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MOVEMENT DISORDERS
IN CHILDHOOD
THIRD EDITION
 https://www.elsevier.com/books-and-journals/book-companion/9780128205525

Movement Disorders in Childhood, Third Edition

Harvey S. Singer, Jonathan W. Mink, Donald L. Gilbert, and Joseph Jankovic

Resources:

Volume table of contents

Video Atlas
Videos of Movement Disorders
T-
his page intentionally left blank

ii
 MOVEMENT
DISORDERS IN
CHILDHOOD
THIRD EDITION
HARVEY S. SINGER
Johns Hopkins University School of Medicine, Department of Neurology, and the Kennedy Krieger Institute,
Baltimore, MD, United States

JONATHAN W. MINK
University of Rochester Medical Center, Department of Neurology, Division of Child Neurology, Rochester,
NY, United States

DONALD L. GILBERT
Division of Neurology, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics,
University of Cincinnati, Cincinnati, OH, United States

JOSEPH JANKOVIC
Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine,
Houston, TX, United States
Academic Press is an imprint of Elsevier
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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
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Practitioners and researchers must always rely on their own experience and knowledge in evaluating and us-
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ISBN: 978-0-12-820552-5

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Publisher: Nikki Levy

Acquisitions Editor: Joslyn Chaiprasert-Paguio
Editorial Project Manager: Kristi Anderson
Production Project Manager: Selvaraj Raviraj
Cover Designer: Matt Limbert
Cover Image: “Boys Afflicted with Chorea Known”,
used with permission from Historia/Shutterstock.
Typeset by TNQ Technologies
 Contents

Preface ix Dystonia 37
Myoclonus 38
Section I Parkinsonism 39
Startle 39
Overview Stereotypies 39
Tics 40
1. Basal Ganglia Anatomy, Biochemistry, Tremor 41
and Physiology Mixed Movement Disorders 41
Atypical Movement Disorders 41
Introduction 4 References 42
Basal Ganglia Circuits, Cell Types, and
Compartments 4 4. Diagnostic Evaluation of Children With
Neurotransmitters 6 Movement Disorders
Other Basal Ganglia Nuclei 7
Inhibiting and Disinhibiting Motor Patterns 9 Introduction 44
Implications for Disease: Focal Lesions and Preclinic 46
Abnormal Movements 10 In Clinic 48
References 11 The Diagnosis 57
Summary 64
2. Cerebellar Anatomy, Biochemistry, References 65
Physiology, and Plasticity
5. Motor Assessments
Introduction and Overview 16
Overview of Cerebellar Structure, Function, and Introduction 70
Symptom Localization 16 Quantitative Measurement in Movement
Cerebellar Integration with Basal Ganglia Disorders 70
Circuits 23 Rating Scales for Pediatric Movement
Neurotransmitters in the Cerebellum 26 Disorders 72
Neuroplasticity in the Cerebellum 28 References 77
Conclusion 30
References 30
Section II
3. Classification of Movement Disorders Developmental Movement Disorders
Introduction 33 6. Transient and Developmental
Ataxia 36 Movement Disorders
Athetosis 36
Ballismus 36 Introduction 85
Chorea 37 References 93

