The Cerebral Cortex: Principles of Structure, Function and Development

Cerebral cortex (last structure to develop)

o Allocortex
Palaeocortex = olfactory cortex, parahippocampal gyrus
Archicortex = hippocampus
o Isocortex/neocortex = rest of cerebral hemispheres
About 80% of the total brain volume is taken up by neuropil
o Neuropil
dendrites and axons
Where the synaptic action is
Movement along radial dimensions traversing through cortical
layers
Movement along tangential dimension traverse through cortical
areas
Cortical layers
o L1 Molecular
Cell sparse & only inhibitory neurons
o L2/3 Supragranular
Small-to-medium sized pyramidal cells
o L4 Granular
Small spiny stellate cells
o L5/6 Infragranular
Large pyramidal cells (layer 5)
Polymorphic cells (layer 6)
Primary Sensory (areas 3, 17, 41) & prefrontal cortex (areas 8, 9,
10)
o They are granular (with a well-developed layer 4)
Primary motor and premotor cortex (areas 4,6)
o They are agranular (minimal or absent layer 4)
Primary areas of the cortex receive their main input from thalamic
relay nuclei
Secondary areas of the cortex receive their main input from:
o Primary areas
o Associational (high-order) thalamic nuclei
Multimodal areas receive converging input from secondary areas and
from associational nuclei
Excitatory Cortical neurons
o Their dendrites are covered with dendritic spines, upon which
they receive all of their excitatory synaptic inputs
o They receive inhibitory inputs on dendritic spines, dendritic
shafts, cell bodies or axon initial segment
o Composed of:

Pyramidal cells
Spiny stellate cells
Pyramidal Neurons
o Found in all layers except layer 1
o The primary apical dendrite branches into an apical tuft
o They are glutamatergic excitatory
o Their dendrites densely spiny
o Form long-distance connections & local connections (via axon
collaterals which are used to communicate with their immediate
neighbors
Spiny Stellate cells
o They are glutamatergic and function as excitatory
interneurons
o They are essentially degenerated pyramidal cells that have lost
their apical dendrites and their subcortical projection
o Found in layer 4 (granule cells)
This is also the site of Thalamocortical terminations
o Main recipients of sensory Thalamocortical inputs, and are
responsible for relaying this incoming information to other layers
(mostly layer 2/3)
Cortical tracts originate in pyramidal cells
o Corticothalamic neurons are mostly restricted to layer 6
o Corticospinal, corticotectal, corticostriatal are made by
layer 5
Dendritic spines
o They receive all of their excitatory synapses. Learning and
forgetting must therefore be reflected in formation,
elimination or morphological changes in spines
Inhibitory neurons
o Found in all layers
o They are usually inhibitory interneurons
o Their dendrites have few or no spines
o Basket cells
Target somata and proximal dendrites of pyramidal
neurons
o Martinotti cells
Target distal dendrites and dendritic tufts in layer 1
o Chandelier cells
Target the axon initial segment
Cortical columns
o Local intracortical information transfer is predominantly
vertical
o Neurons within the same vertical column of 0.5 mm in diameter
tend to display similar response properties

o In the course of mammalian evolution, the cerebral cortex has

evolved mostly by increasing its areathereby adding additional
columns
o Stereotypical (canonical) circuit within each column
Information enters predominantly in middle layers
Then relayed from middle layers to upper layers
Then from upper layers to deep layers
From deep layers information is projected to subcortical
structures

Cortical Development
o (1) Neurogenesis & (2) Migration
Occur prenatally
Radial glia cells act as the railway for migrating
neurons
Neurons are deposited on the pial surface, forming a
dense cortical plate
o Younger cells are deposited closer to the
surface and older neurons in deep layers
Inside-out layering scheme
o (3) Differentiation (extension of dendrites & axons) & (4)
Myelination
Start prenatally, but continue through early adulthood
o (5) Synapse formation and elimination
Continues throughout life
o Excitatory cortical neurons are generated in the ventricular
wall
o Inhibitory interneurons are generated in the ventral forebrain,
within embryonic structures called ganglionic eminences
From the ganglionic eminences they migrate laterally
(tangentially), enter the dorsal forebrain and disperse
within all cortical layers
Filamin A
o Actin-binding protein important for initiation of migration
o Male carriers die since this is an X-linked mutation
o In Heterozygous females:
Periventricular (nodular) heterotopia
Cortical neurons which failed to migrate clump near
the ventricles
This results in late-onset seizures and (in some
cases) mild retardation
Doublecortin (DCX)
o Microtubule-associated protein important for proper migration

o Male carriers
X-linked lissencephaly (smooth brain with no gyri) or
pachygyria (fewer than normal gyri) and severe
retardation
o Heterozygous females
Migrating neurons fall off the rails midway, resulting in
double cortex (subcortical laminar band heterotopia,
SBH)
A band of gray matter underneath the cortical white
matter
LIS1 gene
o Codes for a microtubule-associated protein important for
maintaining the proper speed of migration
Mutations in this gene causes Type-1 Lissencephaly with
severe mental retardation
Reelin
o Secreted by Cajal-Retzius cells (Early-born neurons in layer 1)
o During normal migration, reelin triggers detachment of the
migrating cell from the radial glia fiber
o Without reelin, earlier-born neurons stay attached and block the
migration of later-born neurons, resulting in inverted lamination
younger neurons deeper to older ones
o Mutations are linked to autosomal-recessive lissencephaly

