Movement Disorders in Childhood

Movement Disorders in Childhood

Second Edition

Harvey S. Singer

Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA

Jonathan W. Mink

Division of Child Neurology, University of Rochester Medical Center, Rochester, NY, USA

Donald L. Gilbert

Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Joseph Jankovic

Department of Neurology, Baylor College of Medicine, Houston, TX, USA

Table of Contents

Cover image

Title page

Copyright

Preface

Acknowledgment

Section I: Overview

Chapter 1. Basal Ganglia Anatomy, Biochemistry, and Physiology

Abstract

Introduction

Circuits and Neurotransmitters in the Basal Ganglia

Subthalamic Nucleus (STN)

Output Nuclei: Globus Pallidus Interna (GPi) and Substantia Nigra pars reticulata (SNpr)

Globus Pallidus externa (GPe)

Inhibiting and Disinhibiting Motor Patterns

Implications for Disease: Focal Lesions and Abnormal Movements

References

Chapter 2. Cerebellar Anatomy, Biochemistry, Physiology, and Plasticity

Abstract

Introduction

Overview of Cerebellar Structure, Function, and Symptoms

Macroscopic to Microscopic Cerebellar Structure

Neurotransmitters in the Cerebellum

Neuroplasticity in the Cerebellum

Cerebellar Stimulation

Conclusion

References

Chapter 3. Classification of Movement Disorders

Abstract

Introduction

Ataxia (Chapter 14)

Athetosis (Chapter 10)

Ballismus (Chapter 10)

Chorea (Chapter 10)

Dystonia (Chapter 11)

Myoclonus (Chapter 12)

Parkinsonism (Chapter 15)

Stereotypies (Chapter 8)

Tics (Chapter 7)

Tremor (Chapter 13)

References

Chapter 4. Diagnostic Evaluation of Children with Movement Disorders

Abstract

Introduction

Preclinic

In Clinic

The Diagnosis

Summary

References

Chapter 5. Motor Assessments

Abstract

Introduction

Quantitative Measurement in Movement Disorders

Rating Scales for Pediatric Movement Disorders

References

Section II: Developmental Movement Disorders

Chapter 6. Transient and Developmental Movement Disorders in Children

Abstract

Benign Neonatal Sleep Myoclonus

Benign Myoclonus of Early Infancy (Benign Infantile Spasms)

Jitteriness

Shuddering

Paroxysmal Tonic Upgaze of Infancy

Spasmus Nutans

Head Nodding

Benign Paroxysmal Torticollis

Benign Idiopathic Dystonia of Infancy

Sandifer Syndrome

Posturing During Masturbation

References

Section III: Paroxysmal Movement Disorders

Chapter 7. Tics and Tourette Syndrome

Abstract

Introduction

Tic Phenomenology

Tic Disorders

Epidemiology

Scales

Outcome

Associated Behaviors and Psychopathologies in Tic Disorders

Etiology

Pathophysiology of Tic Disorders

Treatment

References

Chapter 8. Motor Stereotypies

Abstract

Introduction

Definition

Differentiating Stereotypies from Other Disorders

Pathophysiology

Classification of Motor Stereotypies

Therapy

Patient and Family Resources

References

Chapter 9. Paroxysmal Dyskinesias

Abstract

Introduction

Clinical Characteristics

Specific Disorders

References

Section IV: Hyperkinetic and Hypokinetic Movement Disorders

Chapter 10. Chorea, Athetosis, and Ballism

Abstract

Introduction and Overview

Definitions of Chorea, Athetosis, and Ballism

Clinical Characteristics—Phenomenology of Chorea, Athetosis, and Ballism in Children

