Movement Disorders in Childhood

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

Movement Disorders in Childhood, Third Edition provides the most up-to-date information on the diseases and disorders that affect motor control, an important area of specialization within child neurology. In this new edition, each chapter has been fully revised to include all of the latest scientific and therapeutic advances. Updates include new insights in motor development, control, goal-directed and habitual behaviors, classifications of movements and their complex and integrated circuitry. The authors also discuss developments in pathophysiologic mechanisms, immunology and metabolic disorders. New chapters include coverage of genetics of movement disorders and movement disorders in psychiatric conditions.Appendices include an updated and revised drug index and genetic search strategy.

An updated Companion website hosts selected educational videos to help diagnose movement disorders.

• Provides the only current reference specifically focused on childhood movement disorders
• Investigates the underlying etiologies and mechanisms of these disorders
• Revised and updated with new materials and a more disease-oriented approach
• Contains new chapters on the genetics of movement disorders and movement disorders in psychiatric conditions
• Includes new videos of instructive and unusual childhood movement disorders

• Language: English
• Publisher: Academic Press
• Release date: Jul 12, 2022
• ISBN: 9780323900072

Harvey S. Singer

Harvey S. Singer MD is currently Professor Emeritus at the Johns Hopkins University School of Medicine and active faculty member at the Kennedy Krieger Institute. He grew up in the Bronx and Long Island, went to college and medical school in Ohio (Oberlin College and Western Reserve Univ.), did his pediatric training in Chicago and Cleveland, and his pediatric neurology residency at the Johns Hopkins Hospital. After completing his training, Dr Singer remained on the active faculty at Hopkins for 45 years. He was Director of Pediatric Neurology from 1991 – 2011. He was the first recipient (2013) of the Child Neurology Society’s Blue Bird Circle Training Program Director Award and a Hower Award lecturer (2016). His clinical research interests include movement disorders, especially Tourette syndrome, stereotypic movements, and proposed autoimmune disorders. His translational research-oriented laboratory focuses on the neurobiology of stereotypic movements and tics. He has been the recipient of federal and private grants, authored numerous original articles, chapters, and three books. He enjoys biking, travel, visiting his five grandchildren, and work.

Book preview

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

Table of Contents

Cover image

Title page

Companion Website

Copyright

Preface

Section I. Overview

Chapter 1. Basal Ganglia Anatomy, Biochemistry, and Physiology

Introduction

Basal Ganglia Circuits, Cell Types, and Compartments

Neurotransmitters

Other Basal Ganglia Nuclei

Inhibiting and Disinhibiting Motor Patterns

Implications for Disease: Focal Lesions and Abnormal Movements

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

Introduction and Overview

Overview of Cerebellar Structure, Function, and Symptom Localization

Cerebellar Integration with Basal Ganglia Circuits

Neurotransmitters in the Cerebellum

Neuroplasticity in the Cerebellum

Conclusion

Chapter 3. Classification of Movement Disorders

Introduction

Ataxia (Chapter 14)

Athetosis (Chapter 10)

Ballismus (Chapter 10)

Chorea (Chapter 10)

Dystonia (Chapter 11)

Myoclonus (Chapter 12)

Parkinsonism (Chapter 15)

Startle (Chapter 12)

Stereotypies (Chapter 8)

Tics (Chapter 7)

Tremor (Chapter 13)