Cortex: Localization of Function

Useful BA to memorize
o 4 Primary Motor cortex
o 1,2 Somatosensory cortex
o 17, 18 Visual cortex
o 41,42 Auditory cortex
o 22+39+40 Wernickes area
o 44+45 Brocas area
Taste
o Gustatory cortex VPM (thalamus) Solitary nucleus CNs
7,9,10
Smell
o No initial relay through thalamus
o Ant. Olfactory nucleus Olfactory tubercle Piriform cortex
Amygdala Periamygdaloid cortex Parahippocampal g.
Motor cortex (Area 4)
o Lesion here results in contralateral hemiparesis and spasticity
Premotor cortex (Area 6)
Supplementary motor cortex (SMA)
Primary somatosensory cortex (Areas 3,2,1)
Phantom pain
Electricity
o Transcranial direct current stimulation (tDCS)
In trials for treating depression, anxiety, Parkinsons,
chronic pain
Electromagnetism
o Electroconvulsive therapy (ECT)

Shock therapy
For psychiatric treatment:
Resistant major depressive disorder
Mania
Catatonia
o Transcranial magnetic therapy (TMS)
Treatment:
Major depressive disorder
Schizophrenia (in trials)
Stroke recovery (in trials)
Stimulate brain lesions to examine functions
Visual Cortex (V1)
o Bilateral V1 lesion loss of conscious awareness of visual
stimuli,but can still see location if forced to reach out and
touch object
o blindsight can result in survivors of carbon monoxide (CO)
poisoning

Visual cortex
o Dorsal pathway (Where is it?)
Processes vision for action relative to your body
representations
Spatial relationships between object in your 3-D world
Bilateral lesion Balint Syndrome
Simultanagnosia Unable to see more than one
object at a time
Optic ataxia Fixation of gaze with severe
problems in voluntarily moving fixation
Optic apraxia Inability to reach towards the
correct location of perceived objects (problem in
visually guided reaching)
o Ventral pathway (What is it?)
Processes vision for perception
Color
Object and form perception
Face perception
Lesion
From CO poisoning
Lost object vision
Visual agnosia

Impaired ability to recognize visually

presented objects (despite good visual acuity
and vision)
o Not able to:
See shape or form of objects
See faces (prosopagnostic)
Distinguish a circle from a triangle
Distinguish a knife from a fork
Perceive shape from motion
Primary Auditory cortex (area 41)
o Inputs from MGN to transverse temporal gyri
o Unilateral lesion has relative little effect
o Some difficulty localizing sound on contralateral side
o Laterally anterior and laterally posterior along the cortex
for more meaningful information
Auditory association cortices (area 22)
o Lesion here (superior temporal gyrus)
Left hemisphere severe language problems
o

Aphasia
o Inability to use language

o Wernickes aphasia
Fluent, but deficient in comprehension of language
Meaningless words
o Brocas aphasia
non-fluent, but comprehension os ok
Affects the left inferior frontal cortex
Words are produced with great difficulty
o Conduction aphasia
Due to damage of arcuate fasciculus
Disconnection syndromes
o Alexia without agraphia
Visual output from right occipital cortex blocked by lesion
in splenium
Not able to read words, but can write
It is important to map language functions (fMRI) prior to
surgical resection procedures to determine which hemisphere is
their dominant
Prosody
o Right hemisphere Processes prosody and emotional
content

Parietal cortex
o Lesion to inferior parietal lobe (left dominant)
Gerstmanns syndrome
Difficulty with calculations
Right-left confusion
Inability to identify fingers by name
Difficulties with written language
o Lesion to inferior parietal lobe (non-dominant)
Contralateral neglect
Ignore left side of space
Fail to shave left half of face
Not dress left half of body
Prefrontal cortices
o Dorso-lateral
Involved in working memory
o Ventro-medial
Associated with limbic connections (with amygdala)
Lesion
Impulsive behavior
Trouble suppressing inappropriate responses and
emotional reactions

