Epidemiological Research

Donna L. Gruol · Noriyuki Koibuchi

Mario Manto · Marco Molinari

Jeremy D. Schmahmann · Ying Shen Editors

Essentials of

Cerebellum

and Cerebellar

Disorders

A Primer For Graduate Students

Essentials of Cerebellum and Cerebellar Disorders

Donna L. Gruol • Noriyuki Koibuchi

Mario Manto • Marco Molinari

Jeremy D. Schmahmann • Ying Shen

Editors

Essentials of Cerebellum

and Cerebellar Disorders

A Primer For Graduate Students

ISBN 978-3-319-24549-2 ISBN 978-3-319-24551-5 (eBook)

DOI 10.1007/978-3-319-24551-5

Library of Congress Control Number: 2016954967

© Springer International Publishing Switzerland 2016

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Editors

Donna L. Gruol

Molecular and Cellular Neuroscience

Department

The Scripps Research Institute

La Jolla , CA , USA

Mario Manto

FNRS, ULB-Erasme

Bruxelles , Belgium

Service des Neurosciences

Université de Mons

Mons , Belgium

Jeremy D. Schmahmann

Ataxia Unit, Cognitive Behavioral

Neurology Unit, Laboratory for

Neuroanatomy and Cerebellar

Neurobiology, Department of Neurology

Massachusetts General Hospital, Harvard

Medical School

Boston , MA , USA

Noriyuki Koibuchi

Department of Integrative Physiology

Gunma University Graduate School

of Medicine

Maebashi, Gunma , Japan

Marco Molinari

Clinical Translational Research

Santa Lucia Foundation

Rome , Italy

Ying Shen

Department of Neurobiology

Zhejiang University School of Medicine

Hangzhou , People’s Republic of China

v

Contents

1 Introduction ............................................................................................. 1

Donna L. Gruol , Noriyuki Koibuchi , Mario Manto , Marco Molinari ,

Jeremy D. Schmahmann , and Ying Shen

Part I Brief Historical Note

2 A Brief History of the Cerebellum......................................................... 5

Jeremy D. Schmahmann

3 Pivotal Insights: The Contributions of Gordon Holmes

(1876–1965) and Olof Larsell (1886–1964) to Our

Understanding of Cerebellar Function and Structure ........................ 21

Duane E. Haines

Part II Anatomy and Histology of the Cerebellum

4 Gross Anatomy of the Cerebellum ........................................................ 33

Jan Voogd and Enrico Marani

5 Vascular Supply and Territories of the Cerebellum ............................ 39

Qiaoshu Wang and Louis R. Caplan

6 The Olivocerebellar Tract ...................................................................... 55

Yuanjun Luo and Izumi Sugihara

7 Precerebellar Nuclei ................................................................................ 63

Mayumi Yamada and Mikio Hoshino

8 Vestibular Nuclei and Their Cerebellar Connections .......................... 69

Neal H. Barmack

9 Spinocerebellar and Cerebellospinal Pathways ................................... 79

Tom J. H. Ruigrok

vi

10 Visual Circuits ......................................................................................... 89

Manuel Jan Roth , Axel Lindner , and Peter Thier

11 The Cerebrocerebellar System ............................................................... 101

Jeremy D. Schmahmann

12 Cerebello-Cerebral Feedback Projections ............................................ 117

Kim van Dun , Mario Manto , and Peter Mariën

Part III Embryology and Development of the Cerebellum

13 Cerebellar Neurogenesis ......................................................................... 127

Ketty Leto , Richard Hawkes , and G. Giacomo Consalez

14 Zones and Stripes .................................................................................... 137

Carol Armstrong and Richard Hawkes

15 Specification of Cerebellar Neurons ...................................................... 143

Mikio Hoshino

16 Cerebellar Nucleus Development........................................................... 149

Hong-Ting Prekop and Richard J. T. Wingate

17 Development of Glutamatergic and GABAergic Synapses ................. 155

Marco Sassoè-Pognetto

18 Synaptogenesis and Synapse Elimination in Developing

Cerebellum ............................................................................................... 161

Kouichi Hashimoto , Masahiko Watanabe , and Masanobu Kano

19 Cerebellar Epigenetics: Transcription of MicroRNAs

in Purkinje Cells ...................................................................................... 167