Mixed Movement Disorders

Atypical Movement Disorders

Chapter 4. Diagnostic Evaluation of Children With Movement Disorders

Introduction

Preclinic

In Clinic

The Diagnosis

Summary

Chapter 5. Motor Assessments

Introduction

Quantitative Measurement in Movement Disorders

Rating Scales for Pediatric Movement Disorders

Section II. Developmental Movement Disorders

Chapter 6. Transient and Developmental Movement Disorders

Introduction

Section III. Paroxysmal Movement Disorders

Chapter 7. Tics and Tourette Syndrome

Introduction

Definition of Tics

Clinical Characteristics—Phenomenology and Classification of Tics

Localization and Pathophysiology

Specific Tic Disorder Diagnoses

Treatment

Chapter 8. Motor Stereotypies

Introduction and Overview

Definitions

Clinical Characteristics, Classifications, and Differentiation

Pathophysiology

Major Diseases and Disorders

Stereotypy Rating Scales

Treatment

Chapter 9. Paroxysmal Dyskinesias

Introduction and Overview

Clinical Characteristics

Diseases and Disorders

Section IV. Hyperkinetic and Hypokinetic Movement Disorders

Chapter 10. Chorea, Athetosis, and Ballism

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

Chapter 11. Dystonia

Introduction and Overview

Classification of Dystonias

Localization and Pathophysiology

Diseases and Disorders

Diagnostic Approach to Dystonia

Management and Treatment

Patient and Family Resources

Chapter 12. Myoclonus

Introduction and Overview

Definition of Myoclonus

Clinical Characteristics—Phenomenology of Myoclonus in Children

Localization and Neurophysiology

Diseases and Disorders

Summary of Diagnostic and Therapeutic Approach

Chapter 13. Tremor

Introduction and Overview

Definition of Tremor

Clinical Characteristics—Phenomenology and Classification of Tremor in Children

Localization and Pathophysiology

Diseases and Disorders

Approach to Diagnosis and Management

Chapter 14. Ataxia

Introduction and Overview

Definition of Ataxia

Clinical Characteristics—Phenomenology of Ataxia in Children

Localization and Pathophysiology

Diseases and Disorders

Approach to Diagnosis and Management

Chapter 15. Parkinsonism

Introduction and Overview

Clinical Features of Parkinsonism

Pathophysiogy of Parkinsonism

Diseases and Disorders

Treatment of Parkinsonism

Chapter 16. Hereditary Spastic Paraplegia

Introduction and Overview

Definitions of Spasticity and Hypertonia

Clinical Characteristics—Phenomenology of Spastic Paraplegia in Children

Localization and Pathophysiology

Diseases and Disorders

Approach to Diagnosis and Management

Summary

Section V. Selected Secondary Movement Disorders

Chapter 17. Metabolic Disorders With Associated Movement Abnormalities

Pediatric Neurotransmitter Disorders

Storage Disorders

Leukodystrophies

Aminoacidemias

Organic Acidemias

Glycolysis, Pyruvate Metabolism, and Krebs Cycle Disorders

Mitochondrial Disorders

Purine Metabolism Disorders

Creatine Metabolism Disorders

Congenital Disorders of Glycosylation

Cofactor, Mineral, and Vitamin Disorders

Neuroacanthocytosis Syndromes

Other Metabolic Conditions

Chapter 18. Movement Disorders in Autoimmune Diseases

Introduction

Immunology Overview

Diseases and Disorders

Chapter 19. Movement Disorders in Sleep

Introduction

Overview of Sleep Physiology

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

Chapter 20. Cerebral Palsy

Introduction

Epidemiology

Etiology

Diagnosis

History and Physical Examination

Assessment Scales

Clues for Determining the Motor CP Type

Cerebral Palsy Syndromes

Management

Chapter 21. Movement Disorders and Neuropsychiatric Conditions

Introduction and Overview

Attention Deficit Hyperactivity Disorder

Obsessive Compulsive Disorder

Autism Spectrum Disorder

Conclusions

Chapter 22. Drug-Induced Movement Disorders in Children

Introduction and Overview

Definition of Drug-Induced Movement Disorders

Clinical Characteristics—Phenomenology of Drug-Induced Movement Disorders in Children

Drug-Induced Movement Disorders

Conclusion

Chapter 23. Functional Movement Disorders

Introductions

Epidemiology

Clinical Features of Functional Movement Disorders

Pathophysiology

Diagnosis

Conclusion

Appendix A. Drug Appendix

Appendix B. Search Strategy for Genetic Movement Disorders

Index

Companion Website

icon

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1650, San Diego, CA 92101, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2022 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

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 necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

ISBN: 978-0-12-820552-5

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

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

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, imaging, and clinical care continue to transform our knowledge, concepts, and approaches to patients. This new edition has integrated many of the advances in pediatric movement disorders gained over the past several years. While chapter titles may look familiar, the contents have been updated, revised, and expanded substantially. 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 experienced 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. Jankovic, a highly regarded expert academic 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 6years 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 differences between experts, all authors carefully 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 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 movement disorder.

Harvey S. Singer, MD

Jonathan W. Mink, MD, PhD

Donald L. Gilbert, MD, MS

Joseph Jankovic, MD

March 2022

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. Singer ¹ , Jonathan W. Mink ² , Donald L. Gilbert ³ , and Joseph Jankovic ⁴       ¹ Department of Neurology, Johns Hopkins Hospital and the Kennedy Krieger Institute, Baltimore, MD, United States      ² Division of Child Neurology, University of Rochester Medical Center, Rochester, NY, United States      ³ Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States      ⁴ Department of Neurology, Baylor College of Medicine, Houston, TX, United States

Abstract

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. Indeed, most diseases of the basal ganglia cause a combination of movement, affective, and cognitive disorders with the movement disorder being predominant. 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.

