in perfusion.
Consider two hoses each supplying an overlapping sprinkler area of a specific
radius, but both originating from the same hose. If perfusion pressure and flow in that
primary hose is reduced, the radius of areas supplied by the sprinklers will be reduced
once a 70% reduction in diameter is achieved. By reducing the area sprinkled,
the area of overlap, the watershed will no longer receive an adequate perfusion.
21 Case History Problem Solving 639
Neurological Examination
1. Mental status and language function: The patient was oriented and presented a
relevant history. There was no evidence of a nominal aphasia. Reading and writ-
ing were intact. Repetitions and ability to follow spoken and written directions
were intact.
2. Cranial nerves II–XII: All were intact except for a minimal right central (supra
nuclear) weakness of facial movements.
3. Motor system: Strength was intact. There was a minimal decrease in swing of the
right arm in walking, but otherwise gait was intact. Cerebellar findings were
within normal limits.
4. Reflexes: There was a minimal increase in deep tendon reflexes at the right biceps,
triceps, patella tendon, and Achilles tendon. Plantar responses were flexor.
5. Sensation: Pain, position, and touch were within normal limits. There was no
extinction on simultaneous stimulation. There was a minimal decrease in vibra-
tory sensation at the toes as compared to the ankles.
Laboratory Data
1. CBC: Hct 45; WBC 6800; sedimentation rate 8 mm. All normal.
2. Thyroid function studies indicated a border line hyper thyroid state.
3. Chest x-rays: The heart was enlarged. Chest fluoroscopy showed evidence of
mitral valvular disease.
4. Skull x-rays were normal.
Question
1. What is your diagnosis at this point in time?
Subsequent Courses
The patient was treated with digitalis and with anticoagulants. She was dis-
charged to her home and did well for 4 months. She then had the sudden onset of
pain, numbness, and paralysis of the left lower extremity. Examination indicated
that the right popliteal pulse was present but the left was absent. The left leg was
cold and pale with demarcation above the knee and no pain sensation below this
level. Atrial fibrillation was still present. A left popliteal endarterectomy was imme-
diately performed with a return of pulses, sensation, and movement. Anticoagulation
had to be temporarily suspended during the surgical period.
Question
2. What additional diagnosis must now be made?
Subsequent Course
On the ninth postoperative day, at 10 AM, the patient suddenly stopped speaking
in midsentence and was noted to have a complete right hemiplegia.
Question
3. Neurological history and knowledge of the probability of common events for a
particular age and is responsible for 75% of diagnosis. What is your diagnosis?
21 Case History Problem Solving 641
Neurological Examination
1. Mental status: The patient was somnolent but could be aroused. She was unable
to produce any intelligible words and was unable to follow any verbal
commands.
2. Cranial nerves:
(a) No response to visual threat on the right occurred.
(b) Head and eyes deviated to the left. Eye movements were full in response to
head turning.
(c) A right central facial weakness was present.
(d) There was a decreased response to pin prick on the right side of the face.
3. Motor system:
(a) The right arm and leg were immobile. Only minimal movement occurred
even on pinprick stimulation.
(b) A minor degree of spasticity was present on the right side.
4. Reflexes:
(a) Deep tendon:
Biceps: right, 2; left, 2+
Triceps: right, 1; left, 2
Radial: right, 1; left, 2
Quadriceps: right, 3; left, 2+.
Achilles: right, 3; left, 2+
(b) Plantar responses: extensor on the right, flexor on the left. Grasp was absent
on the right.
5. Sensation:
(a) The patient responded to pain over the left side of the body. There was a
questionable response on the right.
(b) The patient was described as “ignoring” the right side.
6. Carotid pulses were strong in the neck.
Question
4. What is your diagnosis as to the specific vessel and vascular territory involved
and the nature of the vascular pathophysiology?
Subsequent Course
Neurological follow-up examination 4 months after this catastrophic event
revealed little return of language function. Almost no spontaneous speech was pres-
ent. Patient was able to answer yes and no to some questions. She had return of
certain automatic gestures and speech; e.g., in responding to greeting, she would
smile and say hello. At conclusion of examination, she would grasp the hand of the
642 21 Case History Problem Solving
doctor and say “thank you.” The patient was able to understand simple one-stage
commands but was unable to carry out more complex commands. Perseveration was
evident. Other findings were unchanged.
Questions
5. What is the anatomical significance of the language disturbance?
6. The deep tendon reflexes at the biceps, triceps, and radial on the right never
became particularly hyperactive. What prognosis do you attach to this?
7. In a patient who has suffered a dense hemiparesis, is the absence of spasticity
several days after the stroke a good or bad prognostic sign?
Clinical diagnosis: Cardiogenic cerebral emboli with major event total left middle
cerebral artery (MCA) territory infarction due to left main stem MCA occlusion.
A systemic embolus had also occurred to the left popliteal artery.
Comment: This patient had underlying atrial fibrillation and evidence of mitral steno-
sis. Both of these problems undoubtedly reflected a previously unrecognized rheu-
matic heart disease. The alternative diagnosis of bacterial endocarditis was considered
but could not be confirmed. The initial two episodes of transient speech disturbance
were undoubtedly related to small emboli passing to cortical branches of the left
MCA branches supplying the speech areas. Often emboli break up and the symptoms
rapidly resolve. Total MCA territory infarcts often are associated with considerable
brain swelling due to edema and secondary hemorrhagic transformation. The degree
of increased brain volume may be sufficient to produce temporal lobe herniation
through the tentorium, with brain stem compression which may be fatal.
