Essentials of Cerebellum and Cerebellar Disorders: A Primer For Graduate Students [2 ed.] 3031150694, 9783031150692

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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 Second Edition

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 Second Edition

Editors Donna L. Gruol Neuroscience Department The Scripps Research Institute La Jolla, CA, USA

Noriyuki Koibuchi Department of Integrative Physiology Gunma University Graduate School of Medicine Maebashi, Gunma, Japan

Mario Manto Service de Neurologie CHU-Charleroi Charleroi, Belgium

Marco Molinari Clinical Translational Research Santa Lucia Foundation Rome, Italy

Jeremy D. Schmahmann Ataxia Center, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology Massachusetts General Hospital, Harvard Medical School Boston, MA, USA

Ying Shen Department of Physiology Zhejiang University School of Medicine Hangzho, China

ISBN 978-3-031-15069-2    ISBN 978-3-031-15070-8 (eBook) https://doi.org/10.1007/978-3-031-15070-8 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2016, 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

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�����������������������������������������������������������������������  15 Duane E. Haines Part II Anatomy and Histology of the Cerebellum 4 Gross  Anatomy of the Cerebellum ���������������������������������������������������������������������������  23 Jan Voogd and Enrico Marani 5 Vascular  Supply and Territories of the Cerebellum �����������������������������������������������  29 Qiaoshu Wang and Louis R. Caplan 6 The Olivocerebellar Tract �����������������������������������������������������������������������������������������  41 Yuanjun Luo and Izumi Sugihara 7 Precerebellar  Nuclei: Embryological Principles �����������������������������������������������������  47 Mayumi Yamada and Mikio Hoshino 8 Vestibular  Nuclei and Their Cerebellar Connections ���������������������������������������������  51 Neal H. Barmack 9 Spinocerebellar  and Cerebellospinal Pathways�������������������������������������������������������  61 Tom J. H. Ruigrok 10 Visual Circuits�������������������������������������������������������������������������������������������������������������  69 Manuel Jan Roth, Axel Lindner, and Peter Thier 11 The Cerebrocerebellar System�����������������������������������������������������������������������������������  77 Jeremy D. Schmahmann 12 Cerebello-Cerebral Feedback Projections ���������������������������������������������������������������  87 Kim van Dun, Mario Manto, and Peter Mariën Part III Embryology and Development of the Cerebellum 13 Cerebellar Neurogenesis���������������������������������������������������������������������������������������������  93 Richard Hawkes and G. Giacomo Consalez v

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14 Zones and Stripes�������������������������������������������������������������������������������������������������������  99 Carol Armstrong and Richard Hawkes 15 Specification  of Cerebellar Neurons������������������������������������������������������������������������� 107 Satoshi Miyashita and Mikio Hoshino 16 Cerebellar Nucleus Development������������������������������������������������������������������������������ 111 Hong-Ting Kwok and Richard J. T. Wingate 17 Development  of Glutamatergic and GABAergic Synapses������������������������������������� 115 Marco Sassoè-Pognetto 18 Synaptogenesis  and Synapse Elimination in Developing Cerebellum������������������� 121 Kouichi Hashimoto, Masahiko Watanabe, and Masanobu Kano 19 Cerebellar  Epigenetics: Transcription of microRNAs in Purkinje Neurons as an Approach to Neuronal Plasticity������������������������������������������������������� 127 Neal H. Barmack 20 The  Genetic Programs Behind Cerebellar Development ��������������������������������������� 137 Kathleen J. Millen Part IV Cerebellar Circuits: Biochemistry, Neurotransmitters and Neuromodulation 21 Granule  Cells and Parallel Fibers����������������������������������������������������������������������������� 149 Egidio D’Angelo 22 Purkinje Cells ������������������������������������������������������������������������������������������������������������� 155 Théo Rossi and Philippe Isope 23 Stellate Cells ��������������������������������������������������������������������������������������������������������������� 163 Siqiong June Liu and Christophe J. Dubois 24 Basket Cells����������������������������������������������������������������������������������������������������������������� 169 Masahiko Watanabe 25 Golgi Neurons������������������������������������������������������������������������������������������������������������� 173 Stéphane Dieudonné 26 Lugaro Cells���������������������������������������������������������������������������������������������������������������� 177 Moritoshi Hirono 27 Unipolar Brush Cells ������������������������������������������������������������������������������������������������� 181 Marco Martina and Gabriella Sekerková 28 Glial Cells��������������������������������������������������������������������������������������������������������������������� 187 Katharine L. Dobson and Tomas C. Bellamy 29 GABA  Pathways and Receptors ������������������������������������������������������������������������������� 191 Tomoo Hirano and Shin-ya Kawaguchi 30 Glutamatergic  Pathways and Receptors������������������������������������������������������������������� 197 Susumu Tomita 31 Norepinephrine  in the Cerebellum��������������������������������������������������������������������������� 201 Haven K. Predale, Daniel J. Chandler, and Barry D. Waterhouse 32 Serotonin  in the Cerebellum ������������������������������������������������������������������������������������� 209 Johannes A. van Hooft and Marlies Oostland

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33 Nitric Oxide����������������������������������������������������������������������������������������������������������������� 215 Sho Kakizawa 34 Cannabinoids��������������������������������������������������������������������������������������������������������������� 221 Gary J. Stephens 35 Purinergic  Signaling in the Cerebellum������������������������������������������������������������������� 225 Mark J. Wall 36 Neuropeptides  in the Cerebellum ����������������������������������������������������������������������������� 231 Georgia A. Bishop and James S. King 37 Neuroactive Steroids��������������������������������������������������������������������������������������������������� 237 C. Fernando Valenzuela and Samantha Varela 38 Role  of Unipolar Brush Cells in the Vestibulocerebellum��������������������������������������� 243 Rachel N. Koops, Cathrin B. Canto, Bin Wu, Martijn Schonewille, Beerend H. J. Winkelman, and Chris I. De Zeeuw 39 Distributed  Plasticity in the Cerebellar Circuit������������������������������������������������������� 259 Egidio D’Angelo Part V Basic Physiology 40 Simple  Spikes and Complex Spikes��������������������������������������������������������������������������� 265 Thomas S. Otis 41 Rebound Depolarizations������������������������������������������������������������������������������������������� 269 Steven Dykstra and Ray W. Turner 42 Cerebellar Nuclei�������������������������������������������������������������������������������������������������������� 275 Dieter Jaeger and Huo Lu 43 Plasticity  of the Cerebellum��������������������������������������������������������������������������������������� 281 Xin-Tai Wang and Ying Shen 44 Long-Term  Depression at Parallel Fiber–Purkinje Cell Synapses������������������������� 287 Michisuke Yuzaki 45 Regulation  of Calcium in the Cerebellum���������������������������������������������������������������� 293 Donna L. Gruol 46 Neurotrophic  Factors in Cerebellar Development and Function��������������������������� 299 Juan Pablo Zanin and Wilma J. Friedman 47 The  Cerebellar Neuroimmune System��������������������������������������������������������������������� 305 Donna L. Gruol 48 Restoring  a Loss of Mossy Fiber Plasticity in a Model of Fragile X Syndrome����������������������������������������������������������������������������������������������� 313 Xiaoqin Zhan and Ray W. Turner Part VI Neuroimaging of the Cerebellum 49 Cerebellar Closed Loops ������������������������������������������������������������������������������������������� 321 Christophe Habas 50 MRI  Aspects: Conventional, SWI, and DTI������������������������������������������������������������� 325 Thomas M. Ernst, Andreas Deistung, Marc Schlamann, and Dagmar Timmann

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51 SPECT and PET��������������������������������������������������������������������������������������������������������� 333 Martina Minnerop 52 MR Spectroscopy ������������������������������������������������������������������������������������������������������� 339 Vladimír Mlynárik 53 Functional  Topography of the Human Cerebellum������������������������������������������������� 343 Catherine J. Stoodley and Jeremy D. Schmahmann 54 fMRI-Based  Anatomy: Mapping the Cerebellum��������������������������������������������������� 351 Xavier Guell and Jeremy D. Schmahmann Part VII Functional Properties of the Cerebellum 55 Cerebro-Cerebellar Networks����������������������������������������������������������������������������������� 359 Iolanda Pisotta and Marco Molinari 56 Clinical  Functional Topography in Cognition ��������������������������������������������������������� 363 Maria Leggio 57 Sequencing������������������������������������������������������������������������������������������������������������������� 371 Marco Molinari 58 Speech and Language������������������������������������������������������������������������������������������������� 375 Peter Mariën and Kim van Dun 59 Theory  of Mind and Cerebellum������������������������������������������������������������������������������� 379 Giusy Olivito, Libera Siciliano, and Maria Leggio 60 Cerebellum and Decision-Making����������������������������������������������������������������������������� 387 Ben Deverett and Marlies Oostland Part VIII Cellular and Animal Models of Cerebellar Disorders 61 The Zebrafish Cerebellum����������������������������������������������������������������������������������������� 393 Jan Kaslin and Michael Brand 62 The Teleost Fish����������������������������������������������������������������������������������������������������������� 399 Takanori Ikenaga 63 Lurcher Mouse ����������������������������������������������������������������������������������������������������������� 403 Jan Cendelin, Jan Tuma, and Zdenka Purkartova 64 The Tottering Mouse��������������������������������������������������������������������������������������������������� 409 Russell E. Carter and Timothy J. Ebner 65 The  Rolling Nagoya Mouse ��������������������������������������������������������������������������������������� 413 Jaap J. Plomp, Arn M. J. M. van den Maagdenberg, and Else A. Tolner 66 Lesions  of the Cerebellum ����������������������������������������������������������������������������������������� 419 Maria Teresa Viscomi and Marco Molinari 67 The  Staggerer Mouse: RORα Deficiency Induces Cerebellar Neurodegeneration����������������������������������������������������������������������������������� 425 Natalie Morellini, Ann M. Lohof, Jean Mariani, and Rachel M. Sherrard 68 Alcohol  and the Cerebellum��������������������������������������������������������������������������������������� 431 David J. Rossi 69 Moonwalker Mouse ��������������������������������������������������������������������������������������������������� 441 Mohamed F. Ibrahim and Esther B. E. Becker

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Part IX Human Cerebellar Symptoms: From Movement to Cognition 70 Cerebellum  and Oculomotor Deficits����������������������������������������������������������������������� 451 Olwen Murphy and Amir Kheradmand 71 Speech Disorders��������������������������������������������������������������������������������������������������������� 457 Maria Caterina Silveri 72 Deficits  of Limbs Movements������������������������������������������������������������������������������������� 463 Giuliana Grimaldi 73 The  Three Cornerstones of the Cerebellar Syndrome��������������������������������������������� 469 Pierre Cabaraux and Mario Manto 74 Lesion-Symptom Mapping����������������������������������������������������������������������������������������� 479 Dagmar Timmann, Thomas M. Ernst, Winfried Ilg, and Opher Donchin 75 The  Cerebellar Cognitive Affective Syndrome and the Neuropsychiatry of the Cerebellum������������������������������������������������������������� 485 Jeremy D. Schmahmann 76 Ataxia  Scales for the Clinical Evaluation����������������������������������������������������������������� 493 Katrin Bürk 77 The Ataxic Gait����������������������������������������������������������������������������������������������������������� 501 Pierre Cabaraux and Mario Manto 78 The  Social Cerebellum and Human Interactions����������������������������������������������������� 511 Elien Heleven and Frank Van Overwalle Part X Human Cerebellar Disorders: From Prenatal Period to Elderly 79 Genetics  and Differential Diagnosis of Cerebellar Ataxias������������������������������������� 521 Francesc Palau and Javier Arpa 80 Overview  of Ataxia in Childhood ����������������������������������������������������������������������������� 531 Eugen Boltshauser 81 Cerebellar Pathology in Autism��������������������������������������������������������������������������������� 537 S. Hossein Fatemi and Justin W. Aman 82 Cerebellar  Pathology in Schizophrenia, Bipolar Disorder, and Major Depression ����������������������������������������������������������������������������������������������� 541 S. Hossein Fatemi and Justin W. Aman 83 Autosomal Recessive Ataxias������������������������������������������������������������������������������������� 547 Marie Beaudin, Ikhlass Haj Salem, and Nicolas Dupré 84 X-Linked Ataxias ������������������������������������������������������������������������������������������������������� 555 Josef Finsterer 85 Imaging  of Malformations of the Hindbrain and Craniocervical Junction ��������� 561 Christian Herweh 86 Cerebellar Stroke ������������������������������������������������������������������������������������������������������� 567 Keun-Hwa Jung and Jae-Kyu Roh 87 Immune-Mediated Cerebellar Ataxias��������������������������������������������������������������������� 575 Marios Hadjivassiliou and Hiroshi Mitoma 88 Paraneoplastic Cerebellar Syndrome����������������������������������������������������������������������� 583 Raffaele Iorio and Lucia Campetella

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89 Essential Tremor��������������������������������������������������������������������������������������������������������� 595 Elan D. Louis 90 Toxic Agents����������������������������������������������������������������������������������������������������������������� 599 Alexandra Bakolas and Mario Manto 91 Endocrine Disorders��������������������������������������������������������������������������������������������������� 607 Mario Manto and Christiane S. Hampe 92 Friedreich Ataxia�������������������������������������������������������������������������������������������������������� 617 Mario Manto 93 Ataxia Telangiectasia ������������������������������������������������������������������������������������������������� 621 Rob A. Dineen and William P. Whitehouse 94 Neuroimmune  Mechanisms of Cerebellar Ataxias ������������������������������������������������� 631 Hiroshi Mitoma and Mario Manto 95 Primary Autoimmune Cerebellar Ataxia (PACA)��������������������������������������������������� 641 Marios Hadjivassiliou and Hiroshi Mitoma 96 Gluten Ataxia��������������������������������������������������������������������������������������������������������������� 645 Marios Hadjivassiliou 97 Cerebrotendinous Xanthomatosis����������������������������������������������������������������������������� 649 Evelien Hendriks, Bianca M. L. Stelten, and Aad Verrips 98 Cerebellar  Variant of Multiple System Atrophy (MSA-C)������������������������������������� 655 Marios Hadjivassiliou 99 Cerebellar Tumors ����������������������������������������������������������������������������������������������������� 659 Thomas Beez 100 Post-traumatic Cerebellar Syndromes��������������������������������������������������������������������� 665 Jordi Gandini and Mario Manto 101 Superficial Siderosis��������������������������������������������������������������������������������������������������� 671 Hiroyuki Katoh and Masahiko Watanabe 102 Ataxia in Multiple Sclerosis��������������������������������������������������������������������������������������� 679 Giacomo Koch and Danny Adrian Spampinato 103 CANVAS ��������������������������������������������������������������������������������������������������������������������� 685 Mario Manto and Joao Lemos 104 Spastic Paraplegia Type 7 (SPG7)����������������������������������������������������������������������������� 691 Gorka Fernández-Eulate, Aurora Pujol, and Adolfo López de Munain Part XI Therapies of Cerebellar Ataxias 105 Drugs in Selected Ataxias������������������������������������������������������������������������������������������� 699 Dagmar Timmann and Winfried Ilg 106 Cerebellar Stimulation����������������������������������������������������������������������������������������������� 705 Giuliana Grimaldi 107 Motor Rehabilitation of Cerebellar Disorders��������������������������������������������������������� 709 Winfried Ilg and Dagmar Timmann 108 Editing the Genome ��������������������������������������������������������������������������������������������������� 715 Jordi Gandini and Mario Manto

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109 Grafting����������������������������������������������������������������������������������������������������������������������� 719 Jan Cendelin and Zdenka Purkartova 110 Cerebellar Reserve����������������������������������������������������������������������������������������������������� 725 Hiroshi Mitoma and Mario Manto

Index������������������������������������������������������������������������������������������������������������������������������������� 735

Editors and Authors

About the Editors and Authors International Panel of Editors  The six editors collectively have extensive experience in the basic science and clinical neurology of cerebellar disorders. They are all international leaders in the field of ataxiology and highly regarded teachers in their respective institutions as well as at national and international conferences. Their stewardship of this volume and their influence on their students and trainees will contribute to the popularity and dissemination of this book. International Panel of Authors  The editors gathered an international field of authors to contribute to this volume. Located in leading academic medical centers and universities throughout the USA, Europe, and Asia, this panel of scientists and clinicians includes world leaders in their respective fields. Many of these have contributed authoritative chapters to the Handbook, and the invitees include both seasoned investigators and talented younger clinician scientists.

About the Editors Donna  L.  Gruol, PhD  is Professor Emeritus in the Department of Neuroscience, Scripps Research Institute, and adjunct Associate Professor in the Neuroscience Department, University of California at San Diego. Dr. Gruol obtained a PhD from the Illinois Institute of Technology and did postdoctoral training at the University of Maryland Medical School, The National Institutes of Health, and The Salk Institute. She has been a member of several NIH grant review panels and has served on journal editorial boards and advisory committees. Her primary research interests are on neuroadaptive changes in CNS neurophysiology produced by neuroinflammatory factors and drugs of abuse at the molecular to systems levels. Marco  Molinari, MD, PhD  (Neurologist, Physical medicine and rehabilitation specialist, PhD in Neuroscience), is the Director of Neurorehabilitation 1 and Spinal Center at IRCCS Fondazione Santa Lucia, Rome. The Department integrates Neuroscience research and clinical neurological rehabilitation units. Research activities span from basic science approaches in animal models to clinical investigations with special focus on cerebellar function and pathology. Dr. Molinari is author of over 250 articles published in indexed journals. He is Review Editor of The Cerebellum. His cerebellar research activity has been focused on cerebellar role in cognition and theories on cerebellar operational modalities. Dr. Molinari served as member in several European grant review panels. Ying Shen, PhD  is a QiuShi distinguished professor of Zhejiang University and a national distinguished young investigator of China. He obtained a PhD from Zhejiang University and completed postdoctoral training at the Johns Hopkins University School of Medicine. He is a member of NSFC grant review panels and has served as editorial board member of several scientific journals. His primary research interests are on cerebellar regulation on motor and mental diseases and cellular and circuitry mechanisms. xiii

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Noriyuki Koibuchi, MD, PhD  is Professor of Department of Integrative Physiology, Gunma University Graduate School of Medicine. He obtained his MD and PhD from Gunma University, followed by postdoctoral training at the Rockefeller University, New York. He has been serving as a Secretary General of The Society for Research on the Cerebellum and Ataxias. He is an Associate Editor of The Cerebellum and Frontiers in Endocrinology. His research interests are focused on the molecular mechanisms of thyroid/steroid hormone actions on brain development and the modulation of environmental chemicals on its process. Jeremy D. Schmahmann, MD, FAAN, FANA, FANPA  is Professor of Neurology at Harvard Medical School, and at the Massachusetts General Hospital he is a Senior Clinical Neurologist, Founding Director of the Ataxia Center, Director of the Laboratory for Neuroanatomy and Cerebellar Neurobiology, and a founding member of the Cognitive Behavioral Neurology Unit. He graduated with distinction from the University of Cape Town Medical School and completed Postdoctoral Fellowship in neuroanatomy with Professor Deepak Pandya at the Boston University School of Medicine. Dr. Schmahmann is a member of the National Ataxia Foundation Medical and Scientific Research Advisory Board, executive member of the Society for Research on the Cerebellum and Ataxias, and a member of the Clinical Research Consortium for the Study of Cerebellar Ataxia, the Ataxia Global Initiative, and the Global Multiple System Atrophy Working Group. Dr. Schmahmann’s clinical and research programs played a pioneering role in discovering the contribution of the cerebellum to neuropsychiatry and to elucidating the cerebral and cerebellar substrates of movement, cognition, and emotion. Mario Manto, MD, PhD  is Neurologist and Professor of Neuroanatomy at the University of Mons. He is also teaching the Pathophysiology of the Nervous System in adults and in children. He is focusing his research on cerebellum and cerebellar disorders. He is the founding Editor of the journal The Cerebellum (Springer Nature) and co-founder of the Society for Research on the Cerebellum and Ataxias. He has received several research grants from international agencies including the NIH and European Commissions. He is author, co-author, or co-editor of several books on the cerebellum. He has served on several grant review panels.

Editors and Authors

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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 dealing with the cerebellum and its disorders are highly specialized, usually written for neurologists with a particular interest in cerebellar disorders. The four-volume Handbook of the Cerebellum and Cerebellar Disorders (Springer 2022, second edition) is the most comprehensive monograph on the cerebellum published to date covering both fundamental 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 overview of the subject. The editors, therefore, concluded that there is a compelling need to distill the vast amount of basic science D. L. Gruol Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA e-mail: [email protected] N. Koibuchi Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan e-mail: [email protected] M. Manto (*) Service de Neurologie, CHU-Charleroi, Charleroi, Belgium e-mail: [email protected] M. Molinari Clinical Translational Research, Santa Lucia Foundation, Rome, Italy e-mail: [email protected] J. D. Schmahmann Ataxia Center, 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] Y. Shen Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China e-mail: [email protected]

and clinical information in the four-volume text into a clear and concise precis of the work accessible to clinicians and students. Hence, this work, Essentials of the Handbook of the Cerebellum and Cerebellar Disorders. The first edition was an enormous success, with dissemination throughout the student community worldwide. This second edition is expanded and includes the most recent advances in the field, from both the research and clinical standpoint. Keywords

Essentials · Cerebellum · Cerebellar disorders · Ataxia Students

The depth and breadth of knowledge regarding cerebellar functions in health and disease continue to grow exponentially. Most of the currently available books dealing with the cerebellum and its disorders are highly specialized, usually written for neurologists with a particular interest in 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 treatise 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 precis of the work accessible to clinicians and students. Hence, this work, Essentials of the Handbook of the Cerebellum and Cerebellar Disorders Cerebellar disorders, has been prepared with the aim of providing a concise book for students, neuroscientists, trainees and clinicians. Following the enormous success of the first edition, the editors of Essentials have decided to proceed with a second edition, including updates and novelties in the field. The editors have selected what we believe to be major topics with direct scientific and clinical implications for understanding

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_1

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cerebellar anatomy, physiology, clinical neurology, and the management of cerebellar disorders. With this monograph, which gathers contributions from leading scientists around the world, 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 the many facets of ataxiology, from 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 11 sections covering fundamental, translational, and clinical aspects of the cerebellum and cerebellar disorders. The length of each

D. L. Gruol et al.

chapter is approximately four to six printed pages, enabling the reader to review the necessary information rapidly and efficiently. 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 second edition of the volume achieves its purpose of stimulating students, trainees, and practitioners to enhance their knowledge of the cerebellum and its disorders and promotes further clinical and scientific exploration in the field.

Part I Brief Historical Note

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A Brief History of the Cerebellum Jeremy D. Schmahmann

Abstract

Keywords

Cerebellar structure and function have intrigued investigators and clinicians 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 experimental observations starting around the same time, but attention to their importance rose to the fore only recently. Functional localization was first derived from comparative 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 refined 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 neuropsychiatry 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 the 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 relevant to contemporary clinical neurology and neuropsychiatry.

Historical background · Cerebellum · Ataxia · Dysmetria Cognition · Vestibular

J. D. Schmahmann (*) Ataxia Center, 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]

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 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) (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 flimsy or fanciful evidence, were rather prescient.

2.1 Early and Evolving Views of Cerebellar Organization and Function Rolando (1809) first demonstrated that ablation of the cerebellum results in disturbances of posture and voluntary movement. Fodéra (1823) showed the release of postural mechanisms, and extensor hypotonia following acute cerebellar injury in pigeons, guinea pigs, and rabbits. 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 (1824) lesion studies led to the understanding that the cerebellum is essential for equilibrium. Disturbances of motor control following focal cerebellar lesions in monkeys were demonstrated by Luciani (1891), Ferrier and Turner (1893), and Russell (1894).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_2

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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 cerebellar hemispheres coordinate unilateral movements of the limbs, and the development 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 flocculonodular lobe, archicerebellum, and vestibulocerebellum became synonymous. The anterior lobe, pyramis, and uvula in the vermis of the posterior lobe, and the paraflocculus 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 the cerebellum into three bilaterally symmetrical longitudinal corticonuclear zones. These studies (see Dow and Moruzzi 1958 for review) showed that the medial zone (vermis and fastigial 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 intermediate zone (paravermal cortex and nucleus interpositus) regulates spatially organized and skilled movements and the tone and posture associated with these movements of the ipsilateral limb, and lesions in the intermediate zone produced motor deficits including tremor, ataxia, and postural instability. The lateral zone (hemispheral cortex and dentate nucleus) was thought to be involved in skilled and spatially organized movements of the ipsilateral limbs, although lateral hemispheres or dentate nucleus lesions produced only minor impairments of the distal extremities, without clear somatotopic organization. Dow (1942, 1974) identified the dentate nucleus in man and anthropoid apes as consisting of two parts, a dorsomedial microgyric, magnocellular older part homologous to the dentate nucleus of lower forms, and an expanded new part comprising the bulk of the dentate nucleus, the ventrolateral macrogyric parvicellular part. He postulated that the newer “neodentate” expanded in concert with, and was connected to, the frontal, temporal, and parietal association areas of

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higher primates and man, an idea he later expanded upon with Leiner et al. (1986). The study of the cerebellar role in nonmotor functions has a rich history (see Schmahmann 1991, 1997a, b, 2010 for review and citations). Physiological and ablation studies demonstrated cerebellum to be engaged in autonomic functions such as pupil diameter, blood pressure, and sleep wake cycle. Cerebellar stimulation influenced the size of stroke following middle cerebral artery ligation in rats, produced generalized arousal of the electroencephalogram, evoked hyperactivity in monkeys and cats, and produced complex behaviors including grooming, predatory attack, aggression, and sham rage. Studies also showed the cerebellum to be essential for conditional associative learning including fear-­ conditioned bradycardia in the rat and the nictitating membrane response in rabbits, in addition to its role in spatial navigation and visual-spatial learning.

2.2 Cerebellar Cortex Jan Evangelista Purkynĕ (1787–1869) described the cell that would come to bear his name (Purkinyě 1837), and Ramón y Cajal (1909) provided the first detailed description of the neuronal architecture of the cerebellar cortex, including mossy fibers, granule cell glomeruli, and parallel and climbing fibers (Eccles et  al. 1967; Palay and ChanPalay 1974; Brodal et al. 1975) (Fig. 2.1). Later investigators described Lugaro cells (Fox 1959; Palay and Chan-Palay 1974) and unipolar brush cells in the vestibulocerebellum (Mugnaini and Floris 1994). Using acetylcholinesterase, Voogd and colleagues (Voogd 1967, 1969; Marani and Voogd 1977) demonstrated parasagittal zonal organization in cerebellar white matter: zones A and B at the vermis, paravermal zones C1, 2, and 3, and zones D1 and 2 in the hemispheres. Hawkes and colleagues (Gravel and Hawkes 1990) demonstrated this zonal pattern in the cortex using monoclonal antibodies. Histochemical markers confirmed these parasagittal zones, each with topographically arranged connections with the deep cerebellar nuclei (Haines 1981) and inferior olive (Groenewegen and Voogd 1977; Hoddevik and Brodal 1977; Groenewegen et al. 1979). The demonstration of fractured somatotopy in sensory projections to cerebellum (Shambes et  al. 1978; Bower and Kassel 1990) is consistent with the observation that Purkinje cells (PCs) can be activated by the ascending axons of granule cells (Llinas 1984; Cohen and Yarom 1998) as well as by beams of parallel fibers.

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Fig. 2.1  General organization of the cerebellar cortex. (a) Santiago Ramón y Cajal (1911/1995) diagram of the neurons in the cerebellar cortex-oriented perpendicular to the long axis of the folium, as well as fibers and glial cells. A molecular layer, a Purkinje cell, B granular layer, b basket cell, C white matter of the folium, d pericellular baskets around the PC soma formed by the basket cell axon, e superficial stellate cell, f Golgi cell, g granule cell, h mossy fiber, i ascending axon of granule cell, j Bergmann glial cell, m astroglial cell, n climbing fiber, o recurrent collateral branches of a PC. (b) Diagram redrawn from Eccles et al. (1967) in Gray’s Anatomy (1995). A single cerebellar folium is shown sectioned in its longitudinal axis (diagram right) and transversely (left). Purkinje cells are red; superficial and deep stellate, basket and Golgi cells are black; granule cells and ascending axons and parallel fibers are yellow; mossy and climbing fibers are blue. Also shown are the glomeruli with mossy fiber rosettes, claw-like dendrites of granule cells, and Golgi axons. Lugaro and unipolar brush cells are not shown (Figures reproduced with permission)

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2.3 Connectional Anatomy Myelin and degeneration studies in the nineteenth and early twentieth centuries revealed that cerebellar connections with spinal cord, vestibular system, brainstem, and cerebral cortex are topographically arranged. Bechterew (1888) showed that the caudal pons is linked with the cerebellar anterior lobe, but rostral pons is linked with the cerebellar posterior lobe. Sherrington’s (1906) physiological studies showed cerebellar afferents from the proprioceptive system (he viewed cerebellum as the “head ganglion of the proprioceptive system”), and others showed topographically arranged inputs to cerebellum following proprioceptive, cutaneous (Dow and Anderson 1942; Snider and Stowell 1942; Hampson et  al. 1952) vagal, visual, and auditory stimulation (Snider and Stowell 1942; Dow and Moruzzi 1958). Cerebellar somatotopy was subsequently confirmed in anatomical and physiological investigations of afferents to the cerebellum from the spinal cord (Chambers and Sprague 1955a, b; Grant 1962a, b; Oscarsson 1965), with spinocerebellar tracts terminating exclusively in the anterior lobe and lobule VIII (sensorimotor areas of cerebellum). Spinal-­ recipient olivary nuclei project to sensorimotor cerebellum (anterior lobe and lobule VIII), whereas most of the principal olive (devoid of spinal afferents) projects to the cerebellar posterior lobe (Oscarsson 1980; Ruigrok et  al. 1992; Groenewegen et al. 1979). Anatomical studies of the feedforward loop of the cerebrocerebellar system (Brodal 1978; Glickstein et  al. 1985; see Schmahmann 2004), and electrophysiological experiments of the cerebrocerebellar system (Henneman et al. 1952; Sasaki et  al. 1975; Allen and Tsukuhara 1974) demonstrated predominantly motor connections of cerebellum in a topographically precise manner. Studies also linked cerebellum with limbic structures  – hippocampus, septum, and amygdala (Maiti and Snider 1975; Heath and Harper 1974), the hypothalamus (Haines et al. 1997), and the ventral tegmental area (Snider and Maiti 1976) that gives rise to the mesolimbic dopaminergic system critical for behavioral modulation (Carta et  al. 2019). Anterograde isotope studies of corticopontine pathways demonstrated precisely arranged inputs from motor and supplementary motor areas (Schmahmann et al. 2004), and also from associative and paralimbic regions of the prefrontal, posterior parietal, superior temporal, and parastriate cortices concerned with higher order functions (Schmahmann and Pandya 1997a, 1997b; see Schmahmann

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2010). Trans-synaptic viral tracing studies revealed that cerebellar linkage with association areas is reciprocal – cerebral areas that project via pons to cerebellum in turn receive projections back via thalamus from the cerebellum (Middleton and Strick 1994). They also showed that cerebellar anterior lobe and dorsal dentate nucleus are linked with motor cortices, whereas cerebellar posterior lobe and ventral dentate nucleus are linked with prefrontal and posterior parietal regions (Clower et al. 2001; Dum and Strick 2003).

2.4 The Cerebellar Motor Syndrome Early studies in patients with Friedreich’s ataxia, cerebellar cortical atrophy, and penetrating gunshot injuries of the cerebellum (Brown 1892; Marie 1893; Babinski 1899; Holmes 1907) established the critical role of cerebellum in coordination of extremity movement, gait, posture, equilibrium, and speech. Holmes (1939) later analyzed the motor and speech deficits resulting from focal cerebellar injury. Much of Holmes’ terminology and neurologic examination remain in contemporary use (see Chap. 3). These clinical studies confirmed in human that the vestibular cerebellum was important for posture and equilibrium, the spinocerebellum for locomotion and extremity movement, and they suggested that the neocerebellum was important for manual dexterity. The anterior superior cerebellar vermis was particularly important for gait. Hypotonicity was a frequent accompaniment of bilateral cerebellar lesions. Lesions involving both cerebellar hemispheres produced characteristic cerebellar dysarthria. More than a century of clinical neurology has further refined the understanding of the cerebellar motor syndrome, and now clinical rating scales are helpful in defining the nature and severity of the motor incapacity.

2.5 The Cerebellar Cognitive Affective Syndrome From the earliest days of clinical case reporting, at least since 1831 (Combette 1831), instances of mental and intellectual dysfunction were described in the setting of cerebellar pathology (Schmahmann 1991). Sizable posterior lobe strokes may produce only nausea and vertigo at the onset, and gait impairment subsides once the vestibular syndrome improves (Duncan et  al. 1975; Schmahmann et  al. 2009). Surgically induced dentate nucleus lesions in humans do not produce motor disability (Zervas et  al. 1967). Cerebellar abnormalities have been identified in autism (Bauman and Kemper 1985), schizophrenia (Moriguchi 1981; Snider 1982), and attention-deficit disorder (Berquin et  al. 1998). Cognitive impairments were noted in patients with cerebellar stroke (Botez-Marquard et  al. 1994; Silveri et  al. 1994),

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c­erebellar cortical atrophy (Grafman et  al. 1992), and in those with cerebellar developmental disorders (Joubert et al. 1969; see Schmahmann 1991, 1997a). The spinocerebellar ataxias have changes in cognition to varying degrees throughout the course of the illness (Manto 2014); and in children, mutism and subsequent dysarthria occur following excision of cerebellar tumors (Wisoff and Epstein 1984), often accompanied by regressive personality changes, emotional lability, and poor initiation of voluntary movement (Pollack et  al. 1995; Levisohn et al. 2000; Gudrunardottir et al. 2016). Schmahmann and Sherman (1998) described the cerebellar cognitive affective syndrome (CCAS) in patients with acquired cerebellar lesions characterized by impairment of executive functions such as planning, set-shifting, verbal fluency, abstract reasoning, and working memory; difficulties with spatial cognition including visual-spatial organization and memory; personality change with blunting of affect or disinhibited and inappropriate behavior; and language deficits including agrammatism and dysprosodia. The CCAS occurred following lesions of the cerebellar posterior lobe, and the vermis was usually involved when there was a prominent affective component. The CCAS was then described in children (Levisohn et al. 2000) with a similar pattern of cognitive deficits, the affective changes reflecting damage to the vermis, and it has been replicated widely (e.g., Neau et al. 2000; Riva and Giorgi 2000; Tedesco et  al. 2011). Metalinguistic deficits (Guell et  al. 2015) are related to impaired social cognition (Hoche et al. 2015), and neuropsychiatric symptoms occur in the domains of attention, mood, social cognition, autism, and psychosis spectrum behaviors (Schmahmann et al. 2007). It is now apparent that there is a double dissociation in the motor vs cognitive dichotomy of cerebellar clinical neurology. Holmes’ (1917) cerebellar motor syndrome of ataxia, dysmetria, and dysarthria arises following lesions of the sensorimotor anterior lobe but not the posterior lobe; the CCAS/Schmahmann syndrome (Manto and Mariën 2015) arises from the cognitive – affective posterior lobe, but not the anterior lobe (Schmahmann and Sherman 1998; Levisohn et al. 2000; Schmahmann et al. 2009). The cognitive and limbic consequences of cerebellar injury and the underlying neurobiology and theory of the putative cerebellar role in cognition were crystallized in the 1997 monograph on this topic (Schmahmann 1997b).

2.6 Atlases and Functional Neuroimaging Vincenzo Malacarne provided the first detailed description of the cerebellum (Malacarne 1776), naming the vermis, lingula, and tonsil. The atlas of Vicq-d’Azyr (1786) showed the structure of the cerebellum. Depictions of cerebellum and brainstem were included in drawings by Franz Joseph Gall (Gall and Spurzheim 1810) and Herbert Mayo (1827), and in

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Fig. 2.2  Depictions of the cerebellum by early anatomists. (a) Image from the atlas of Vicq-d’Azyr (1786). His Plate IV includes the cerebellum. The image is flipped vertically, as in the atlas the cerebellum is shown at the top. (b) Images from the atlas of Gall and Spurzheim (Gall and Spurzheim 1810). i Gall and Spurzheim’s Plate IV, shows the base of the brain with cerebral hemispheres, cerebellum and brainstem. ii Plate XIII, shows dissections of the cerebral hemisphere and cerebel-

lum. iii Plate X shows cerebral and cerebellar hemispheres partially dissected in the sagittal plane. (c) Depictions of white matter dissections of the cerebral hemisphere, cerebellum, and brainstem by Mayo (1827). i Plate III shows dissection of the middle cerebellar peduncle. In ii Plate IV, brainstem and cerebellar dissection with removal of the MCP reveals the inferior and superior cerebellar peduncles

numerous volumes on cerebellum (Bolk 1906; Edinger 1909; Ingvar 1918; Riley 1929; Ziehen 1934; Larsell and Jansen 1972) (Fig.  2.2). The most detailed human atlas available was that of Angevine et al. (1961), until the introduction of the three-dimensional MRI Atlas of the Human Cerebellum (Schmahmann et al. 2000) for use with anatomic and functional neuroimaging. It depicted cerebellum in the three cardinal planes in Montreal Neurologic Institute stereotaxic space, included histological specimens with cerebellar nuclei, and revised Larsell’s nomenclature. This atlas facilitated the development of the on-line SUIT atlas (Diedrichsen 2006) for functional neuroimaging. Magnetic resonance imaging (MRI) revolutionized the ability to visualize posterior fossa structures and lesions. Task-based functional MRI reliably shows cerebellar activation by motor (Fox et al. 1985) and nonmotor tasks (Petersen et al. 1989; Gao et al. 1996). The topography of functions in

cerebellum is exemplified in fMRI meta-analyses and prospective studies showing areas of cerebellum dedicated to motor control, cognition, and emotion (Stoodley and Schmahmann 2009; Stoodley et al. 2012; Guell et al. 2018; King et al. 2019). Resting state functional connectivity MRI has added physiological connectivity evidence to the connectional data from non-human primates, showing functionally and anatomically distinct cerebrocerebellar circuits (Buckner et al. 2011; Habas et al. 2009; O’Reilly et al. 2010).

2.7 Theories Snider (1952) proposed that cerebellum is the great modulator of neurologic function, and Heath (1977) regarded it as an emotional pacemaker for the brain. Gilbert and Thach (1977) confirmed the hypothesis of Marr (1969) and Albus

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(1971) that cerebellar climbing fibers and mossy fibers work in collaboration to facilitate a cerebellar role in motor learning. Ito used the model of the vestibular ocular reflex (Lisberger and Fuchs 1978) to suggest that the cerebellum engages in error correction in the realms both of movement (Ito 1984) and of thought (Ito 1993). Leiner et al. (1986) and Leiner and Leiner (1997) drew on evolutionary considerations of the dentate nucleus expanding in concert with cerebral association areas to propose that cerebellum serves as a multipurpose computer designed to smooth out performance of mental operations. Thach (1996) suggested that the cerebellum uses the mechanism of context-response linkage for motor adaptation, motor learning, and higher function. Llinas and Welsh (1993) highlighted the role of the olivocerebellar system in entraining cerebellar neuronal firing, focusing on the cerebellar role in movement. Other ideas include the view that the cerebellum is critical for timing (Ivry and Keele 1989), sensory perception (Bower 1995), anticipation and prediction (Courchesne and Allen 1997), and sequence learning (Molinari et al. 1997). Schmahmann’s dysmetria of thought theory (Schmahmann 1991, 2000, 2010) holds that there is a universal cerebellar transform that maintains function around a homeostatic baseline according to context; information being modulated is determined by topographically arranged anatomical circuits; the universal cerebellar impairment is dysmetria – resulting in the motor ataxia syndrome when the motor cerebellum is damaged, the CCAS when the cognitive-limbic cerebellum is damaged.

2.8 Evolving Techniques and Therapies Walker (1938) showed that stimulation of the cerebellum alters electrical activity of the motor cortex. Cerebellar stimulation in patients produced amelioration of aggression (Heath 1977) and reduced the frequency of seizures (Riklan et al. 1974). The recognition of the cerebellar incorporation into the distributed neural circuits subserving cognition and emotion as well as motor control has opened the way to brain modulation using transcranial magnetic stimulation and transcranial direct current stimulation of the cerebellum. These approaches have been used to study cerebrocerebellar interactions in health (Hashimoto and Ohtsuka 1995; Schutter and van Honk 2006; Halko et  al. 2014) and disease (e.g., Wessel et al. 1996; Brady Jr et al. 2019). They have also been used to treat motor and cognitive/emotional manifestations in individuals with cerebellar disorders, and to improve motor learning, stroke recovery, speech and language functions, and non-ataxic neuropsychiatric and movement disorders (Demirtas-Tatlidede et  al. 2010; Grimaldi et  al. 2014;

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Cattaneo et  al. 2021; Manto et  al. 2021). Magnetoencephalography (MEG) can record activity in the human cerebellum (Tesche and Karhu 1997) and provides a temporal dimension to the study of cerebellar circuitry and function. Magnetic resonance spectroscopy (MRS) is sensitive to metabolic changes (Ross and Michaelis 1996), is abnormal in patients with cerebellar degeneration (Tedeschi et  al. 1996), and together with morphometric studies of volumetric change may be useful as a biomarker of cerebellar dysfunction in the spinocerebellar and other ataxias (Őz et al. 2011, 2020). Diffusion tensor MRI (Takahashi et  al. 2014) and optical coherence tomography (Liu et  al. 2021) also now enable novel insights into cerebellar anatomy, connections, and disease. Physical, occupational, and speech rehabilitation strategies have long been the mainstay of therapy for ataxia. Therapeutic nihilism has given way to the appreciation that many symptoms experienced by ataxia patients can be treated successfully with medications. Rest tremor, spasticity, camps, dystonia, neuropathic pain, dysphagia, urogenital symptoms, orthostasis, fatigue, mood and attention, among others symptoms, can all be effectively managed by repurposing medications from other neurological disorders, mandating that ataxia clinicians be more proactive in the care of these patients (Stephen et  al. 2019; Perlman 2020). Medications are also being repurposed or newly developed for the treatment of kinetic ataxia that address the underlying molecular and physiological defects that produce cerebellar motor, cognitive, and other syndromes. Since the discovery of the genetic basis of Friedreich’s ataxia (Campuzano et al. 1996), the understanding of autosomal dominant spinocerebellar ataxias and recessive ataxias has produced a paradigm shift in the care of patients and families with heritable cerebellar disorders. Exome sequencing and genome analysis have catapulted this further forward. Advances in understanding the genetics of the ataxias and the development of novel approaches to gene-related therapies such as the introduction of antisense oligonucleotides, modulation of downstream common pathway mechanisms, and direct implantation of genes using viral vectors (Ashizawa et al. 2018) hold out real promise for amelioration, cessation, and perhaps even prevention of the phenotypic manifestations of the genetic ataxias. Acknowledgements Supported in part by the National Ataxia Foundation, the MINDlink foundation, and Mary Jo Reston. The images in Figs.  2.1 and 2.2 were acquired in the Harvard Medical School Countway Library of Medicine Rare Books and Special Collections Department, and are reproduced from Schmahmann and Pandya (2006).

2  A Brief History of the Cerebellum

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3

Pivotal Insights: The Contributions of Gordon Holmes (1876–1965) and Olof Larsell (1886–1964) to Our Understanding of Cerebellar Function and Structure Duane E. Haines

Abstract

Among the notables who have contributed to our knowledge of cerebellar structure and function, two individuals stand out. The neurologist Gordon M.  Holmes, consequent to his clinical observations on patients with cerebellar damage, especially those with injuries in WW I, provided a remarkable understanding of deficits, their laterality in relation to lesion location, and whether or not it involved cortex, nuclei, or both. He also defined, and refined, the clinical terminology describing cerebellar deficits to a level of accuracy, and especially relevance, that it is commonly used today. The anatomist Olof Larsell, in 1920, embarked on a line of investigation that would result, over 25+ years later, in a coherent and organized terminology for the lobes and lobules of the cerebellum that is widely used today and was the structural basis for numerous later experimental investigations. In this effort Larsell used a developmental approach, mapped the sequential approach of the cerebellar fissures and folia, and offered a terminology that clarified the existing, and confusing, approach that existed prior to 1920. Keywords

Gordon Holmes · Olof Larsell · Cerebellum · History of neuroscience

Letter: Larsell to CJ Herrick, July 20, 1948, The Herrick Collection, Neurology Collection, C.  J. Herrick papers, Kenneth Spencer Research Library, University of Kansas Libraries, Lawrence, Kansas. *Although Larsell began writing his monographs in the early 1940s, at his death in 1964 it fell to Jan Jansen, a friend D. E. Haines (*) Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC, USA e-mail: [email protected]

of many years, to assume the significant task of seeing the partially finished manuscripts to completion (Larsell and Jansen 1967, 1970, 1973). Discoveries in function commonly follow the clarification provided by dogged investigations of brain morphology. Based on chronology, one could argue that the reverse is seen in the contributions of the protagonists in this brief story: the British clinical neurologist, Gordon Morgan Holmes (Feb. 22, 1876–Dec. 29, 1965), and the American neuroanatomist Olof Larsell (Mar. 13, 1886–April 8, 1964).

3.1 Gordon M. Holmes Holmes (Fig. 3.1) received his medical training at Trinity College, Dublin (1899). Consequent to a successful stint at the Richmond Asylum, Dublin, he spent over 2 years studying with Karl Weigert and Ludwig Edinger where he gained an appreciation for the intricacies of brain morphology. He went on to hold positions at the National, Charing Cross, and Moorfields Ophthalmic Hospitals. With the beginning of World War (WW) I, Holmes attempted to enlist but was rejected (he was myopic). He bypassed this obstacle by joining a Red Cross hospital immediately behind the front where he rose through the ranks. The combination of his work ethic, skill as a neurologist, and the unfortunate availability of injured solders provided the means for Holmes to make clinical observations that were remarkably insightful for their time. This great World War provided literally hundreds of soldiers with injury to the occipital region and the cerebellum, due to poorly designed helmets. This provided Holmes the opportunity to observe, study, and refine clinical concepts of cerebellar function that stand to this day. Quotes are liberally used here to clearly illustrate the contemporary nature of Holmes’ (and Larsell’s) descriptions. Holmes published a large body of information regarding cerebellar influence on somatomotor activity from his clini-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_3

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D. E. Haines

Fig. 3.1  Holmes (light suit, hands in pockets) during a stay at the Senkenberg Institute. Back row, L to R: Juliusberg, Rosenberg, Jensen, Philipp, Franz. Front row, L to R: Von Jagic, Southard, Edinger, Holmes,

Herxheimer, Tiegel, Kunicke, Friedmann. Sitting, Weigert (Courtesy of The Cerebellum, 2007; 6: 141–156)

cal research (Holmes 1917) and presented it in his Croonian Lectures of 1922 (Holmes 1922a, b, c, d). He acknowledged that his cases were:

previous misconceptions but also expanded the understanding of cerebellar function at that time. Many ideas and concepts were clarified, or discovered, by Holmes and described in terms/phrases that could come from any twenty-first-­ century comprehensive textbook. First, Holmes definitively clarified the fact that

…determined largely by the opportunities I have had of observing the effects of local lesions of the cerebellum in both warfare and civil life.

While he acknowledged the numerous prior studies that attempted to answer fundamental questions he noted:

The effects of cerebellar injuries fall almost exclusively upon the motor system, … of the same side.

…there is still a remarkable divergence between the symptoms attributed in various text-books and monographs to lesions of the cerebellum in man.

This is now a well-established concept, along with the newer recognition of the wider role of the cerebellum. Second, Holmes noted the difficulty of sorting out what difference may exist between lesions of only the cerebellar cortex versus cortex plus nuclei. He described deficits resultant from clearly superficial lesions (cortex) and those with deeper damage (cortex + nuclei) and concluded:

Holmes made detailed studies of patients (acute and long term) with cerebellar lesions to clarify the unique traits of particular somatomotor deficits. Using this patient population, he made definitive observations that not only clarified

3  Pivotal Insights: The Contributions of Gordon Holmes (1876–1965) and Olof Larsell (1886–1964) to Our Understanding… … we find that when the lesion is so superficial that the nuclei cannot have been directly injured the symptoms are less intense, less regular, and that they disappear much more rapidly. … rapid improvement is never seen when the damage extends to the neighborhood of the central nuclei.

This is observed in the contemporary clinic: a distal PICA lesion (cortex) results in a cascade of vestibular and motor deficits that resolve quickly, within days to very few weeks, while SCA lesion (cortex + nuclei) results in a similar cascade of motor deficits lasting weeks, months, or years. Third, Holmes noted that a “… most striking feature…” is a decrease in muscle tone. He reported that: When a lesion involves a large part of one-half of the cerebellum, … the hypotonia is rigidly limited to … the same side … often most pronounced at the proximal than at the distal joints.

He clarified the variety of tests that could be used to arrive at an accurate diagnosis. Fourth, Holmes accurately described the variety of movement disorders that characterize cerebellar lesions: Dysmetria … striking abnormality in the affected limbs … their movements are not correctly adapted or proportioned … they are ill-measured.

He noted that dysmetria may exist in two forms: “… the range of movement is most commonly excessive …” (hypermetria) or that “… the movement is arrested or slowed down before the point the patient wishes to attain is reached …” (hypometria).

Fifth, three common cerebellar deficits are the rebound phenomenon, diadochokinesia, and the intention tremor. Concerning the first, Holmes noted (see also Koehler et al. 2000):

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In the early part of the movement the limb sways about in a purposeless manner as soon as it is raised from its support … in trying to touch his nose, his finger, for instance, often comes to his cheek or eye.

A remarkable element of the work by Holmes on the cerebellum is its accuracy, detail, insights, and relevance to modern-­ day neurology. In fact, one can read Holmes and get information that is just as detailed, correct, and useful with respect to the motor phenomena following cerebellar injury as in any contemporary text.

3.2 Olof Larsell Larsell (Fig. 3.2; March 13, 1886–April 8, 1964) was born in Rättvik, Sweden, and came to the United States with his mother at age 5; his father had established a home in Tacoma, Washington. He received B.S degree (in Biology) from McMinnville (now Linfield) College in 1910. His academic travels were circuitous. He taught at Linfield (1910–1913), attended Northwestern University (1913–1914, M.S. degree in Zoology), taught at Linfield (1914–1915), re-entered Northwestern in 1915, and received his Ph.D. degree in 1918 (Haines 1999). During the summers of 1913 and 1914, Larsell took summer courses at the University of Chicago under the renowned American neuroanatomist, Charles Judson Herrick. These fortuitous summer experiences greatly

… resistance that effectively prevents a movement of a normal limb in response to a strong voluntary effort be suddenly released, the limb, after moving a short distance … is arrested abruptly by the action of the antagonist muscles… this sudden arrest fails frequently in cerebellar disease … when the grasp is suddenly relaxed the hand on the affected side swings violently toward his face or shoulder, and … may be flung above his head.

Diadochokinesia is the inability of a patient to rapidly … pronate and supinate his forearms … a very striking difference is noticed between the movements on the two sides ….

Holmes noted that if the limb was hypotonic the abnormal movements may be slow, irregular in “… rate and range …” and “… become more pronounced the longer the effort is continued …”. Holmes described the intention tremor as complex movements, its individual components are disrupted, uncoordinated, and largely ineffective. He noted:

Fig. 3.2  Olof Larsell in his office at the University of Oregon Medical School, ca. 1945. Author’s collection (Courtesy of Mr. Robert Larsell)

D. E. Haines

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influenced Larsell’s thinking, research direction, and lifelong fascination with brain anatomy.

3.3 The Problem During the period spanning the 1880s and up to about the mid-1940s, the terminology utilized to designate the lobes/lobules, folia, and fissures of the cerebellum was highly variable. It consisted of different names being given to the same folia/lobes/lobules; in some cases, lower and upper case letters intermixed with numbers/numerals (Arabic and Roman), and what constituted a lobe was inconsistently applied (Angevine et al. 1961). For example, the vermis part of the culminate lobule (IV and V of Larsell) was called the culmen, culmen monticule, pars culminus of the lobus anterior, lobe B, or lobules 3 and 4. This represented a significant confusion of terminology. Stemming from his time with Herrick, Larsell began a series of studies that would span over 40 years and focus on the morphology of the cerebellum utilizing a developmental approach. Whether or not Larsell realized it, this approach would reveal homologies in lobes, lobules, and fissures across a wide range of biological forms that are not evident in a study of the adult form. This would clearly establish a broad-based biological pattern. Larsell’s first paper, published in 1920, identifies the source of his motivation: It was at the suggestion of Professor Herrick that the present study was begun. It is a pleasure for the writer to acknowledge his sense of indebtedness to Professor Herrick….

3.4 Early Studies, 1920–1932 Larsell’s first paper, “The cerebellum of Amblystoma” appeared in 1920. This early period focused on non-­ mammalian forms. Interestingly, Larsell listed his first affiliation as the “Anatomical Laboratories of the University of Chicago” and “the University of Wisconsin” where he was an Assistant Professor (1918–1920). While Herrick had influenced the study, and provided some material, Larsell was not in residence at Chicago. In this time frame, Larsell methodically detailed the cerebelli of the tiger salamander, frog, newt, and a variety of snakes and lizards. He used silver impregnation methods (Golgi, Cajal), myelin and hematoxylin stains, and the Marchi method. He described the aspects of development and the external anatomy of adult forms, specified a larger corpus cerebelli and a smaller auricular lobe, the cortical histology of these primitive forms, and the primordial cerebellar nuclei. He did not use a lobule designation, but the dye was cast (Larsell 1920, 1923, 1925, 1926, 1931, 1932a, b).

3.5 The Middle Period, 1932–1947 In this period, Larsell expanded on the concept of a large cerebellar mass, the corpus cerebelli. The first superficial feature to appear was a shallow fissure along the caudal and lateral edge of the cerebellar anlage. Larsell identified the lateral part of this groove as the “parafloccular fissure” and the medial part as the “uvulonodular fissure” (or floccular fissure), terms used by the previous investigators. This combined fissure separated a large rostral part of the cerebellum, the “corpus cerebelli,” from a smaller caudal part, the “vestibular floccular lobe” (Larsell 1931, 1932a, 1934, 1936a, b, 1937, 1947a, b). In studies during this period on opossum, bat, and human specimens, Larsell carefully refined the basis for his new nomenclature. He noted that a “posterolateral fissure” (his term) replaced the combined terms of parafloccular and uvulonodular fissures that this fissure was first to appear in the cerebellar anlage dividing it into a “flocculonodular lobe” and “corpus cerebelli, ” and that the “primary fissure” was the second to appear and divided the corpus cerebelli into anterior and posterior lobes. Larsell (1935, 1936a, b, 1945, 1947a, b) noted: The flocculonodular lobe and the corpus cerebelli are the fundamental cerebellar divisions morphologically, and … functionally.

At this point, two old concepts were disproven; first, the primary fissure was not the first to appear in development, and second, the concept of a “median lobe” was no longer viable.

3.6 Later Studies and the Solution, 1948–1954 After 10  years of study on the avian cerebellum, Larsell used, for the first time (1948), the unique terminology that he had been working toward since 1920. He noted that the posterolateral fissure was the first to appear in the cerebellar plate dividing it into a flocculonodular lobe and the corpus cerebelli. Larsell (1948) indicated that an orderly appearance of subsequent fissures in the corpus cerebelli resulted in an adult structure of 10 main folia (Roman numerals I–X). For convenience of description, they will be numbered I to X beginning anteriorly.

In this introduction of his method, Larsell used the term “… folia…” recognizing the simple structure of the avian cerebellum, which lacked a hemisphere, and the vermis consisted of leaf-like structures. Between 1952 and 1954, Larsell reported his extensive observations on the cerebellum of the white rat, cat, monkey,

3  Pivotal Insights: The Contributions of Gordon Holmes (1876–1965) and Olof Larsell (1886–1964) to Our Understanding…

pig, and human using developmental stages and adult specimens (Larsell 1952, 1953a, b, 1954; Larsell and Dow 1939; Larsell and Whitlock 1952). Using these mammals, he clearly showed that the mature mammalian cerebellum was composed of subdivisions called “… lobules…”. I have pointed out…the striking similarities between folia I–X of birds and the vermian segments of the rat which the present investigation has brought to light … I shall call these segments lobules I–X, corresponding to the similarly named avian folia.

Each lobule of the vermis, beginning with the lingual and ending with the nodulus, was identified by Roman numerals (I, II, III … X). The lateral extension of each vermis lobule, the hemisphere portion, was identified by the same Roman numeral but with the prefix H (HII, HIII … HX) specifying “hemisphere portion of…”. Larsell recognized that the basic pattern of a cerebellar plate being transected by two fissures (joining to make one – the posterolateral) formed a larger corpus cerebelli and a smaller flocculonodular lobe. In concert, he noted that the development of the primary fissure, the second to appear and first in the corpus cerebelli, resulted in an anterior lobe (lobules I–V) and a posterior lobe (lobules VI–IX); the further development of additional fissures in these lobes clearly established to a fundamental plan. He postulated that this 10 lobule arrangement would prove to be applicable to a wide range of forms, a point well-taken. In studying Larsell’s correspondence with Herrick, it is clear that he was a quiet, reserved man who was concerned about the wider impact of his life-long work. In a letter to Herrick (dated July 20, 1948), Larsell says: I treaded on Brouwer’s and Ingvar’s toes somewhat  – gently enough I hope…, but I do not think my work will need repeating.

Indeed, it did not merit repeating, and by the late 1950s and 1960s was adopted by giants of the day and, to the present, is the standard.