Keywords

Basal ganglia; Cholinergic interneurons; Dopamine; GABA; Globus pallidus; Neurotransmitters; Striatum

Introduction

Basal Ganglia Circuits, Cell Types, and Compartments

Circuits

Cell Types

Compartments

Neurotransmitters

Dopamine

GABA

Acetylcholine

Other Basal Ganglia Nuclei

Subthalamic Nucleus

Output Nuclei: Globus Pallidus Interna and Substantia Nigra Pars Reticulata

Globus Pallidus Externa

Substantia Nigra Pars Compacta

Inhibiting and Disinhibiting Motor Patterns

Implications for Disease: Focal Lesions and Abnormal Movements

References

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 predominant. 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.

Basal Ganglia Circuits, Cell Types, and Compartments

Circuits

The basal ganglia include the striatum (caudate, putamen, nucleus accumbens), the subthalamic nucleus (STN), the globus pallidus (internal segment—GPi, external segment—GPe, ventral pallidum—VP), and the substantia nigra (pars compacta—SNpc and pars reticulata—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 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 neurons ⁷ 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 multiply 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.

Figure 1.1  Simplified schematic diagram of basal ganglia—thalamo-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%–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, 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 function of these neurons have been linked to the pathobiology of involuntary movements. ¹¹–¹³

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 regions within more heavily stained regions. ¹⁴ 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. ¹⁵ 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 that may be maintained by differential influences of dopamine. ¹⁶ While preferential involvement of the striosome or matrix compartments has been suggested in some disorders, ¹⁷ the clinical significance of this organization 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 receptors 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 neurons and at D2 receptors to inhibit postsynaptic neurons. ²⁰ Indeed, this is a fundamental concept for some models of basal ganglia pathophysiology. ²¹ , ²² 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. 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 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. 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 colocalized peptide neurotransmitters. ²⁹ , ³⁰ 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). ²¹

Acetylcholine

Cholinergic interneurons densely innervate the striatum ³¹ and modulate dopamine release. ³² Additional cholinergic input into striatum comes from the pedunculopontine nucleus 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 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 STN ³⁶ 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 1mm 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 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 (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 indirect striatopallidal pathway to GPi ⁴² (Fig. 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. ⁴³ 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.

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 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 (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 inhibitory. Third, the excitatory route through STN is faster than the inhibitory route through striatum. 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 basis 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 surround 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 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. ³⁵ , ⁴⁸

Figure 1.2  Schematic diagram of the hyperdirect cortico-subthalamo-pallidal, direct cortico-striato-pallidal, 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 hyperdiect cortico-subthalamo-pallidal (middle) and direct cortico-striato-pallidal (bottom) pathways. Modified from Ref. [44].

Implications for Disease: Focal Lesions and Abnormal Movements

This scheme provides a framework for understanding both the pathophysiology of parkinsonism ³⁵ , ⁴⁹ and involuntary movement. ³⁵ , ⁴⁸ 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. ⁴⁹ Furthermore, loss of dopamine results in abnormal synchrony of GPi neuronal discharge and loss of the normal spatial and temporal focus of GPi activity. ⁴⁹–⁵¹ 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. ⁵² 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. ⁵³ Lesions of putamen may cause dystonia due to the loss of focused inhibition in GPi. ⁴⁸ Lesions of STN produce continuous involuntary movements of the contralateral limbs (hemiballism or hemichorea). ⁴⁸ 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 , ⁴⁸

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. [46].

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. ⁵⁴–⁵⁶

References

1. Baez-Mendoza R, Schultz W. The role of the striatum in social behavior.  Front Neurosci . 2013;7:233.

2. Kemp J.M, Powell T.P.S. The corticostriate projection in the monkey.  Brain . 1970;93:525–546.

3. Fudge J, Kunishio K, Walsh C, Richard D, Haber S. Amygdaloid projections to ventromedial striatal subterritories in the primate.  Neuroscience . 2002;110:257–275.

4. Cherubini E, Herrling P.L, Lanfumey L, Stanzione P. Excitatory amino acids in synaptic excitation of rat striatal neurones in vitro.  J Physiol (Lond) . 1988;400:677–690. .

5. Kelly R, Strick P.L. Macro-architecture of basal ganglia loops with the cerebral cortex: use of rabies virus to reveal multisynaptic circuits.  Prog Brain Res . 2004;143:449–459.

6. Alexander G.E, DeLong M.R, Strick P.L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex.  Annu Rev Neurosci . 1986;9:357–381.

7. Wilson C.J, Groves P.M. Fine structure and synaptic connections of the common spiny neuron of the rat neostriatum: a study employing intracellular injection of horseradish peroxidase.  J Comp Neurol . 1980;194:599–614.

8. Selemon L.D, Goldman-Rakic P.S. Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey.  J Neurosci . 1985;5:776–794.

9. Flaherty A.W, Graybiel A.M. Corticostriatal transformations in the primate somatosensory system. Projections from physiologically mapped body-part representations.  J Neurophysiol . 1991;66:1249–1263.