v
vi
Section III
Paroxysmal Movement Disorders
7. Tics and Tourette Syndrome
Introduction 100
Definition of Tics 101
Clinical CharacteristicsdPhenomenology and
Classification of Tics 101
Localization and Pathophysiology 102
Specific Tic Disorder Diagnoses 112
Treatment 119
References 126
8. Motor Stereotypies
Introduction and Overview 142
Definitions 142
Clinical Characteristics, Classifications, and
Differentiation 142
Pathophysiology 146
Major Diseases and Disorders 151
Stereotypy Rating Scales 157
Treatment 157
References 158
9. Paroxysmal Dyskinesias
Introduction and Overview 165
Clinical Characteristics 166
Diseases and Disorders 168
References 176
Section IV
Hyperkinetic and Hypokinetic
Movement Disorders
10. Chorea, Athetosis, and Ballism
Introduction and Overview 184
Definitions of Chorea, Athetosis, and
Ballism 184
Clinical CharacteristicsdPhenomenology of Chorea,
Athetosis, and Ballism in Children 185
Localization and Pathophysiology 187
Diseases and Disorders 189
CONTENTS
Summary of Diagnostic and Therapeutic
Approach 217
References 218
11. Dystonia
Introduction and Overview 230
Classification of Dystonias 231
Localization and Pathophysiology 238
Diseases and Disorders 239
Diagnostic Approach to Dystonia 250
Management and Treatment 251
Patient and Family Resources 253
References 253
12. Myoclonus
Introduction and Overview 264
Definition of Myoclonus 265
Clinical CharacteristicsdPhenomenology of
Myoclonus in Children 265
Localization and Neurophysiology 268
Diseases and Disorders 270
Summary of Diagnostic and Therapeutic
Approach 295
References 296
13. Tremor
Introduction and Overview 306
Definition of Tremor 306
Clinical CharacteristicsdPhenomenology and
Classification of Tremor in Children 307
Localization and Pathophysiology 310
Diseases and Disorders 314
Approach to Diagnosis and Management 324
References 325
14. Ataxia
Introduction and Overview 334
Definition of Ataxia 335
Clinical CharacteristicsdPhenomenology of Ataxia
in Children 335
Localization and Pathophysiology 336
Diseases and Disorders 336
Approach to Diagnosis and Management 379
References 382
 CONTENTS vii
15. Parkinsonism 18. Movement Disorders in Autoimmune
Diseases
Introduction and Overview 396
Clinical Features of Parkinsonism 396 Introduction 536
Pathophysiogy of Parkinsonism 397 Immunology Overview 536
Diseases and Disorders 399 Diseases and Disorders 537
Treatment of Parkinsonism 407 References 552
References 408
19. Movement Disorders in Sleep
16. Hereditary Spastic Paraplegia
Introduction 562
Introduction and Overview 416 Overview of Sleep Physiology 563
Definitions of Spasticity and Sleep-Related Movement Disorders 565
Hypertonia 417 Hyperkinetic Movement Disorders that Are Present
Clinical CharacteristicsdPhenomenology of Spastic During the Daytime and Persist During
Paraplegia in Children 417 Sleep 580
Localization and Pathophysiology 419 Seizures in and Around the Time of Sleep 580
Diseases and Disorders 420 References 581
Approach to Diagnosis and
Management 433 20. Cerebral Palsy
Summary 435
References 435 Introduction 592
Epidemiology 593
Section V Etiology 593
Diagnosis 595
Selected Secondary Movement History and Physical Examination 595
Disorders Assessment Scales 596
Clues for Determining the Motor CP Type 597
17. Metabolic Disorders With Associated Cerebral Palsy Syndromes 598
Movement Abnormalities Management 606
References 610
Pediatric Neurotransmitter
Disorders 445 21. Movement Disorders and
Storage Disorders 456
Leukodystrophies 474
Neuropsychiatric Conditions
Aminoacidemias 475
Organic Acidemias 479 Introduction and Overview 620
Glycolysis, Pyruvate Metabolism, and Krebs Cycle Attention Deficit Hyperactivity Disorder 621
Disorders 484 Obsessive Compulsive Disorder 623
Mitochondrial Disorders 488 Autism Spectrum Disorder 625
Purine Metabolism Disorders 493 Conclusions 629
Creatine Metabolism Disorders 497 References 629
Congenital Disorders of Glycosylation 499
Cofactor, Mineral, and Vitamin 22. Drug-Induced Movement Disorders
Disorders 500 in Children
Neuroacanthocytosis Syndromes 503
Other Metabolic Conditions 506 Introduction and Overview 638
References 508
viii CONTENTS