References Angevine JB, Mancall EL, Yakolev PI (1961) The human cerebellum: an atlas of gross topography in serial sections. Little Brown and Company, Boston, pp 1–138 Haines DE (1999) In: Garraty JA, Carnes MC (eds) American national biography, vol 13. Oxford University Press, New York, pp 204–206 Holmes G (1917) The symptoms of acute cerebellar injuries due to gunshot. Brain 40:461–535 Holmes G (1922a) Clinical symptoms of cerebellar disease and their interpretation, lecture I. Lancet 202:1178–1182 Holmes G (1922b) Clinical symptoms of cerebellar disease and their interpretation, lecture II. Lancet 202:1232–1237

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Holmes G (1922c) Clinical symptoms of cerebellar disease and their interpretation, lecture III. Lancet 203:59–65 Holmes G (1922d) Clinical symptoms of cerebellar disease and their interpretation, lecture IV. Lancet 203:111–115 Koehler PJ, Bruyn GW, Pearce JMS (2000) Neurological eponyms. Oxford University Press, Oxford, pp 172–178 Larsell O (1920) The cerebellum of amblystoma. J Comp Neurol 31:259–282 Larsell O (1923) The cerebellum of the frog. J Comp Neurol 36:89–112 Larsell O (1925) The development of the cerebellum in the frog (Hyla regilla) in relation to the vestibular and lateral-line systems. J Comp Neurol 39:249–289 Larsell O (1926) The cerebellum of reptiles: lizards and snake. J Comp Neurol 41:59–94 Larsell O (1931) The cerebellum of Triturus torosus. J Comp Neurol 53:1–54 Larsell O (1932a) The cerebellum of reptiles: chelonians and alligator. J Comp Neurol 56:299–345 Larsell O (1932b) The development of the cerebellum in amblystoma. J Comp Neurol 54:357–435 Larsell O (1934) Morphogenesis and evolution of the cerebellum. Arch Neurol Psychiatry (Chicago) 31:373–395 Larsell O (1935) The development and morphology of the cerebellum in the opossum. Part I. Early development. J Comp Neurol 63:65–94 Larsell O (1936a) The development and morphology of the cerebellum in the opossum. Part II. Later development and adult. J Comp Neurol 63:251–291 Larsell O (1936b) Cerebellum and corpus pontobulbare of the bat (Myotis). J Comp Neurol 64:275–302 Larsell O (1937) The cerebellum: a review and interpretation. Arch Neurol Psychiatry (Chicago) 38:580–607 Larsell O (1945) Comparative neurology and present knowledge of the cerebellum. Bull Minn Med Found 5:73–85 Larsell O (1947a) The cerebellum of myxinoids and petro-myzonts, including developmental stages in the lampreys. J Comp Neurol 86:395–445 Larsell O (1947b) The development of the cerebellum in man in relation to its comparative anatomy. J Comp Neurol 87:85–129 Larsell O (1948) The development and subdivisions of the cerebellum of birds. J Comp Neurol 89:123–189 Larsell O (1952) The morphogenesis and adult pattern of the lobules and fissures of the cerebellum of the white rat. J Comp Neurol 97:281–356 Larsell O (1953a) The cerebellum of the cat and the monkey. J Comp Neurol 99:135–199 Larsell O (1953b) The anterior lobe of the mammalian and the human cerebellum. Anat Rec 115:341 Larsell O (1954) The development of the cerebellum of the pig. Anat Rec 118:73–107 Larsell O, Dow RS (1939) The cerebellum: a new interpretation. West J Surg Obstet Gynaecol 47:256–263 Larsell O, Jansen J (1967) The comparative anatomy and histology of the cerebellum from myxinoid through birds. The University of Minnesota Press, Minneapolis, pp 1–291 Larsell O, Jansen J (1970) The comparative anatomy and histology of the cerebellum from monotremes through apes. The University of Minnesota Press, Minneapolis, pp 1–269 Larsell O, Jansen J (1973) The comparative anatomy and histology of the cerebellum: the human cerebellum, cerebellar connections, and cerebellar cortex. The University of Minnesota Press, Minneapolis, pp 1–268 Larsell O, Whitlock DG (1952) Further observations on the cerebellum of birds. J Comp Neurol 97:545–566

Part II Anatomy and Histology of the Cerebellum

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Gross Anatomy of the Cerebellum Jan Voogd and Enrico Marani

Abstract

After the first description of the cerebellar foliation by Vincenzo Malacarne (1744–1816) in his “Vera struttura del cervelletto umano” (the genuine structure of the human cerebellum, Malacarne Nuova espozisione della vera struttura del cervelletto umano, G.  Briolo, Torino, 1776) many different nomenclatures have been proposed for the gross anatomy of the cerebellum (Angevine Jr et al. The human cerebellum, Little Brown and Company, Boston, 1961). Here we will consider the classical nomenclature of the human cerebellum and the comparative anatomical nomenclatures of Bolk (Das cerebellum der säugetiere, Fischer, Haarlem, 1906), Larsell (J Comp Neurol 97:281–356, 1952), and Larsell and Jansen (The comparative anatomy and histology of the cerebellum. III.  The human cerebellum, cerebellar connections, and cerebellar cortex, University of Minnesota Press, Minneapolis, 1972) and their application to the human cerebellum, and to the small cerebellum of the mouse. Keywords

Vermis · Hemisphere · Fissures · Lobules · Folal cains Mouse cerebellum · Human cerebellum

J. Voogd (*) Department of Neuroscience, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands e-mail: [email protected] E. Marani MIRA Institute for Biomedical Engineering and Technical Medicine, Department of Electrical Engineering, Mathematics and Computer Science, Biomedical Signals and Systems Group, University of Twente, Enschede, The Netherlands

After the first description of the cerebellar foliation by Vincenzo Malacarne (1744–1816) in his “Vera struttura del cervelletto umano” (the genuine structure of the human cerebellum, 1776) many different nomenclatures have been proposed for the gross anatomy of the cerebellum (Angevine Jr et al. 1961). Here we will consider the classical nomenclature of the human cerebellum and the comparative anatomical nomenclatures of Bolk (1906), Larsell (1952), and Larsell and Jansen (1972) and their application to the human cerebellum, and to the small cerebellum of the mouse. In the classical nomenclature of the human cerebellum vermis and hemispheres, separated by the paramedian sulcus, are distinguished (Figs. 4.1, right panel and 4.2). The paramedian sulcus is shallow in the anterior cerebellum but is a deep cleft posterior to the posterior superior sulcus. Here, the cortex can be interrupted, with white matter appearing at the surface. In the antero-posterior subdivision, the cerebellum is divided into anterior and posterior lobes, separated by the primary fissure, the deepest fissure on a midsagittal section of the cerebellum. Names of the lobules are derived from their shape or their resemblance to particular structures (Malacarne 1776; Glickstein et al. 2009). Bolk (1906) based his nomenclature on the comparison of numerous species of mammals. Bolk considered the vermis and the hemispheres as folial chains (Figs. 4.1, left panel and 4.2e). The cortex within a chain is always continuous, in the paramedian sulcus the cortex, or more precisely, the parallel fibers in the molecular layer may be interrupted. In the anterior lobe and in the simplex lobule, located immediately caudal to the primary fissure, the folial chains of the vermis and hemisphere are aligned and the transverse fissures continue uninterruptedly from the vermis into the hemisphere. Caudal to the simplex lobule, the folial chain of the hemisphere makes two loops, the ansiform lobule and the paraflocculus. The most caudal lobule of the folial chain of the hemisphere, the flocculus, is reflected upon the distal part of the paraflocculus. The cortex in the center of the ansiform lobule, lateral

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_4

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J. Voogd and E. Marani

Fig. 4.1  Nomenclature of the cerebellum. Left panel illustrates the comparative anatomical nomenclature for the hemisphere and Larsell’s (1952) numbering system for the lobules of the vermis and hemispheres. Right panel shows the classical nomenclature of the human

cerebellum. The homology of these lobules is indicated using the same color. Asterisks denote areas devoid of cortex in the center of folial rosettes of the ansiform lobule and the paraflocculus. Cop copula pyramidis, PMV posterior medullary velum

to the folium/tuber (Larsell’s lobule VII) is interrupted. The rostral and caudal limbs of the folial loop of the ansiform lobule are known as the Crus I and II. The cortex is absent between the caudal vermal lobules, the uvula and the nodulus (IX and X), and the paraflocculus (HIX) and the flocculus (HX). The rostral and caudal limbs of the paraflocculus are known as the dorsal and ventral paraflocculus. At the level of the paramedian lobule, located between the ansiform lobule and the paraflocculus, the folial chains of vermis and hemispheres are aligned and the paramedian sulcus is indistinct. Interlobular fissures, if present, continue uninterruptedly from the pyramis (VIII) into the paramedian lobule. Larsell (1952) emphasized the medio-lateral continuity of the lobules of vermis and hemispheres. He distinguished 10 lobules in the vermis, indicated with the roman numerals I–X (Fig.  4.1, left panel). Their hemispheral counterparts are indicated with the prefix H.  From Larsell’s description, it becomes clear that the paramedian lobule consists of rostral and caudal subdivisions. Its rostral portion (lobule HVIIB, the gracile lobule) is continuous with vermal lobule VII, and

its caudal portion (HVIII: the copula pyramidis) is continuous with lobule VIII (the pyramis). Several MRI atlases of the human cerebellum have been published (Schmahmann et al. 2000; Dietrichsen et al. 2009). They use a mixture of the classical and comparative anatomical nomenclatures, retaining the terms Crus I and II of the ansiform lobule. In applying Larsell’s numeral system, they discarded the prefix H for lobules of the hemisphere, thus introducing some confusion because it is not always clear whether lobules of vermis or hemispheres are meant. For the homology of the paraflocculus and the flocculus with lobules in the human cerebellum, it is important to note that the cortex of the flocculus can be subdivided into five longitudinal Purkinje cell zones (Voogd and Barmack 2006; Schonewille et  al. 2006). Two zonal pairs connect through vestibulo-oculomotor neurons with the external eye muscles. In most mammals, these floccular zones extend for some distance on the ventral paraflocculus. In monkeys, they occupy the entire ventral paraflocculus. A narrow cortical bridge connects the ventral with the dorsal paraflocculus. In the

4  Gross Anatomy of the Cerebellum

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a

d

b

e

c

f

Fig. 4.2 (a–c) Anterior, dorsal, and posterior views of the human cerebellum. Red lines indicate the direction of the folial chains of vermis and hemispheres. (d) Midsagittally sectioned human cerebellum. (e) Bolk (1906) diagram of the folial chains of vermis and hemispheres. (e) Dissection of the posterior cerebellum after removal of the tonsil. (f)

folial loops of the ansiform lobule and the paraflocculus, Ce central lobule, Cu culmen, De declive, Fol/Tu folium and tuber vermis, N nodulus, PFLD dorsal paraflocculus, PFLV ventral paraflocculus, Py pyramis, Uv uvula, Vma anterior medullary velum

human cerebellum, this cortical bridge is broken. The dorsal paraflocculus is represented by the tonsil and the ventral paraflocculus by the accessory paraflocculus. In most mammals, the folial loop of the paraflocculus is directed laterally. The folial loop of the tonsil, however, is directed medially (Fig. 4.2f). The cerebellum of the mouse conforms to Bolk’s general pattern (Marani and Voogd 1979). In the anterior lobe, the lobules (H) I and II and (H) IV and V are fused (Fig.  4.3). A paramedian sulcus is absent in the anterior

lobe and the simplex lobule.1 An area without cortex is present lateral to lobule VII in the center of the ansiform lobule and lateral to the rostral paramedian lobule. White matter in the paramedian sulcus separates lobules IX and Because the vermis projects to the fastigial and vestibular nuclei, the lateral border of the vermis is located latral to the Purkuinje cell zone B that projects to the lateral vestibular nucleus. The location of the B zone in the anterior cerebellum and lobule VIII was established for the rat by Voogd and Ruigrok (2004) the corresponding white matter comprtment was located for the mouse by Marani (1986). 1 

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J. Voogd and E. Marani

e

b

c

f

d

Fig. 4.3  The cerebellum of the mouse. (a–d) Anterior, dorsal, posterior, and ventral views of the cerebellum of the mouse. Interruptions of the cortex are indicated in red. (e) View of the midsagittaly sectioned molecular layer of the cerebellum of the mouse. Dotted line indicates the attachment of the roof of the fourth ventricle. (f) Lateral view of a reconstruction of the molecular layer of the cerebellum of the mouse.

Note continuity between the copula pyramidis and the paraflocculus. Arrows point to regions where the cortex is interrupted [Modified from Marani and Voogd (1979)]. Drawings by Jan Tinkelenberg. ANS ansiform lobule, COP copula pyramidis, CrI, II Crus I II of the ansiform lobule, FLO flocculus, PFL paraflocculus, PMD paramedian lobule, SIM simplex lobule

X from the paraflocculus and the flocculus. The cortexless areas extend from the paramedian sulcus into the superior part of the lobules IX and X. The copula pyramidis (HVIII) lateral continues into the dorsal paraflocculus. The folial loop of the paraflocculus remains separated from the para-

median lobule by the white matter in the parafloccular sulcus, an extension of the white matter surrounding the cerebellum. The paraflocculus is incompletely divided into dorsal and ventral limbs by the intraparafloccular sulcus on the medial side of this lobule.

4  Gross Anatomy of the Cerebellum

References Angevine JNB Jr, Mancall EL, Yakovlev PI (1961) The human cerebellum. Little Brown and Company, Boston Bolk L (1906) Das cerebellum der säugetiere. Fischer, Haarlem Dietrichsen J, Balsters JH, Flavell J, Cussans E, Ramnani M (2009) A probabilistic MR atlas of the human cerebellum. Neuroimage 46:39–46 Glickstein M, Strata P, Voogd J (2009) Cerebellum: history. Rev Neurosci 162:549–559 Larsell O (1952) The morphogenesis and adult pattern of the lobules and tissues of the cerebellum of the white rat. J Comp Neurol 97:281–356 Larsell O, Jansen J (1972) The comparative anatomy and histology of the cerebellum. III.  The human cerebellum, cerebellar connections, and cerebellar cortex. University of Minnesota Press, Minneapolis

27 Malacarne V (1776) Nuova esposizione della vera struttura del cervelletto umano. G. Briolo, Torino Marani E (1986) Topographic histochemistry of the cerebellum. Prog Histol Cytochem 16:1–169 Marani E, Voogd J (1979) The morphology of the mouse cerebellum. Acata Morphol Neerl Scand 17:33–52 Schmahmann JD, Doyon D, Toga AW, Petrides M, Evans AC (2000) MRI atlas of the human cerebellum. Academic Press, San Diego Schonewille M, Luo G, Ruigrok TJ, Voogd J, Schmolesky MT, Rutteman M, Hoebeek FE, de Jeu FE, de Zeeuw CI (2006) Zonal organization of the mouse flocculus: physiology, input and output. J Comp Neurol 497:670–682 Voogd J, Barmack NH (2006) Oculomotor cerebellum. Prog Brain Res 151:231–268 Voogd J, Ruigrok TJ (2004) The organization of the corticonuclear and olivocerebellar climbing fiber projections to the rat cerebellar vermis: the congruence of projection zones and the zebrin pattern. J Neurocytol 33:5–21

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Vascular Supply and Territories of the Cerebellum Qiaoshu Wang and Louis R. Caplan

Abstract

Within the posterior circulation, Caplan and colleagues characterized brain and vascular structures as involving the proximal, middle, and distal posterior circulation territories. The proximal intracranial posterior circulation territory includes regions supplied by the intracranial vertebral arteries (ICVAs) – the medulla oblongata, and the posterior inferior cerebellar arteries (PICAs)  – supplied region of the cerebellum. The ICVAs join at the medullopontine junction to form the basilar artery (BA). The middle intracranial posterior circulation territory includes the portion of the brain supplied by the BA up to its superior cerebellar artery (SCA) branches – the pons and the anterior inferior cerebellar arteries (AICAs)  – supplied portions of the cerebellum. The BA divides to form the two posterior cerebral arteries (PCAs) at the junction between the pons and the midbrain, just beyond the origins of the SCAs. The distal intracranial posterior circulation territory includes all of the territory supplied by the rostral BA and its SCA, PCA, and their penetrating artery branches – midbrain, thalamus, SCA – supplied cerebellum and PCA territories. Keywords

Cerebellum · Vertebral artery · Brainstem · Basilar artery Cerebellar arteries

Q. Wang (*) Shanghai General Hospital, Shanghai, China L. R. Caplan Beth Israel deaconess Medical Center, Boston, MA, USA e-mail: [email protected]

5.1 Overview Within the posterior circulation, Caplan and colleagues characterized brain and vascular structures as involving the proximal, middle, and distal posterior circulation territories (Caplan 1996, 2000; Caplan et al. 2004, 2005; Chaves et al. 1994; Savitz and Caplan 2005). The proximal intracranial posterior circulation territory includes regions supplied by the intracranial vertebral arteries (ICVAs)  – the medulla oblongata, and the posterior inferior cerebellar arteries (PICAs)  – supplied region of the cerebellum. The ICVAs join at the medullopontine junction to form the basilar artery (BA). The middle intracranial posterior circulation territory includes the portion of the brain supplied by the BA up to its superior cerebellar artery (SCA) branches, the pons, and the AICA –supplied portions of the cerebellum. The BA divides to form the two posterior cerebral arteries (PCAs) at the junction between the pons and the midbrain, just beyond the origins of the superior SCAs. The distal intracranial posterior circulation territory includes all of the territory supplied by the rostral BA and its SCA, PCA, and their penetrating artery branches – midbrain, thalamus, SCA – supplied cerebellum and PCA territories. This distribution is shown diagrammatically in Fig. 5.1. The three surfaces of the cerebellum are: tentorial (or superior) facing the tentorium cerebelli, petrosal facing toward the petrous bone, and suboccipital facing the suboccipital bone located between the lateral and sigmoid dural sinuses (Lister et al. 1982). The PICAs encircle the medulla and supply the suboccipital cerebellar surface; the AICAs course around the pons and supply the petrosal surface of the cerebellum, and the SCAs encircle the midbrain and supply the tentorial, superior surface of the cerebellum (Lister et al. 1982). The arteries to the cerebellum are distributed rostrocaudally so that the PICAs arise from the ICVAs, the anterior inferior cerebellar arteries (AICAs) arise from the BA, and the most rostral arteries, the SCAs, arise near the BA bifurcation (Fig. 5.2). The PICAs and the SCAs, the two largest arte-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_5

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Fig. 5.1  Schema of the proximal, middle, and distal intracranial territories of the vertebrobasilar arterial system (Drawn by Laurel Cook-Lowe 1978, modeled after a figure in Duvernoy 1978)

5  Vascular Supply and Territories of the Cerebellum

Fig. 5.2  Schematic diagram of the cerebellar arteries. 1 Superior cerebellar artery (SCA); 2 medial branch of the SCA; 3 lateral branch of the SCA; 4 anterior inferior cerebellar artery (AICA); 5 posterior inferior cerebellar artery (PICA); 6 medial branch of PICA; 7 lateral branch of PICA; 8 basilar artery; 9 vertebral artery (From Amarenco 1991)

rial pairs have medial branches that supply mostly the vermian and paravermian portions of their respective regions of the cerebellum, and lateral branches which supply the cerebellar hemispheres. Infarcts in the cerebellum are often limited to the territory of one of these branches, e.g., medial PICA (mPICA), lateral SCA (lSCA), etc. These cerebellar branch territory infarcts correspond to functional regions such as the inferior vermis or superior lateral neocerebellum. The AICAs, in contrast, supply only a small part of the anterior inferior cerebellum and the flocculus, but their major supply is to the lateral pontine tegmentum and the brachium pontis. The AICAs do not divide into medial and lateral major cerebellar branches but give off twigs to various structures.

5.2 Posterior Inferior Cerebellar Arteries (PICAs) The PICAs usually originate from the ICVAs about 2  cm below the origin of the basilar artery, and, on average, about 8.6 mm above the foramen magnum (Marinkovic et al. 1995). The site of origin, however, varies from 14 mm below the foramen magnum to 26  mm above the foramen magnum (Marinkovic et  al. 1995). About 10% arise from the basilar artery (Amarenco and Hauw 1989). Size varies; the diameters varied between 0.58 and 2.10 mm in one analysis (Amarenco and Hauw 1989). Some ICVAs end in PICA, and PICA can be absent in which case there usually is a large artery that arises from the proximal basilar artery that supplies both the PICA and AICA territories. Occasionally, PICA is duplicated. After coursing laterally and downward to go around the lateral medulla (the lateral medullary segment), the PICAs

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Fig. 5.3  Sketch showing course and branching of the posterior inferior cerebellar artery (PICA). 1 PICA; 2 lateral branch of PICA; 3 medial branch of PICA; 4 cerebellar hemisphere; 5 cerebellar vermis; 6 cerebellar tonsil (Reproduced with permission from Amarenco et al. 1993)

make a cranially directed loop and ascend between the dorsal portion of the medulla and the caudal part of the cerebellar tonsil on that side (the tonsillomedullary segment) (Lister et al. 1982; Marinkovic et al. 1995). They then make a second loop above the cranial portion of the tonsil and descend along the inferior vermis coursing between the inferior medullary velum and the rostral portion of the tonsil (the telovelotonsillar segment). Finally, the artery becomes superficial and supplies branches to the tonsil, medulla, choroid plexus, and cerebellar cortex. Medial and lateral branches (mPICA, and lPICA) arise from the main trunks (Fig. 5.3) at variable locations between the two PICA loops. mPICA supplies the inferior vermis including the nodulus, pyramis, uvula, tuber, and sometimes the declive and the medial portions of the semilunar lobule, gracile lobule, and the tonsil (Chaves et al. 1994; Amarenco and Hauw 1989; Amarenco et al. 1989, 1993; Amarenco 1991; Gilman et  al. 1981; Duvernoy 1978). mPICA often sends a supply to the dorsal medulla. lPICA supplies the inferior twothirds of the biventer, most of the inferior portion of the semilunar and the gracile lobules, and the anterolateral portion of the tonsil (Chaves et  al. 1994; Amarenco and Hauw 1989; Amarenco et al. 1989, 1993; Amarenco 1991; Gilman et al. 1981; Duvernoy 1978). Figures  5.4, 5.5, and 5.6 show diagrammatically the supply territories of PICA, mPICA, and lPICA, respectively. The PICAs sometimes supply the deep cerebellar structures including the fastigial nuclei but usually do not supply the dentate nuclei (Amarenco and Hauw 1989). Although many equate the Wallenberg syndrome with an occlusion of PICA causing infarction in the lateral medulla, PICA does not supply the lateral medullary tegmentum. This region is supplied by a group of parallel small arteries that originate directly from the intracranial vertebral artery and pass through the lateral medullary fossa to supply the lateral medulla (Fig. 5.7) (Duvernoy 1978). Sometimes the medial

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c Fig. 5.6  The supply zone of the lateral branch of the posterior inferior cerebellar artery (PICA) [Reproduced with permission from Amarenco (1991)]

Fig. 5.4  The supply zone of the posterior inferior cerebellar artery (PICA). (a) Shows the cerebellar supply on a dorsal view of the cerebellum. (b) Shows a lateral view of the cerebellum. (c) Shows the PICA territory on cut sections of the cerebellum and brainstem (Reproduced with permission from Amarenco 1991)

Fig. 5.5  The supply zone of the medial branch of the posterior inferior cerebellar artery (Reproduced with permission from Amarenco 1991)

Fig. 5.7  Right lateral medullary fossa. 1 Vertebral artery; 2 Posterior inferior cerebellar artery (PICA); 4 lateral medullary fossa; 5 vagus nerve; 6 IV ventricle choroids plexus; 7 glossopharyngeal nerve; 8 vestibulocochlear nerve; 9 facial nerve; 10 lateral pontine vein; 11 pons; 12 abducens nerve; 13 olive; (a) A’—rami arising from PICA; (b) rami arising from the vertebral artery to supply the lateral medulla; (c) rami arising from the basilar artery; (c, d) Rami arising from AICA (From Duvernoy 1978)

5  Vascular Supply and Territories of the Cerebellum

branch of PICA supplies a small area in the dorsal medulla that includes vestibular nuclei and the dorsal motor nucleus of the vagus. The medial branch of PICA supplies a triangular area with a dorsal base and a ventral apex toward the fourth ventricle on an axial mid-medullary and cerebellar section (Amarenco and Hauw 1989). Figure 5.8 is a sagittal section MRI showing a PICA infarct. Figure  5.9 shows a brain specimen with a medial PICA territory infarct. Figure 5.10 is a axial section MRI of a mPICA infarct.

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5.3 Anterior Inferior Cerebellar Arteries (AICAs) The AICAs are nearly constant arteries but their origins, sizes, and supply zones vary greatly. In 4% of people, there is no AICA branch (Lazorthes 1961). The AICAs have the smallest territory of supply of any of the cerebellar arteries. The AICAs usually arise about 1 cm above the vertebrobasilar artery junction (Fig. 5.11), and sometimes from the middle third of the basilar artery. Occasionally, they can arise directly from the ICVA, or from a common trunk with PICA. The internal auditory arteries are usually branches of the AICAs but in some individuals they arise directly from the basilar artery. In one study, the diameters of AICA ranged from 0.38 to 1.8  mm (mean 1.1  mm) (Marinkovic et  al. 1995). After arising from the basilar artery, the AICAs travel toward the cerebellopontine angle, passing below the Vth nerve, crossing the VIth nerve, and meeting the VIIth and VIIIth nerves at the cerebellopontine angle (Marinkovic et  al. 1995; Amarenco and Hauw 1989, 1990a; Amarenco et  al. 1993; Amarenco 1991; Gilman et al. 1981; Duvernoy 1978; Perneczky et al. 1981). After crossing the VIIIth nerve, the AICAs give rise to the internal auditory arteries and then divide into two branches. One branch courses laterally and inferiorly to sup-

Fig. 5.8  MRI sagittal T2-weighted scan showing a posterior inferior cerebellar artery territory infarct (From Caplan 1996)

Fig. 5.9  Necropsy specimen showing an infarct in the territory of the medial branch of the posterior inferior cerebellar artery [From Amarenco et al. (1989) with permission]

Fig. 5.10  MRI sagittal diffusion-weighted scan showing a medial posterior inferior cerebellar artery territory infarct

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Fig. 5.11  Base of the brain at necropsy showing the origin of the anterior inferior cerebellar arteries

ply the anterior inferior portion of the cerebellum on the petrosal surface. The other branch loops around the bundle made by the VIIth and VIIIth nerves, and supplies the flocculus, brachium pontis, middle part of the cerebellar hemisphere, and the lateral part of the pons (Marinkovic et  al. 1995; Amarenco and Hauw 1989, 1990a; Amarenco et  al. 1993; Amarenco 1991; Perneczky et al. 1981). The internal auditory arteries supply the facial and vestibulocochlear nerves as well as the structures of the inner ear. Asymmetry and reciprocal size relationship of AICA and PICA are common. Studies show a balance between AICA and PICA.  In some individuals, AICA can substitute for a hypoplastic PICA, taking over the supply of the inferior ­surface of the cerebellum (Stopford 1915–1916; Foix and Hillemand 1925; Atkinson 1949; Takahashi 1974). Usually, the flocculus is always irrigated by AICAs, but for 3–5% of people, the AICA is replaced by the PICA (Lazorthes 1961). According to Lazorthes, in 40% of individuals, the AICA terminates on the flocculus; (Lazorthes 1961) in others it

Q. Wang and L. R. Caplan

Fig. 5.12  Blood supply of the caudolateral pons from the anterior inferior cerebellar artery (AICA). The shaded area to the right is the supply of a lateral branch of AICA. (a) Basilar artery; (b) medial pontine segment of AICA; (c) loop segment of AICA around flocculus; (d) paramedian basilar artery branches; (e) brainstem branches of AICA; (f) flocculus; (h) IV ventricle; (i) brachium pontis; (j) medial lemniscus; (k) lateral spinothalamic tract; (l) motor nucleus of the trigeminal nerve; (m) spinal tract of the trigeminal nerve; (n) principal sensory nucleus of the trigeminal nerve; (o) Vll and Vlll cranial nerves; (p) internal acoustic meatus [From Perneczky et  al. (1981) with permission]

passes through the sulcus separating the anterior lobes and the semilunar lobules and the terminal branches supply the nearby lobules: anterior, simplex, superior semilunar, inferior semilunar, gracilis, and biventer in 18–50% of individuals (Lazorthes 1961; Takahashi et  al. 1968). Figure  5.12 shows the schematic drawing of the AICA and its supply (Perneczky et al. 1981). Figure 5.13 shows the brainstem and cerebellar distribution of the AICA supply territory. Figure  5.14 represents a necropsy specimen showing an AICA territory infarct at the level of the pons. Figure 5.15 shows a sagittal and axial section MRI of a AICA infarct.

5  Vascular Supply and Territories of the Cerebellum

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Fig. 5.13  Diagrammatic depiction of the supply zones of the anterior inferior cerebellar arteries. (a) Shows the pontine territory. 1 Flocculus, 2 brachium pontis, 3 restiform body, 4 brachium conjunctivum, 5 dentate nucleus, 6 vestibular nuclei, 7 spinothalamic tract, 8 central tegmental tract, 9 medial lemniscus, 10 cerebellar nodulus. (b) Shows the

cerebellar supply on a lateral view of the cerebellum and (c) shows the supply on cut sections of the cerebellum and brainstem. The supply zones are shaded (Reproduced with permission from Amarenco et al. 1993)

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Fig. 5.14  Necropsy specimen (H&E stained) showing an anterior inferior cerebellar artery territory infarct

Fig. 5.15  MRI sagittal T1 (left) and axial diffusion-weighted scan showing an anterior inferior cerebellar artery territory infarct

5.4 Superior Cerebellar Arteries (SCAs) The SCAs arise as the last pair of branches from the basilar artery just before the basilar artery bifurcates into the paired PCAs (Fig. 5.16). The third cranial nerves run between the SCAs and the PCAs near the posterior communicating arteries. In about 15% of patients there are bifid SCAs. In one series, the diameters ranged from 0.7 to 1.93  mm (mean

1.1  mm) (Marinkovic et  al. 1995). The SCA encircles the brainstem close to or within the pontomesencephalic sulcus, just below the third nerve and just above the trigeminal nerve. While coursing around the midbrain, the SCAs give off branches that supply the brainstem including the superior portion of the lateral pontine tegmentum and the pontine and mesencephalic tectum. The SCAs have an early division within the cerebellomesencephalic cistern where it divides

5  Vascular Supply and Territories of the Cerebellum

Fig. 5.16  Brain at necropsy showing the superior cerebellar arteries circling the midbrain and giving off branches

into the mSCA and lSCA branches. Figure 5.17 shows the usual branching of the SCAs and the course of the lateral and medial branches. The mSCA branch extends more laterally than the mPICA. Occasionally, these branches arise directly from the basilar artery and the SCAs. Both the major branches of the SCAs course towards the pedunculo-cerebellar sulcus and reach the superior and anterior aspects of the cerebellum above the horizontal fissure. At the pedunculo-cerebellar sulcus, lSCA turns off at a right angle and follows the anterosuperior margin of the cerebellum anteriorly and laterally. A terminal deep branch of lSCA follows the superior cerebellar peduncle and reaches the dentate nucleus (Duvernoy 1978). The mSCAs mostly supply the superior portions of the vermis including the central, culmen, declive, and folium lobules; the lSCAs supply mostly

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Fig. 5.17  Schematic diagram of the superior cerebellar artery (SCA) and its medial (mSCA) and lateral (lSCA) branches. The top branch is the mSCA and the lower branch is the lSCA [From Amarenco et  al. (1991) with permission]

the lateral portions of the cerebellar hemispheres including the anterior, simplex, and superior portion of the semilunar lobules. The SCAs also supply the cerebellar nuclei (dentate, fastigial, emboliform, and globose) as well as the bulk of the cerebellar white matter (Amarenco and Hauw 1989, 1990b; Amarenco et al. 1991, 1993; Amarenco 1991). Figures 5.18 and 5.19 show the cerebellar and brainstem supply territories of the SCA. Figure 5.20 is a necropsy specimen showing a large SCA territory infarct. Figure  5.21 shows three MRI scans that illustrate the imaging distribution of various SCA territory infarcts. The distribution of the supply territories of the cerebellar arteries as found on CT and MRI scanning has been illustrated and reviewed (Savoiardo et  al. 1987; Courchesne et al. 1989; Press et al. 1989, 1990).

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Fig. 5.18  The SCA supply territories are shaded. (a–d) Sections from the rostral to the caudal cerebellum (From Amarenco and Hauw 1989)

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Fig. 5.19  Supply zones of the superior cerebellar arteries. (a) Shows the superior pontine supply. 4 Brachium conjunctivum, 7 lateral lemniscus, 8 cortico-tegmental tract, 9 medial lemniscus, 11 spinothalamic tract, 12

decussation of IV, 13 mesencephalic tract of V, 14 locus coeruleus, 15 medial longitudinal fasciculus. (b) Shows an antero-posterior view and (c) a lateral view of the cerebellum (From Amarenco and Hauw 1989)

5  Vascular Supply and Territories of the Cerebellum

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Fig. 5.20  Necropsy specimens showing a superior cerebellar artery territory infarct in the rostral pons. The pontine tectum and a small part of the dorsolateral pontine tegmentum are involved [From Amarenco and Hauw (1990), with permission]

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Fig. 5.21  MRI T2-weighted scans (From Caplan 1996). (a) Sagittal view showing a superior cerebellar artery (SCA) territory infarct. (b) Axial section showing small vermal cerebellar infarct in the territory of

the medial branch of the superior cerebellar artery ( mSCA). (c) Coronal section showing a bilateral SCA territory infarct appearing like “icing on a cake”

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5.5 Cerebellar Veins

Q. Wang and L. R. Caplan

cerebello-pontine angle tumours. J Neurol Neurosurg Psychiatry 12:137–151 Caplan LR (1996) Posterior circulation disease: clinical findings, diagThe venous drainage of the cerebellum is divided into supernosis, and management. Blackwell Scientific, Boston ficial veins, deep veins, and draining groups. Superficial veins Caplan LR (2000) Posterior circulation ischemia: then, now, and tomorrow the Thomas Willis Lecture—2000. Stroke 31:2011–2013 are divided according to the cortical surfaces they drain: Caplan LR, Wityk RJ, Glass TA et al (2004) New England medical censuperior hemispheric and superior vermian veins (tentorial ter posterior circulation registry. Ann Neurol 56:389–398 surface), inferior hemispheric and inferior vermian veins Caplan LR, Wityk RJ, Pazdera L et  al (2005) New England Medical Center posterior circulation stroke registry: II.  Vascular lesions. J (suboccipital surface), and anterior hemispheric veins (petroClin Neurol 1:31–49 sal surface) (Tschabitscher 1979; Kapp and Schmidek 1984; Chaves CJ, Caplan LR, Chung C-S, Amarenco P (1994) Cerebellar Matsushima et  al. 1983). The major deep veins course in infarcts. In: Appel S (ed) Current neurology, vol 14. C.V.  Mosby, ­fissures between the cerebellum and brain stem. These are St Louis, pp 143–177 designated as the veins of the cerebellomesencephalic, cere- Cook-Lowe L (1978) Modeled after a figure. In: Duvernoy HM (ed) Human brainstem vessels. Springer, Berlin, p 41 bellopontine, and cerebellomedullary fissures. The veins Courchesne E, Press GA, Murakami J et  al (1989) The cerebellum that drain the cerebellar peduncles are referred to as the veins in sagittal plane-anatomic-MR correlation: 1. The vermis. AJNR of superior, middle, and inferior cerebellar peduncles 10:659–665 (Matsushima et  al. 1983). There are diffuse anastomosis Duvernoy HM (1978) Human brainstem vessels. Springer, Berlin between veins before they are collected into draining groups. Foix C, Hillemand P (1925) Les arteres de l’axe encephalique jusqu’au diencephale inclusivement. Rev Neurol 2:705–739 The groups are designated according to the dural sinuses into Gilman S, Bloedel J, Lechtenberg R (1981) Disorders of the cerebelwhich they drain. The Galenic group drains via the vein of lum. FA Davis, Philadelphia Galen and the straight sinus. The petrosal group drains via the Huang YP, Wolf BS (1974) Veins of posterior fossa. In: Newton TH, Potts DG (eds) Radiology of the skull and brain: angiography, vol 2. petrosal sinuses. The tentorial group drains into the torcula C.V. Mosby, St Louis, pp 2155–2219 and transverse sinuses. Kapp JP, Schmidek HH (eds) (1984) The cerebral venous system and its The superior and inferior veins of the cerebellum usually disorders. Grune and Stratton, New York, pp 20–22 collected and drain into the midline draining groups: vein of Lasjaunias P, Berenstein A, Raybaud C (1990) Intracranial venous system. In: Lasjaunias P, Berenstein A (eds) Surgical neuro-­ Galen, straight sinus, or torcular. Many small veins drain into angiography: functional vascular anatomy of brain, spinal cord and superior or inferior vermian veins before their connection spine, vol 3. Springer, Berlin, pp 223–296 with the vein of Galen or straight sinus. Some of the superior Lazorthes G (1961) Vascularisation et circulation cérébrales. Masson, Paris and inferior veins run laterally to the transverse sigmoid Lister JR, Rhoton AL, Matsushima T, Peace DA (1982) Microsurgical sinuses, or to the superior or inferior petrosal sinuses. The anatomy of the posterior inferior cerebellar artery. Neurosurgery superior petrosal sinus collects anterior cerebellar veins, 10:170–199 including branches from the precentral fissure, the medial Marinkovic S, Kovacevic M, Gibo H, Milisavljevic M, Bumbasirevic L (1995) The anatomical basis for the cerebellar infarcts. Surg Neurol tonsillar veins, the veins of the lateral recess, and some tribu44:450–461 taries related to the cerebellar hemispheres (Huang and Wolf Matsushima T, Rhoton AL Jr, de Oliveira E et al (1983) Microsurgical 1974; Lasjaunias et al. 1990; Rhoton 2000). anatomy of the veins of the posterior fossa. J Neurosurg 59:63–105 Perneczky A, Perneczky G, Tschabitscher M, Samec P (1981) The relation between the caudolateral pontine syndrome and the anterior inferior cerebellar artery. Acta Neurochir 58:245–257 References Press GA, Murakami J, Courchesne E et al (1989) The cerebellum in sagittal plane-anatomic-MR correlation: 2. The cerebellar hemiAmarenco P (1991) The spectrum of cerebellar infarctions. Neurology spheres. AJNR 10:667–676 41:973–979 Press GA, Murakami JW, Courchesne E et al (1990) The cerebellum: Amarenco P, Hauw J-J (1989) Anatomie des arteres cerebelleuses. Rev 3. Anatomic-MR correlation in the coronal plane. AJNR 11:41–50 Neurol 145:267–276 Rhoton AL (2000) The posterior fossa veins. Neurosurgery 47:S69–S92 Amarenco P, Hauw J-J (1990a) Cerebellar infarction in the territory of Savitz SI, Caplan LR (2005) Current concepts: vertebrobasilar disease. the anterior and inferior cerebellar artery. Brain 113:139–155 N Engl J Med 352:2618–2626 Amarenco P, Hauw JJ (1990b) Cerebellar infarction in the territory of Savoiardo M, Bracchi M, Passerini A, Visciani A (1987) The vascuthe superior cerebellar artery: a clinicopathologic study of 33 cases. lar territories in the cerebellum and brainstem: CT and MR study. Neurology 40:1383–1390 AJNR 8:199–209 Amarenco P, Hauw J-J, Henin D et  al (1989) Les infarctus du terri- Stopford JSB (1915–1916) The arteries of the pons and medulla oblontoire de l’artère cérébelleuse postéro-inférieure; étude clinico-­ gata. Part 2. J Anat Physiol (London) 50:255–280 pathologique de 28 cas. Rev Neurol 145:277–286 Takahashi M (1974) The anterior inferior cerebellar artery. In: Newton Amarenco P, Roullet E, Goujon C et al (1991) Infarction in the anterior TH, Potts DG (eds) Radiology of the skull and brain, vol 2. rostral cerebellum (the territory of the lateral branch of the superior C.V. Mosby, St Louis, pp 1796–1808 cerebellar artery). Neurology 41:253–258 Takahashi M, Wilson G, Hanafee W (1968) The anterior inferior cerAmarenco P, Hauw J-J, Caplan LR (1993) Cerebellar infarctions. ebellar artery: its radiographic anatomy and significance in the In: Lechtenberg R (ed) Handbook of cerebellar diseases. Marcel diagnosis of extra-axial tumors of the posterior fossa. Radiology Dekker, New York, pp 251–290 90:281–287 Atkinson WJ (1949) The anterior inferior cerebellar artery: its varia- Tschabitscher M (1979) Die venen des menschlichen kleinhirns. Acta tions, pontine distribution, and significance in the surgery of Anat (Basel) 105:344–366

6

The Olivocerebellar Tract Yuanjun Luo and Izumi Sugihara

Abstract

Neurons in the inferior olive nucleus, the sole origin of cerebellar climbing fibers, project their axons to the cerebellum through the olivocerebellar tract. A single olivocerebellar axon gives rise to multiple climbing fibers (about seven in rats), which often terminate into a single longitudinal compartment defined by the cerebellar cortex’s longitudinal striped molecular expression pattern. According to an intriguing topographic relationship, axons originating from a subarea of the inferior olive project to a particular compartment. As a result of this topographic arrangement, the olivocerebellar projection relays synchronous activity of the electrically coupled adjacent inferior olive neurons to complex spike firing of Purkinje cells in a longitudinal compartment. Olivocerebellar axons show a dynamic morphogenetic process. An immature axon has abundant terminal branches that innervate many Purkinje cells. Several terminal branches (climbing fibers) grow to eventually establish a powerful one-to-one synaptic connection between a single climbing fiber terminal and a single target Purkinje cell. Furthermore, these axons are capable of strong compensatory re-innervation after lesion, even in the adult.

6.1 Introduction The olivocerebellar tract is the axonal path of inferior olive neurons. The olivocerebellar axons form the climbing fiber projection, one of the two major afferent systems in the cer-

Y. Luo · I. Sugihara (*) Department of Systems Neurophysiology and Center for Brain Integration Research, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan e-mail: [email protected]

ebellar cortex. The olivocerebellar climbing fiber projection system is unique in morphological, physiological, and developmental aspects, making a sharp contrast with the mossy fiber system, the other of the two major afferent systems of the cerebellum. The olivocerebellar projection system contributes significantly to characterize the functional organization of the cerebellum. This short article summarizes the olivocerebellar projection’s essential morphological, physiological, and developmental characteristics to show its uniqueness based on relevant studies, including ours.

6.2 Morphology of Single Olivocerebellar Axons The inferior olive nucleus, located in the caudoventral medulla, is a complex multi-lamella structure packed with small neurons with round somata and curved dendrites. Except for the negligible number of scattered GABAergic neurons, all neurons in the inferior olive nucleus project to the cerebellum, terminating as climbing fibers. The inferior olive is the sole origin of climbing fibers. Therefore, the inferior olive is a critical node in the input circuitry of the cerebellum. The olivocerebellar tract is the bundle of axons of the inferior olive neurons projecting to the cerebellar cortex. The axons run medially, crossing the midsagittal plane and continuing through or above the contralateral inferior olive, before entering the white matter under the lateral surface of the medulla that connects to the inferior cerebellar peduncle (Fig. 6.1a, Sugihara et al. 1999). Before entering the cerebellum through the inferior cerebellar peduncle, the axons that terminate in the vermis pass through the most rostral part of the cerebellar peduncle dorsal to the superior cerebellar peduncle intermingled with the uncinate fasciculus and the ventral spinocerebellar tract (arrowhead in Fig. 6.1). Other olivocerebellar axons pass through the conventional inferior cerebellar peduncle.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_6

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Fig. 6.1  Axonal path of a single olivocerebellar axon. (a) Lateral view of a trajectory of a reconstructed single olivocerebellar axon labeled by localized injection of biotinylated dextran amine in the rat. This axon originated from the medial and caudal part of the medial accessory olive, a subnucleus of the inferior olive, and terminated in lobules VI and VII in the vermis. Arrowhead indicates the most rostral part of the

inferior cerebellar peduncle. (b) Distribution of climbing fibers originating of this axon (red) and other axons labeled (black) mapped in the unfolded scheme of the rat cerebellar cortex. (c) Magnified drawing of the area surrounded by the square in (b). II–Xb lobule II—lobule Xb, C caudal, IO inferior olive, Lt left, MN medial nucleus, R rostral, Rt right

Upon entering the cerebellum, each axon gives rise to collaterals to the deep cerebellar nuclei and branches into multiple (seven on average in rat) axons, each of which terminates on a single adult Purkinje cell as a climbing fiber. Thus, a “climbing fiber” discovered by Ramón y Cajal (1911) is the terminal arbor of one of a number of branches of the olivocerebellar axon. Besides giving rise to nuclear collaterals and cortical branches that terminate as climbing fibers, olivocerebellar axons also give rise to several thin collaterals, mainly terminating in the granular layer with a small number of swellings. Synaptic contact and functional significance of these collaterals are not well clarified (Sugihara et al. 1999). The multiple climbing fibers originating from a single axon are usually, but not always, distributed in a narrow longitudi-

nal band-shaped area (Fig.  6.1b, c, Sugihara et  al. 2001) inside one zebrin stripe (later section). The olivocerebellar axon’s longitudinal projection pattern contrasts with the transversely wide projection pattern of mossy fiber axons (Biswas et al. 2019).

6.3 Topography in the Olivocerebellar Tract The olivocerebellar projection has a topographic arrangement. Thus, the inferior olive subdivides into many subareas, usually a portion of a single lamella (Fig. 6.2a). Neurons in each subarea of the inferior olive project topographically to a par-

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6  The Olivocerebellar Tract

a

b

Fig. 6.2  Aldolase C stripe-linked topography of the olivocerebellar projection. (a) Subareas of the inferior olive. Two coronal sections of the inferior olive of the mouse, labeled with immunostaining of FoxP2, a marker molecule of the nucleus of inferior olive neurons (Fujita and Sugihara 2012) at the caudal and rostral levels (reversed epifluorescence image). The percentile indicates the relative caudorostral levels within the whole inferior olive. The superimposition of colors on the right side shows the subareas of the inferior olive. (b) Dorsal view of the whole-mount preparation of the Aldoc-Venus mouse (Fujita et al. 2014), in which aldolase C (zebrin) stripes are visible with fluorescence (reversed epifluorescence image). On the left side, the cerebellar cortex is divided into multiple zonal areas (colored) that receive the topographic olivocerebellar projection from subareas of the inferior olive. The boundaries of colored stripes mostly match with the boundaries of aldolase C stripes. The color-coding indicates the topographic relationship between A and B. The dark gray area in A and the gray area in B do not have corresponding parts appearing in the other panel. Based on Sugihara and Shinoda (2004), Sugihara and Quy (2007) and Fujita et al. (2020). V–IX lobule V–lobule IX, a, b, c, d subnucleus a, b, c, d of the caudal part of the medial accessory olive, beta subnucleus beta, DM dorsomedial subnucleus, DC/VLO dorsal cap, and ventrolateral outgrowth subnucleus, dDAO dorsal fold of the dorsal accessory olive, dPO dorsal lamella of the principal olive, rMAO rostral part of the medial accessory olive, vPO ventral lamella of the principal olive, Sim simple lobule, Cr I crus I, Cr II crus II, Par paramedian lobule, Cop copula pyramidis, PFl paraflocculus

ticular subarea in the cerebellar nuclei and a specific striped subarea in the cerebellar cortex (Sugihara and Shinoda 2004, 2007). These subareas in the cortex and nuclei are topographically connected to each other by the corticonuclear Purkinje cell projection (Sugihara et al. 2009). The specific subarea in the cerebellar nuclei also topographically projects to the par-

ticular subarea in the inferior olive (Ruigrok and Voogd 1990). As a whole, a triangular topographic loop of neuronal connections forms among subareas in the inferior olive, cerebellar cortex, and cerebellar nuclei. Each set of topographically connected subareas in the cerebellar cortex, cerebellar nuclei, and inferior olive is designated as a cerebellar module (Ruigrok 2011). A standing question of how many modules constitute the entire cerebellum remains. Conventionally, the basic six modules (A, B, C1, C2, C3, and D) have been recognized (Voogd and Bigaré 1980). However, most of these modules have been further subdivided into smaller modules (Ruigrok 2011; Sugihara et  al. 2009). In addition, the flocculus and nodulus have distinct modules (Sugihara et  al. 2004). Most cerebellar modules are consistent with the cortical compartments defined by the molecular expression profile in Purkinje cells (Sugihara and Shinoda 2004, Sugihara et al. 2009). Aldolase C (zebrin II, or just “zebrin,” Brochu et al. 1990), which is the representative of such molecules, is highly expressed in Purkinje cells arranged in tens of alternate longitudinal stripes in the cerebellar cortex (Fig. 6.2b, right). The topographic relationship between the subarea of the inferior olive and aldolase C stripes has been well identified (colorcoded in Fig. 6.2), although details may still be revised in the future. In the cerebellar nuclei, to which the collaterals of olivocerebellar axons project topographically, the arrangement of subareas (or modules) is different from that in the cerebellar cortex. Subareas linked with aldolase C-positive and -negative compartments are all located in the caudoventral and rostrodorsal parts of the cerebellar nuclei, respectively (Sugihara and Shinoda 2007). Output neurons in different subareas of the cerebellar nuclei linked with aldolase C stripes generally project to distinct targets and are involved in different cerebellar functions (Fujita et al. 2020).

6.4 Physiological Properties The inferior olive neurons show the oscillatory fluctuation of membrane potential at about 10 Hz (Llinás and Yarom 1986). This activity synchronizes among nearby neurons through dendro-dendritic gap junctions (Llinás and Yarom 1986; Long et  al. 2002). Excitatory input to the inferior olive, which mainly originates from the somatosensory and vestibular systems in the medulla and spinal cord and visual, corticofugal, and other systems in the midbrain and mesodiencephalic junction (see Sugihara and Shinoda 2004), may reset the oscillatory rhythm to evoke firing (Leznik and Llinás 2005). Olivary cells may fire at the peak of the oscillation of one action potential or a few action potentials in a burst. The firing of an action potential (or a brief burst of action potentials) occurs as a solitary event or in sequence with about 100-ms intervals (Marthy et al. 2009). On average, the firing frequency of the olivary neuron is about 1 Hz (Eccles et al. 1966).

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The firing of olivary neurons is conveyed to the axon terminals, i.e., climbing fiber terminals, with a conduction time of approximately 4  ms (in rat, Sugihara et  al. 1993). An action potential (or a brief burst of action potentials) in the climbing fiber produces a complex spike response in target Purkinje cells (Eccles et al. 1966). In addition, olivocerebellar axon collaterals elicit an excitatory effect in the cerebellar nuclei (Blenkinsop and Lang 2011). However, its effect on the granular layer is yet unclear. Since adjacent inferior olive neurons generally project to a narrow longitudinal striped area in the cerebellar cortex, it often matches with a single aldolase C stripe (Sugihara et al. 2007). Because of this property in the olivocerebellar projection, Purkinje cells arranged in the longitudinal band (width = ~0.25 mm) tend to fire complex spikes synchronously in awake and anesthetized states (Sasaki et al. 1989; Lang et al. 1999). The band of complex spike synchrony generally matches with a single aldolase C stripe (Sugihara et al. 2007). Functionally, climbing fiber inputs in each aldolase C stripe are activated in particular timing/aspects during the sensorimotor behavior of animals (Horn et  al. 2010; Tsutsumi et  al. 2019). This synchronous complex spike firing of Purkinje cells may be functionally important to form cerebellar output in the cerebellar nuclei (Blenkinsop and Lang 2011).

6.5 Development of the Olivocerebellar Projection The immature olivocerebellar axonal projection is formed in the late embryonic stage when Purkinje cells form clusters before settling into striped compartments in rats and mice (Fujita et  al. 2012). A basic topographic projection pattern appears in the olivocerebellar bundle at this stage (Chédotal and Sotelo 1992). Axonal terminals form a delicate plexus with abundant branching known as the creeper terminal (Sugihara 2005). In the second postnatal week, many axonal branches disappear, leaving only those that begin to form a dense arbor around a single Purkinje cell soma (nest terminal). The nest terminals grow to an entire climbing fiber terminal in the following few weeks. The above process of climbing fiber development leads to the establishment of a one-to-one synaptic connection between a single climbing fiber terminal and a single target Purkinje cell. A loss of granule cells caused by X-ray irradiation or other procedures and some genetic mutations prevent the normal development of climbing fiber morphology (Sugihara et al. 2000). In these situations, multiple climbing fibers originating from one olivocerebellar axon (pseudo-­ multiple innervation) of different olivocerebellar axons (true multiple innervations) may remain to innervate a single Purkinje cell (impairment of one-to-one innervation, Sugihara et al. 2000).

Y. Luo and I. Sugihara

6.6 Plasticity of Olivocerebellar Axons Since the average olivocerebellar projection is nearly exclusively contralateral, an increase of ipsilateral projection indicates a plastic change in the projection. Such plastic change is seen after a unilateral cut of the cerebellar peduncle in the neonatal stage in rats (Sugihara et al. 2003). A similar transcommissural olivocerebellar projection to the ipsilateral cerebellum is seen even in adults after administering substances that can facilitate axonal plasticity (Dixon and Sherrard 2006). Semitotal lesion of the inferior olive by neurotoxin 3-­aminopyridine (3-AP) induces axonal sprouting of remaining olivary neurons to compensate for the loss of many olivocerebellar axonal terminals (Rossi et  al. 1991). Axonal sprouting occurs only in their terminal portions, mainly in the terminal arbor of climbing fibers and possibly also at the terminal of thin collaterals in the granular layer and cerebellar nuclei. However, no axonal sprouting from the stem axon in the cerebellar white matter was evident, at least in adults (Aoki and Sugihara 2012).

6.7 Conclusion Our current knowledge of the olivocerebellar projection’s morphological, physiological, and developmental aspects are summarized above. The olivocerebellar projection is an essential component of the cerebellar system. The projection is well organized at the level of single axons and at the level of topographic compartmentalization of the whole cerebellar cortex. The input from the olivocerebellar system produces significant effects on the activity of Purkinje cells and the output of neurons of the cerebellar nucleus. To consider the significance of such effect in various cerebellar functions, the general morphological property of the olivocerebellar system as summarized here would be necessary.

References Aoki H, Sugihara I (2012) Morphology of single olivocerebellar axons in the denervation–reinnervation model produced by subtotal lesion of the rat inferior olive. Brain Res 1449:24–37 Biswas MS, Luo Y, Sarpong GA, Sugihara I (2019) Divergent projections of single pontocerebellar axons to multiple cerebellar lobules in the mouse. J Comp Neurol 527:1966–1985 Blenkinsop TA, Lang EJ (2011) Synaptic action of the olivocerebellar system on cerebellar nuclear spike activity. J Neurosci 31:14708–14720 Brochu G, Maler L, Hawkes R (1990) Zebrin II: a polypeptide antigen expressed selectively by Purkinje cells reveals compartments in rat and fish cerebellum. J Comp Neurol 291:538–552 Chédotal A, Sotelo C (1992) Early development of olivocerebellar projections in the fetal rat using CGRP immunocytochemistry. Eur J Neurosci 4:1159–1179 Dixon KJ, Sherrard RM (2006) Brain-derived neurotrophic factor induces post-lesion transcommissural growth of olivary axons

6  The Olivocerebellar Tract that develop normal climbing fibers on mature Purkinje cells. Exp Neurol 202:44–56 Eccles JC, Llinás R, Sasaki K (1966) The excitatory synaptic action of climbing fibres on the Purkinje cells of the cerebellum. J Physiol 182:268–296 Fujita H, Sugihara I (2012) FoxP2 expression in the cerebellum and inferior olive: development of the transverse stripe-shaped expression pattern in the mouse cerebellar cortex. J Comp Neurol 520:656–677 Fujita H, Morita N, Furuichi T, Sugihara I (2012) Clustered fine compartmentalization of the mouse embryonic cerebellar cortex and its rearrangement into the postnatal striped configuration. J Neurosci 32:15688–15703 Fujita H, Aoki H, Ajioka I, Yamazaki M, Abe M, Oh-Nishi A, Sakimura K, Sugihara I (2014) Detailed expression pattern of aldolase C (Aldoc) in the cerebellum, retina and other areas of the CNS studied in Aldoc-Venus knock-in mice. PLoS One 9:e86679 Fujita H, Kodama T, du Lac S (2020) Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis. Elife 9:e58613 Horn KM, Pong M, Gibson AR (2010) Functional relations of cerebellar modules of the cat. J Neurosci 30:9411–9423 Lang EJ, Sugihara I, Welsh JP, Llinás R (1999) Patterns of spontaneous complex spike activity in the awake rat. J Neurosci 19:2728–2739 Leznik E, Llinás R (2005) Role of gap junctions in synchronized neuronal oscillations in the inferior olive. J Neurophys 94:2447–2456 Llinás R, Yarom Y (1986) Oscillatory properties of guinea-pig inferior olivary neurones and their pharmacological modulation: an in vitro study. J Physiol 376:163–182 Long MA, Deans MR, Paul DL, Connors BW (2002) Rhythmicity without synchrony in the electrically uncoupled inferior olive. J Neurosci 22:10898–10905 Marthy A, Ho SSN, Davie JT, Duguid IC, Clark BA, Häusser M (2009) Encoding of oscillations by axonal bursts in inferior olive neurons. Neuron 62:388–399 Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et des verébrés, vol 2. Maloine, Paris Rossi F, Wiklund L, Van der Want JJL, Strata P (1991) Reinnervation of cerebellar Purkinje cells by climbing fibers surviving a subtotal lesion of the inferior olive in the adult rat. I.  Development of new collateral branches and terminal plexuses. J Comp Neurol 308:513–535 Ruigrok TJ (2011) Ins and outs of cerebellar modules. Cerebellum 10:464–474 Ruigrok TJ, Voogd J (1990) Cerebellar nucleo-olivary projections in the rat: an anterograde tracing study with Phaseolus vulgaris leucoagglutinin (PHA-L). J Comp Neurol 298:315–333 Sasaki K, Bower JM, Llinás R (1989) Multiple Purkinje cell recording in rodent cerebellar cortex. Eur J Neurosci 1:572–586

45 Sugihara I (2005) Microzonal projection and climbing fiber remodeling in single olivocerebellar axons of new born rats at postnatal days 4–7. J Comp Neurol 487:93–106 Sugihara I, Quy PN (2007) Identification of aldolase C compartments in the mouse cerebellar cortex by olivocerebellar labeling. J Comp Neurol 500:1076–1092 Sugihara I, Shinoda Y (2004) Molecular, topographic and functional organization of the cerebellar cortex: a study with combined aldolase C and olivocerebellar labelling. J Neurosci 24:8771–8785 Sugihara I, Shinoda Y (2007) Molecular, topographic and functional organization of the cerebellar nuclei: analysis by three-dimensional mapping of the olivonuclear projection and aldolase C labeling. J Neurosci 27:9696–9710 Sugihara I, Lang EJ, Llinás R (1993) Uniform olivocerebellar conduction time underlies Purkinje cell complex spike synchronicity in the rat cerebellum. J Physiol Lond 470:243–271 Sugihara I, Wu H-S, Shinoda Y (1999) Morphology of single olivocerebellar axons labeled with biotinylated dextran amine in the rat. J Comp Neurol 414:131–148 Sugihara I, Bailly Y, Mariani J (2000) Olivocerebellar climbing fibers in the granuloprival cerebellum: morphological study of individual axonal projections in the X-irradiated rat. J Neurosci 20:3745–3760 Sugihara I, Wu H-S, Shinoda Y (2001) The entire trajectories of single olivocerebellar axons in the cerebellar cortex and their contribution to cerebellar compartmentalization. J Neurosci 21:7715–7723 Sugihara I, Lohof AM, Letellier M, Mariani J, Sherrard RM (2003) Post-lesion transcommissural growth of olivary climbing fibres creates functional synaptic microzones. Eur J Neurosci 18:3027–3036 Sugihara I, Ebata S, Shinoda Y (2004) Functional compartmentalization in the flocculus and the ventral dentate and dorsal group y nuclei: an analysis of single olivocerebellar axonal morphology. J Comp Neurol 470:113–133 Sugihara I, Marshall SP, Lang EJ (2007) Relationship of complex spike synchrony bands and climbing fiber projection determined by reference to aldolase C compartments in crus IIa of the rat cerebellar cortex. J Comp Neurol 501:13–29 Sugihara I, Fujita H, Na J, Quy PN, Li BY, Ikeda D (2009) Projection of reconstructed single Purkinje cell axons in relation to the cortical and nuclear aldolase C compartments of the rat cerebellum. J Comp Neurol 512:282–304 Tsutsumi S, Hidaka N, Isomura Y, Matsuzaki M, Sakimura K, Kano M, Kitamura K (2019) Modular organization of cerebellar climbing fiber inputs during goal-directed behavior. eLife 8:e47021 Voogd J, Bigaré F (1980) Topographical distribution of olivary and corticonuclear fibers in the cerebellum: a review. In: Courville J, de Montigny C, Lamarre Y (eds) The inferior olivary nucleus anatomy and physiology. Raven Press, New York, pp 207–234

7

Precerebellar Nuclei: Embryological Principles Mayumi Yamada and Mikio Hoshino

Abstract

Keywords

The cerebellar cortex receives several inputs from the surrounding nuclei, the precerebellar systems. Two major types of precerebellar systems are known: mossy fiber (MF) and climbing fiber (CF) systems. MF neurons are found in several nuclei in the brain stem. Four major nuclei in the hindbrain contain MF neurons; the pontine gray nucleus (PGN), the reticulotegmental nucleus (RTN), the lateral reticular nucleus (LRN), and the external cuneate nucleus (ECN). In addition, MF neurons also reside in the spinal trigeminal nucleus (Sp5) in the hindbrain and Clarke’s column (CC) in the spinal cord. MF neurons extend their glutamatergic projection to granule cells conveying peripheral and cortical information to the cerebellum. In contrast, CF neurons are located exclusively in the inferior olive nucleus (ION), which receive inputs from the cerebral cortex, the red nucleus, spinal cord, and other brain stem nuclei, and extend their glutamatergic projection to Purkinje cells. Both types of precerebellar neurons also project to neurons in the cerebellar nuclei. It is thought that these precerebellar systems transmit the external and internal information to the cerebellar cortex to modulate cerebellar function, including the regulation of animal movement.