10. Mallet N, Le Moine C, Charpier S, Gonon F. Feedforward inhibition of projection neurons by fast-spiking GABA interneurons in the rat striatum in vivo.  J Neurosci . 2005;25:3857–3869.

11. Kataoka Y, Kalanithi P.S, Grantz H, et al. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome.  J Comp Neurol . 2010;518:277–291.

12. McCairn K.W, Bronfeld M, Belelovsky K, Bar-Gad I. The neurophysiological correlates of motor tics following focal striatal disinhibition.  Brain . 2009;132:2125–2138.

13. Gittis A.H, Leventhal D.K, Fensterheim B.A, Pettibone J.R, Berke J.D, Kreitzer A.C.Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.  J Neurosci . 2011;31:15727–15731.

14. Graybiel A.M, Aosaki T, Flaherty A.W, Kimura M. The basal ganglia and adaptive motor control.  Science . 1994;265:1826–1831.

15. Gerfen C.R. The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia.  Annu Rev Neurosci . 1992;15:285–320.

16. Prager E.M, Dorman D.B, Hobel Z.B, Malgady J.M, Blackwell K.T, Plotkin J.L.Dopamine oppositely modulates state transitions in striosome and matrix direct pathway striatal spiny neurons.  Neuron . 2020;108:1091–1102.e5.

17. Crittenden J.R, Graybiel A.M. Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments.  Front Neuroanat . 2011;5:59.

18. Bouyer J.J, Park D.H, Joh T.H, Pickel V.M. Chemical and structural analysis of the relation between cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatum.  Brain Res . 1984;302:267–275.

19. Sibley D.R, Monsma F.J. Molecular biology of dopamine receptors.  Trends Pharmacol Sci . 1992;13:61–69.

20. Gerfen C.R, Engber T.M, Mahan L.C, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons.  Science . 1990;250:1429–1432.

21. Albin R.L, Young A.B, Penney J.B. The functional anatomy of basal ganglia disorders.  Trends Neurosci . 1989;12:366–375.

22. DeLong M.R. Primate models of movement disorders of basal ganglia origin.  Trends Neurosci . 1990;13:281–285.

23. Hernandez-Lopez S, Bargas J, Surmeier D.J, Reyes A, Galarraga E. D1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca²+ conductance.  J Neurosci . 1997;17:3334–3342.

24. Nicola S, Surmeier J, Malenka R. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens.  Annu Rev Neurosci . 2000;23:185–215.

25. Jog M, Kubota Y, Connolly C, Hillegaart V, Graybiel A. Building neural representations of habits.  Science . 1999;286:1745–1749.

26. Schultz W, Romo R, Ljungberg T, Mirenowicz J, Hollerman J.R, Dickinson A. Reward-related signals carried by dopamine neurons. In: Houk J.C, Davis J.L, Beiser D.G, eds.  Models of Information Processing in the Basal Ganglia . Cambridge: MIT Press; 1995:233–249.

27. Matsumoto N, Hanakawa T, Maki S, Graybiel A.M, Kimura M. Role of nigrostriatal dopamine system in learning to perform sequential motor tasks in a predictive manner.  J Neurophysiol . 1999;82:978–998.

28. Wood A.N. New roles for dopamine in motor skill acquisition: lessons from primates, rodents, and songbirds.  LID . 2020 doi: 10.1152/jn.00648.

29. Kreitzer A.C. Physiology and pharmacology of striatal neurons.  Annu Rev Neurosci . 2009;32:127–147.

30. Penny G.R, Afsharpour S, Kitai S.T. The glutamate decarboxylase-, leucine enkephalin-, methionine enkephalin- and substance P-immunoreactive neurons in the neostriatum of the rat and cat: evidence for partial population overlap.  Neuroscience . 1986;17:1011–1045. .

31. Kawaguchi Y, Wilson C.J, Augood S.J, Emson P.C. Striatal interneurones: chemical, physiological and morphological characterization.  Trends Neurosci . 1995;18:527–535.

32. Threlfell S, Lalic T, Platt N.J, Jennings K.A, Deisseroth K, Cragg S.J. Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons.  Neuron . 2012;75:58–64.

33. Dautan D, Huerta-Ocampo I, Witten I.B, et al. A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem.  J Neurosci . 2014;34:4509–4518.

34. Bennett B.D, Callaway J.C, Wilson C.J. Intrinsic membrane properties underlying spontaneous tonic firing in neostriatal cholinergic interneurons.  J Neurosci . 2000;20:8493–8503.