Definition of Drug-Induced Movement Clinical Features of Functional Movement

Disorders 639 Disorders 670
Clinical CharacteristicsdPhenomenology of Pathophysiology 670
Drug-Induced Movement Disorders in Diagnosis 671
Children 639 Conclusion 676
Drug-Induced Movement Disorders 640 References 676
Conclusion 658
References 658 Appendix A Drug Appendix 681
23. Functional Movement Disorders Appendix B Search Strategy for Genetic
Movement Disorders 705
Introductions 667 Index 713
Epidemiology 668
 Preface
The authors of this text are pleased to
present the third edition of Movement
Disorders in Childhood. New understandings
in the fields of genetics, neurobiology, im-
aging, and clinical care continue to trans-
form our knowledge, concepts, and
approaches to patients. This new edition has
integrated many of the advances in pedia-
tric movement disorders gained over the
past several years. While chapter titles may
look familiar, the contents have been
updated, revised, and expanded substan-
tially. Furthermore, new videos illustrating
the phenomenology of novel and unusual
disorders have been added. We hope that
this new edition continues to be of value to
readers at all levels of experience and
training.
Historically, three of the authors (Drs.
Singer, Mink, and Gilbert), first discussed the
concept of a pediatric neurology textbook
devoted solely to movement disorders at the
2008 Child Neurology Society meeting in
Santa Clara, CA. We were unanimous in the
belief that a high-quality text should be
written and critically reviewed by experi-
enced pediatric movement disorder experts.
We also concurred that visualization of the
various movements, not just descriptive
words, were essential for both diagnostic
and educational purposes. Following an
initial agreement on these basic objectives,
initial chapters were assigned and Dr. Jan-
kovic, a highly regarded expert academic
ix
movement disorder specialist was recruited
to assist with the book’s organization and
video preparations. It has subsequently
become a tradition that the pediatric
neurology authors meet yearly at the CNS
meeting to discuss future goals.
The first edition of this book, a slim text
containing 279 pages, was published in 2010.
Six years later (2016), an updated 587-page
second edition followed. The second edition
included both an expansion of new scientific
and clinical information as well as more
chapters and appendices. Publication of the
enlarged current third edition also comes
6 years after its predecessor. Several changes
were implemented to enable the growth of
this comprehensive resource including a
request to the publisher for additional pages
to allow more comprehensive discussion of
underlying pathophysiology, disease review,
and patient care. In addition, recognizing
that each chapter is written by a single
author and that there are occasionally dif-
ferences between experts, all authors care-
fully reviewed and edited the chapters prior
to submission.
In conclusion, the authors are pleased to
once again provide a comprehensive review
of movement disorders that affect children.
While remaining an academic effort of
enjoyment and learning, we are all grateful
for the support and understanding of our
wives, children, and grandchildren. We also
wish to express our appreciation to the
x PREFACE
publisher, and specifically to Kristi Anderson,
Senior Editorial Project Manager, Selvaraj
Raviraj, Project Manager, and Nikki Levy,
Publisher, Elsevier.
We look forward to the future advances in
the field of neuroscientific research and
improved care for all children with a move-
ment disorder.
Harvey S. Singer, MD
Jonathan W. Mink, MD, PhD
Donald L. Gilbert, MD, MS
Joseph Jankovic, MD
March 2022
S E C T I O N I

Overview
This page intentionally left blank
 C H A P T E R

1
Basal Ganglia Anatomy,
Biochemistry, and Physiology
Harvey S. Singer1, Jonathan W. Mink2,
Donald L. Gilbert3 and Joseph Jankovic4
1
Department of Neurology, Johns Hopkins Hospital and the Kennedy Krieger Institute,
Baltimore, MD, United States; 2Division of Child Neurology, University of Rochester Medical
Center, Rochester, NY, United States; 3Division of Neurology, Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, United States; 4Department of Neurology, Baylor College of
Medicine, Houston, TX, United States

O U T L I N E

Introduction 4 Subthalamic Nucleus 7

Output Nuclei: Globus Pallidus Interna
Basal Ganglia Circuits, Cell Types, and
and Substantia Nigra Pars Reticulata 8
Compartments 4
Globus Pallidus Externa 8
Circuits 4
Substantia Nigra Pars Compacta 9
Cell Types 5
Compartments 6 Inhibiting and Disinhibiting Motor
Patterns 9
Neurotransmitters 6
Dopamine 6 Implications for Disease: Focal Lesions
GABA 7 and Abnormal Movements 10
Acetylcholine 7
References 11
Other Basal Ganglia Nuclei 7