Thalamus & Sleep Cycle

The thalamus is an obligatory synaptic relay for nearly all neural

information entering the neocortex
The inputs to the neocortex not originating in the thalamus come from
the neuromodulatory systems (bioamines)
The thalamus is the gateway to the consciousness because the
neocortex is thought to give rise to consciousness
The three groups of thalamic nuclei are:
o Intralaminar
o Principal
o Reticular
The 2 intralaminar nuclei are the centromedian and parafascicular
o They are reciprocally connected with the basal ganglia
o They receive projections from the globus pallidus and project to
the striatum
o They are also connected reciprocally with wide regions of frontal
cortex, although individual nuclei have specific target
Reticular thalamic nucleus
o Only thalamic nucleus which is purely GABAergic and therefore
inhibitory
o Also unique in that it projects to other thalamic nuclei, not to
the cortex
Principal thalamic nuclei
o 6 ventral
4 relay (specific) Reciprocally connected with
primary cortical areas
VPL/VPM, MGN, LGN Sensory
VL Motor
o 7 associational (Non-specific) Reciprocally connected
with unimodal and multimodal association cortical areas
VO, VA (ventral)
Anterior/LD, MD, and Pulvinar/LP (dorsal)
o The Thalamocortical neuron (excitatory glutamatergic) is the
major neuronal type in the principal thalamic nuclei
They undergo retrograde degeneration when their
cortical target is removed
Specific pathway-Relay
o The Thalamocortical projections terminate heavily in the middle
layers of the cortex (layer 4 in the granular cortex; lower layer 3
in agranular cortex), with a more sparse termination in upper
layer 6/lower 5
o Focused

o Topological
o Reciprocal
It is reciprocated by a topological and excitatory ipsilateral
corticothalamic projections from pyramidal neurons in
cortical layer 6

Non-Specific
o Terminates mostly in layer 1
o Widespread
o Not topological
o Reciprocal
The reciprocating corticothalamic axons originate in lower
layer 5, not 6

EEG Rhythms
Alpha rhythm
o Typical of the awake with eyes closed state
o Most pronounced over occipital cortex
o Rhythm over frontal cortex may occur during anesthesia or
coma
The higher the synchrony of the neurons, then the stronger will be the
signal amplitude and the lower its frequency
Wakefulness
o Activated EEG (low-amplitude, high-frequency)
o Not a lot of synchrony
o Full perceptual engagement, full motor control
Sleep
o NREM (slow-wave sleep, SWS)
Deactivated EEG (high amplitude, low-frequency)
Muscle tonus, intact reflexes, vague dreams
o REM (Rapid Eye Movement) sleep
Activated EEG (low amplitude, high-frequency,
resembling wakefulness)
Muscle atonia, saccades (hence REM), vivid dreams,
genital erections (unrelated to dream content)
Epileptic seizure
o Synchronized, very high amplitude EEG
Coma, anesthesia
o Loss of consciousness
o Appearance of alpha waves in the frontal cortex
As you go from awake relaxed Stage 1 Stage 2/3 Stage 4
REM

o There is an increase in amplitude and a decrease in frequency

Increased synchrony

Thalamus as the gate to Consciousness

o Awake/attentive state
Thalamus acts as a high-fidelity relay, allowing sensory
information to reach the cortex
o Drowsiness, sleep, coma states
Thalamus acts as a pacemaker
Thalamic firing
o Tonic mode
Thalamic neurons are slightly depolarized
Fire regularly upon synaptic stimulation
The spike frequency encodes the strength of the synaptic
input
Seen in the awake and REM states
Sensory information is transmitted to the cortex via
the thalamus
o Due to the sensory inputs being
asynchronous, the synaptic currents
generated in the cortex will partially cancel
each other, resulting in low-amplitude, high
frequency EEG rhythms typical of the active
(wake or dreaming) cortex
o Phasic/Burst mode
Thalamic neurons are hyperpolarized
They fire an all-or-none burst of 2-5 action potentials upon
depolarization
This action potential rides on a slow hump, which is
a Ca spike generated by low-threshold Ca channels
(T-current)
Seen in the slow-wave sleep
Neurons are hyperpolarized and fire phasically
Fired synchronously (many neurons burst together)
o High-amplitude, low frequency EEG
rhythms
o Reduced consciousness
The thalamic bursts repeat at the delta frequency (34) thanks to the interplay between relay neurons and
the reticular thalamic nucleus (RTN)
Transition from wakefulness to sleep and dreaming
o During wakefulness
VLPO is quiescent