Case history 21.13. This 32-year-old right-handed married white male spray painter
at a computer factory was referred for evaluation of a several neurological symp-
toms including a possible movement disorder. The patient was unclear about the
reasons for his evaluation, and much of the history was provided by his wife. She
reported that the patient had undergone a personality change in the last several
months. She had noticeable mood swings, and on one occasion the patient had
reported to her that people were outside the window when no one actually had been
there. He had some problems with remembering incidental matters, but no major
problems and his job performance had remained intact. He was described as always
having been “fidgety.”
Past medical history: Mild hypertension had been present for 3 years.
Family history: The patient’s initial history indicated that the family had
“Parkinson’s” disease.
His father had died in his 40s at the state hospital after a 10–15-year illness. The
patient indicated that he was a child at the time and his mother never really told him
much about the father or let him visit the father in the hospital, but he did recall that
perhaps his father had some excessive movements of the hands and face. The records
were subsequently obtained, and these indicated the father had been admitted to the
local state hospital at age 37. At that time, he had already had three previous hospi-
talizations for “nervous breakdowns.” At the time of his final admission, he had
developed hallucinations, seeing people in his room. He had threatened his wife and
21 Case History Problem Solving 643
other relatives. He had difficulty sleeping and he had also developed a problem with
his legs: “they are jumping.” The father’s examination had demonstrated a mumbled
speech with repetition of the same phrases. His responses would often be tangential
and then incoherent with impairment of memory and judgment. His mood was
depressed. He was noted to have involuntary movements of the fingers and occa-
sional facial grimacing. The deep tendon reflexes were hyperactive and the plantar
responses were extensor. His gait was ataxic. The subsequent course indicated
increasing ataxia, choreiform movements and rigidity with increasing weakness,
difficulty in swallowing, and the final development of bronchial pneumonia with
death at age 42. The diagnosis was confirmed at autopsy.
The paternal grandfather had expired at age 67 with a similar diagnosis, mani-
fested by “nervous breakdowns, inability to sleep, and movement disorder.”
The father’s three siblings apparently did not manifest the disease.
The patient had two siblings, a brother aged 28 and a sister aged 35, all without
known disease.
He had two children aged 9 and 5 with no neurological symptoms or signs.
Neurological Examination
1. Mental status: The patient was anxious, often appeared blunted in emotional
expression or in answering questions. He avoided eye contact. He was oriented
for time, place, and person. He was able to name objects and colors. His delayed
recall was 2/5 without assistance and 4/5 with assistance.
2. Cranial nerves: Cranial nerves II–XII were intact, except for the occurrence of
occasional, sudden darting movements of the eyes to either left or right. In addition,
occasional facial grimacing was noted occurring in a rather irregular manner.
3. Motor system:
(a) Strength and gait were intact.
(b) There were occasional, sudden, irregular, lateral, tremulous movements of
the fingers of a choreiform type.
4. Reflexes:
(a) Deep tendon reflexes including the jaw jerk were everywhere hyperactive.
(b) Plantar responses were bilaterally extensor (bilateral Babinski signs).
5. Sensory system: intact.
Questions
1 . What is the diagnosis?
2. What is the location and nature of the pathology?
Clinical diagnosis: Huntington’s disease
Laboratory Data
1. All blood chemistries, including glucose; BUN, calcium, electrolytes, liver func-
tion studies, ceruloplasmin level, thyroid studies, and serological test for syphilis
were within normal limits. Ceruloplasmin levels are low in Wilson’s disease but
normal in Huntington’s disease.
644 21 Case History Problem Solving
prominent feature. At the initial evaluation, the patient was unclear as to why he had
come for neurological evaluation. Was this a neurological or a psychological denial
of illness? Most likely both factors were operational. It was of considerable interest
that this patient when first seen, although he was aware of some neurological prob-
lem that had occurred in the family, was unclear as to the specific diagnosis. It was
also evident that almost no genetic counseling had been done in a disorder that was
very clearly an autosomal-dominant disorder. The significant family impact and
social and economic impact of the disease sre clearly evident in this patient. There
are significant psychological implications of presymptomatic detection. Testing of
relatives should be performed in a genetic clinic that is able to offer the full gamut
of psychological and social services.
As to the progression in cases of Huntington’s disease, the earlier the age of onset,
the greater the number of CAG trinucleotide repeats and the earlier the age of onset,
the more rapid the rate of progression. Early onset cases often demonstrate a signifi-
cant degree of rigidity. In late onset cases, the movement disorder is usually a presen-
tation of chorea without significant rigidity. Note that Parkinsonian features may
emerge in cases treated with dopamine antagonists such as haloperidol, as in this case.
Case history 21.14: This 63-year-old, right-handed female librarian, 11 years prior
to admission, experienced several generalized convulsive seizures. Her neurological
examination at that time was not remarkable, and the additional laboratory imaging
studies at that time which did not include CT scan or MRI (but did include a radio-
active brain scan) were not remarkable. She experienced no additional difficulties
until 8 months prior to admission, when she had the first of recurrent focal seizures
involving the left hand: uncontrollable jerking and twitching of the hand caused her
to drop packages. One month prior to admission, the patient experienced a focal
seizure in the left hand which spread up the arm and then involved the leg, resulting
in a loss of consciousness. The patient was taken to the emergency room of her local
hospital. There another seizure was observed. This began with focal movements of
the left wrist and hand, then the head turning to the left, and then clonic movements
of the left leg.
Neurological Examination
1. Mental status: intact.
2. Cranial nerves: All were intact including sense of smell.
3. Motor system:
(a) Strength was everywhere intact.