Localization and Pathophysiology

Diseases and Disorders

Summary of Diagnostic and Therapeutic Approach

References

Chapter 11. Dystonia

Abstract

Introduction

Classification of Dystonias

Localization and Pathophysiology

Etiologies

Diagnostic Approach to Dystonia

Management and Treatment

Patient and Family Resources

References

Chapter 12. Myoclonus

Abstract

Introduction and Overview

Definition of Myoclonus

Clinical Characteristics—Phenomenology of Myoclonus in Children

Localization and Pathophysiology

Diseases and Disorders

Autosomal Dominant, Cortical Myoclonus without Epilepsy

Hemifacial Spasm

Summary of Diagnostic and Therapeutic Approach

References

Chapter 13. Tremor

Abstract

Introduction and Overview

Definition of Tremor

Clinical Characteristics—Phenomenology of Tremor in Children

Localization and Pathophysiology

Diseases and Disorders

Approach to Diagnosis and Management

References

Chapter 14. Ataxia

Abstract

Introduction and Overview

Definition of Ataxia

Clinical Characteristics—Phenomenology of Ataxia in Children

Localization and Pathophysiology

Diseases and Disorders

Approach to Diagnosis and Management

Summary

References

Chapter 15. Parkinsonism

Abstract

Introduction

Clinical Features of Parkinsonism

Pathophysiology of Parkinsonism

Etiologies of Parkinsonism in Children

Secondary Parkinsonism

Treatment of Parkinsonism

References

Chapter 16. Hereditary Spastic Paraplegia

Abstract

Introduction and Overview

Definitions of Spasticity and Hypertonia

Clinical Characteristics—Phenomenology of Spastic Paraplegia in Children

Localization and Pathophysiology

Diseases and Disorders

Treatment

Diagnostic and Management Approach

Summary

References

Section V: Selected Secondary Movement Disorders

Chapter 17. Inherited Metabolic Disorders with Associated Movement Abnormalities

Abstract

Pediatric Neurotransmitter Disorders

Metabolic Disorders

References

Chapter 18. Movement Disorders in Autoimmune Diseases

Abstract

Complication of a Systemic Autoimmune Disorder

Post-Streptococcal Infections

Autoimmune Basal Ganglia Encephalitis

Autoimmune Encephalopathies

Other Paraneoplastic Syndromes

References

Chapter 19. Movements that Occur in Sleep

Abstract

Overview of Sleep Physiology

Classification of Movements in Sleep

Sleep-Related Movement Disorders

Hyperkinetic Movement Disorders that are Present during the Daytime and Persist during Sleep

Seizures in and Around the Time of Sleep

References

Chapter 20. Cerebral Palsy

Abstract

Introduction

Epidemiology

Etiology

Differentiating Hypertonia in Children

Cerebral Palsy Syndromes

Diagnostic Tests

Management of Cerebral Palsy

References

Chapter 21. Movement Disorders and Neuropsychiatric Conditions

Abstract

Attention Deficit Hyperactivity Disorder

Obsessive Compulsive Disorder

Autism Spectrum Disorder

Conclusion

References

Chapter 22. Drug-Induced Movement Disorders in Children

Abstract

Introduction and Overview

Definition of DIMDs

Clinical Characteristics—Phenomenology of DIMDs in Children

Drug-Induced Movement Disorders

Conclusion

References

Chapter 23. Functional (Psychogenic) Movement Disorders

Abstract

Introduction

Conclusion

References

Appendices

Appendix A. Drug Appendix

Acetazolamide

Amantidine

Amphetamine

Aripiprazole

Atomoxetine

Baclofen

Baclofen; Intrathecal Pump

Benztropine

Botulinum Toxin

Carbamazepine

Carbidopa/Levodopa

Clonazepam

Clonidine

Clozapine

Coenzyme Q10

Creatine

Cyclophosphamide

Dantroline

Fluphenazine

Gabapentin

Guanfacine

Haloperidol

IVIG

Levetiracetam

Methylphenidate

Modafinil/Armodafinil

Olanzapine

Penicillamine

Pimozide

Piracetam

Pramipexole

Prednisone and Methylprednisolone

Pregabalin

Primidone

Propranolol

Quetiapine

Reserpine

Risperidone

Rituximab

Ropinirole

Sodium Oxybate

Tetrabenazine

Tetrathiomolybdate (TM)

Tizanidine

Topiramate

Trientine

Trihexyphenidyl

Valproic Acid

Zinc

Ziprasidone

Zonisamide

Appendix B. Search Strategy for Genetic Movement Disorders

Using OMIM to Aid in Diagnosis

Example 1 Advanced Search: OMIM

Example 2 Advanced Search: Clinical Synopsis

Example 3 Advanced Search: Gene Map Advanced Search

Next Steps after the OMIM search

Using Simulconsult to Aid in Diagnosis

Example 1 Simulconsult Search

Summary

Appendix C. Video Atlas

Chapter 6 Transient and Developmental Movement Disorders in Children

Chapter 7 Tics and Tourette Syndrome

Chapter 8 Motor Stereotypies

Chapter 9 Paroxysmal Dyskinesias

Chapter 10 Chorea, Athetosis, and Ballism

Chapter 11 Dystonia

Chapter 12 Myoclonus

Chapter 13 Tremor

Chapter 14 Ataxia

Chapter 15 Parkinsonism

Chapter 17 Inherited Metabolic Disorders with Associated Movement Abnormalities

Chapter 18 Movement Disorders in Autoimmune Diseases

Chapter 20 Cerebral Palsy

Chapter 22 Drug-Induced Movement Disorders

Chapter 23 Functional Movement Disorders

Index

Copyright

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Preface

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

Movement disorders are an expanding area of specialization within the field of child neurology. Clinics devoted to pediatric movement disorders are rapidly appearing in the United States and in developed countries throughout the world. The number of fellowship training positions and child neurology residents entering the field continues to grow, although not sufficient to satisfy the growing need for pediatric movement disorder experts. National and international societies are devoting major segments of their conferences, or even entire meetings, to issues pertaining to movement disorders in children. We are also pleased to note increasing collaborations, among pediatric and adult neurologists and basic scientists, with the common goal to better understanding the etiology, mechanism, and treatment of conditions discussed in this book.

It is likely that multiple factors have contributed to the expansion of interest in the field of pediatric movement disorders. Researchers are providing new insights into the development and maintenance of motor control, volitional, and habitual behaviors. Advances have been made in identifying the underlying pathophysiologic mechanisms in several hyper- and hypokinetic movement disorders, especially regarding the circuitry interconnecting the cerebral cortex, basal ganglia, cerebellum, and brainstem. Recognizing that these same circuits are also involved in cognition and emotion, the interest and number of multi-faceted, multi-disciplinary research protocols has expanded. Progress in the areas of molecular and clinical genetics, developmental and metabolic disorders, and immunologic disorders, such as autoimmune encephalitis, has provided investigators with exciting methodologies with which to diagnose and better understand underlying disease processes. Lastly, there is the ever present awareness and desire to improve care and to develop new and improved therapies for children affected with movement disorders.