Neal H. Barmack

Part IV Cerebellar Circuits: Biochemistry, Neurotransmitters

and Neuromodulation

20 Granule Cells and Parallel Fibers ......................................................... 177

Egidio D’Angelo

21 The Purkinje Cell: As an Integrative Machine .................................... 183

Anais Grangeray , Kevin Dorgans , Sebastien Roux ,

and Jean-Louis Bossu

22 Stellate Cells ............................................................................................ 189

Siqiong June Liu and Christophe J. Dubois

23 Basket Cells .............................................................................................. 195

Masahiko Watanabe

24 Golgi Neurons .......................................................................................... 201

Stéphane Dieudonné

Contents

vii

25 Lugaro Cells............................................................................................. 207

Moritoshi Hirono

26 Unipolar Brush Cells .............................................................................. 213

Marco Martina and Gabriella Sekerková

27 Glial Cells ................................................................................................. 219

Katharine L. Dobson and Tomas C. Bellamy

28 GABA Pathways and Receptors ............................................................ 225

Tomoo Hirano

29 Glutamatergic Pathways and Receptors ............................................... 231

Susumu Tomita

30 Norepinephrine and Synaptic Transmission in the Cerebellum ......... 237

Gerard Zitnik , Daniel J. Chandler , and Barry D. Waterhouse

31 Serotonin in the Cerebellum .................................................................. 243

Marlies Oostland and Johannes A. van Hooft

32 Nitric Oxide ............................................................................................. 249

Sho Kakizawa

33 Cerebellar Circuits: Biochemistry, Neurotransmitters

and Neuromodulators ............................................................................. 255

Gary J. Stephens

34 Purinergic Signalling in the Cerebellum ............................................... 261

Mark J. Wall

35 Neuropeptides in the Cerebellum .......................................................... 267

Georgia A. Bishop and James S. King

36 Neurosteroids ........................................................................................... 273

C. Fernando Valenzuela

37 Cerebellar Modules and Networks Involved

in Locomotion Control............................................................................ 279

Carla da Silva Matos , María Fernanda Vinueza Veloz ,

Tom J. H. Ruigrok , and Chris I. De Zeeuw

38 Distributed Plasticity in the Cerebellar Circuit ................................... 285

Egidio D’Angelo

Part V Basic Physiology

39 Oscillation in the Inferior Olive Neurons:

Functional Implication ........................................................................... 293

Rodolfo R. Llinas

40 Simple Spikes and Complex Spikes ....................................................... 299

Thomas S. Otis

Contents

viii

41 Rebound Depolarization and Potentiation ........................................... 305

Steven Dykstra and Ray W. Turner

42 Cerebellar Nuclei..................................................................................... 311

Dieter Jaeger and Huo Lu

43 Plasticity of the Cerebellum ................................................................... 317

Ying Shen

44 Physiology of Olivo-Cerebellar Loops ................................................... 323

Robin Broersen , Beerend H.J. Winkelman , Ozgecan Ozyildirim

and Chris I. De Zeeuw

45 Long-Term Depression at Parallel Fiber- Purkinje

Cell Synapses ........................................................................................... 329