(b) Repetitive finger-thumb tapping was slightly slower on the left side than on
the right. The patient, however, was right-handed.
4. Reflexes:
(a) Deep tendon reflexes were slightly asymmetrical in the upper extremities.
Finger jerks were more active on the left than on the right. There was no
asymmetry in lower extremities.
(b) Plantar responses were flexor.
646 21 Case History Problem Solving
Abstract This chapter reviews movies from Hollywood that illustrate the effects of
many diseases on the brain. These movies cover developmental disorders, disease in
the spinal cord, brain stem, and cerebrum. The causes of these disparate injuries
include congenital malformations, genetic abnormalities, trauma to the brain, vas-
cular insufficiencies, tumors and infections. All of these selected movies are very
entertaining and informative.
A series of films which depict the effects of various disorders on the brain. *Indicates more signifi-
cant films from a medical standpoint.
The chapters and times indicated in some of the citations refer to points on the actual DVD where
the critical scenes may be found.
The Activities of the Neurosurgeon. Film: The Man with Two Brains (1983)
Several of the films below such as Dark Victory detail the role of the neurosur-
geon in the treatment of neurological disease. This film stars one of the outstanding
comedians and writers of recent years Steve Martin as he manages successfully a
traumatic brain injury. Refer to Chaps. 2 and 3 (5′10”to 7′25″).
The Creativity of the Neurologist. Film: Freud (1962)
This film, directed by John Huston, dissects the early professional career of
Sigmund Freud in the practice of neurology in late 1800s, Vienna. Freud played by
Montgomery Clift had already significant contributions in the area of neuroanatomy
and neuropathology, when he encountered patients with hysterical paralysis. He
described these patients in a monograph with an older colleague Joseph Breuer
played by Larry Parks. These early studies led to Freud’s development of the theo-
ries of psychoanalysis, psychosexual development, defense mechanisms, etc.
The Neurological Examination. Film: The Fortune Cookie (1966)
This film was directed and written by Billy Wilder. The two stars, Jack Lemmon
and Walter Matthau, were to appear together in a number of comedies over the
years. Lemon is a TV cameraman covering a professional football game. He is run
over on the sidelines by a star running back and sustains a concussion. His brother-
in-law played by Matthau is an ambulance chasing lawyer who sees many more
exciting possibilities of a million dollar settlement from the insurance company. It
is in this context that Lemmon encounters the several neurologists who exam him.
One “cynical” neurologist suggests in the asides commentary that Lemon may be
malingering. Refer to Chaps. 6 and 7 (46′40″ to 52′ 15″).
This film features a severely disabled detective and author played by Denzel
Washington who with the help of a young assistant (Angelina Jolie) does crime
scene investigations and solves crimes. Jeffery Deaver, the author of the original
book, has written a series of books featuring this detective Lincoln Rhyme. Of
particular interest is the scene which occurs in Chap. 14: 1 h 22′ to 1 h 24′ 50″ in
which a urinary catheter blockage produces a marked change in blood pressure
sufficient to lead to a seizure.
Neurological Disorder: Traumatic Cervical Cord Transaction Producing
Quadriplegia. Film: Whose Life Is It Anyway? (1981)
In this film a 32-year-old gifted sculptor and art teacher Ken Harrison played by
Richard Dreyfuss is involved in a catastrophic automobile accident and sustains a C4
spinal cord transection and multiple other life-threatening injuries rendering him
quadriplegic. After months of life-prolonging treatment, he arrives at a conscious
decision to fore go any additional treatment. This results in conflicts with the medical
establishment as represented by the chief of staff of the spinal cord treatment center;
Dr. Emerson (played by John Cassavetes) sets the stage for a legal proceeding.
Neurological Disorder: Thoracic Spinal Cord Injury. Film: Passion Fish
(1992)
In this film a soap opera actress (played by Mary McDonnell) sustains a thoracic
spinal cord injury in a New York taxi accident resulting in paraplegia. She is reduced
to an embittered wheel chair existence. With the help of a strong nurse (played by
Alfre Woodard), she must face up to her disability.
Neurological Disorder: Poliomyelitis (FDR Subsequently Died of a
Hypertensive Intracerebral Hemorrhage). Film: Sunrise at Campobello (1960)
This film traces the career of another wartime president Franklin Roosevelt (por-
trayed by Ralph Bellamy) who after serving as assistant secretary of the navy and
running for vice-president developed poliomyelitis. He overcame this severe dis-
ability to become governor of the state of New York. Eleanor Roosevelt was por-
trayed by Greer Garson. The original play from which the film was adapted received
a Tony Award. A later dramatization of the personal lives of the two and of the
impact of polio was presented on television in 1976. The film entitled Eleanor and
Franklin was based on the book by Joseph Lash and starred Edward Hermann and
Jane Alexander.
*Neurological Disorder: Amyotrophic Lateral Sclerosis. Film: The Pride of
the Yankees (1942)
This famous is a biography of a famous baseball player Lou Gehrig who died
with amyotrophic lateral sclerosis. His record for career grand slam home runs and
of single season runs batted in for the American league remains to this day. The film
starred Gary Cooper as Lou Gehrig and Teresa Wright as his wife. Former team-
mates, Babe Ruth, Bill Dickey, and Bob Meusel, also appeared. A later retelling of
the story (Love Affair: The Eleanor and Lou Gehrig Story) appeared on television in
1977 and starred Edward Herrmann and Blythe Danner.