Movement Disorders in Childhood, Third Edition

https://doi.org/10.1016/B978-0-12-820552-5.00012-7 3 © 2022 Elsevier Inc. All rights reserved.
4 1. Basal Ganglia Anatomy, Biochemistry, and Physiology

Introduction
The basal ganglia are large subcortical structures comprising several interconnected nuclei
in the forebrain, diencephalon, and midbrain. Historically, the basal ganglia have been
viewed as a component of the motor system. However, there is now substantial evidence
that the basal ganglia interact with all of frontal cortex and with the limbic system. Thus,
the basal ganglia likely have a role in cognitive and emotional function in addition to their
role in motor control.1 Indeed, most diseases of the basal ganglia cause a combination of
movement, affective, and cognitive disorders with the movement disorder being predomi-
nant. The motor circuits of the basal ganglia are better understood than the other circuits,
but because of similar organization of the circuitry, conceptual understanding of basal
ganglia motor function can provide a useful framework for understanding cognitive and af-
fective function, too.

Basal Ganglia Circuits, Cell Types, and Compartments

Circuits
The basal ganglia include the striatum (caudate, putamen, nucleus accumbens), the sub-
thalamic nucleus (STN), the globus pallidus (internal segmentdGPi, external segmentdGPe,
ventral pallidumdVP), and the substantia nigra (pars compactadSNpc and pars reticulatad
SNpr) (Fig. 1.1). The striatum and STN receive the majority of inputs from outside of the basal
ganglia. Most of those inputs come from cerebral cortex, but thalamic nuclei also provide
strong inputs to striatum. The bulk of the outputs from the basal ganglia arise from the
globus pallidus internal segment, VP, and substantia nigra pars reticulata. These outputs
are inhibitory to the pedunculopontine area in the brainstem and to thalamic nuclei that in
turn project to frontal lobe.
The striatum receives the bulk of extrinsic input to the basal ganglia. The striatum
receives excitatory input from virtually all of cerebral cortex.2 In addition, the ventral stria-
tum (nucleus accumbens and rostroventral extensions of caudate and putamen) receives in-
puts from hippocampus and amygdala.3 The cortical input uses glutamate as its
neurotransmitter and terminates largely on the heads of the dendritic spines of medium
spiny neurons.4 The projection from the cerebral cortex to striatum has a roughly topo-
graphic organization that provides the basis for an organization of functionally different
circuits in the basal ganglia.5,6 Although the topography implies a certain degree of parallel
organization, there is also evidence for convergence and divergence in the corticostriatal
projection. The large dendritic fields of medium spiny neurons7 allow them to receive input
from adjacent projections, which arise from different areas of cortex. Inputs to striatum from
several functionally related cortical areas overlap and a single cortical area projects diver-
gently to multiple striatal zones.8,9 Thus, there is a multiply convergent and divergent or-
ganization within a broader framework of functionally different parallel circuits. This
organization provides an anatomical framework for the integration and transformation of
cortical information in the striatum.

I. Overview
 Basal Ganglia Circuits, Cell Types, and Compartments 5

FIGURE 1.1 Simplified schematic diagram of basal gangliadthalamo-cortical circuitry. Excitatory connections
are indicated by open arrows, inhibitory connections by filled arrows. The modulatory dopamine projection is indicated
by a three-headed arrow. Abbreviations: dyn, dynorphin, enk, enkephalin, GABA, gamma-amino-butyric acid, glu,
glutamate, GPe, globus pallidus pars externa, GPi, globus pallidus pars interna, IL, intralaminar thalamic nuclei, MD,
mediodorsal nucleus, PPA, pedunculopontine area, SC, superior colliculus, SNpc, substantia nigra pars compacta,
SNpr, substantia nigra pars reticulata, SP, substance P, STN, subthalamic nucleus, VA, ventral anterior nucleus, VL,
ventral lateral nucleus.