Hypothalamic sleep centers excite the bioaminergic

brainstem nuclei, which fire tonically
The released bioamines depolarize the thalamus and
maintain it in the relay mode
o Fall asleep
VLPO starts firing
Inhibits the sleep centers
o Firing rate in the bioaminergic nuclei
diminishes
o Thalamus gradually hyperpolarizes as we fall
deeper and deeper into slow-wave sleep
o REM sate
Mesopontine cholinergic centers (MRF) turn on when
the raphe and locus coeruleus are totally turned off
Ach is released thalamus is switched to relay
mode
Brainstem glycinergic neurons are activated which
inhibit spinal motor neurons
Cortex depolarizes as well
Why Sleep?
o Sleep as the ultimate detoxifier
Sleeping-Behavior Disorders (Parasomnias)
o Narcolepsy Uncontrolled entry from waking directly into REM
sleep
Can be caused by mutations in the orexin gene, orexin
receptor gene, or loss of orexin neurons due to
autoimmune action
Symptoms:
Excessive daytime sleepiness
Cataplexy (sudden loss of muscle tone during the
awake state)
Sleep paralysis
o REM sleep behavior disorder
The REM-state muscle atonia is lacking, and the person
tries to act out his/her dreams, with potentially dangerous
consequences to himself or others
o Somnambulism (sleep walking) & Pavor nocturnus (sleep
terrors)
Mostly childhood disorders and occur during non-REM
sleep
o Jet lag
o Shift-Work Sleep disorder
o Delayed Sleep Phase disorder

Impairments of Consciousness

Seizure
o Transient episode of synchronous and rhythmic firing
o They can occur in nonepileptic people
o Partial seizure
Originates in a defined focus and spreads to adjacent
areas
Simple No alteration of consciousness
Complex Involves some alteration of consciousness
o General seizure
Involves the whole cerebral mantle bilaterally
Primary Originates bilaterally with no discernible focus
Secondary Begins as a partial seizure in a discrete,
unilateral focus, and then generalizes
Epilepsy
o A disorder manifested by recurrent seizures
o Epileptic focus
Region where balance between excitation and inhibition
has been disrupted recurrent synchronous firing
Manifested as interictal spikes in the EEG
o Transient large-amplitude EEG events on only
one or a small number of electrodes
o Good indicator for the location of the focus
Seizure generation
o In conditions of reduced inhibition, interictal activity can spread
to surrounding cortical areas, generating a partial seizure

o The spread of the seizure can occur via local synaptic

connections or through associational and commissural axons
o Onset can be felt as an aura
o Persistent partial complex or secondarily generalized seizures
can often be treated by surgical removal of the epileptic focus
Absence Epilepsy
o Abnormal manifestation of the same oscillator circuitry
underlying slow-wave sleep, resulting in large-amplitude, 3 Hz
oscillations, manifested as spike and wave bouts in the EEG
Arousal
o Degree of wakefulness
o Depends on the level of activity in the ascending bioaminergic
systems
Awareness
o Understanding of an appropriately interacting with the
environment
o Depends on the coordinated activity of the thalamus, cerebral
cortex and multimodal association areas
Coma
o Prolonged state of total unresponsiveness (> 1hr)
o Loss of consciousness (loss of both arousal & awareness)
o Causes:
Loss of awareness due to widespread, diffuse,
bihemispheric damage to cortical grey and/or white
matter
Loss of arousal due to focal but bilateral damage in the
rostral brainstem (rostral pons/midbrain) or the caudal
diencephalon, disrupting the bioaminergic pathways
Diffuse forebrain injury
o Causes:
Metabolic (anoxia/ischemia)
Prognosis is dire
Physical (traumatic brain injury)
Prognosis is better
Pharmacological (overdose)
Prognosis is excellent because the drugs depress
neural activity, but do not kill the neurons
Focal brainstem injury
o Causes:
Compressive
From excessive intracranial pressure

Herniation (uncal/tonsillar) that causes pressure on

brainstem regions
Prognosis is good as long as the elevated pressure is
relieved in a timely manner
Full recovery is possible
Destructive
From a bilateral vascular occlusion or hemorrhage
Prognosis varies depending on the degree of damage
Paramedian tegmentum of the midbrain and rostral
pons
Brainstem lesion here will most likely induce a coma
Vegetative State (VS)
o Two dimensions of consciousness are dissociated:
Arousal (sleep-wake cycle) is restored
Awareness of self, others or the environment is NOT
o If lasts > 1 month after injury Persistent Vegetative State
o Persistent Vegetative State (PVS)
Patients can move their limbs but not in a reflexive, nonpurposeful manner
Non-communicative
They can vocalize but unintelligibly, and show no
purposeful response
Lack the higher brain functions that we consider the
essence of humanity
o Permanent Vegetative State
If VS lasts > 3 months (for metabolic causes)
If VS lasts > 12 months (for traumatic brain injury)
Minimally Conscious State (MCS)
o Intermediate state between VS and the fully conscious state
o Appearance of one or more of these:
Fixation on, or eye pursuit of people/objects
Purposeful reaching/grabbing movements
Yes/No responses (verbal or gestural) to simple
questions, even if inaccurate
Intelligible verbalization, even if out of context
Following simple commands
Context-appropriate emotional responses (smiling or
crying)
Locked-In Syndrome (LIS)
o From bilateral damage to the basal and tegmental pons
o Consciousness (both arousal and awareness) may be intact
Imprisoned in ones own body
Brain Death