35. Mink J.W. The basal ganglia: focused selection and inhibition of competing motor programs.  Progr Neurobiol . 1996;50:381–425.

36. Nambu A, Takada M, Inase M, Tokuno H. Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area.  J Neurosci . 1996;16:2671–2683.

37. Percheron G, Yelnik J, Francois C. A golgi analysis of the primate globus pallidus. III. Spatial organization of the striato-pallidal complex.  J Comp Neurol . 1984;227:214–227.

38. Parent A. Extrinsic connections of the basal ganglia.  Trends Neurosci . 1990;13:254–258.

39. Francois C, Percheron G, Yelnik J, Tande D. A topographic study of the course of nigral axons and of the distribution of pallidal axonal endings in the centre median-parafascicular complex of macaques.  Brain Res . 1988;473:181–186.

40. Hoover J.E, Strick P.L. Multiple output channels in the basal ganglia.  Science . 1993;259:819–821.

41. Haber S.N, Fudge J.L, McFarland N.R. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum.  J Neurosci . 2000;20:2369–2382.

42. Alexander G.E, Crutcher M.D. Functional architecture of basal ganglia circuits: neural substrates of parallel processing.  Trends Neurosci . 1990;13:266–271.

43. Bolam J.P, Hanley J.J, Booth P.A, Bevan M.D. Synaptic organisation of the basal ganglia.  J Anat . 2000;196:527–542.

44. Nambu A, Tokuno H, Hamada I, et al. Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the monkey.  J Neurophysiol . 2000;84:289–300.

45. Parent A, Hazrati L.-N. Anatomical aspects of information processing in primate basal ganglia.  Trends Neurosci . 1993;16:111–116.

46. Mink J.W. Basal ganglia dysfunction in Tourette's syndrome: a new hypothesis.  Pediatr Neurol . 2001;25:190–198.

47. Ozaki M, Sano H, Sato S, et al. Optogenetic activation of the sensorimotor cortex reveals local inhibitory and global excitatory inputs to the basal ganglia.  Cereb Cortex . 2017;27:5716–5726.

48. Mink J. The basal ganglia and involuntary movements: impaired inhibition of competing motor patterns.  Arch Neurol . 2003;60:1365–1368.

49. Boraud T, Bezard E, Bioulac B, Gross C.E. From single extracellular unit recording in experimental and human Parkinsonism to the development of a functional concept of the role played by the basal ganglia in motor control.  Progr Neurobiol . 2002;66:265–283.

50. Raz A, Vaadia E, Bergman H. Firing patterns and correlations of spontaneous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Vervet model of parkinsonism.  J Neurosci . 2000;20:8559–8571.

51. Tremblay L, Filion M, Bedard P.J. Responses of pallidal neurons to striatal stimulation in monkeys with MPTP-induce parkinsonism.  Brain Res . 1989;498:17–33.

52. Mink J.W, Thach W.T. Basal ganglia motor control. III. Pallidal ablation: normal reaction time, muscle cocontraction, and slow movement.  J Neurophysiol . 1991;65:330–351.

53. Hikosaka O, Wurtz R.H. Modification of saccadic eye movements by GABA-related substances. II. Effects of muscimol in monkey substantia nigra pars reticulata.  J Neurophysiol . 1985;53:292–308.

54. Asmus F, Gasser T. Dystonia-plus syndromes.  Eur J Neurol . 2010;17(Suppl 1):37–45.

55. Poletti M, De Rosa A, Bonuccelli U. Affective symptoms and cognitive functions in Parkinson's disease.  J Neurol Sci . 2012;317:97–102.

56. Ross C.A, Aylward E.H, Wild E.J, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics.  Nat Rev Neurol . 2014;10:204–216.

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

Harvey S. Singer ¹ , Jonathan W. Mink ² , Donald L. Gilbert ³ , and Joseph Jankovic ⁴       ¹ Department of Neurology, Johns Hopkins Hospital, Baltimore, MD, United States      ² Division of Child Neurology, University of Rochester Medical Center, Rochester, NY, United States      ³ Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States      ⁴ Department of Neurology, Baylor College of Medicine, Houston, TX, United States

Abstract

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 as they relate to motor function and diseases affecting motor control. Understanding structures, pathways, circuits, and receptor systems will gain increasing importance to pediatric neurologists as insights are gained into disease pathophysiology and options for treatments emerge. The information in this chapter provides a context for understanding the development of motor control in healthy children as well as the failure to develop, or loos of, normal cerebellar function in conditions such as the ataxias, cerebellar structural malformation syndromes, and acquired cerebellar injuries (see Chapter 14). Involvement of cerebellar circuits in cognition and mood is not emphasized herein. Topics of anatomy of limited relevance to children, such as the circulatory system, are not discussed.