Neurological Disorder: Amyotrophic Lateral Sclerosis. Film: Tuesdays with
Morrie (1999)
22.4 Disorders of Motor Systems and Motor Control 651
This made for TV movie was based on a real-life drama. A sports writer, Mitch
Albom (played by Hank Azaria), in Detroit finds out that his old college professor
in Boston, Morrie Schwartz (played by Jack Lemmon), has developed ALS. He
visits the professor and they undertake a series of weekly discussions regarding life,
purpose, and death.
Neurological Disorder: Locked-In Syndrome Due to Basilar Artery Thrombosis.
Film: The Diving Bell and the Butterfly (2007)
This film is in French with English subtitles. It is based on an actual case history
and received multiple awards. The film demonstrates the complications of a cata-
strophic stroke affecting a relatively young individual. He is conscious but unable to
initially demonstrate his level of consciousness.
Martin Scorsese and also featured Alan Alda as Senator Brewster and Alec Baldwin
as Juan Trippe, the founder and CEO of Pan American Airways.
Neurological Disorder: Obsessive Compulsive Disorder Plus Personality
Disorder. Film: As Good as It Gets (1997)
This film directed by James L. Brooks concerns the romance of an unpleasant
obsessive-compulsive novelist and the only person who can tolerate his behavior, a
waitress at his favorite local restaurant. He can only sit at his table and be waited on
by this waitress. During the course of the film, his behavior improves and his
attitudes change. Jack Nicholson who played Melvin Udall is the writer with an
obsessive-compulsive disorder. He received an Academy Award as Best Actor.
Helen Hunt played Carol the waitress and received an Academy Award as Best
Actress.
Neurological Disorder: Huntington’s Disease. Films: Bound For Glory and
Alice’s Restaurant (1976)
The first film presents an excellent biography of the famous American song
writer and folk singer Woody Guthrie (portrayed by David Carradine) for the period
1936–1940 a time of protest and union-organizing activities. He subsequently mani-
fested the progressive neurological disease Huntington’s disease characterized by a
movement disorder and cognitive changes. The film does demonstrate the personal-
ity changes already beginning to occur. The second film released in 1969 and
directed by Arthur Penn is centered on another period of protest, the hippie era of
the late 1960s when the Vietnam War, the draft, drugs, and free love were prominent
issues. Arlo Guthrie, Woody’s son and also a folk singer, and Pete Seeger play them-
selves. The terminal bedridden stages of Woody’s progressive Huntington’s disease
are demonstrated.
Several films demonstrating focal seizures are presented below in the seizure and
epilepsy section. Prefrontal syndromes are presented in the limbic section below.
*Neurological Disorder: Foreign Arm/Hand Syndrome. Film: Dr. Strangelove
Or: How I Learned To Stop Worrying And Love The Bomb (1964)
This classic film was directed by Stanley Kubrick dealt with one of the great
fears of the Cold War, a nuclear confrontation between the great powers the United
States and the Soviet Union. The national security adviser has been injured during
World War II. As a result, he is confined to a wheel chair and has a prosthetic right
hand. At times of stress, he cannot control the right arm which performs in a foreign
manner taking on postures which reflect his previous life as a Nazi leader and
adviser. Peter Sellers in a remarkable performance portrayed three characters: Dr.
Strangelove as well as the sensible Canadian Group Captain Mandrake and the
American President Maffley George Scott. The American air force commander
General Buck Turgidson was based on General Curtis LeMay, who masterminded
the firebombing of the Japanese cities in World War II. He was one of the hawks of
22.6 Limbic System 653
the cold war. Sterling Hayden played General Ripper. The nuclear confrontation is
triggered when General Jack Ripper sends off a squadron of nuclear armed B-52
bombers. He is concerned with a plot by the Soviets to rob Americans of their vital
fluids, and he aims to preserve “the purity of essence.”
Problems in Reading. Film: The Reader (2008)
This film featured a powerful Academy Award* winning performance by the
actress Kate Winslet. She plays a morally flawed individual whose life is complicated
by a basic problem in communication. She is unable to read but is unwilling to
indicate that she has this disorder. Refer to Chap. 20 (1 h 28′ 48″ to 1 h 33′ 47″).
A Possible Acute Syndrome of the Corpus Callosum. Film: All of Me (1984)
This fantasy film directed by Carl Reiner features two of the best comedians of
the 1980s. A dying wealthy woman Edwina Cutwater played by Lily Tomlin has her
spirit/soul introduced into the brain of another healthier and more attractive young
woman. Unfortunately, a mistake is made, and her consciousness and controls end
up occupying one hemisphere of the brain of her young lawyer Roger Cobb played
by Steve Martin. The result is an apparent but fantastic acute callosal disconnection
syndrome in which antagonistic motor actions are triggered. Refer to Chaps. 5/6 of
the film (22′47″ to 27′ 38″).
Terherne the young beautiful and wealthy socialite patient with a glioma in love
with her neurosurgeon. The performance by Bette Davis who had previously won
two Academy Awards is considered one of her finest. Although nominated for an
Academy Award, she did not win, 1939 was the year of Gone with the Wind. She
was also nominated for her other remarkable performance in All about Eve in 1950
but did not win. The actors and actresses reflected almost the full acting company of
the studio system at Warner Brothers including Humphrey Bogart and Ronald
Reagan, with Henry Travers as the caring sympathetic general practitioner Dr.
Parsons and Geraldine Fitzgerald as the close friend and secretary. This film pro-
vided Ronald Reagan with his worst role portraying a drunken playboy followed by
Bogart as his Irish horse trainer. Other films concerned with brain tumors include
Crisis. In this film released in 1950, a famous somewhat cynical American neuro-
surgeon (played by Cary Grant) vacationing with his wife in a Latin American coun-
try is forced to operate on a paranoid and oppressive dictator (played by Jose Ferrer)
with a brain tumor (? frontal) while his wife is held hostage. The patient’s recovery
is complicated by a successful revolution led by Gilbert Roland.