Our decision to write the first edition of this book was based on a perceived need for a high-quality, comprehensive text devoted to movement disorders in children. In order to develop this useful resource, several working guidelines were established. First and foremost, each chapter was to be written by a neurologist with a strong clinical and scientific background and expertise in the field of childhood movement disorders. Second, the number of authors would be limited, in order to maintain an active dialogue and comprehensive review of each chapter. Lastly, recognizing the educational limitations of written descriptions of abnormal movements, the inclusion of videos was a requirement. These same guidelines, successfully implemented in the first book, were again used in this second edition.

In the six years since publication of the first edition, our understanding of processes responsible for typical motor development and those underlying pathologic disorders has grown dramatically. Advances in basic and translational neuroscience, expanded clinical characterizations, availability of new diagnostic tests, and the discovery of new therapies has required a substantial revision of each chapter. However, based on the positive feedback from the initial edition, the basic format of the book was maintained. We have also added four new chapters reflecting expanded information on motor assessments, hereditary spastic paraplegias, movement disorders in autoimmune diseases, and motor disorders in neuropsychiatric conditions. We have once again attempted to provide a resource that provides a fundamental background of neuronal circuitry, a guide to efficient patient evaluation, and a comprehensive review of disorders. We hope that this information is of interest and value to readers at all levels of experience. In closing, we look forward with great anticipation to future clinical and scientific advances in the area of ‘movement disorders in childhood.’

Fall 2015

Acknowledgment

The authors would like to thank the staff at Elsevier for their assistance and flexibility. In particular, we acknowledge the efforts of Melanie Tucker, Kristi Anderson and Caroline Johnson.

Section I

Overview

Outline

Chapter 1 Basal Ganglia Anatomy, Biochemistry, and Physiology

Chapter 2 Cerebellar Anatomy, Biochemistry, Physiology, and Plasticity

Chapter 3 Classification of Movement Disorders

Chapter 4 Diagnostic Evaluation of Children with Movement Disorders

Chapter 5 Motor Assessments

Chapter 1

Basal Ganglia Anatomy, Biochemistry, and Physiology

Harvey S. Singer¹, Jonathan W. Mink², Donald L. Gilbert³ and Joseph Jankovic⁴,    ¹Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA,    ²Division of Child Neurology, University of Rochester Medical Center, Rochester, NY, USA,    ³Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,    ⁴Department of Neurology, Baylor College of Medicine, Houston, TX, USA

Abstract

The basal ganglia are the site of dysfunction or pathology for the majority of movement disorders. They are organized in complex circuits in close association with the frontal lobes of the cerebral cortex and with the brainstem. Despite the complexity of these circuits, ­specific organizing principles provide a framework for understanding their function and how ­disruption of normal function at different levels results in the characteristic movement disorders of chorea, dystonia, tics, stereotypies, and Parkinsonism.

Keywords

Caudate; putamen; globus pallidus; subthalamic nucleus; substantia nigra; basal ganglia-thalamocortical circuits; dopamine

Outline

Introduction 4

Circuits and Neurotransmitters in the Basal Ganglia 4

Cell types in the Basal Ganglia 4

Dopamine 6

GABA 6

Acetylcholine 7

Subthalamic Nucleus (STN) 7

Output Nuclei: Globus Pallidus Interna (GPi) and Substantia Nigra pars reticulata (SNpr) 7

Globus Pallidus externa (GPe) 8

Inhibiting and Disinhibiting Motor Patterns 8

Implications for Disease: Focal Lesions and Abnormal Movements 10

References 11

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, diseases of the basal ganglia often cause a combination of movement, affective, and cognitive disorders. 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 affective function too.

Circuits and Neurotransmitters in the Basal Ganglia

The basal ganglia include the striatum (caudate, putamen, and nucleus accumbens), the subthalamic nucleus (STN), the globus pallidus (internal segment (GPi), external segment (GPe), and ventral pallidum (VP)), and the substantia nigra (pars compacta (SNpc) and pars reticulata (SNpr)) (Figure 1.1). The striatum and STN receive the majority of their 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 GPi, VP, and SNpr. These outputs are inhibitory to the pedunculopontine area in the brainstem and to thalamic nuclei that in turn project to frontal lobe.

Figure 1.1 Simplified schematic diagram of basal ganglia-thalamocortical circuitry. Excitatory connections are indicated by open arrows and inhibitory connections by filled arrows. The modulatory dopamine projection is indicated by a three-headed arrow. 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.

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 striatum (nucleus accumbens and rostroventral extensions of caudate and putamen) receives inputs 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 topographic 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 divergently to multiple striatal zones.⁸,⁹ Thus, there is a multiple convergent and divergent organization 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.