Keywords

Ataxias; Basal ganglia; Cerebellar structural malformation syndromes; Cerebellum; Vestibular system

Introduction and Overview

Overview of Cerebellar Structure, Function, and Symptom Localization

Macroscopic to Microscopic Cerebellar Structure

Cerebellar Structural Threes

The Three Anatomic Regions—Structures and Afferent Connections

The Three Cerebellar Functional Regions Connect to Three Deep Cerebellar Nuclei

The Three Paired Cerebellar Peduncles

Types of Afferent Fibers

The Three Layers of Cerebellar Cortex and Their Cell Types

Cerebellar Integration with Basal Ganglia Circuits

Neurotransmitters in the Cerebellum

Glutamate

Gamma-Aminobutyric Acid

Acetylcholine, Dopamine, Norepinephrine, and Serotonin

Endocannabinoids

Neuroplasticity in the Cerebellum

Cerebellar Stimulation

Conclusion

References

Introduction and Overview

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 as they relate to motor function and diseases affecting motor control. Understanding structures, pathways, circuits, and receptor systems will gain increasing importance to pediatric neurologists as insights are gained into disease pathophysiology and options for treatments emerge. The information in this chapter provides a context for understanding the development of motor control in healthy children as well as the failure to develop, or loos of, normal cerebellar function in conditions such as the ataxias, cerebellar structural malformation syndromes, and acquired cerebellar injuries (see Chapter 14). Involvement of cerebellar circuits in cognition and mood is not emphasized herein. Topics of anatomy of limited relevance to children, such as the circulatory system, are not discussed.

Pediatric neurologists encounter many challenges in the diagnosis and management of cerebellar disorders. 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 discerning 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. This chapter will review some emerging information about why this occurs. 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.

The goal of this chapter is to provide a clinically relevant overview. For more comprehensive descriptions of emerging neuroscience and techniques that are producing insights, readers are referred to a number of excellent reviews and technical papers. ¹–⁵

Overview of Cerebellar Structure, Function, and Symptom Localization

This section addresses cerebellar structure, emphasizing systems important for motor control. Our present understanding of cerebellar structure and motor function has evolved over the last 100 years through painstaking clinical and pathologic observation and gross ablation and neurophysiologic studies in animals. ⁶–⁸ More recently, insights from imaging studies ⁹ have been augmented through experiments utilizing trans-neuronal virus tracers to identify cerebellar projections and loops to motor and nonmotor cerebral and basal ganglia nodes. ¹⁰ 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 rodent and primate models. ¹¹ , ¹² Combining ablation and optogenetic stimulation in animal models has allowed for a greater understanding of loss of motor control in cerebellar disease through characterizing the roles of specific cell types in deep cerebellar nuclei. ¹³ , ¹⁴

Increasingly, it has become possible to test and validate some of these relationships noninvasively in healthy (primarily adult) humans via cerebellar stimulation using transcranial magnetic stimulation (TMS; single pulse, paired pulse, or repetitive) and transcranial direct current stimulation (tDCS; anodal or cathodal). ¹⁵ , ¹⁶ Although many scientific questions remain, methods for more precise invasive stimulation of cerebellar cortex and deep cerebellar nuclei may be on the horizon as treatments for a variety of diseases affecting motor control. ¹⁷ 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.

The canonical view is that the cerebellum is an integral component of the motor system, integrating sensory input, supporting motor learning, and coordinating movements through utilization of models predicting the outcome of motor commands. Of particular recent interest is the testing of models to understand basic operations by which the cerebellum integrates sensory information to produce adaptive, controlled movements. ⁴ , ⁵ , ¹⁸ Proprioceptive, visual, and tactile information are transmitted to cerebellum via afferent pathways, providing online feedback about movements. While critical for precise motor control and learning, the inherent delay of this feedback is problematic. Therefore, for certain types of tasks, precise motor control also relies on cerebellar internal copies of motor commands, implemented as forward models for more rapid online correction based on predicted movement outcomes. ¹⁹ These models account for the necessary time interval between motor activities and the sensory feedback from these motor activities and function as an estimate of future motor positions in order to perform fast and accurate movements. Differences between predicted movement outcomes and actual movement outcomes, that is, error signals, generate calcium spikes in Purkinje cell dendrites. ²⁰ These signals, so-called complex spikes, over time induce plastic changes on upstream inputs from mossy fibers. The integration of sensory information and detected errors into updated internal models is cerebellar dependent supervised motor learning. ¹⁸ A general model of motor commands, sensory input, model implementation and adaptation is shown in Fig. 2.1.