Neurological Disorder: Glioma in an Adolescent. Film: Death Be Not Proud
(1975)
In this made for television film, an adolescent (played by Robby Benson) is
treated for a malignant glioma. The film which starred Arthur Hill and Jane
Alexander as the parents is based on the true story by John Gunther concerning his
son’s illness and death at age 17.
22.10 Infections
and the screenwriter was Graham Greene, and it was filmed in Vienna shortly after
the end of World War II.
*Neurological Disorder: Neurosyphilis (General Paresis) Producing Dementia
and a Change in Personality. Film: Young Winston (1972)
This film was directed by Richard Attenborough, and it depicts the childhood
and early adult life of the famous British politician Winston Churchill played by
Simon Ward who trained as a military officer at Sandhurst but later pursued a career
as a combat reporter and author. He subsequently rose to political prominence just
prior to and during World War I as the First Lord of the Admiralty. Our interest here
is in his father Lord Randolph Churchill played by Robert Shaw who at the peak of
a brilliant political career as Lord of the Exchequer began to demonstrate in his late
30s erratic behavior and a progressive impairment of his mental and physical capac-
ities all of which is extensively demonstrated in the film. His wife portrayed by
Anne Bancroft (remember Mrs. Robinson in The Graduate and Annie Sullivan in
The Miracle Worker) was told that the disorder was an inflammation of the brain and
that intimate contact with the patient was to be avoided. The film received the 1973
Golden Globe Award as Best Foreign Film. Ward bore a remarkable resemblance to
the young Churchill. The cast included a veritable gallery of fine English actors
portraying various politicians, journalists, and military leaders: John Mills, Jack
Hawkins, Ian Holm, Patrick Magee, Edward Woodward, etc. The movie was actu-
ally based on Winston Churchill’s autobiography My Roving Life: A Roving
Commission.
Neurological Disorder: Syphilis. Film: Dr. Ehrlich’s Magic Bullet (1940)
This film presented a biography of Dr. Ehrlich (played by Edward G. Robinson)
the physician who helped to develop a treatment for diphtheria and then went on to
develop a treatment for syphilis which was utilized until penicillin came into use.
There were questions at the time as to whether the film should be released but the
US Public Health Service supported the release of the film.
Robinson was more famous for his role of Rico in the 1930 drama “Little Caesar.”
See also Sunrise At Campobello under spinal cord, poliomyelitis.
Rabies. Two Films Have Been Concerned with this Subject: The Story of
Louis Pasteur (1936)
This film starred Paul Muni in an *Oscar winning performance.
Old Yeller (1957)
This film by Walt Disney studios concerned the relationship of a boy and his dog
in rural 1869 Texas and the problems that occur when the dog develops rabies. Fess
Parker and Dorothy McGuire starred this film.
teaching hospital, the Manhattan Medical Center, for a routine medical checkup. He
undergoes an unnecessary renal biopsy, has a botched nephrectomy, following
which he has an allergic reaction, and develops renal failure resulting in coma. He
recovers from coma but continues to present a picture of pseudocoma. He now
manifests a highly developed paranoid psychosis with hallucinations. With the
assistance of the hospital’s own inefficient systems and the incompetence of multi-
ple house officers, attending physicians, and nurses, he begins to secretly eliminate
the physicians and nurses who have caused the various mishaps. The chief of medi-
cine of the hospital Dr. Bock (George Scott) who has his own problems of excessive
alcohol intake, impotence, and depression attempts to sort out the series of deaths,
assisted by Dr. Drummond’s daughter (played by Diana Rigg). The film also
featured Richard Dysart as Dr. Welbeck, the incompetent urologic surgeon more
interested in business than in quality of care, and Nancy Marchand as Ms. Christie,
the director of the nursing service who has to deal with multiple incompetents. She
was later cast as the matriarch of the Sopranos.
Filmed at Metropolitan Hospital in New York, the movie exposed the problems
of operating a large city teaching hospital at a time of fiscal restraints and inner city
conflicts. The screen play was written by Paddy Chayefsky (Academy Award).
Neurological Disorder, Drug Addiction: Barbiturate’s Plus. Film: Dead
Ringers (1988)
This disturbing film directed by David Cronenberg was based on a real series of
events concerning the fictional named identical twins Elliot and Beverly Mantle
(both played by Jeremy Irons). They are brilliant students from Toronto, educated
and trained at Harvard, and now back in Toronto as academic gynecologists work-
ing together. They share their medical patients, research, and women. Elliot is con-
fident and ruthless; the other Beverly is modest and sensitive. A failed love affair
with an actress, who is a patient with a congenitally malformed uterus, triggers a
descent into mental collapse and barbiturate addiction. Both die possibly because of
drug overdose or barbiturate withdrawal or murder and suicide. The real-life twins
were Stewart and Cyril Marcus who were recruited from Harvard to the Cornell
New York Hospital. Jeremy Irons won the New York Film Critics Award for Best
Actor and Genevieve Bujold the award as Best Supporting Actress.