Cell Types
Medium spiny striatal neurons make up 90%e95% of the striatal neuron population. They
project outside of the striatum and receive a number of inputs in addition to the important

I. Overview
6 1. Basal Ganglia Anatomy, Biochemistry, and Physiology

cortical input, including (1) excitatory glutamatergic inputs from thalamus; (2) cholinergic
input from striatal interneurons; (3) gamma-amino-butyric acid (GABA), substance P,
and enkephalin input from adjacent medium spiny striatal neurons; (4) GABA input
from fast-spiking interneurons; (5) a large input from dopamine-containing neurons in
the SNpc; (6) a more sparse input from the serotonin-containing neurons in the dorsal
and median raphe nuclei.
The fast-spiking GABAergic striatal interneurons make up only 2%e4% of the striatal
neuron population, but they exert powerful inhibition on medium spiny neurons. Like me-
dium spiny neurons, the striatal interneurons receive excitatory input from cerebral cortex.
They appear to play an important role in limiting the activity of medium spiny neurons
and in focusing the spatial pattern of their activation.10 Abnormalities in the number or func-
tion of these neurons have been linked to the pathobiology of involuntary movements.11e13

Compartments
Although there are no apparent regional differences in the striatum based on cell type, an
intricate internal organization has been revealed with special stains. When the striatum is
stained for acetylcholinesterase (AChE), there is a patchy distribution of lightly staining re-
gions within more heavily stained regions.14 The AChE-poor patches have been called strio-
somes and the AChE-rich areas have been called the extrastriosomal matrix. The matrix
forms the bulk of the striatal volume and receives input from most areas of cerebral cortex.
Within the matrix are clusters of neurons with similar inputs that have been termed matri-
somes. The bulk of the output from cells in the matrix is to both segments of the GP, VP, and
to SNpr. The striosomes receive input from prefrontal cortex and send output to SNpc.15
Immunohistochemical techniques have demonstrated that many substances such as sub-
stance P, dynorphin, and enkephalin have a patchy distribution that may be partly or
wholly in register with the striosomes. The striosome-matrix organization suggests a level
of functional segregation within the striatum that may be maintained by differential
influences of dopamine.16 While preferential involvement of the striosome or matrix com-
partments has been suggested in some disorders,17 the clinical significance of this organiza-
tion is still not well understood.

Neurotransmitters

Dopamine
The dopamine input to the striatum terminates largely on the shafts of the dendritic
spines of medium spiny neurons where it is in a position to modulate transmission from
the cerebral cortex to the striatum.18 The action of dopamine on striatal neurons depends
on the type of dopamine receptor involved. Five types of G protein-coupled dopamine recep-
tors have been described (D1.D5).19 These have been grouped into two families based on
their linkage to adenyl cyclase activity and response to agonists. The D1 family includes
D1 and D5 receptors and the D2 family includes D2, D3, and D4 receptors. The conventional
view has been that dopamine acts at D1 receptors to facilitate the activity of postsynaptic neu-
rons and at D2 receptors to inhibit postsynaptic neurons.20 Indeed, this is a fundamental

I. Overview
 Other Basal Ganglia Nuclei 7
concept for some models of basal ganglia pathophysiology.21,22 However, the physiologic ef-
fect of dopamine on striatal neurons is more complex. While activation of dopamine D1 re-
ceptors potentiates the effect of cortical input to striatal neurons in some states, it reduces the
efficacy of cortical input in others.23 Activation of D2 receptors more consistently decreases
the effect of cortical input to striatal neuron.24 Dopamine contributes to focusing the spatial
and temporal patterns of striatal activity.
In addition to short-term facilitation or inhibition of striatal activity, there is evidence that
dopamine can modulate corticostriatal transmission by mechanisms of long-term depression
(LTD) and long-term potentiation (LTP). Through these mechanisms, dopamine strengthens
or weakens the efficacy of corticostriatal synapses and can thus mediate reinforcement of spe-
cific discharge patterns. LTP and LTD are thought to be fundamental to many neural mecha-
nisms of learning and may underlie the hypothesized role of the basal ganglia in habit
learning.25 SNpc dopamine neurons fire in relation to behaviorally significant events and
reward.26 These signals are likely to modify the responses of striatal neurons to inputs that
occur in conjunction with the dopamine signal resulting in the reinforcement of motor and
other behavior patterns. Striatal lesions or focal striatal dopamine depletion impairs the
learning of new movement sequences,27 supporting a role for the basal ganglia in certain types
of procedural learning. Dopamine may also play a role in other aspects of motor learning.28