Macroscopic to Microscopic Cerebellar Structure

The cerebellum contains more than half of all neurons in the central nervous system, with cerebellar granule cells outnumbering any other single type of neuron. ²¹ 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. ²² 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 how perturbations produce symptoms 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.

Figure 2.1  Model of cerebellar circuits for motor control, shown here for arm and hand movements. Motor commands from cerebral motor centers, integrating cerebellar code predicting motor outcomes, activate muscles. The muscle's actions in turn evoke sensory feedback into cerebellar circuits. This feedback as well as the movement's outcome is integrated into updated cerebellar models for future actions. From Ref. [5].

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 Fig. 2.2 and described in Table 2.1.

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. ²¹ Functional anatomy of the cerebellum and associated, localizing signs of cerebellar diseases is presented in Table 2.2 and Fig. 2.2.

Figure 2.2  Schematic of the three lobes of the cerebellum (anterior, posterior, and flocculonodular) and three anatomic regions (hemispheres, vermis, and nodulus). From Ref. [21].

Table 2.1

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 2.2

Table 2.3

The Three Paired 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. Ascending connections from the spinal cord largely do not. Fig. 2.3 shows a schema of the key pathways through the peduncles, and additional detail is provided in Table 2.4.

Figure 2.3  Schematic of the three primary afferent (inferior 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 1993. From Ref. [23].

Table 2.4

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 fibers 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. ²⁴ Both of these fiber types send a few collateral axons to the deep cerebellar nuclei.

The Three Layers of Cerebellar Cortex and Their Cell Types

Three layers make up the cerebellar cortex. ²⁵ A schema of the predominant cells and their interactions is shown in Fig. 2.4, and additional detail about these layers and their predominant cell types and functional connections are shown in Table 2.6.

Cerebellar Integration with Basal Ganglia Circuits

To review, motor control involves basal ganglia circuits (see Chapter 1) and cerebellar circuits. These circuits have dense interactions at multiple nodes and have overlapping cortical targets. ¹ See Fig. 2.5 for schematic model of pathways between nodes of cortical areas, basal ganglia, and cerebellar circuits.

Cerebellar motor circuit An inhibitory signal from the Purkinje cells in cerebellar cortex travels to deep cerebellar nuclei, for example, the dentate nuclei. The dentate nucleus sends an excitatory signal to thalamus which sends an excitatory signal to cerebral cortex. Cerebral cortex projects via corticofugal neurons to pontine nuclei which in turn signal cerebellar cortex via mossy fibers, completing the circuit.

Basal ganglia motor circuit (See Chapter 1 for more comprehensive discussion.) Excitatory signals from cortical neurons project to striatum. The striatum is inhibitory, projecting to globus pallidus interna (GPi) (direct pathway) or first to globus pallidus externa (GPe) followed by subthalamic nucleus, then GPi (indirect pathway). GPi projections to thalamus are inhibitory. The thalamic projection back to cortex is excitatory. This completes the circuit.

Table 2.5

Figure 2.4  Schema of the three primary cell layers: molecular (outermost), Purkinje, granular (innermost) of the cerebellum. Note climbing fibers from the inferior olive and mossy fibers from brainstem nuclei and their synaptic connections. From Ref. [26].

Figure 2.5  Simplified model showing primary connections between structural nodes of the motor control network. Solid arrows are excitatory, dashed arrows are inhibitory. DCN, deep cerebellar nuclei; GPe/i, globus pallidus externa/interna; STN, subthalamic nucleus. Adapted from Ref. [31].

Table 2.6

Cerebellum to basal ganglia The dentate nucleus projects to ventral thalamus, which, in turn, projects to the sensorimotor regions of the putamen. These putamenal neurons may predominantly project to GPe and not the GPi. Thus, cerebellar output may modulate signals in the indirect pathway. ¹ Cerebellar output via thalamus also influences motor cortex, which projects densely to sensorimotor regions of the putamen.

Basal ganglia to cerebellum The motor and nonmotor regions of the subthalamic nucleus send topographically organized projections to pontine nuclei which in turn project to cerebellar cortex. Animal studies of subthalamic nucleus DBS show that stimulation reduces STN firing, and that this concurrently reduces firing in cerebellar Purkinje cells, which in turn disinhibits/increases the firing rate of deep cerebellar nuclei.