Precerebellar system · Mossy fiber neuron · Climbing fiber neuron · PGN · RTN · LRN · ECN · ION Cerebellum · Transcription factor · Rhombomere Neuroepithelial domain

M. Yamada Graduate School of Biostudies, Kyoto University, Kyoto, Japan

7.1 Anatomy and Histology of the Precerebellar Nuclei The cerebellar cortex receives several inputs from the surrounding nuclei, the precerebellar systems. Two major types of precerebellar systems are known: mossy fiber (MF) and climbing fiber (CF) systems. MF neurons are found in several nuclei in the brain stem. Four major nuclei in the hindbrain contain MF neurons; the pontine gray nucleus (PGN), the reticulotegmental nucleus (RTN), the lateral reticular nucleus (LRN), and the external cuneate nucleus (ECN) (Altman and Bayer 1987) (Fig. 7.1a–c). In addition, MF neurons also reside in the spinal trigeminal nucleus (Sp5) in the hindbrain and Clarke’s column (CC) in the spinal cord (Fig. 7.1a–d). MF neurons extend their glutamatergic projection to granule cells conveying peripheral and cortical information to the cerebellum. In contrast, CF neurons are located exclusively in the inferior olive nucleus (ION) (Fig. 7.1a, c), which receive inputs from the cerebral cortex, the red nucleus, spinal cord, and other brain stem nuclei, and extend their glutamatergic projection to Purkinje cells (Ruigrok et al. 1995). Both types of precerebellar neurons also project to neurons in the cerebellar nuclei. It is thought that these precerebellar systems transmit external and internal information to the cerebellar cortex to modulate cerebellar function, including the regulation of animal movement.

M. Hoshino (*) Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_7

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M. Yamada and M. Hoshino

a

b

c

d

e

Fig. 7.1  Precerebellar systems in the brain stem. (a–d) Two types of precerebellar afferent systems; MF (red) and CF (blue) systems. Cb cerebellum, CN cerebellar nucleus. (e) In the caudal hindbrain (rhombomere 6–8), the dorsal neuroepithelium can be divided into six

domains (dP1–dP6) according to the expression pattern of transcription factors during embryonic development. While MF neurons (red) are derived from the dP1 domain, CF neurons (blue) are generated from the dP4 domain

7  Precerebellar Nuclei: Embryological Principles

7.2 Specification of Precerebellar Nuclei Neurons Birthdating studies using 3H-thymidine and BrdU in mice showed that CF neurons are produced at relatively early neurogenesis stages [embryonic day (E) 9.5–11.5] and MF neurons are generated at slightly later stages (E10.5–16.5) (Pierce 1973). Avian grafting studies as well as mammalian fate map analyses have revealed that in the hindbrain, both MF and CF neurons are generated from the caudal part, around rhombomeres 6–8 (Fig.  7.1e) (Ambrosiani et  al. 1996; Cambronero and Puelles 2000; Farago et  al. 2006; Kawauchi et al. 2006). In contrast, MF neurons in Clarke’s nucleus are produced in the spinal cord (Bermingham et al. 2001). Classic anatomical and immunohistochemical studies have suggested that these precerebellar nuclei neurons in the hindbrain are generated from the dorsal part of the rhombomere and migrate circumferentially to their final loci (Bloch-­Gallego et al. 1999; Yee et al. 1999; Kyriakopoulou et al. 2002). However, they take slightly different pathways; MF and CF neurons migrate extramurally and intramurally, respectively (Fig.  7.1e). Introduction of a GFP-expressing vector into the embryonic dorsal hindbrain enabled the dramatic visualization of migrating precerebellar nuclei neurons during development (Kawauchi et  al. 2006; Okada et  al. 2007; Shinohara et  al. 2013). Recent studies have revealed that precerebellar neuron migration is regulated by various molecules or signaling cascades, such as netrin, SLIT/ROBO proteins, bone morphogenetic protein (BMP) signaling, sonic hedgehog signaling (SHH), and Calmodulin (Dominici et al. 2018; Martinez-Chavez et al. 2018; MorenoBravo et  al. 2018; Yung et  al. 2018; Qin et  al. 2019; Kobayashi et al. 2015). Several transcription factors are reportedly expressed within the dorsal neuroepithelium of the caudal rhombomeres 6–8 during embryonic development and have been used to try to define domains along the dorsoventral axis. Lmx1a is expressed in the roof plate, the dorsal-most part of rhombomere, which gives rise to the choroid plexus (Chizhikov et  al. 2006). Other transcription factors are expressed in the dorsal neuroepithelium, which can be divided into six domains (dP1–dP6) according to the pattern of transcription factors, such as Atoh1, Ngn1, Ascl1, Ptf1a, Pax6, and Olig3 (Fig.  7.1e). Using genetic lineage tracing methods, a series of studies have tried to clarify the precise origins of MF and CF neurons. Analyses of genetically engineered mice that express lacZ or Cre recombinase under the control of the endogenous or exogenous Atoh1 promoter revealed that MF neurons of PGN, RTN, LRN, and ECN were generated from the Atoh1-­ expressing neuroepithelial domain (dP1, Ben-Arie et  al. 2000; Rodriguez and Dymecki 2000; Landsberg et al. 2005;

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Wang et al. 2005). Loss of the Atoh1 gene resulted in a defect in the production of these MF neurons, suggesting the involvement of Atoh1 in MF neuron development. Landsberg et al. also performed lineage tracing using two variants of FLP (Flippase recombinase) with different recombinase activities that were expressed under the control of the Wnt1 promoter whose strength is the highest at the dorsal-most part and decreases ventrally. They observed that CF neurons are generated from the neuroepithelial region where Wnt1 is very weakly expressed, whereas MF neurons are derived from the strong Wnt1-expressing region (Landsberg et  al. 2005). In addition, Nichols and Bruce showed that in mice carrying a Wnt1-enhancer/lacZ transgene, MF neurons but not CF neurons were labeled by β-gal (Nichols and Bruce 2006). These findings suggested that CF neurons are derived from the neuroepithelial region ventral to the Atoh1-expressing domain. Yamada et  al. performed Cre-loxP-based lineage trace analysis and showed that all CF neurons in the ION are generated from the Ptf1a-expressing neuroepithelial domain (Yamada et al. 2007). Targeted disruption of the Ptf1a gene caused defects in the production of these CF neurons and in fate change of some CF neurons to MF neurons, suggesting that Ptf1a plays a critical role in fate determination of CF neurons. They also showed that Ptf1a is important for migration, differentiation, and survival of CF neurons. Storm et al. used Cre-loxP-based linage tracing to show that not only MF neurons but also CF neurons are generated from the Olig3-­ expressing neuroepithelial region that broadly expands within the dorsal hindbrain (Storm et al. 2009). Loss of the Olig3 gene resulted in the disorganized development of MF neurons and complete loss of CF neurons (Liu et al. 2008; Storm et al. 2009). Moreover, ectopic co-expression of Olig3 and Ptf1a induced the expression of a CF neuron marker in chick embryos (Storm et  al. 2009). These findings suggest that CF neurons are derived from the Ptf1a/Olig3-expressing neuroepithelial domain (dP4) and that Ptf1a and Olig3 cooperatively regulate the development of CF neurons. The domain structure of the dorsal neuroepithelium in the caudal hindbrain is shown in Fig. 7.1e.

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50 Bermingham NA, Hassan BA, Wang VY, Fernandez M, Banfi S, Bellen HJ, Fritzsch B, Zoghbi HY (2001) Proprioceptor pathway development is dependent on Math1. Neuron 30:411–422 Bloch-Gallego E, Ezan F, Tessier-Lavigne M, Sotelo C (1999) Floor plate and netrin-1 are involved in the migration and survival of inferior olivary neurons. J Neurosci 19:4407–4420 Cambronero F, Puelles L (2000) Rostrocaudal nuclear relationships in the avian medulla oblongata: a fate map with quail chick chimeras. J Comp Neurol 427:522–545 Chizhikov VV, Lindgren AG, Currle DS, Rose MF, Monuki ES, Millen KJ (2006) The roof plate regulates cerebellar cell-type specification and proliferation. Development 133:2793–2804 Dominici C, Rappeneau Q, Zelina P, Fouquet S, Chédotal A (2018) Non-cell autonomous control of precerebellar neuron migration by Slit and Robo proteins. Development 145(2):150375. https://doi. org/10.1242/dev.150375 Farago AF, Awatramani RB, Dymecki SM (2006) Assembly of the brainstem cochlear nuclear complex is revealed by intersectional and subtractive genetic fate maps. Neuron 50:205–218 Kawauchi D, Taniguchi H, Watanabe H, Saito T, Murakami F (2006) Direct visualization of nucleogenesis by precerebellar neurons: involvement of ventricle-directed, radial fibre-associated migration. Development 133:1113–1123 Kobayashi H, Saragai S, Naito A, Ichio K, Kawauchi D, Murakami F (2015) Calm1 signaling pathway is essential for the migration of mouse precerebellar neurons. Development 142(2):375–384. https://doi.org/10.1242/dev.112680 Kyriakopoulou K, de Diego I, Wassef M, Karagogeos D (2002) A combination of chain and neurophilic migration involving the adhesion molecule TAG-1 in the caudal medulla. Development 129:287–296 Landsberg RL, Awatramani RB, Hunter NL, Farago AF, DiPietrantonio HJ, Rodriguez CI, Dymecki SM (2005) Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by Pax6. Neuron 48:933–947 Liu Z, Li H, Hu X, Yu L, Liu H, Han R, Colella R, Mower GD, Chen Y, Qiu M (2008) Control of precerebellar neuron development by Olig3 bHLH transcription factor. J Neurosci 28:10124–10133 Martinez-Chavez E, Scheerer C, Wizenmann A, Blaess S (2018) The zinc-finger transcription factor GLI3 is a regulator of precerebellar neuronal migration. Development 145(24):166033. https://doi. org/10.1242/dev.166033 Moreno-Bravo JA, Roig Puiggros S, Blockus H, Dominici C, Zelina P, Mehlen P et  al (2018) Commissural neurons transgress the CNS/

M. Yamada and M. Hoshino PNS boundary in absence of ventricular zone-derived netrin 1. Development 145(2):159400. https://doi.org/10.1242/dev.159400 Nichols DH, Bruce LL (2006) Migratory routes and fates of cells transcribing the Wnt-1 gene in the murine hindbrain. Dev Dyn 235:285–300 Okada T, Keino-Masu K, Masu M (2007) Migration and nucleogenesis of mouse precerebellar neurons visualized by in utero electroporation of a green fluorescent protein gene. Neurosci Res 57:40–49 Pierce ET (1973) Time of origin of neurons in the brain stem of the mouse. Prog Brain Res 40:53–65 Qin L, Ahn KJ, Wine Lee L, de Charleroy C Jr, Crenshaw EB 3rd (2019) Analyses with double knockouts of the Bmpr1a and Bmpr1b genes demonstrate that BMP signaling is involved in the formation of precerebellar mossy fiber nuclei derived from the rhombic lip. PLoS One 14(12):e0226602. https://doi.org/10.1371/journal. pone.0226602 Rodriguez CI, Dymecki SM (2000) Origin of the precerebellar system. Neuron 27:475–486 Ruigrok TJ, Cella F, Voogd J (1995) Connections of the lateral reticular nucleus to the lateral vestibular nucleus in the rat. An anterograde tracing study with Phaseolus vulgaris leucoagglutinin. Eur J Neurosci 7:1410–1413 Shinohara M, Zhu Y, Murakami F (2013) Four-dimensional analysis of nucleogenesis of the pontine nucleus in the hindbrain. J Comp Neurol 521:3340–3357 Storm R, Cholewa-Waclaw J, Reuter K, Brohl D, Sieber M, Treier M, Muller T, Birchmeier C (2009) The bHLH transcription factor Olig3 marks the dorsal neuroepithelium of the hindbrain and is essential for the development of brainstem nuclei. Development 136:295–305 Wang VY, Rose MF, Zoghbi HY (2005) Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48:31–43 Yamada M, Terao M, Terashima T, Fujiyama T, Kawaguchi Y, Nabeshima Y, Hoshino M (2007) Origin of climbing fiber neurons and their developmental dependence on Ptf1a. J Neurosci 27:10924–10934 Yee KT, Simon HH, Tessier-Lavigne M, O'Leary DM (1999) Extension of long leading processes and neuronal migration in the mammalian brain directed by the chemoattractant netrin-1. Neuron 24:607–622 Yung AR, Druckenbrod NR, Cloutier JF, Wu Z, Tessier-Lavigne M, Goodrich LV (2018) Netrin-1 confines rhombic lip-derived neurons to the CNS.  Cell Rep 22(7):1666–1680. https://doi.org/10.1016/j. celrep.2018.01.068

8

Vestibular Nuclei and Their Cerebellar Connections Neal H. Barmack

Abstract

Keywords

The vestibular nuclei and the vestibulocerebellum comprise the anatomical crossroads where primary vestibular information is collected, stored, and modified by other sensory inputs (visual, proprioceptive, autonomic) and central cortical commands. Secondary vestibular neurons are clustered into five nuclei in which different subsets of vestibular primary afferents terminate. This distributed organization may be based on the targeted outputs of the clustered secondary neurons rather than on selective afferent targeting. Vestibular primary and secondary afferent mossy fibers activate a large mediolateral extent of granule cells in multiple folia of vermal lobules IX–X.  However, the vermal and hemispheric lobules IX–X are organized in three dimensions by vestibular and visual climbing fiber inputs that are arrayed in narrow sagittal strips. In vermal lobules IX–X, these climbing fiber strips encode linear acceleration imposed by changes in head movement with respect to gravity using the ­utricular otoliths and angular acceleration of the head about the anatomical axes of the two vertical semicircular canals. Hemispheric lobule X encodes self-motion using climbing fiber structured optokinetic feedback imposed by the three axes of the semicircular canals. Vestibular and visual adaptation of this circuitry is needed to maintain balance during postural perturbations. Secondary neurons in the vestibular nuclei and cerebellar neurons may contribute to storage and modification of postural reflexes. Compensation of postural reflexes following unilateral damage to the vestibular nerve provokes changes in cellular expression of protein kinase C-δ without causing a change in transcription of PKC-δ mRNA.

Flocculus · Nodulus · Uvula · Purkinje cells · PKC Compensation

N. H. Barmack (*) Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, USA e-mail: [email protected]

8.1 Introduction The cerebellum and vestibular nuclei are two major components of a larger neural system that controls how vestibular information is received, how it is stored, and how it is modified. This review describes connections between the cerebellum and vestibular nuclei that are multiple and complex.

8.2 Vestibular Nuclei Five vestibular nuclei are located just below the dorsal surface of the medullary brainstem (Fig.  8.1A1). They include descending, lateral, medial, and superior nuclei (DVN, LVN, MVN, and SVN) as well as the parasolitary nucleus (Psol). All five vestibular nuclei receive a mixture of ipsilateral vestibular primary afferents. Each vestibular nucleus is differentiated by a combination of cytological features, axonal boundaries, cell sizes, and immunohistological characteristics. The DVN, LVN, MVN, and SVN contain a variety of cell types. The LVN contains the largest neurons in the brain, Dieter’s neurons, whose soma are ~50 μm in diameter. The LVN also contains many smaller cell types (Brodal and Pompeiano 1957; Brodal 1974; Barmack et al. 1998a). This variability in cell size within a nucleus is regional, suggesting that these nuclei may have multiple circuits and functions. At the other extreme, neurons in the Psol are uniformly small, 5–7 μm in diameter, and are immunolabeled by an antiserum to glutamic decarboxylase, the synthetic enzyme for the neurotransmitter gamma amino butyric acid (GABA) (Barmack et  al. 1998b). The distributed organization of the vestibular nuclei may be based on common targeted outputs rather than on selected afferent targeting of homogeneous circuitry.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_8

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Fig. 8.1  Projections of vestibular primary and secondary mossy and climbing fiber afferents to the vestibular nuclei and lobules IX–X and how these projections are embedded in cerebellar circuitry. (A1) Viewed dorsally, five horizontal semicircular canal afferents, intra-axonally labeled with HRP project to all vestibular nuclei except the LVN. Modified from (Sato and Sasaki 1993). (A2) Mossy fiber terminals from a BDA-labeled lateral reticular nucleus neuron project bilaterally as they reach the anterior cerebellar vermis. (A3) Sagittal view of several BDA-labeled climbing fibers that project in narrow sagittal bands to the contralateral lobules IX–X.  Modified from (Wu et  al. 1999). (B1) Vestibular primary afferents are labeled with the C fragment of tetanus toxin (TTC) injected into the left labyrinth of rabbit. TTC is transported orthogradely and trans-synaptically and labels MFTs and granule cells in lobules IX–X. Arrows bracket the regions of profuse labeling. Note absence of labeling in other folia. (B2) A horizontal section through lobules IX–X shows that the projection of TTC-labeled vestibular primary afferents is unilateral. Modified from (Barmack et al. 1993b). (B3)

Vestibular secondary afferents, labeled with an injection of WGA–HRP into the caudal medial and descending vestibular nuclei, reveals labeling of mossy fiber terminals in lobules IX–X. (c) Schematic illustrates the vestibular mossy (green) and climbing fiber (blue) projections to the brainstem and posterior cerebellar cortex. Vestibular primary afferent mossy fibers (mf) (green) project to the ipsilateral parasolitary, medial, descending, superior vestibular nuclei (Psol, MVN, DVN and SVN). GABAergic Psol neurons (dashed red lines) project to the ipsilateral β-nucleus (β) and dorsomedial cell column (DMCC) in the inferior olive (yellow). Y-group neurons (Y) (purple) project to contralateral DC, β and DMCC (purple lines). Neurons in β and DMCC project as climbing fibers (blue) (cf) to contralateral lobules VIII–X.  Modified from (Barmack and Yakhnitsa 2000). cf climbing fiber, DC dorsal cap, LVN lateral vestibular nuclei, Gc granule cell, LCN, IntP and MCN lateral, interpositus and medial cerebellar nuclei, Pc Purkinje cell, mf mossy fiber, Nsol nucleus solitarius

8.3 Cerebellum

vestibular primary afferent. (2) A vestibular mossy fiber projection to granule cells in both vermal and hemispheric lobules IX–X is bilateral and originates from vestibular secondary mossy fiber afferents from the vestibular nuclei. (3) A third pathway to vermal lobule X is conveyed by vestibular climbing fibers (Fig.  8.1A3). Vestibular climbing fibers originate from two subnuclei of the contralateral inferior olive, β-nucleus, and dorsomedial cell column. The dendritic tree of each Purkinje cell receives ~500 synaptic

Lobules IX (uvula) and X (nodulus), including the hemispheric X (flocculus), are the principal, but not exclusive cerebellar focus for interactions with vestibular nuclei. The circuitry embedded within these lobules is engaged by three distinct vestibular inputs. (1) Granule cells within vermal lobules IX and X receive a vestibular primary afferent collateral mossy fiber projection from every ipsilateral

8  Vestibular Nuclei and Their Cerebellar Connections

contacts from a single climbing fiber. However, a single climbing fiber may synaptically contact the dendritic trees of as many as 15 Purkinje cells. The vestibular climbing fiber projections to vermal lobules IX–X (uvula, nodulus) are arrayed in two narrow sagittal strips that encode vestibular space in two rotational axes encoded by the anterior and posterior semicircular canal ampullae and utricular otoliths (Fig. 8.1A3, c). The width of these climbing fiber strips is ~0.4  mm in the mouse and ~1.0 mm in the rabbit. A third axis, rotation encoded by the horizontal semicircular canal ampullae is absent (Fushiki and Barmack 1997; Barmack and Yakhnitsa 2003). A similar array of sagittal climbing fiber strips, encoding a three-dimensional optokinetic space, originates from the dorsal cap (DC) of the inferior olive and projects onto hemispheric lobule X (flocculus). The coordinates of these spaces correspond physically to the planar orientation of the three semicircular canals (Simpson et al. 1981; Van der Steen et al. 1994; Billig and Balaban 2004; Foster et al. 2007; Yakusheva et al. 2010).

8.4 Vestibular End Organs The peripheral vestibular apparatus consists of three semicircular canals and two otoliths. The semicircular canals are oriented orthogonally and sense angular acceleration about horizontal, vertical, and oblique axes. Otoliths (saccule and utricle) sense linear acceleration imposed by movement of the head with respect to the gravitational vector during ­roll-­tilt of the head about the longitudinal axis (utricle) and during pitch about the intra-aural axis (saccule).

8.5 Vestibular Primary Afferent Cerebellar Projections Each vestibular endorgan contributes primary vestibular afferents to the vestibular nerve that branches into two fiber bundles of unequal thickness as they enter the brain stem. The thicker fiber bundle enters the medulla between the ventral aspect of the inferior cerebellar peduncle and the dorsal aspect of the spinal tract of the trigeminal nucleus. It turns caudally and passes into the vestibular complex to terminate on secondary vestibular neurons. The thinner fiber bundles branch as the primary afferent passes through the inferior cerebellar peduncle and then though superior and lateral vestibular nuclei. The thinner branch ascends to the cerebellum where it terminates as mossy fiber terminals on granule cells in ipsilateral vermal lobules IXd–X (Cajal 1911) (Fig. 8.1A1, B1, 2). The unilateral projection of vestibular primary afferent mossy fibers is shown best using the transsynaptic orthograde tracer, Tetanus toxin C fragment (TTC),

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injected into a labyrinth. TTC is orthogradely transported to the cerebellum where it labels only ipsilateral mossy fiber terminals and granule cells (Fig.  8.1B1, 2) (Barmack et  al. 1993b).

8.6 Vestibular Primary Afferents’ Projections to Vestibular Nuclei Primary afferents of the main branch terminate in each of the five vestibular nuclei (Brodal and Pompeiano 1957; Brodal 1972, 1974; Barmack et  al. 1998a; Barmack and Yakhnitsa 2000) (Fig.  8.1A1). Within the cerebellum, vestibular primary afferents branch again and distribute mossy fiber terminals (MFTs) both sagittally and medio-laterally within vermal lobules IXd–X.  The mossy fiber branching pattern is illustrated best by the spatial patterning of MFTs that originate from the lateral reticular nucleus (LRN) labeled with biotin dextran amine (BDA) (Wu et al. 1999) (Fig.  8.1A2). A single mossy fiber branch develops ~40 MFTs that contact dendrites of ~15 granule cells. In total, a single mossy fiber makes synaptic contact with ~600 granule cells (Palkovits et al. 1972). Primary and secondary vestibular afferents account for ~90% of the total mossy fiber projection to vermal lobules IXd–X (Korte and Mugnaini 1979; Kevetter and Perachio 1986; Gerrits et al. 1989; Sato et al. 1989; Barmack et al. 1993b; Akaogi et al. 1994; Purcell and Perachio 2001; Newlands et al. 2002, 2003; Maklad and Fritzsch 2003). The projection of primary afferent MFTs to vermal lobules IX–X is not restricted to a single folium. Vestibular primary afferent MFTs from, say, the left posterior semicircular canal (LPC), project primarily not only to left vermal lobule X, but also, more sparsely to left vermal lobule IXd. The left saccule projects to the left vermal lobule IX, but more sparsely to the left vermal lobule X (Maklad and Fritzsch 2003). This widely distributed pattern of projections of vestibular primary afferent MFTs creates regions within lobules IX–X where MFTs from a particular endorgan may be concentrated, but not exclusively represented. For example, neurons that respond to stimulation of the ipsilateral anterior semicircular canal are found in the SVN more laterally than are neurons in the SVN that respond to stimulation of the ipsilateral posterior semicircular canal (Abend 1977). Horizontal semicircular canal primary afferents project to the DVN, MVN, and SVN, but not the LVN and Psol. The activity of Psol neurons is driven by stimulation of ipsilateral anterior and posterior semicircular canals, as well as the ipsilateral utricle. However, Psol activity is not driven by stimulation of the horizontal semicircular canals. Secondary neurons within the LVN receive a primary vestibular projection from the ipsilateral saccule, but not from the utricle (Sato and Sasaki 1993).

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8.7 Visual Projections to Vestibular Nuclei Vestibular primary afferents comprise only one of the sensory inputs to the vestibular complex. Most secondary vestibular neurons are also driven by visual (optokinetic) stimulation (Henn et al. 1974). Although visual signals to the vestibular nuclei originate from a variety of brainstem and cortical sources, the best understood pathways by which optokinetic signals reach the vestibular nuclei originate from the accessory optic system (AOS) (Simpson et  al. 1988). Direction selective retinal ganglion cells project to the AOS. AOS neurons, in turn, project to vestibular nuclei, the cerebellum, and the inferior olive. The AOS also receives a descending projection from the visual cortex. In primates, this projection originates from the pre-striate cortex (areas OAa and PGa) (Ilg and Hoffmann 1996). Selective stimulation or inactivation of this region modifies the directional selectivity of neurons in the AOS.

8.8 Neck-Proprioceptive Afferents to Vestibular Nuclei Signals from proprioceptors embedded in the intertransverse muscles at the base of the cervical vertebrae activate secondary vestibular neurons (McCouch et  al. 1951; Hikosaka and Maeda 1973). Injection of HRP into the caudal MVN and DVN retrogradely labels neurons in ipsilateral C2–C3 spinal ganglia and in the contralateral central cervical nucleus and bilaterally in C1–C6 dorsal horn cells (Bankoul and Neuhuber 1990; Sato et al. 1997). Neurons in the vestibular complex also receive secondary cervical afferents relayed through the external cuneate nucleus (Ecu) (Prihoda et al. 1991). Movement of the head with respect to the body stimulates neck proprioceptors and evokes reflexive eye movements as well as postural adjustments of the limbs (McCouch et  al. 1951; Hikosaka and Maeda 1973; Barmack et al. 1981).

8.9 Autonomic Influences of the Vestibular Nuclei The vestibular nuclei not only participate in reflexes mediated by skeletal muscles, but also are part of the circuitry through which autonomic reflexes (blood flow, respiration rate, and heart rate) are regulated (Rossiter et  al. 1996; Kerman et al. 2000; Kaufmann et al. 2002). Specifically, this circuitry includes projections from the caudal vestibular nuclei (DVN, MVN and Psol) to the solitary nucleus (Nsol). The Nsol receives autonomic afferents, from the heart, esophagus and stomach, carried chiefly by branches of the IX and X cranial nerves.

8.10 Internal Connections Within the Vestibular Nuclei The pattern of interconnections within the vestibular complex has been mapped with microinjections of HRP into the vestibular complex of the rabbit. Interconnections between the SVN–DVN and SVN–MVN are reciprocal (Epema et  al. 1988). A group of larger neurons in the rostro-ventral MVN, SVN, and LVN receives inputs from smaller cell regions of MVN, SVN, and DVN, but do not reciprocate (Ito et  al. 1985). The MVN has a non-reciprocal projection to the DVN.

8.11 Bilateral Connections Between Vestibular Nuclei The vestibular nuclei, with the exceptions of the LVN and Psol, are interconnected through a commissural system. The commissural projections are multiple. First, a primary afferent that projects to one nucleus may also project to the same or different contralateral nucleus. Second, the commissural projections of secondary vestibular afferents are not restricted to homotypic nuclei. Rather, cells within a nucleus on one side of the brainstem, say the left MVN, project to the contralateral SVN and DVN as well as the contralateral MVN (Epema et  al. 1988; Newlands et  al. 1989; Wayman et  al. 2008). Electrical stimulation of the utricular macula evokes excitation in ipsilateral secondary vestibular neurons and inhibition in more than 50% of the contralateral secondary vestibular neurons. Only 10% of secondary neurons responsive to ipsilateral stimulation of the saccule are inhibited by contralateral saccular stimulation. These data support the idea that the utricles are wired reciprocally, while the sacculae are not.

8.12 Ascending Projections of Vestibular Nuclei Targets of secondary vestibular afferents are diverse. Secondary afferents from the DVN and MVN project to both vermal and hemispheric lobules VIII–X, the anterior vermis, and paraflocculus (Thunnissen et  al. 1989; Epema et  al. 1990). Most of these ascending projections are cholinergic (Tago et al. 1989; Barmack et al. 1992a, b, c). Neurons in rostral DVN, MVN, and SVN provide an ascending input to cranial motor nuclei III, IV, and VI, controlling the reciprocal contractions of extraocular muscles (Deecke et al. 1977; Büttner and Lang 1979; Graf et al. 1983; Büttner-Ennever 1992). Other brainstem nuclei that receive ascending projections from secondary vestibular neurons include nucleus Darkschewitsch, sensory trigeminal nucleus, interstitial nucleus of Cajal, and the sub-parafascicular com-

8  Vestibular Nuclei and Their Cerebellar Connections

plex (Barmack et al. 1979). The sub-parafascicular complex also projects reciprocally to the ipsilateral MVN. Several ascending projections to the thalamus originate from the rostral part of the vestibular complex to the ventralbasal thalamus (VPL, VPM and VPI). Neurons in the ventral-basal complex are driven by stimulation of deep proprioceptors and joint receptors as well as vestibular inputs (Deecke et al. 1977; Lang et al. 1979; Shiroyama et al. 1999; Bacskai et al. 2002). These thalamic nuclei, in turn, project to Areas 3aV and parietotemporal association cortices (Fukushima 1997). These cortical areas receive optokinetic and somatosensory inputs as well. The importance of this projection is illustrated by the observation that humans with damage to parietal cortex, and without visual cues, do not recognize true vertical (Leigh 1994). Vestibular cortices project reciprocally to vestibular nuclei, suggesting that these cortical regions may supersede reflexes evoked by primary vestibular afferents (Akbarian et  al. 1993, 1994; Nishiike et al. 2000).

8.13 Cholinergic and GABAergic Secondary Vestibular Projections A subset of vestibular secondary neurons is cholinergic and projects bilaterally to both vermal and hemispheric lobules IX–X as well as the nucleus prepositus hypoglossi (NPH) (Epema et al. 1990; Barmack 2003). NPH neurons, in turn, project bilaterally to the caudal vestibular nuclei as well as the inferior olive (McCrea and Baker 1985). The projection from NPH to the dorsal cap is both cholinergic and GABAergic (Barmack et al. 1993a; De Zeeuw et al. 1993). Neurons in the Y-group, a group of cells distributed between the inferior cerebellar peduncle and the lateral vestibular nucleus, also receive bilateral projections from the SVN. The ventral division of the Y-group projects to the ipsilateral flocculus, nodulus, and contralateral oculomotor complex. The dorsal division projects contralaterally to the dorsal cap and beta nucleus of the inferior olive. This projection is excitatory (Kumoi et  al. 1987). Y-group and NPH neurons project directly to the cerebellum as mossy fibers. Y-group and NPH neurons also influence the activity of neurons in the inferior olive that make overlapping projections to the cerebellum as climbing fibers.

8.14 Descending Projections of Vestibular Nuclei Descending lateral and medial vestibulospinal tracts originate from the LVN and MVN and DVN (Brodal 1981). The lateral vestibulospinal tract is organized within the LVN topographically. Fibers to the lumbosacral spinal cord origi-

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nate from the dorsal-caudal LVN. Fibers to the cervical cord originate from the rostro-ventral LVN. Axons in the lateral vestibulospinal tract terminate in the ipsilateral lumbosacral region where they make monosynaptic and polysynaptic connections with motoneurons (Rose et al. 1992). Axons in the medial vestibulospinal tract terminate bilaterally in the medial part of the cervical ventral horn. The bilateral representation of vestibulospinal axons is most dense in the cervical enlargements from which motoneurons supplying the suboccipital muscles originate. These motoneurons participate in vestibulocollic reflexes. Psol neurons differ from the other vestibular nuclear neurons in that they make no secondary mossy fiber projections to the cerebellum. The output of Psol is GABAergic. It descends to the ipsilateral inferior olive where it modulates the activity of cells in the β-nucleus and dorsomedial cell column (DMCC) (Fig. 8.1c) (Barmack et al. 1993c, 1998a). These olivary neurons terminate as climbing fibers in the contralateral vermal lobule X. As they descend to the inferior olive, Psol axons distribute collaterals to nuclei in the reticular formation, particularly in the nucleus reticularis gigantocellularis (Fagerson and Barmack 1995).

8.15 Cerebellar Projections to Vestibular Nuclei Cerebellar projections to the vestibular nuclei include, but are not restricted to lobule X (Walberg and Dietrichs 1988). While Purkinje cells project onto the same vestibular nuclei from which secondary vestibular mossy fiber projections originate, the reciprocal overlap is incomplete. This projection can be examined by labeling Purkinje cell axon terminals with a marker that is uniquely expressed by them and then mapping the regions of the vestibular complex where the marker is expressed. Protein Kinase C is a family of isoforms implicated in subcellular signal transduction. Several PKC isoforms (PKC-α, β, γ, δ, and ε) are expressed within major cerebellar cell types. Some are expressed in cerebellar projection target neurons, cerebellar nuclear neurons, and secondary vestibular neurons. Of all these isoforms, only two, PKC-γ and PKC-δ, are highly expressed in Purkinje cells and are not expressed in secondary vestibular neurons or cerebellar nuclear neurons (Barmack et al. 2000). PKC-γ is expressed in all Purkinje cells, whereas the expression of PKC-δ is restricted to lobules VI–X (Fig.  8.2a–c). Within the cerebellar nuclei, PKC-δ-immunolabeled Purkinje cell axon terminals are found within the medial aspect of the caudal half of the ipsilateral interpositus nucleus. Both PKC-δ and PKC-γimmunolabeled axon terminals are found within the caudal MVN and DVN, Psol, and NPH. The projection patterns of PKC-immunolabeled Purkinje cells are confirmed by abla-

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tion experiments in which unilateral ablations of lobules VII–X deplete PKC-immunolabeled terminals in the vestibular complex ipsilateral to the ablation, but leave the terminals intact in the contralateral vestibular complex (Fig. 8.2d, e). LVN and SVN neurons also receive a uniformly dense projection of PKC-δ- and PKC-γ-­

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Fig. 8.2  Identification of Purkinje cell axon terminal projections to vestibular nuclei. (a, b) Sagittal sections through rat cerebellum are hybridized with an oligonucleotide probe for of PKC-γ (a) and PKC-δ mRNA (b). The PKC-γ probe hybridized with all Purkinje cells in lobules IX–X. The PKC-δ probe hybridized strongly with Purkinje cells in lobules VI–X. (c) A PKC-δ antiserum immunolabels Purkinje cells in lobules IX-X. (d, e) A unilateral ablation of left lobules VII–X, illustrated in (d) reduces PKC-γ immunolabeled Purkinje cell terminals projecting to the caudal left MVN (e). The Purkinje cell terminals in the right MVN, although sparse, remain intact. (f) Horizontal sections through the brainstem illustrate the anterior–posterior extent of the vestibular complex. Three transverse sections through the brainstem illus-

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trate the presence of PKC-γ immunolabeled terminals in each division of the vestibular complex. The antero-posterior location of each section is indicated by the dashed lines (1–3). The density of immunolabeled Purkinje cell terminals is illustrated by brown overlays. DVN, LVN, MVN SVN descending, lateral, medial and superior vestibular nuclei, Ecu external cuneate nucleus, NPH nucleus prepositus hypoglossi, Nsol solitary tract nucleus, Psol parasolitary nucleus, SpV spinal trigeminal nucleus, PO posterior thalamic nuclear group, VL ventrolateral nucleus, VM ventromedial division of LVN, VPL ventral posterior lateral nucleus, Y Y-group. [Modified from (Deecke et al. 1977; Büttner and Lang 1979; Graf et  al. 1983; Büttner-Ennever 1992; Barmack et  al. 2000)]

8  Vestibular Nuclei and Their Cerebellar Connections

Purkinje cell projections to MVN, NPH, SVN, DVN, and Psol are less complete, suggesting that many secondary vestibular neurons, particularly in the posterior half of the vestibular complex, operate independently of direct cerebellar feedback (Fig.  8.2f). The dorsal-caudal MVN and DVN receive dense projections from Purkinje cells in lobules IX–X. However, the descending cerebellar projection to the ventral divisions of the MVN, DVN, and Psol is sparse (Fig. 8.2f). Cells in this region of the MVN, DVN, and LVN give rise to the medial vestibulo-spinal tract.

8.16 Cerebellar and Vestibular Compensation One of the classic attempts to understand interactions between the cerebellum and vestibular nuclei focuses on the change in postural stability following a unilateral labyrinthectomy (UL). The recovery following such damage is termed “compensation.” Others have speculated that the vestibulo-­cerebellum could ameliorate the consequences of the unilateral loss of vestibular primary afferents by reducing the discharge of ipsilateral Purkinje cell “simple spikes” (SSs) and thereby decrease the GABAergic inhibition of ipsilateral secondary vestibular neurons (McCabe and Ryu 1969). However, following a UL in the mouse, the discharge of Purkinje cell SSs decreases in contralateral (not ipsilateral) lobules IX–X (Barmack and Yakhnitsa 2013). This contralateral reduction of SSs can be attributed to a loss of spontaneous primary vestibular afferent activation of Psol neurons (Fig. 8.1c). This reduces inhibitory (GABAergic) signaling to inferior olivary neurons in the ipsilateral β-nucleus and DMMC, increasing the climbing fiber-evoked discharge of “complex spikes” (CSs) in contralateral Purkinje cells. The increased discharge of CSs in contralateral Purkinje cells decreases SSs, probably through climbing fiber-evoked stellate cell inhibition, thereby increasing the Purkinje cell-evoked GABAergic inhibition (Montarolo et al. 1982; Barmack and Yakhnitsa 2003, 2008, 2013). So, the immediate consequence of a UL is a reduction of activity of secondary vestibular neurons in the contralateral vestibular complex. The UL also causes a loss of vestibularly-­evoked modulation of the discharge of CSs and SSs in Purkinje cells in contralateral lobules IX–X normally evoked by roll-tilt. This modulation is only slightly impaired in Purkinje cells ipsilateral to the UL. Chronically, the modulation of both CSs and SSs partially recovers.

8.17 Subcellular Evidence of Cerebellar Plasticity When PKC expression is reduced in L7-PKC-mutant transgenic mice, long-term depression (LTD) is reduced in cere-

57

bellar Purkinje cells (Ito and Karachot 1992). Adaptation of the vestibuloocular reflex to altered conditions of optokinetic stimulation is also impaired (De Zeeuw et al. 1998). Following a UL in rats, the immunolabeling of PKC-δ, of Purkinje cell axon terminals in the caudal ipsilateral vestibular complex decreases (Qian and Barmack 1996). After a UL, Western blots prepared from the ipsilateral uvula-­ nodulus show that cytosolic PKC-δ increases and membrane-­ associated PKC-δ decreases (Barmack et  al. 2001). Hybridization histochemistry and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) demonstrate no change in transcription of PKC-δ and PKC-γ mRNA in the lobules IX–X after a UL. These data indicate that PKC-δ and PKC-γ are constitutively expressed, but that their distribution within Purkinje cells depends upon cellular activity. Since PKC-δ is independent of calcium concentration, it could provide a regulatory signal for synaptic release that is independent of the calcium influx associated with excitation–secretion at synaptic terminals (Azzi et  al. 1992; Sossin and Schwartz 1993). Alternatively, PKC has been linked to the regulation of the GABA transporter through a plasma membrane protein, Syntaxin 1A (Beckman et  al. 1968). By modulating the GABA transporter, the interaction of PKC and Syntaxin 1A could influence the net release of GABA. Following a UL, compensation could occur if decreased Purkinje cell activity contributed to a decreased release of GABA, homeostatically compensating for the loss in primary afferent excitation of secondary vestibular neurons. Reduced expression of 14-3-3-θ and PKC-γ in Purkinje cells reduces the serine phosphorylation of GABAAγ2, critical for its insertion into the post-synaptic membrane (Qian et al. 2012).

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58 Bacskai T, Szekely G, Matesz C (2002) Ascending and descending projections of the lateral vestibular nucleus in the rat. Acta Biol Hung 53:7–21 Bankoul S, Neuhuber WL (1990) A cervical primary afferent input to vestibular nuclei as demonstrated by retrograde transport of wheat germ agglutinin-horseradish peroxidase in the rat. Exp Brain Res 79:405–411 Barmack NH (2003) Central vestibular system: vestibular nuclei and posterior cerebellum. Brain Res Bull 60:511–541 Barmack NH, Yakhnitsa V (2000) Vestibular signals in the parasolitary nucleus. J Neurophysiol 83:3559–3569 Barmack NH, Yakhnitsa V (2003) Cerebellar climbing fibers modulate simple spikes in cerebellar Purkinje cells. J Neurosci 23:7904–7916 Barmack NH, Yakhnitsa V (2008) Functions of interneurons in mouse cerebellum. J Neurosci 28:1140–1152 Barmack NH, Yakhnitsa V (2013) Modulated discharge of Purkinje and stellate cells persists after unilateral loss of vestibular primary afferent mossy fibers in mice. J Neurophysiol 110:2257–2274 Barmack NH, Henkel CK, Pettorossi VE (1979) A subparafascicular projection to the medial vestibular nucleus of the rabbit. Brain Res 172:339–343 Barmack NH, Nastos MA, Pettorossi VE (1981) The horizontal and vertical cervico-ocular reflexes of the rabbit. Brain Res 224:261–278 Barmack NH, Baughman RW, Eckenstein FP (1992a) Cholinergic innervation of the cerebellum of rat, rabbit, cat and monkey as revealed by choline acetyltransferase activity and immunohistochemistry. J Comp Neurol 317:233–249 Barmack NH, Baughman RW, Eckenstein FP (1992b) Cholinergic innervation of the cerebellum of the rat by secondary vestibular afferents. In: Cohen B, Tomko DL, Guedry F (eds) Sensing and controlling motion: vestibular and sensorimotor function. New  York Academy of Sciences, New  York, pp 566–579 Barmack NH, Baughman RW, Eckenstein FP, Shojaku H (1992c) Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers. J Comp Neurol 317:250–270 Barmack NH, Fagerson M, Errico P (1993a) Cholinergic projection to the dorsal cap of the inferior olive of the rat, rabbit and monkey. J Comp Neurol 328:263–281 Barmack NH, Baughman RW, Errico P, Shojaku H (1993b) Vestibular primary afferent projection to the cerebellum of the rabbit. J Comp Neurol 327:521–534 Barmack NH, Fagerson M, Fredette BJ, Mugnaini E, Shojaku H (1993c) Activity of neurons in the beta nucleus of the inferior olive of the rabbit evoked by natural vestibular stimulation. Exp Brain Res 94:203–215 Barmack NH, Fredette BJ, Mugnaini E (1998a) Parasolitary nucleus: a source of GABAergic vestibular information to the inferior olive of rat and rabbit. J Comp Neurol 392:352–372 Barmack NH, Park S-H, Mugnaini E (1998b) Vestibular modulation of neuronal activity in the parasolitary nucleus of the rabbit. Soc Neurosci 24:1405 Barmack NH, Qian Z-Y, Yoshimura J (2000) Regional and cellular distribution of protein kinase C in rat cerebellar Purkinje cells. J Comp Neurol 427:235–254 Barmack NH, Qian Z-Y, Kim HJ, Yoshimura J (2001) Activity-­ dependent distribution of protein kinase C-δ in rat cerebellar Purkinje cells following unilateral labyrinthectomy. Exp Brain Res 141:6–20 Beckman ML, Bernstein EM, Quick MW (1968) Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A. J Neurosci 18:6103–6112 Bernard J-F (1987) Topographical organization of olivocerebellar and corticonuclear connections in the rat—an WGA-HRP study: I. Lobules IX, X, and the flocculus. J Comp Neurol 263:241–258

N. H. Barmack Billig I, Balaban CD (2004) Zonal organization of the vestibulo-­ cerebellum in the control of horizontal extraocular muscles using pseudorabies virus: I. Flocculus/ventral paraflocculus. Neuroscience 125:507–520 Brodal A (1972) Anatomy of the vestibuloreticular connections and possible "ascending" vestibular pathways from the reticular formation. In: Brodal A, Pompeiano O (eds) Basic aspects of central vestibular mechanisms. Progress in brain research, vol 37. Elsevier, Amsterdam Brodal A (1974) Anatomy of the vestibular nuclei and their connections. In: Kornhuber HH (ed) Handbook of sensory physiology, vestibular system, morphology, vol 6. Springer, Berlin Brodal A (1981) Neurological anatomy, 3rd edn. Oxford University Press, New York Brodal A, Pompeiano O (1957) The vestibular nuclei in the cat. J Anat 91:438–454 Büttner U, Lang W (1979) The vestibulocortical pathway: neurophysiological and anatomical studies in the monkey. In: Granit R, Pompeiano O (eds) Reflex control of posture and movement. Elsevier, Amsterdam, pp 581–588 Büttner-Ennever J (1992) Patterns of connectivity in the vestibular nuclei. In: Cohen B, Tomko DL, Guedry F (eds) Sensing and controlling motion. Annals of the New  York Academy of Sciences, New York, pp 363–378 Cajal SR (1911) Histologie du système nerveux de l'homme et des vertebrés. Maloine, Paris De Zeeuw CI, Wentzel P, Mugnaini E (1993) Fine structure of the dorsal cap of the inferior olive and its GABAergic and non-GABAergic input from the nucleus prepositus hypoglossi in rat and rabbit. J Comp Neurol 327:63–82 De Zeeuw CI, Hansel C, Bian F, Koekkoek SK, Van Alphen AM, Linden DJ, Oberdick J (1998) Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron 20:495–508 Deecke L, Schwarz DWF, Fredrickson JM (1977) Vestibular responses in the rhesus monkey ventroposterior thalamus. II.  Vestibulo-­ proprioceptive convergence at thalamic neurons. Exp Brain Res 30:219–232 Epema AH, Gerrits NM, Voogd J (1988) Commissural and intrinsic connections of the vestibular nuclei in the rabbit: a retrograde labeling study. Exp Brain Res 71:129–146 Epema AH, Gerrits NM, Voogd J (1990) Secondary vestibulocerebellar projections to the flocculus and uvulo-nodular lobule of the rabbit: a study using HRP and double fluorescent tracer techniques. Exp Brain Res 80:72–82 Fagerson MH, Barmack NH (1995) Responses to vertical vestibular stimulation of neurons in the nucleus reticularis gigantocellularis in rabbits. J Neurophysiol 73:2378–2391 Foster IZ, Hanes DA, Barmack NH, McCollum G (2007) Spatial symmetries in vestibular projections to the uvula-nodulus. Biol Cybern 96:439–453 Fukushima K (1997) Corticovestibular interactions: anatomy, electrophysiology, and functional considerations. Exp Brain Res 117:1–16 Fushiki H, Barmack NH (1997) Topography and reciprocal activity of cerebellar Purkinje cells in the uvula-nodulus modulated by vestibular stimulation. J Neurophysiol 78:3083–3094 Gerrits NM, Epema AH, Van Linge A, Dalm E (1989) The primary vestibulocerebellar projection in the rabbit: absence of primary afferents in the flocculus. Neurosci Lett 105:27–33 Graf W, McCrea RA, Baker R (1983) Morphology of posterior canal related secondary vestibular neurons in rabbit and cat. Exp Brain Res 52:125–138 Henn V, Young L, Finley C (1974) Vestibular nucleus units in alert monkeys are also influenced by moving visual fields. Brain Res 71:144–149 Hikosaka O, Maeda K (1973) Cervical effects on abducens motoneurons and their interaction with vestibulo-ocular reflex. Exp Brain Res 18:512–530

8  Vestibular Nuclei and Their Cerebellar Connections Ilg UJ, Hoffmann KP (1996) Responses of neurons of the nucleus of the optic tract and the dorsal terminal nucleus of the accessory optic tract in the awake monkey. Eur J Neurosci 8:92–105 Ito M, Karachot L (1992) Protein kinases and phosphatase inhibitors mediating long-term desensitization of glutamate receptors in cerebellar Purkinje cells. Neurosci Res 14:27–38 Ito JI, Matsuoka I, Sasa M, Takaori S (1985) Commissural and ipsilateral internuclear connection of vestibular nuclear complex of the cat. Brain Res 341:73–81 Kaufmann H, Biaggioni I, Voustianiouk A, Diedrich A, Costa F, Clarke R, Gizzi M, Raphan T, Cohen B (2002) Vestibular control of sympathetic activity—an otolith-sympathetic reflex in humans. Exp Brain Res 143:463–469 Kerman IA, McAllen RM, Yates BJ (2000) Patterning of sympathetic nerve activity in response to vestibular stimulation. Brain Res Bull 53:11–16 Kevetter GA, Perachio A (1986) Distribution of vestibular afferents that innervate the sacculus and posterior canal in the gerbil. J Comp Neurol 254:410–424 Korte G, Mugnaini E (1979) The cerebellar projection of the vestibular nerve in the cat. J Comp Neurol 184:265–278 Kumoi K, Saito N, Tanaka C (1987) Immunohistochemical localization of γ-aminobutyric acid- and aspartate-containing neurons in the guinea pig vestibular nuclei. Brain Res 416:22–23 Lang W, Büttner-Ennever JA, Büttner U (1979) Vestibular projections to the monkey thalamus: an autoradiographic study. Brain Res 177:3–17 Leigh RJ (1994) Human vestibular cortex. Ann Neurol 35:383–384 Maklad A, Fritzsch B (2003) Partial segregation of posterior crista and saccular fibers to the nodulus and uvula of the cerebellum in mice, and its development. Dev Brain Res 140:223–236 McCabe BF, Ryu JH (1969) Experiments on vestibular compensation. Laryngoscope 79:1728–1736 McCouch GP, Deering ID, Ling TH (1951) Location of receptors for tonic neck reflexes. J Neurophysiol 14:191–196 McCrea RA, Baker R (1985) Anatomical connections of the nucleus prepositus of the cat. J Comp Neurol 237:377–407 Montarolo PG, Palestini M, Strata P (1982) The inhibitory effect of the olivocerebellar input on the cerebellar Purkinje cells in the rat. J Physiol 332:187–202 Newlands SD, Kevetter GA, Perachio AA (1989) A quantitative study of the vestibular commissures in the gerbil. Brain Res 487:152–157 Newlands SD, Purcell IM, Kevetter GA, Perachio AA (2002) Central projections of the utricular nerve in the gerbil. J Comp Neurol 452:11–23 Newlands SD, Vrabec JT, Purcell IM, Stewart CM, Zimmerman BE, Perachio AA (2003) Central projections of the saccular and utricular nerves in macaques. J Comp Neurol 466:31–47 Nishiike S, Guldin WO, Bäurle J (2000) Corticofugal connections between the cerebral cortex and the vestibular nuclei in the rat. J Comp Neurol 420:363–372 Palkovits M, Magyar P, Szentagothai J (1972) Quantitative histological analysis of the cerebellar cortex in the cat. IV. Mossy fiber-Purkinje cell numerical transfer. Brain Res 45:15–29 Prihoda M, Hiller MS, Mayr R (1991) Central projections of cervical primary afferent-fibers in the Guinea-pig—an HRP and WGA/HRP tracer study. J Comp Neurol 308:418–431 Purcell IM, Perachio AA (2001) Peripheral patterns of terminal innervation of vestibular primary afferent neurons projecting to the vestibulocerebellum in the gerbil. J Comp Neurol 433:48–61 Qian Z-Y, Barmack NH (1996) Distribution of protein kinase C-δ in cerebellar Purkinje cells following unilateral labyrinthectomy in rat. Soc Neurosci 22:1832–1832

59 Qian Z, Micorescu M, Yakhnitsa V, Barmack NH (2012) Climbing fiber activity reduces 14-3-3-θ regulated GABAA receptor phosphorylation in cerebellar Purkinje cells. Neuroscience 201:34–45 Rose PK, Wainwright K, Neuber-Hess M (1992) Connections from the lateral vestibular nucleus to the upper cervical spinal cord of the cat: a study with the anterograde tracer PHA-L. J Comp Neurol 321:312–324 Rossiter CD, Hayden NL, Stocker SD, Yates BJ (1996) Changes in outflow to respiratory pump muscles produced by natural vestibular stimulation. J Neurophysiol 76:3274–3284 Sato F, Sasaki H (1993) Morphological correlations between spontaneously discharging primary vestibular afferents and vestibular nucleus neurons in the cat. J Comp Neurol 333:554–556 Sato Y, Kanda K-I, Ikarashi K, Kawasaki T (1989) Differential mossy fiber projections to the dorsal and ventral uvula in the cat. J Comp Neurol 279:149–164 Sato H, Ohkawa T, Uchino Y, Wilson VJ (1997) Excitatory connections between neurons of the central cervical nucleus and vestibular neurons in the cat. Exp Brain Res 115:381–386 Shiroyama T, Kayahara T, Yasui Y, Nomura J, Nakano K (1999) Projections of the vestibular nuclei to the thalamus in the rat: a Phaseolus vulgaris leucoagglutinin study. J Comp Neurol 407:318–332 Shojaku H, Sato Y, Ikarashi K, Kawasaki T (1987) Topographical distribution of Purkinje cells in the uvula and the nodulus projecting to the vestibular nuclei in cats. Brain Res 416:100–112 Simpson JI, Graf W, Leonard C (1981) The coordinate system of visual climbing fibers to the flocculus. In: Fuchs AF, Becker W (eds) Developments in neuroscience, vol 12: progress in oculomotor research. Elsevier, Amsterdam, pp 475–484 Simpson JI, Leonard CS, Soodak RE (1988) The accessory optic-­ system—analyzer of self-motion. Ann N Y Acad Sci 545:170–179 Sossin WS, Schwartz JH (1993) Ca2+-independent protein kinase Cs contain an amino-terminal domain similar to the C2 consensus sequence. Trends Biochem Sci 18:207–208 Tabuchi T, Umetani T, Yamadori T (1989) Corticonuclear and corticovestibular projections from the uvula in the albino rat: differential projections from sublobuli of the uvula. Brain Res 492:176–186 Tago H, McGeer PL, McGeer EG, Akiyama H, Hersh LB (1989) Distribution of choline acetyltransferase immunopositive structures in the rat brainstem. Brain Res 495:271–297 Thunnissen IE, Epema AH, Gerrits NM (1989) Secondary vestibulocerebellar mossy fiber projection to the caudal vermis in the rabbit. J Comp Neurol 290:262–277 Van der Steen J, Simpson JI, Tan J (1994) Functional and anatomic organization of three-dimensional eye movements in rabbit cerebellar flocculus. J Neurophysiol 72:31–46 Walberg F, Dietrichs E (1988) The interconnection between the vestibular nuclei and the nodulus: a study of reciprocity. Brain Res 449:47–53 Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, Marks D, Obrietan K, Soderling TR, Goodman RH, Impey S (2008) An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP.  Proc Natl Acad Sci U S A 105:9093–9098 Wu HS, Sugihara I, Shinoda Y (1999) Projection patterns of single mossy fibers originating from the lateral reticular nucleus in the rat cerebellar cortex and nuclei. J Comp Neurol 411:97–118 Yakusheva T, Blazquez PM, Angelaki DE (2010) Relationship between complex and simple spike activity in macaque caudal vermis during three-dimensional vestibular stimulation. J Neurosci 30:8111–8126

9

Spinocerebellar and Cerebellospinal Pathways Tom J. H. Ruigrok

Abstract

The cerebellum participates in many different functions, yet its coordinating role in the learning and execution of movements remains the most visible aspect of our behavior. Multiple pathways convey information from the body to the cerebellum. These spinal pathways can be divided into systems that, either directly or indirectly, enter the cerebellar cortex to terminate as mossy fibers and in pathways that reach the cerebellum by way of the inferior olive and as a consequence will terminate as climbing fibers. Cerebellar processing, subsequently, is mediated back to the spinal cord by a multitude of routes. Corticospinal, rubrospinal, tectospinal, vestibulospinal, and reticulospinal tracts may all, at least to some extent, be controlled by cerebellar output, which may even affect spinal processing directly. Keywords

Mossy fibers · Climbing fibers · Cerebellar nuclei Spinal cord · Dorsal column nuclei · Corticospinal Rubrospinal · Vestibulospinal · Reticulospinal

Among the many different functions that the cerebellum is involved in, its role in the control and coordination of reflexive as well as voluntary movements has been its most visible contribution to our behavior. In order to execute these tasks, the cerebellum requires considerable input from the body by way of multiple spinocerebellar routes. Similarly, the output of the cerebellum participating in the control of movements reaches its destination by several pathways. This chapter reviews the tracts that reach the cerebellum with information

T. J. H. Ruigrok (*) Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands e-mail: [email protected]

from the body as well as provides an overview of descending corridors used by the cerebellum to influence movements.

9.1 Information Routes from Spinal Cord to the Cerebellum Information from the body to the cerebellum is divided into pathways that reach the cerebellum by way of the mossy fiber system and routes that reach the cerebellum by way of the inferior olive and its climbing fibers to the cerebellar Purkinje cells. In both the mossy fiber as well as the climbing fiber pathways, a distinction can be made into direct routes from the spinal cord to the cerebellum and inferior olive (Fig. 9.1a, b), respectively, or by way of pathways that use an intermediary in the (lower) brainstem.

9.1.1 Spinocerebellar Mossy Fiber Systems The organization of spinal fiber systems that reach the cerebellum is complex and consists of many different components and subsystems each with its own characteristics and termination pattern within the cerebellar cortex. Here, we only will mention the main routes. It should be stressed that although in some forms of spinocerebellar ataxia (SCA), some of these spinocerebellar systems might be involved, in most cases, SCA’s refer to a more general pathological condition involving the cerebellum.