*Neurological Disorder: Cocaine Addiction. Film: The Seven-Per-Cent
Solution (1976)
This film combines the activities of the most famous fictional detective, Sherlock
Holmes (portrayed by Nicol Williamson) with the real-life detective of the mind,
Sigmund Freud portrayed by Alan Arkin. The Seven Per-Cent Solution refers to the
usual solution of cocaine. The plot concerns the addiction of Sherlock Holmes and
of the damsel in distress (played by Vanessa Redgrave) as well as the background of
Holmes’s obsession with Professor Moriarty (Lawrence Olivier). Freud’s early
methods of analysis are portrayed as well as his work with cocaine and cocaine
addiction. Dr. Watson is played by Robert Duvall. Joel Grey played one of several
villains. The author of the original book and screen play, Nicholas Meyer has resur-
rected the characters originally created by Dr. Arthur Conan Doyle.
660 22 Movies on the Brain
22.14 Coma
22.15 Memory
Abstract This section will identify and discuss many of these structures seen in:
Figs. 23.1–23.10 (gross brain sections in the coronal, horizontal and sagittal plain
sections).
Fig. 23.2 Medial surface of the hemisphere-gross brain, sulci, lobes, gyri
670 23 Descriptive Atlas
Fig. 23.3 Coronal Slice I. Level: genu of the corpus callosum. In this slice, only the cerebral cor-
tex and medullary center of the telencephalon are present. Gyri. Portions of the frontal and cingu-
late lobes are present on this slice. The temporal lobe pole is present beneath the inferior surface
of the brain. Arteries. Note that the anterior cerebral arteries are curving around the genu of the
corpus callosum. This vessel supplies the medial surface of the hemisphere up to the parieto-
occipital fissure
23.4 Gross Brain Slices: Coronal 671
Fig. 23.4 Coronal Slice II. Level: rostrum of corpus callosum. In this section, a portion of the
deep telencephalic gray is now seen (caudate and putamen). The temporal lobe is still separated
from the remainder of the cerebrum. The corpus callosum is now a thick band of fibers forming the
roof of the anterior horn of the lateral ventricle. The olfactory stalk in the olfactory sulcus on
the base of the frontal lobe is attached to the inferior surface of the frontal lobe. Frontal Lobe.
The following gyri are present: superior, middle, inferior, orbital, and rectus. These are the frontal
associational areas. Temporal Lobe. The most anterior tip of the superior, and middle, inferior gyri
is present. Cingulate Lobe. This cortex is found above the corpus callosum in all levels from the
genu through the splenium. White Matter. The anterior limb of the internal capsule separates cau-
date from putamen. Arteries. Note that the anterior cerebral arteries are seen in the interhemi-
spheric sulcus above and below the corpus callosum. The middle cerebral arteries are seen entering
the lateral fissure
672 23 Descriptive Atlas
Fig. 23.5 Coronal Slice III. Level: anterior commissure. The temporal lobe is now connected to
the remainder of the cerebral hemisphere. Frontal Lobe. The same gyri are present as in slice II.
Temporal Lobe. The superior, middle, inferior, occipital-temporal, and parahippocampal gyri are
present from the lateral to the medial surface. Note the location of the insular and cingulate cortex.
White Matter. The optic chiasm is seen attached to the base of the brain. The optic recess of the III
ventricle is the lumen above the optic chiasm. The septum forms the medial wall separating the
body of the lateral ventricles. The anterior limb of the internal capsule is seen between the caudate
and putamen. Arteries. The middle cerebral artery is seen at its point of origin from the internal
carotid and in the lateral fissure. Note the anterior cerebrals in the interhemispheric fissure.
Hypophyseal Stalk. This structure is seen medially on the inferior surface of the brain
23.4 Gross Brain Slices: Coronal 673
Fig. 23.6 Coronal Slice IV. Level: anterior nucleus of the thalamus. This is the first level to include
part of the diencephalon. Frontal Lobe. The superior, middle, inferior, and precentral gyri are
present. Parietal Lobe. This is the first slice to include parietal cortex. The postcentral (sensory)
gyrus is seen forming the roof of the lateral fissure. Temporal Lobe. The superior, middle, inferior,
occipitotemporal, and parahippocampal gyri are present. A portion of the transverse temporal gyri
(auditory cortex) is found internal to the superior temporal gyri in the depths of the lateral fissure.
The hippocampal formation, with the inferior horn of the lateral ventricle at its medial surface, is
the most medial portion of the temporal lobe. Thalamus. The anterior nucleus protrudes into the
floor of the lateral ventricle (body). The mammillothalamic tract is seen entering the inferior sur-
face of the anterior nucleus. Hypothalamus. The mammillary bodies are prominent on the base of
the diencephalon. The fornix is seen suspended from the body of the corpus callosum, and the
column of the fornix is seen in the hypothalamus. This tract connects the hippocampus to the
hypothalamus. White Matter. The posterior limb of the internal capsule is seen lateral to the thala-
mus. Many of the fibers of the internal capsule continue to the inferior surface of the brain where
they form the cerebral peduncle
674 23 Descriptive Atlas
Fig. 23.7 Coronal Slice V. Level: habenular nucleus. In this section, only a small portion of the
caudate and putamen remains. Frontal Lobe. Only the most medial portion of the precentral gyrus
(motor cortex) remall1s. Parietal Lobe. The postcentral and inferior parietal lobule is present.