Cell types in the Basal Ganglia

Medium spiny striatal neurons make up 90–95% of the striatal neuron population. They project outside of the striatum and receive a number of inputs in addition to the important 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 2–4% of the striatal neuron population, but they exert powerful inhibition on medium spiny neurons. Like medium spiny neurons, they receive excitatory inputs 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 function of these neurons have been linked to the pathobiology of involuntary movements.¹¹–¹³

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.¹⁴ The action of dopamine on striatal neurons depends on the type of dopamine receptor involved. Five types of G protein-coupled dopamine receptors have been described (D1 … D5).¹⁵ 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 neurons and at D2 receptors to inhibit postsynaptic neurons.¹⁶ Indeed, this is a fundamental concept for currently popular models of basal ganglia pathophysiology.¹⁷,¹⁸ However, the physiologic effect of dopamine on striatal neurons is more complex. While activation of dopamine D1 receptors potentiates the effect of cortical input to striatal neurons in some states, it reduces the efficacy of cortical input in others.¹⁹ Activation of D2 receptors more consistently decreases the effect of cortical input to striatal neuron.²⁰ 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 specific discharge patterns. LTP and LTD are thought to be fundamental to many neural mechanisms of learning and may underlie the hypothesized role of the basal ganglia in habit learning.²¹ SNpc dopamine neurons fire in relation to behaviorally significant events and reward.²² 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,²³ supporting a role for the basal ganglia in certain types of procedural learning.

GABA

Medium spiny striatal neurons contain the inhibitory neurotransmitter GABA and co-localized peptide neurotransmitters.²⁴,²⁵ Based on the type of neurotransmitters and the predominant 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 expresses D2 dopamine receptors. These neurons project to the external segment of the globus pallidus (GPe).¹⁷

Acetylcholine

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 regions within more heavily stained regions.²⁶ The AChE-poor patches have been called striosomes 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 matrisomes. 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.²⁷ Immunohistochemical techniques have demonstrated that many substances such as substance 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. The clinical significance of this organization is not well understood.

Subthalamic Nucleus (STN)

The STN receives an excitatory, glutamatergic input from many areas of frontal lobes with especially large inputs from motor areas of cortex.²⁸ The STN also receives an inhibitory GABA 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 STN²⁹ and a relative topographic separation of motor and cognitive inputs to STN.

Output Nuclei: Globus Pallidus Interna (GPi) and Substantia Nigra pars reticulata (SNpr)

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.³⁰ 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 region of the pedunculopontine nucleus.³¹ Other output neurons (20%) project to intralaminar nuclei of the thalamus, to the lateral habenula, or to the superior colliculus.³²

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.³³ Thus, GPi neurons that project via thalamus 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 thalamus to orbitofrontal cortex. The anatomic segregation of basal ganglia-thalamocortical outputs suggests functional segregation at the output level, but other anatomic evidence suggests interactions between circuits within the basal ganglia.⁵,³⁴

Globus Pallidus externa (GPe)

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.¹⁷ 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 indirect striatopallidal pathway to GPi³⁵ (Figure 1.1). In addition, there is a monosynaptic GABAergic inhibitory output from GPe directly to GPi and to SNpr and a GABAergic projection back to striatum.³⁶ Thus, GPe neurons are in a position to provide feedback inhibition 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.

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,³⁴ but with overlap. 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 primary 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 (Figure 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 inhibitory. Third, the excitatory route through STN is faster than the inhibitory route through striatum.³⁷ Finally, the STN projection to GPi is divergent and the striatal projection is more focused.³⁸ 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. This organization provides an anatomical basis for focused inhibition and surround excitation of neurons in GPi and SNpr (Figure 1.3). Because the output of GPi and SNpr is inhibitory, this results in focused facilitation and surround inhibition of basal ganglia-thalamocortical targets. The tonically active inhibitory output of the basal ganglia acts as a brake on motor pattern generators (MPGs) in the cerebral 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 movements are prevented from interfering with the desired one.²⁸,³⁹

Figure 1.2 (A) Schematic diagram of the hyperdirect cortico-subthalamo-pallidal, direct cortico-striatopallidal, and indirect cortico-striato-GPe-subthalamo-GPi pathways. White and black arrows represent excitatory glutamatergic (glu) and inhibitory GABAergic (GABA) projections, respectively. GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; Str, striatum; Th, thalamus. (B) A schematic diagram explaining the activity change over time (t) in the thalamocortical projection (Th/Cx) following the sequential inputs through the hyperdirect cortico-subthalamo-pallidal (middle) and direct cortico-striatopallidal (bottom) pathways. Modified from Ref. [37].

Figure 1.3 Schematic of normal functional organization of the basal ganglia output. Excitatory projections are indicated with open arrows; inhibitory projections are indicated with filled arrows. Relative magnitude of activity is represented by line thickness. Modified from Ref. [40].

Implications for Disease: Focal Lesions and Abnormal Movements

This scheme provides a framework for understanding both the pathophysiology of Parkinsonism²⁸,⁴¹ and involuntary movement.²⁸,³⁹ Different involuntary movements such as Parkinsonism, chorea, dystonia, or tics result from different abnormalities in the basal ganglia circuits. Loss of dopamine input to the striatum results in a loss of normal pauses of GPi discharge during voluntary movement. Hence, there is excessive inhibition of MPGs and ultimately bradykinesia.⁴¹ Furthermore, loss of dopamine results in abnormal synchrony of GPi neuronal discharge and loss of the normal spatial and temporal focus of GPi activity.⁴¹–⁴³ Broad lesions of GPi or SNpr disinhibit both desired and unwanted motor patterns leading to inappropriate activation of competing motor patterns, but normal generation of the wanted movement. Thus, lesions of GPi cause cocontraction of multiple muscle groups and difficulty turning off unwanted motor patterns, similar to what is seen in dystonia, but do not affect movement initiation.⁴⁴ Lesions of SNpr cause unwanted saccadic eye movements that interfere with the ability to maintain visual fixation, but do not impair the initiation of voluntary saccades.⁴⁵ Lesions of putamen may cause dystonia due to the loss of focused inhibition in GPi.³⁹ Lesions of STN produce continuous involuntary movements of the contralateral limbs (hemiballism or hemichorea).³⁹ Despite the involuntary movements, voluntary movements can still be performed. Although structural lesions of putamen, GPi, SNpr, or STN produce certain types of unwanted movements or behaviors, they do not produce tics. Tics are more likely to arise from abnormal activity patterns in the striatum.¹²,³⁹