GABA
Medium spiny striatal neurons contain the inhibitory neurotransmitter GABA and colocal-
ized peptide neurotransmitters.29,30 Based on the type of neurotransmitters and the predom-
inant type of dopamine receptor they contain, the medium spiny neurons can be divided into
two populations. One population contains GABA, dynorphin, and substance P and primarily
expresses D1 dopamine receptors. These neurons project to the basal ganglia output nuclei,
GPi, and SNpr. The second population contains GABA and enkephalin and primarily ex-
presses D2 dopamine receptors. These neurons project to the external segment of the globus
pallidus (GPe).21

Acetylcholine
Cholinergic interneurons densely innervate the striatum31 and modulate dopamine
release.32 Additional cholinergic input into striatum comes from the pedunculopontine nu-
cleus and the laterodorsal tegmental nuclei in the brainstem.33 Via muscarinic acetylcholine
receptors, cholinergic interneurons influence both dopamine D1 and D2 receptor-
expressing medium spiny neurons. A key property of cholinergic interneurons is their tonic
spiking activity, and thus they are also referred to as tonically active neurons.34

Other Basal Ganglia Nuclei

Subthalamic Nucleus
The STN receives an excitatory, glutamatergic input from many areas of frontal lobes with
especially large inputs from motor areas of cortex.35 The STN also receives inhibitory

I. Overview
8 1. Basal Ganglia Anatomy, Biochemistry, and Physiology

GABAergic input from GPe. The output from the STN is glutamatergic and excitatory to the
basal ganglia output nuclei, GPi, VP, and SNpr. STN also sends an excitatory projection back
to GPe. There is a somatotopic organization in STN36 and a relative topographic separation of
“motor” and “cognitive” inputs to STN.

Output Nuclei: Globus Pallidus Interna and Substantia Nigra Pars Reticulata
The primary basal ganglia output arises from GPi, a GPi-like component of VP, and SNpr.
As described above, GPi and SNpr receive excitatory input from STN and inhibitory input
from striatum. They also receive an inhibitory input from GPe. The dendritic fields of GPi,
VP, and SNpr neurons span up to 1 mm diameter and thus have the potential to integrate
a large number of converging inputs.37 The output from GPi, VP, and SNpr is inhibitory
and uses GABA as its neurotransmitter. The primary output is directed to thalamic nuclei
that project to the frontal lobes: the ventrolateral, ventroanterior, and mediodorsal nuclei.
The thalamic targets of GPi, VP, and SNpr project, in turn, to frontal lobe, with the strongest
output going to motor areas. Collaterals of the axons projecting to thalamus project to an area
at the junction of the midbrain and pons in the area of the pedunculopontine nucleus.38 Other
output neurons (20%) project to intralaminar nuclei of the thalamus, to the lateral habenula,
or to the superior colliculus.39
The basal ganglia motor output has a somatotopic organization such that the body below
the neck is largely represented in GPi, and the head and eyes are largely represented in SNpr.
The separate representation of different body parts is maintained throughout the basal
ganglia. Within the representation of an individual body part, it also appears that there is
segregation of outputs to different motor areas of cortex and that an individual GPi neuron
sends output via thalamus to just one area of cortex.40 Thus, GPi neurons that project via thal-
amus to motor cortex are adjacent to, but separate from, those that project to premotor cortex
or supplementary motor area. GPi neurons that project via thalamus to prefrontal cortex are
also separate from those projecting to motor areas and from VP neurons projecting via thal-
amus to orbitofrontal cortex. The anatomic segregation of basal ganglia-thalamocortical out-
puts suggests functional segregation at the output level, but other anatomic evidence
suggests interactions between circuits within the basal ganglia (see above).5,41