9.1.1.1 The Dorsal Spinocerebellar Tract The column of Clarke (located medially in lamina VII at thoracic and upper lumbar levels, also called “dorsal nucleus” or “posterior thoracic nucleus”) is the origin of the dorsal spinocerebellar tract. It ascends ipsilaterally in the superficial aspect of the dorsal half of the lateral funiculus and enters the cerebellum by way of the inferior cerebellar peduncle (Fig.  9.1a). It conveys mostly proprioceptive information

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_9

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T. J. H. Ruigrok

a

b

Fig. 9.1  Schematic diagrams showing the main ascending pathways from the spinal cord to the cerebellum (CBL) and the cerebellar influence on descending spinal tracts. These diagrams are based on experimental tracer and physiological studies in a variety of animals. The course of the fiber bundles throughout the spinal cord may be different in different species (cf. course of corticospinal tract in rodents vs primates). (a) The direct spinocerebellar tracts. These tracts involve the dorsal spinocerebellar tract (DSCT), the ventral spinocerebellar tract (VSCT), the rostral spinocerebellar tract (RSCT), the sacral spinocerebellar tract (SSCT) and the cervicocerebellar tract (CCT). Due to the homology with the DSCT the external cuneocerebellar tract (ECCT) is also included in the direct spinocerebellar tracts. Note that some tracts take a contralateral course to the cerebellum but mainly terminate ipsilateral to their origin. Fibers mostly use the inferior cerebellar peduncle (icp), but some tracts enter the cerebellum by way of the superior cerebellar peduncle (scp). (b) Essentially three spino-olivocerebellar paths (SOCPs) are recognized, although some paths can be further subdivided. A direct route from spinal cells to the inferior olive essentially takes a route by way of the contralateral ventral funiculus (VF-SOCP). A second route courses via the ipsilateral dorsal funiculus (DF-SOCP), synapses at the dorsal column nuclei from where the contralateral inferior olive is targeted. This path, at least partly, originates from so-called postsynaptic dorsal funiculus interneurons located in the dorsal horn. The third spinocerebellar path follows the ipsilateral dorsolateral funiculus (DLFSOCP) and has one or two synaptic stations of unknown location before reaching the inferior olive. Single cerebellar cortical zones can receive

c

input from multiple SOCPs. (c) Descending pathways influenced by cerebellar output. The corticospinal tract (SCT) is influenced by all cerebellar nuclei as these all reach the motor thalamus. The tectospinal tract (TST) can be influenced by the medial (M, MedCN), posterior interposed (P, Post Int CN) and lateral (L, Lat CN) cerebellar nuclei. It descends mostly contralateral to cervical levels. The rubrospinal tract (RbST) is activated by the anterior interposed (A, Ant Int CN) nucleus. It descends in the lateral funiculus throughout the cord. In human its importance is doubted. The vestibulospinal tracts can be divided into the lateral vestibulospinal tract (LVST), originating from the lateral vestibular nucleus (LV) and whose cells are directly controlled by Purkinje cells of the lateral vermis, and the medial vestibulospinal tract (MVST) which is specifically controlled by M. The reticulospinal tracts (RST) can be divided into a medial tract, which originates from the pontine reticular formation and a more laterally positioned tract, which predominantly originates from the medullar reticular formation. For the sake of clarity, the reticular tracts are only depicted on the contralateral side although they essentially are present bilaterally. Also note that the interstitiospinal tract is not depicted in this scheme. In mice, direct cerebellospinal projections to the contralateral cervical cord arise from M and P (projections from P are not indicated). In addition, ipsilateral direct cerebellospinal projections terminating throughout the cord arise from A (not indicated) and P (Sathyamurthy et al. 2020), but their route has not yet been described and is therefore indicated by hatched lines. C cuneate nucleus, CC column of Clarke, CCN central cervical nucleus, G gracile nucleus, SB spinal border cells, SN Stilling’s nucleus

9  Spinocerebellar and Cerebellospinal Pathways

from the ipsilateral lower body half. As such, it is thought to provide the cerebellum with information on the position of the hindlimb relative to the body. Recent evidence, however, indicates that several subgroups, each with different projection patterns can be recognized in the mouse (Luo et  al. 2018). Stilling’s nucleus, located medially within lamina VII at sacral levels, is thought to be the tail equivalent of the column of Clarke (Edgley and Grant 1991). Similarly, activity of the neurons of the central cervical nucleus, located centrally within the upper cervical segments, reflects mostly neck (head) position. However, in contrast to the dorsal spinocerebellar tract, fibers from Stilling’s nucleus and the central cervical tract reach the cerebellum by way of a mostly contralateral route and by way of the superior cerebellar peduncle (Matsushita et al. 1995).

9.1.1.2 The Ventral Spinocerebellar Tract Other clusters of spinocerebellar neurons are the so-called spinal border cells within the lateral part of the ventral horn of the lumbosacral cord, and cells located within the intermediate gray of the cervical enlargement. Finally, there are many cells scattered throughout the dorsal, intermediate, and ventral parts of the entire cord that send projections to the cerebellum. Most of these other spinocerebellar fibers originating from the ventral horn ascend by way of the contralateral ventral (or anterior) spinocerebellar tract (Kitamura and Yamada 1989), and enter the cerebellum along the superior cerebellar peduncle (Fig. 9.1a). Spinocerebellar neurons following the ventral spinocerebellar tract convey information from wide receptive fields and are also targeted by descending supraspinal systems. In addition, they have local collaterals which may be incorporated in spinal networks (Jankowska and Hammar 2013). 9.1.1.3 The Spino-Cuneo-Cerebellar Tract Although the spino-cuneo-cerebellar pathway involves a brainstem nucleus, it can be considered the forelimb homologue of the dorsal spinocerebellar tract. The main intermediary is formed by the external cuneate nucleus which receives mostly proprioceptive input from forelimb primary afferents travelling within the dorsal funiculus. It enters the cerebellum by way of the ipsilateral inferior cerebellar peduncle terminating mostly unilaterally in the cortex of the spinocerebellum without targeting the cerebellar nuclei (Quy et  al. 2011). In addition, the internal cuneate and gracile nuclei also supply cutaneous information from, respectively, the upper and lower halves of the body to the cerebellum. 9.1.1.4 The Rostral Spinocerebellar Tract The rostral spinocerebellar tract is considered to be the forelimb equivalent of the ventral spinocerebellar tract. It arises mostly from neurons at the intermediate laminae of the cord throughout the cervical levels but, in contrast to its lower limb homolog, their axons reach the cerebellum by way of an

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ipsilateral route passing through the ventral part of the lateral funiculus and entering the cerebellum by either the inferior or superior peduncles (Fig. 9.1a).

9.1.1.5 Indirect Spinocerebellar Mossy Fiber Tracts The lateral reticular nucleus, situated ventrolaterally in the caudal medulla, is an important intermediary supplying spinal information to the cerebellum. It can be divided into a magnocellular dorsomedial, a parvocellular ventrolateral, and a subtrigeminal part. In cat, physiological studies, often corroborated by tracing studies, have shown that the ventrolateral part mediates information from both lower limbs by way of the ventral flexor reflex tract, while the dorsomedial part receives proprioceptive information from the ipsilateral forelimb specifically (Azim et al. 2014; Pivetta et al. 2014). Other reticular regions in the brainstem as well as the vestibular nuclei may also function as brainstem intermediaries transmitting spinocerebellar information (Luo et  al. 2018). For example, the central cervical nucleus supplies afferents to predominantly the magnocellular part of the medial vestibular nucleus which may be used in the control of the vestibulocollicular reflex (Matsushita et  al. 1995). Similar to the vestibulo-ocular reflexes, the vestibulocerebellum is likely to be involved in the adaptive control of this reflex (Barmack 2003). 9.1.1.6 Cerebellar Targets of Spinocerebellar Mossy Fiber Tracts Within the cerebellum, both the direct and indirect spinocerebellar mossy fiber projections are distributed bilaterally with an ipsilateral preponderance which indicates that the contralaterally ascending fibers recross in the cerebellum (Matsushita and Yaginuma 1989). Spinocerebellar mossy fibers are mostly found in the so-called spinocerebellum, which consists of the vermal and paravermal regions of the anterior lobe (and adjacent simple lobule) as well as in vermal and paravermal parts of lobule VIII and adjacent parts of VII and IX. A coarse somatotopy can be recognized in that the hindlimb is represented anterior to the forelimb in the rostral cerebellar lobules but posterior to it in its caudal representation. It is not known to what extent terminal clusters from axons travelling by way of the dorsal spinocerebellar tract overlap with those from the ventral spinocerebellar tract. Spinocerebellar systems collateralize to the cerebellar nuclei but from the external cuneate nucleus these projections are sparse (Quy et al. 2011).

9.1.2 Spino-Olivocerebellar Pathways Several spino-olivocerebellar pathways (SOCPs) provide climbing fibers to the cerebellar cortex. They have been extensively studied in cat using electrophysiological tech-

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niques employing selective lesions of the spinal white matter (Oscarsson and Sjolund 1977). As such it was established that spinal afferents can affect olivary processing by way of the ventral (or ventrolateral), (dorso-)lateral, and dorsal funiculi (Fig. 9.1b). The ventral funiculus SOCP originates from several clusters of neurons located at the deeper layers of the contralateral cord and includes the lateral cervical nucleus. These neurons relay mostly not only proprioceptive, but also cutaneous, information which, after crossing at segmental level ascends just ventral to the ventral spinocerebellar tract to reach the caudal part of contralateral medial accessory and entire dorsal accessory olive. Olivocerebellar axons from the caudal halves of the accessory olives again cross the midline to reach the cerebellum by way of the inferior cerebellar peduncle to terminate unilaterally in A and B zones of the vermis (caudal parts of medial and dorsal accessory olives, respectively) or in the paravermal C1 and C3 zones (rostral part of the dorsal accessory olive) of the spinocerebellum. A second pathway from the spinal cord to the inferior olive uses the dorsal funiculus and relays at the dorsal column nuclei (DFSOCP). At least part of this pathway originates from neurons from the deeper layers of the dorsal horn and is also referred to as the postsynaptic dorsal column pathway to the inferior olive. Available evidence suggests that the postsynaptic dorsal column pathway originates from different spinal sources and mediates less sensitive and/or nociceptive signals to the inferior olive as compared to the direct spino-olivary route (Flavell et al. 2014). Finally, the third spino-olivocerebellar route passes mostly through the ipsilateral lateral funiculus and relays through several, as yet not further specified, brainstem intermediaries before activating the contralateral inferior olive (i.e., rostral part of the medial accessory and the principal olives) that supply climbing fibers to the C2 and D1 zones (Voogd et al. 2022). SOCPs can activate climbing fibers of all major cerebellar zones (excepting those of the vestibulocerebellum) but do so with different latencies (Lawrenson et al. 2016). Transmission within the SOCPs varies within, e.g., different phases of the stepcycle (Lidierth and Apps 1990).

9.2 Information Routes from the Cerebellum to the Spinal Cord From the brain arises a multitude of pathways that descend to the spinal cord. Many of these can be influenced by output from the cerebellum. As the cerebellar nuclei constitute the main output station of cerebellar processing, the organization of their output will determine how the cerebellum influences these descending pathways and spinal cord. Although

T. J. H. Ruigrok

the cerebellum may control several autonomic descending pathways (Fujita et al. 2020; Zhu et al. 2006), we will concentrate on the cerebellar control of pathways that are mostly involved in motor control. Classically, these are separated into medial descending systems, which course through the ventral funiculus and lateral descending systems, which pass the lateral funiculus (Lawrence and Kuypers 1968). Medial systems comprise the uncrossed medial corticospinal tract and the tectospinal, vestibulospinal, reticulospinal, and interstitiospinal pathways. The lateral systems involve the crossed corticospinal tract and the rubrospinal tract. In addition, the cerebellum itself may directly control spinal processing.

9.2.1 Lateral Systems 9.2.1.1 The Crossed Corticospinal Tract The crossed corticospinal tracts originates mostly from the primary motor (area 4), premotor (area 6) and, to a lesser extent, from somatosensory cortices (areas 1–3). As output from all cerebellar nuclei will reach the ventral lateral and ventral anterior parts of the thalamus (i.e., the classic “motor” thalamus), but not the ventral posterior nucleus, cerebellar processing will be important for voluntary movement control as directed by primary and secondary motor cortices (Fig. 9.1c). Presently, it is debated to what extent cerebellar output is involved in corticospinal information processing within somatosensory cortical regions (Aoki et  al. 2019; Proville et al. 2014; Schafer and Hoebeek 2018). 9.2.1.2 The Rubrospinal Tract The rubrospinal tract originates from the magnocellular part of the red nucleus. Its fibers cross at the level of the nucleus and descend in the ventrolateral medulla to take up position in the lateral funiculus just ventral to, and partly intermingled with, the fibers from the crossed corticospinal tract. Although in most mammals the tract terminates throughout the spinal cord, its contribution to cervical processing seems to have increased in animals with reaching capacities of their forelimbs. However, in higher primates the importance of the rubrospinal tract seems to have degraded as in man only a few hundred rubrospinal fibers are described that may not even reach caudal cervical levels (Onodera and Hicks 2009). The rubrospinal tract is under the exclusive control of the anterior interposed nucleus (i.e., C1 and C3 cortical zones; Fig. 9.1c) (Voogd et al. 2022).

9.2.2 Medial Systems 9.2.2.1 The Uncrossed Corticospinal Tract The origin of the uncrossed corticospinal tract seems to be similar to that of the crossed corticospinal tract. However,

9  Spinocerebellar and Cerebellospinal Pathways

caudal to the pyramidal decussation, it takes an ipsilateral route through the ventral funiculus to terminate predominantly contralaterally on interneurons in the medial part of the ventral horn (Fig. 9.1c). Cerebellar control is likely to be similar to that of the crossed corticospinal tract.

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ebellum (flocculus and nodulus) that project directly to the vestibular nuclei. The rostral part of the medial cerebellar nucleus, receiving input from the vermal A zone (Voogd et  al. 1996), projects by way of the superior cerebellar peduncle to the ipsilateral medial vestibular nucleus. The same area is also reached by the contralateral medial cerebel9.2.2.2 The Tectospinal Tract lar nucleus by way of the uncinate tract that crosses in the The superior colliculus is involved in directing gaze to cerebellar commissure. In mice, the ipsilateral nucleo-­ objects of interest by inducing saccades, head movements, or vestibular connections are glycinergic, whereas the contraa combination of both. However, arm or even whole body lateral projections are glutamatergic, suggesting that the movements may also be evoked by its stimulation. As such, cerebellum can exert a push–pull mechanism on balancing/ it has been suggested to control reflexive behaviors such as posturing control (Bagnall et al. 2009). defensive and orienting behavior. The tectospinal tract, arisThe lateral vestibulospinal tract originates from the ipsiing from large cells in the deeper layers of the caudolateral lateral lateral vestibular nucleus (Deiters’ nucleus), is excitpart of the superior colliculus mostly decussates in the dorsal atory, and descends by way of the anterolateral fascicle to tegmental tract and descends in the ventral funiculus but thoracic levels of the cord where it shifts more toward the does not project beyond the cervical segments from where ventral funiculus. The lateral tract terminates throughout the the neck muscles are innervated (Nudo and Masterton 1989). length of the cord in the ventromedial laminae of the spinal Tectospinal fibers also have ample brainstem collaterals, grey (lamina VII–VIII: Fig. 9.1c), and may make direct synwhich can affect cervical muscles by way of reticulospinal aptic contacts with motoneurons that control anti-gravity pathways (Isa et al. 2020). muscles (Arshavsky et al. 1986). The main afferent source of Cerebellar output from the fastigial, posterior interposed the lateral vestibular neurons is the axons of the Purkinje and lateral cerebellar nucleus reaches predominantly the cells of the B zone that is found in the lateral vermis of the deeper layers of the superior colliculus. As such, all these anterior lobe and lobule VIII. Indeed, as most lateral vestiburegions are likely to influence tectospinal processing (Niemi-­ lar neurons are active during the stance phase of locomotion, Junkola and Westby 2000). it was shown that cooling of the anterior cerebellar vermis results in prolonged stance phases (Arshavsky et  al. 1986; 9.2.2.3 The Vestibulospinal Tracts Udo et al. 1976). The vestibular nuclear complex, classically divided into a medial, spinal, lateral, and a superior vestibular nucleus, is 9.2.2.4 The Reticulospinal Tracts intimately and reciprocally connected with the cerebellar Many regions in the medial and medioventral pontomedulcortex as well as its nuclei. Indeed, the vestibular complex is lary reticular formation are at the origin of several long special because it is the only brainstem system that receives descending tract systems travelling ipsilaterally in a medial afferents from the cerebellar nuclei as well as directly from (mostly from pontine levels) and bilaterally in ventral and the cerebellar cortex. Descending output of the vestibular ventrolateral reticulospinal tracts (mostly from medullary nuclei is directed to the spinal cord by way of the medial and levels: Fig.  9.1c) (Newman 1985a, b; Torvik and Brodal lateral vestibulospinal tracts (Fig. 9.1c), which are involved 1957). Many fibers provide collaterals to cervical as well as in balance and antigravitational control. lumbar levels. Reticulospinal systems have been described The medial vestibulospinal tract descends by way of the as subserving many different functions as they are involved medial longitudinal fascicle, entering and coursing in the in maintaining and controlling ongoing motor activity (e.g., ventral funiculus at its dorsal aspects. Fibers of the medial Esposito et al. 2014), in the gating of somatosensory inforvestibulospinal tract originate from the ipsilaterally located mation to segmental as well as supraspinal levels, and in the inhibitory neurons and from excitatory, but contralaterally control of autonomic activity including pain modulatory syslocated vestibular neurons. The medial tract terminates bilat- tems (Fields 2004). Four regions of the cerebellar nuclei superally in the ventromedial aspects of the spinal grey where ply projections to the reticular formation and, as such, may they have both inhibitory and excitatory actions on their influence processing in reticulospinal systems. postsynaptic targets. The medial tract does not seem to Detailed functional control of the medial cerebellar descend beyond midthoracic levels and mostly influences nucleus on reticulospinal pathways has been provided by motoneurons that innervate neck and axial musculature Fujita et  al. (2020). In general, the caudal aspect of the (Fig. 9.1c). medial cerebellar nucleus, which is specifically targeted by Vestibular neurons contributing to the medial vestibulo- vermal oculomotor areas of lobules VI and VII, projects conspinal tract may receive information from either the medial tralaterally to the medial pontine reticular formation as well cerebellar nucleus or from Purkinje cells of the vestibulocer- as to the dorsomedial medullary reticular formation which

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seem to be mostly involved in control of eye and neck movements, respectively. More intermediate and dorsolateral parts of the medial nucleus reach intermediate and lateral (i.e., parvocellular) parts of the contralateral reticular formation. The rostral part of the medial nucleus, although mostly supplying terminals to the vestibular nuclei, also projects to intermediate (mediolateral) levels of the reticular formation and to the lateral paragigantocellular nucleus. Specific regions of the medial cerebellar nucleus may be involved in the control of several autonomic functions including control of cardiovascular reflexes (Fujita et  al. 2020; Nisimaru 2004). In the rat, several cell groups, intercalated between the medial and the interposed nuclei, are the target of the Purkinje cells of the X and CX zone (Buisseret-Delmas et al. 1998). They have been shown to have projections to selective regions of the contralateral pontomedullary reticular formation, such as the gigantocellular reticular nucleus. However, the interstitial cell groups also supply afferents to the ­vestibular nuclei and the interstitial nucleus of Cajal. In rodents, furthermore, a prominent ipsilateral projection emerges from the enlarged lateral part of the anterior interposed nucleus, termed the dorsolateral hump, and which supplies afferents not only to the parvicellular regions of the ipsilateral pontomedullary reticular formation but also invades the deeper layers of the spinal trigeminal nucleus. Stimulation evokes movements of lips, neck, and forelimb (Cicirata et  al. 1992). The dorsolateral hump receives its Purkinje fiber input from the D0 zone, which is intercalated between the D1 and D2 zones of lobules V–VII.  It is not known if a primate equivalent exists. Finally, the connections of the lateral nucleus with the pontomedullary reticular formation are well documented for rodents, cats, and monkey and are particularly dense to the contralateral gigantocellular reticular nuclei (Fig.  9.1c) (Kebschull et  al. 2020; Teune et  al. 2000). The projection originates mostly from the dorsal, magnocellular, aspects of the nucleus and has been shown to activate reticulospinal neurons monosynaptically (Tolbert et al. 1980). The role of this disynaptic dentate-reticulo-spinal connection is not yet clear.

9.2.2.5 The Interstitiospinal Tract The interstitiospinal tract originates from a region with scattered large neurons located within and surrounding the medial longitudinal fascicle at midbrain levels, and which is known as the interstitial nucleus of Cajal. This region is known to be involved in oculomotor control but at least some of its fibers descend ipsilaterally by way of the ventral funiculus to the spinal cord where they terminate in laminae VII and VIII of the spinal gray. It has been suggested to be involved in orienting behavior (Fujita et al. 2020). The inter-

T. J. H. Ruigrok

stitiospinal tract has not only excitatory monosynaptic contacts with neck musculature but also provides di- and polysynaptic, mostly excitatory, activation of back, fore-, and hindlimb muscles (Fukushima et al. 1978; Holstege and Cowie 1989). Cerebellar projections to the interstitial nucleus of Cajal arise predominantly from the medial cerebellar nucleus, but other cerebellar nuclear areas also contribute.

9.2.3 Direct Cerebellospinal Projections Although the cerebellum exerts its influence on descending pathways primarily by its nuclear projections to the brainstem and diencephalon, some cerebellar nuclear efferents also reach the spinal cord directly. Classical studies in cat determined that cerebellar projections, arising mostly from the contralateral medial and medial interposed cerebellar nuclei did not descend beyond high cervical levels (Matsushita and Hosoya 1978). Recent studies, however, show that, in mice, a more prominent bilateral direct spinal control can be exerted by neurons located in the medial and interposed nuclei. Spinal projections to cervical as well as lumbosacral level originate from the ipsilateral anterior interposed nucleus, whereas contra- as well as ipsilateral connections to the cervical cord are reported to arise from both interposed as well as from the medial cerebellar nucleus (Fig. 9.1c). The ispi- and bilaterally descending direct spinal projections may be differentially controlling motor performance and motor learning, respectively (Sathyamurthy et al. 2020).

9.3 Conclusion The cerebellum is widely known as a structure with a uniform internal circuitry that processes information in a stereotypic way. Within the internal circuitry, a number of parasagittally organized modules are recognized which form functional entities (Apps and Hawkes 2009; Ruigrok 2011). The organization of the input to these modules and the organization of their output channels, therefore, will determine the type of information processed within such a cerebellar module and which structures will be informed of its result. The overview presented in this chapter demonstrates that detailed knowledge of the spino-cerebellar and cerebello-­ spinal connections with these modules is still not at a level that enables a deeper understanding of cerebellar functions. A detailed description of the interaction of the various spinocerebellar systems with the cerebellar modular circuitry is required together with an improved perception of how the output of modules is distributed to the centers from which descending tracts originate.

9  Spinocerebellar and Cerebellospinal Pathways

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10

Visual Circuits Manuel Jan Roth, Axel Lindner, and Peter Thier

Abstract

The cerebellum receives substantial input from visual and eye movement-related areas through the pontine nuclei. These signals are used to guide and refine motor behavior and to establish spatial orientation. Accordingly, damage to the cerebellum can lead to imprecise eye movements and deficits in visual perception. Here, we discuss these cerebro-cerebellar circuits supporting vision. Keywords

Cerebellum · Cerebellar anatomy · Eye movements Visual perception · Sensory predictions · Forward models

10.1 Anatomical Considerations Visual information processing in the cerebrum engages various areas that make up a large amount of the cerebral cortex. Many of these areas also project to the cerebellum. There, visual information, in combination with other inputs such as vestibular signals, is integrated in order to inform spatial orientation and to (visually) guide and refine motor behavior, such as eye movements (Thier 2011).

M. J. Roth · A. Lindner Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health (TüCMH), University Hospital of Tübingen, Tübingen, Germany e-mail: [email protected] P. Thier (*) Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany e-mail: [email protected]

To allow for such close interaction, both cerebral and cerebellar cortices must share information. Hence, it is not surprising that the extensive projection system connecting these two structures by way of the pontine nuclei constitutes one of the largest circuits in the human brain. Information from sensory and motor areas of the cerebral cortex, which account for the largest portion of pontine afferents, and also from additional subcortical structures such as the superior colliculus (Glickstein 2013; Schwarz and Thier 1999), enters the cerebellum mainly via the pontine nuclei (PN) and other precerebellar nuclei such as the nucleus reticularis tegmenti pontis (NRTP), which will not be discussed here. The PN are located below the cerebral peduncles in the ventral portion of the pons and are subdivided into several nuclei based on their cytoarchitecture and their general location. They consist of roughly 20,000,000 neurons, accounting for almost 40% of pontine brainstem volume (Matano et al. 1985; Tomasch 1969). A large majority of these neurons are considered projection neurons connecting the cerebral and cerebellar cortex (Cooper and Fox 1976). Because of its intermediate position between the two cortices receiving not only cerebrocortical but also collicular visual and eye movement-related signals (see Thier and Möck 2006 for review), the PN are believed to be an important integrative relay of the visual and eye movement pathways on which we focus here.

10.1.1 Cerebrocortical Areas Projecting to the Pons Using retrograde tracers injected into the PN to study the distribution and density of corticopontine projections, Glickstein and colleagues found labeled layer 5 pyramidal cells within a contiguous region covering parts of frontal, parietal, and temporal lobe (Glickstein et  al. 1985; Fig. 10.1a). More precisely, the region containing substantial numbers of labeled cells ranged from the insular cortex

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Fig. 10.1 (a) Cortical region (shaded areas) that has been found to project to the PN using retrograde tracers in a monkey. Layer 5 pyramidal cells (black dots) within a region involving parts of frontal, parietal, and temporal lobe, ranging from the insular cortex within the sylvian fissure laterally to the ventral edge of the cingulate cortex medially and from the arcuate sulcus rostrally to the superior temporal sulcus caudally project to the PN (modified from Glickstein et  al. 1985). (b) Schematic drawing of a caudal view of cerebellar cortex with the location of the two main oculomotor regions highlighted. The oculomotor vermis (OMV) is shown in blue and the dorsal paraflocculus in red (adapted from Thier and Möck 2006). (c) Exemplary data on visually guided saccades of a cerebellar patient (empty circles) and a control

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subject (dark grey dots). Note the wide spread of saccade endpoints of the patient (dysmetria) compared to the control (modified from Golla et al. 2005). (d) Performance in smooth pursuit of a patient suffering from cerebellar degeneration compared to a healthy control group. (d1) Eye movement traces (red lines) in a task where the subject was supposed to track a moving target at 8°/s (black line). The pursuit velocity is insufficient to stay on the target, which leads to compensatory corrective saccades. (d2–d4) Psychophysical evidence for impaired visual analysis of a moving object (d2) as a result of smooth pursuit deficits (d3–d4) in a cerebellar patient (empty circles) compared to a healthy control group (modified from Haarmeier and Thier 1999). DPF dorsal paraflocculus, FL flocculus, PML paramedian lobule

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within the sylvian fissure laterally to the ventral edge of the cingulate cortex medially and from the arcuate sulcus rostrally to the superior temporal sulcus caudally (Brodmann’s areas 1–10, 13, 14, 19, 23–25; Brodmann 1909). Importantly, this contiguous region comprises all parts of cortex contributing to the control of movement and to spatial orientation, among others. These areas include the frontal eye fields (FEF; Bruce et al. 1985; Gottlieb et al. 1994), supplementary eye fields (SEF, Heinen 1995; Schlag and Schlag-­ Rey 1985, 1987), lateral intraparietal (LIP) and medial parietal areas (MP; Andersen et al. 1990; Barash et al. 1991a, 1991b; Thier and Andersen 1997, 1998), medial superior temporal area (MST; Kawano et  al. 1994; Newsome and Wurtz 1988; Thier and Erickson 1992), and middle temporal area (MT; Dursteler and Wurtz 1988; Newsome et al. 1988). Further analyses of the cerebro-pontine projections of these regions showed that most of them terminate in the dorsal part of the ipsilateral PN within several elongated lamellae that often span several subnuclei (Schmahmann and Pandya 1989, 1993). This suggests that the cytoarchitectonic subdivision of the PN into several nuclei does not correspond to the organization of afferent terminations (Thier and Möck 2006).

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ence how and where visual information is actively acquired. Moreover, ocular reflexes such as the vestibulo-ocular reflex (VOR) or the ocular following response (OFR) contribute to the stabilization of visual perception despite the movements of the observer (Dash and Thier 2014; Thier 2011). The ability to precisely direct gaze toward objects of interest as well as to perceive a stable visual world despite one’s own movements lies at the heart of the visual perceptual abilities we are capable of. At this point, it is important to note, however, that the cerebellum is of course not only involved in directing and optimizing eye movements. Rather it contributes to any form of sensory guided movement such as limb movements (Bastian 2011).

10.2.1 Cerebellar Lesions Impair Saccades and Smooth Pursuit Eye Movements

Saccades are fast and goal-directed eye movements that serve to bring the image of an object of interest onto the fovea, i.e., the part of the retina that accommodates the highest visual acuity. Being able to perform precise saccades is important for ensuring proper object analysis. In cases in which an object of interest is moving and/or the 10.1.2 Pontocerebellar Projections observer is moving, smooth pursuit eye movements are and Cerebellar Output additionally engaged to track the object by matching eye velocity to target velocity and thereby keeping it on the The axons of pontine projection neurons enter the cerebel- fovea (often supported by additional head and body lum by way of the middle cerebellar peduncle and terminate movements). as mossy fibers in the granular layer of the cerebellar cortex. Immediate insights into the importance of the cerebelGranular cells in turn give rise to the parallel fibers, which lum for eye movements are provided by lesion studies. connect to Purkinje cells which are the only output neurons Barash and colleagues showed that after lesioning small of the cerebellar cortex. While most of the pontocerebellar parts of the oculomotor vermis in macaque monkeys, fibers terminate in the contralateral part of the cerebellum, visually guided saccades became hypometric, i.e., sacthere seem to be also ipsilateral projections (Rosina et  al. cades fell too short relative to the saccade target (Barash 1980). Major projection sites of these neurons that show et al. 1999). While the hypometria disappeared over time, involvement in eye movements and will be discussed in the saccadic endpoints remained imprecise, arguably forever. following section are lobuli VII and VIc of the posterior ver- Similarly, also human subjects suffering from cerebellar mis, the caudal vermis as well as the neighboring dorsal damage involving the posterior vermis exhibit saccades paraflocculus (Thier 2011; Fig. 10.1b). characterized by variable endpoints (Golla et  al. 2005; Visual and eye movement-related signals leave the cere- Fig. 10.1c). An analogous loss of precision is exhibited by bellum through the projection of Purkinje cells to the deep smooth pursuit eye movements (Takagi et al. 2000). While cerebellar nuclei (DCN). The major targets of eye movement-­ healthy subjects are capable of smoothly tracking a conrelated signals are the caudal fastigial and the posterior inter- stantly moving visual target, patients with cerebellar damposed nuclei (Sun et al. 2016; Thier 2011). age and animals with experimental lesions fail in doing so. This is because their eye velocity is typically too small to match target velocity. Therefore, the distance between 10.2 Cerebellum and Eye Movements the tracked object and the fovea continuously increases during the course of a tracking movement and this “foveaThe cerebellum is of utmost importance for visual percep- tion error” then needs to be repeatedly compensated by tion because it optimizes goal-directed eye movements such subjects with “catch-up” saccades (Haarmeier and Thier as saccadic and smooth pursuit eye movements that influ- 1999; Fig. 10.1d).

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10.2.2 Cerebellar Adaptation of Eye Movements As we have seen in the previous paragraph, damage to specific parts of the cerebellum causes imprecise visually guided eye movements. The role of the cerebellum thus seems to be the optimization of these movements. Compromised precision is not only confined to visually guided eye movements but also other forms of sensory-guided motor behavior (“ataxia”; Markanday et al. 2018). The cerebellar role in refining motor output is a direct consequence of its ability to adjust key parameters characterizing the necessary sensorimotor transformations as revealed in typical adaptation paradigms. As said before, in the study by Barash and colleagues, the hypometric saccades of monkeys with vermal lesions returned to pre-lesion amplitudes after a few weeks, although displaying larger endpoint variations. What was completely abolished, however, was the capacity to adapt saccade amplitudes in a short-term adaptation paradigm, requiring modifications of saccade amplitude in order to compensate intrasaccadic shifts of target position (Barash et al. 1999). This finding agrees with a large body of l­ iterature describing adaptation deficits of saccades and smooth pursuit due to cerebellar disease and experimental lesions in animals, respectively (e.g. Straube et  al. 2001; Takagi et  al. 1998). Analogous deficits have also been reported for skeletomotor movements in tasks that call for an adaptation of motor output in response to altered sensorimotor relationships [e.g. prism adaptation (Martin et al. 1996)]. In fact, deficits in adaptation or motor learning are key symptoms of patients suffering from cerebellar damage (Bastian 2011). Adaptation deficits revealed in experimental settings reflect the capacity of the cerebellum to continuously recalibrate motor output in order to ensure optimal motor behavior. Hence, the occurrence of imprecise visually guided eye movements hand in hand with a loss of the ability to adapt them have the same mechanistic basis. A major influence calling for recalibration on a short time scale is “fatigue,” a loss of the vigor of movement not only due to use-dependent changes of the movement effectors (Prsa et  al. 2010), but also due to a loss of motivation and attention to the movement (Markanday et al. 2018). Thus, vermal pathology also causes the inability to compensate changes due to fatigue (Golla et al. 2008). Motor output recalibration or motor updating is believed to depend on “forward models” which predict the sensory consequences of movements on the basis of motor commands and (sensory) information about the current state of the system. Using these predictions, movements can be corrected on the fly and no longer depend on delayed sensory feedback errors, thereby guaranteeing fast and accurate movements (Wolpert and Ghahramani 2000). There is now broad agreement that the role of the cerebellum can be traced

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back to its ability to predict the sensory consequences of movements and to ensure that forward model predictions are precisely tuned (Bastian 2006; Wolpert et al. 1998).

10.3 Cerebellar Contributions to Visual Perception Precise eye movements are needed to make full use of visual information for perception. Hence, the cerebellum clearly serves visual perception, yet indirectly, namely through its central role in optimizing motor output. However, does it also have a direct influence on visual perception? In the following sections, we will focus on direct cerebellar contributions to vision, some of which seem independent of eye movements. We argue that these contributions can be traced back to the same computational principle that contributes to motor behavior, namely the optimization of predictions within the framework of forward modelling.

10.3.1 A Role of the Cerebellum in Global Visual Motion Perception A visual deficit not explainable by insufficient eye movements that has been consistently reported over the last years is a deficit in detecting a global visual motion component embedded in randomly moving dots (Händel et  al. 2009; Jokisch et  al. 2005; Nawrot and Rizzo 1995; Thier et  al. 1999). Compared to healthy controls, cerebellar patients need a much higher degree of coherently moving dots within a moving random dot pattern to establish a global visual motion percept (Fig. 10.2a). The reason behind this deficit is most likely that parietooccipital processing of motion signals in area MT and neighboring areas of parietooccipital cortex is corrupted, arguably due to a loss of essential functional input from the cerebellum (Händel et al. 2009). Indirect support for this pathway stems from experiments in nonhuman primates, which show that electrical microstimulation of the deep cerebellar nuclei gives rise to activity in motion processing cortex (Sultan et al. 2012). Furthermore, cerebellar fibers indirectly contacting motion processing areas thought to be homologous to primate area MT were also found in the cat (Sasaki et al. 1972; Wannier et al. 1992). The need for cerebellar input to motion processing cortex may be based on the fact that visual motion on the retina can be caused by both motion in the environment and by ego-­ motion. In order to extract the respective contributions of these different motion signals, each of which is relevant for different types of behavior, the visual system resorts to predictions about the visual consequences of performed ego-­ motion (Haarmeier et  al. 2001; von Holst and Mittelstaedt 1950). Specifically, the predicted motion information is

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Fig. 10.2 (a) Deficits of a cerebellar patient suffering from spinocerebellar ataxia type 6 (SCA6) in global visual motion perception. When measuring the percentage of coherently moving dots necessary to evoke a percept of global motion in a display of otherwise randomly moving dots, this SCA6 patient (light grey bar) has not only a strongly elevated threshold compared to a healthy population (red line), but her perceptual threshold is in fact closer to the one of a motion blind patient due to cortical lesions; data from (Scherer, Thier & Haarmeier, unpublished data; Zihl et al. 1983). (b) Depiction of a forward model used to predict and perceptually cancel self-induced motion of the world during smooth pursuit eye movements. If one is tracking a moving object with the eyes in order to stabilize its retinal image, a motor command is generated to achieve this desired state (specification of movement). At the same time, the system uses this motor command to form a prediction about the sensory outcome of the respective behavior (predicted state). This

prediction can then be used for feed-forward movement control (dotted lines), but also to cancel self-caused retinal motion of the world (dashed lines; adapted from Lindner et  al. 2005). (c) Deficit of cerebellar patients in recalibrating a spatiotemporal prediction in response to altered stimulus statistics. (c1) Subjects had to predict the time of reappearance of a constantly moving visual target that transiently disappeared behind an occluder. The time the visual target spent behind the occluder was manipulated in such a way, that – as compared to a baseline condition – the target reappeared consistently too late. (c2) While healthy controls recalibrated their prediction about when the target should reappear in response to the target reappearing too late, as indicated by a shift of the psychometric function toward more positive delays (dT), cerebellar patients did not show such a pronounced recalibration (adapted from Roth et al. 2013)

attributed as self-produced, whereas any residual (not predicted) motion information is interpreted as externally caused (Fig. 10.2b). And it is the cerebellum that is responsible for generating this prediction and for keeping it optimal based on forward modelling (Lindner et al. 2006). Thus, it

could be the loss of such a precise “reference signal” that may clutter motion processing in cerebral cortex – even in the absence of ego motion. Also, from a theoretical point of view, such sensory predictions or forward models need to undergo constant recalibration

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in order to match not only the changing properties of the motor plant but also the ever-changing sensory environment (brightness, contrast etc.). These forward models therefore need to incorporate information on actual body states, on motor commands issued, as well as on incoming sensory information (and probably context information) – a job that fits to the integrative position the cerebellum holds in the brain.

10.3.2 The Cerebellum Contributes to Predictive Visual Perception In the last decades, many studies have tried to identify other perceptual or cognitive deficits in cerebellar patients. In fact, the idea of forward models predicting upcoming sensory afference based on the current state and contextual information could, in principle, be easily transferred also to other perceptual and cognitive domains not dependent on movement information (Ito 2008). Yet, arguably any cognitive function is influenced by motor behavior in one or the other form. Perceptual and cognitive dysfunctions due to cerebellar disease may thus be much more pervasive, given the importance of optimized motor behavior; a notion supported by findings that basically any sensory representation in cerebral cortex receives cerebellar input (Sultan et al. 2012). Arguably, the relevance of information on motor behavior and in general the state of the observer might not only be confined to current sensory input but also be of relevance for the processing of future sensory input and, in turn, relevant for the planning of future behavior. Indeed, there is evidence that the cerebellum is involved in predictive vision. A study by Roth and colleagues showed that the cerebellum plays a role in predicting spatiotemporal aspects of visual motion, a process that likewise needs to undergo adaptation to reflect the ever-changing (sensory) environment (Roth et al. 2013). In this study, cerebellar patients showed a clear deficit in updating their spatiotemporal prediction of a visual event in response to a constant change in stimulus statistics when compared to healthy controls (Fig. 10.2c). Importantly, this difference was not due to eye movement differences between groups. Deficits in predicting future events should also affect the perception of time intervals. Hence, it is not surprising that patients with cerebellar damage have difficulties in tasks requiring the precise use of such temporal information (Breska and Ivry 2021), a deficit that parallels the effects of poorly timed motor behavior. Predicting upcoming events is a very crucial ability of our central nervous system. It allows us, for example, to direct attention, to react faster to predictable stimuli, and to attenuate or even cancel out self-induced sensory afference. It seems likely that at least some parts of the already existing cerebellar machinery used predominantly for action could additionally be employed in predicting and recalibrating upcoming visual or other sensory events for perception (Therrien and Bastian 2015).

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10.4 Conclusion The cerebellum receives massive input from visual and oculomotor regions in cerebral cortex and from various subcortical structures such as the superior colliculus. Projections from there reach the pontine nuclei (PN) that in turn contact the cerebellum through the middle cerebellar peduncle to the granular layer of cerebellar cortex. The most important oculomotor and visual regions of cerebellar cortex that have been identified so far are lobuli VII and VIc of the posterior vermis and a complex in the caudal cerebellum that involves the flocculus, the paraflocculus, and the caudal part of the vermis. Damage to the posterior vermis causes deficient saccadic and smooth pursuit eye movements and absent adaptation of these movements. Such adaptation is believed to depend on updating of forward models of movement commands. Also, for perceptual purposes, such forward models are important to cancel or attenuate self-induced retinal image slip due to ego-motion and therefore contribute to the perception of a stable world despite eye movements. Compatible with this idea, cerebellar patients show deficits in coherent motion perception, supporting the importance of the cerebellum also for such perceptual tasks. Furthermore, evidence suggests cerebellar involvement in spatiotemporal predictions for perception also in non-motor tasks. It therefore seems that the circuits of the cerebellum that are involved in visual information processing chiefly serve the optimization of eye movements and thereby vision. The principle computations realized by these circuits are, in addition, seemingly used for optimizing (visual) perception directly. The patterning of cerebellar projections to cerebral cortex strengthens this notion.

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76 temporal precision targeting motor and extensive sensory and parietal networks. Nat Commun 3:924. https://doi.org/10.1038/ ncomms1912 Sun Z-P, Barash S, Thier P (2016) Chapter 8—The role of the cerebellum in optimizing saccades. In: Heck DH (ed) The neuronal codes of the cerebellum. Academic Press, New York, pp 173–196. https:// doi.org/10.1016/B978-­0-­12-­801386-­1.00008-­3 Takagi M, Zee DS, Tamargo RJ (1998) Effects of lesions of the oculomotor vermis on eye movements in primate: saccades. J Neurophysiol 80(4):1911–1931. https://doi.org/10.1152/jn.1998.80.4.1911 Takagi M, Zee DS, Tamargo RJ (2000) Effects of lesions of the oculomotor cerebellar vermis on eye movements in primate: smooth pursuit. J Neurophysiol 83(4):2047–2062. https://doi.org/10.1152/ jn.2000.83.4.2047 Therrien AS, Bastian AJ (2015) Cerebellar damage impairs internal predictions for sensory and motor function. Curr Opin Neurobiol 33:127–133. https://doi.org/10.1016/j.conb.2015.03.013 Thier P (2011) The oculomotor cerebellum. In: Liversedge SP, Gilchrist I, Everling S (eds) The Oxford handbook of eye movements. Oxford University Press, Oxford Thier P, Andersen RA (1997) Multiple parietal “eyefields”: insights from electrical microstimulation. In: Thier P, Karnath H-O (eds) Parietal lobe contributions to orientation in 3D space. Springer, Berlin, pp 95–108 Thier P, Andersen RA (1998) Electrical microstimulation distinguishes distinct saccade-related areas in the posterior parietal cortex. J Neurophysiol 80(4):1713–1735. https://doi.org/10.1152/ jn.1998.80.4.1713

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The Cerebrocerebellar System

11

Jeremy D. Schmahmann

Abstract

Keywords

The cerebellum has massive reciprocal interconnections with the cerebral cortex and with cerebral subcortical structures that complement its interconnections with the spinal cord and brainstem. The major cerebrocerebellar link is mediated by the feedforward/afferent corticopontine projections and mossy fibers emanating from the pontocerebellar projections, and the feedback/efferent cerebellothalamic and thalamocortical projections. These highly arranged connections link sensorimotor, associative, and limbic regions of cerebral cortex with the cerebellum and the intervening pontine nuclei and thalamus in a topographically precise manner. The cerebellum also has reciprocal links with the basal ganglia and hypothalamus, and with structures in the limbic circuit. In addition to these mossy fiber afferents to cerebellum, the inferior olive receives indirect input from motor and associative regions of the cerebral cortex by way of the red nucleus and zona incerta, and it conveys these inputs to cerebellum via climbing fibers. The cerebrocerebellar pathways are organized into segregated loops of information processing and stand in contrast to the cerebellar cortical architecture that is essentially uniform. Knowledge of cerebrocerebellar circuits is critical to understanding theories of the cerebellar contribution to motor and nonmotor function, and to the diagnosis and management of patients with lesions in these pathways.

Cerebellum · Cerebral · Anatomy · Connections Projections · Neural circuits · Corticopontine Pontocerebellar · Cerebellothalamic · Thalamocortical Pons · Thalamus · Olive

The cerebellum has massive reciprocal interconnections with the cerebral hemispheres. The cerebrocerebellar circuit consists of a two-stage feedforward, or afferent limb, and a two-stage feedback, or efferent limb. The feedforward limb synapses in the nuclei of the basis pontis and comprises the corticopontine projections and the pontocerebellar pathway. The feedback limb originates in the deep cerebellar nuclei (DCN) with an obligatory synaptic step in the thalamus; the thalamocortical projection forms the final stage of this feedback system. The cerebral cortex communicates mostly with the contralateral cerebellum. Cerebral cortex projects to the ipsilateral pons, pontocerebellar fibers cross to the other side of the pons and course through the middle cerebellar peduncle to the contralateral cerebellum. The cerebellar feedback travels via the superior cerebellar peduncle, decussates in the brachium conjunctivum, and terminates in the contralateral thalamus; the thalamocortical projection is ipsilateral. This chapter provides an overview of the connectional anatomy of the cerebrocerebellar circuit derived from tract tracing studies in animal models, mostly the monkey, with a particular focus on the feedforward limb of the circuit. Further details and discussion of important earlier studies can be found in the references cited here.

J. D. Schmahmann (*) Ataxia Center, 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] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_11

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11.1 The Feedforward Limb of the Cerebrocerebellar System Corticopontine projections arise from neurons in layer Vb (Glickstein et al. 1985), and course in the anterior limb of the internal capsule from prefrontal regions, and in the sagittal stratum and/or posterior limb of the internal capsule from posterior regions (Schmahmann and Pandya 1992, 1997a, 2006). They course above and then medial to the lateral geniculate nucleus before descending into the cerebral peduncle where prefrontal fibers are most medial, premotor and motor cortices occupy its middle third, and parietal, temporal and occipital fibers are in the lateral third (Schmahmann and Pandya 1992, 1997a). The relative size of the cerebral peduncle comprised of fibers derived from association cortices is larger in human than monkey, reflecting evolutionary expansion (Ramnani et al. 2006).

11.1.1 Patterns of Termination in the Pons Each cortical area gives rise to topographically arranged terminations in a unique mosaic of patches around the neurons of the basis pontis, distributed within transverse and rostrocaudal dimensions. Terminations interdigitate with each other but do not overlap.

J. D. Schmahmann

medial. Projections from the ventral precentral gyrus (M1 face representation) are also medial, but lateral to those from SMA-face. M1 hand projections are in medially placed curved lamellae in mid and caudal pons. Dorsal trunk projections are in medial and ventral locations, ventral trunk/hip projections encircle the peduncle in the caudal pons, and projections from the foot representation are heaviest caudally in laterally placed curved lamellae (Schmahmann et al. 2004b) (Fig. 11.1). Corticopontine projections from the sensory cortex also terminate mostly in the caudal half of the pons (Brodal 1978; Brodal and Bjaalie 1992). Motor topography is apparent in the human pons as shown in structure–function correlations in patients with stroke (Schmahmann et al. 2004a) (Fig. 11.2). Face movement and articulation are in rostral and medial basilar pons, hand coordination and dexterity are medial and ventral in rostral and mid-pons, and arm coordination is represented ventral and lateral to the hand. Leg coordination is in the caudal half of the pons, with lateral predominance. Gait is represented in medial and lateral locations throughout the rostral-caudal extent of the pons. The pons receives heavy projections from multiple cerebral association areas (Fig. 11.3).

• Prefrontal projections to pons arise mostly in dorsolateral and dorsomedial prefrontal cortices from areas concerned with attention as well as with conjugate eye movements (area 8), the spatial attributes of memory and working memory (area 9/46d), planning, foresight, and judgment 11.1.2 Neurons of the Basis Pontis (area 10), motivational behavior and decision-making capabilities (areas 9 and 32), and from areas considered to Pontine neurons in the monkey are arranged in nuclei accordbe homologous to the language area in human (areas 44 ing to location and cytoarchitecture. These are the dorsal tier and 45). Terminations are in the medial pons in its rostral (the dorsomedial, dorsal, dorsolateral, and extreme dorsolatthird, favoring the median, paramedian, dorsomedial, and eral nuclei), intermediate tier (median, paramedian, intra-­ medial part of the peripeduncular pontine nuclei peduncular and peri-peduncular, and lateral nuclei), and a (Schmahmann and Pandya 1995, 1997b). ventral pontine nucleus (Nyby and Jansen 1951; Schmahmann • Posterior parietal projections arise from both gyral and and Pandya 1989). The nucleus reticularis tegmenti pontis sulcal cortices including the multimodal caudal regions. (NRTP) is immediately adjacent to the dorsal tier nuclei. In Inferior parietal lobule projections to pons are predomihuman, these architectonic features are less persuasive nantly rostral, those from superior parietal lobule distrib(Schmahmann et al. 2004a). ute throughout the rostro-caudal extent of the pons. Parietal projections are mostly in the intermediate and lateral sectors of the pons, with topographic organization 11.1.3 Corticopontine Projections determined by their site of origin (May and Andersen 1986; Schmahmann and Pandya 1989). Projections from motor cortices terminate preferentially in • Temporal lobe projections arise from the multimodal the caudal half of the pons, in close proximity to traversing regions of the cortex of the upper bank of the superior corticofugal fibers (Nyby and Jansen 1951; Brodal 1978; temporal sulcus, the superior temporal gyrus and supraWiesendanger et  al. 1979; Hartmann-von Monakow et  al. temporal plane, and terminate in lateral and dorsolateral 1981; Schmahmann et al. 2004b). Projections from the face pontine regions (Schmahmann and Pandya 1991, 1992). region of the supplementary motor area (SMA) are most

11  The Cerebrocerebellar System

Fig. 11.1  Composite color-coded summary diagram of projections to the basis pontis from motor and supplementary motor cortices in the rhesus monkey. Injection sites in the cerebral cortex (top left) are shaded in solid colors. The corresponding termination patterns in the nine rostro-­caudal levels of the pons taken at the level shown in the brainstem view (lower left) are represented by similarly colored regions.

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SMA  – red; Trunk and Leg  – green; Hand  – light blue; Face–Hand overlapping area – dark blue. The terminations are predominantly in the caudal half of the pons, each cortical area projecting to a unique subpopulations of neurons within the pons. The SMA projections are most medial, and the face, hand, and leg projections are progressively more laterally situated (From Schmahmann et al. 2004b)

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• Parastriate cortices at the dorsomedial and dorsolateral convexity, as well as the posterior parahippocampal gyrus, project to the lateral and dorsolateral pontine regions (Schmahmann and Pandya 1993). • Rostral cingulate projections are directed to the medial pontine nuclei, the caudal cingulate to more lateral regions (Vilensky and Van Hoesen 1981; Schmahmann and Pandya 2006). • Pontine projections arise also from the anterior insular cortex (Glickstein et al. 1985). There is a dichotomy in the corticopontine projections according to the dorsal versus ventral streams of cognitive processing (Schmahmann and Pandya 1997a). Visual areas concerned with visual motion and the peripheral visual field (the “where” pathway) project to pons (dorsal part of the prelunate gyrus, caudal lower bank of the cortex in the superior temporal sulcus, polymodal convergence zones in the lower bank of the cortex in the intraparietal sulcus, and paralimbic parts of the caudal inferior parietal lobule). Cortical regions concerned with visual feature discrimination and the central visual field (the “what” pathway) do not have pontine projections (ventral prelunate gyrus, rostral lower bank of the superior temporal sulcus, middle and inferior temporal gyri, lateral aspects of the posterior parahippocampal gyrus). In the frontal lobe, pontine projections arise from the dorsolateral and dorsomedial prefrontal cortices that are concerned with spatial features of working memory, but not from the ventral prefrontal and orbitofrontal cortices that are part of the ventral stream of cognitive operations (Pandya et  al. 2015). These anatomic arrangements suggest that the cerebellum plays a role in spatial awareness, and in attentional, executive, auditory, and linguistic functions subserved by the dorsal stream of cognitive processing. They complement the cerebellar connections with the cingulate gyrus, posterior parahippocampal gyrus, and with subcortical limbic structures (discussed below) that form part of the anatomical basis of the cerebellar role in emotional processing.

11.1.4 Pontocerebellar Projections

Fig. 11.2  Color-coded composite summary diagram to illustrate the topographic map of motor representations in the human pons derived from analysis of ischemic stroke in the basis pontis. Pontine levels I through III from rostral to caudal pons. Face – red; dysarthria – orange; hand dexterity – dark blue; arm dysmetria – light blue; leg dysmetria – green; gait  – black. A arm strength, H hand strength, L leg strength (From Schmahmann et al. 2004a)

Pontocerebellar fibers course to the contralateral cerebellum by first running horizontally in a focused aggregate toward the midline. They then fan out in multiple directions to travel in most of the transverse pontocerebellar fiber bundles across the entire extent of the opposite side of the basis pontis at approximately the same rostro-caudal level. They then regroup in the middle cerebellar peduncle before entering the cerebellum (Schmahmann et  al. 2004c). This anatomical arrangement has clinical implications for the phenomenon of ataxic hemiparesis arising from lesions of the basis pontis in patients (Fisher and Cole 1965; Schmahmann et al. 2004a) (Fig. 11.4).

11  The Cerebrocerebellar System

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a

b

c

Fig. 11.3  Color-coded summary diagram illustrating the distribution within the nuclei of the basis pontis (levels I–IX) of the rhesus monkey of projections derived from association and paralimbic cortices in the prefrontal (purple), posterior parietal (blue), temporal (red), and parastriate and parahippocampal regions (orange), and from motor, premotor and supplementary motor areas (green). The medial (a), lateral (b), and ventral (c) surfaces of the cerebral hemisphere are shown above. Cerebral areas that have been shown to project to the pons by other

investigators using either anterograde or retrograde tracers are depicted in white. Areas that have no pontine projections (according to anterograde and retrograde studies) are shown in yellow; those with no pontine projections according to retrograde studies are in gray. Dashed lines on the hemispheres represent sulcal cortices. Dashed lines in the pons represent pontine nuclei, and solid lines demarcate corticospinal fibers (From Schmahmann 1996)

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a

b

c

11  The Cerebrocerebellar System

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Fig. 11.4  Schematic diagram of the motor consequences of basis pontis infarction. A ventral view of the monkey pons is shown with the median, paramedian, and peduncular pontine nuclei represented. Partial views of coronal sections of human cerebellum are seen on either side. (a) Normal arrangement, showing the pontine neurons, pontocerebellar fibers, and descending corticofugal pathways to spinal cord. (b) Anatomical and clinical consequences following a small lesion in the basis pontis (shaded black area). Some pontine neurons are destroyed

(marked by X), and the pontocerebellar fibers emanating from the lesioned neurons are affected (dotted lines). Pontocerebellar fibers arising from neurons in the contralateral hemipons are interrupted by the lesion (dashed lines), as are the descending corticofugal fibers (heavy dashed lines). (c) Large pontine lesions (shaded black area) destroy many pontine neurons and descending corticofugal fibers, and interrupt most of the pontocerebellar fibers traveling through the lesion from the normal hemipons (From Schmahmann et al. 2004c)

Neurons in the caudal pons project mainly to the cerebellar anterior lobe, and the intrapeduncular nucleus projects to vermal lobule VIIIB (Brodal and Walberg 1977). Thus, the anterior lobe (particularly lobules IV and V) and paramedian lobule (lobule VIII) which contain sensorimotor representations of the upper and lower extremities (Snider and Stowell 1944; Snider 1952), receive afferents from pericentral motor and sensory cortices. The dorsolateral pontine region and the NRTP project to lobule VIII and IX (dorsal paraflocculus, uvula) and the vermal visual area in lobule VII. Neurons in the dorsomedial nucleus also project to the vermal visual area (Brodal 1979). The rostral pons receives input from cerebral association areas, and is linked with the cerebellar posterior lobe. Medial parts of the rostral pons project to crus I, and neurons in the medial, ventral, and lateral pons send their axons to crus II (Brodal 1979). Crus I therefore receives inputs from premotor and prefrontal cortices, crus II is not only linked with posterior parietal areas, but also with prefrontal cortices (Kelly and Strick 2003). These anatomical observations are consistent with conclusions derived from earlier physiological studies (Allen and Tsukuhara 1974). The pattern of divergence and convergence in the corticopontine and pontocerebellar pathways suggests that information from functionally diverse parts of the cerebral cortex and subcortical nuclei are brought together and integrated in the cerebellar cortex (Brodal and Bjaalie 1992; Schmahmann 1996).

tus [NI] posterior, equivalent in human to globose nucleus, and NI anterior to emboliform nucleus).

11.2 The Feedback Limb of the Cerebrocerebellar System

11.2.3 Thalamocortical Projections

11.2.1 The Cerebellar Corticonuclear Microcomplex Apart from the vestibulocerebellum (lobule X  – flocculus and nodulus, and the vermal part of lobule IX – uvula) that projects directly to the vestibular nuclei, efferents from the cerebellum are conveyed exclusively through the DCN (Voogd 2004). The cerebellar cortex projects to the DCN with a medio-lateral topography (Haines et al. 1997). Midline cortex projects to medial nuclear regions (fastigial nucleus), lateral hemisphere to the lateral/dentate nucleus, and intervening cortex to the interpositus nucleus (nucleus interposi-

11.2.2 Cerebellothalamic Projections The superior cerebellar peduncle (SCP) carries efferents from the DCN; fibers from the NIP are situated most medially, NIA fibers are intermediate, and dentate fibers are most lateral (Voogd 2004). Ascending axons from the fastigial nucleus course medially adjacent to the SCP. Each cerebellar nuclear region projects to three to seven rostrocaudally oriented rod-like aggregates within a dorsoventral curved lamella in the thalamus (Thach and Jones 1979). Cerebellar projections from the DCN are directed to motor thalamic nuclei (pars oralis of the ventral posterolateral nucleus – VPLo, the caudal and pars postrema aspects of the ventrolateral nucleus – VLc and VLps, and nucleus X); intralaminar nuclei (including the central lateral, paracentral, paraventricular, and centromedian-parafascicular nuclei); and the medial dorsal thalamic nucleus in its paralaminar parts  – the laterally situated pars multiformis (MDmf) and more caudal pars densocellularis (MDdc). Fastigial and lateral/dentate nucleus projections to thalamus are directed to motor, intralaminar, and medial dorsal nuclei. Interpositus nucleus projections terminate in motor-related ventrolateral and ventral anterior nuclei (Jones 2007; Ilinsky and Kultas-­ Ilinsky 1987; Schmahmann 1996).