Although the focus of this discussion of basal ganglia circuits has been on motor control and movement disorders, it is likely that the fundamental principles of function in the somatomotor, oculomotor, limbic, and cognitive basal ganglia circuits are similar. If the basic scheme of facilitation and inhibition of competing movements is extended to encompass more complex behaviors and thoughts, many features of basal ganglia disorders can be explained as a failure to facilitate wanted behaviors and simultaneously inhibit unwanted behaviors due to abnormal basal ganglia output patterns. Indeed, many movement ­disorders are accompanied by cognitive and affective symptoms.⁴⁶–⁴⁸

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Chapter 2

Cerebellar Anatomy, Biochemistry, Physiology, and Plasticity

Harvey S. Singer¹, Jonathan W. Mink², Donald L. Gilbert³ and Joseph Jankovic⁴,    ¹Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, USA,    ²Division of Child Neurology, University of Rochester Medical Center, Rochester, NY, USA,    ³Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA,    ⁴Department of Neurology, Baylor College of Medicine, Houston, TX, USA

Abstract

This chapter discusses the anatomy of the cerebellum, from its gross architecture to its synapses. This chapter provides a basis for understanding the role of cerebellum in development and maintenance of motor control in the healthy, developing child. It also provides context for understanding the symptoms and signs of the large number of congenital structural, genetic, and acquired diseases of the cerebellum that affect children. The objective is to aid clinicians in making decisions about a diagnostic assessment, particularly in cases where the initial clinical presentation and neuroimaging findings are nonspecific. Concepts related to disease-related and potentially modifiable neural transmission and neuroplasticity are also reviewed.

Keywords

Cerebellum; vermis; vestibular system; proprioception; Purkinje cells; deep cerebellar nuclei; motor control; motor development; eye movements; cerebellar plasticity

Outline

Introduction 14

Overview of Cerebellar Structure, Function, and Symptoms 14

Macroscopic to Microscopic Cerebellar Structure 15

Cerebellar Structural Threes 15

The Three Anatomic Regions—Structures and Afferent Connections 15

The Three Cerebellar Functional Regions Connect to Three Deep Cerebellar Nuclei 15

The Three Cerebellar Peduncles 16

Types of Afferent Fibers 19

The Three Layers of Cerebellar Cortex 20

Neurotransmitters in the Cerebellum 21

Glutamate 21

Glutamate Transporters 22

Gamma-Aminobutyric Acid 22

Acetylcholine, Dopamine, Norepinephrine, and Serotonin 22

Endocannabinoids 22

Neuroplasticity in the Cerebellum 23

Cerebellar Stimulation 23

Conclusion 24

References 24

Introduction

The objective of this chapter is to provide an overview of the basic anatomic and functional organization of the cerebellum and its inflow and outflow pathways. Structures, pathways, circuits, and receptor systems are emphasized with regard to their relevance to diagnosis and management in children. This information provides a context for understanding the development of motor control in healthy children as well as the failure to develop it, or loss of it, in conditions such as the ataxias. Topics of anatomy of more limited relevance to children, such as the circulatory system, are omitted.

A number of challenges make diagnosis of cerebellar disorders and diseases more difficult in pediatrics. First, in children, symptoms of cerebellar dysfunction emerge in the context of a developing motor system. The child is developing motor control of eye movements, muscles of speech, axial truncal muscles, and distal muscles. Clinical experience with the range of trajectories of typical development in healthy children is often vital for detecting pathology. Second, movement disorders in children are usually mixed. For example, diseases named for their ataxia may have prominent dystonia, and complicated spastic paraplegias may involve cerebellum and basal ganglia. Third, in the presence of epilepsy, cognitive dysfunction, or behavior problems, medications may be prescribed that ­precipitate, exacerbate, or cause cerebellar dysfunction. These issues are addressed more specifically in the chapters on the relevant disease phenomenologies.

This chapter provides a clinically relevant overview. For more comprehensive descriptions, readers are referred to a number of excellent reviews.¹–⁷

Overview of Cerebellar Structure, Function, and Symptoms

Our present understanding of cerebellar function and disease has evolved over the last 100 years through painstaking clinical and pathologic observation and gross ablational studies in animals.⁸,⁹ More recently, insights from imaging studies¹⁰ have been augmented through experiments utilizing virus transneuronal tracers to identify cerebellar projections and loops to motor and nonmotor cerebral and basal ganglia nodes.⁴ Understanding the roles of specific cell types, synapses, and calcium, flux in motor control and neuroplasticity has expanded due to electrophysiological recording and targeted mutations in transgenic mice.²,³ Increasingly, it has become possible to test and validate some of these relationships noninvasively in healthy (primarily adult) humans stimulating cerebellum using transcranial magnetic stimulation (TMS; single pulse, paired pulse, or repetitive) and transcranial direct current stimulation (tDCS; anodal or cathodal).¹¹ Collectively, these techniques will continue to advance our understanding of motor and nonmotor functions of the cerebellum and improve our therapeutics for diseases of the cerebellum.