Kazuhisa Kohda , Wataru Kakegawa , and Michisuke Yuzaki

46 Regulation of Calcium in the Cerebellum............................................. 335

Donna L. Gruol

Part VI Neuroimaging of the Cerebellum

47 Cerebellar Closed-Loops ........................................................................ 343

Christophe Habas

48 MRI Aspects: Conventional, SWI, DTI................................................. 349

Thomas M. Ernst , Marc Schlamann , and Dagmar Timmann

49 SPECT and PET ..................................................................................... 359

Martina Minnerop

50 MR Spectroscopy .................................................................................... 367

Vladimír Mlynárik

51 Functional Topography of the Human Cerebellum ............................. 373

Catherine J. Stoodley and Jeremy D. Schmahmann

Part VII Functional Properties of the Cerebellum

52 Cerebro-Cerebellar Networks ................................................................ 385

Iolanda Pisotta and Marco Molinari

53 Clinical Functional Topography in Cognition ...................................... 391

Maria Leggio

54 Sequencing ............................................................................................... 397

Marco Molinari

55 Speech and Language ............................................................................. 403

Peter Mariën and Kim van Dun

Contents

ix

Part VIII Cellular and Animal Models of Cerebellar Disorders

56 The Zebrafish Cerebellum ..................................................................... 411

Jan Kaslin and Michael Brand

57 The Teleost Fish ....................................................................................... 423

Takanori Ikenaga

58 Lurcher Mouse ........................................................................................ 429

Jan Cendelin , Jan Tuma , and Zdenka Purkartova

59 The Tottering Mouse ............................................................................... 437

Russell E. Carter and Timothy J. Ebner

60 The Rolling Nagoya Mouse .................................................................... 443

Jaap J. Plomp , Arn M. J. M. van den Maagdenberg ,

and Else A. Tolner

61 Ataxic Syrian Hamster ........................................................................... 449

Kenji Akita

62 Lesions of the Cerebellum ...................................................................... 455

Maria Teresa Viscomi and Marco Molinari

63 Cellular and Animal Models of Cerebellar Disorders:

Staggerer Mouse ...................................................................................... 463

N. Morellini , A. M. Lohof , R. M. Sherrard , and J. Mariani

Part IX Human Cerebellar Symptoms: From Movement to Cognition

64 Cerebellum and Oculomotor Deficits .................................................... 471

Amir Kheradmand , Ji Soo Kim , and David Zee

65 Speech Deficits ......................................................................................... 477

Maria Caterina Silveri

66 Deficits of Limbs Movements ................................................................. 481

Giuliana Grimaldi

67 Lesion-Symptom Mapping ..................................................................... 489

Dagmar Timmann , Thomas M. Ernst , Winfried Ilg ,

and Opher Donchin

68 The Cerebellar Cognitive Affective Syndrome

and the Neuropsychiatry of the Cerebellum ......................................... 499

Jeremy D. Schmahmann

69 Ataxia Scales for the Clinical Evaluation ............................................. 513

Katrin Bürk

Contents

x

Part X Human Cerebellar Disorders: From Prenatal Period to Elderly

70 Differential Diagnosis of Cerebellar Ataxias

on the Basis of the Age at Onset ............................................................. 523

Francesc Palau and Javier Arpa

71 Overview of Ataxias in Children ............................................................ 531

Andrea Poretti and Eugen Boltshauser

72 Cerebellar Pathology in Autism ............................................................. 539

S. Hossein Fatemi

73 Autosomal Recessive Ataxias ................................................................. 545

Marie Beaudin and Nicolas Dupré

74 X-Linked Ataxias .................................................................................... 553

Josef Finsterer

75 Imaging of Malformations of the Hindbrain

and Craniocervical Junction .................................................................. 561

Christian Herweh

76 Cerebellar Stroke .................................................................................... 569

Keun-Hwa Jung and Jae-Kyu Roh

77 Immune Diseases ..................................................................................... 581

Marios Hadjivassiliou

78 Paraneoplastic Cerebellar Degeneration .............................................. 587

Raffaele Iorio and Peter Sillevis Smitt

79 Essential Tremor ..................................................................................... 595

Elan D. Louis

80 Toxic Agents ............................................................................................. 601

Mario Manto

81 Endocrine Disorders ............................................................................... 613

Mario Manto and Christiane S. Hampe

Part XI Therapies of Cerebellar Ataxias

82 Drugs in Selected Ataxias ....................................................................... 627

Dagmar Timmann and Winfried Ilg

83 Cerebellar Stimulation ........................................................................... 635

Giuliana Grimaldi

84 Motor Rehabilitation of Cerebellar Disorders ..................................... 641

Winfried Ilg and Dagmar Timmann

Index ................................................................................................................. 649

Contents

© Springer International Publishing Switzerland 2016 1

D.L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders,

DOI 10.1007/978-3-319-24551-5_1

Chapter 1

Introduction

Donna L. Gruol , Noriyuki Koibuchi , Mario Manto , Marco Molinari ,

Jeremy D. Schmahmann , and Ying Shen

Abstract The depth and breadth of knowledge regarding cerebellar functions in health

and disease continue to grow exponentially. Most of the currently available books deal￾ing with the cerebellum and its disorders are highly specialized, usually written for

neurologists with a particular interest in the cerebellar disorders. The four-volume

Handbook of the Cerebellum and Cerebellar Disorders (Springer 2013) is the most

comprehensive monograph on the cerebellum published to date covering both funda￾mental and clinical aspects. As valuable a resource as this has proven to be, however,

the treatise is too extensive for students, and not practical as a brief, authoritative over￾view of the subject. The editors therefore concluded that there is a compelling need to

distill the vast amount of basic science and clinical information in the four-volume text

into a clear and concise précis of the work accessible to clinicians and students. Hence,

this work, Essentials of the Handbook of the Cerebellum and Cerebellar Disorders.