Motor thalamic nuclei project to motor-related cortices, as well as to multimodal association cortices in the temporal lobe (from VLc and VLps), posterior parietal cortex (from VLc, VLps, VPLo and nucleus X), and the prefrontal cortex (from VLc, VPLo and nucleus X). The cerebellar-recipient MDmf and MDdc thalamic nuclei project to prefrontal cortices (area 8, area 46 at both banks of the principal sulcus, and area 9), as well as to the cingulate gyrus, posterior parietal cortex, and multimodal parts of the superior temporal sulcus. Further, the intralaminar nuclei (notably centralis lateralis and paracentralis) project widely throughout the hemispheres to associative and paralimbic cortices in the cingulate and parahippocampal gyrus (see Schmahmann 1996; Schmahmann and Pandya 1990, 1997b).

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11.2.4 Cerebrocerebellar Loops Transynaptic viral tracing studies reveal that primary motor cortex is reciprocally connected with vermal and hemispheric lobules IV–VI, and lobules VIIB and VIIIA, whereas dorsolateral prefrontal cortex areas 46 and 9 are linked with crus II of the cerebellar posterior lobe (Kelly and Strick 2003). The DCN projections back to the cerebral cortex are also topographically arranged (Middleton and Strick 1994; Dum and Strick 2003). Primary motor cortex receives projections via thalamus from the dorsal part of the dentate nucleus (microgyric, large cells, phylogenetically older) at mid rostrocaudal levels, and from the caudal portions of the AIN – which contain neurons activated by arm movement (Thach 1978; Van Kan et  al. 1993). Premotor cortex receives input from the mid-rostrocaudal part of the dentate, ventral to the M1 projecting neurons. Frontal eye field projecting neurons are located in the caudal third of the dentate that is correlated with saccadic eye movements. And the prefrontal cortex (areas 46 and 9) receives projections from the ventral part of the dentate nucleus (macrogyric, small cells, phylogenetically newer) mostly in its middle third rostrocaudally. Projections to the posterior parietal cortex arise from neurons in the ventral and lateral parts of the dentate nucleus (Dum et al. 2002). In addition to the topographically arranged projections from the dentate nucleus and the interpositus nuclei to thalamus and cerebral hemispheres, the fastigial nucleus has neuronal subpopulations that target different regions of brainstem and diencephalon, subserving motor, vestibular, autonomic, attentional, and limbic circuits (Fujita et al. 2020).

11.3 Other Cerebral Hemisphere Connections with Cerebellum

J. D. Schmahmann

and from the parvicellular red nucleus (RNpc) linked with the supplementary motor cortices, the postcentral gyrus, and area 5  in the superior parietal lobule (Cintas et  al. 1980; Saint-Cyr and Courville 1980). It also receives projections from the zona incerta which is linked with motor as well as with association and limbic cortices in the rostral cingulate cortex, posterior parietal cortex, and dorsolateral and medial prefrontal regions (Shah et al. 1997). The inferior olive is the sole source of climbing inputs to the cerebellum. The olivocerebellar system is discussed in Chap. 8.

11.3.3 Hypothalamus Posterior and dorsal hypothalamic regions project medially, dorsomedially, and laterally within the caudal third of the pontine nuclei (Aas and Brodal 1988). Histaminergic neurons of the tuberomammillary nucleus in the posterior hypothalamus, the dorsomedial and ventromedial nuclei, and the periventricular zone terminate diffusely in the cerebellum. The ventromedial, dorsomedial, and dorsal hypothalamic nuclei are linked with the cerebellar anterior lobe, and the lateral and posterior hypothalamic areas are linked with both anterior and posterior lobe (Haines and Dietrichs 1984). The DCN convey cerebellar projections back to the contralateral hypothalamus. The hypothalamus is integrally involved in the regulation of the internal menu, the autonomic nervous system, and a wide range of social emotional behaviors (Saper and Lowell 2014). The existence of these reciprocal hypothalamo-cerebellar connections provides the anatomic underpinning for a cerebellar role in the modulation of these multifaceted behaviors under the control of the hypothalamus.

11.3.1 Basal Ganglia

11.3.4 Mammillary Body

The cerebellum and basal ganglia are anatomically interconnected. Motor and non-motor domains of the subthalamic nucleus project by way of the pons to motor and non-motor regions of the cerebellar cortex (Bostan et  al. 2010), and DCN projections via thalamus are directed back to sensorimotor and associative territories of the putamen and caudate nucleus (Hoshi et al. 2005). This has clinical relevance, for example, in the phenomenon of dystonia that occurs in some patients with cerebellar lesions (Batla et al. 2015).

The medial mammillary nucleus, incorporated into the Papez circuit for emotion (Papez 1937) and implicated in Korsakoff’s amnestic syndrome projects ventromedially at all rostrocaudal levels of the pontine nuclei (Aas and Brodal 1988). The lateral mammillary and supramammillary nuclei project directly to cerebellar anterior and posterior lobes.

11.3.2 Inferior Olive

These regions important for memory and emotion are also interconnected with the cerebellum (Anand et  al. 1959; Harper and Heath 1973; Snider and Maiti 1976). In addition, there are reciprocal connections between cerebellum and brainstem serotonin, norepinephrine and dopaminergic

The inferior olivary complex receives afferents via the central tegmental tract from the magnocellular division of the red nucleus (RNmc) linked with the precentral motor cortex,

11.3.5 Septal Nuclei, Hippocampus, Amygdala, and Ventral Tegmental Area

11  The Cerebrocerebellar System

nuclei that have widespread projections to cerebral cortex (Dempsey et al. 1983; Marcinkiewicz et al. 1989). Notably, this includes the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic system. Fastigial nucleus projections to the VTA have long been recognized (Snider and Maiti 1976), and optogenetic manipulation of this cerebellar-­ VTA connection induces changes in socially relevant behaviors in a mouse model (Carta et al. 2019). Tract tracing studies in animal models thus reveal the rich complexity of cerebrocerebellar communications. Different areas of the cerebral cortex – motor, associative and limbic, are reciprocally linked with the cerebellum via anatomical circuits, or closed loops, which demonstrate topographic precision at each stage of the feedforward and feedback limbs. These anatomical connections are the essential substrates that enable cerebellar contributions to movement, cognition, emotion, and autonomic control. Acknowledgements Supported in part by the National Ataxia Foundation, the MINDlink foundation, and Mary Jo Reston.

References Aas J-E, Brodal P (1988) Demonstration of topographically organized projections from the hypothalamus to the pontine nuclei: an experimental study in the cat. J Comp Neurol 268:313–328 Allen GI, Tsukuhara N (1974) Cerebrocerebellar communication systems. Physiol Rev 54:957–1008 Anand BK, Malhotra CL, Singh B, Dua S (1959) Cerebellar projections to limbic system. J Neurophysiol 22(4):451–457 Batla A, Sánchez MC, Erro R et al (2015) The role of cerebellum in patients with late onset cervical/segmental dystonia? Evidence from the clinic. Parkinsonism Relat Disord 21(11):1317–1322 Bostan AC, Dum RP, Strick PL (2010) The basal ganglia communicate with the cerebellum. Proc Natl Acad Sci U S A 107(18):8452–8456 Brodal P (1978) The corticopontine projection in the rhesus monkey. Origin and principles of organization. Brain 101(2):251–283 Brodal P (1979) The pontocerebellar projection in the rhesus monkey: an experimental study with retrograde axonal transport of horseradish peroxidase. Neuroscience 4(2):193–208 Brodal P, Bjaalie JG (1992) Organization of the pontine nuclei. Neurosci Res 13(2):83–118 Brodal P, Walberg F (1977) The pontine projection to the cerebellar anterior lobe. An experimental study in the cat with retrograde transport of horseradish peroxidase. Exp Brain Res 29(2):233–248 Carta I, Chen CH, Schott AL, Dorizan S, Khodakhah K (2019) Cerebellar modulation of the reward circuitry and social behavior. Science 363(6424):eaav0581 Cintas HM, Rutherford JG, Gwyn DG (1980) Some midbrain and diencephalic projections to the inferior olive in the rat. In: Courville J, de Montigny C, Lamarre Y (eds) The inferior olivary nucleus: anatomy and physiology. Raven Press, New York, pp 73–96 Dempsey CW, Tootle DM, Fontana CJ, Fitzjarrell AT, Garey RE, Heath RG (1983) Stimulation of the paleocerebellar cortex of the cat: increased rate of synthesis and release of catecholamines at limbic sites. Biol Psychiatry 18:127–132 Dum RP, Strick PL (2003) An unfolded map of the cerebellar dentate nucleus and its projections to the cerebral cortex. J Neurophysiol 89(1):634–639

85 Dum RP, Li C, Strick PL (2002) Motor and nonmotor domains in the monkey dentate. Ann N Y Acad Sci 978:289–301 Fisher CM, Cole M (1965) Homolateral ataxia and crural paresis: a vascular syndrome. J Neurol Neurosurg Psychiatry 28:48–55 Fujita H, Kodama T, du Lac S (2020) Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis. Elife 8(9):e58613 Glickstein M, May JG 3rd, Mercier BE (1985) Corticopontine projection in the macaque: the distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei. J Comp Neurol 235(3):343–359 Haines DE, Dietrichs E (1984) An HRP study of hypothalamo-­ cerebellar and cerebello-hypothalamic connections in squirrel monkey (Saimiri sciureus). J Comp Neurol 229:559–575 Haines DE, Dietrichs E, Mihailoff GA, McDonald EF (1997) The cerebellar-­hypothalamic axis: basic circuits and clinical observations. In: Schmahmann JD (ed) The cerebellum and cognition, vol 41. Academic Press, San Diego, pp 83–107 Harper JW, Heath RG (1973) Anatomic connections of the fastigial nucleus to the rostral forebrain in the cat. Exp Neurol 39:285–292 Hartmann-von Monakow K, Akert K, Künzle H (1981) Projection of precentral, premotor and prefrontal cortex to the basilar pontine grey and to nucleus reticularis tegmenti pontis in the monkey (Macaca fascicularis). Schweiz Arch Neurol Neurochir Psychiatr 129(2):189–208 Hoshi E, Tremblay L, Féger J, Carras PL, Strick PL (2005) The cerebellum communicates with the basal ganglia. Nat Neurosci 8(11):1491–1493 Ilinsky IA, Kultas-Ilinsky K (1987) Sagittal cytoarchitectonic maps of the Macaca mulatta thalamus with a revised nomenclature of the motor-related nuclei validated by observations on their connectivity. J Comp Neurol 262(3):331–364 Jones EG (2007) The thalamus, 2nd edn. Cambridge University Press, Cambridge Kelly RM, Strick PL (2003) Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci 23(23):8432–8444 Marcinkiewicz M, Morcos R, Chretien M (1989) CNS connections with the median raphe nucleus: retrograde tracing with WGA-apoHRP-­ gold complex in the rat. J Comp Neurol 289:11–35 May JG, Andersen RA (1986) Different patterns of corticopontine projections from separate cortical fields within the inferior parietal lobule and dorsal prelunate gyrus of the macaque. Exp Brain Res 63(2):265–278 Middleton FA, Strick PL (1994) Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 266(5184):458–461 Nyby O, Jansen J (1951) An experimental investigation of the corticopontine projection in Macaca mulatta. Skrifter utgitt av Det Norske Videnskaps-Akademi: Oslo; 1. Mat Naturv Klasse 3:1–47 Pandya DN, Seltzer B, Petrides M, Cipolloni PB (2015) Cerebral cortex: architecture, connections, and the dual origin concept. Oxford University Press, Oxford Papez J (1937) A proposed mechanism of emotion. Arch Neurol Psychiatry 38(4):725–743 Ramnani N, Behrens TE, Johansen-Berg H et al (2006) The evolution of prefrontal inputs to the cortico-pontine system: diffusion imaging evidence from macaque monkeys and humans. Cereb Cortex 16(6):811–818 Saint-Cyr JA, Courville J (1980) Projections from the motor cortex, midbrain, and vestibular nuclei to the inferior olive in the cat: anatomical and functional correlates. In: Courville J, de Montigny C, Lamarre Y (eds) The inferior olivary nucleus: anatomy and physiology. Raven Press, New York, pp 97–124 Saper CB, Lowell BB (2014) The hypothalamus. Curr Biol 24(23):R1111–R1116

86 Schmahmann JD (1996) From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp 4:174–198 Schmahmann JD, Pandya DN (1989) Anatomical investigation of projections to the basis pontis from posterior parietal association cortices in rhesus monkey. J Comp Neurol 289:53–73 Schmahmann JD, Pandya DN (1990) Anatomical investigation of thalamic projections to the posterior parietal cortices in rhesus monkey. J Comp Neurol 295:299–326 Schmahmann JD, Pandya DN (1991) Projections to the basis pontis from the superior temporal sulcus and superior temporal region in the rhesus monkey. J Comp Neurol 308:224–248 Schmahmann JD, Pandya DN (1992) Course of the fiber pathways to pons from parasensory association areas in the rhesus monkey. J Comp Neurol 326:159–179 Schmahmann JD, Pandya DN (1993) Prelunate, occipitotemporal, and parahipppocampal projections to the basis pontis in rhesus monkey. J Comp Neurol 337:94–112 Schmahmann JD, Pandya DN (1995) Prefrontal cortex projections to the basilar pons: implications for the cerebellar contribution to higher function. Neurosci Lett 199:175–178 Schmahmann JD, Pandya DN (1997a) The cerebrocerebellar system. In: Schmahmann JD (ed) The cerebellum and cognition, vol 41. Academic Press, San Diego, pp 31–60 Schmahmann JD, Pandya DN (1997b) Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. J Neurosci 17:438–458 Schmahmann JD, Pandya DN (2006) Fiber pathways of the brain. Oxford University Press, New York Schmahmann JD, MacMore J, Ko R (2004a) The human basis pontis. Clinical syndromes and topographic organization. Brain 127:1269–1291 Schmahmann JD, Rosene DL, Pandya DN (2004b) Motor projections to the basis pontis in rhesus monkey. J Comp Neurol 478:248–268

J. D. Schmahmann Schmahmann JD, Rosene DL, Pandya DN (2004c) Ataxia after pontine stroke: insights from pontocerebellar fibers in monkey. Ann Neurol 55:585–589 Shah VS, Schmahmann JD, Pandya DN, Vaher PR (1997) Associative projections to the zona incerta: possible anatomic substrates for extension of the Marr-Albus hypothesis to non-motor learning. Soc Neurosci 23:1829 Snider RS (1952) Interrelations of cerebellum and brainstem. In: Bard P (ed) Patterns of organization of the central nervous system, vol 30. Williams & Wilkins Co., Baltimore, pp 267–281 Snider RS, Maiti A (1976) Cerebellar contribution to the Papez circuit. J Neurosci Res 2:133–146 Snider RS, Stowell A (1944) Receiving areas of the tactile, auditory, and visual systems in the cerebellum. J Neurophysiol 7:331–358 Thach WT (1978) Correlation of neural discharge with pattern and force of muscular activity, joint position, and direction of intended next movement in motor cortex and cerebellum. J Neurophysiol 41:654–676 Thach WT, Jones EG (1979) The cerebellar dentatothalamic connection: terminal field, lamellae, rods and somatotopy. Brain Res 169(1):168–172 van Kan PL, Houk JC, Gibson AR (1993) Output organization of intermediate cerebellum of the monkey. J Neurophysiol 69:57–73 Vilensky JA, van Hoesen GW (1981) Corticopontine projections from the cingulate cortex in the rhesus monkey. Brain Res 205(2):391–395 Voogd J (2004) Cerebellum and precerebellar nuclei. In: Paxinos G, Mai JK (eds) The human nervous system, 2nd edn. Elsevier, Amsterdam, pp 321–392 Wiesendanger R, Wiesendanger M, Rüegg DG (1979) An anatomical investigation of the corticopontaine projection in the primate (Macaca fascicularis and Saimiri sciureus)—II.  The projection from frontal and parietal association areas. Neuroscience 4(6):747–765

Cerebello-Cerebral Feedback Projections

12

Kim van Dun, Mario Manto, and Peter Mariën

Abstract

The functional neuroanatomy of cerebellar systems has been extensively studied during the past decades by means of experimental animal studies, anatomoclinical studies, as well as structural and functional neuroimaging studies in patients and healthy subjects. Within a system of closed-loop circuits, this wealth of studies identified reciprocal projections between the cerebellar structures and the supratentorial areas subserving sensorimotor, cognitive, and affective functions. It has been shown that cerebellar output is mediated by the deep cerebellar nuclei, mainly by the dentate nucleus (DN), which project to the supratentorial cortex via the thalamus (cerebello-­ thalamo-­cortical pathway). In turn, the cortical areas that are the target of cerebellar output project back to the cerebellum via the pons (cortico-ponto-cerebellar pathway). Regions of the cerebellar cortex that receive input from a specific supratentorial area are the same regions that project back to that supratentorial area, thus forming closed-­ loop circuits. These projections are largely crossed, connecting the cerebral hemispheres primarily with the contralateral cerebellar hemispheres. Keywords

Corticocerebellar pathways · Cerebello-cerebral network Dentate nucleus · Functional neuroanatomy

12.1 Introduction The functional neuroanatomy of cerebellar systems has been extensively studied during the past decades by means of experimental animal studies, anatomoclinical studies, as well as structural and functional neuroimaging studies in patients and healthy subjects. Within a system of closed-loop circuits, this wealth of studies identified reciprocal projections between the cerebellar structures and the supratentorial areas subserving sensorimotor, cognitive, and affective functions. It has been shown that cerebellar output is mediated by the deep cerebellar nuclei, mainly by the dentate nucleus (DN), which project to the supratentorial cortex mainly via the thalamus (cerebello-thalamo-cortical pathway). In turn, the cortical areas that are the target of cerebellar output project back to the cerebellum via the pons (cortico-ponto-­ cerebellar pathway) (Schmahmann and Pandya 1995; Stoodley and Schmahmann 2010; Strick et al. 2009). Kelly and Strick (2003) demonstrated that the regions of the cerebellar cortex that receive input from a specific supratentorial area are the same regions that project back to that supratentorial area, thus forming closed-loop circuits (Allen and Tsukahara 1974). These projections are largely crossed, connecting the cerebral hemispheres primarily with the contralateral cerebellar hemispheres (Stoodley and Schmahmann 2010). These crossed cerebello-cerebral projections are visualized in Fig. 12.1.

K. van Dun Department of Clinical Neurolinguistics (CLIN), Vrije Universiteit Brussel, Brussels, Belgium M. Manto Service de Neurologie, CHU-Charleroi, Charleroi, Belgium e-mail: [email protected] P. Mariën (*) Department of Clinical Neurolinguistics (CLIN), Vrije Universiteit Brussel, Brussels, Belgium Department of Neurology and Memory Clinic, ZNA Middelheim Hospital, Antwerp, Belgium © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_12

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a

SEGREGATED CEREBELLO-CEREBRAL LOOPS PONTINE NUCLEI

b MOTORRELATED CORTICES

ASSOCIATION CORTEX PROJECTIONS Prefrontal fibers

Posterior Cerebral hemisphere

CEREBELLUM

THALAMIC NUCLEI

CAUDAL HALF OF PONS

MEDIAL ROSTRAL PONS

DORSAL/LATERAL VENTRAL PONTINE NUCLEI

PREFRONTAL CORTEX

PARIETAL CORTEX

CONTRALATERAL CEREBELLAR ANT.LOBE

CONTRALATERAL CEREBELLAR POST.LOBE

PARALIMBIC CORTEX

SUPERIOR TEMPORAL SULCUS

Fig. 12.1 (a) Illustration of the segregated loops between the cerebellum and prefrontal cortex, parietal cortex, paralimbic cortex, and superior temporal sulcus (Adapted from Grimaldi and Manto 2011). (b) Topographic distribution of motor-related cortices and association cortex projections to the cerebellum. Both motor corticopontine projec-

tions and association cortex projections (from prefrontal, posterior parietal, superior temporal, parastriate, parahippocampal, and cingulated regions) are somatotopically organized in the pons (see also Stoodley and Schmahmann 2010). (Adapted from Grimaldi and Manto 2012)

12.2 Projections

(Strick et al. 2009). This division is also represented by a neurochemically different composition within the DN, as shown by immunostaining with antibodies (Strick et  al. 2009). Functional connectivity Magnetic Resonance Imaging (fcMRI) and Diffusion Tensor Imaging (DTI)based tractography studies have confirmed these connections in primates, and in the human brain (Habas et  al. 2013; Schlerf et  al. 2014). DTI-based tractography is an important tool to track direct corticocerebellar pathways in humans. However, due to its low spatial resolution, partial coverage of the brain, and impossibility to track in low anisotropic regions, the technique faces a number of limitations preventing a full mapping of all the corticopontocerebellar fibers (Habas et  al. 2009). Functional connectivity studies additionally indicate the existence of indirect connections that could be mediated by a third region. Both methods (functional connectivity and tractography) are therefore complementary and offer excellent opportunities to disentangle all cerebello-cerebral functional networks.

Over the past decades, neuroanatomical studies established the foundation to substantially modify the traditional view of the cerebellum as a sole coordinator of sensorimotor function by showing that the cerebellum, in addition to the motor areas, also targets some associative areas crucially implicated in cognition and affect (Strick et  al. 2009). Tracing methods in primates (Middleton and Strick 2001; Dum and Strick 2003; Akkal et al. 2007) linked the cerebellum to both frontal motor and premotor areas, and associative prefrontal and parietal regions (Strick et al. 2009; Habas et al. 2013). Some of the targeted cortical areas are visualized in Fig. 12.2. Output channels from the DN are segregated. Projections to the motor areas originate from the dorsal portions of the DN, while projections to the associative cortices originate from the ventral portions of the DN (Dum and Strick 2003; Strick et al. 2009). This means that the DN contains anatomically separate and functionally distinct motor and nonmotor domains

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12  Cerebello-Cerebral Feedback Projections

9m

PreSMA

SMA arm CgS

M1 leg 9l

PS

PrePMd

46d 46v

M1 arm

FEF PMv arm

12

IP

CS

PMd arm

7a 7b AIP

M1 face

AS

Lu

LS

ST

TE 10 mm

Fig. 12.2  Targets of cerebellar output. Red labels indicate areas of the cerebral cortex that are the target of cerebellar output. Blue labels indicate areas that are not the target of cerebellar output. These areas are indicated on lateral and medial views of the cebus monkey brain. The numbers refer to cytoarchitectonic areas. AIP anterior intraparietal area, AS arcuate sulcus, CgS cingulate sulcus, FEF frontal eye field, IP intraparietal sulcus, LS lateral sulcus, Lu lunate sulcus, M1, face, arm, and

leg areas of the primary motor cortex, PMd arm arm area of the dorsal premotor area, PMv arm arm area of the ventral premotor area, PrePMd predorsal premotor area, PreSMA presupplementary motor area, PS principal sulcus, SMA arm arm area of the supplementary motor area, ST superior temporal sulcus, TE area of inferotemporal cortex (Adapted from Strick et al. 2009)

A motor/nonmotor subdivision also holds within the cerebellum. The sensorimotor cerebellum, which projects to the motor areas via the dorsal part of the DN, is primarily situated in the hemispheric parts of lobules IV/V/VI and VIII (Habas et al. 2013). There is little to no overlap between this sensorimotor network and the cognitive neocerebellar regions found to participate in the right/left executive control networks involved in working memory, attention, response selection, and flexibility (especially crus I and II), the salience network required for processing and integration of interoceptive, autonomic, and emotional information (lobule VI), and the default-mode network involved in stream of consciousness, mental imagery, episodic memory retrieval, and self-reflection (lobule IX) (Habas et  al. 2009, 2013). Therefore, a functional dichotomy is suggested between the anterior cerebellum (lobules I–V) and lobule VIII, which are part of the sensorimotor network, and lobules VI and VII (including Crus I and II, and lobule VIIB), and possibly also

lobule IX, contributing to higher-level processing (Stoodley and Schmahmann 2010).

12.2.1 Sensorimotor Network Functional connectivity studies have shown that the sensorimotor network consists of cortical and subcortical structures comprising the sensorimotor cortex (M1/S1), the premotor cortex (BA 6), the supplementary motor area (SMA), the anterior cingulate cortex (BA 24), the occipital cortex (BA 19/37), the temporal cortex (BA 21), the insula, the lentiform and caudate nuclei, the ventral thalami, the rostral part of the left red nucleus, and the bilateral hemispheric portions of lobules IV/V/VI and VIII of the cerebellum (Habas et al. 2009, 2013). Virus tracing studies in primates found direct projections of the dorsal part of the DN to M1, the ventral premotor area

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(PMv), and the SMA (Strick et al. 2009). DTI-based tractography confirmed the connections between the DN and the supratentorial sensorimotor areas M1/S1 via the ventral part of the thalamus (Habas et al. 2013).

12.2.2 Cognitive Networks Three different cognitive networks have been studied by means of functional connectivity studies: (1) the default-­ mode network, (2) the executive network, and (3) the salience network. The default-mode network consists at the cortical level of the prefrontal cortex (BA 9/10, 32), the superior parietal cortex (BA 7), the angular gyrus (BA 39), the posterior cingulate cortex (BA 23/31), the retrosplenial cortex (BA 29/30), the medial temporal lobe, and the ventral temporal cortex (BA 20). At the subcortical level, this network includes the thalamus, the left red nucleus, the midbrain and both caudodorsal hemispheres of lobule IX, and a small cluster in the right hemisphere of lobule VIIB) of the cerebellum (Habas et al. 2009). The executive network consists of a right (RECN) and a left (LECN) executive network. These networks entail the following cortical and subcortical areas: the prefrontal cortex (LECN: BA 45/46, 9, and 8; RECN: BA 44/45/46), the orbitofrontal cortex (BA 47), the superior parietal cortex (BA 7), and the angular gyrus (BA 39), the caudate nucleus, and primarily crus I and crus II of the cerebellum with limited extensions into lobules VI and VIIB and the rostral hemisphere of lobule IX (Habas et al. 2009). The RECN additionally activates the caudal cingulate cortex (BA 23 bilaterally), the supramarginal gyrus (BA 40), and the left red nucleus. The salience network comprises functional connectivity between the medial frontal cortex (BA 32), the dorsal anterior cingulate cortex (BA 24), the dorsolateral prefrontal cortex (BA 46), the frontoinsular cortex (BA 47/12), the thalamus, the red nuclei with a left predominance, and the lateral and ventral parts of both hemispheres of lobule VI of the cerebellum, more laterally located and closer to the posterosuperior fissure than the sensorimotor network (Habas et al. 2009). Virus studies traced projections from the cerebellum to prefrontal areas BA 8A, 9l/9m, 10 and 46d (Strick et  al. 2009; Schmahmann and Pandya 1995). Projections were also found to the preSMA, which can be regarded as a region of the associative prefrontal cortex instead of a motor area since it is densely interconnected with the prefrontal areas (Stoodley and Schmahmann 2010; Strick et  al. 2009). In addition to the prefrontal cortex, the cerebellum is also connected with the posterior parietal cortex (BA 7b), the anterior intraparietal area, and possibly also with the medial and lateral banks of the intraparietal sulcus. Cerebellar projections to the parietal lobe, however, are complex and currently still incompletely understood (Strick et  al. 2009). Tractography

confirms the connectivity between the DN and the temporal, prefrontal (BA 9), and parietal (BA 7) cortices (Habas et al. 2013).

12.3 Conclusion Neuroanatomical studies in primates, and functional connectivity analyses and DTI-based tractography studies in humans have confirmed a crossed closed-loop cerebello-­ cerebral feedback projection system. These dense connections not only link the cerebellum with the supratentorial motor areas such as M1/S1, but also with the associative cortical areas in the frontal, temporal, and parietal lobes. Due to these connections, the cerebellum participates in the sensorimotor network, as well as in cognitive networks such as the default-mode network, the executive network, and the salience network.

References Akkal D, Dum RP, Strick PL (2007) Supplementary motor area and presupplementary motor area: targets of basal ganglia and cerebellar output. J Neurosci 27:10659–10673 Allen GI, Tsukahara N (1974) Cerebrocerebellar communication systems. Physiol Rev 54:957–1006 Dum RP, Strick PL (2003) An unfolded map of the cerebellar dentate nucleus and its projections to the cerebral cortex. J Neurophysiol 89:634–639 Grimaldi G, Manto M (2011) Clinical and pathophysiological features of cerebellar dysfunction. In: Jankovic J, Albanese A (eds) Hyperkinetic disorders. Blackwell Publishing Limited, Oxford Grimaldi G, Manto M (2012) Topography of cerebellar deficits in humans. Cerebellum 11:336–351 Habas C, Kamdar N, Nguyen D, Prater K, Beckmann CF, Menon V, Greicius MD (2009) Distinct cerebellar contributions to intrinsic connectivity networks. J Neurosci 29:8586–8594 Habas C, Shirer WR, Greicius MD (2013) Delineation of cerebrocerebellar networks with MRI measures of functional and structural connectivity. In: Manto M, Gruol DL, Schmahmann JD, Koibuchi N, Ross F (eds) Handbook of the cerebellum and cerebellar disorders. Springer Science + Business Media, Dordrecht, pp 571–585 Kelly RM, Strick PL (2003) Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci 23:8432–8444 Middleton FA, Strick PL (2001) Cerebellar projections to the prefrontal cortex of the primate. J Neurosci 15:700–712 Schlerf J, Wiestler T, Verstynen T, Diedrichsen J (2014) Big challenges from the “little brain”—imaging the cerebellum. In: Dorina Papageorgiou T, Christopoulos GI, Smirnakis SM (eds) Advanced brain neuroimaging topics in health and disease—methods and applications. Intech, London, pp  191–215. http://cdn.intechopen. com/pdfs-­wm/46098.pdf Schmahmann JD, Pandya DN (1995) Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function. Neurosci Lett 199:175–178 Stoodley CJ, Schmahmann JD (2010) Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 46:831–844 Strick PL, Dum RP, Fiez JA (2009) Cerebellum and nonmotor function. Annu Rev Neurosci 32:413–434

Part III Embryology and Development of the Cerebellum

Cerebellar Neurogenesis

13

Richard Hawkes and G. Giacomo Consalez

Abstract

The mechanisms of cerebellar neurogenesis have been redefined in the last few years, showing the precise spatiotemporal sequence of neuronal generation from neurochemically heterogeneous pools of progenitors. Here we describe these processes, highlighting the principal strategies used within this system to generate appropriate cell numbers and phenotypes. Keywords

Cerebellar primordium · Neurogenesis · Microdomains · Glutamatergic · GABAergic

13.1 Introduction The murine cerebellum represents an ideal model to study mechanisms of neural development and specification, as it is composed of a limited number of phenotypes, arranged in a finely patterned network and unambiguously identified by morphological features and by the expression of distinctive neurochemical markers (Ramón y Cajal 1911; Palay and ChanPalay 1974; Miale and Sidman 1961; Ito 1984; Altman and Bayer 1997; Sotelo 2004). In addition, the principal dynamics regulating the whole period of cerebellar ontogenesis have been elucidated (Ramón y Cajal 1911; Altman and Bayer 1997; Sotelo 2004; Hatten and Heintz 1995; Carletti and Rossi 2008; Hoshino 2012). Here we discuss the major features of cerebelR. Hawkes Genes and Development Research Group, Department of Cell Biology and Anatomy, Faculty of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada e-mail: [email protected] G. G. Consalez (*) Università Vita-Salute San Raffaele, Milan, Italy Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy e-mail: [email protected]

lar neurogenesis, highlighting both cell-­intrinsic programs and environmental influences governing neuronal generation and specification within cerebellar circuitries.

13.2 Cerebellar Territory and Germinal Zones A series of studies using the chick/quail chimeric approach have shown that the cerebellum arises from a specialized region at the midbrain/hindbrain boundary (Hallonet et  al. 1990; Hallonet and Le Douarin 1993; Hallonet and Alvarado-­ Mallart 1997). Here, at embryonic day 8.5 (E8.5: all times are murine), the interaction between homeobox genes Otx2 and Gbx2 defines the isthmic organizer region (Broccoli et al. 1999; Li et al. 2005), which orchestrates the development of cerebellar structures through the morphogenetic activity of secreted factors, Fgf8 and Wnt1 (Sotelo 2004; Martinez et  al. 1991, 1999). After territorial specification, cerebellar histogenesis starts at E9 in the mouse. At this age, the cerebellar anlage is made by two separated and symmetric bulges that during the following days grow and merge together, giving rise to the unitary cerebellar plate comprising the vermis and the two hemispheres (Altman and Bayer 1997). Such developmental phase is also characterized by the formation of two germinative compartments just above the opening of the fourth ventricle: the rhombic lip (RL), located at the outer aspect of the cerebellar plate adjacent to the roof plate, and the ventricular zone (VZ), placed in the inner side, covering the fourth ventricle. These germinative districts are defined by the region-specific expression of two basic helix–loop–helix transcription factors: the pancreas transcription factor 1-a (PTF1A), expressed in the VZ (Hoshino et al. 2005), and the mouse homolog of Drosophila atonal (ATOH1), present in the RL (Akazawa et al. 1995). This spatially restricted expression pattern defines the neurochemical compartmentalization of cerebellar precursors, as all GABAergic neurons (Purkinje cells, PCs, nucleo-olivary

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_13

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projection neurons of the cerebellar nuclei, CN, and all inhibitory interneurons – basket, stellate, Golgi, and Lugaro cells) originate from PTF1A+ precursors (Hoshino et  al. 2005; Seto et al. 2014; Yamada et al. 2014), while glutamatergic lineages (large projection neurons of CN, unipolar brush cells, UBCs, and granule cells) derive from Atoh-1+ progenitors (Yamada et al. 2014; Alder et al. 1996; Wingate 2001; Machold and Fishell 2005; Wang et  al. 2005; Fink et al. 2006; Englund et al. 2006). The two primary germinative epithelia disappear at birth. Dividing VZ precursors emigrate into the cerebellar prospective white matter (PWM), whereas those of the RL move along the pial cerebellar surface, where they form the external granular layer (EGL). Postnatal neurogenesis is active in secondary PWM and EGL epithelia up to the third postnatal week, in order to generate appropriate numbers of GABAergic and glutamatergic interneurons, respectively (Altman and Bayer 1997; Carletti and Rossi 2008). The temporal schedule of generation of cerebellar phenotypes is also finely organized. Birthdating studies showed that projection neurons are produced first, at the onset of cerebellar neurogenesis, while both inhibitory and excitatory interneurons are generated later, during late embryonic and early postnatal life (Miale and Sidman 1961; Altman and Bayer 1997; Sekerkova et al. 2004).

13.3 Glutamatergic Neurogenesis From the rostral portion of the RL (rRL), named the germinal trigone, distinct cerebellar glutamatergic cell populations are generated during subsequent embryonic phases, as demonstrated by genetic fate mapping experiments (Wingate 2001; Machold and Fishell 2005; Wingate and Hatten 1999; Lin et al. 2001; Machold et al. 2007). Atoh1 expression in the RL begins at E9.5 in mice (Akazawa et al. 1995) and it is regulated by the antagonistic interaction between Notch1 in the cerebellar primordium and bone morphogenetic proteins secreted by the roof plate. Such interaction produces subsequent streams of migratory cells directed to the cerebellum: large glutamatergic CN projection neurons, unipolar brush cells (UBCs), and granule cells (Machold and Fishell 2005; Machold et al. 2007; Consalez et al. 2020). First, from E10.5 to E12.5, progenitors leaving the rRL give rise to large CN projection neurons, which migrate to the surface of the cerebellar anlage and aggregate in the nuclear transitory zone. From here, CN neurons move inward beyond the developing Purkinje cell plate to form the four pairs of cerebellar nuclei (Machold and Fishell 2005; Wang et  al. 2005; Fink et  al. 2006; Machold et al. 2007; Morales and Hatten 2006). Atoh1 expression is switched off as soon as these neurons leave the RL (Ben-Arie et al. 1996). Secondly, progenitors migrating from the rRL between E14 and E21 give rise to two different

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subsets of UBCs, distinguished on the basis of their birthdating and neurochemical profiles (Sekerkova et al. 2004; Nunzi et al. 2001). Thirdly, the following wave exiting out from the rRL is represented by granule cell progenitors (GCPs) that migrate tangentially along the cerebellar surface, maintaining the expression of Atoh-1 and other transcription factors as Zic1, Zic3, and RU49 (Wingate 2001). GCPs move tangentially toward their secondary germinal zone, the EGL, which by E16 covers the entire surface of the cerebellar anlage (Rakic 1990). It is initially composed of a single row of proliferating cells, but after birth it expands to a layer of about eight cells in thickness and its outer portion is occupied by actively proliferating GCPs (Miale and Sidman 1961; Fujita et al. 1966; Komuro et al. 2001). The proliferation window of murine GCPs closes at the end of the second postnatal week, when the last postmitotic granule cells from the deepest portion of the EGL migrate inwardly to the nascent adult granular layer, marking the end of the EGL and ceasing Atoh-1 expression (Akazawa et al. 1995; Ben-­Arie et al. 1996; Helms and Johnson 1998). Evidence from transplantation (Gao and Hatten 1994), retroviral labelling (Zhang and Goldman 1996a, b), and in  vitro studies (Alder et al. 1996; Gao and Hatten 1994) demonstrates that the EGL gives rise to granule cells only. Interestingly, it has been shown that GCPs are also generated by some proliferative GFAP+ astroglial cells present in the neonatal EGL (Silbereis et al. 2010). Another salient feature of granule cell neurogenesis is the active control exerted by PC-derived mitogenic factors. In fact, the relative number of granule cells is abnormally reduced in animal models characterized by a primary PC degeneration (Sonmez and Herrup 1984; Vogel et al. 1989; Smeyne et al. 1995), whereas if the loss of PCs occurs later in postnatal period the granule cell layer appears near normal (Smeyne et  al. 1995; Mullen et  al. 1976). Sonic hedgehog (SHH) produced by PCs is the most efficacious mitogen acting on granule cell development. Treatment of GCPs with SHH prevents the differentiation and induces a long-lasting proliferative response, while an inhibition of SHH signal dramatically reduces the mitotic activity of these precursors (Dahmane and Ruiz-i-Altaba 1999; Wallace 1999; Wechsler-­ Reya and Scott 1999; Lewis et al. 2004). Recent studies have uncovered the important contribution of several SHH-­ independent pathways and genes to the process of GCP clonal expansion. One of them is started by WNT-3 and suppresses GCP growth through a non-canonical Wnt signaling pathway (Aguado et al. 2013). Another pathway regulated by oxygen tension changes during GCP clonal expansion in the EGL is a new and complementary pathway to SHH that regulates GCP proliferation. In this pathway, the hypoxia-­ inducing factor 1a gene stimulates GCP proliferation independently of SHH signaling (Kullmann et al. 2020).

13  Cerebellar Neurogenesis

13.3.1 Primary Cilia and GCP Proliferation

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the prospective cortex, where they form the multicell-thick Purkinje cell plate (Morales and Hatten 2006). As early as The primary cilium, a sensory cellular organelle mediating E14–15, they aggregate in clusters and finally align into a chemo- and mechanotransduction, plays a central role in monolayer through a process that is completed around P4 GCP proliferation (Chizhikov et  al. 2007; Spassky et  al. (Altman and Bayer 1997). The double-step migration allows 2008). Several signaling molecules are trafficked in the cil- the anteroposteriorly migrating PCs to constitute the adult ium and its surroundings (May et al. 2005; Corbit et al. 2005; parasagittal stripes, characterized by the expression of speLiu et al. 2005; Huangfu and Anderson 2005; Haycraft et al. cific markers, that achieve a stable pattern in the third post2005). The primary cilium is required for SHH signal trans- natal week (Larouche and Hawkes 2006; Consalez and duction, to promote expansion of the GCP pool (Chizhikov Hawkes 2013). GABAergic interneurons comprise multiple subsets of et  al. 2007) and the fact that mutations in genes encoding components of the primary cilium cause Joubert and Meckel morphologically and neurochemically distinct phenotypes syndrome, characterized by vermis hypoplasia or aplasia integrated at different levels of the cerebellar cortex and (e.g., Valente et al. 2006). Proliferation and the response to CN. These cells are produced from late embryonic life to the SHH are severely impaired in Joubert or Meckel syndrome second postnatal week; the peak is around P5 and the propatients (Aguilar et  al. 2012). More recently, ZNF423/ duction of 75% of all inhibitory interneurons occurs prior to Zfp423, a gene implicated in rare cases of Joubert syndrome, P7 (Weisheit et al. 2006). The origin of these cells has been was found to be required for the response to SHH (Hong and controversial for a long time. Until a few years ago, molecular layer (ML) interneurons were thought to derive from the Hamilton 2016). ATOH1 has been long known to positively regulate the EGL, the only germinal layer known to be active during SHH transduction pathway but is also required for the main- postnatal development (Ramón y Cajal 1911; Altman 1972). tenance of primary cilia, which keep GCPs competent to More recently, analysis of chick-quail chimeras, transplantarespond to SHH (as mentioned, the loss of primary cilia tion experiments and retroviral injections demonstrated that causes GCPs to exit their proliferative state). ATOH1 acti- EGL exclusively generates granule cells, suggesting that ML vates ciliogenesis by transcriptionally regulating Cep131, interneurons derive from the VZ (Hallonet et al. 1990; Gao whose gene product facilitates the clustering of centriolar and Hatten 1994; Zhang and Goldman 1996a, b; Napieralski satellites at the basal body. Importantly, ectopic expression and Eisenman 1993). Marichich and Herrup (1999) identiof Cep131 counteracts the effects of Atoh1 loss in GCPs by fied the progenitors of inhibitory interneurons as a popularestoring the proper localization of centriolar satellites and tion of Pax2+ cells, which appear in the VZ around E12 and consequently ciliogenesis. This pro-proliferative pathway is later emigrate into the cerebellar parenchyma. Inhibitory also conserved in SHH-type medulloblastoma, a pediatric interneuron precursors continue to proliferate during their migration in the PWM (Zhang and Goldman 1996a; Weisheit brain tumor arising from GCPs (Chang et al. 2019). et al. 2006; Leto et al. 2006) and they generate interneuron phenotypes according to an inside-out progression. CN interneurons are the first to be born during embryonic and early 13.4 GABAergic Neurogenesis postnatal life, followed by granular layer (GL) interneurons + GABAergic neurons are produced starting from Ptf1-a VZ (Golgi and Lugaro cells) and, finally, by ML ones (basket progenitors according to a two-step process (reviewed in and stellate cells) (Weisheit et al. 2006; Maricich and Herrup Carletti and Rossi 2008). First, projection neurons (nucleo-­ 1999; Leto et al. 2006; Sudarov et al. 2011). Transplantation olivary CN neurons and PCs) are generated locally, from fate experiments have demonstrated that all types of cerebellar committed precursor populations. Secondly, some inhibitory interneurons derive from a single population of ­progenitors become restricted to interneuron identities and multipotent progenitors that acquire mature phenotypic traits emigrate from the VZ to the nascent cerebellar nuclei or cor- under the influence of local instructive cues provided by the tical layers, where they will acquire final phenotypic identi- PWM microenvironment (Leto et al. 2006, 2009). It has been shown that proliferative progenitors of GABAergic interneuties under the influence of environmental instructive cues. Nucleo-olivary CN neurons are generated between E10.5 rons in the PWM are PTF1A+ cells that start expressing Pax2 and E12.5  in the mouse cerebellar primordium and follow during their last S phase (Maricich and Herrup 1999; Leto the same migratory pathway as their glutamatergic counter- et  al. 2009; Fleming et  al. 2013). Importantly, it has been parts (Palay and Chan-Palay 1974). PC progenitors undergo recently demonstrated that SHH delivered by PCs maintains their terminal mitosis between E11 and E13 and populate the PWM niche and sustains the proliferation of neural-stem-­ different cortical regions according to their birthdate (Altman cell-like primary progenitors able to generate both CD15+ and Bayer 1997). Postmitotic PCs migrate radially toward astroglial precursors and PTF1A+ GABAergic interneuron

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progenitors (Fleming et  al. 2013). The same morphogen secreted by the choroid plexi in the embryonic cerebrospinal fluid is critically involved in the amplification of early VZ-derived GABAergic progenitors (Huang et  al. 2010), suggesting that similar influences could sustain neurogenesis in the embryonic and postnatal cerebellum.

13.5 Neurogenesis and Purkinje Cell Type Specification A PTF1A → neurogenin 1/2 (Neurog1/2) → Early B-cell factor 2 (EBF2) regulatory network is implicated in PC subtype specification (Zordan et al. 2008; Florio et al. 2012). By this model, the early-born PC cohort expresses neither Neurog1/2 nor Ebf2, and expresses the zebrin II (ZII+) phenotype in the adult. Soon after E11, Neurog1 and 2 are upregulated by PTF1A in the later-born PC progenitors (e.g., Henke et  al. 2009). In this context, Neurog2 regulates cell cycle progression, neuronal output, and early dendritogenesis in PC progenitors (Florio et al. 2012), but neither Neurog1 nor 2 deletions affect the specification of PC subtypes (Hawkes, unpublished observation). In turn, late-born PC precursors express Ebf2, which represses the ZII+ phenotype (Chung et al. 2008; Croci et al. 2006): Ebf2 deletion results in transdifferentiated PCs that express markers characteristic of both the ZII+ and ZII− subtypes – the only manipulation known to alter a PC subtype phenotype. In addition, EBF2 plays a subtype-specific anti-apoptotic role in ZII− PCs by locally regulating Igf1 gene expression (Croci et al. 2011). As a result of these events, early-born PCs become ZII+ in the adult, while late-born PCs adopt the ZII− phenotype. Interestingly, a molecular interactor of EBF transcription factors known as ZFP423 has been implicated in PC neurogenesis. Among other locations, this protein is expressed in progenitors of the cerebellar ventricular zone, where it regulates the response to DNA damage and the maintenance of the stem cell progenitor pool (Casoni et  al. 2017). Interestingly, ZFP423 is also required for hindbrain choroid plexus development (Casoni et al. 2020). The hindbrain choroid plexus has been implicated in the control of cerebellar VZ neurogenesis through SHH secretion (see above, Huang et al. 2010).

13.6 Concluding Remarks Different strategies active within cerebellar neurogenic niches determine the precise sequence of phenotype generation: projection neurons are produced by defined pools of fate-restricted progenitors, whose specification programs mainly develop early in embryogenesis, while interneuron precursors proliferate until the second postnatal week,

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acquiring mature phenotypes under the influence of local instructive cues. The cellular/molecular mechanisms underlying these processes remain to be clarified, as the biological significance of the diverse differentiation strategies. It is possible that these different mechanisms might support the correct establishment of topographically patterned long-­distance connections on one side and local experience-­dependent networks on the other. Further analysis will be required to fully address these questions. Acknowledgements  We thank Ketty Leto for her past contribution to this work.

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98 Machold RP, Kittell DJ, Fishell GJ (2007) Antagonism between notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip. Neural Dev 2:5 Maricich SM, Herrup K (1999) Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol 41(2):281–294. https://doi.org/10.1002/ (sici)1097-­4695(19991105)41:23.0.co;2-­5 Martinez S, Wassef M, Alvarado-Mallart RM (1991) Induction of a mesencephalic phenotype in the 2-day-old chick prosencephalon is preceded by the early expression of the homeobox gene en. Neuron 6(6):971–981 Martinez S, Crossley PH, Cobos I, Rubenstein JL, Martin GR (1999) FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression. Development 126(6):1189–1200 May SR, Ashique AM, Karlen M, Wang B, Shen Y, Zarbalis K et  al (2005) Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol 287(2):378–389. https://doi. org/10.1016/j.ydbio.2005.08.050 Miale IL, Sidman RL (1961) An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol 4:277–296. https://doi. org/10.1016/0014-­4886(61)90055-­3 Morales D, Hatten ME (2006) Molecular markers of neuronal progenitors in the embryonic cerebellar anlage. J Neurosci 26(47):12226– 12236. https://doi.org/10.1523/JNEUROSCI.3493-­06.2006 Mullen RJ, Eicher EM, Sidman RL (1976) Purkinje cell degeneration, a new neurological mutation in the mouse. Proc Natl Acad Sci U S A 73(1):208–212. https://doi.org/10.1073/pnas.73.1.208 Napieralski JA, Eisenman LM (1993) Developmental analysis of the external granular layer in the meander tail mutant mouse: do cerebellar microneurons have independent progenitors? Dev Dyn 197(4):244–254. https://doi.org/10.1002/aja.1001970403 Nunzi MG, Birnstiel S, Bhattacharyya BJ, Slater NT, Mugnaini E (2001) Unipolar brush cells form a glutamatergic projection system within the mouse cerebellar cortex. J Comp Neurol 434(3):329–341 Palay SL, Chan-Palay V (1974) Cerebellar cortex: cytology and organization. Springer, Berlin Rakic P (1990) Principles of neural cell migration. Experientia 46(9):882–891. https://doi.org/10.1007/BF01939380 Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et des vertébrés. Maloine, Paris Sekerkova G, Ilijic E, Mugnaini E (2004) Time of origin of unipolar brush cells in the rat cerebellum as observed by prenatal bromodeoxyuridine labeling. Neuroscience 127(4):845–858. https://doi. org/10.1016/j.neuroscience.2004.05.050 Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y et  al (2014) Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. Nat Commun 5:3337. https://doi.org/10.1038/ncomms4337 Silbereis J, Heintz T, Taylor MM, Ganat Y, Ment LR, Bordey A et al (2010) Astroglial cells in the external granular layer are precursors of cerebellar granule neurons in neonates. Mol Cell Neurosci 44(4):362–373. https://doi.org/10.1016/j.mcn.2010.05.001 Smeyne RJ, Chu T, Lewin A, Bian F, Salih S, Kunsch C et al (1995) Local control of granule cell generation by cerebellar Purkinje cells. Mol Cell Neurosci 6(3):230–251

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14

Zones and Stripes Carol Armstrong and Richard Hawkes

Abstract

The cerebellar cortex is built around different classes of Purkinje cell, which form distinct anterior–posterior transverse zones, each of which is further divided into parasagittal stripes. There are >200 stripes, which are reproducible between individuals and fundamentally conserved across birds and mammals. Other features of cerebellar organization, including the topography of afferent projections and cerebellar interneurons and glial cells, are built around the Purkinje cell framework. Zone-and-stripe architecture is established early in cerebellar development. Purkinje cells are born between embryonic day (E)10 and E13 (in mouse) in the ventricular zone of the fourth ventricle (VZ). Purkinje cell subtype specification likely happens at this time. Postmitotic Purkinje cells migrate via the cerebellar plate into the cerebellar anlage and form a stereotypical array of clusters (E14–E18). Clusters are the forebears of the stripes and the targets of ingrowing afferent projections, and thereby determine the afferent topography. In addition to ingrowing afferents, Purkinje cell clusters are likely also mustering points for subsets of glial cells and interneurons (and eventually migrating granule cells) and so can be considered as topographical organizing centers (TOCs). Reelin signaling at around birth triggers the rostrocaudal dispersal of the clusters into the adult stripes. In parallel, phenotype

C. Armstrong (*) Department of Biology, Mount Royal University, Calgary, AB, Canada Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada e-mail: [email protected] R. Hawkes Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada e-mail: [email protected]

s­ pecification in the upper rhombic lip forms distinct subpopulations of granule cell precursors that migrate over the embryonic cerebellar surface and show restriction at the underlying Purkinje cell cluster boundaries. When the postmitotic granule cells migrate and settle in the granular layer, this topography is retained. This complex topographical organization of Purkinje cells, granule cells, and afferents is further reflected in the cerebellar functional map and explains the patterned distribution of many cerebellar pathologies. Keywords

Cerebellum · Purkinje cell · Zebrin · Climbing fiber Mossy fiber · Granular layer · Pattern formation

14.1 Adult Zones and Stripes The cerebellar cortex is traditionally described as comprising lobes and lobules separated by fissures. However, lobulation does not reflect the functional organization of the cerebellum, its connectivity, or its embryology. A more fundamental architecture is shown by intrinsic differences between subsets of Purkinje cells (PCs), seen through the expression of molecular markers such as zebrin II/aldolase C (Brochu et al. 1990), the small heat shock protein (HSP)25 (Armstrong et  al. 2000) and phospholipase C (PLC)β4 (Sarna et al. 2006: see Fig. 14.1). These reveal an elaborate and reproducible pattern of transverse zones and parasagittal stripes that is the scaffold around which the rest of the cerebellar cortex is organized (reviewed in Apps et al. 2018). The mammalian cerebellum comprises at least five transverse zones (Fig.  14.1): regions of the cerebellar cortex, ranging from anterior to posterior and distinguished as distinct expression domains. The boundaries between transverse zones do not align with classical anatomical boundaries such as lobules. The anterior zone (AZ) is roughly equivalent to lobules I–V (“roughly” because transverse zones inter-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_14

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Fig. 14.1  Zones and stripes. Newborn Purkinje cells (PCs) exit the ventricular zone (VZ) and stack by birthdate. Subsequently, they migrate to form a symmetrical array of clusters. Reelin-disabled signaling triggers cluster dispersal into the adult transverse zones [anterior zone (AZ), central zone A and B (CZa, CZb), posterior zone (PZ), nodular zone (NZ)] and parasagittal stripes (seen here in an adult mouse transverse section immunoperoxidase-­ stained for PLCβ4: Sarna et al. 2006). Mutations in the Reelin→Dab1 pathway, both in human and mouse, result in a failure of PC cluster dispersal with consequent ataxia

digitate). The central zone (CZ) comprises lobules VI and VII and can be further divided into an anterior CZa (~lobule VI) and a posterior CZp (~lobule VII). The posterior zone (PZ) occupies lobule VIII and the dorsal half of lobule IX. The nodular zone (NZ) includes the ventral half of lobule IX and lobule X. In birds (Pakan et al. 2007; Marzban et al. 2010) and bats (Kim et al. 2009), a sixth transverse zone – the lingular zone (LZ) – has been identified in lobule I. Within each transverse zone, PCs are further divided into stripes arranged mediolaterally across the vermis and hemispheres (reviewed in Armstrong and Hawkes 2013: Fig. 14.1). For example, alternating stripes of zebrin II+/−

PCs are found in the AZ and PZ (Hawkes and Leclerc 1987; Brochu et  al. 1990), and HSP25+/− stripe arrays are found in the CZ and NZ (Armstrong et  al. 2000). However, no single marker reveals the full complexity of the cerebellar architecture: distinct stripes shown by one marker are revealed as a composite with another. For example, zebrin II−/PLCβ4+ stripes in the AZ are subdivided by L7/pcp2-lacZ expression (Ozol et al. 1999), and zebrin II+ stripes are subdivided by HSP25 in the PZ during development (Armstrong et  al. 2001) and the NZ in the adult (Armstrong et al. 2000: reviewed in Armstrong and Hawkes 2013).

14  Zones and Stripes

The intrinsic zone-and-stripe organization of the cerebellar cortex is not restricted to PCs – it also encompasses granule cells, inhibitory interneurons (Consalez and Hawkes 2013), glial cells (e.g., Scott 1964; Eisenman and Hawkes 1989), and afferent terminal fields (e.g., Voogd and Ruigrok 2004). Granule cells expression boundaries in the adult granular layer and the developing external granular layer (EGL) align with the PC transverse boundaries (reviewed in Consalez et al. 2021). Similarly, several granule cell mutation phenotypes are restricted to a particular transverse zone. For instance, in the meander tail mutant (meaJ), the AZ lacks granule cells (Hamre and Goldowitz 1997) while in contrast a Neurod1 deletion results in an apparently normal granular layer in the AZ, but a reduction of granule cells in the CZ and a complete lack of granule cells in the PZ and NZ (Miyata et al. 1999). At the other extreme, several markers (e.g., neuronal nitric oxide synthase (nNOS) and dystrophin: reviewed in Consalez et al. 2021) reveal several thousand reproducible “patches” in the granular layer that in turn may represent the topographical “quantum” of cerebellar action (reviewed in Apps et al. 2018). Next, inhibitory interneurons also align with PC stripes. For example, Golgi cell dendrites in the molecular layer are restricted at PC stripe boundaries (Sillitoe et al. 2008) and the expression of neurofilament antigens by basket cells is striped and in register with the PC expression of zebrin II (reviewed in Consalez and Hawkes 2013). In the latter case, the alignment appears to be secondary to PC activity (Zhou et  al. 2020). Similarly, unipolar brush cells are primarily restricted to the NZ, and within this transverse zone, calretinin-­expressing unipolar brush cells are organized into parasagittal stripes that align with zebrin II-expressing PCs (Dino et al. 1999; Chung et al. 2009). Glial cells also show a zone-and-stripe organization. For instance, VZ glial progenitors in chick are organized into parasagittal clonal stripes (Lin and Cepko 1999); a subset of neuropeptide Y-expressing Bergmann glia is restricted to the CZ and NZ, and within these transverse zones form parasagittal stripes that align with HSP25+ PCs (Armstrong et  al. 2000; Reeber et al. 2018); and 5′-nucleotidase expression by Bergmann glial fibers precisely mirrors the PC zebrin expression pattern (Eisenman and Hawkes 1989). Finally, afferent tract tracing has shown that both climbing fiber and mossy fiber afferent terminal fields are restricted to specific stripes (reviewed in Ruigrok 2011). For example, climbing fibers originating in the inferior olive terminate selectively on the PC somata and proximal dendrites within parasagittal stripes of zebrin II+/− PCs and similarly, mossy fiber terminal fields in the granule cell layer of the vermis align with specific zebrin II+/− (e.g., Sugihara and Shinoda 2004; Voogd and Ruigrok 2004) and

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HSP25+/− (Armstrong et  al. 2009) PC stripes. Finally, although less striking than the mossy and climbing fiber topography, noradrenergic afferents to the molecular layer also show a clear bias toward a parasagittal orientation (Longley et al. 2021). The importance of the architecture is further emphasized by its evolutionary conservation: things that are conserved are important. The same zone-and-stripe pattern is found in all mammals (>20 species: Sillitoe et al. 2005; Marzban and Hawkes 2011) and birds (4 species: Pakan et  al. 2007; Iwaniuk et  al. 2009; Marzban et  al. 2010; Corfield et  al. 2015) studied to date. Distinct zebrin II+/− PC phenotypes and/or evidence of stripes are also found in fish and reptiles (Meek et al. 1992; Wylie et al. 2016). However, although the basic ground plan is conserved transverse zone sizes vary widely, consistent with ecological diversity and mosaic evolution. Thus, in bats, the CZ, which receives mossy fiber innervation associated with sonar, is greatly enlarged (Kim et al. 2009), whereas in blind mammals such as naked mole rats (Marzban et  al. 2011) and star-nosed moles (Marzban et  al. 2015), the CZ and NZ, zones which receive visual inputs, are unusually small.

14.2 Pattern Formation The zone-and-stripe architecture seen in the adult cerebellum is established during development. It arises from the coordinated interactions of two germinal zones: the VZ that produces the GABAergic neurons (PCs and inhibitory interneurons) and the upper rhombic lip that produces the glutamatergic granule cells and unipolar brush cells (reviewed in Dastjerdi et al. 2012; Hashimoto and Hibi 2012; Galas et al. 2017; Consalez et al. 2021).