o A person is dead if an only if his/her brain stopped functioning

irreversibly
o Determination requires:
That all brain functions ceased (no brainstem reflexes, no
autonomous respiration, flat EEG*) during at least 6 hrs
The results have to be replicated at least 2x
Identifying the cause and determining that it is irreversible
(e,g NOT drug-induced and not due to hypothermia)
o It does NOT require cessation of spinal reflexes (Babinski sign) or
heartbeatwhich are not dependent on brain activity

Hypothalamus:

The hypothalamus plays a pivotal role in drive-related behaviors

o Homeostasis (maintenance of the internal environment)
o Survival (feeding, maternal care, reproduction)
Inputs to hypothalamus:
o Visceral
From aortic arch and carotid bodies (via CNs IX, X)
Nucleus solitaries Hypothalamus (Paraventricular
nucleus) DMNX
o Endocrine
From all endocrine glands via the blood
Circulating hormones are detected by receptors on
hypothalamic cells. These cells secrete releasing factors
or inhibitory factors that pass down the portal system to
control secretion of other peptides from the anterior lobe of
the pituitary

Cortisol Paraventricular nucleus CRF released reach

anterior pituitary ACTH release cortisol release from
adrenal cortex
o Homeostatic
Via blood (glucose, osmolarity, temperature, lipids)
Hypothalamic Internal Sensing System
o Sensory
Retinal afferents (direct)/Reticular activating system
(indirect) Suprachiasmatic nucleus/Ventrolateral preoptic
nucleus Sleep Wake cycle/Alertness
Suprachiasmatic nucleus Involved with circadian
rhythm regulation
Ventrolateral preoptic nucleus Projects to the
monoaminergic ascending arousal system
o Cognitive-Affective
From projections from frontal, orbitofrontal, cingulate
cortices, amygdala Diverse hypothalamic areas
Flight, Fight, Fear..
The hypothalamus coordinates responses via its diverse outputs
o Net result: Homeostasis
Nissl stains form the basis of hypothalamic anatomical diagrams
where nuclei are identified
The nuclei of the hypothalamus are tightly packed
o Traumas can all present as a constellation of disturbances,
depending on which nuclei are affected
Nuclei
o Medial Preoptic nucleus
Plays a role in the tendency to approach, court, mate with,
and partner with others
o Preoptic nuclei
Controls behavior necessary for reproductive and maternal
behaviors
Its development is under control of testosterone during
critical periods
Sexually dimorphic
It has different structural and functional
characteristics in males vs. females.
The development of sexual characteristics and later sexual
behaviors could be experimentally manipulated in rats by
exposure to testosterone during development
It is larger in males than females
Males rats that have been castrated develop female
like POA nuclei

Females rats that are given testosterone develop

male-like POA nuclei
The interstitial Nucleus of the Anterior Hypothalamus is the
human analog of the POA in rodents
Male primate preoptic area neurons fire before and during
sexual encounters
Female primate MPOA responsiveness occurs prior to that
of the male
Interstitial nuclei of the anterior hypothalamus
INAH 3 was more than twice as large in the heterosexual
men as in the women. It was also, however, more than
twice as large in the heterosexual men as in the
homosexual men
This indicates that INAH is dimorphic with
sexual orientation, at least in men, and
suggests that sexual orientation has a
biological substrate
The activation of the anterior hypothalamus correlates
strongly with the degree of sexual arousal in heterosexual
males
Supraoptic nucleus
Receives information about uterine distension, nipple
suckling, blood volume
Sends axons to the posterior pituitary
Produces oxytocin and vasopressin
Lesions lead to diabetes insipidus with polyuria
SIADH
Paraventricular nucleus (PVN)
Receives information about blood volume, suckling, cortisol
levels
Produces oxytocin and vasopressin
Lesions lead to diabetes insipidus with polyuria and
polydipsia
SIADH
Suprachiasmatic nucleus (SCN)
Info from peripheral retinal ganglion cells with luminance;
neurons have melatonin receptors
Efferent to pineal gland site of melatonin synthesis