Globus Pallidus Externa

The GPe and the GPe-like part of VP may be viewed as intrinsic nuclei of the basal ganglia.
Like GPi and SNpr, GPe receives an inhibitory projection from the striatum and an excitatory
one from STN. Unlike GPi, the striatal projection to GPe contains GABA and enkephalin but
not substance P.21 The output of GPe is quite different from the output of GPi. The output
from GPe is GABAergic and inhibitory, and the majority of the output projects to STN.
The connections from striatum to GPe, from GPe to STN, and from STN to GPi form the “in-
direct” striatopallidal pathway to GPi42 (Fig. 1.1). In addition, there is a monosynaptic
GABAergic inhibitory output from GPe directly to GPi and to SNpr and a GABAergic pro-
jection back to striatum.43 Thus, GPe neurons are in a position to provide feedback inhibition

I. Overview
 Inhibiting and Disinhibiting Motor Patterns 9
to neurons in striatum and STN and feedforward inhibition to neurons in GPi and SNpr. This
circuitry suggests that GPe may act to oppose, limit, or focus the effect of the striatal and STN
projections to GPi and SNpr as well as focus activity in these output nuclei.

Substantia Nigra Pars Compacta

Dopamine input to the striatum arises from SNpc and the ventral tegmental area (VTA).
SNpc projects to most of the striatum; VTA projects to the ventral striatum. The SNpc and
VTA are made up of large dopamine-containing cells. SNpc receives input from the striatum,
specifically from the striosomes. This input is GABAergic and inhibitory. The SNpc and VTA
dopamine neurons project to caudate and putamen in a topographic manner,41 but with over-
lap. The nigral dopamine neurons receive inputs from one striatal circuit and project back to
the same and to adjacent circuits. Thus, they appear to be in a position to modulate activity
across functionally different circuits.

Inhibiting and Disinhibiting Motor Patterns

Although the basal ganglia intrinsic circuitry is complex, the overall picture is of two pri-
mary pathways through the basal ganglia from cerebral cortex with the output directed via
thalamus at the frontal lobes. These pathways consist of two disynaptic pathways from cortex
to the basal ganglia output (Fig. 1.2). In addition, there are several multisynaptic pathways
involving GPe. The two disynaptic pathways are from cortex through (1) striatum (the direct
pathway) and (2) STN (the hyperdirect pathway) to the basal ganglia outputs. These pathways
have important anatomical and functional differences. First, the cortical input to STN comes
only from frontal lobe, whereas the input to striatum arises from virtually all areas of cerebral
cortex. Second, the output from STN is excitatory, whereas the output from striatum is inhib-
itory. Third, the excitatory route through STN is faster than the inhibitory route through stria-
tum.44 Finally, the STN projection to GPi is divergent and the striatal projection is more
focused.45 Thus, the two disynaptic pathways from cerebral cortex to the basal ganglia output
nuclei, GPi and SNpr, provide fast, widespread, divergent excitation through STN and
slower, focused, inhibition through striatum.17 This organization provides an anatomical ba-
sis for focused inhibition and surround excitation of neurons in GPi and SNpr (Fig. 1.3).
Because the output of GPi and SNpr is inhibitory, this results in focused facilitation and sur-
round inhibition of basal ganglia thalamocortical targets.47 The tonically active inhibitory
output of the basal ganglia acts as a “brake” on motor pattern generators (MPGs) in the ce-
rebral cortex (via thalamus) and brainstem. When a movement is initiated by a particular
MPG, basal ganglia output neurons projecting to competing MPGs increase their firing
rate, thereby increasing inhibition and applying a “brake” on those generators. Other basal
ganglia output neurons projecting to the generators involved in the desired movement
decrease their discharge, thereby removing tonic inhibition and releasing the “brake” from
the desired motor patterns. Thus, the intended movement is enabled and competing move-
ments are prevented from interfering with the desired one.35,48

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