Of particular recent interest is testing of models to understand the basic operations by which the cerebellum integrates sensory information to produce adaptive, controlled movements. Models account for the necessary time interval between motor activities and the sensory feedback of those motor activities and posit a need to estimate future motor positions in order to perform fast and accurate movements. Trial and error in motor learning may involve climbing fiber inputs carrying error signals to specific Purkinje neurons. Motor learning may also generate internal models in the cerebellum which would allow for subsequent movements to be assembled and performed without conscious control of specific movement of elements.⁷

Macroscopic to Microscopic Cerebellar Structure

The cerebellum contains more than half of all neurons in the central nervous system.¹² Its organization is hierarchic and has been considered to be highly regular. Some recent evidence has emerged that the mammalian cerebellar cortex’s cytoarchitecture contains microcircuits with differing properties, underlying functional variations in information processing.¹³ This section presents a simplified, hierarchical model of cerebellar anatomy, circuits, and neurotransmission as a basis for understanding the cerebellum’s role in development of motor and behavioral control as well as symptoms of and treatments for cerebellar diseases.

Cerebellar Structural Threes

Heuristically, three is a helpful mnemonic for remembering cerebellar anatomy. The cerebellum has three major anatomic components that may be affected by focal pathologic processes; three major functional regions that correspond moderately to these components and subserve somewhat distinct functions; three sets of paired peduncles that carry information into and out of the cerebellum via the pons; three cortical cell layers that interconnect via predominantly glutamatergic and GABAergic signals; and three deep cerebellar output nuclei that transmit cerebellar signal out to the cerebrum.

The Three Anatomic Regions—Structures and Afferent Connections

The cerebellum has surface gray matter, medullary white matter, and deep gray matter nuclei. Analogous to cerebral gyri and sulci, folia make up the surface of the cerebellum. Beneath the folia, the myelin develops during childhood and is susceptible to a wide variety of diseases affecting white matter. Innermost are the deep cerebellar nuclei.

The clefts between folia run transversely, demarcating the three main anatomic regions, the flocculonodular, anterior, and posterior lobes, as shown in Figure 2.1 and described in Table 2.1.

Figure 2.1 Schematic of the three lobes of the cerebellum (anterior, posterior, and flocculonodular) and three anatomic regions (hemispheres, vermis, and nodulus). From Ref. [14].

Table 2.1

Lobes and Pathways in the Cerebellum

The Three Cerebellar Functional Regions Connect to Three Deep Cerebellar Nuclei

At a gross structural level, it can be helpful to think about the motor control and signs of cerebellar disease in terms of the three functional divisions of the cerebellum: (1) the vestibulocerebellum, in the flocculonodular lobe, involved in axial control and balance and ­positional reflexes; (2) the spinocerebellum, in the vermis and medial portion of the cerebellar hemispheres, involved in ongoing maintenance of tone, execution, and control of axial and proximal (vermis) and distal movements; and (3) the cerebrocerebellum, in the lateral part of the hemisphere, involved in initiation, motor planning, and timing of coordinated movements. Functional anatomy of the cerebellum and associated, localizing signs of cerebellar diseases are presented in Table 2.2.

Table 2.2

Functional Anatomy of the Cerebellum

The vestibulocerebellum, spinocerebellum, and cerebrocerebellum subserve basic functions of execution and integration of information about balance, body position and movement, and motor planning and timing. Output from these regions goes to the deep cerebellar nuclei.

The deep cerebellar nuclei, arranged medially to laterally, are the fastigial, interposed, and dentate nuclei. The interposed nucleus consists of the globose (medial) and emboliform (lateral) nuclei. Anatomy, output nuclei, and function of these regions are described in Table 2.3.

Table 2.3

Summary of Cerebellar Structure and Function

The Three Cerebellar Peduncles

Three paired sets of peduncles carry fibers to and from the cerebellum. The cerebellum has a direct connection to the spinal cord. Cerebellar connections with the spinal cord and body (spinocerebellar) are ipsilateral. Cerebellar connections with the cerebrum (cerebrocerebellar, via dentate-rubral-thalamic tract) are contralateral. That is, motor control of the right side of the body is controlled by the left cerebrum with the right cerebellum. Motor control of the left side of the body is controlled by the right cerebrum with the left cerebellum. Connections from the cerebrum to the cerebellum, via pons, therefore cross on entry and exit, whereas ascending connections from the spinal cord largely do not. Figure 2.2 shows a schema of the key pathways through the peduncles, and additional detail is provided in Table 2.4.

Figure 2.2 Schematic of the three primary afferent (inferior peduncles and middle peduncles) and efferent (superior peduncles) pathways of the cerebellum. See Table 2.4. From lectures by Dr. T. Thach (deceased); used with permission from the Washington University School of Medicine Neuroscience Tutorial. Basal ganglia and cerebellum. Copyright 1997.¹⁵

Table 2.4

Cerebellar Peduncles, Fiber Bundles, and Deep Cerebellar Nuclei Targets

Types of Afferent Fibers

There are two distinct types of afferent fibers that carry excitatory signals, predominantly via the inferior and middle peduncles, into the cerebellum. These are the mossy and climbing fibers, as shown in Table 2.5. Single mossy fibers project to multiple branches in multiple folia where they synapse at tens of granule cells. Climbing fibers ascend from the inferior olive to provide excitatory input at Purkinje cells. In immature cerebellum, multiple climbing fibers innervate individual Purkinje cells. These connections are pruned during development so that ultimately one climbing fiber innervates a single Purkinje cell.¹⁶ Both of these fiber types send a few collateral axons to the deep cerebellar nuclei.