Temporal Lobe. The transverse temporal (auditory cortex), superior, middle, inferior, occipitotem-
poral, and parahippocampal gyrus and hippocampus are found in this level. Cingulate and insular
cortex are also evident. Brain Stem. The bulk of the thalamus at this level consists of the pulvinar
nuclei. The laminated lateral geniculate nucleus is found at the inferior, lateral margin of the telen-
cephalon. The fibers of the optic tract synapse in this nucleus. The habenular nucleus of the epi-
thalamus protrudes into the third ventricle. The red nucleus and the pigmented substantia nigra are
prominent in the tegmentum of the midbrain. The visual radiation is seen leaving the lateral surface
of the geniculate nucleus. White Matter. The body of the fornix is suspended from the undersurface
of the corpus callosum. The visual radiation is seen leaving the lateral surface of the lateral genicu-
late. The massive brachium pontis forms the base of the brain. The posterior commissure is seen
crossing below the habenular nuclei; this fiber bundle interconnects the pretectal, tectal, and pos-
terior portion of the thalamus
23.4 Gross Brain Slices: Coronal 675
Fig. 23.8 Coronal Slice VI. Level: splenium of the corpus callosum. Brain Stem. This level is
posterior to the thalamus and includes a coronal cut through the inferior colliculus which receives
direct and indirect input from cranial nerve VIII. One notes in this section the tegmentum and
middle cerebellar peduncle of the pons and the upper end of the medullary pyramid. Frontal and
insular cortex are absent from this level. Cranial Nerves. The rootlets of cranial nerves VII and VIII
are seen in the cerebellar pontine angle with the rootlets of cranial nerve XII seen on the lateral
surface of the medullary pyramid. Parietal Lobe. The bulk of the cerebrum temporal gyri is present
from the lateral to the medial surface. Note the location of the insular and cingulate cortex: respec-
tively internal to the lateral fissure and above the corpus callosum.Occipital Lobe. The deep calca-
rine fissure marks the location of the primary visual cortex, V1. The anterior commissure is seen
below the lenticular nuclei (globus pallidus and putamen) and above the olfactory area. White
Matter. The optic chiasm is seen attached to the base of the brain. The optic recess of the third
ventricle is the lumen above the optic chiasm. The septum forms the medial wall separating the
body of the lateral ventricles. The anterior limb of the internal capsule is seen between the caudate
and putamen. Arteries. The middle cerebral artery is seen at its point of origin from the internal
carotid and in the lateral fissure. Identify the anterior cerebrals in the interhemispheric fissure.
Hypophyseal Stalk. This structure is seen medially on the inferior surface of the brain
676 23 Descriptive Atlas
Fig. 23.9 Coronal Slice VII. Level: calcarine fissure. In this section, parietal, occipital, and tem-
poral gyri are present.Brain Stem. The medulla is present with the wide fourth ventricle evident
below the choroid plexus in the fourth ventricle. Parietal Lobe. The superior parietal lobule and
angular gyrus can be seen. Occipital Lobe. The lateral occipital gyrus, lingula, and cuneus are pres-
ent. Temporal Lobe. The superior, middle, inferior, and occipitotemporal gyri form the main por-
tion of the temporal lobe seen at this level. Brain Stem. The cerebellar hemispheres and vermis
cover the medulla. Arteries. The posterior cerebral artery is seen adjacent to the calcarine fissure.
Ventricular System. The posterior horn of the lateral ventricles and the fourth ventricle are present.
Note the choroid plexus in the fourth ventricle
23.5 Gross Brain Slices Horizontal 677
Fig. 23.10 Horizontal Slice. Level: internal capsule. In this slice, both hemispheres are present
and connected by the corpus callosum. Gyri. Identify the lateral fissure and the location of the
frontal and occipital poles. Note that the interhemispheric fissure is wider in the occipital regions.
White Matter. Identify the anterior limb, genu, and posterior limb of the internal capsule. Note the
relationship between the anterior limb, head of the caudate and putamen, posterior limb, thalamus,
and globus pallidus. Locate the fornix. Blood Vessels. Identify the anterior, middle, and posterior
cerebrals. Ventricular System. Locate the third ventric1e, anterior horn, body, and inferior horn of
the lateral ventricle and note their relationship to the caudate and thalamus
Chapter 24
Myelin-Stained
Abstract This section will identify and discuss many of the structures seen in
Figs. 24.1–24.13 (myelin-stained sections in the coronal, horizontal, and sagittal
plain).
24.1 M
yelin-Stained Coronal Brain Sections (Figs. 24.1, 24.2,
24.3, 24.4, 24.5, 24.6, and 24.7)
Fig. 24.1 Level: genu of the corpus callosum. This level consists of the tip of the frontal lobe with
its orbital surface. The genu of the corpus callosum is prominent as is the anterior pole of the lateral
ventricle and the most rostral portion of the head of the caudate
CINGULATE CINGULATE
GYRUS SUP. FRONTAL SULCUS BODY:
GYRUS CORPUS CALLOSUM
MID. FRONTAL SUP. FRONTAL
GYRUS SULCUS
EXTERNAL
CAPSULE
INF. FRONTAL
SULCUS
INT. FRONTAL
GYRUS
SEPTUM
PELLUCIDUM
ASCENDING LIMB
LAT. FISSURE
EXTREME CAPSULE
PRE COMMISSURAL
ORBITAL FORNIX
GYRUS
TEMPORAL LOBE
Fig. 24.2 Level: septum. The septum is seen as a thin membrane between the bodies of the lateral
ventricles. The thin portion attached to the undersurface of the corpus callosum is made up of glia,
while the base of the septal region consists of the septal nuclei which have strong connections to
the hypothalamus and amygdala. The anterior limb of the internal capsule lies between the head of
the caudate and the putamen. At this level, the external and extreme capsules are present
24.1 Myelin-Stained Coronal Brain Sections 681
GENU: INTERNAL
CAPSULE
EXTERNAL
FORNIX
CAPSULE
EXTREME
CAPSULE
SUP. TEMPORAL
LAT. FISSURE
GYRUS
PUTAMEN
CLAUSTRUM
GLOBUS PALLIDUS
MID. TEMPORAL
GYRUS OPTIC NERVE
INF. TEMPORAL
GYRUS OCCIPITOTEMPORAL OLFACTORY FORNIX
GYRUS CORTEX
Fig. 24.3 Level: anterior nuclei of the thalamus. Examine Fig. 8.12 for details on individual tha-
lamic nuclei. The anterior nucleus of the thalamus protrudes into the body of the lateral ventricle—
this nucleus has a strong projection onto the anterior cingulate gyrus. This section is near the genu
of the internal capsule, and the globus pallidus and putamen are seen lateral to the capsule. The
anterior commissure is seen crossing underneath the basal ganglia interconnecting the rostral ends
of the temporal lobe including the Amygdaloid nuclei; the columns of the fornix are seen entering
the hypothalamus above crossing fibers of the anterior commissure. The uncus (amygdaloid nuclei
with olfactory cortex on the surface) forms the medial surface of the rostral temporal lobe
bilaterally
682 24 Myelin-Stained
Fig. 24.4 Level: middle thalamus. Examine Fig. 8.11 for details on individual thalamic nuclei.