Melatonin is a popular OTC cure for jet lag

Functions in maintaining circadian rhythms of sleeping,
eating, melatonin synthesis
A PVN-Pineal projection via the Stria medullaris
thalami

o Ventromedial nucleus
Satiety center
Lesions result in overeating
o Lateral Hypothalamic area
Feeding center
Lesions result in undereating
o Arcuate nucleus
Receives nucleus tractus solitaries information about
stomach distension
Contains receptors for leptin (decreases appetite) and
ghrelin (stimulates feeding)
o Anterior hypothalamic nucleus
Detects high body temperatures and cools down body
through vasodilation and increase in panting/respiration
o Posterior nucleus
Stimulation increases body temperature through
vasoconstriction and shivering
Mammillary bodies
o Limbic System component
o Memory consolidation
o Susceptible to thiamine deficiency
Steroid sensitive neurons are distributed throughout the
hypothalamus and brain and likely account for the array of genderpreferred behaviors seen in animals and humans
Gender identity
o The INAH3 and 4(uncinate nucleus) was found in male-tofemale transsexual people to small (of female size and number).
One case in the other direction so far finds a female to male
transsexual INAH to be larger (male-sized)
o The bed nucleus of the stria terminalis is more female-like in a
male to female transsexual
Oxytocin
o Love peptide to promote affiliative and maternal behaviors

Neuroplasticity

Neuroplasticity
o The ability of neurons to make relatively permanent changes in
function, chemical profile or structure in responses to internal
and external environments
Can be Positive or Negative
There is an increase in folding (cortical convolutions) as you approach
gestational age
Organization of the nervous system (differentiation, axonal and
dendritic growth, overproduction and subsequent pruning of
connections) occur during the 6th gestational month to maturity
Myelination lasts half of gestation to age 18: mostly before age 2
o Is nutritional dependent
Neurogenesis begins as soon as the neural tube forms (3-4 weeks);
peaks at 7 weeks and is largely completed by 18 weeks
Glia continue to be produced throughout life
Myelination is rapid in the first two years and decreases through
first decade
It is in the connectivity (axons & dendrites) that most lifelong
plasticity occurs
Synaptogenesis
o Where the real function of brain development occurs
o Begins by the 5th week, but is prolonged and persists throughout
life
Influences that guide the establishment of Neuronal connections
o Genetic programming
It tells neurons to grow, die or learn
Once a neuron has planted its cell body in a permanent
position, it sends out an axon shoot with an enlarged tip
known as a growth cone
It has tentacles that pick up navigational signals
(nerve growth factors)
o The NGFs are emitted by target organs (e.g,
muscles) and guide these axonal shoots to the
target
o An abundance of connections is produced
Apoptosis is a natural and important developmental
phenomenon
o Synchronicity of firing
Initially there are multiple olivary projections per Purkinje cells, but
then as the dendritic tree expands, only one climbing fiber is left
The volume of gray matter decreases with age

A.
B.
C.
D.
E.

Autism
o A disorder of connectivity of the brain
o NOT a disorder of gross anatomy
o Early overgrowth followed by arrest of growth, particularly
in the frontal and temporal lobes and amygdala
Excess neurons due to cell cycle dysregulation
Failure of naturally occurring apoptosis
A normals child brain grows more slowly
Principle One
o Apoptosis is a normal & Essential part of brain
development
Deprivation studies show that the deprived area regresses AND the
associated area expands
o Believed to be due to sprouting to cover synaptic sites
o There is a critical period
The Rene Spitz studies shows that human affection and interaction is
essential for development within a critical period
Enrichment
o Higher order dendritic branching associated with enrichment
o Environmental enrichment effects cognitive development via the
hippocampus
o The synapse is laid down (driven by genes) But that
permanence of the synapse depends on its activation during
stimulation
o During critical periodsRequires social interaction, not just
exposure
Just listening or watching doesnt do it
Functional neuroimaging studies have shown that in the absence of
visual input, occipital region (visual) begin to respond to sound and
spoken language
Critical period
o Organisms most sensitive to environmental inputs
o Plasticity is maximal
Principle two
o Functional validation of the Synapse Use it or lose it
Learning is splasticity (this is from a figure)
Short term enhancement is mediated by Ca++ effects in presynaptic
endings. A1.
Short term depression can be mediated presynaptically or
postsynaptically by mechanisms including depletion of vesicles A2.
Binging of transmitter by presynaptic receptors A 3
A4 retrograde signaling
A5 desensitization

F. B Long term potentiation and depression at glutamate synapses is

initiated by Ca entering through postsynaptic NMDA n methyl D
aspartate receptors
G. B 1. Large amounts of ca cause more AMPA receptors to be inserted
causing LTP B2. Small amounts cause fewer.
H. Note AMPA is ionotrophic receptor for glutamate

Learning is enhanced by:

o Practice
o Attention/Alerting
o Engagement with the Subject (personal interaction)

Principle three
o Neuroplasticity underlies learningIn order to learn we
have to be engaged
Studies have shown that there are neuroprotective effects of using
the brain consistently