Table 2.5

Functional Anatomy of Mossy and Climbing Fibers

The Three Layers of Cerebellar Cortex

Three layers make up the cerebellar cortex.¹⁷ A schema of the predominant cells and their interactions is shown in Figure 2.3, and additional detail about these layers and their predominant cell types and functional connections are shown in Table 2.6.

Figure 2.3 Schematic of the three primary cell layers (granular, molecular, and Purkinje) of the cerebellum. From Ref. [18].

Table 2.6

Cerebellar Layers, Cell Types, and Function

Neurotransmitters in the Cerebellum

Understanding the neurotransmitter systems provides a basis for identifying potentially beneficial pharmacological symptomatic interventions for diseases affecting the cerebellum.

Glutamate

Glutamate, the main excitatory neurotransmitter in the brain, acts at both ionotropic and metabotropic receptors. The ionotropic glutamate receptors are a diverse group classified into three types—AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), NMDA (N-methyl-D-aspartic acid), and kainate. These are ligand-gated ion channels, meaning that when glutamate binds, charged ions pass through a channel in the receptor center. Both basket and stellate cells in the molecular layer express presynaptic AMPA receptors, to which overflowing glutamate from the climbing fibers can bind.²²

The metabotropic glutamate receptors, which are G-protein–coupled receptors acting via second messengers, are expressed in a developmentally dependent fashion in the cerebellum,²³ with mGluR1 receptors playing a significant role in postsynaptic, dendritic calcium flux and Purkinje cell signaling.⁵ Metabotropic glutamate receptors also mediate plasticity at the mossy fiber/granule cell/Golgi cell glomerulus (junction).² Developmentally, these processes are vital for short- and long-term plasticity underlying learning motor control. Pathophysiologically, this is relevant in paraneoplastic and autoimmune cerebellar diseases.²⁴ For example, mGluR1 antibodies, which can occur in Hodgkin’s disease, cause a combination of acute, chronic/plastic, and degenerative effects in Purkinje cells.²⁵ In NMDA receptor encephalitis, in vitro methods showed that antibodies in patients’ cerebrospinal fluid (CSF) bind to NMDA receptors in cerebellar granule cells and suppress calcium influx.²⁶

Glutamate Transporters

Glutamate transporters are important for glutamatergic neurotransmission, as well as excitatory neuropathology. Excitatory amino acid transporters (EAAT) 1, 2, and 3 are expressed in the motor cortex, but EAAT1 predominates in the cerebellum,²⁷ where it is expressed in Bergmann glial cell processes and is also known as the glutamate aspartate transporter. This plays an important role in glutamate reuptake shortly after synaptic release. EAAT4 is found on extrasynaptic regions of Purkinje cell dendrites and reduces spillover of glutamate to adjacent synapses.²⁸ Co-localization of these transporters with perisynaptic mGluR1 receptors results in competition for glutamate, and this interaction modulates neuroplasticity in the cerebellum.²⁹,³⁰

Gamma-Aminobutyric Acid

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the cerebellum, as well as the cerebrum. Its synthesis from glutamate is catalyzed by the enzyme glutamic acid decarboxylase (GAD). Anti-GAD antibodies have been reported in adults with ataxia.³¹ GABA acts via chloride channels to hyperpolarize neurons. GABA receptors include GABA-A and GABA-C receptors, which are ionotropic, and GABA-B receptors, which are metabotropic, G-protein–coupled receptors. GABA-A receptors also have allosteric binding sites for other compounds including barbiturates, ethanol, neurosteroids, and picrotoxin. Baclofen is a GABA-B agonist.

GABA-A receptors are found in the granule cell layer,³² where they receive GABA input from the Golgi cells, as well as molecular layer interneurons, the basket and stellate cells.³³ GABA-B receptors are predominantly in the molecular layer.³⁴ Ethanol affects cerebellar function via GABA-A receptor binding, but may also suppress responses in Purkinje cells to mGluR1 excitation from climbing fibers.³⁵

Acetylcholine, Dopamine, Norepinephrine, and Serotonin

Acetylcholine, dopamine, norepinephrine, and serotonin²¹ and their receptors occur in the cerebellum. However, the clinical effects of these neurotransmitter systems in the cerebellum are poorly understood and at this time seem not to be very helpful for ataxia. In general, the medications involving these neurotransmitter systems, when prescribed to improve mood, motor function, or cognition, do not improve or worsen ataxia. Recognition, in mixed movement disorders, of the cerebellar ataxia component can help with realistic assessment of the probable benefits of pharmacologic interventions. For example, in mixed dystonia and ataxia, the dystonia may respond to anticholinergics but cerebellar symptoms will not.