The thalamus at this level is divided in the more heavily myelinated lateral and ventral nuclei and
the lightly myelinated medial dorsal region. The posterior limb of the internal capsule forms the
lateral margin of the thalamus. The mammillary bodies of the hypothalamus are seen below the
hypothalamic recess of the III ventricle. The hippocampi are prominent on the medial surface of
the temporal lobe
24.1 Myelin-Stained Coronal Brain Sections 683
Fig. 24.5 Level: posterior thalamus. Examine Fig. 8.10 for details on individual thalamic nuclei. The
thick splenium of the corpus callosum interconnects the hemispheres with the crus of the fornix on its
lateral margin. The habenulopeduncular tract originates from the habenular nuclei and interconnects
the epithalamus with the hypothalamus, interpeduncular nucleus, and tegmentum of the midbrain. The
thalamus in this level contains major subnuclei of the medial and lateral thalamic nuclei, and also the
medial geniculate which receives input forms the ascending auditory fibers. The cerebral peduncles of
the midbrains with the substantia nigra are seen on the base of the diencephalon
Fig. 24.6 Level: splenium of the corpus callosum. The column of the fornix extends from the
lateral margin of the parahippocampal gyrus and lies under the splenium surface of the corpus cal-
losum on its way to the mammillary bodies in the hypothalamus. The pulvinar nuclei form the bulk
of the thalamus in this level with the medial geniculate on its inferior border. Note the pineal gland
in the midline above the posterior commissure in the tegmentum of the midbrain. The red nucleus
can also be seen in the tegmentum of the midbrain above the substantia nigra which is found
behind the cerebral peduncle
684 24 Myelin-Stained
Fig. 24.7 Level: visual cortex. The visual radiation can be seen in the calcarine sulcus surround-
ing the calcarine fissure; this region is the primary visual cortex, V1, and receives its input from the
lateral geniculate nucleus of the thalamus. The pontine region of the midbrain is seen with the
medial lateral cerebellar peduncle extending into the cerebellum
24.2 Myelin-Stained Horizontal Sections 685
24.2 M
yelin-Stained Horizontal Sections (Figs. 24.8, 24.9,
24.10, and 24.11)
Fig. 24.8 Level: splenium of the corpus callosum. This section consists of the cerebrum, its med-
ullary center, basal nuclei, and thalamus. In this horizontal section, one can see the anterior limb
genu and posterior limb of the internal capsule separating medially the thalamus from the basal
ganglia (lenticular nuclei—the globus pallidus parts I and II and putamen). The head of the caudate
is separated from the putamen by the anterior limb of the internal capsule
686 24 Myelin-Stained
Fig. 24.9 Level: anterior commissure. In this section, two fiber commissures, the anterior and
habenular, and one gray commissure, the massa intermedia, are seen. The thalamus is found lateral
to the third ventricle
24.2 Myelin-Stained Horizontal Sections 687
Fig. 24.10 Level: superior colliculus of the midbrain. In this section, note the location of the optic
tract, mammillary bodies, and cerebral peduncles. The hippocampi are prominent on the medial
surface of the temporal lobe internal to the inferior horn of the lateral ventricle
688 24 Myelin-Stained
MAMMILLARY CEREBRAL
BODY PEDUNCLE
HIPPOCAMPUS
INF. HORN
LATERAL VENTRICLE
INF. TEMPORAL
GYRUS
RED
NUCLEUS
INFERIOR COLLICULUS
PARIETO-OCCIPITAL CEREBRAL
FISSURE AQUEDUCT
CEREBELLUM
Fig. 24.11 Level: inferior colliculus of the midbrain. The gyrus recti and medial orbital gyri of the
frontal lobes are prominent. In this section, again note the cerebral peduncles with the substantia
nigra and the mammillary bodies in frontal of the peduncles. The optic tract is seen rostral to the
mammillary bodies in the hypothalamus
24.3 Myelin-Stained Sagittal Sections 689
Fig. 24.12 Level: thalamus sagittal section near the midline. Note the prominent corpus callosum
with its divisions the rostrum, genu, body, and splenium. The anterior tubercle and medial thalamic
nuclei are also prominent. The optic nerve is seen on the base of the thalamus. The extent of the
vermis of the cerebellum is also demonstrated
Fig. 24.13 Level: hippocampus. This section contains the cerebrum and cerebellum with a very
prominent hippocampal formation found below the inferior horn of the lateral ventricle in the
temporal lobe. The medullary center of the cerebrum is very prominent in these sections