14.2.1 Pattern Formation in the Ventricular Zone (VZ) PCs undergo terminal mitosis (E10–E13 in mice: Miale and Sidman 1961) within a Ptf1a+ expression domain in the VZ (Hoshino et al. 2005; Zordan et al. 2008) and migrate dorsally to form the transient cerebellar plate by E14. At this stage, PC progenitors and glial precursors (but not cerebellar interneurons) express the transcription factor early B cell factor 2 (Ebf2: Badaloni et  al. 2019). Within a few days, Ebf2 is suppressed in a subset of PCs that is born early and destined to become zebrin II+ but maintained in PCs that are born later and destined to become zebrin II−/Ebf2+ [Ebf2 acts to specify the zebrin II− phenotype by suppressing expression of the zebrin II+ phenotype (Chung et al. 2008)].

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Birthdating studies also reveal a direct correlation between PC birthdates and their final zone-and-stripe location, suggesting that both subtype specification and positional information are acquired at this stage (e.g., Karam et  al. 2000; Hashimoto and Mikoshiba 2003; Chung et al. 2008; Namba et al. 2011). Between E14 and E17, PCs in the cerebellar plate undergo a choreographed migration to create a reproducible array of some 50 clusters (Vibulyaseck et al. 2017) that can be distinguished based on differential gene expression (reviewed in Armstrong and Hawkes 2013). These clusters serve as topographic organizing centers (TOCs) – mustering yards for the cerebellar components (afferents, interneurons, glial cells) that will form the adult stripes (Fig. 14.2). GABAergic interneurons – basket and stellate cells of the molecular layer and Golgi cells of the granular layer, etc. – are also born from a common progenitor pool in the VZ (Leto et al. 2006; Sudarov et al. 2011). From the VZ, they enter the immature white matter through which they migrate while continuing to divide (so-called transit amplification) until joining the PC clusters (Fig. 14.2; Sudarov et al. 2011; Schilling 2018). Once the PC clusters begin to disperse and lobules appear, the interneurons are carried along. Because dispersal is restricted to the rostrocaudal axis, and involves a >20-fold extension, each cluster is drawn out into a long, parasagittal stripe. The interneuron axons and dendrites are also drawn out along with the PCs and as a result, cerebellar interneurons show a parasagittal orientation and their pro-

Z- Z+

VZ

PCs

MFs CFs

TOC

TOC

INs E10-13

E14

E18

P20

Fig. 14.2 The development of topographical organizing centers (TOCs) in the developing cerebellum. Purkinje cell (PC) precursors arise from the ventricular zone (VZ) and undergo an elaborate rearrangement into ~50 multilayered clusters [future zebrin+ (Z+) or zebrin− (Z−)]. These serve as topographical organizing centers (TOCs), mustering the afferent inputs [mossy fibers (MF) and climbing fibers (CF) and GABAergic interneurons (INs)] that comprise the adult cerebellar cortical stripe. As the PC clusters disperse into long stripes, all other components disperse along with them, thereby adopting a parasagittal architecture while remaining confined to their individual cluster/stripe

cesses show restriction at stripe boundaries (reviewed in Consalez and Hawkes 2013). PC clusters are also the embryonic targets of the cerebellar afferents (Fig. 14.2). Afferent topography is established around E15–E16 (Paradies and Eisenman 1993; Grishkat and Eisenman 1995) presumably by chemospecific mapping on PCs at the cluster stage (reviewed in Rahimi-Balaei et al. 2015; Lackey and Sillitoe 2020): thus, the TOCs include both climbing and mossy fiber afferents that respect the nascent PC stripe topography (e.g., Wilson et  al. 2019). Mossy fiber afferents are varied with respect to origin and timing of innervation but do form a transitory relationship with particular PC clusters. As the granular layer matures, the mossy fiber terminals detach from the PCs and connect with local postmitotic granule cells. This preserves the alignment of mossy fiber terminal fields and the overlying PC stripes.

14.2.2 Pattern Formation in the Rhombic Lip During early embryogenesis, all granule cells are derived from an atonal (Atoh1+) lineage in the upper rhombic lip, which expands to cover the cerebellar surface as the EGL (reviewed in Consalez et al. 2021). Within the EGL at least three transverse granule cell progenitor zones are identified by gene expression, with boundaries aligned with the underlying PC zones (Fig.  14.3). For example, homeobox transcription factors reveal that different EGL expression domains overlay the AZ and the CZ (e.g., Lmx1a expression distinguishes AZ from CZ (Chizhikov et al. 2010) while Tlx3 distinguishes the PZ from the NZ (Logan et al. 2002)). The same boundaries are revealed by birth dating  – early born granule cell progenitors (Lmx1a−) form the anterior EGL, while later born progenitors (Lmx1a+) form the posterior EGL (Fig. 14.3). The PC cluster-EGL boundary alignments suggest that granule cell progenitor dispersal is restricted at PC transverse zone boundaries. Once postmitotic, granule cells migrate from the EGL to the granular layer guided by Bergmann glial fibers. In this way, the EGL topography is projected into the nascent granular layer. Secondary patterning of the granular layer happens postnatally and involves formative interactions with both PCs and mossy fiber afferents (e.g., reviewed in Consalez et al. 2021). Under the influence of the mossy fiber afferents via nNOS signaling, an elaborate patch topography evolves in the granular layer, comprising several thousand discrete patches, each consisting of a few dozen PCs and their associated interneurons and mossy fiber afferents (reviewed in White et al. 2014; Consalez et al. 2021). Similar patches are found in recordings of the trigeminal afferent sensory fields (Welker 1976: reviewed in Apps et al. 2018).

14  Zones and Stripes Fig. 14.3 Distinct populations of progenitors in the external granule cell layer. A first wave of Lmx1a− / Otx1+ granule cells creeps across the surface of the cerebellar cortex to form the (red) EGL situated above the AZ PCs. A second wave (teal) of Lmx1a+/Otx1/2+ granule cells follow suit but stops at the A/-CZ transverse zone boundary seen in the adult. The Lmx1a+ granule cells will populate the granular layers of the CZ, PZ, and NZ. A third boundary of Tlx3 expression is seen in the EGL and correlates with the PZ/NZ boundary

103 Lmx1a+ Ebf2Otx1/2+ Tlx3+

PZ CZ

Lmx1aEbf2+ Otx1+ Tlx3+

NZ

Tlx3-

AZ

14.3 Pattern Formation of Afferent and Efferent Projections As noted above, the afferent topography of the cerebellar cortex is established in the TOCs. Perinatally, climbing fibers have already entered specific clusters and synapsed on the PC somata (Sotelo and Wassef 1991). Similarly, mossy fibers make transient connections with the PCs in the clusters. Later, as Reelin signaling triggers cluster dispersal into the adult stripe, the afferents disperse along with them. As the stripes mature, climbing fibers refine their projections by the elimination of supernumerary connections (Kano et al. 2018) and mossy fibers detach from the PCs and form new synaptic connections with local granule cells and interneurons, thus generating the striped afferent pathways. Finally, the topographical distribution of corticonuclear efferents from PCs to the cerebellar nuclei and medial and lateral vestibular nuclei is quite complex (e.g., there are at least six distinct compartments in the medial nuclei alone: Chung et al. 2009: see also Kebschull et al. 2020) but broadly the projections are organized from medial to lateral (Ruigrok 2011; Sugihara 2011).

14.4 Functional and Clinical Implications The fact that zone-and-stripe architecture is conserved across species and manifested in the topography of afferents, cortical neurons, and efferents strongly suggests that it has important functional and clinical implications. However, the functional and clinical significance of cerebellar architecture has only recently begun to be revealed. For example, several studies have identified intrinsic functional differences between PC subtypes and shown that the spiking activity of

PCs is correlated with their zebrin II+/− phenotype (White et al. 2014; Xiao et al. 2014; Zhou et al. 2014). In particular, resting simple-spike firing activity differs between zebrin II+/− PCs with zebrin II+ PCs firing action potentials at a lower rate and frequency (60  Hz) than zebrin II− (90  Hz) PCs, even though the cells are directly adjacent. This difference is intrinsic and independent of synaptic input (Xiao et al. 2014; Zhou et al. 2014). These functional differences may be linked to the activity of a transient receptor potential cation channel type C3 (TRPC3) that is associated with zebrin II− PCs, as blocking TRPC3 decreased PC firing frequency (Zhou et al. 2014). In a similar fashion, modulation of PC complex-spike activity in PC in the avian cerebellum shows that zebrin II+/− PCs respond differently to optic flow (Long et al. 2018). Cerebellar patterning also shows up in instances of cerebellar learning. As an example, cerebellar circuits are crucial to various aspects of ocular motor control including eyeblink conditioning and vestibular-ocular responses. Each of these types of motor learning has been associated with different PC subsets: long-term depression (LTD), or a decrease in synaptic strength, as seen in eyeblink conditioning is typically associated with zebrin II− PCs (De Zeeuw and Ten Brinke 2015), while long-term potentiation (LTP), or an increase in synaptic strength, as seen with vestibular-ocular responses is associated with zebrin II+ PCs (Voges et  al. 2017). Furthermore, goal-directed, or reward-response behaviors are also positively correlated to PC stripes: when mice conditioned to associate a 10 Hz tone with a reward, climbing fiber activation was predominantly seen in the zebrin II+ stripes (Tsutumi et  al. 2019). Functional differences in the expression of LTD between stripes are mirrored in molecular differences in the molecular pathways believed to underpin them (Hawkes 2014). For instance, synaptic

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plasticity at the parallel fiber-PC dendrite synapse can be modulated by cannabinoid receptor 1 which is restricted to differentiating granule cells in the AZ and CZa, suggesting selective functional and topographical pathways within the cerebellar endocannabinoid signaling system (Martinez et al. 2020). Finally, the zone-and-stripe architecture has clinical implications for cerebellar pathologies (typically ataxias). For example, developmental failures of cell migration that result in abnormal cerebellar architecture are routinely accompanied by ataxia. As noted in Fig. 14.1, the transformation of the embryonic PC clusters into adult stripes is triggered by the Reelin → Dab1 signaling pathway and mutations result in a failure of PC cluster dispersal, abnormal adult patterning, and ataxia (reviewed in Lee and D’Arcangelo 2016). Similarly, patterned pathology is seen in the wide range of insults and genetic defects that result in PC death. Indeed, in a survey of PC death phenotypes, a great majority showed a preferential sensitivity of one PC subtypes or another and consequently zone or stripe restricted PC loss (reviewed in Sarna and Hawkes 2003). In summary, while the first functional implications of the zone-and-stripe architecture are beginning to emerge, the broader implications of this complex and intricate topography remain largely unknown. It is expected that future iterations of this chapter will include much more of the functional significance of the zone-and-stripe organization of the cerebellum.

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14  Zones and Stripes Lee GH, D’Arcangelo GD (2016) New insights into Reelin-mediated signalling pathways. Front Cell Neurosci 10:122 Leto K, Carletti B, Williams IM et al (2006) Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci 26:11682–11694 Lin JC, Cepko CL (1999) Biphasic dispersion of clones containing Purkinje cells and glia in the developing chick cerebellum. Dev Biol 211:177–197 Logan C, Millar C, Bharadia V et al (2002) Onset of Tlx-3 expression in the chick cerebellar cortex correlates with the morphological development of fissures and delineates a posterior transverse boundary. J Comp Neurol 448:138–149 Long RM, Pakan JMP, Graham DJ et al (2018) Modulation of complex spike activity differs between zebrin-positive and -negative Purkinje cells in the pigeon cerebellum. J Neurophysiol 120:250–262 Longley M, Ballard J, Andres-Alonso M et al (2021) A patterned architecture of monoaminergic afferents in the cerebellar cortex: noradrenergic and serotonergic fibre distributions within lobules and parasagittal zones. Neuroscience 462:106–121 Martinez L, Black KC, Telas Webb B et  al (2020) Components of endocannabinoid signaling system are expressed in the perinatal mouse cerebellum and required for its normal development. eNeuro 7:0471–0419 Marzban H, Hawkes R (2011) On the architecture of the posterior zone of the cerebellum. Cerebellum 10:422–434 Marzban H, Chung SH, Pezhouh MK et al (2010) Antigenic compartmentation of the cerebellar cortex in the chicken (Gallus domesticus). J Comp Neurol 518:2221–2239 Marzban H, Hoy N, Aavani T et  al (2011) Compartmentation of the cerebellar cortex in the naked mole-rat (Heterocephalus glaber). Cerebellum 10:435–448 Marzban H, Hoy N, Buchok M et al (2015) Compartmentation of the cerebellar cortex: adaptation to lifestyle in the star-nosed mole Condylura cristata. Cerebellum 14:106–118 Meek J, Hafmans TG, Maler L et al (1992) Distribution of zebrin II in the gigantocerebellum of the mormyrid fish Gnathonemus petersii compared with other teleosts. J Comp Neurol 316:17–13 Miale IL, Sidman RL (1961) An autoradiographic analysis of histogenesis in the mouse cerebellum. Exp Neurol 4:277–296 Miyata T, Maeda T, Lee JE (1999) NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev 13:1647–1652 Namba K, Sugihara I, Hashimoto M (2011) Close correlation between the birth date of Purkinje cells and the longitudinal compartmentalization of the mouse adult cerebellum. J Comp Neurol 519:2594–2614 Ozol K, Hayden JM, Oberdick J et al (1999) Transverse zones in the vermis of the mouse cerebellum. J Comp Neurol 412:95–111 Pakan JMP, Iwaniuk AN, Wylie DRW et  al (2007) Purkinje cell compartmentation as revealed by zebrin II expression in the cerebellar cortex of pigeons (Columba livia). J Comp Neurol 501:619–630 Paradies MA, Eisenman LM (1993) Evidence of early topographic organization in the embryonic olivocerebellar projection: a model system for the study of pattern formation processes in the central nervous system. Dev Dyn 197:125–145 Rahimi-Balaei M, Afsharinezhad P, Bailey K et al (2015) Embryonic stages in cerebellar afferent development. Cerebellum Ataxias 2:7 Reeber SL, Arancillo M, Sillitoe RV (2018) Bergmann glia are patterned into topographic molecular zones in the developing and adult mouse cerebellum. Cerebellum 17:392–403 Ruigrok TJ (2011) Ins and outs of cerebellar modules. Cerebellum 10:464–474

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Specification of Cerebellar Neurons

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Satoshi Miyashita and Mikio Hoshino

Abstract

The cerebellum consists of about ten types of neurons that have distinct characteristics in terms of their location, morphology, immunoreactivity and physiology. They can be categorized into two groups; glutamatergic excitatory and GABAergic inhibitory neurons. Excitatory neurons are comprised of glutamatergic deep cerebellar nuclei (DCN) neurons, granule cells and unipolar brush cells (UBCs). Inhibitory neurons include GABAergic DCN neurons, Purkinje cells, Golgi cells, Lugaro cells, basket cells, and stellate cells. GABAergic DCN neurons are interneurons that contribute to local circuitry and projection neurons that extend axons toward the inferior olivary nucleus. As all cerebellar GABAergic interneurons express Pax2 (Maricich and Herrup J Neurobiol 41:281– 294, 1999), they are called Pax2+ interneurons (Pax2+ INs). Recent studies have partly uncovered the molecular machinery for neuronal subtype specification in the cerebellum. Keywords

Neural progenitor · Rhombic lip · Ventricular zone Glutamatergic · GABAergic · bHLH · Transcription factor · Spatiotemporal regulation

S. Miyashita Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata-shi, Niigata, Japan Institute for Research Promotion, Niigata University, Niigata, Japan e-mail: [email protected] M. Hoshino (*) Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan e-mail: [email protected]

15.1 Birthplaces and Birthdates of Cerebellar Neurons The cerebellum consists of about 10 types of neurons that have distinct characteristics in terms of their location, morphology, immunoreactivity, and physiology. They can be categorized into two groups: glutamatergic excitatory and GABAergic inhibitory neurons. Excitatory neurons are comprised of glutamatergic deep cerebellar nuclei (DCN) neurons, granule cells, and unipolar brush cells (UBCs). Inhibitory neurons include GABAergic DCN neurons, Purkinje cells, Golgi cells, Lugaro cells, candelabrum cells, basket cells, and stellate cells. GABAergic DCN neurons are interneurons that contribute to local circuitry and projection neurons that extend axons toward the inferior olivary nucleus. As all cerebellar GABAergic interneurons express Pax2 (Maricich and Herrup 1999), they are called Pax2+ interneurons (Pax2+ INs). All neurons in the cerebellum emerge from the cerebellar neuroepithelium which includes the dorsally located rhombic lip (RL) and the ventrally located ventricular zone (VZ). In the cerebellum, the RL produces all glutamatergic neurons (Ben-Arie et al. 1997; Machold and Fishell 2005; Wang et  al. 2005). The VZ generates all GABAergic neurons (Hoshino et  al. 2005), although postnatally produced neurons, such as stellate and basket cells, do not directly emerge from the VZ but from the prospective white matter (PWM) thought to be derived from the VZ (Leto et al. 2009). Birthdates of GABAergic neurons can be estimated by BrdU or tritium incorporation studies or adenoviral infection studies (Chan-Palay et al. 1977; Batini et al. 1992; De Zeeuw and Berrebi 1995; Sultan et  al. 2003; Leto et  al. 2006; Hashimoto and Mikoshiba 2003). In mice, Purkinje cells are generated at embryonic day (E) 10.5–E13.5, GABAergic DCN neurons at E10.5–E11.5, and Golgi cells at approximately E13.5 ~ postnatal (peak around E13.5–E15.5). Late-­ born GABAergic neurons, including stellate and basket cells, emerge from GABAergic progenitor cells in the PWM at

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_15

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later stages (approximately E13.5 ~ perinatal, peak around E17.5  ~  perinatal). Somatic recombination-based clonal analyses have revealed that Purkinje, Golgi, and basket/stellate cells belong to the same lineage (Mathis et al. 1997; Mathis and Nicolas 2003). This suggests that not only Purkinje and Golgi cells but also GABAergic progenitors in the PWM are derived from the VZ. As to glutamatergic neurons, glutamatergic DCN neurons leave the RL at early stages (E10.5–12.5) and granule cells and UBCs at middle to late stages (granule cells; E13.5~, UBCs; E13.5–E18.5) (Machold and Fishell 2005; Wang et al. 2005; Englund et al. 2006).

15.2 Molecular Machinery to Specify Distinct Types of Cerebellar Neurons Two basic helix–loop–helix proteins are involved in the specification of glutamatergic vs. GABAergic neurons. Atoh1 (also called Math1) is expressed in the RL and involved in producing glutamatergic neurons (Ben-Arie et al. 1997; Machold and Fishell 2005; Wang et al. 2005). Ptf1a is expressed in the VZ and specifies the GABAergic neuron lineage (Hoshino et  al. 2005; Pascual et  al. 2007). When the expression of Atoh1 and Ptf1a is switched, the RL and the VZ produce GABAergic and glutamatergic neurons, respectively (Yamada et al. 2014), suggesting that these two bHLH proteins are sufficient to specify glutamatergic and GABAergic fates. These observations imply that neural progenitors in the RL and the VZ have spatially regulated distinct identities to produce glutamatergic and GABAergic neurons, respectively. At early neurogenesis stages such as E11.5, there are two types of GABAergic neuron progenitors in the VZ that express Ptf1a; Pax2+ IN-producing progenitors (PIPs) and Purkinje cell-producing progenitors (PCPs). PIPs and PCPs express transcription factors, Gsx1 (also called Gsh1) and Olig2, respectively. At the early stages, only a small number of PIPs are located at the ventral most region within the VZ and a large number of PCPs occupy the remaining regions in the VZ. As development proceeds, PCPs gradually transit to become PIPs starting from ventral to dorsal regions. This temporal identity transition of cerebellar GABAergic neuron progenitor causes the loss of PCPs in the VZ by E14.5, correlating with the observations that Purkinje cells are produced only at early neurogenesis stages (E10.5–E13.5). Therefore, it was assumed that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, which may contribute to proper numbers of distinct subtypes of neurons being produced (Seto et al. 2014). In contrast, recent lineage trace analyses have reported that Olig2 lineage cells derived from the VZ seem to mainly give rise to the Purkinje

S. Miyashita and M. Hoshino

cells (Ju et  al. 2016; Lowenstein et  al. 2021). Lowenstein et  al. have also found that Olig3 is expressed in newborn Purkinje cells or “fate-committed Purkinje cell precursors” and regulate the specification of Purkinje cells by suppressing the Pax2 expression together with Olig2. It is still unknown whether GABAergic projection neurons in the DCN are derived from PCPs or PIPs is unknown. Considering the birthdates of distinct Pax2+ INs, PIPs may first produce GABAergic interneurons in the DCN (E10.5~), and then generate Golgi cells (E13.5~). PIPs at late neurogenesis stages may give rise to progenitor cells in the PWM that eventually generate stellate, basket cells, and candelabrum cells (Sudarov et al. 2011). Previous transplantation studies suggested that distinct Pax2+ Ins are derived from the same progenitor pool and that extrinsic instructive cues in the microenvironment may affect the terminal neuronal type commitment. One candidate for the cue may be sonic hedgehog (SHH) (Fleming et  al. 2013; De Luca et  al. 2015). In addition, Lhx1 and Lhx5 as well as their cofactor Lbd1 are known to postmitotically participate in Purkinje cell differentiation (Zhao et al. 2007). Recently, it was reported that transcription factors, Tfap2A and Tfap2B, are involved in the specification of Pax2+ Ins (Zainolabidin et al. 2017). In contrast to GABAergic neurons, the machinery to specify each cerebellar glutamatergic neuron subtype remains elusive. Some transcription factors, such as Tbr1, Irx3, Meis2, Lhx2, Lhx9, and Olig2 are expressed in subsets of postmitotic progenitors of glutamatergic DCN neurons, but their function is still unclear (Morales and Hatten 2006; Seto et al. 2014). As to granule cells, it is known that intrinsic and extrinsic molecules such as Zic1, Meis1, and SHH play important roles in cell migration, differentiation, and survival (Aruga et al. 1998; Dahmane and Ruiz-i-Altaba 1999; Lewis et  al. 2004; Wallace 1999; Wechsler-Reya and Scott 1999; Owa et  al. 2018), but the cell-type specification machinery remains to be identified. UBCs are another type of excitatory interneurons in the cerebellar cortex, which strongly express Tbr2 (Englund et al. 2006). Yeung et al. reported that the RL is subdivided into two compartments by the Wls expression and that UBCs may be originated from the boundary region between the compartments (Yeung et al. 2014). The molecular machinery to specify cerebellar neuronal cell types is summarized in Fig.  15.1. Neuronal cell types seem to be defined according to the spatiotemporal identities of neural progenitors in the neuroepithelium. The bHLH transcription factors, Atoh1 and Ptf1a, confer the spatial identities of the RL and the VZ on neural progenitors, letting them produce glutamatergic and GABAergic neurons, respectively. Glutamatergic and GABAergic neuron progenitors in the RL and the VZ change their temporal identities to produce distinct types of neurons during development. Recent transcriptome analyses have powerfully advanced our understandings of the machinery for cerebellar neuron

15  Specification of Cerebellar Neurons Fig. 15.1  Specification of cerebellar neurons by spatiotemporal regulation of neural progenitor identities

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Temporal Identities

Spatial Identities of Progenitors

of GABAergic Progenitors

Purkinje cell progenitors

Glutamatergic Athoh1 GABAergic

Purkinje cells Olig2 brake

Temporal identity transition

RL Ptf1a

VZ Gsx1 accelerator

Pax2+ IN progenitors Pax2+ interneurons interneurons

specification and differentiation. They clearly visualize the heterogenic populations in cerebellar neuron progenitors within the EGL, RL, or the VZ, although characteristics of each subset of progenitors are still elusive (Adachi et al. 2021; Aldinger et al. 2021; Carter et al. 2018; Kozareva et al. 2021; Peng et al. 2019; Vladoiu et al. 2019; Wizeman et al. 2019). Comprehensive transcriptome analysis and in vivo validations will be required to fully understand the mechanisms underlying cerebellar neuronal type specification.

References Adachi T, Miyashita S, Yamashita M, Shimoda M, Okonechnikov K, Chavez L, Kool M, Pfister SM, Inoue T, Kawauchi D, Hoshino M (2021) Notch signaling between cerebellar granule cell progenitors. eNeuro 8(3):ENEURO.0468-20.2021 Aldinger KA, Thomson Z, Phelps IG, Haldipur P, Deng M, Timms AE, Hirano M, Santpere G, Roco C, Rosenberg AB, Lorente-Galdos B, Gulden FO, O'Day D, Overman LM, Lisgo SN, Alexandre P, Sestan N, Doherty D, Dobyns WB, Seelig G, Glass IA, Millen KJ (2021) Spatial and cell type transcriptional landscape of human cerebellar development. Nat Neurosci 24(8):1163–1175 Aruga J, Minowa O, Yaginuma H, Kuno J, Nagai T, Noda T, Mikoshiba K (1998) Mouse Zic1 is involved in cerebellar development. J Neurosci 18:284–293 Batini C, Compoint C, Buisseret-Delmas C, Daniel H, Guegan M (1992) Cerebellar nuclei and the nucleocortical projections in the rat: retrograde tracing coupled to GABA and glutamate immunohistochemistry. J Comp Neurol 315:74–84 Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, Guo Q, Matzuk MM, Zoghbi HY (1997) Math1 is essential for genesis of cerebellar granule neurons. Nature 390:169–172 Carter RA, Bihannic L, Rosencrance C, Hadley JL, Tong Y, Phoenix TN, Natarajan S, Easton J, Northcott PA, Gawad C (2018) A single-­ cell transcriptional atlas of the developing murine cerebellum. Curr Biol 28(18):2910–2920 Chan-Palay V, Palay SL, Brown JT, Van Itallie C (1977) Sagittal organization of olivocerebellar and reticulocerebellar projections: autoradiographic studies with 35S-methionine. Exp Brain Res 30:561–576

Dahmane N, Ruiz-i-Altaba A (1999) Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126:3089–3100 De Luca A, Parmigiani E, Tosatto G, Martire S, Hoshino M, Buffo A, Leto K, Rossi F (2015) Exogenous sonic hedgehog modulates the pool of GABAergic interneurons during cerebellar development. Cerebellum 14:72–85 De Zeeuw CI, Berrebi AS (1995) Postsynaptic targets of Purkinje cell terminals in the cerebellar and vestibular nuclei of the rat. Eur J Neurosci 7:2322–2333 Englund C, Kowalczyk T, Daza RA, Dagan A, Lau C, Rose MF, Hevner RF (2006) Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. J Neurosci 26:9184–9195 Fleming JT, He W, Hao C, Ketova T, Pan FC, Wright CV, Litingtung Y, Chiang C (2013) The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors. Dev Cell 27:278–292 Hashimoto M, Mikoshiba K (2003) Mediolateral compartmentalization of the cerebellum is determined on the “birth date” of Purkinje cells. J Neurosci 23:11342–11351 Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura YV, Fukuda A, Fuse T, Matsuo N, Sone M, Watanabe M, Bito H, Terashima T, Wright CV, Kawaguchi Y, Nakao K, Nabeshima Y (2005) Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47:201–213 Ju J, Liu Q, Zhang Y, Liu Y, Jiang M, Zhang L, He X, Peng C, Zheng T, Lu QR, Li H (2016) Olig2 regulates Purkinje cell generation in the early developing mouse cerebellum. Sci Rep 6:30711 Kozareva V, Martin C, Osorno T, Rudolph S, Guo C, Vanderburg C, Nadaf N, Regev A, Regehr WG, Macosko E (2021) A transcriptomic atlas of mouse cerebellar cortex comprehensively defines cell types. Nature. 598(7879):214–219. https://doi.org/10.1038/ s41586-021-03220-z. Leto K, Carletti B, Williams IM, Magrassi L, Rossi F (2006) Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci 26:11682–11694 Leto K, Bartolini A, Yanagawa Y, Obata K, Magrassi L, Schilling K, Rossi F (2009) Laminar fate and phenotype specification of cerebellar GABAergic interneurons. J Neurosci 29:7079–7091 Lewis PM, Gritli-Linde A, Smeyne R, Kottmann A, McMahon AP (2004) Sonic hedgehog signaling is required for expansion of gran-

110 ule neuron precursors and patterning of the mouse cerebellum. Dev Biol 270:393–410 Lowenstein ED, Rusanova A, Stelzer J, Hernaiz-Llorens M, Schroer AE, Epifanova E, Bladt F, Isik EG, Buchert S, Jia S, Tarabykin V, Hernandez-Miranda LR (2021) Olig3 regulates early cerebellar development. Elife 10:e64684 Machold R, Fishell G (2005) Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48:17–24 Maricich SM, Herrup K (1999) Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol 41:281–294 Mathis L, Nicolas JF (2003) Progressive restriction of cell fates in relation to neuroepithelial cell mingling in the mouse cerebellum. Dev Biol 258:20–31 Mathis L, Bonnerot C, Puelles L, Nicolas JF (1997) Retrospective clonal analysis of the cerebellum using genetic laacZ/lacZ mouse mosaics. Development 124:4089–4104 Morales D, Hatten ME (2006) Molecular markers of neuronal progenitors in the embryonic cerebellar anlage. J Neurosci 26:12226–12236 Owa T, Taya S, Miyashita S, Yamashita M, Adachi T, Yamada K, Yokoyama M, Aida S, Nishioka T, Inoue YU, Goitsuka R, Nakamura T, Inoue T, Kaibuchi K, Hoshino M (2018) Meis1 coordinates cerebellar granule cell development by regulating Pax6 transcription, BMP signaling and Atoh1 degradation. J Neurosci 38(5):1277–1294 Pascual M, Abasolo I, Mingorance-Le Meur A, Martinez A, Del Rio JA, Wright CV, Real FX, Soriano E (2007) Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression. Proc Natl Acad Sci U S A 104:5193–5198 Peng J, Sheng AL, Xiao Q, Shen L, Ju XC, Zhang M, He ST, Wu C, Luo ZG (2019) Single-cell transcriptomes reveal molecular specializations of neuronal cell types in the developing cerebellum. J Mol Cell Biol 11(8):636–648 Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, Hamaguchi A, Inoue YU, Inoue T, Miyashita S, Fujiyama T, Yamada M, Chapman H, Campbell KJ, Magnuson MA, Wright CV, Kawaguchi Y, Ikenaka K, Takebayashi H, Ishiwata S, Ono Y, Hoshino M (2014) Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. Nat Commun 5:3337

S. Miyashita and M. Hoshino Sudarov A, Turnbull RK, Kim EJ, Lebel-Potter M, Guillemot F, Joyner AL (2011) Ascl1 genetics reveals insights into cerebellum local circuit assembly. J Neurosci 31(30):11055–11069 Sultan F, Czubayko U, Thier P (2003) Morphological classification of the rat lateral cerebellar nuclear neurons by principal component analysis. J Comp Neurol 455:139–155 Vladoiu MC, El-Hamamy I, Donovan LK, Farooq H, Holgado BL, Sundaravadanam Y, Ramaswamy V, Hendrikse LD, Kumar S, Mack SC, Lee J, Fong V, Juraschka K, Przelicki D, Michealraj A, Skowron P, Luu B, Suzuki H, Morrissy AS, Cavalli F, Taylor MD (2019) Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature 572(7767):67–73 Wallace VA (1999) Purkinje-cell-derived sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9:445–448 Wang VY, Rose MF, Zoghbi HY (2005) Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48:31–43 Wechsler-Reya RJ, Scott MP (1999) Control of neuronal precursor proliferation in the cerebellum by sonic hedgehog. Neuron 22:103–114 Wizeman JW, Guo Q, Wilion EM, Li JY (2019) Specification of diverse cell types during early neurogenesis of the mouse cerebellum. Elife 8:e42388 Yamada M, Seto Y, Taya S, Owa T, Inoue YU, Inoue T, Kawaguchi Y, Nabeshima Y, Hoshino M (2014) Specification of spatial identities of cerebellar neuronal progenitors by Ptf1a and Atoh1 for proper production of GABAergic and glutamatergic neurons. J Neurosci 34:4786–4800 Yeung J, Ha TJ, Swanson DJ, Choi K, Tong Y, Goldowitz D (2014) Wls provides a new compartmental view of the rhombic lip in mouse cerebellar development. J Neurosci 34(37):12527–12537 Zainolabidin N, Kamath SP, Thanawalla AR, Chen AI (2017) Distinct activities of Tfap2A and Tfap2B in the specification of GABAergic interneurons in the developing cerebellum. Front Mol Neurosci 10:281 Zhao Y, Kwan KM, Mailloux CM, Lee WK, Grinberg A, Wurst W, Behringer RR, Westphal H (2007) LIM-homeodomain proteins Lhx1 and Lhx5, and their cofactor Ldb1, control Purkinje cell differentiation in the developing cerebellum. Proc Natl Acad Sci U S A 104:13182–13186

Cerebellar Nucleus Development

16

Hong-Ting Kwok and Richard J. T. Wingate

Abstract

The cerebellar nuclei play a role in integrating cerebellar cortical output with inputs from other brain regions. Made up of a complex collection of both excitatory and inhibitory projection neurons as well as subtypes of interneurons, the cerebellar nuclei are developed from two germinal regions, the rhombic lip and the ventricular zone. In this chapter, we describe the developmental timeline of the cell types in relation to the development of the rest of the cerebellum, and how although the gross nuclei structures vary along the evolutionary tree, the cell types within are mostly conserved across evolution. Keywords

Cerebellar nuclei · Development · Rhombic lip Ventricular zone · Rhombomere 1

The cerebellar nuclei (CN) are the final output structures of the cerebellum, integrating inputs from the forebrain, brainstem, and spinal cord with the cerebellar cortical output from Purkinje cells. In contrast to the remarkably evolutionarily conserved connectivity between granule cells and Purkinje cells in the cerebellar cortex, the size, foliation, and number of CN vary between animals (1 in amphibians, 2 in reptiles and birds, and 3–5 in mammals) (Nieuwenhuys et al. 1998). In humans, there are four nuclei: the medial (fastigial), anterior and posterior interposed are classed as separate nuclei.

Historically, much of what is known concerning CN cell morphologies and neuronal circuitry comes from Golgi and Nissl preparations of the mammalian lateral nucleus observed by light and electron microscopy (Chan-Palay 1977). Neurotransmitter content and neuronal connectivity identified glutamatergic cells and three inhibitory cell classes. Recent single-cell RNA analysis combined with anatomical tracing identified that glutamatergic output cells are of two different types but confirmed that there are two glycinergic populations and a GABAergic inhibitory output neuron projecting to the inferior olive (Kebschull et  al. 2020; Batini et  al. 1992; Chen and Hillman 1993; Fredette et  al. 1992) (Fig.16.1). CN receive inhibitory projections from the Purkinje cells from the overlying cerebellar cortex in a broadly topographic manner. The lateral nuclei are innervated by the lateral cerebellum and medial nuclei by the medial vermis (Voogd and Glickstein 1998). CN also integrate collateral inputs from axons projecting from the pontine nucleus and inferior olive to the cerebellar cortex (Fig.16.1). The output of each CN is then directed to different central neural systems as determined by the pattern of their efferent connections (Larsell and Jansen 1972). Of these, the connection from the lateral nucleus to the ventrolateral thalamus is a uniquely mammalian adaptation and completes a closed-loop cortico-pontine-­ cerebellar relay circuit (Kelly and Strick 2003) that is heavily implicated in modulating higher cognitive function in humans (Schmahmann 2010).

H.-T. Kwok · R. J. T. Wingate (*) MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK e-mail: [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_16

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Fig. 16.1  Connections and circuitry of the human lateral nucleus. Left: The lateral CN receives input from Purkinje cells (PC) and innervates the thalamus, which in turn modulates cortical activity. The nucleus also receives climbing fibers (CF) collateral input from the inferior olive (IO), and mossy fibers (MF) collaterals, originating principally from the pons. Climbing and mossy fibers terminate on PC and granule cells (GC) in the cerebellar cortex, respectively. The CN also

contains GABAergic projection neurons that send inhibitory signals to the IO. Right: Within the nucleus, each PC axon fans out into a cone that innervates a number of excitatory and GABAergic projection neurons. Small GABAergic and glycinergic interneurons provide local inhibition. Inputs from MF and CF collaterals run perpendicular to the afferent Purkinje cell axons [adapted from (Chan-Palay 1977)]

16.1 Concepts of CN Development Have Changed Markedly in Recent Years

(Fig.16.2). A small number of large glycinergic projection neurons, which are only found in the medial nucleus (Bagnall et al. 2009), are the exception, being potentially derived from the RL despite being inhibitory (Kebschull et  al. 2020). The following description exemplifies CN development using the embryonic mouse model over its 21 days of gestation.

Cell types of the cerebellum arise from two germinal regions within the most anterior neuromere of embryonic hindbrain, rhombomere 1: the ventricular zone (VZ) and the rhombic lip (RL). The VZ is a neuroepithelial zone that lines the dorsolateral part of the fourth ventricle, while the RL comprises the interface of this neuroepithelium with the roof plate of the fourth ventricle (Wingate 2001). Until the last decade, it was thought that all CN neurons originate from the VZ then migrate radially into the white matter (Altman and Bayer 1985a, b; Goldowitz and Hamre 1998). It is now known that CN neurons of different neurotransmitter types are born from both the RL and VZ. Research by classical birth dating and genetic fate mapping has shown that all cerebellar excitatory neurons are derived from RL progenitors, specified by the expression of Atoh1, while inhibitory neurons arise from the VZ, where progenitors are specified by the early expression of Ptf1a (Hoshino et al. 2005). The bHLH proteins, Ptf1a and Atoh1, have both been shown to be necessary (Machold and Fishell 2005; Wang et al. 2005) and sufficient (Yamada et al. 2014) for the production of all GABAergic and glutamatergic neurons in the cerebellum, respectively

16.1.1 Glutamatergic Neurons are Born at the Rhombic Lip Atoh1-expressing progenitor cells from the RL produce glutamatergic CN projection neurons between embryonic day (e)10–e12.5 prior to making granule cell precursors that populate the external granule layer (EGL) (Machold and Fishell 2005; Wang et al. 2005). From e12.5 to e14.5, the CN cells migrate from the RL across the dorsal surface of rhombomere 1 via the subpial rhombic lip migratory stream (RLS), then congregate at the nuclear transitory zone (NTZ) at the boundary of the cerebellar anlage (Fig.16.2). The NTZ is thought to be a transient differentiation zone (Altman and Bayer 1985a), where nuclear neurons are defined by specific, temporally restricted, developmental transcription factor profiles (Fink et al. 2006).

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Fig. 16.2  Cerebellar nucleus neurons have a dual origin. Different neuronal subtypes in the cerebellum develop from separate germinal regions. Precursors continue to migrate, proliferate, differentiate, and mature postnatally. The CN glutamatergic cells form first at the RL and migrate via the nuclear transitory zone (NTZ). CN GABAergic projection neurons are also born early and migrate to the ventral part of the

NTZ. The RL then gives rise to granule cell precursors, which form the external granule layer (EGL) that later migrates in to form the internal granule layer (IGL). All cortical GABAergic cells originate from the VZ, migrate into the intermediate zone (IZ), and finally to the molecular (ML) and granule (GL) cell layers

The CN are born in a lateral to medial sequence subsequent to the first-born RL derivatives, which become extra-­ cerebellar neurons (Machold and Fishell 2005). Like these extra-cerebellar neurons, nuclear cells in the lateral nucleus of mammals express the LIM-homeodomain gene Lhx9 (Wang et  al. 2005; Green and Wingate 2014). Both these early populations project to the thalamus suggesting a role for Lhx9  in specifying axonal projection (Green and Wingate 2014). Subsequently, RL-derived projection neurons of the interposed and medial nuclei are defined by their expression of Tbr2 and Tbr1, respectively (Fink et al. 2006; Engelkamp et al. 1999; Landsberg et al. 2005) and extend axons to various hindbrain, midbrain, and ventral diencephalic targets. From e14.5 to e16.5, CN cells in the NTZ descend into the white matter. It is unclear whether this is due to active migration toward the VZ (Altman and Bayer 1985a) or displacement by gross morphogenic changes to cerebellar shape as granule cell precursors in the EGL proliferate to produce the most abundant neuronal population in the brain.

late adjacent and inferior to the NTZ before descending to their destination (Prekop et al. 2018). From e13.5, Olig2 is downregulated and subsequent populations of GABAergic neurons express Gsx1 (Seto et  al. 2014) and Pax2 (Maricich and Herrup 1999; Weisheit et al. 2006). Pax2-positive precursors proliferate within the white matter through to P15 and migrate radially to sequentially form various GABAergic interneuron populations: first the CN interneurons, then Golgi cells of the granule cell layer, and finally basket and stellate cells of the molecular layer (Leto et al. 2006). A growing body of evidence shows that specification is controlled post-mitotically by factors in the local microenvironment (Leto et  al. 2009; Grimaldi et  al. 2009; Zordan et  al. 2008), although their identity, and the contribution, if any, of intrinsic cues are still largely undefined.

16.1.2 GABAergic Neurons are Derived from the Ventricular Zone

Our current understanding outlines basic principles of CN development in terms of progenitor zones, temporal patterning, and the function of a few key transcription factors. Recent studies have illustrated how the discovery of new molecular and genetic markers has allowed fate mapping of distinct cell types. Detailed studies of cell organization within the lateral nucleus have revealed intricate cell arrangements and alignment of projections along a polarized axis within the nucleus (Chan-Palay 1977). In addition, single cell and spatial omics analysis have made possible deeper interrogation of developing cell types, as well as postulate how conserved cell types may form an archetypal nucleus

Fate-mapping studies indicate that GABAergic CN cells are derived from Ptf1a-positive precursors in the VZ in two phases (Hoshino et al. 2005). First, GABAergic neurons that project long axons from the CN to the inferior olive (Mugnaini and Oertel 1985; Ruigrok 1997) are born within a distinct temporal window alongside Purkinje cells (e10.5– e12.5), both characterized by the expression of Olig2. In synchrony with the glutamatergic projection neurons being derived from the RL, these nucleo-olivary neurons accumu-

16.2 Future Studies will Need to Address Fine-Grain Patterning of Different Nuclei

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that has duplicated with variation over evolution. This has shown that while the ventricular zone-derived inhibitory cells are genetically uniform across nuclei, it is the rhombic lip derived glutamatergic populations that confer genetic diversity on the cerebellar nuclei (Kebschull et al. 2020). How neuroblasts migrate, differentiate, and successfully form functional circuits are important open questions. The identity of cues that shape CN circuits will be important targets for future research. This will also help in assessing the impact of CN dysgenesis on a broad spectrum of cerebellar disorders that can produce both classical motor symptoms and an emerging range of cognitive effects in syndromes such as Autistic Spectrum Disorder and Joubert Syndrome (Schmahmann 2010; Wang et al. 2014; Holroyd et al. 1991).

References Altman J, Bayer SA (1985a) Embryonic development of the rat cerebellum. II. Translocation and regional distribution of the deep neurons. J Comp Neurol 231:27–41 Altman J, Bayer SA (1985b) Embryonic development of the rat cerebellum. III. Regional differences in the time of origin, migration, and settling of Purkinje cells. J Comp Neurol 231:42–65 Bagnall MW, Zingg B, Sakatos A, Moghadam SH, Zeilhofer HU, Du Lac S (2009) Glycinergic projection neurons of the cerebellum. J Neurosci 29:10104–10110 Batini C, Compoint C, Buisseret-Delmas C, Daniel H, Guegan M (1992) Cerebellar nuclei and the nucleocortical projections in the rat: retrograde tracing coupled to GABA and glutamate immunohistochemistry. J Comp Neurol 315:74–84 Chan-Palay V (1977) Cerebellar dentate nucleus: organization, cytology and transmitters. Springer, Berlin Chen S, Hillman DE (1993) Colocalization of neurotransmitters in the deep cerebellar nuclei. J Neurocytol 22:81–91 Engelkamp D, Rashbass P, Seawright A, van Heyningen V (1999) Role of Pax6  in development of the cerebellar system. Development 126:3585–3596 Fink AJ, Englund C, Daza RA, Pham D, Lau C, Nivison M, Kowalczyk T, Hevner RF (2006) Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. J Neurosci 26:3066–3076 Fredette BJ, Adams JC, Mugnaini E (1992) GABAergic neurons in the mammalian inferior olive and ventral medulla detected by glutamate decarboxylase immunocytochemistry. J Comp Neurol 321:501–514 Goldowitz D, Hamre K (1998) The cells and molecules that make a cerebellum. Trends Neurosci 21:375–382 Green MJ, Wingate RJ (2014) Developmental origins of diversity in cerebellar output nuclei. Neural Dev 9:1 Grimaldi P, Parras C, Guillemot F, Rossi F, Wassef M (2009) Origins and control of the differentiation of inhibitory interneurons and glia in the cerebellum. Dev Biol 328:422–433 Holroyd S, Reiss AL, Bryan RN (1991) Autistic features in Joubert syndrome: a genetic disorder with agenesis of the cerebellar vermis. Biol Psychiatry 29:287–294 Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura YV, Fukuda A, Fuse T, Matsuo N, Sone M et  al (2005) Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47:201–213 Kebschull JM, Richman EB, Ringach N, Friedmann D, Albarran E, Kolluru SS, Jones RC, Allen WE, Wang Y, Cho SW (2020)

H.-T. Kwok and R. J. T. Wingate Cerebellar nuclei evolved by repeatedly duplicating a conserved cell-type set. Science 370(6523):eabd5059 Kelly RM, Strick PL (2003) Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci 23:8432–8444 Landsberg RL, Awatramani RB, Hunter NL, Farago AF, Dipietrantonio HJ, Rodriguez CI, Dymecki SM (2005) Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by pax6. Neuron 48:933–947 Larsell O, Jansen J (1972) The comparative anatomy and histology of the cerebellum: the human cerebellum, cerebellar connections, and cerebellar cortex. University of Minnesota, Minnesota Leto K, Carletti B, Williams IM, Magrassi L, Rossi F (2006) Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci 26:11682–11694 Leto K, Bartolini A, Yanagawa Y, Obata K, Magrassi L, Schilling K, Rossi F (2009) Laminar fate and phenotype specification of cerebellar GABAergic interneurons. J Neurosci 29:7079–7091 Machold R, Fishell G (2005) Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors. Neuron 48:17–24 Maricich SM, Herrup K (1999) Pax-2 expression defines a subset of GABAergic interneurons and their precursors in the developing murine cerebellum. J Neurobiol 41:281–294 Mugnaini E, Oertel W (1985) An atlas of the distribution of GABAergic neurons and terminals in the rat CNS as revealed by GAD immunohistochemistry. In: Handbook of chemical neuroanatomy, vol 4, pp 436–622 Nieuwenhuys R, ten Donkelaar HJ, Nicholson C (eds) (1998) The central nervous system of vertebrates. Springer, Berlin Prekop HT, Kroiss A, Rook V, Zagoraiou L, Jessell TM, Fernandes C, Delogu A, Wingate RJT (2018) Sox14 is required for a specific subset of cerebello-olivary projections. J Neurosci 38:9539–9550 Ruigrok TJ (1997) Cerebellar nuclei: the olivary connection. Prog Brain Res 114:167–192 Schmahmann JD (2010) The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Neuropsychol Rev 20:236–260 Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, Hamaguchi A, Inoue YU, Inoue T, Miyashita S et al (2014) Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum. Nat Commun 5:3337 Voogd J, Glickstein M (1998) The anatomy of the cerebellum. Trends Neurosci 21:370–375 Wang VY, Rose MF, Zoghbi HY (2005) Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum. Neuron 48:31–43 Wang SS, Kloth AD, Badura A (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518–532 Weisheit G, Gliem M, Endl E, Pfeffer PL, Busslinger M, Schilling K (2006) Postnatal development of the murine cerebellar cortex: formation and early dispersal of basket, stellate and Golgi neurons. Eur J Neurosci 24:466–478 Wingate RJT (2001) The rhombic lip and early cerebellar development. Curr Opin Neurobiol 11:82–88 Yamada M, Seto Y, Taya S, Owa T, Inoue YU, Inoue T, Kawaguchi Y, Nabeshima Y, Hoshino M (2014) Specification of spatial identities of cerebellar neuron progenitors by ptf1a and atoh1 for proper production of GABAergic and glutamatergic neurons. J Neurosci 34:4786–4800 Zordan P, Croci L, Hawkes R, Consalez GG (2008) Comparative analysis of proneural gene expression in the embryonic cerebellum. Dev Dyn 237:1726–1735

Development of Glutamatergic and GABAergic Synapses

17

Marco Sassoè-Pognetto

Abstract

Due to its stereotyped cellular architecture, the cerebellum has always constituted a useful model system for studying the basic organization and development of synaptic circuits. This chapter describes the current state of knowledge relating to the development of cerebellar glutamate and GABA synapses and highlights observations on the molecular and activity-dependent mechanisms that control the spatial specificity of synaptogenesis. Keywords

Glutamate synapse · GABA synapse · Synaptogenesis Synaptic specificity

The cerebellum has a prolonged course of development that largely extends into postnatal life (Wang and Zoghbi 2001). This feature, together with the availability of several natural mutants and of cell-specific genetic tools (Sotelo 2004; Sajan et al. 2010), makes the cerebellum one of the most accessible brain regions for studying synaptogenesis in situ. The cerebellar cortex has a relatively simple organization, consisting of only a few cell types that integrate two major inputs (Fig.  17.1). Purkinje cells (PCs), which are GABAergic, provide the only output of the cerebellar cortex,

sending their axons to the deep cerebellar nuclei (DCN). PCs receive direct connections from climbing fibers (CFs), which originate from inferior olive neurons, and indirect connections from mossy fibers (MFs), which connect to granule cell dendrites within glomeruli in the granule cell layer (GCL). The axons of granule cells ascend to the molecular layer (ML), where they bifurcate and give rise to parallel fibers (PFs), which make synapses with the dendrites of PCs as well as other cerebellar neurons. Local inhibitory interneurons comprise stellate and basket cells, which modulate PC output in the ML, and Golgi cells, which provide feedback and feedforward inhibition to granule cells in the GCL. In the cerebellar cortex, synaptogenesis is entirely postnatal, although it occurs at rather different rates in different lobules (Altman 1972a, b, c). In both mice and rats, synapses start to form in the first postnatal week, and reach adult densities at the end of the third week (Fig. 17.2). The entire period of synaptogenesis is characterized by a progressive growth of the granular and molecular layers, and a proliferation of synapses from the bottom upward. Only a few studies have specifically investigated the development of synaptic connectivity in the deep cerebellar nuclei (Eisenman et al. 1991; Garin and Escher 2001). These investigations have suggested that synaptogenesis may start in the nuclei well before the emergence of the first synapses in the cerebellar cortex, but the precise pattern remains to be determined.

M. Sassoè-Pognetto (*) Department of Neuroscience, C.so Massimo d’Azeglio, Turin, Italy e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_17

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Fig. 17.1  Neuronal elements and basic circuitry of the cerebellar cortex. Two major afferent systems reach the cerebellar cortex: climbing fibers (CF) provide direct excitatory contacts to Purkinje cells (PC) and mossy fibers (MF) terminate in glomerular structures in the granule cell layer (GCL), in which they establish excitatory synapses (+) with the dendrites of granule cells (GC). A glomerulus is a complex of synapses, consisting of mossy fiber terminals (rosettes), surrounded by granule cell dendrites and Golgi cell axon terminals (gray circle). The ascending axons of granule cells reach the molecular layer (ML) and form parallel fibers (PF), which make glutamatergic synapses with Purkinje,

M. Sassoè-Pognetto

stellate (SC), basket (BC), and Golgi (GO) cells. With the exception of granule cells, all cerebellar cortical neurons, including Purkinje cells, make inhibitory synaptic connections (−). A peculiar assembly of GABAergic axons is the pinceau, which is formed as basket cell axons surround the axon initial segment of Purkinje cells. The recently described Golgi-to-Golgi inhibitory synapses are not indicated in the diagram. Unipolar brush cells, globular cells, and candelabrum cells are also not represented. DCN deep cerebellar nuclei, LU Lugaro cell, PCL Purkinje cell layer

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STELLATE CELLS development of the pinceau

BASKET CELLS PARALLEL FIBERS GOLGI CELLS synaptic waning

primary growth stage

MOSSY FIBERS somato-dendritic translocation

pericellular nest

CLIMBING FIBERS

E19

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Fig. 17.2  Graphic representation of the development of synapses made by different types of cerebellar neurons and by cerebellar cortical afferents. The diagram is based on the studies of the mouse and rat cerebellum. There is still uncertainty about the precise dates of the

17.1 Development of Glutamate Synapses

P15

P21

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onset and the conclusion of the synaptogenic period, as symbolized by the grading colors. Significant phases of the development of specific types of synapses are indicated

and repulsive factors that prevent the invasion of MFs into the external granular layer and promote the removal of transient synapses with PCs. Synaptogenic factors that stimulate 17.1.1 Mossy Fiber Synapses the formation of synapses between MFs and granule cells The main types of glutamate synapses in the cerebellum are comprise Wnt7a, fibroblast growth factor 22 and cadherin-7 those established by MFs, PFs, and CFs. MFs arise from a (Hall et al. 2000; Umemori et al. 2004). Notably, in agranuvariety of different sources in the brainstem and spinal cord, lar cerebella (e.g., in weaver and reeler mice), aberrant and terminate forming characteristic “rosettes” within glom- MF-PC synapses are maintained, suggesting that the absence eruli in the GCL, where they make glutamatergic synaptic of the correct target neurons can result in a stabilization of contacts with the dendrites of granule cells (Palay and Chan-­ mismatched synapses (Sotelo 1990). Palay 1974). In rodents, MFs invade the gray matter at P3– P5 and start establishing the first synapses onto granule cells at the end of the first postnatal week. However, it is only 17.1.2 Parallel Fiber Synapses during the second postnatal week that synapse number increases considerably, reaching a peak at P15 (Altman PFs are oriented perpendicularly to the plane of PC dendrites 1972c; Hámori and Somogyi 1983). During development, and establish excitatory synapses with spines located on the MF synapses undergo an extensive structural remodeling, distal dendrites (the so-called spiny branchlets), causing the that is accompanied by changes of their electrophysiological PCs to discharge single action potentials, named “simple properties (Larramendi 1969; Cathala et al. 2005). This mat- spikes.” PF synapses are distinguished by the presence of the uration comprises the elimination of surplus synapses and postsynaptic δ2 glutamate receptor (GluD2), which is not the segregation of long synaptic appositions into smaller present at synapses made by CFs (see below). Rather than active zones (synaptic “waning”). Several investigations acting as a glutamate receptor, GluD2 has a fundamental role have demonstrated that the specificity of MF connectivity in mediating synaptic adhesion (Yuzaki 2003). PFs establish the first synapses as soon as PCs start growdepends on the interplay of positive signals that mediate synapse formation with the appropriate targets (granule cells), ing their dendrites in the developing ML at the end of the first

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postnatal week (Altman 1972a, b). The progressive proliferation of synapses from the bottom upward results initially in a gradient in the density of synaptic contacts between the deep regions and the cerebellar surface. This gradient is no longer seen after P21, when synapse density becomes relatively uniform throughout the ML (Larramendi 1969). Interestingly, this developmental sequence is accompanied by a progressive switch of the vesicular glutamate transporters, VGlut1 and VGlut2, in PF terminals (Miyazaki et  al. 2003). Thus, early PF terminals express VGlut2, which is gradually replaced by VGlut1 following an inside-out gradient. This replacement is accomplished by P30, after which PFs and CFs express differentially VGlut1 and VGlut2 (Ichikawa et al. 2002). The formation and maintenance of PF synapses depends on trans-synaptic interactions between postsynaptic GluD2 and cerebellin 1 (Cbln1), a C1q family member secreted from granule cell axons (Yuzaki 2010). Cbln1 binds GluD2 and also interacts with presynaptic neurexins, establishing a trimeric trans-synaptic complex that links pre- and postsynaptic specializations (Matsuda et al. 2010; Uemura et al. 2010).

CFs provide the earliest synaptic inputs to PCs in the developing cerebellar cortex (Fig. 17.2) and their synapses undergo a remarkable structural remodeling throughout development. During the first postnatal week, these afferents establish a dense plexus around the cell body of PCs, making asymmetric synapses with somatic spine-like protrusions (Cajal 1890; Sotelo 2008; Ichikawa et al. 2011). Subsequently, activity-dependent competition among CFs results in regression of multiple innervation and dendritic translocation of a single “winner” CF from the soma to the proximal dendrites (Hashimoto et al. 2009). The translocation of CFs from the soma to the proximal dendrites starts at P9 and is almost completed by P15. The elimination of CFs critically depends on neuronal activity and involves competition among afferent CFs, as well as heterosynaptic competition with PFs. Several molecules and signaling pathways that mediate CF elimination have been identified (for a detailed review of the mechanisms involved in CF synapse refinement, see Chap. 14 by Kano and Watanabe in this Volume).

17.1.3 Climbing Fiber Synapses

17.2.1 Stellate/Basket Cell Synapses

CFs make synapses on spines located on the proximal dendritic domain of PCs, and normally do not invade the distal dendrites innervated by PFs. In the mature cerebellum, inferior olivary neurons contact on average seven PCs, while an individual PC is innervated by a single CF; this one-to-one relationship is the result of the postnatal elimination of supernumerary CFs, which occurs during the second and third postnatal weeks (see below). Synapses made by CFs are so strong that they generate massive bursts of action potentials known as “complex spikes.” CFs are crucial for cerebellar function as they convey signals regarding errors in motor control and they induce long-term depression (LTD) in co-activated PF synapses. As a fact, deprivation of CF input causes severe movement disorders that are similar to the defects observed after cerebellum damage (Apps and Garwicz 2005). CF synapses differ from those made by PFs in that they do not contain the GluD2 receptor (Landsend et  al. 1997). Interestingly, another member of the C1q family, the C1q-­ like family protein C1ql1, has been implicated in CF synaptogenesis. C1ql1 is expressed in inferior olive neurons, is secreted by CFs, and interacts in PCs with the cell-adhesion G-protein coupled receptor 3BAI3 (brain angiogenesis inhibitor; Sigoillot et al. 2015). Experimental analyses have shown that the C1ql1/3BAI3 interaction contributes to regulate the formation and maintenance of CF synapses and the extent of CF synaptic territory in PCs (Kakegawa et al. 2015; Sigoillot et al. 2015).