Endocannabinoids

The potential role of the endocannabinoid (endogenous cannabinoid) system and exogenous administration of various cannabinoids has been of interest for 25 years.³⁶–³⁸ This system is involved in the so-called retrograde signaling in the hippocampus, basal ganglia, and cerebellum. In cerebellum, strong depolarization of Purkinje cells triggering Ca²+ influx or activation of metabotropic glutamate receptors (mGluR1) evokes dendritic release of endocannabinoids. These endocannabinoids bind to cannabinoid receptor 1 (CB1R) on the ­presynaptic terminal, resulting in a transient suppression of presynaptic neurotransmitter excitatory and inhibitory synaptic activity, a form of short-term neuroplasticity.²,⁵ GABAergic basket and stellate cells, in the molecular layer, regulate presynaptic neurotransmission from excitatory parallel fibers from the granule cells. The significance of pathology within this system in children is currently unknown, although both active marijuana use and the exposure to cannabis prenatally may have adverse cognitive effects involving the cerebellum.³⁹–⁴¹

Neuroplasticity in the Cerebellum

Multiple forms of cerebellar plasticity have been identified and characterized in increasing physiological and molecular detail.² A fundamental form of plasticity in cerebellum is long-term depression (LTD) in Purkinje cells. The genesis of this involves repeated paired associated stimulation into Purkinje cells from one afferent climbing fiber plus multiple parallel fibers from granule cells. Through repeated motor performance (practice), differential induction of LTD downgrades synaptic connections associated with errors.⁴²

More recently, multiple, coordinated forms of plasticity in cerebellar cortex and deep cerebellar nuclei have been identified and circuit-tested through combining physiological recording, targeted mutations, and vestibular system and other behavioral testing.² In addition to synaptic plasticity, there is intrinsic plasticity, involving neuronal spike- or synaptic activity-induced changes in ion channel expression in the neuron membrane.⁴³ Presynaptic, short-term plasticity at the parallel fiber to Purkinje cell synapse may fine-tune memory formation.⁴⁴,⁴⁵ Bidirectional plasticity, i.e., both LTD and LTP, occurs in Purkinje cells guided by input from climbing fibers⁴⁶ and at the mossy fiber/granule cell synapse.⁴⁷

The various forms of presynaptic and postsynaptic LTP and LTD may operate synergistically to create diverse and redundant systems for learning and storing for decades a vast array of procedural memories in cerebellar cortex.

Cerebellar Stimulation

TMS and tDCS are forms of noninvasive stimulation that can be used to probe cerebellar projections to cerebrum. Most research to date has used this method to externally excite or inhibit cerebellar cortex and evaluate readouts in motor cortex or motor behaviors. The basic idea is one of quantifying cerebellar to cerebral inhibition. Cerebellar cortical output via Purkinje cells inhibits dentate/deep cerebellar nuclei which in turn send excitatory projections to thalamus and again to cortex. The extent to which these phenomena occur depends on the integrity of the pathways. So, e.g., a disease causing degeneration of Purkinje cells would reduce cerebellar to cerebral inhibition.

Noninvasive brain stimulation with TMS can be used in simple experimental paradigms to evaluate these pathways. The most basic protocol involves single pulse stimulation of motor cortex and paired pulse stimulation of cerebellum and motor cortex. The single pulses over motor cortex quantify baseline excitability by generating a motor-evoked potential, measured using surface electromyography (EMG) in an intrinsic muscle in contralateral hand. The paired pulses involve a conditioning, initial pulse over cerebellum followed by the pulse over motor cortex. If the cerebellar conditioning stimulation pulse precedes the test motor cortex stimulation by 5–7 ms, the motor cortex is less excited (due to Purkinje, dentate, thalamus, cortex output). Then the pulse over the motor cortex generates a smaller evoked potential, ­reflecting the evoked cerebellar inhibitory capacity.⁴⁸

These same input/output relationships can be evaluated using neuromodulatory noninvasive brain stimulation. Repetitive TMS (rTMS) or tDCS protocols which activate cells on the surface of the cerebellum should therefore have inhibitory downstream effects in cerebrum. rTMS or tDCS protocols which inhibit cells on the surface of the cerebellum should disinhibit this pathway to cerebrum, thereby increasing cortical excitation. Various rTMS and prolonged sessions of tDCS over cerebellum have stimulatory or inhibitory effects that outlast the stimulation period.¹¹ These effects have been demonstrated with single and paired pulse motor cortex stimulation and are under investigation as biomarkers of cerebellar plasticity. Of additional interest is their potential as therapies, as preliminary investigations suggest specific stimulation protocols may modify locomotor adaptation,⁴⁹ improve verbal working memory,⁵⁰ improve tremor,⁵¹ and alter behavioral function in other ways.¹¹

Conclusion

This overview of cerebellar function provides a framework for understanding cerebellar disorders and diseases and current and future treatments.

References

1. Strick PL, Dum RP, Fiez JA. Cerebellum and nonmotor function. Annu Rev Neurosci. 2009;32:413–434.

2. Gao Z, van Beugen BJ, De Zeeuw CI. Distributed synergistic plasticity and cerebellar learning. Nat Rev Neurosci. 2012;13(9):619–635.

3. Lamont MG, Weber JT. The role of calcium in synaptic plasticity and motor learning in the cerebellar cortex. Neurosci Biobehav Rev. 2012;36(4):1153–1162.

4. Bostan AC, Dum RP, Strick PL. Cerebellar networks with the cerebral cortex and basal