Keywords Essentials • Cerebellum • Cerebellar disorders • Ataxia • Students

D. L. Gruol

Molecular and Cellular Neuroscience Department , The Scripps Research Institute ,

La Jolla , CA , USA

e-mail: [email protected]

N. Koibuchi , M.D., Ph.D.

Department of Integrative Physiology , Gunma University Graduate School of Medicine ,

Maebashi , Gunma , Japan

M. Manto (*)

FNRS, ULB-Erasme , 808 Route de Lennik, 1070 Bruxelles , Belgium

Service des Neurosciences , Université de Mons , 7000 Mons , Belgium

e-mail: [email protected]

M. Molinari

Clinical Translational Research, Santa Lucia Foundation , Rome , Italy

J. D. Schmahmann

Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and

Cerebellar Neurobiology, Department of Neurology , Massachusetts General Hospital,

Harvard Medical School , Boston , MA , USA

Y. Shen

Department of Neurobiology , Zhejiang University School of Medicine ,

Hangzhou 310058 , People’s Republic of China

2

The depth and breadth of knowledge regarding cerebellar functions in health and

disease continue to grow exponentially. Most of the currently available books deal￾ing with the cerebellum and its disorders are highly specialized, usually written for

neurologists with a particular interest in the cerebellar disorders. The four-volume

Handbook of the Cerebellum and Cerebellar Disorders (Springer 2013) is the most

comprehensive monograph on the cerebellum published to date on fundamental and

clinical aspects. As valuable a resource as this has proven to be, however, the trea￾tise is too extensive for students, and not practical as a brief, authoritative overview

of the subject. The editors therefore concluded that there is a compelling need to

distill the vast amount of basic science and clinical information in the four- volume

text into a clear and concise précis of the work accessible to clinicians and students.

Hence, this work, Essentials of the Handbook of the Cerebellum and Cerebellar

Disorders.

The editors of Essentials have selected what we believe to be major topics with

direct scientifi c and clinical implications for understanding cerebellar anatomy,

physiology, clinical neurology, and management of cerebellar disorders. With this

monograph, we hope to foster a deeper understanding of the most important aspects

of the complex phenomena that characterize cerebellar neurology. In so doing, we

hope to encourage students to further explore its many facets, ranging from ataxiol￾ogy (the study of cerebellar motor disorders) to the cognitive neuroscience of the

cerebellum and its connections.

The pocket format of the book makes it readily available for consultation. The

chapters are arranged in eleven sections covering fundamental, translational and

clinical aspects of the cerebellum and cerebellar disorders. The length of each chap￾ter is approximately four printed pages, enabling the reader to review the necessary

information rapidly and effi ciently. Critical references provided at the end of each

chapter can be consulted for more in-depth information.

The editors are grateful for the outstanding contributions to this work by the

renowned international panel of experts in some of the premier clinical centers,

universities, and research centers in the USA, Europe, and Asia. We hope that this

concise volume achieves its purpose of stimulating students, trainees, and practitio￾ners to enhance their knowledge of the cerebellum and its disorders, and promote

further clinical and scientifi c exploration in the fi eld.

D.L. Gruol et al.

Part I

Brief Historical Note

© Springer International Publishing Switzerland 2016 5

D.L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders,

DOI 10.1007/978-3-319-24551-5_2

Chapter 2

A Brief History of the Cerebellum

Jeremy D. Schmahmann

Abstract Cerebellar structure and function have intrigued investigators and clini￾cians for millennia. Major anatomic features were recognized early, and the role of

the cerebellum in coordinating movements was established two centuries ago.

Cerebellar involvement in nonmotor functions was described in clinical and experi￾mental observations starting around the same time, but attention to their importance

rose to the fore only recently. Functional localization was fi rst derived from com￾parative morphology. Ablation degeneration and physiological studies in animals

and neurological observations in patients with focal injury led to the lobular theory

of organization. This was refi ned by delineation of the mediolateral parasagittal

zonal organization of cerebellar connections. Histological studies date back to

Cajal, with descriptions of additional neuronal elements and circuitry evolving over

the years. Recognition of the cerebellar cognitive affective syndrome and the neuro￾psychiatry of the cerebellum, observations from connectional neuroanatomy, and

advances in anatomic, task-based, and functional connectivity magnetic resonance

neuroimaging provide contemporary support for the earliest notions that cerebellum

is engaged in a wide range of neurological functions. Together with new theories of

cerebellar function, and elucidation of the genetic basis of inherited or sporadic

ataxias and neurobehavioral disorders, the cerebellum has become increasingly rel￾evant to contemporary clinical neurology and neuropsychiatry.