Synaptic inhibition in the supragranular layers is mediated mainly by basket and stellate cells. Basket cells make synapses with the cell body and the proximal dendrites of PCs, and also form a unique plexus around the axon initial segment (AIS), called a pinceau (Cajal 1911). In contrast, stellate cells establish contacts with the dendrites of PCs and of other cerebellar interneurons (Briatore et al. 2010). Basket cells start innervating the cell body of PCs at the end of the first postnatal week (Sotelo 2008; Viltono et al. 2008). The number of perisomatic synapses then increases, together with a strong decrease in the number of somatic spines innervated by CFs. In the same period, basket cell synapses undergo a process of “waning” (Larramendi 1969), consisting in a fragmentation of long synaptic appositions into multiple shorter active zones. These morphological rearrangements are accompanied by a gradual loss of the scaffolding molecule gephyrin from postsynaptic specializations (Viltono et  al. 2008), as well as a decrease in the amplitude of IPSCs recorded from PCs (Pouzat and Hestrin 1997). The period of inhibitory synapse development terminates in the fourth postnatal week, when synapse density becomes uniform throughout the ML (Patrizi et al. 2008; Viltono et al. 2008). The formation and maturation of the pinceau is a prolonged process that begins in the second postnatal week and extends well after P21 by a progressive recruitment of basket terminals (Sotelo 2008). The descending branches of basket axons first enwrap the cell body of PCs, making perisomatic synapses (P7), and then reach the AIS by P9. The targeting of

17.2 Development of GABA Synapses

17  Development of Glutamatergic and GABAergic Synapses

basket axons to the AIS depends on Semaphorin3A (Sema3A) and its receptor neuropilin-1 (NRP1; Telley et  al. 2016). Sema3A secreted by PCs attracts basket cell axons expressing NRP1 toward the AIS. Moreover, it appears that NRP1 also mediates subcellular target recognition through trans-­ synaptic interaction with neurofascin 186 (NF 186), a cell adhesion molecule of the L1 immunoglobulin family which is required for the formation and maintenance of the pinceau (Ango et al. 2004; Zonta et al. 2011). Interestingly, another member of the same family of adhesion molecules, CHL1, localizes along Bergmann glia fibers and stellate cells during the formation of stellate axon arbors. In the absence of CHL1, stellate axons show aberrant branching and orientation, and synapse formation with PC dendrites is impaired (Ango et al. 2008). Thus, different members of the L1 family contribute to axon patterning and subcellular synapse organization in different types of interneurons.

17.2.2 PC Axon Collaterals The axon collaterals of PCs also establish GABA synapses with different types of cerebellar neurons, including other PCs (Cajal 1911; Palay and Chan-Palay 1974). The synaptic targets of PC collaterals have been the subject of controversy, although there is substantial consensus that PC axons connect with other PCs and distinct types of interneurons (Witter et  al. 2016 and references therein). A recent study based on a combination of anatomical, optogenetic, and electrophysiological approaches revealed that both in juveniles and adult mice the axon collaterals make synapses with other PCs in such a way that essentially all PCs are inhibited by other PCs (Witter et al. 2016). In the same study, PC collaterals were found to make synapses also with interneurons. It has also been reported that PC collaterals directly inhibit granule cells regulating their excitability on multiple timescales (Guo et al. 2016). Interestingly, these connections are region-specific, as they are mostly found in cerebellar lobules involved in processing vestibular information and regulating eye movements.

17.2.3 Golgi Cell Synapses Golgi cells are interneurons that provide inhibition to the granule cells (Ito 2006; Schilling et al. 2008; Galliano et al. 2010). It has been suggested that Golgi cells act as an adaptable spatiotemporal filter that controls information flow through the cerebellar cortex (D’Angelo 2008). Ablation of Golgi cells by immunotoxin-mediated cell targeting impairs motor coordination, revealing a crucial role for cerebellar function (Watanabe et  al. 1998). Golgi cell axons are restricted to the GCL and surround the glomeruli, making

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inhibitory synapses with the dendrites of granule cells. Most Golgi cells contain both GABA and glycine and can mediate GABAergic or glycinergic inhibition based on differential expression of either GABAA or glycine receptors in the target neurons (Dugué et  al. 2005). Immunohistochemical investigations have revealed that Golgi cell synapses mature with a time course similar to that of MF synapses. The axon terminals of Golgi cells develop rapidly during the second postnatal week, forming ring-like arrangements at the periphery of the glomeruli (McLaughlin et al. 1975). During this period, granule cells undergo a marked acceleration of inhibitory postsynaptic currents, which may be due to changes in the subunit composition of GABAA receptors (Brickley et  al. 1999). It has been demonstrated that the BDNF receptor TrkB controls the formation and maintenance of synapses between Golgi cells and granule cells (Rico et al. 2002), primarily by regulating the assembly of pre- and postsynaptic adhesion molecules (Chen et al. 2011). Other types of interneurons that mediate synaptic inhibition in the cerebellar cortex include Lugaro, globular, and candelabrum cells (Schilling et  al. 2008). Like Golgi cells, these neurons are situated in the GCL and have a dual GABAergic/glycinergic phenotype. However, unlike Golgi cells, their axons are not restricted to the granule cell layer, but they distribute throughout the ML. Knowledge of the connectivity and physiology of these cerebellar neurons is incomplete, and very little is known about their development.

References Altman J (1972a) Postnatal development of the cerebellar cortex in the rat. I.  The external germinal layer and the transitional molecular layer. J Comp Neurol 145:353–398 Altman J (1972b) Postnatal development of the cerebellar cortex in the rat. II. Phases in the maturation of Purkinje cells and of the molecular layer. J Comp Neurol 145:399–464 Altman J (1972c) Postnatal development of the cerebellar cortex in the rat. III. Maturation of the components of the granular layer. J Comp Neurol 145:465–514 Ango F, di Cristo G, Higashiyama H et al (2004) Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment. Cell 119:257–272 Ango F, Wu C, Van der Want JJ et  al (2008) Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites. PLoS Biol 6:e103 Apps R, Garwicz M (2005) Anatomical and physiological foundations of cerebellar information processing. Nat Rev Neurosci 6:297–311 Briatore F, Patrizi A, Viltono L et al (2010) Quantitative organization of GABAergic synapses in the molecular layer of the mouse cerebellar cortex. PLoS One 5:e12119 Brickley SG, Cull-Candy SG, Farrant M (1999) Single-channel properties of synaptic and extra-synaptic GABAA receptors suggest differential targeting of receptor subtypes. J Neurosci 19:2960–2973 Cajal S (1890) Sobre ciertos elementos bipolares del cerebelo joven y algunos detalles mas acerca del crecimiento y evolución de las fibras cerebelosas. Gaceta Sanitaria, Barcelona, pp 1–20

120 Cajal S (1911) Histologie du système nerveux de l’homme et des vertébrés. Maloine, Paris Cathala L, Holderith NB, Nusser Z et  al (2005) Changes in synaptic structure underlie the developmental speeding of AMPA receptor-­ mediated EPSCs. Nat Neurosci 8:1310–1318 Chen AI, Nguyen CN, Copenhagen DR et  al (2011) TrkB (tropomyosin-­related kinase B) controls the assembly and maintenance of GABAergic synapses in the cerebellar cortex. J Neurosci 31:2769–2780 D’Angelo E (2008) The critical role of Golgi cells in regulating spatio-­ temporal integration and plasticity at the cerebellum input stage. Front Neurosci 2:35–46 Dugué GP, Dumoulin A, Triller A et al (2005) Target-dependent use of co-released inhibitory transmitters at central synapses. J Neurosci 25:6490–6498 Eisenman LM, Schalekamp MP, Voogd J (1991) Development of the cerebellar cortical efferent projection: an in-vitro anterograde tracing study in rat brain slices. Dev Brain Res 60:261–266 Galliano E, Mazzarello P, D’Angelo E (2010) Discovery and rediscoveries of Golgi cells. J Physiol 588:3639–3655 Garin N, Escher G (2001) The development of inhibitory synaptic specializations in the mouse deep cerebellar nuclei. Neuroscience 105:431–441 Guo C, Witter L, Rudolph S et al (2016) Purkinje cells directly inhibit granule cells in specialized regions of the cerebellar cortex. Neuron 91:1330–1341 Hall AC, Lucas FR, Salinas PC (2000) Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100:525–535 Hámori J, Somogyi J (1983) Differentiation of cerebellar mossy fiber synapses in the rat: a quantitative electron microscope study. J Comp Neurol 220:367–377 Hashimoto K, Ichikawa R, Kitamura K et al (2009) Translocation of a “winner” climbing fiber to the Purkinje cell dendrite and subsequent elimination of “losers” from the soma in developing cerebellum. Neuron 63:106–118 Ichikawa R, Miyazaki T, Kano M et al (2002) Distal extension of climbing fiber territory and multiple innervation caused by aberrant wiring to adjacent spiny branchlets in cerebellar Purkinje cells lacking glutamate receptor delta 2. J Neurosci 22:8487–8503 Ichikawa R, Yamasaki M, Miyazaki T (2011) Developmental switching of perisomatic innervation from climbing fibers to basket cell fibers in cerebellar Purkinje cells. J Neurosci 31:16916–16927 Ito M (2006) Cerebellar circuitry as a neuronal machine. Prog Neurobiol 78:272–303 Kakegawa W, Mitakidis N, Miura E et  al (2015) Anterograde C1ql1 signaling is required in order to determine and maintain a single-­ winning climbing fiber in the mouse cerebellum. Neuron 85:316–329 Landsend AS, Amiry-Moghaddam M, Matsubara A et  al (1997) Differential localization of delta glutamate receptors in the rat cerebellum: coexpression with AMPA receptors in parallel fiber-­ spine synapses and absence from climbing fiber-spine synapses. J Neurosci 17:834–842 Larramendi LMH (1969) Analysis of synaptogenesis in the cerebellum of the mouse. In: Llinás R (ed) Neurobiology of cerebellar evolution and development. American Medical Association, Chicago Matsuda K, Miura E, Miyazaki T et al (2010) Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science 328:363–368 McLaughlin BJ, Wood JG, Saito K (1975) The fine structural localization of glutamate decarboxylase in developing axonal processes and presynaptic terminals of rodent cerebellum. Brain Res 85:355–371

M. Sassoè-Pognetto Miyazaki T, Fukaya M, Shimizu H et  al (2003) Subtype switching of vesicular glutamate transporters at parallel fibre-Purkinje cell synapses in developing mouse cerebellum. Eur J Neurosci 17:2563–2572 Palay S, Chan-Palay V (1974) Cerebellar cortex: cytology and organization. Springer, Berlin Patrizi A, Scelfo B, Viltono L et al (2008) Synapse formation and clustering of neuroligin-2 in the absence of GABAA receptors. Proc Natl Acad Sci U S A 105:13151–13156 Pouzat C, Hestrin S (1997) Developmental regulation of basket/stellate cell → Purkinje cell synapses in the cerebellum. J Neurosci 17:9104–9112 Rico B, Xu B, Reichardt LF (2002) TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 5:225–233 Sajan SA, Waimey KE, Millen KJ (2010) Novel approaches to studying the genetic basis of cerebellar development. Cerebellum 9:272–283 Schilling K, Oberdick J, Rossi F et al (2008) Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex. Histochem Cell Biol 130:601–615 Sigoillot SM, Iyer K, Binda F et al (2015) The secreted protein C1QL1 and its receptor BAI3 control the synaptic connectivity of excitatory inputs converging on cerebellar Purkinje cells. Cell Rep 10:820–832 Sotelo C (1990) Cerebellar synaptogenesis: what can we learn from mutant mice. J Exp Biol 153:225–249 Sotelo C (2004) Cellular and genetic regulation of the development of the cerebellar system. Prog Neurobiol 72:295–339 Sotelo C (2008) Development of “Pinceaux” formations and dendritic translocation of climbing fibers during the acquisition of the balance between glutamatergic and gamma-aminobutyric acidergic inputs in developing Purkinje cells. J Comp Neurol 506:240–262 Telley L, Cadilhac C, Cioni JM et al (2016) Dual function of NRP1 in axon guidance and subcellular target recognition in cerebellum. Neuron 91:1276–1291 Uemura T, Lee SJ, Yasumura M et  al (2010) Trans-synaptic interaction of GluRdelta2 and neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell 141:1068–1079 Umemori H, Linhoff MW, Ornitz DM et al (2004) FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118:257–270 Viltono L, Patrizi A, Fritschy JM et  al (2008) Synaptogenesis in the cerebellar cortex: differential regulation of gephyrin and GABAA receptors at somatic and dendritic synapses of Purkinje cells. J Comp Neurol 508:579–591 Wang VY, Zoghbi HY (2001) Genetic regulation of cerebellar development. Nat Rev Neurosci 2:484–491 Watanabe D, Inokawa H, Hashimoto K et  al (1998) Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination. Cell 95:17–27 Witter L, Rudolph S, Pressler RT et  al (2016) Purkinje cell collaterals enable output signals from the cerebellar cortex to feed back to Purkinje cells and interneurons. Neuron 91:312–319 Yuzaki M (2003) The delta2 glutamate receptor: ten years later. Neurosci Res 46:11–22 Yuzaki M (2010) Synapse formation and maintenance by C1q family proteins: a new class of secreted synapse organizers. Eur J Neurosci 32:191–197 Zonta B, Desmazieres A, Rinaldi A (2011) A critical role for Neurofascin in regulating action potential initiation through maintenance of the axon initial segment. Neuron 69:945–956

Synaptogenesis and Synapse Elimination in Developing Cerebellum

18

Kouichi Hashimoto, Masahiko Watanabe, and Masanobu Kano

Abstract

Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex and play pivotal roles in the coordination, control, and learning of movements. In adult cerebellum, they receive two distinctive excitatory synaptic inputs from parallel fibers (PFs), the axons of granule cells (GCs), and climbing fibers (CFs) arising from the inferior olivary nucleus in the medulla oblongata. Each PC receives functionally weak but numerous (c.a. 100,000  in mice) PF synapses, on spines of distal dendrites. In contrast, most PCs are innervated by single but functionally very strong CFs on stubby spines of proximal dendrites. PCs receive GABAergic inhibitory synaptic inputs from basket and stellate cells (BCs and SCs) in the molecular layer. These synaptic organizations are established mostly during the first 3 weeks of a rodent’s life. In this chapter, we briefly review how these microcircuits around PCs are organized, maintained, and modified during postnatal development. Keywords

Purkinje cell · Basket cell · Stellate cell · Granule cell Parallel fiber · Climbing fiber · Synaptogenesis · Synapse elimination · Cerebellum

K. Hashimoto Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan e-mail: [email protected] M. Watanabe Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan e-mail: [email protected] M. Kano (*) Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan e-mail: [email protected]

18.1 Synaptogenesis and Refinement of CF to PC Synapses 18.1.1 Synaptogenesis of CFs to Immature PCs Olivocerebellar axons reach the immature cerebellum around embryonic day (E) 18 in rodent. They start to form synapses just after their arrival but do not have a typical “climbing” morphology at this stage. Immature olivocerebellar axons extensively ramify in the white matter and the GC layer and give rise to many collaterals around PCs (creeper stage) (Chedotal and Sotelo 1993). Since immature PCs are devoid of large primary dendrites, CFs mainly form terminals on abundant perisomatic protrusions and thorns emerging from the PC somata.

18.1.2 Postnatal Refinement of CF to PC Synapses While most PCs are innervated by single CFs in the adult cerebellum, each PC receives synaptic inputs from multiple CFs at birth. Adult-like mono innervation is gradually established during postnatal development by the elimination of surplus CFs (Crepel 1982), which proceeds in at least four distinct phases (Kano et al. 2018). Around P2–P3, individual CFs of each multiply-­ innervated PC form synapses with relatively similar synaptic strength (Fig. 18.1). During the first postnatal week, a single CF is selectively strengthened on the soma of each PC both functionally and morphologically (termed “functional differentiation”). Mice with PC-specific deletion of Cav2.1, the α-subunit of the P/Q-type voltage-dependent Ca2+ channel (VDCC), show impairment in the selective strengthening of a single CF (Hashimoto et al. 2011), suggesting that activity-­ dependent Ca2+ influx through P/Q-type VDCCs is crucial for establishing a single “winner” CF in each PC (Hashimoto et al. 2011; Kawamura et al. 2013).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_18

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Fig. 18.1  Synaptogenesis and synapse elimination around PCs during postnatal development. PC Purkinje cell, CF climbing fiber, PF parallel fiber, BC basket cell, SC stellate cell, GC granule cell, MF mossy fiber. Note that PF synapses onto BCs and SCs are not illustrated for simplicity

Several molecules have been shown to be involved in strengthening of CF synaptic inputs. These include: (1) Semaphorin 3A (Sema3A), a secreted form of semaphorin, which is secreted from PCs and acting retrogradely on Plexin A4 (PlxnA4) on CF terminals (Uesaka and Kano 2018; Uesaka et  al. 2014), (2) C1ql1, a member of C1q family proteins, which derives from CFs and anterogradely acts on brain-specific angiogenesis inhibitor 3 (Bai3) in PCs (Kakegawa et al. 2015; Sigoillot et al. 2015), and (3) progranulin, a growth factor, which derives from PCs and acts retrogradely on Sort1 on CF terminals (Uesaka et al. 2018). Then, the strongest CF extends its innervation territory from the soma to dendrites, which is known as “CF translocation” (Fig. 18.1). As mentioned above, CFs initially establish synaptic contacts on the fine process emerging from the soma, and form a plexus on the lower part of the PC somata (“pericellular nest” stage) (Cajal 1911). While the stem dendrite of PCs starts to grow into the molecular layer from around P6, multiple CFs continue to innervate PC somata until around P9. After the functional differentiation of CFs, only the strongest (winner) CF extends its innervation territory from the soma to stem dendrites from P9 (“capuchin” stage) (Cajal 1911). Translocation of a single “winner” CF to PC dendrite has been shown to require the P/Q-type VDCC in PCs (Hashimoto et  al. 2011), the C1ql1 to Bai3 anterograde signaling (Kakegawa et al. 2015; Sigoillot et al. 2015), and the progranulin to Sort1 retrograde signaling (Uesaka et al. 2018).

In the “dendritic” stage (Cajal 1911), CF synapses progressively translocate to growing PC dendrites. On the other hand, weaker (loser) CFs remain around the soma, and are then eventually eliminated in two distinct phases (the “early and late phases of CF elimination”) (Kano and Watanabe 2019; Kano et al. 2018). The early phase of CF synapse elimination starts at around P7 just after the functional differentiation. Unlike the late phase of CF synapse elimination, the early phase is not dependent on proper formation of PF–PC synapses. Several lines of evidence suggest that neuronal activity is crucial for this event (Kano and Watanabe 2019; Kano et al. 2018). The P/Q-type VDCC in PCs is crucial for the early phase of CF synapse elimination (Hashimoto et al. 2011; Miyazaki et al. 2012) but it is currently unknown how Ca2+ influx through the P/Q-type VDCC into PCs leads to elimination of weaker CF synapses from the soma. The late phase of CF synapse elimination starts at around P12 (Kano and Watanabe 2019; Kano et al. 2018). This process is critically dependent on proper formation of excitatory PF synapses (Hashimoto et al. 2009) and inhibitory BC synapses on PCs (Nakayama et al. 2012). In mice deficient in the type 1 metabotropic glutamate receptor (mGluR1) or any of its downstream signaling molecules (Gαq, PLCβ3, PLCβ4, and PKCγ), the late phase of CF elimination is severely impaired (Kano and Watanabe 2019; Rai et al. 2021). The impaired CF elimination is rescued by introducing PC’s major mGluR1 splice variant, mGluR1a, but not another mGluR1 splice variant, mGluR1b, into PCs of mGluR1 knockout mice (Ichise et  al. 2000; Ohtani et  al. 2014). These results indicate that mGluR1a and its downstream signaling to PKCγ in PCs are crucial for the late phase of CF elimination. In the cascade downstream of mGluR1, Sema7A, a GPI linked subtype of semaphorin, in postsynaptic PCs and its receptors (ItgB1 and PlxnC1) on CFs are demonstrated to be involved (Uesaka and Kano 2018; Uesaka et al. 2014). Moreover, at the downstream of mGluR1, brain-derived neurotrophic factor (BDNF) derived from postsynaptic PCs is demonstrated to act retrogradely on its high affinity receptor TrkB in CFs to promote the late phase of CF synapse elimination (Choo et al. 2017). Besides mGluR1 signaling cascade, the immediate early gene Arc/Arg3.1 activated by Ca2+ influx through the P/Q-type VDCC into PCs is found to be involved in the late phase of CF synapse elimination (Mikuni et al. 2013).

18.2 Synaptogenesis and Refinement of PF to PC Synapses 18.2.1 Synaptogenesis of PFs to Immature PCs During the prenatal period, GC precursors migrate to the cerebellar surface and form the external granular layer. After birth, they proliferate and descend in the molecular and PC

18  Synaptogenesis and Synapse Elimination in Developing Cerebellum

layers to form the internal granular layer (Altman and Bayer 1997). In the premigratory zone of the external granular layer, postmitotic spindle-shaped GCs extend future PFs to both directions in the transverse plane parallel to the cortical surface (Fig. 18.1). Then, GCs start to migrate along radial fibers of the Bergmann glia (Bergmann fibers) in the molecular layer by extending downward fibers. As consequence, T-shaped axon of GCs is constructed. Because horizontal beams of newly generated PFs pile up on previously formed PFs in the superficial or upper zone of the molecular layer, formation and maturation of PFs proceed in an orderly “inside-out” manner. This sequential development of PFs and synaptic transmission is shown to be crucial for proper network formation and motor function in the cerebellum (Park et al. 2019). During the first 10  days of a rodent’s life, proliferation and migration of GCs are slow in rate (Altman and Bayer 1997). Moreover, PC dendrites are immature, particularly, in the upper zone of the molecular layer, where dendrites extend filopodium-like protrusions, PF–PC synapses are few in number, PC spines are often free of innervation, and synaptic coverage by lamellate processes of Bergmann glia is incomplete (Kurihara et al. 1997; Yamada et al. 2000). In the next 10  days, PC dendrites grow dynamically, the bulk of GCs come into existence, and PF–PC synapses explosively increase in number (Takacs and Hamori 1994). Moreover, almost all spines form synaptic contact with PF terminals, and PF–PC synapses are equipped with well-developed postsynaptic density and complete coverage by Bergmann glia (Kurihara et  al. 1997; Spacek 1985; Yamada et  al. 2000). Analyses of agranular and hypogranular animal models have demonstrated that PF synapse formation in PCs plays a critical role in the elongation, branching, and planer development of PC dendritic trees (Sotelo 2004). GluD2 and Cbln1 play an important role in PF–PC synapse formation (Mishina et al. 2012; Yuzaki 2011). GluD2 is a member of ionotropic glutamate receptors but does not function as a glutamate-gated ion channel. GluD2 is expressed predominantly in PCs and selectively localized at PF but not CF synapses (Mishina et al. 2012). Cbln1, which was originally identified as a precursor of the PC-specific peptide cerebellin, belongs to the C1q/tumor necrosis factor superfamily and is released into culture medium as a hexamer (Yuzaki 2011). Cbln1 is highly expressed in GCs, and accumulated in the synaptic cleft at PF–PC synapses (Yuzaki 2011). In GluD2 or Cbln1 knockout mice, the density of PF synapses is significantly reduced. Moreover, many free spines and frequent mismatching of pre- and post-synaptic specialization at PF synapses are conspicuous and unique to these mutants (Hirai et  al. 2005; Kashiwabuchi et  al. 1995; Kurihara et al. 1997). Tripartite molecular complex formed by GluD2 on PC dendritic spines, Cbln1 released from GCs, and specific neurexin variant (S4+-neurexin) on PF terminals act as a bidirectional synaptic organizer that strengthens and

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stabilizes the connectivity of PF–PC synapses (Matsuda et al. 2010; Uemura et al. 2010). This trans-synaptic molecular bridge is also functional in adult brains, as defects of PF– PC synapses are induced after drug-induced GluD2 ablation in adult mice (Takeuchi et al. 2005).

18.2.2 Postnatal Refinement of PF to PC Synapses In addition to mono-innervation by CFs, segregation of the PF and CF territories on PC dendrites is another distinguished feature in excitatory synaptic organization of PC.  Until P9, CF and PF territories are separated, because CFs innervate the soma and PFs form synaptic contacts only on the dendrite. Then, these two territories become overlapped by commencement of dendritic translocation of a single “winner” CF from P9 to P15, when PFs remain to innervate the whole extent of PC dendritic tree (Ichikawa et al. 2016). From P15 to P20, the territories segregate again by massive elimination of PF synapses from the proximal compartment of PC dendrites (Ichikawa et  al. 2016). This developmental process of PF synapse elimination is impaired in mutant mouse strains lacking mGluR1, PKCγ, or P/Q-­type VDCC, leading to sustained overlapping territories of CF and PF innervation at the proximal compartment of PC dendrites (Ichikawa et al. 2016; Miyazaki et al. 2004, 2012).

18.3 Synaptogenesis of BCs and SCs to PCs The basket cell (BC) and stellate cell (SC) are GABAergic interneurons in the molecular layer, which receive excitatory inputs from PFs and send feed-forward inhibition to PCs. Both types of interneurons are derived from dividing progenitors in the white matter of postnatal cerebellum, and later migrate into the molecular layer (Zhang and Goldman 1996). They also share similar molecular expression and firing profiles and are often called molecular layer interneurons (MLIs) collectively. Nevertheless, they are distinct in innervation domains of target PCs (also see Chap. 23 “Basket cells”). In the mature cerebellum, BCs innervate the soma and construct the pinceau formation around the axon initial segment (AIS) of PCs, while SCs form synapses on PC dendrites (Fig. 18.1).

18.3.1 Synaptogenesis of BC Axon to Immature PCs The BC migrates across the PC layer to the molecular layer and starts to form synapses on the PC soma at the end of the first postnatal week (Ango et al. 2004). Around P9, most of

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the perisomatic synapses are formed by CFs. Thereafter until P20, BC axons take over somatic synaptic sites, concomitant with the progressive elimination of somatic CF synapses (Ichikawa et al. 2011). From around P9, BC axons reach the AIS and begin to form the pinceau. Targeting of BS axons to the AIS is mediated by several molecules including membrane-associated adaptor protein ankyrin-G and one of its binding partner, neurofascin 186 (NF186), a PC-specific splice variant of neurofascin of the L1 family immunoglobulin cell adhesion molecule (L1CAM) (Ango et  al. 2004; Brummendorf et  al. 1998; Huang et  al. 2007; Williams et al. 2010). NF186 exhibits a sharp concentration gradient from the AIS toward the soma and dendrites of PCs, being highest at the AIS (Ango et  al. 2004). This gradient is already formed at the end of the first postnatal week when BC axons first contact the somata of PCs. Ankyrin-G is expressed exclusively at AISs in PCs. Ankyrin-­ G-­deficient mice show a defect in distribution of NF186 and abnormal widespread coverage of AISs with BC axons instead of the focal ensheathment of AIS in wild-type mice (Ango et al. 2004; Huang et al. 2007; Williams et al. 2010). Conditional deletion of NF186 from PCs of developing mice also prevents maturation of the AIS and causes disorganization of the pinceau (Buttermore et al. 2012). Besides NF186, Sema3A and its cognate receptor neuropilin-­1 (NRP1) are essential for establishment of BC–PC wiring during postnatal development (Cioni et  al. 2013; Telley et al. 2016). It is suggested that NRP1 in BCs contributes to axon collateral guidance to the PC soma (Telley et al. 2016), collateral contact and recognition of the PC soma/AIS (Telley et al. 2016), and terminal branching of BC axons at the PC’s AIS (Cioni et al. 2013).

18.3.2 Synaptogenesis of SC Axon to Immature PCs SC precursors migrate into the molecular layer a few days after migration of BC precursors, which continue until around P14 (Yamanaka et al. 2004). Between P12 and P16, SCs become bipolar and extend neurites in horizontal orientation (Ango et al. 2008). Then, at P16–P18, SC axons extend ascending and descending collaterals, which are further elaborated with appearance of plexus of finer branches up to P40 (Ango et al. 2008). Importantly, both ascending and descending collaterals of SC axons are strictly associated with Bergmann fibers (Ango et  al. 2008). During the second to fourth postnatal weeks, Bergmann fibers are transformed into a highly elaborate meshwork by extending numerous fine lamellate processes that enwrap PC synapses (Yamada et al. 2000). SC axons appear to be guided toward PC dendrites by using Bergmann fibers as an intermediate scaffold, and terminals are formed at the intersection between

K. Hashimoto et al.

Bergmann fibers and PC dendrites. Thus, Bergmann fibers may function as an intermediate scaffold to guide SC axons along the characteristic trajectories toward multiple PC dendrites and to form synaptic contacts. Close homologue of L1 (CHL1) is another member of L1CAM, and localized to apical Bergmann fibers and SCs during development. In CHL1 knockout mice, SC axons exhibit abnormal branching and orientation, and SC–PC synapses are reduced and cannot be maintained, leading to progressive atrophy of axon terminals, whereas the formation of the pinceau by BC axons is intact (Ango et al. 2008). These abnormalities in SC axons are also observed in Bergmann glia-specific CHL1-deleted mice. These lines of evidence demonstrate that CHL1 expressed in the Bergmann glia works as guiding scaffolds to organize SC axon arbors and formation of SC–PC synapses (Ango et al. 2008; Williams et al. 2010).

References Altman J, Bayer SA (1997) Development of the cerebellar system: in relation to its evolution, structure, and functions. CRC Press, Boca Raton Ango F, di Cristo G, Higashiyama H, Bennett V, Wu P, Huang ZJ (2004) Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment. Cell 119:257–272 Ango F, Wu C, Van der Want JJ, Wu P, Schachner M, Huang ZJ (2008) Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites. PLoS Biol 6:e103 Brummendorf T, Kenwrick S, Rathjen FG (1998) Neural cell recognition molecule L1: from cell biology to human hereditary brain malformations. Curr Opin Neurobiol 8:87–97 Buttermore ED, Piochon C, Wallace ML, Philpot BD, Hansel C, Bhat MA (2012) Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development. J Neurosci 32:4724–4742 Cajal SR (1911) Histologie du systeme nerveux de l'homme et des vertebres, vol 2. Maloine, Paris Chedotal A, Sotelo C (1993) The ‘creeper stage’ in cerebellar climbing fiber synaptogenesis precedes the ‘pericellular nest’-ultrastructural evidence with parvalbumin immunocytochemistry. Dev Brain Res 76:207–220 Choo M, Miyazaki T, Yamazaki M, Kawamura M, Nakazawa T, Zhang J, Tanimura A, Uesaka N, Watanabe M, Sakimura K et  al (2017) Retrograde BDNF to TrkB signaling promotes synapse elimination in the developing cerebellum. Nat Commun 8:195 Cioni JM, Telley L, Saywell V, Cadilhac C, Jourdan C, Huber AB, Huang JZ, Jahannault-Talignani C, Ango F (2013) SEMA3A signaling controls layer-specific interneuron branching in the cerebellum. Curr Biol 23:850–861 Crepel F (1982) Regression of functional synapses in the immature mammalian cerebellum. Trends Neurosci 5:266–269 Hashimoto K, Yoshida T, Sakimura K, Mishina M, Watanabe M, Kano M (2009) Influence of parallel fiber-Purkinje cell synapse formation on postnatal development of climbing fiber-Purkinje cell synapses in the cerebellum. Neuroscience 162:601–611 Hashimoto K, Tsujita M, Miyazaki T, Kitamura K, Yamazaki M, Shin HS, Watanabe M, Sakimura K, Kano M (2011) Postsynaptic P/Q-­-

18  Synaptogenesis and Synapse Elimination in Developing Cerebellum type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum. Proc Natl Acad Sci U S A 108:9987–9992 Hirai H, Pang Z, Bao D, Miyazaki T, Li L, Miura E, Parris J, Rong Y, Watanabe M, Yuzaki M et al (2005) Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci 8:1534–1541 Huang ZJ, Di Cristo G, Ango F (2007) Development of GABA innervation in the cerebral and cerebellar cortices. Nat Rev Neurosci 8:673–686 Ichikawa R, Yamasaki M, Miyazaki T, Konno K, Hashimoto K, Tatsumi H, Inoue Y, Kano M, Watanabe M (2011) Developmental switching of perisomatic innervation from climbing fibers to basket cell fibers in cerebellar Purkinje cells. J Neurosci 31:16916–16927 Ichikawa R, Hashimoto K, Miyazaki T, Uchigashima M, Yamasaki M, Aiba A, Kano M, Watanabe M (2016) Territories of heterologous inputs onto Purkinje cell dendrites are segregated by mGluR1-­ dependent parallel fiber synapse elimination. Proc Natl Acad Sci U S A 113:2282–2287 Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R, Katsuki M, Aiba A (2000) mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288:1832–1835 Kakegawa W, Mitakidis N, Miura E, Abe M, Matsuda K, Takeo YH, Kohda K, Motohashi J, Takahashi A, Nagao S et  al (2015) Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. Neuron 85:316–329 Kano M, Watanabe T (2019) Developmental synapse remodeling in the cerebellum and visual thalamus. F1000Res 8:F1000 Kano M, Watanabe T, Uesaka N, Watanabe M (2018) Multiple phases of climbing fiber synapse elimination in the developing cerebellum. Cerebellum 17:722–734 Kashiwabuchi N, Ikeda K, Araki K, Hirano T, Shibuki K, Takayama C, Inoue Y, Kutsuwada T, Yagi T, Kang Y et al (1995) Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluRδ2 mutant mice. Cell 81:245–252 Kawamura Y, Nakayama H, Hashimoto K, Sakimura K, Kitamura K, Kano M (2013) Spike timing-dependent selective strengthening of single climbing fibre inputs to Purkinje cells during cerebellar development. Nat Commun 4:2732 Kurihara H, Hashimoto K, Kano M, Takayama C, Sakimura K, Mishina M, Inoue Y, Watanabe M (1997) Impaired parallel fiber→Purkinje cell synapse stabilization during cerebellar development of mutant mice lacking the glutamate receptor δ2 subunit. J Neurosci 17:9613–9623 Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R et al (2010) Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Science 328:363–368 Mikuni T, Uesaka N, Okuno H, Hirai H, Deisseroth K, Bito H, Kano M (2013) Arc/Arg3.1 is a postsynaptic mediator of activity-­dependent synapse elimination in the developing cerebellum. Neuron 78:1024–1035 Mishina M, Uemura T, Yasumura M, Yoshida T (2012) Molecular mechanism of parallel fiber-Purkinje cell synapse formation. Front Neural Circuits 6:90 Miyazaki T, Hashimoto K, Shin HS, Kano M, Watanabe M (2004) P/Q-­type Ca2+ channel α1A regulates synaptic competition on developing cerebellar Purkinje cells. J Neurosci 24:1734–1743 Miyazaki T, Yamasaki M, Hashimoto K, Yamazaki M, Abe M, Usui H, Kano M, Sakimura K, Watanabe M (2012) Cav2.1  in cerebellar Purkinje cells regulates competitive excitatory synaptic wiring,

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Cerebellar Epigenetics: Transcription of microRNAs in Purkinje Neurons as an Approach to Neuronal Plasticity

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Neal H. Barmack

Abstract

Cerebellar plasticity is often investigated using brief electrical coactivation of climbing and parallel fiber pathways to evoke Long Term Depression (LTD), a temporary decrease in the excitability of Purkinje cell Simple Spikes (SSs). The mechanistic importance of individual proteins in climbing fiber-evoked depression of simple spikes can be approached by examining the longer-term role of regulated microRNA transcription. In this review, we examine the consequences of longer activation (1–30 h) of climbing fibers on the expression of microRNAs, mRNAs and proteins in targeted Purkinje cells of the mouse. Horizontal optokinetic stimulation (HOKS) of unanesthetized mice increases climbing fiber discharge of floccular Purkinje cells ipsilateral to the stimulated eye. This increased climbing fiber discharge increases the expression of several microRNA and mRNA transcripts. One of these transcripts, miR335, increases 18X after 24  h of HOKS. Pri-miR335 transcripts increase 28X after 24 h of HOKS. miR335 transcripts decay with a time constant of ~2.5 h. Increases in miR335 transcripts are coupled with decreases in the expression of calbindin, 14-3-3-θ and protein kinase C-γ (PKC-ɣ). This interaction is critical for the serine phosphorylation of the GABAA-ɣ2 receptor and its membrane expression in Purkinje cells and may contribute to homeostatic regulation of Purkinje cell discharge of SSs. Keywords

Flocculus · Plasticity · Climbing fiber

N. H. Barmack (*) Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, USA e-mail: [email protected]

19.1 Introduction This review explores neuronal plasticity of Purkinje cells in the cerebellar flocculus. Two major afferent systems influence the excitability of Purkinje cells: (1) Climbing fibers originate from the contralateral inferior olive. Each climbing fiber originates from the inferior olive and makes ~500 glutamatergic synapses on the dendritic tree of a Purkinje cell in the contralateral cerebellum (Cajal 1911; Granit and Phillips 1956; Eccles et al. 1967; Konnerth et al. 1990; Harvey and Napper 1991). Climbing fibers evoke long duration (3–5 ms) “complex spikes” (CSs) that have spontaneous discharge frequencies of 0.2–0.9 imp/s (Eccles et  al. 1966a; Goossens et al. 2004; Yakhnitsa and Barmack 2006). (2) Mossy fibers originate from multiple brainstem nuclei and make synaptic contact with a granule cell dendrite in a ‘glomerular synapse’ that includes a Golgi cell inhibitory terminal (Eccles et  al. 1966b; Fox et al. 1967). Granule cell axons ascend through the molecular layer and then divide into parallel fibers that make excitatory synapses on sagittally arrayed Purkinje cell dendrites (Cajal 1911; Fox and Barnard 1957; Eccles et al. 1965). The summed activity of excitatory parallel fiber terminals and inhibitory interneurons modulates the discharge of Purkinje cell “simple spikes” (SSs) (Granit and Phillips 1956; Eccles et al. 1965; Barmack and Yakhnitsa 2008). SSs have a short-duration action potential (~1 ms) that discharges spontaneously at 10–30 imp/s (Goossens et  al. 2004; Yakhnitsa and Barmack 2006). Cerebellar neuronal plasticity has often been characterized electrophysiologically by the phenomenon of ‘long-­ term depression’ (LTD). LTD is induced by repeated pairings of short electrical tetanus to climbing fibers in conjunction with an electrical stimulus to a parallel fiber bundle. Repeated pairings reduce the efficacy of the parallel fiber stimulus to evoke its pre-­paired response from the Purkinje cell. The decay of LTD lasts several minutes, serving as a model for cerebellar ‘learning.’ The occurrence of Purkinje cell depolarization evoked by climbing fiber stimulation during LTD

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_19

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may be substituted by direct depolarization of the recorded Purkinje cell in conjunction with parallel fiber volley (Ito et  al. 1982; Sakurai 1987; Narasimhan and Linden 1996; Linden and Connor 2001; Crepel 2009). This seemingly simple example of neuronal plasticity, modeled by LTD, may reflect the transcription, translocation and targeting of as many as 100 proteins (Sanes and Lichtman 1999). LTD is impaired in mice in which the expression of protein kinase C (PKC) in Purkinje cells is reduced by a transgenic L7-Protein Kinase C Inhibitor (Goossens et al. 2001, 2004). Despite the loss of LTD, L7-PKCI mouse mutants are still able to learn and perform sensory-motor tasks that typically reveal cerebellar impairment (Schonewille et al. 2011). There remains no consensus on the molecular mechanisms required to yield LTD. Modification of sensory-motor behaviors that the cerebellum is thought to influence, such as optokinetic modification of the vestibuloocular reflex, occur within a time course of hours. Consequently, the longer-­term molecular and biochemical consequences of sustained climbing fiber activity on functionally clustered Purkinje cells might be more amenable to experimental analysis. A sustained discharge of floccular Purkinje cells can be controlled by horizontal optokinetic stimulation (HOKS) (Maekawa and Simpson 1973; Simpson and Alley 1974; Alley et al. 1975; Maekawa and Takeda 1976; Leonard et al. 1988). Unlike natural activation of other cerebellar sensory pathways, HOKS of floccular Purkinje cells can be sustained and tolerated for up to 30 h in unanesthetized mice and rabbits (Barmack and Nelson 1987; Pettorossi et al. 1999). The subcellular consequences of prolonged HOKS can be examined subcellularly by screening floccular Purkinje cells by using assays for microRNA (miRNA) and mRNA. miRNA screens have particular appeal because of the possibility that a single miRNA could account for changes in the transcription of multiple protein mRNAs. These screens provide molecular clues that may

N. H. Barmack

account for the subcellar changes induced in Purkinje cells by sustained climbing fiber activity and may contribute to our understanding of cerebellar plasticity.

19.2 Biological Consequences of Prolonged HOKS of a Climbing Fiber Pathway to the Flocculus Optimal HOKS is achieved by placing a mouse at the center of a contrast-rich sphere, that rotates about the vertical axis at ~5  deg./s (Barmack and Hess 1980). HOKS excites direction-­selective “on” ganglion cells in the right eye while reducing the activity of such cells in the left eye (Oyster et al. 1980) (Fig.  19.1a, b). HOKS increases CSs in floccular Purkinje cells contralateral to the eye stimulated in the posterior→anterior (P→A) direction. If HOKS is maintained for more than 1  h it evokes a prolonged optokinetic after-­ nystagmus that lasts for several hours (Barmack and Nelson 1987; Pettorossi et  al. 1999). Following HOKS the stimulated and control flocculi can be removed and prepared for subcellular analysis using microarrays for mRNA and microRNA (miRNA) (Fig.  19.1a, b). Ganglion cell axons from the right eye project to the left nucleus of the optic tract (NOT) in the dorsal midbrain. The axons of neurons in the left NOT descend to the inferior olive where they excite neurons in the left dorsal cap (DC) of the left inferior olive (Maekawa and Simpson 1973; Alley et  al. 1975; Barmack and Hess 1980; Simpson et al. 1988). Neurons in the left dorsal cap project as climbing fibers to the right flocculus where they excite Purkinje cells (Leonard et al. 1988; Schonewille et al. 2006). Since the visual projections to the flocculus are lateralized, HOKS of the right eye in the P→A direction for 0–24 h increases climbing fiber discharge in the right flocculus while decreasing climbing fiber discharge in the left flocculus. HOKS can be maintained for 0–30 h.

19  Cerebellar Epigenetics: Transcription of microRNAs in Purkinje Neurons as an Approach to Neuronal Plasticity

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Fig. 19.1  Horizontal optokinetic stimulation (HOKS) evokes climbing fiber-induced increases in microRNA transcription in the flocculus. (a) Cartoon depicts an optokinetic pathway from the retina to the ipsilateral flocculus (see text for details). The dashed lines indicate the excitatory pathway that originates from the right eye during counter-clockwise HOKS. The solid lines indicate the “disfacilitated” pathway caused by HOKS of the left eye. (b) Mice are restrained at the center of an optokinetic sphere that rotates CCW at 6 deg./s and excites ganglion cells in the right eye. Mice receive binocular HOKS for fixed durations of 0–30 h. (c) The left and right flocculi are dissected and RNA extracted. cDNAs are synthesized and amplified by PCR. The U6 promoter is co-­ amplified as a loading control. Each reaction is run on a gel and the optical density of the bands is measured photometrically. When the

ratio of PCR band density (R.Floc./L.Floc.) is >1 it indicates increased transcription of miR335  in the right flocculus. Two microRNAs, miR125 or miR147 (gray bars), are run as controls. HOKS duration is indicated above each gel pair and for each histogram bar. (d) Transcripts of miR335 in the right flocculus decay rapidly. The transcripts are measured at the indicated times after HOKS is stopped. (e) A digoxigenin-­ labeled oligonucleotide complementary to miR335 and immunolabeled with an antibody to digoxigenin hybridizes in the cytoplasm of Purkinje cells. The area denoted by the small box is shown at a higher magnification in the larger insert. DC dorsal cap of the inferior olive, Fl flocculus, NOT the nucleus of the optic tract, vPFl ventral paraflocculus. [Modified from (Barmack et al. 2010)]

19.3 Transcription of miRNAs in Purkinje Cells

(Reinhart et  al. 2000; Ambros 2004; Cullen 2004; Harfe 2005; Kosik 2006; Schratt et  al. 2006; Bushati and Cohen 2007), oncogenesis (Hayes et al. 2014), epilepsy (Alsharafi et  al. 2015) and microbial defense (Bartel 2004; Cullen 2004; Zeng et al. 2005). microRNAs also regulate the functions of adult neurons (Schratt 2009; Smalheiser and Lugli 2009; Barmack et  al. 2010; Konopka et  al. 2011; Mellios et al. 2011; Tognini et al. 2011). After HOKS stops, mice are anesthetized, the left and right flocculi are removed and total RNA is extracted from each flocculus. cDNAs are synthesized and amplified for initial analysis by a microarray (GeneChip® microRNA 2.0, Affymetrix Co). Three miRNAs (miR126, miR335 and miR379) are differen-

The regulation of gene transcription, translation and targeting of proteins could be simplified if the proteins are regulated by common precursors such as microRNAs; small, non-coding RNAs derived from “junk” DNA. A single microRNA could target the 3′-untranslated regions of as many as 5–30 mRNAs and limit their translation by complementary repression and degradation (Cullen 2004; Robins and Press 2005; Landgraf et al. 2007; Hobert 2008; Eulalio et al. 2009; Guo et al. 2010). The transcription of microRNAs has been linked to cellular development, and apoptosis

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tially expressed in stimulated flocculi stimulated by HOKS relative to contralateral controls. The positive identification of specific miRNAs is confirmed by subsequent measurements using specific primer pairs with greater accuracy. These confirming tests use either PCR amplification and northern blot gels or polymerase chain reaction (qPCR).

19.4 HOKS Increases miR335 Transcripts and this Increase Decays Rapidly Depending on HOKS Duration The minimal duration of HOKS necessary to evoke a detectable increase in microRNA transcripts is measured by experiments in which mice receive HOKS for different durations (0, 3, 6, 12, 24, 30 h) before they are euthanized. Increases in miR335 transcripts can be detected after 6  h of HOKS. Transcripts of miR335 continue to increase linearly from 6 to 30 h (Fig. 19.1c). The increase in miR335 transcripts evoked by HOKS rapidly decreases when HOKS stops. This question is addressed specifically by exposing mice to a constant duration of HOKS for 24 h. The HOKS then stops and the mice remain within the illuminated sphere for 0.0, 1.5, 3.0, 6.0, or 12 h before they are euthanized. Transcripts of miR335 are then measured at each of the specified post-stimulus intervals. miR335 transcripts decay to control levels with a time constant of ~2.5 h (Fig. 19.1d). This rapid decay suggests that miR335 transcripts cannot account singularly for long-­ lasting changes in Purkinje neuronal excitability.

19.5 Hybridization Histochemistry Localizes miRNA Transcripts to Purkinje Cells While HOKS increases microRNA transcripts in the flocculus, it is by no means certain that the transcripts are localized exclusively to Purkinje cells. This is tested using “locked nucleic acid-modified oligonucleotide probes” to examine whether they hybridize with mature microRNAs. A probe for

N. H. Barmack

miR335 hybridizes with Purkinje cell soma, but not with Purkinje cell nuclei (Fig. 19.1e). This confirms the cytoplasmic location of the mature miR335 in Purkinje cells. Other probes for microRNA transcripts that increase with HOKS, miR15, miR21 and miR361, also hybridize with Purkinje cells and weakly with stellate cells. A scrambled probe, having the same GC content as the probe for miR335, fails to hybridize with either Purkinje cells or other cerebellar neurons. These data confirm that microRNAs evoked by climbing fiber activity are localized to Purkinje cells.

19.6 Central Floccular Zone is a Homogeneous Source of Purkinje Cells Excited by HOKS The mouse flocculus comprises a single spindle-shaped folium with an axial length of 1.1 mm. The linear extent of the floccular folium is ~400  μm at its peak. It weighs ~400 μg. The climbing fibers that are activated by HOKS project to the middle third of the flocculus. Climbing fiber zones are established by electrophysiological recordings from Purkinje cells during optokinetic stimulation (Goossens et  al. 2004). Such recordings reveal a central zone in which the climbing fiber responses of Purkinje cells are modulated by P→A HOKS of the ipsilateral eye. This central zone is flanked by two zones in which Purkinje cell activity is modulated by vertical optokinetic stimulation (VOKS). Purkinje cells in the most caudal floccular C2 zone are unresponsive to optokinetic stimulation and may be linked to the control of head movement (De Zeeuw and Koekkoek 1997). Excising the middle third of the flocculus increases the concentration of Purkinje cells in the sample that are excited by HOKS (Fig.19.2a). After 24 h of HOKS miR335 transcripts from this central zone (red) are 3X more abundant than in previous experiments where transcripts in the total right flocculus were compared to transcripts in the total left flocculus (Figs.  19.1c vs 19.2a). HOKS does not influence miR335 transcripts in flanking floccular zones. In these zones the right/left flocculus ratio is ~1.

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19  Cerebellar Epigenetics: Transcription of microRNAs in Purkinje Neurons as an Approach to Neuronal Plasticity

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Fig. 19.2  HOKS-increases pri-miR335 and miR335 and increases their interaction with proteins. (a) Purkinje cells removed from the horizontal floccular zone contain 3X more concentrated miR335 transcripts than do Purkinje cells removed from the total flocculus following 24 h of HOKS. miR335 transcripts in the flanking floccular regions are not increased by HOKS. (b) The relative number of transcripts of both primiR335 and mature miR335 are measured to determine if the HOKSevoked mi335 transcripts could be attributed to increased transcription of miR335 or perhaps decreased degradation of constitutive transcription of miR335. Floccular samples from the right central floccular are compared with samples from the entire left flocculus. HOKS evokes larger increases in pri-miR335 transcripts than mature miR335 transcripts. (c) HOKS for 24 h decreases 14-3-3-θ transcripts of the flocculus onto which HOKS-excited climbing fibers project. mRNA transcripts for only one 14-3-3 isoform, 14-3-3-θ, decrease (ANOVA, p 15  μm), although the activity of more cell types has been distinguished through the labeling of GABAergic and glycinergic cells (Uusisaari et al. 2007; Uusisaari and Knöpfel 2012). Different rebound phenotypes can be defined, with several different patterns reported following hyperpolarizing stimuli (Czubayko et  al. 2001; Uusisaari et al. 2007; Hoebeek et al. 2010; Pedroarena 2010; Sangrey and Jaeger 2010; Tadayonnejad et al. 2010; Engbers et al. 2011; Steuber et al. 2011).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_41

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generate synchronous input by climbing fiber afferents to Purkinje cells (Hoebeek et al. 2010; Bengtsson et al. 2011; Several ion channels are known to contribute to rebound Steuber and Jaeger 2013). The specific patterns of Purkinje responses. T-type calcium channels are partially inactivated cell firing that can elicit a rebound response in DCN cells during the resting tonic discharge of DCN cells, with hyper- was uncertain, given reports of only tonic firing of Purkinje polarizations acting to remove inactivation. A return to rest- cells in decerebrate cats (Bengtsson et al. 2011) compared to ing potential then triggers a larger T-type current (calcium regular spiking patterns in rats or mice (Shin et al. 2007; De spike) to drive a rebound depolarization (Molineux et  al. Schutter and Steuber 2009; Engbers et al. 2013), pauses in 2006, 2008; Alviña et  al. 2009; Tadayonnejad et  al. 2010; firing (Shin and De Schutter 2006; Steuber et al. 2007; De Engbers et  al. 2011; Schneider et  al. 2013; Steuber and Schutter and Steuber 2009; Yartsev et  al. 2009; Cao et  al. Jaeger 2013). The expression pattern of different T-type cal- 2012; Heiney et al. 2014; Zhou et al. 2015; Hong et al. 2016), cium channel isoforms was found to distinguish different and a degree of synchronicity of Purkinje cell firing or pauses classes of transient vs. weak burst DCN neurons (Molineux (Shin and De Schutter 2006; De Schutter and Steuber 2009; et  al. 2006, 2008). The hyperpolarization-activated cyclic Person and Raman 2012; Heck et  al. 2013; Herzfeld et  al. nucleotide-gated (HCN) channel is directly activated by 2015). In vitro analyses in cerebellar slices have traditionally membrane hyperpolarization in DCN cells, and upon return to resting potential deactivates slowly enough to generate a used a square wave hyperpolarizing current pulse or a brief depolarization that controls first spike latency and spike pre- train of inhibitory synaptic input delivered at a fixed frecision, and augments the role of T-type current by shortening quency to evoke rebound firing in DNC cells (Fig. 41.1a, b). the membrane time constant (Raman et  al. 2000; Sangrey Yet the patterns of Purkinje cell firing that DCN cells need to and Jaeger 2010; Engbers et  al. 2011). Non-inactivating translate to the final output from the cerebellum in vivo are sodium current(s) are proposed to contribute to at least the far richer in both spatial and temporal information (De slow phase of rebound, as these channels will also undergo Schutter and Steuber 2009; De Zeeuw et  al. 2011; Person inactivation at rest and recovery from inactivation during and Raman 2012; Heck et  al. 2013; Herzfeld et  al. 2015; hyperpolarization. Return to resting potential then evokes a Bareš et al. 2019; Zang and De Schutter 2021). To assess the slowly inactivating sodium current that helps drive the late ability for physiological patterns of Purkinje cell firing to rebound component (plateau depolarization) (Jahnsen 1986; trigger rebound bursts in DCN cells, spike trains recorded Llinás and Mühlethaler 1988; Aman and Raman 2007; from rat Purkinje cells in vivo in response to perioral whisker Sangrey and Jaeger 2010). Analysis of the effects of apply- stimuli (Shin et  al. 2007) were delivered as stimulus teming pharmacological blockers suggests a contribution by vir- plates to activate Purkinje cell inputs in vitro (Dykstra et al. tually all classes of high voltage-activated calcium channels 2016). The strength of this method is that the widely ranging to the burst and plateau depolarization (Zheng and Raman patterns of Purkinje cell firing around a baseline rate of dis2009). The role of potassium channels has been considered, charge could be assessed in direct relation to the occurrence with the pharmacological, knockout mouse, and dynamic of DCN cell rebound busts. To do this, a form of reverse corclamp studies uncovering differences in the role of voltage- relation was used where the first spike of a statistically or calcium-gated potassium channels in controlling tonic fir- defined burst in a DCN cell recording was identified (Time ing vs rebound responses (Aizenman and Linden 1999; 0) to extract the record of Purkinje cell input 1 s before and Alviña and Khodakhah 2008; Molineux et al. 2008; Joho and after this time point (Dykstra et al. 2016). Surprisingly, DCN Hurlock 2009; Tadayonnejad et al. 2010; Pedroarena 2011; cell bursts were not detected in relation to Purkinje cell firing associated with any of the parameters of perioral whisker Feng et al. 2013). stimulation, regular firing patterns defined by a CV2 analysis (Shin and De Schutter 2006; Shin et al. 2007), or for climbing fiber-evoked complex spike discharge. Yet superimpos41.2 Rebound Depolarizations Encode ing average values of Purkinje and DCN cell firing rates in Purkinje Cell Input Patterns relation to statistically defined bursts revealed a characterisThe endpoint of DCN cell rebound responses is to encode tic “Elevation-Pause” pattern in Purkinje cell firing that prepatterns of afferent inhibitory input that reflects the firing ceded and followed the occurrence of DCN cell bursts patterns of Purkinje cells. In vivo work has shown that (Fig. 41.1c). To better define the aspect of Purkinje cell firing rebounds can be successfully activated using a high-­ best correlated to DCN cell bursts, five different components frequency stimulus applied directly to Purkinje cells of the of the Elevation-Pause pattern in Purkinje cell firing were overlying cerebellar cortex (Hoebeek et al. 2010), by optoge- defined for selective analysis (Fig.  41.1d). These tests netic modulation of Purkinje cell firing (Witter et al. 2013; revealed that the relevant pattern of presynaptic input correHeiney et al. 2014), or activation of inferior olivary nuclei to sponded to an elevation in Purkinje cell firing rate to

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Fig 41.1 (a, b) Representative recordings of spike output from two large diameter DCN cells exhibiting spontaneous discharge. (a) Injecting a 500  ms hyperpolarizing current step elicits a rebound response in a Transient burst cell. (b) A 25 pulse 50 Hz train of Purkinje cell inhibitory synaptic inputs elicits a weaker rebound response. (c–f) Reverse correlation analysis of the mean Purkinje cell firing pattern underlying DCN rebound depolarizations and spike bursts. Purkinje cell spike patterns evoked by perioral whisker stimulation in vivo were used as templates to stimulate afferent axon inputs to DCN cells in vitro. (c) Superimposed plots of the mean DCN cell spike frequency response (blue) to the corresponding mean Purkinje cell firing rate (red) 1  sec before and after the first spike (Time 0) of statistically defined

DCN cell bursts of 2–8 ISIs (n = 122 bursts). Black lines reflect mean values and shaded areas are SEM. (d) Schematic of the components measured from the mean Purkinje cell firing identified by reverse correlation from DCN cell spike bursts in (e, f). (e) Representative mean Purkinje cell firing pattern identified through reverse correlation as evoking a 6–7 spike burst in Transient burst DCN cells (n = 8). Black line reflects mean values and shaded area is the calculated SEM. (f) Scatter plot of the duration of pauses in Purkinje cell firing (as defined in d) following a brief elevation in firing rate compared to the number of spike ISIs evoked in each DCN cell rebound burst (n = 17). Red line reflects a linear fit to the data. Figure frames in (c–f) are modified from Dykstra et al. (2016)

30–60 Hz above baseline over at least 100 ms, followed by a rapid drop in frequency or pause in firing for at least 50 ms and up to 500  ms. Interestingly, the parameter most correlated to the occurrence or intensity of a rebound burst was the duration of the pause in Purkinje cell firing (Fig. 41.1e, f). This finding would support the previous reports of the importance of pauses in Purkinje cell firing (Shin and De Schutter

2006; De Schutter and Steuber 2009; Yartsev et al. 2009; Cao et  al. 2012; Heiney et  al. 2014; Zhou et  al. 2015), and the degree of synchronicity of Purkinje cell firing or pauses (Shin and De Schutter 2006; De Schutter and Steuber 2009; Heck et al. 2013; Herzfeld et al. 2015). The results gained from reverse correlation of firing patterns in vitro can be interpreted in terms of a requirement

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for Purkinje cell inhibitory input to lower the rate of spontaneous DCN cell firing long enough to promote a recovery from inactivation of T-type calcium channels and activation of HCN channels to drive the initial phase of a rebound response. With this depolarization, multiple calcium channel isoforms and sodium channels then contribute to determining the duration of a burst response or a plateau depolarization. The work also highlights the difficulty of interpreting significant features of a spike train without computational analysis, and the comparative weakness of traditional approaches of using square wave pulses or fixed frequency input trains as more than a tool for pharmacological assessments. Our knowledge of the patterns of Purkinje cell firing in response to sensory inputs is also rapidly evolving, indicating that many roles for DCN cell rebound responses in defining cerebellar output remain to be determined.