Integrated cerebellar and basal ganglia signaling, motor control, and motor learning Basal ganglia circuits receive reward-related dopaminergic input from the ventral tegmental area. This circuit plays a critical role in reward-based learning, guided by in part by reward reinforcement. Cerebellar circuits receive sensory input, including online feedback from movement (See Fig. 2.1). This allows motor adaptation and learning to occur. Efficient motor performance and learning may result from integration of cerebellar and basal ganglia circuits, linking critical sensorimotor adaptation to reinforcement. ¹ , ¹⁸ , ³² One mechanism whereby this integration may occur is through excitatory glutamatergic output from deep cerebellar nuclei to the ventral tegmental area. Optogenetic stimulation of this pathway has been shown to be as rewarding as direct optogenetic stimulation of dopaminergic neurons in the ventral tegmental area, supporting that cerebellar circuits modulate reward driven behaviors important for learning and suggesting that cerebellar circuits may also receive information about reward likelihood. ³³

Diseases localizing to cerebellum may impair function in basal ganglia. In addition to ataxia and kinetic tremor (see Chapter 14), cerebellum has been implicated in many other movement disorders including essential tremor (see Chapter 13), dystonia (see Chapter 11), chorea (see Chapter 10), and parkinsonism (see Chapter 15).

Neurotransmitters in the Cerebellum

Understanding the neurotransmitter systems provides a basis for identifying potentially beneficial pharmacological symptomatic interventions for diseases affecting the cerebellum. Input into the cerebellum via mossy and climbing fibers (Table 2.5, Figs. 2.3 and 2.4) is excitatory/glutamatergic. While glutamatergic signaling from a climbing fiber to a Purkinje cell is direct, mossy fiber input is transmitted to granule cells which form parallel fibers in the outer, molecular layer, which then have glutamatergic synapses with Purkinje cells. Output from Purkinje cells to deep cerebellar nuclei is inhibitory/GABAergic. Thus, understanding the roles of glutamate in gamma-aminobutyric acid (GABA) in cerebellum is critical for understanding healthy cerebellar function and cerebellar disease.

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 overflow glutamate from climbing fibers can bind. ³⁴ Glutamate release from climbing fibers and from parallel fibers at synapses with Purkinje cells results in activation of postsynaptic AMPA, mediating fast synaptic transmission, prior to its rapid reuptake.

The metabotropic glutamate receptors, which are G-protein–coupled receptors acting via second messengers, are expressed in a developmentally dependent fashion in the cerebellum. ³⁵ These receptors are expressed at perisynaptic sites. Glutamate reaches these receptors when repetitive presynaptic firing releases glutamate that exceeds the binding capacity of AMPA receptors and reuptake capacity of glutamate transporters. In this case, glutamate binds mGluR1 receptors, which then mediates several downstream, postsynaptic processes via the G protein second messenger system, including calcium flux and protein kinase C activation. These processes then induce plastic changes at the parallel fiber/Purkinje cell synapse. ²⁰ , ³⁶ Metabotropic glutamate receptors also mediate plasticity at the mossy fiber/granule cell/Golgi cell glomerulus (junction). ¹² Developmentally, these processes are vital for developmental pruning and short- and long-term plasticity underlying learning motor control. Pathophysiologically, genetic diseases that affect transcription or function of these receptors and proteins can cause both impaired motor function and neuronal degeneration, as can autoimmune diseases that disrupt these receptors and transporters. ³⁶ , ³⁷

Glutamate transporters remove glutamate from the synapse, a key process for both modulating neuroplasticity and preventing neurotoxicity. Most removal is done by glial transporters, for example, the GLAST glial glutamate transporters on Bergmann glial cells. The cerebellum also has neuronal transporters excitatory amino acid transporter 4 (EAAT4) and excitatory amino acid carrier 1 (EAAC1). Excitatory amino acid transporter 4 (EAAT4) is found on extrasynaptic regions of Purkinje cell dendrites and reduces spillover of glutamate to adjacent synapses ³⁸ as well as modulating the availability of glutamate to bind at mGluR1. ³⁶ Colocalization of these transporters with receptors results in competition for glutamate, and this interaction modulates neuroplasticity in the cerebellum. ³⁶ , ³⁹ , ⁴⁰

Projections out of the cerebellum from deep cerebellar nuclei are excitatory/glutamatergic. Cerebellar axons innervate brainstem premotor centers via the red nucleus and cortical areas via the thalamic ventrolateral, ventromedial, and intralaminar nuclei. ⁴¹

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. 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. The most used GABA-B agonist is baclofen.

GABA-B receptors colocalize with mGluR1 receptors in Purkinje cells, where they participate in Calcium-dependent mediation of mGluR1 signaling. ⁴² GABA-A receptors are found in the granule cell layer, ⁴³ where they receive GABA input from the Golgi cells, as well as molecular layer interneurons, the basket, and stellate cells. ⁴⁴ Output from the cerebellar cortex occurs via Purkinje cells. Purkinje cell output to deep cerebellar nuclei is inhibitory/GABAergic and topographically organized into zones in parasagittal orientation. ⁴⁵

Acetylcholine, Dopamine, Norepinephrine, and