Keywords Historical background • Cerebellum • Ataxia • Dysmetria • Cognition •

Vestibular

The cerebellum has been recognized since antiquity. Notions regarding its functions

included the belief that it imparted strength to the motor nerves (Galen A.D.

129/130–200/201), was a center for memory (Nemesius, c.A.D. 390, and Albert von

Bollstädt/Albertus Magnus, 1193–1280), controlled sensory functions including

unconscious sensibility (Co(n)stanzo Varolio/Variolus, 1543–1575), was involved

J. D. Schmahmann (*)

Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and

Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital,

Harvard Medical School , Boston , MA , USA

e-mail: [email protected]

6

with involuntary activity including the functions of the heart and respiration

(Thomas Willis, 1621–1675), and was the seat of amative love (Franz Joseph Gall,

1758–1828) (Citations in Neuburger, 1897 /1981; Clarke and O’Malley 1996 ;

Schmahmann and Pandya 2006 ). As is apparent from the historical account below,

the conclusions of these pioneers, although based on fl imsy or fanciful evidence,

were actually rather prescient.

2.1 Early and Evolving Views of Cerebellar Organization

and Function

Luigi Rolando ( 1809 ) fi rst demonstrated that ablation of the cerebellum results in

disturbances of posture and voluntary movement. Michele Foderà ( 1823 ) showed

release of postural mechanisms, and extensor hypotonia following acute cerebellar

injury in pigeons, guinea pigs and rabbits. Marie-Jean-Pierre Flourens ( 1824 )

showed in pigeons that the cerebellum is responsible for the coordination, rather

than generation, of voluntary movement and gait, a concept that has remained the

guiding principle of cerebellar function. François Magendie’s lesion studies ( 1824 )

led to the understanding that the cerebellum is essential for equilibrium. Disturbances

of motor control following focal cerebellar lesions in monkeys were demonstrated

by Luigi Luciani ( 1891 ), David Ferrier and William Aldren Turner ( 1893 ) and

Rissien Russell ( 1894 ).

Comparative anatomists such as Lodewijk ‘Louis’ Bolk (Bolk 1902 ; Glickstein

and Voogd 1995 ) derived structure-function correlations by comparing the size of a

cerebellar region with the characteristics of the species to which it belonged. They

concluded that the vermis coordinates bilateral symmetrical movements, the cere￾bellar hemispheres coordinate unilateral movements of the limbs, and the develop￾ment of manual dexterity corresponded with the expansion of the lateral cerebellar

hemispheres. The lobular theory (Fulton and Dow 1937 ; Larsell 1970 ; Brodal 1967 ;

see Angevine et al. 1961 ) held that the cerebellum is functionally organized into

lobes. The fl occulonodular lobe, archicerebellum, and vestibulocerebellum became

synonymous. The anterior lobe, pyramis and uvula in the vermis of the posterior

lobe, and the parafl occulus were termed the paleocerebellum or spinocerebellum.

The lateral parts of the cerebellar hemispheres and the middle portion of the vermis

were termed the neocerebellum, or pontocerebellum.

Ablation-degeneration studies in animals (Jansen and Brodal 1940 ; Chambers

and Sprague 1955a , b ) introduced the concept of the organization of cerebellum into

three bilaterally symmetrical longitudinal corticonuclear zones. These studies (see

Dow and Moruzzi 1958 for review) showed that the medial zone (vermis and fasti￾gial nucleus) regulates vestibular function and the tone, posture, locomotion, and

equilibrium of the body, with somatotopic localization in the vermal cortex – the

head, neck and eyes at the posterior vermis, the tail and lower limbs at the rostral

aspect of the anterior vermis, and the upper limbs situated in between. The interme￾diate zone (paravermal cortex and nucleus interpositus) regulates spatially orga￾nized and skilled movements and the tone and posture associated with these

J.D. Schmahmann