Principle four
o Neuroplasticity is NOT a state only of the young brainit
is a state of all brains
While the speed changes and ultimate capacity
decreasethey have not found an age or a study
where there is 0 capacity for neuroplasticity (i.e.
learning)

Neuroplasticity of Recovery
o If digit 3 is amputated its cortical representation goes away
Neurons in its former area become responsive to tactile
stimulation of the adjacent digits (2 and 4)
o Cortical neurons in adjacent areas will invade the missing area,
increasing their representational size on the cortical map and
obliterating the area no longer receiving afferent input
o Also true for motor neurons structural and functional plasticity
occurs within the motor cortex after training
o Functional and structural changes take place in the
cerebral cortex after injury
Motor skill and plasticity within the motor cortex occur at different
rates
o Skill first within 3 days
o Structure (synaptic density) within 7 days
o Function (reorganization of motor map) within 10 days
persists for up to 6-8 months

Principle five
o The CNS has time and dose-dependent responses to
rehabilitation post-injury
o 2 weeks and at 4 month intervals

Mirror neurons
o Monkeys picking up food fire neurons as if they are watching food
be picked upthis has implications for human social learning
(e.g, abuse)

Limbic System

Limbic constituents
o Prefrontal, orbitofrontal and anterior cingulate cortices
Executive oversight for when and where to release survival
related behaviors
o Hypothalamus, septal nuclei, medial and basolateral
amygdala
Neurons directly in charge of survival related behaviors
(and emotions)
o Hypothalamic and brainstem autonomic nuclei
Neurons that directly initiate the optimal sympathetic and
parasympathetic physiological environments
o Parahippocampal gyrus and uncus, amygdala, entorhinal
cortex
Unconscious perception of olfactory stimuli
o Dorsomedial thalamus, orbitofrontal cortex
Conscious perception of smell

Septal area
o Reward: The nucleus accumbens septi (ventral striatum)
o Center for reward
o Dopaminergic cells that inhabit the ventral tegmentum of the
midbrain and substantia nigra pars compacta release DA into the
nucleus accumbens
In response to a job well done, food
Some drugs elicit a massive release of dopamine here
The D3 receptors in the nucleus accumbens are
implicated in addiction
Hippocampus
o Important for contextual learning
o Three-layer construction (Archicortex)
o Lesions results in deficits in short-term memory
Amygdala
o Involved in sensation of fear
o Evolved to increase the probability of survival
o Stress
Subjective feeling that we experience when our fear
system is activated
Any stimulus, internal or external which is perceived as
threatening can cause a stress response

Fear circuit

o Low road
o Shorter and therefore information traveling here projects to
the amygdala sooner
o Unconscious
o This road may be responsible for anxiety disorders
o High road
o Relayed to primary and associational sensory cortices
o Requires more synapses (more neurons in the pathway)
o Arrives later than low road
Amygdalar initiation of fear depends on sensory input arriving at the
LA nucleus
The output of the systems is from the central nucleus

The stress response affects the entire body

Prefrontal cortex
o In charge of executive control of activities
o It weights consequences of actions
o It is the seat of personality and self-reflection
o Develops until we are age 25
o A more slowly developing prefrontal cortex accounts for some
developmental disorders feature impulsivity and distractibility
(ADHD)
Anxiety disorders
o Early developmental exposure to stress in humans alters the
brains development and later ability to cope with stress
o Developing an anxiety disorder depends upon an interplay
between genetics and environment

Amygdala also plays a role in recognizing emotions from facial

expressions (especially fearful faces)
Physically abused children recognize angry faces with fewer cues than
do non-abused children
The prefrontal cortex sends all clear signals to the amygdala when a
stimulus or situation is no longer a danger
o Like an override to reduce the excitability
Treatment of anxiety disorders
o Cognitive behavior therapy
Gradually exposed to the things they are afraid of and then
do relaxation exercise. They relearn that the stimulus that
used to make them fearful is no longer something to be
afraid of
o Medication

Neuropsych
Amnesia:

Encoding
o Getting info in
o Give them three words
o By the thalamus
Consolidation
o Putting info away
o By the hippocampus
o Conditions that affect this:
Complex-partial seizures
Anoxia
Herpes encephalitis
Paraneoplastic limbic encephalitis
Retrieval
o Getting info out
o By the frontal lobes
Implicit memory/Procedural memory
o Previous experience aids performance without awareness
o Motor based (works outside the typical memory structure)
Wernicke Korsakoff
o Vitamin deficiency
o Wernicke stage (acute)
o Korsakoff (chronic)
o Lesions to thalamic and mammillary body
o In alcoholism
o In pregnancy
Morning sickness
Goes to hospital gets hydrated thiamine
depletion amnesia
Bilateral Thalamic strokes
o Disconnects mamillothalamic tract
HM
o Had epilepsy
o They took both hippocampus out
No short term memory after that
WADA test

o A test to determine the functionality of the hippocampus

Herpes encephalitis
o Mesio temporal lobes affected
o Memory problems
Colloid Cysts 3rd ventricle
o Obstructs flow of ventricles
o Can often damage both fornixes when being surgically removed
Nothing connecting hippocampus to mammillary bodies
o Results in amnesia (not as dense)
Fornix infarction
o Causes amnesia (not as dense)
Lesion of genu of corpus callosum
o One hand has a life of its own
o Alien hand syndrome
Mammillary body amnesia
o Dense amnesia early on
o Procedural memory seems to stick
Hippocampal and basal ganglia injury
o Develops dense amnesia
o No procedural learning
Lesions outside hippocampus
o Not a dense amnesia
o Frontal lobe lesions
Huntingtons Disease
o Anticipation
Younger and younger with each generation
Multiple Sclerosis
o Subcortical lesions from demyelination
o Memory problems, but not amnesia
Closed Head injury
o Frontal contusion
Small vessel ischemic disease
Plasticity in brain

Aphasia: Disorders of language

Assessment
o Fluent vs nonfluent
Fluent flows
Nonfluent broken speech
o Comprehension
Does the speech make sense?
Can they understand the language?
Ask them a complex command (touch your nose after
touching your right ear)
o Repetition
Nothing to do with functionality
Helps determine classification
o Fluency
Phonemes vs semantics
Give them a letter and ask them to say as many words as
they can
Or ask them to say as many fruits as possible
Naming (see if they can name common objects)
Reading and Writing mimic spontaneous speech
Brocas
Wernickes
Conduction
Transcortical Motor
Transcortical sensory
Repetition is the key
Agraphia
o Problems with angular gyrus (written)
Alexia without agraphia
o Can write but cannot read
o Many can do letter by letter reading (bypass visual and use
auditory)

Dementia:

Mild Cognitive impairment for AD

o Symptoms before the person gets dementia
Important for future treatments that aim to prevent
o Concern about cognitive change from patient, informant (family
members) or clinician
o Evidence of biomarkers for AD
Tau and A
o
Our treatments can delay it but cannot cure it
Dementia
o Had higher intellect but then lost it
o Not necessarily progressive
o It has to impair your life in some way
o Cortical and Subcortical
Alzheimers disease
o Amyloid plaques
o Fibrillary tangles
o Need to have impairment of activity
o Gradual progressive worsening
o APOE 4 allele NOT sufficient to make diagnosing
o Need to have pathology criteria and evidence of clinical
symptoms
o Repetition of information is a hint
o Word finding problems (cannot find the right word)
o Can have other associated symptoms
Depression
Hallucinations
Delusionsparanoia, Capgras
Anxiety
Agitation
wandering
PET
Management
o Acetylcholinesterase inhibitors
o Does not cureit delays onset
o Support

FTD (frontal temporal dementia)

o Often associated with ALS
Lewy Body Dementia
o High rate of suicide

Vascular Disease

To measure the amount of stenosis, find a parallel segment to measure

it
ACA
o Feeds the medioaspect
o Leg area
MCA
o Most common due to being a straight vessel
o Later aspect
PCA
o Occipital (visual pathways)
Stroke
o Embolic
o Thrombotic
Hemorrhagic stroke
o Lobar hemorrhages (difficult to control bleeding if operated on)
Non contrast vs Contrast CT
Hyperdense vs hypodense
MRI
o For brain perfusion and function (where is language function?)
At risk vs dead brain
o The goal is to identify large areas of brain that are not dead, but
almost
o Dont want to reperfuse dead brain, as it will bleed
Subarachnoid Hemorrhage
o Commonly seen in aneurysms
Craniotomy for hemorrhage
Carotid endarterectomy
o Indicated for people with greater than 70% stenosis
Carotid stenosis
o Most lesions (symptoms) are NOT flow limiting, but due to
turbulence and plaques
Stroke
o Result of metabolic/perfusion mismatch
OEF
o To determine if the brain is getting enough blood

Diamox
o Causes the brain to become acidic opens blood vessels
more blood flow
Ruptured aneurysms (subarachnoid hemorrhage)
o worst headache of my life
o Devastating
o Failure to diagnose, or consider aneurysm, may allow patient
with sentinel hemorrhage to die another day
o Cerebral angiography remains the gold standard for evaluating
aneurysms
o Hunt and Hess scale is used to classify the severity of nontraumatic subarachnoid hemorrhage
Vascular malformation
o Shunt
Arteriovenous malformation
Arteries feeding into veins, resulting in enlargement
of veins
Arteriovenous fistula
o Non-shunt
Vascular tumor or vascular abnormalities
Cavernous malformation
Venous angioma (DVA)