References Aizenman CD, Linden DJ (1999) Regulation of the rebound depolarization and spontaneous firing patterns of deep nuclear neurons in slices of rat cerebellum. J Neurophysiol 82:1697–1709 Alviña K, Khodakhah K (2008) Selective regulation of spontaneous activity of neurons of the deep cerebellar nuclei by N-type calcium channels in juvenile rats. J Physiol 586:2523–2538 Alviña K, Ellis-Davies G, Khodakhah K (2009) T-type calcium channels mediate rebound firing in intact deep cerebellar neurons. Neuroscience 158:635–641 Aman TK, Raman IM (2007) Subunit dependence of Na channel slow inactivation and open channel block in cerebellar neurons. Biophys J 92:1938–1951 Bareš M, Apps R, Avanzino L, Breska A, D’Angelo E, Filip P, Gerwig M, Ivry RB, Lawrenson CL, Louis ED, Lusk NA, Manto M, Meck WH, Mitoma H, Petter EA (2019) Consensus paper: decoding the contributions of the cerebellum as a time machine. From neurons to clinical applications. Cerebellum 18:266–286 Bengtsson F, Ekerot C-F, Jörntell H (2011) In vivo analysis of inhibitory synaptic inputs and rebounds in deep cerebellar nuclear neurons. PLoS One 6:e18822 Cao Y, Maran SK, Dhamala M, Jaeger D, Heck DH (2012) Behavior-­ related pauses in simple-spike activity of mouse Purkinje cells are linked to spike rate modulation. J Neurosci 32:8678–8685 Czubayko U, Sultan F, Thier P, Schwarz C (2001) Two types of neurons in the rat cerebellar nuclei as distinguished by membrane potentials and intracellular fillings. J Neurophysiol 85:2017–2029 De Schutter E, Steuber V (2009) Patterns and pauses in Purkinje cell simple spike trains: experiments, modeling and theory. Neuroscience 162:816–826 De Zeeuw CI, Hoebeek FE, Bosman LWJ, Schonewille M, Witter L, Koekkoek SK (2011) Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci 12:327–344 Dykstra S, Engbers JD, Bartoletti TM, Turner RW (2016) Determinants of rebound burst responses in rat cerebellar nuclear neurons to physiological stimuli. J Physiol 594:985–1003 Engbers JDT, Anderson D, Tadayonnejad R, Mehaffey WH, Molineux ML, Turner RW (2011) Distinct roles for I(T) and I(H) in controlling the frequency and timing of rebound spike responses. J Physiol 589:5391–5413

S. Dykstra and R. W. Turner Engbers JDT, Fernandez FR, Turner RW (2013) Bistability in Purkinje neurons: ups and downs in cerebellar research. Neural Netw 47:18–31 Feng SS, Lin R, Gauck V, Jaeger D (2013) Gain control of synaptic response function in cerebellar nuclear neurons by a calcium-­ activated potassium conductance. Cerebellum 12:692–706 Heck DH, De Zeeuw CI, Jaeger D, Khodakhah K, Person AL (2013) The neuronal code(s) of the cerebellum. J Neurosci 33:17603–17609 Heiney SA, Kim J, Augustine GJ, Medina JF (2014) Precise control of movement kinematics by optogenetic inhibition of Purkinje cell activity. J Neurosci 34:2321–2330 Herzfeld DJ, Kojima Y, Soetedjo R, Shadmehr R (2015) Encoding of action by the Purkinje cells of the cerebellum. Nature 526:439–442 Hoebeek FE, Witter L, Ruigrok TJH, De Zeeuw CI (2010) Differential olivo-cerebellar cortical control of rebound activity in the cerebellar nuclei. Proc Natl Acad Sci U S A 107:8410–8415 Hong S, Negrello M, Junker M, Smilgin A, Thier P, De Schutter E (2016) Multiplexed coding by cerebellar Purkinje neurons. Elife 5:e13810. https://doi.org/10.7554/eLife.13810 Jahnsen H (1986) Extracellular activation and membrane conductances of neurones in the Guinea-pig deep cerebellar nuclei in  vitro. J Physiol 372:149–168 Joho RH, Hurlock EC (2009) The role of Kv3-type potassium channels in cerebellar physiology and behavior. Cerebellum 8:323–333 Llinás R, Mühlethaler M (1988) Electrophysiology of Guinea-pig cerebellar nuclear cells in the in vitro brain stem-cerebellar preparation. J Physiol 404:241–258 Molineux ML, McRory JE, McKay BE, Hamid J, Mehaffey WH, Rehak R, Snutch TP, Zamponi GW, Turner RW (2006) Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. Proc Natl Acad Sci U S A 103:5555–5560 Molineux ML, Mehaffey WH, Tadayonnejad R, Anderson D, Tennent AF, Turner RW (2008) Ionic factors governing rebound burst phenotype in rat deep cerebellar neurons. J Neurophysiol 100:2684–2701 Pedroarena CM (2010) Mechanisms supporting transfer of inhibitory signals into the spike output of spontaneously firing cerebellar nuclear neurons in vitro. Cerebellum 9:67–76 Pedroarena CM (2011) BK and Kv3.1 potassium channels control different aspects of deep cerebellar nuclear neurons action potentials and spiking activity. Cerebellum 10:647–658 Person AL, Raman IM (2012) Synchrony and neural coding in cerebellar circuits. Front Neural Circuits 6:97. https://doi.org/10.3389/ fncir.2012.00097 Raman IM, Gustafson AE, Padgett D (2000) Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J Neurosci 20:9004–9016 Sangrey T, Jaeger D (2010) Analysis of distinct short and prolonged components in rebound spiking of deep cerebellar nucleus neurons. Eur J Neurosci 32:1646–1657 Schneider ER, Civillico EF, Wang SS-H (2013) Calcium-based dendritic excitability and its regulation in the deep cerebellar nuclei. J Neurophysiol 109:2282–2292 Shin S-L, De Schutter E (2006) Dynamic synchronization of Purkinje cell simple spikes. J Neurophysiol 96:3485–3491 Shin S-L, Hoebeek FE, Schonewille M, De Zeeuw CI, Aertsen A, De Schutter E (2007) Regular patterns in cerebellar Purkinje cell simple spike trains. PLoS One 2:e485 Steuber V, Jaeger D (2013) Modeling the generation of output by the cerebellar nuclei. Neural Netw 47:112–119 Steuber V, Mittmann W, Hoebeek FE, Silver RA, De Zeeuw CI, Häusser M, De Schutter E (2007) Cerebellar LTD and pattern recognition by Purkinje cells. Neuron 54:121–136 Steuber V, Schultheiss NW, Silver RA, De Schutter E, Jaeger D (2011) Determinants of synaptic integration and heterogeneity in rebound

41  Rebound Depolarizations firing explored with data-driven models of deep cerebellar nucleus cells. J Comput Neurosci 30:633–658 Tadayonnejad R, Anderson D, Molineux ML, Mehaffey WH, Jayasuriya K, Turner RW (2010) Rebound discharge in deep cerebellar nuclear neurons in vitro. Cerebellum 9:352–374 Uusisaari MY, Knöpfel T (2012) Diversity of neuronal elements and circuitry in the cerebellar nuclei. Cerebellum 11:420–421 Uusisaari M, Obata K, Knöpfel T (2007) Morphological and electrophysiological properties of GABAergic and non-GABAergic cells in the deep cerebellar nuclei. J Neurophysiol 97:901–911 Witter L, Canto CB, Hoogland TM, de Gruijl JR, De Zeeuw CI (2013) Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation. Front Neural Circuits 7:133

273 Yartsev MM, Givon-Mayo R, Maller M, Donchin O (2009) Pausing Purkinje cells in the cerebellum of the awake cat. Front Syst Neurosci 3:2 Zang Y, De Schutter E (2021) The cellular electrophysiological properties underlying multiplexed coding in Purkinje cells. J Neurosci 41:1850–1863 Zheng N, Raman IM (2009) Ca currents activated by spontaneous firing and synaptic disinhibition in neurons of the cerebellar nuclei. J Neurosci 29:9826–9838 Zhou H, Voges K, Lin Z, Ju C, Schonewille M (2015) Differential Purkinje cell simple spike activity and pausing behavior related to cerebellar modules. J Neurophysiol 113:2524–2536

42

Cerebellar Nuclei Dieter Jaeger and Huo Lu

Abstract

Understanding the basic physiology of cerebellar nuclei (CN) is essential to the understanding of cerebellar function and disorders as they provide the only output from the cerebellum along with the vestibular nuclei. In addition to integrating the inhibitory input from cerebellar cortical Purkinje cells, CN neurons also receive direct excitation from mossy fibers and this direct excitatory input to the CN may in fact drive a number of behaviorally relevant activities. The complete picture is considerably more complex than that of a simple relay of incoming excitation and inhibition, however. Specifically, the functional significance of synaptic plasticity in the CN, high spontaneous spike rates, post-inhibitory rebound firing, and multiple output pathways including GABAergic inhibition feeding back to the inferior olive remain to be elucidated. Keywords

Mossy fibers · Climbing fiber · Rebound spiking Microzone · Gain control · Learning

42.1 Basic Physiology of CN Neurons 42.1.1 Cellular Physiology CN neurons recorded in brain slices from any of the four nuclei present in rodents (lateral, anterior interposed, posterior interposed, and medial) are spontaneously regularly spiking (Jahnsen 1986), a property which is due to an intrinD. Jaeger (*) Department of Biology, Emory University, Atlanta, GA, USA e-mail: [email protected] H. Lu Biomedical Sciences, PCOM Georgia, Suwanee, GA, USA e-mail: [email protected]

sic depolarizing plateau current (Raman et  al. 2000). A robust property of CN neurons is their ability to fire rebound spike bursts following strong hyperpolarization induced by current injection (Llinas and Muhlethaler 1988; Jahnsen 1986; Aizenman and Linden 1999). The rebound activity has an initial fast burst component carried by T-type calcium currents (Molineux et  al. 2006) and a longer-lasting 2–5  s increase of spike rate associated with persistent sodium currents (Sangrey and Jaeger 2010). The functional implications of CN rebound properties are hotly debated (Alvina et  al. 2008; Hoebeek et al. 2010). While these basic properties are present in excitatory and inhibitory CN neurons, GABAergic cells can be distinguished physiologically by a broader spike width, a slower spike-afterhyperpolarization, and higher spike rate accommodation, and further differences are present between morphologically larger and smaller non-­ GABAergic neurons (Uusisaari et al. 2007).

42.1.2 Synaptic Physiology and Synaptic Plasticity Early in vitro studies provided direct evidence that Purkinje cells’ spiking causes monosynaptic inhibitory postsynaptic potentials (IPSPs) in the CN (Ito et al. 1964). These IPSPs are characterized by a large amplitude, a fast decay, and pronounced short-term depression (Person and Raman 2012). A single CN neuron receives large IPSPs from about 40 Purkinje cells, while smaller IPSPs may derive from many more Purkinje cells with fewer and/or more distal synaptic terminals (Person and Raman 2012). Robust excitatory postsynaptic potentials (EPSPs) can be elicited by stimulation of mossy fibers (Llinas and Muhlethaler 1988), which are collaterals of the same fibers projecting to cerebellar cortex (Shinoda et  al. 1992). Climbing fibers also collateralize in the CN (Sugihara et  al. 1999) and may induce a spike response in vivo (Blenkinsop and Lang 2011). Recent brain slice studies showed that excitatory responses to climbing

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_42

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fiber activation seen with intracellular recordings in CN neurons are small in adult mice, but more prominent in juveniles during development (Lu et al. 2016; Najac and Raman 2017). Long-term plasticity has also been observed for synaptic inputs to the CN.  Excitatory mossy fiber undergoes long-­ term potentiation as a result of a distinct combination of inhibitory and excitatory inputs “that resemble the activity of Purkinje and mossy fiber afferents that is predicted to occur during cerebellar associative learning tasks” (Pugh and Raman 2009). Inhibitory Purkinje cell input can undergo either long-term potentiation or long-term depression, which is dependent on the amount of rebound depolarization produced by a burst of Purkinje cell inputs (Aizenman et  al. 1998). The plasticity-inducing protocols in the CN generally require complex temporal conditions of excitation and inhibition, which may relate to the commonly hypothesized role of the cerebellum in motor timing. In addition, the effects of learning in the CN may also include changes in intrinsic excitability, as observed for the acquisition of eyeblink conditioning (Wang et al. 2018).

42.2 The Control of CN Spiking Output by Input Rates and Patterns One might expect that CN neurons in vivo are silenced by strong inhibition from the inputs from 40 Purkinje cells with a strong conductance (Person and Raman 2012) and a fast spike rate that typically exceeds 50  Hz in awake animals. Contrary to this expectation, CN neurons in awake animals fire fast with a baseline rate between 10 and 100 Hz (Chabrol et al. 2019; Becker and Person 2019). While the spontaneous spiking activity of CN neurons likely contributes to their firing in  vivo (Yarden-Rabinowitz and Yarom 2017), the ­intrinsic depolarizing current underlying it is overcome easily by current injection of only about −30 pA in brain slices (Raman et al. 2000). In contrast, the total Purkinje cell input current easily exceeds −1  nA at a membrane potential at −57  mV (Person and Raman 2012). Thus, a considerable excitatory input conductance is also needed in order to drive CN neurons to spiking in vivo, which can be confirmed by detailed biophysical modeling (Abbasi et  al. 2017). Given the small relative size of climbing fiber inputs to CN neurons and their slow rate of firing, this task falls primarily to mossy fibers, and indeed a study in brain slices showed robust mossy fiber postsynaptic currents (Wu and Raman 2017). An intracellular study in  vivo also confirmed a strong mossy fiber contribution to spiking activity (Yarden-Rabinowitz and Yarom 2017). A number of studies are addressing the question of whether the CN produce spike output based on integrating smooth rates of incoming excitatory and inhibitory inputs, or whether there is a specific decoding mechanism for precisely

D. Jaeger and H. Lu

timed synchronous inputs (Brown and Raman 2018; Najac and Raman 2015; Sarnaik and Raman 2018; Wu and Raman 2017; Abbasi et al. 2017; Sudhakar et al. 2015). In turn, the output of the CN may either convey an output rate code of input rates, or a precise spike time code where the millisecond timing stamp of outgoing spikes conveys important information. Of course, the answer could also be a combination of these possibilities. Indeed evidence is recently accumulating for both rate and temporal coding strategies (Brown and Raman 2018; Sarnaik and Raman 2018) at the level of the CN.  Interestingly, some evidence suggests that distinct cell types in the CN show different coding strategies, namely slow synaptic integration and rate coding in nucleo-olivary cells and faster synaptic integration in larger premotor neurons resulting in a temporal code with precise spike timing following the offset of inhibition (Najac and Raman 2015). Climbing fiber inputs to the cerebellum are well known for millisecond synchronization, and special coding of such synchronous events might be expected in the CN. Indeed, a recent study found that climbing fiber synchronicity is required for CN neurons to develop pronounced pauses of firing upon complex spike input from Purkinje cells (Tang et al. 2019). Notably, this study did not find any evidence for rebound bursts following such complex spike elicited pauses, which had been identified earlier with electrical Purkinje cell input stimulation in awake mice (Hoebeek et  al. 2010). Finally, a recent study shows that rate and temporal coding principles combine in a cerebellar loop where the firing rate of nucleo-olivary cells controls the synchronicity of olivary input to Purkinje cells during a trained reaching movement (Wagner et al. 2021).

42.3 A View at CN Function 42.3.1 Behavioral Correlates of CN Activity Changes A substantial number of studies has been undertaken to study the spiking activity of CN neurons in behaving animals, often revealing complex relationships between CN spike rate increases or decreases and sensory stimuli as well as movements. One of the most studied behaviors with respect to CN activity is the delayed eye blink reflex, where CN activity is clearly related to the learnt timing of the motor command (Thompson and Steinmetz 2009). In a more general sense, CN output activity is congruent with representing an internal or forward model of movement execution (Lisberger 2009; Miall and Reckess 2002) that is important in the predictive control of behavior. Recent experiments in which mice are trained in a reaching task show a close relation of anterior interposed nucleus activity with the deceleration of the reach to grasp movement (Becker and Person 2019). Supporting a

42  Cerebellar Nuclei

causal role of anterior interposed neuron firing in reach deceleration, these authors found that optogenetic activation of the anterior interposed nucleus led to a shortened reach, while optogenetic inhibition resulted in reaches overshoot their target. The activity of the lateral nucleus neurons was probed with similar methods in a locomotor task where head-fixed mice were trained to run through a virtual visual environment (Chabrol et  al. 2019). A specific visual target pattern denoted the impending delivery of reward. Many lateral nucleus neurons robustly increased firing in preparation of the reward delivery, closely resembling preparatory firing properties recorded in anterolateral motor cortex (ALM). Optogenetic silencing lateral nucleus neurons resulted in decreased preparatory activity in ALM, supporting a role of lateral nucleus neurons in cortical motor preparatory processing. A similar preparatory activity was also observed in the medial nucleus in a cued licking task with a delay (Gao et  al. 2018). In this study, optogenetic stimulation experiments also revealed that preparatory activity in ALM depended on medial nucleus neural activity. In addition, the authors show that this loop is closed and preparatory activity in the medial nucleus is also dependent on ALM preparatory activity, presumably via mossy fibers from the pontine nuclei relaying ALM activity (Gao et al. 2018).

42.3.2 Multiple Functional Areas in the CN and Microzonal Organization Each CN nucleus and to some degree different areas in each nucleus will be engaged in controlling behaviors related to the anatomical inputs of the respective nucleus, such as the vestibulo-ocular reflex and balance in the vestibular nuclei (Lisberger and Miles 1980), limb movements in the interposed and dentate nuclei (Strick 1983; Becker and Person 2019), and the control of timing in tasks such as finger tapping in humans (Stefanescu et  al. 2013) in the dentate nucleus. The concept of time estimation as a cerebellar function was also confirmed in monkeys through observing a close relationship between single cell activity in the dentate nucleus and the interval duration in a self-timed saccade task (Ohmae et al. 2017). This activity may be specifically used for the fine adjustment of self-timed intervals (Kunimatsu et  al. 2018). Increasingly, we also understand that the CN output may be involved in multiple cognitive functions including working memory and language processing (Wagner and Luo 2020). The microzonal organization of the cerebellar cortex is preserved in the CN (Apps and Garwicz 2000). This allows for functionally relevant climbing fiber synchrony evoking complex spikes in cerebellar cortical microzones to converge in the CN and elicit behaviorally relevant responses that may

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depend on this synchrony (De Gruijl et al. 2014; Person and Raman 2012; Wagner et al. 2021).

42.3.3 Output of the CN Is Split into Distinctive Pathways GABAergic neurons in CN are traditionally thought to solely project to the inferior olive where they often terminate near gap junctions in olivary glomeruli (De Zeeuw et al. 1998). This arrangement allows CN output to influence both the occurrence and the synchrony of olivary spikes (Lefler et al. 2014; Wagner et al. 2021), which may be important in controlling olivary motor error signals (Simpson et al. 1996). Excitatory CN neurons project to a variety of targets, notably including the motor thalamus, red nucleus, and brainstem motor nuclei. The functional impact of CN activity on these targets is often not clearly understood, but given the high tonic rates of CN firing in  vivo and behaviorally related phasic and tonic changes in CN firing a temporally highly precise effect on motor performance is expected (Heck et al. 2013). Our knowledge of cerebellar anatomy is still expanding, and recent genetic and intersectional labeling techniques allow the identification of new connections. Important recent additions to our anatomical CN connectivity diagram include a GABAergic output to the brain stem (Judd et  al. 2021), excitatory feedback to the cerebellar cortex (Houck and Person 2014), and output to the ventrolateral periaqueductal grey involved in the control of fear memories (Frontera et al. 2020). Our understanding of cerebellar-thalamic pathways is also increasing, showing not only connections to the primary cerebellar motor thalamus, but also to ventromedial and centrolateral thalamic areas (Gornati et al. 2018). The rapid pace of new findings suggests that we have yet to learn a lot about the detailed functional contribution of CN output to the processing of sensory-motor tasks in cortical and brainstem areas.

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D. Jaeger and H. Lu Llinas R, Muhlethaler M (1988) Electrophysiology of Guinea-pig cerebellar nuclear cells in the in vitro brain stem-cerebellar preparation. J Physiol 404:241–258 Lu H, Yang B, Jaeger D (2016) Cerebellar nuclei neurons show only small excitatory responses to optogenetic olivary stimulation in transgenic mice: in vivo and in vitro studies. Front Neural Circuits 10:21. https://doi.org/10.3389/fncir.2016.00021 Miall RC, Reckess GZ (2002) The cerebellum and the timing of coordinated eye and hand tracking. Brain Cogn 48(1):212–226 Molineux ML, McRory JE, McKay BE, Hamid J, Mehaffey WH, Rehak R, Snutch TP, Zamponi GW, Turner RW (2006) Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. PNAS 103(14):5555–5560 Najac M, Raman IM (2015) Integration of Purkinje cell inhibition by cerebellar nucleo-olivary neurons. J Neurosci 35(2):544–549. https://doi.org/10.1523/jneurosci.3583-­14.2015 Najac M, Raman IM (2017) Synaptic excitation by climbing fibre collaterals in the cerebellar nuclei of juvenile and adult mice. J Physiol 595(21):6703–6718. https://doi.org/10.1113/jp274598 Ohmae S, Kunimatsu J, Tanaka M (2017) Cerebellar roles in self-timing for sub- and supra-second intervals. J Neurosci 37(13):3511–3522. https://doi.org/10.1523/jneurosci.2221-­16.2017 Person AL, Raman IM (2012) Purkinje neuron synchrony elicits time-­ locked spiking in the cerebellar nuclei. Nature 481(7382):502–506. https://doi.org/10.1038/nature10732 Pugh JR, Raman IM (2009) Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei. TINS 32(3):170–177. https://doi.org/10.1016/j.tins.2008.12.001 Raman IM, Gustafson AE, Padgett D (2000) Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J Neurosci 20(24):9004–9016 Sangrey T, Jaeger D (2010) Analysis of distinct short and prolonged components in rebound spiking of deep cerebellar nucleus neurons. Eur J Neurosci 32(10):1646–1657. https://doi.org/10.1111/j.1460-­9568.2010.07408.x Sarnaik R, Raman IM (2018) Control of voluntary and optogenetically perturbed locomotion by spike rate and timing of neurons of the mouse cerebellar nuclei. eLife 7:e29546. https://doi.org/10.7554/ eLife.29546 Shinoda Y, Sugiuchi Y, Futami T, Izawa R (1992) Axon collaterals of mossy fibers from the pontine nucleus in the cerebellar dentate nucleus. J Neurophysiol 67(3):547–560 Simpson JI, Wylie DR, DeZeeuw CI (1996) On climbing fiber signals and their consequence(s). Behav Brain Sci 19(3):384 Stefanescu MR, Thürling M, Maderwald S, Wiestler T, Ladd ME, Diedrichsen J, Timmann D (2013) A 7T fMRI study of cerebellar activation in sequential finger movement tasks. Exp Brain Res 228(2):243–254 Strick PL (1983) The influence of motor preparation on the response of cerebellar neurons to limb displacements. J Neurosci 3(10):2007– 2020 Sudhakar SK, Torben-Nielsen B, De Schutter E (2015) Cerebellar nuclear neurons use time and rate coding to transmit Purkinje neuron pauses. PLoS Comput Biol 11(12):e1004641. https://doi. org/10.1371/journal.pcbi.1004641 Sugihara I, Wu HS, Shinoda Y (1999) Morphology of single olivocerebellar axons labeled with biotinylated dextran amine in the rat. J Comp Neurol 414(2):131–148 Tang T, Blenkinsop TA, Lang EJ (2019) Complex spike synchrony dependent modulation of rat deep cerebellar nuclear activity. eLife 8:e40101. https://doi.org/10.7554/eLife.40101 Thompson RF, Steinmetz JE (2009) The role of the cerebellum in classical conditioning of discrete behavioral responses. Neuroscience 162(3):732–755. https://doi.org/10.1016/j.neuroscience.2009.01.041 Uusisaari M, Obata K, Knopfel T (2007) Morphological and electrophysiological properties of GABAergic and non-GABAergic cells in the deep cerebellar nuclei. J Neurophysiol 97(1):901–911

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Plasticity of the Cerebellum

43

Xin-Tai Wang and Ying Shen

Abstract

Since 1990s, long-term depression of (LTD) at parallel fiber–Purkinje cell synapses has been regarded as a cellular phenomenon for motor learning. However, parallel fiber LTD by itself cannot account for motor learning. Here, we review a rich variety of use-dependent plasticity in the cerebellar cortex and nuclei, including long-term potentiation (LTP) and LTD at excitatory and inhibitory synapses, and persistent modulation of intrinsic excitability. Prevailing studies demonstrated that intrinsic and extrinsic factors, including neuronal excitation, specific molecular mechanisms, theta oscillation, and external neuromodulators, are essential to different forms of plasticity in the cerebellum. Keywords

Long-term depression · Long-term potentiation Purkinje cell · Granule cell · Parallel fiber · Climbing fiber

43.1 Parallel Fiber LTD A persistent attenuation of parallel fiber–Purkinje cell synapse is produced when parallel fiber and climbing fiber inputs to a Purkinje cell are stimulated together at low frequency (Ito et  al. 1982). Parallel fiber LTD is associative and saturable

upon repeated parallel fiber stimulation. Strong parallel fiber stimulation or conjunctive climbing fiber/parallel fiber stimulation induces parallel fiber LTD through the activation of postsynaptic metabotropic glutamate receptors (mGluRs) and α-amino-3-hydroxy-5-methyl-4-­isoxazolepropionic acid receptors (AMPARs), and subsequent rise of internal Ca2+. The activation of protein kinase Cα (PKCα) and α-Ca2+/ calmodulin-dependent protein kinase II (αCaMKII) is required for its induction as well. Cytosolic phospholipase A2α (cPLA2α)/cyclooxygenase-2 cascade plays important roles in this plasticity by acting on PKCα. Serotonin type 7 receptor (5-HT7R) also activates PKC and mitogen-activated protein kinase (MAPK) pathway and thereby induces parallel fiber LTD (Lippiello et al. 2016). Cannabinoid receptor 1 (CB1R) and nitric oxide/soluble guanylyl cyclase/cGMP-dependent protein kinase/phosphatase pathways are also involved (Bear and Linden 2000; Safo and Regehr 2005). Parallel fiber LTD is also subject to the modulation of secretary molecules, for example, nitric oxide (NO), which is produced by N-methylD-aspartate receptors (NMDARs) activation at parallel fiberinterneurons synapses (Kono et al. 2019). Parallel fiber LTD is expressed postsynaptically, as a reduction in the number of surface AMPARs produced by clathrin-dependent endocytosis (Wang and Linden 2000). Clathrin complex-associated molecules, Numb and transferrin receptor 1 (TFR1), are able to modulate the trafficking of mGluR1, and their deletion in Purkinje cells inhibits parallel fiber LTD (Zhou et  al. 2015, 2017) (Fig. 43.1).

X.-T. Wang · Y. Shen (*) Department of Physiology, Zhejiang University School of Medicine, Hangzhou, P. R. China e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_43

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Fig. 43.1  A diagram showing signaling cascades that are involved in parallel fiber LTD

43.2 Parallel Fiber LTP

and the production of 2-arachidonoylglycerol (2-AG) that diffuses to presynaptic terminals. Activated CB1R on preParallel fiber–Purkinje cell synapses undergo two forms of synaptic terminals by 2-AG triggers the activation of nitric homosynaptic LTP, depending on stimulus frequency. Four oxide synthase and produces a low level release of nitric to eight Hertz parallel fiber stimulation induces presynapti- oxide from parallel fiber terminals (Wang et  al. 2014). cally expressed LTP, which is ascribed to increased transmit- Afterward, nitric oxide works postsynaptically with serine/ ter release and associated with a decrease in paired-pulse threonine phosphatases to promote the required trafficking facilitation (Salin et  al. 1996) and evoked glutamate trans- of AMPARs. In these processes, nitric oxide activates soluport currents in glial cells (Linden 1998). Furthermore, ble guanylate cyclase, which induces the phosphorylation of 4–8  Hz LTP is mediated by presynaptic adenylyl cyclase/ GluA1-S845 by cGMP-dependent protein kinase II (cGKII) cyclic adenosine monophosphate (cAMP)/protein kinase A and upregulates synaptic expression of AMPARs (Serulle (PKA) pathway (Hansel et al. 2001). Evidence from cerebel- et  al. 2007). Further evidence shows that 5-HT7R particilar cultures shows that 4-Hz LTP is mediated by PKA-­ pates in this form of plasticity via PKC-MAPK signaling mediated phosphorylation of active zone protein RIM1α pathway (Lippiello et al. 2016). The regulation of P/Q-type 2+ (Lonart et al. 2003). Again, presynaptically expressed paral- Ca channels (Cav2.1) by calcium sensor proteins is also lel fiber LTP is also subject to NO modulation (Bouvier et al. required for postsynaptically expressed LTP (Mark et  al. 2016). It is also shown that β-adrenergic receptor (β1AR)/ 2015). Interestingly, this form of LTP requires the change of EPAC signaling participates in this form of LTP upon 10-Hz open probability of GluA3-containing AMPARs, but not the trafficking of GluA1-containing AMPARs (Gutierrez-­ parallel fiber stimulation (Martín et al. 2020). In contrast, 1-Hz parallel fiber stimulation induces a post- Castellanos et al. 2017). Since 1-Hz LTP and parallel fiber synaptically expressed LTP. This LTP requires a low level of LTD are both expressed postsynaptically, it is suggested that Ca2+ in Purkinje cells (Coesmans et al. 2004), which leads to 1-Hz LTP is a resetting mechanism for motor learning and the activation of cPLA2α, the liberation of arachidonic acid, causes the extinction of learned associations (Fig. 43.2).

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43  Plasticity of the Cerebellum Fig. 43.2  A diagram showing signaling cascades that are involved in postsynaptically expressed LTP

43.3 Climbing Fiber LTD Five Hz tetanization of climbing fibers evokes LTD at climbing fiber–Purkinje cell synapse, which is homosynaptic and saturable (Hansel and Linden 2000). Climbing fiber LTD requires intracellular Ca2+ and the activation of mGluR1 and PKC and is expressed postsynaptically (Shen et  al. 2002). Climbing fiber LTD is hypothesized to control the integrative response of Purkinje cell because complex spikes are attenuated after 5 Hz tetanization. Interestingly, 5 Hz tetanization at climbing fibers also induces LTP of glutamate transporter EAAT4, which is expressed on Purkinje neurons (Shen and Linden 2005).

43.4 Interneuron-Purkinje Cell Synaptic LTP The LTP of GABAA receptor-mediated inhibitory postsynaptic currents at interneurons–Purkinje cell GABAergic synapses is induced by repetitive climbing fiber activation (Kano et al. 1992). This inhibitory LTP requires a postsynaptic Ca2+ transient from internal Ca2+ stores and the activation of CaMKII and PKA. An early study showed that simultaneous activity of inhibitory synapses is needed for the induction of

inhibitory LTP (Kano 1996), but another later study showed that simultaneous inhibitory activity suppresses this LTP (Kawaguchi and Hirano 2000). Interneuron-Purkinje cell synaptic LTP has a major influence on Purkinje cell throughput, as it modulates the spike firing pattern of Purkinje cells (Häusser and Clark 1997).

43.5 Plasticity of Mossy Fiber-Granule Cell Synapses Mossy fiber–granule cell synapses provide a large potential substrate for information storage. The activation of mossy fibers combined with postsynaptic depolarization of granule cells results in mossy fiber LTP (D’Angelo et  al. 1999), which requires postsynaptic depolarization, Ca2+ influx and activation of NMDAR, mGluR, and PKC. Besides, the increase of glutamate released by granule cells can activate mGluRs at parallel fiber-Golgi cell synapses, enhancing inward rectifier currents, and hyperpolarizing Golgi cells. The inhibitory input by Golgi cells also affects the expression of mossy fiber LTP. In contrast, protracted low-­frequency stimulation causes mossy fiber LTD (Gall et al. 2005). Mossy fiber LTP and LTD promote the population (summated) and sparse (local) coding, respectively, in the granular layer.

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43.6 Plasticity in the Deep Cerebellar Nuclei (DCN)

TNF-α released from microglia via toll-like receptor 4 induces a potentiation of intrinsic excitability in Purkinje cells (Yamamoto et  al. 2019). LTP of intrinsic plasticity Mossy fiber-DCN plasticity depends on the excitation of occludes subsequent parallel fiber LTP, but facilitates paralDCN cells (Pugh and Raman 2006), while Purkinje cell-­ lel fiber LTD (Coesmans et al. 2004). LTP of intrinsic plasDCN plasticity depends on the excitation of both DCN cells ticity can not only be locally restricted to one synapse but and Purkinje cells (Aizenman et  al. 1998). DCN cells can also affects a large number of synapses, depending on the also generate a plasticity of intrinsic excitability (Aizenman identity and location of intrinsic conductance altered. Both et al. 2003). Mossy fiber-DCN plasticity and intrinsic excit- intrinsic and synaptic plasticities are required for motor ability can work together to generate a coincidence detection memory consolidation (Jang et al. 2020). driven by intracellular calcium transients.

43.7 Plasticity of Intrinsic Excitability in Purkinje Cells Purkinje cell excitability can be enhanced by somatic current injections or parallel fiber stimulation. Signal cascades for LTP of intrinsic excitability include local Ca2+ in spines and protein phosphatases. The interactions between these molecules and PKA and casein kinase 2 result in a downregulation of small conductance Ca2+-activated potassium (SK) channels, thereby reducing an intrinsic inhibitory influence. SK channels contribute to intrinsic excitability and plasticity by regulating firing frequency and Ca2+ transients in Purkinje cells (Grasselli et al. 2020). In addition, mGluR1 and PKA pathways are involved in the homeostatic intrinsic plasticity of Purkinje cells (Shim et al. 2016). Stromal interaction molecule 1 (STIM1) participates somatic Ca2+ influx and regulates intrinsic firing of Purkinje cells (Ryu et al. 2017). More evidence shows that the disease-linked molecules regulate intrinsic excitability as well, for example, tuberous sclerosis complex 1 (TSC1), corticotropin-releasing factor (CRF), and tumor necrosis factor alpha (TNF-α) released from microglia. TSC1 dysfunction results in increased mTOR activity, which is critical to cellular homeostasis (Tsai et  al. 2012). CRF increases the excitability of Purkinje neurons by modulating sodium, potassium, and hyperpolarization-activated cation-selective current (Ih) currents (Libster et  al. 2015).

43.8 Spike–Timing-Dependent Plasticity (STDP) in the Cerebellum Ever since the first report by Ekerot and Kano (1989), a series of studies have determined that parallel LTD is induced best when parallel fiber stimulation precedes climbing fiber-­ evoked complex spikes in Purkinje cells by 50–250 ms, suggesting an anti-Hebbian STDP mechanism in the cerebellum. Cerebellar STDP differs from that at hippocampal synapses, in that it is independent of axonal spike output. Rather, external climbing fiber stimulation and locally elicited Ca2+ spikes play a key role (Piochon et al. 2013).

43.9 Conclusions It is clear now that cerebellar learning is an integrated process involving numerous forms of synaptic plasticity in the cerebellar cortex and nuclei, where various specific spatial patterns are organized. Channeling begins from granular layer and is concluded in the molecular layer, where Purkinje cells integrate signals from different inputs. Plasticity is also organized in specific temporal patterns in the granular and molecular layer. In this view, the mechanisms for cerebellar learning should be viewed as the integration of various forms of plasticity in the cerebellar cortex and nuclei (Fig. 43.3).

43  Plasticity of the Cerebellum

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Fig. 43.3  A summary of plasticity in the cerebellar circuit (modified from Hansel et al. 2001). The occurrence of long-term plasticity is coded with color: red indicating potentiation and blue indicating depression. The intrinsic excitability is labeled with action potentials in somata, whereas conventional synaptic LTP or LTD is labeled with bars of colors at synapses

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Long-Term Depression at Parallel Fiber–Purkinje Cell Synapses

44

Michisuke Yuzaki

Abstract

Long-term depression (LTD) at parallel fiber (PF)– Purkinje cell (PC) synapses plays an important role in cerebellar oculomotor control and classical conditioning. Climbing fiber inputs represent an error signal to generate specific temporal and spatial Ca2+ dynamics at PC spines leading to endocytosis of postsynaptic AMPA receptors at PF synapses during LTD induction. Keywords

Albus · Climbing fiber · LTD · Long-term depression Marr · Motor learning · Nitric oxide · Parallel fiber

44.1 Introduction According to the Marr–Albus–Ito theory, long-term depression (LTD) at parallel fiber (PF)–Purkinje cell (PC) synapses serves as supervised learning machinery underlying cerebellum-­ dependent motor learning (Ito et  al. 2014). Climbing fiber (CF) inputs to PCs represent error signals to trigger endocytosis of postsynaptic AMPA receptors leading to LTD at PF–PC synapses. Motor learning is impaired in animals treated with various pharmacological reagents or genetically engineered to modify signaling cascades involved in LTD at PF-PC synapses (Yuzaki 2013). In recent years, however, many different types of synapses, including PF to molecular-layer interneuron (MLI) synapses, CF–PC synapses, and mossy fiber to granule cell synapses, have been shown to be plastic and contribute to cerebellum-dependent learning (Gao et al. 2012). Thus, many synaptic sites at which a variety of plastic changes can modulate learning in a similar manner M. Yuzaki (*) Department of Physiology, Keio University School of Medicine, Tokyo, Japan e-mail: [email protected]

(Edelman and Gally 2001). However, PF–PC synapses outnumber other types of synapses at least by a factor of 50, indicating the larger capacity of learning (Kawato et  al. 2021). Indeed, the number of postsynaptic AMPA receptors at PF–PC synapses is more variable than that at CF–PC and PF–MLI synapses, indicating that plastic changes mainly occur at PF– PC synapses in vivo (Masugi-Tokita et al. 2007). It was controversial whether long-term potentiation (LTP) (Gutierrez-­Castellanos et al. 2017; Schonewille et al. 2010) or LTD mediates cerebellum-dependent motor learning. Here, we summarize recent findings supporting a crucial role of LTD in the oculomotor control and molecular mechanisms underlying it.

44.2 LTD-Dependent Endocytosis of AMPA Receptors Similar to LTD in many brain regions, LTD at PF–PC synapses is mediated by clathrin-dependent endocytosis of postsynaptic AMPA receptors. A key event triggering this is phosphorylation of the GluA2 subunit of AMPA receptors at serine 880 residue (GluA2-S880) by protein kinase Cα (PKC; Fig.  44.1b) (Matsuda et  al. 2000; Xia et  al. 2000). AMPA receptors are stabilized at synapses via their binding with glutamate-interacting protein (GRIP). Phosphorylation at S880 drastically reduces GluA2’s affinity for GRIP, but not for protein interacting with C kinase 1 (PICK1), another anchoring protein that promotes AMPA receptor endocytosis. Therefore, inhibiting GluA2 interactions with GRIP or PICK1 impairs LTD induction (Matsuda et  al. 2000; Steinberg et al. 2006; Xia et al. 2000). PF inputs activate postsynaptic metabotropic glutamate receptor subtype 1 (mGluR1), leading to phospholipase C activation and production of inositol 1, 4, 5-trisphosphate (IP3) and diacylglycerol. IP3 then induces Ca2+ release through IP3 receptors, while diacylglycerol stimulates PKCα in coordination with Ca2+. On the other hand, CF inputs gen-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_44

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AMPA receptors freed from anchoring proteins diffuse into the endocytic zone located at perisynaptic sites. There, AMPA receptors first associate with clathrin adaptor protein complex-2 (AP-2). AP-2 binds to dephosphorylated forms of transmembrane AMPA receptor regulatory proteins (TARPs) (Matsuda et  al. 2013; Nomura et  al. 2012). Eventually, TARPs change their binding partner to AP-3, which regulates the late endosomal and lysosomal trafficking of AMPA receptors, a step necessary for the late phase of hippocampal (Matsuda et al. 2013) as well as cerebellar (Kim et al. 2017) LTD. Thus, LTD consists of two Ca2+-dependent steps: phosphorylation of GluA2 to dissociate from GRIP at postsynaptic sites, and dephosphorylation of TARPs to recruit AP-2 at the endocytic zone. Aside from activity-dependent changes, morphological changes are also observed at PF–PC synapses after motor learning in  vivo (Aziz et  al. 2014). In cultured PCs, LTD reportedly transits into a late phase (> ~60  min), which requires transcription of mRNAs, such as Arc (Smith-Hicks et al. 2010). However, whether and how late-phase LTD is induced in vivo remains elusive.

44.3 Optogenetic Control of Cerebellar LTD

Fig. 44.1  LTD and its signaling cascades. (a) A typical diagram of LTD in a whole-cell patch-clamp recording. Excitatory postsynaptic currents (EPSCs; insets) of a Purkinje cell were elicited by stimulating parallel fibers (PFs) and their amplitudes are plotted against time. Conjunctive stimulations (CJ-stim) of PFs and a climbing fiber induced enduring reduction of PF-EPSCs. (b) A positive-feedback model together with NO and GluD2 pathways for LTD induction

erate large depolarizations triggering Ca2+ influx through voltage-gated Ca2+ channels. Interestingly, combined PF and CF activity is detected by the supralinear summation of signals coming from two Ca2+ sources: IP3-mediated Ca2+ release from intracellular stores and Ca2+ influx through Ca2+ channels. Temporal and spatial Ca2+ dynamics in dendritic spines can explain several features of LTD, such as synapse specificity and dependence on the timing of PF and CF activation (Finch et al. 2012). Moreover, concurrent activation of PF and CF inputs induces a sustained (>20 min) increases in PKC activity by the positive-feedback cycle, consisting of mitogen-activated protein kinase (MAPK), phospholipase A2 (PLA2), and their related molecules (Fig. 44.1b) (Tanaka and Augustine 2008).

The controversy about the role of LTD in oculomotor learning is partly caused by various LTD induction protocols used in in vitro slice preparations (Suvrathan et al. 2016). In addition, compensatory mechanisms could modify synaptic plasticity in the remaining circuits and affect motor learning in genetically engineered mice (Gao et al. 2012; Ito et al. 2014). To circumvent these problems, an optogenetic tool, termed PhotonSABER, has been developed to inhibit postsynaptic AMPA receptor endocytosis, the final common step of LTD, by neutralizing the lumen of early endosomes with a photosensitive proton pump (Kakegawa et al. 2018) (Fig. 44.2a). Light stimulation acutely and reversibly inhibited LTD in acute slice preparations, in which PhotonSABER was specifically expressed in PCs, without affecting basal synaptic transmission or other forms of synaptic plasticity, such as LTP. Furthermore, fiberoptic illumination to PCs expressing PhotonSABER in vivo inhibited adaptation of the horizontal optokinetic response (Fig. 44.2b) and vestibulo-ocular reflex. Importantly, analyses using quantitative and highly sensitive SDS-digested freeze-fracture replica labeling (SDS-FRL) revealed that the decrease in the number of postsynaptic AMPA receptors in the flocculus after the adaptation of the optokinetic response (Wang et  al. 2014b) was completely inhibited by fiberoptic illumination to PCs expressing PhotonSABER (Kakegawa et al. 2018) (Fig. 44.2c). These

44  Long-Term Depression at Parallel Fiber–Purkinje Cell Synapses

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Fig. 44.2  PhotonSABER regulates AMPA receptor endocytosis and oculomotor learning. (a) Schematic drawing of PhotonSABER. PhotonSABER regulates the endocytosis of AMPARs by de-­acidifying the endosomal lumen through light-stimulated H+ pump activities. LS, light stimulation. (b) PhotonSABER inhibits the optokinetic response (OKR). Without light stimulation (LS(−)), the eye movements increase after 60-min exposures to sinusoidal oscillation (15°) of a checked-pattern screen (black traces, pre-exposure; red traces, post-exposure) in front of mice. Fiberoptic illumination (LS(+)) to the bilateral flocculi inhibits OKR adaptation. (c) PhotonSABER inhibits decrease in AMPA receptors following OKR. The number of AMPA receptors on freeze-fracture replicas from the flocculus decrease after OKR. The decrease is inhibited by fiberoptic illumination to the flocculi during OKR

results indicate a crucial role of LTD in the flocculus in mediating the oculomotor learning in vivo.

44.4 Unique Features of Cerebellar LTD There are several unique features of cerebellar LTD.  First, backpropagation of action potentials to dendrites, which releases voltage-dependent block of NMDA receptors by Mg2+, serves as a coincidence detector for LTP/LTD induction in most neuronal circuits in the cortex, striatum, and hippocampus. In contrast, action potentials do not backpropagate

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to PC dendrites because of their long electrotonic distance (Vetter et  al. 2001) and the low density of Na+ channels (Stuart and Hausser 1994). In addition, functional NMDA receptors are not highly expressed in Purkinje cells in adult rodents (Perkel et al. 1990). Indeed, LTD is normally induced in acute cerebellar slices prepared from PC-specific NMDA receptor knockout mice (Kono et al. 2019). Instead of Ca2+ influx through NMDA receptors, the supralinear summation of Ca2+ signals from PF-evoked Ca2+ release from IP3 receptors and CF-evoked Ca2+ influx through voltage-gated Ca2+ channels serves as a coincidence detector for LTP/LTD in cerebellar PCs. Thus, compared to the detection of coincidence by NMDA receptors with a temporal window of ~10  ms (Markram et  al. 1997) in hippocampalal neurons, CF-evoked Ca2+ changes are very slow, reflecting activation of mGluR1, production of IP3 and Ca2+ release from IP3 receptors in PCs. Therefore, PCs are suited to detect coincidence of PF/CF activities in a wider time window. For example, the window is expected to be ~30  ms for controlling ocular-following responses in the paraflocculus, and longer than 100 ms for regulating reaching tasks in the cerebellar hemisphere (Suvrathan et al. 2016). It remains unclear how such time windows matching the motor-sensory time delay associated with different movements are achieved by PCs located in different cerebellar regions. Instead of NMDA receptors, cerebellar LTD requires the δ2 glutamate receptor (GluD2). GluD2 is highly and predominantly expressed in PC dendrites. While GluD2’s channel activities are not required for LTD induction, its intracellular C-terminal region is indispensable (Kakegawa et al. 2008; Kohda et al. 2007) since it binds to PTPMEG, a protein tyrosine phosphatase that dephosphorylates a tyrosine residue (Y876) of GluA2. Interestingly, prior phosphorylation of Y876 hindered subsequent phosphorylation at S880 by PKC (Kohda et al. 2013). Thus, in GluD2-null or PTPMEG-null PCs, GluA2-Y876 is highly phosphorylated and LTD-­ inducing stimuli fail to phosphorylate S880 (Fig.  44.3). Therefore, GluD2 controls LTD induction by regulating interactions between the two phosphorylation sites of GluA2. Cbln1, a C1q family protein released from PFs, binds to the extracellular N-terminal region of GluD2 (Matsuda et al. 2010). Although it remains unclear why LTD is impaired in Cbln1-null mice (Hirai et al. 2005), PTPMEG signaling at the C-terminus may be regulated by binding of Cbln1 at the N-terminus of GluD2. Nitric oxide (NO), which is produced by NO synthase (NOS) following Ca2+ influx through NMDA receptors, serves as a retrograde messenger to induce long-term potentiation (LTP) in hippocampal neurons (Padamsey and Emptage 2014). LTD is impaired in mice genetically lacking neuronal NOS (Lev-Ram et  al. 1997). LTD and oculomotor learning are impaired in MLI/PC-specific, but not granule cell- or PC-specific NMDA receptor knockout

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involved in LTD induction, but rather plays a role in other aspects, such as the spread of plasticity across synapses. Acknowledgements This work was supported by the JST CREST (JPMJCR1854) and MEXT KAKENHI (20H05628).

References

b

Fig. 44.3  A proposed model of how GluD2 regulates cerebellar LTD. (a) Basal state. GluD2 maintains low phosphorylation levels at Y876 of the GluA2 subunit of AMPA receptors via PTPMEG, a protein tyrosine phosphatase. (b) LTD induction. LTD-inducing stimuli further dephosphorylate this tyrosine residue. Y876 dephosphorylation allows S880 phosphorylation by protein kinase C, which leads to the replacement of GRIP, a membrane anchoring protein, with PICK1 to allow AMPA receptor endocytosis

mice, indicating an important role of NMDA receptors in MLIs (Kono et  al. 2019). Since application of an NO donor restored LTD in MLI/PC-specific NMDA receptor knockout cerebellar slices, NO is likely produced by activation of NMDA receptors in MLIs during LTD.  NO upregulates the MAPK pathway in the positive-feedback loop of LTD induction (Fig. 44.1b). NO is also necessary for postsynaptic LTP induced by stimulation of PFs at 1 Hz (Kakegawa and Yuzaki 2005; Lev-Ram et al. 2002). However, this form of LTP is intact in NMDA receptor knockout mice (Kono et al. 2019). Instead, 1 Hz PF stimulation activates cannabinoid receptor 1 to produce NO in PFs (Wang et  al. 2014a). Thus, NO may not be directly

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44  Long-Term Depression at Parallel Fiber–Purkinje Cell Synapses Markram H, Lubke J, Frotscher M, Sakmann B (1997) Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275:213–215 Masugi-Tokita M, Tarusawa E, Watanabe M, Molnar E, Fujimoto K, Shigemoto R (2007) Number and density of AMPA receptors in individual synapses in the rat cerebellum as revealed by SDS-­ digested freeze-fracture replica labeling. J Neurosci 27:2135–2144 Matsuda S, Launey T, Mikawa S, Hirai H (2000) Disruption of AMPA receptor GluR2 clusters following long-term depression induction in cerebellar Purkinje neurons. EMBO J 19:2765–2774 Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R et al (2010) Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science 328:363–368 Matsuda S, Kakegawa W, Budisantoso T, Nomura T, Kohda K, Yuzaki M (2013) Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression. Nat Commun 4:2759 Nomura T, Kakegawa W, Matsuda S, Kohda K, Nishiyama J, Takahashi T, Yuzaki M (2012) Cerebellar long-term depression requires dephosphorylation of TARP in Purkinje cells. Eur J Neurosci 35:402–410 Padamsey Z, Emptage N (2014) Two sides to long-term potentiation: a view towards reconciliation. Philos Trans R Soc Lond Ser B Biol Sci 369:20130154 Perkel DJ, Hestrin S, Sah P, Nicoll RA (1990) Excitatory synaptic currents in Purkinje cells. Proc Biol Sci 241:116–121 Schonewille M, Belmeguenai A, Koekkoek SK, Houtman SH, Boele HJ, van Beugen BJ, Gao Z, Badura A, Ohtsuki G, Amerika WE et al (2010) Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron 67:618–628

291 Smith-Hicks C, Xiao B, Deng R, Ji Y, Zhao X, Shepherd JD, Posern G, Kuhl D, Huganir RL, Ginty DD et al (2010) SRF binding to SRE 6.9  in the arc promoter is essential for LTD in cultured Purkinje cells. Nat Neurosci 13:1082–1089 Steinberg JP, Takamiya K, Shen Y, Xia J, Rubio ME, Yu S, Jin W, Thomas GM, Linden DJ, Huganir RL (2006) Targeted in  vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron 49:845–860 Stuart G, Hausser M (1994) Initiation and spread of sodium action potentials in cerebellar Purkinje cells. Neuron 13:703–712 Suvrathan A, Payne HL, Raymond JL (2016) Timing rules for synaptic plasticity matched to behavioral function. Neuron 92:959–967 Tanaka K, Augustine GJ (2008) A positive feedback signal transduction loop determines timing of cerebellar long-term depression. Neuron 59:608–620 Vetter P, Roth A, Hausser M (2001) Propagation of action potentials in dendrites depends on dendritic morphology. J Neurophysiol 85:926–937 Wang DJ, Su LD, Wang YN, Yang D, Sun CL, Zhou L, Wang XX, Shen Y (2014a) Long-term potentiation at cerebellar parallel fiber-­ Purkinje cell synapses requires presynaptic and postsynaptic signaling cascades. J Neurosci 34:2355–2364 Wang W, Nakadate K, Masugi-Tokita M, Shutoh F, Aziz W, Tarusawa E, Lorincz A, Molnar E, Kesaf S, Li YQ et al (2014b) Distinct cerebellar engrams in short-term and long-term motor learning. Proc Natl Acad Sci U S A 111:E188–E193 Xia J, Chung HJ, Wihler C, Huganir RL, Linden DJ (2000) Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron 28:499–510 Yuzaki M (2013) Cerebellar LTD vs. motor learning-lessons learned from studying GluD2. Neural Netw 47:36–41

Regulation of Calcium in the Cerebellum

45

Donna L. Gruol

Abstract

45.1 Ca2+ Signaling Is Essential for Cerebellar Function Ca2+ is an important ion in central nervous system (CNS) biology, where it plays a critical role in the basic functions of neurons, glia, and other cell types. In CNS neurons, Ca2+ is a generator of electrical signals, an inducer and regulator of synaptic transmission, and a second messenger that controls many biochemical processes. Ca2+ is also a signal transmitter and second messenger in glial cells. Ca2+ levels in neurons and glia are dynamic but judiciously controlled in order to maintain biological processes at a level compatible with life. An excess or deficit of Ca2+ can result in cell damage or death. A variety of cellular mechanisms, through a process referred to as Ca2+ signaling, enable or contribute to the changes in intracellular Ca2+ that are essential for normal cell function, some of which are present in all eukaryotic cells and others that are unique to the functions of a particular class of cells. This chapter will briefly describe the cellular mechanisms that contribute to Ca2+ signaling in cerebellar and other CNS neurons. These mechanisms are located throughout the neuron including at presynaptic sites (e.g., axon terminals) where they regulate transmitter release, at postsynaptic sites (e.g., dendrites) where they influence synaptic responses, in the cytosol where they regulate biochemical pathways and other physiological functions, and in the nucleus where they regulate gene transcription. Many of these mechanisms are also expressed in non-­neuronal cells. Keywords

Ca2+ signaling · Second messengers · Intracellular Ca2+ stores · Ca2+ channels · ligand-gated receptors · Ca2+binding proteins D. L. Gruol (*) Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA e-mail: [email protected]

Ca2+ signaling occurs in all cell types of the cerebellum and plays an essential role in cerebellar function. Ca2+ signaling can involve extracellular to intracellular Ca2+ signaling and/ or within cell Ca2+ signaling (Lamont and Weber 2012). A variety of cellular components participate in Ca2+ signaling (see Fig. 45.1), although they can vary in type and level of expression across cerebellar cell types. Ca2+ signaling in the cerebellum has been extensively studied in Purkinje neurons, which express an abundance of Ca2+ signaling components, and in Bergman glia, which play an important regulatory role in the physiological function of Purkinje neurons. As the sole output neuron of the cerebellar cortex and an important integrator of cortical signals, Purkinje neurons play a central role in cerebellar functions such as motor coordination and, through connections with other brain regions, the processing of sensory, cognitive, and emotional information. Thus, the characteristics and role of Ca2+ signaling in Purkinje neurons are of particular interest, although Ca2+ signaling is a critical function of all cell types in the cerebellum (Cheron et  al. 2008). Ca2+ is widely but unequally distributed in the cerebellum and other brain regions. In particular, Ca2+ levels are considerably higher in the extracellular fluid that baths the cells (~1–2 mM) than in the cytosol of the cells (~100 nM), a difference that in neurons creates a driving force for Ca2+ influx. In addition, two organelles within the cytosol, the endoplasmic reticulum and mitochondria, serve as Ca2+ storage vessels and have higher intra-organelle Ca2+ levels than cytosol Ca2+ level. There is also a driving force between these intracellular Ca2+ stores and cytosolic Ca2+. These pronounced concentration differences are a consequence of the impermeability of the cellular membranes to Ca2+ and other ions and the actions of various cell mechanisms (e.g., membrane ion channels, Ca2+ pumps) that regulate influx and efflux of Ca2+ to or from the cytosol.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_45

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Fig. 45.1 Ca2+ signaling components in cerebellar neurons. Ca2+ influx from the extracellular fluid occurs through several types of ion channels including Ca2+ channels (CaCh), NMDAR channels, Ca2+ permeable AMPA receptors and TRPC. Increases in cytosolic Ca2+ levels can also occur by Ca2+ release from intracellular Ca2+ stores through the IP3R and RyR channels. Ca2+ is removed from the cytosol by Ca2+ pumps and Na+/Ca2+ exchangers located on the plasma membrane and by various Ca2+ pumps located on the endoplasmic reticulum and mitochondria. Ca2+binding proteins (CBP) at different concentrations are located in all cell regions

In excitable cells such as neurons, Ca2+ acts as a charge carrier during extracellular to intracellular signaling (i.e., Ca2+ influx) and can produce an electrical signal which serves an important role in neuronal excitability. Ca2+ influx has a depolarizing influence on the membrane potential (i.e., the normal charge difference that exists across the cell membrane of neurons and other cell types), which typically has a hyperpolarized value (i.e., a negative value; typically, −50 to −70  mV). The depolarization produced by Ca2+ influx can regulate the activity of a variety of membrane ion channels that are sensitive to the value of the membrane potential (i.e., voltage-sensitive channels) such as voltage-sensitive K+ channels that act to repolarize the membrane potential during action potentials. Ca2+ influx also contributes to intracellular Ca2+, which plays an important role as a second messenger. Numerous proteins and biochemical pathways are regulated by intracellular Ca2+ in neurons and other cell types. In neurons, Ca2+ acting as second messenger regulates transmitter release from presynaptic terminals, pre- and postsynaptic plasticity, the activity of other ion channels (e.g., Ca2+ activated K+

channels) that mediate neuronal excitability, the activation state of intracellular enzymes, and other proteins (e.g., kinases and phosphatases) (Ignarro et  al. 2002) and gene expressions (Brini et  al. 2014; Puri 2020). Through these second messenger actions, Ca2+ can couple electrical signals at the cell surface to physiological events in the cytosol of the soma, processes (i.e., dendrites and axons), and nucleus of the neurons. Ca2+ signaling plays a critical role in synaptic transmission and plasticity, which are basic neuronal mechanisms that mediate cerebellar circuit function and cerebellar learning. Ca2+ influx, Ca2+ release from intracellular stores, and second messenger actions of Ca2+ are instrumental to synaptic transmission and plasticity. Synaptic plasticity is important for cerebellar learning (e.g., motor learning) and is bidirectional. Synaptic plasticity can involve an enhancement of synaptic transmission, referred to as long-term potentiation (LTP), or a reduction in synaptic transmission, referred to as long-term depression (LDP). Both LTD and LTP have been intensely studied at the excitatory parallel fiber and climbing fiber inputs to the Purkinje neurons (see

45  Regulation of Calcium in the Cerebellum

chapter on Synaptic Plasticity). Intracellular Ca2+ levels are a primary determinant of the directionality of synaptic plasticity (LTD or LTP). For example, at parallel fiber to Purkinje neuron synapses, high intracellular Ca2+ levels favor LTD, while more moderate Ca2+ levels favor LTP (Rinaldo and Hansel 2010). Intracellular Ca2+ is also critical for glial cell function, where it serves many of the same biochemical regulatory roles as in neurons. Astrocytes, which are the most abundant glial cell in the brain, have several mechanisms for Ca2+ signaling including Ca2+ influx through Ca2+ permeable membrane channels (e.g., some types of glutamate receptors) and Ca2+ release from intracellular stores (Lalo et  al. 2011). Astrocytes are important regulators of neuronal and synaptic activity and Ca2+ plays a key role in these processes (Fiacco and McCarthy 2006; Verkhratsky 2006). For example, Bergman glia, a specialized type of astrocyte found only in the cerebellum, extend their processes around the excitatory dendritic synapses of Purkinje neurons creating microdomains in which glial/neuronal communication occurs. Bergman glia express many of the same neurotransmitter and neuromodulator receptors as Purkinje neurons, and two-­ way communication between Purkinje neurons and Bergman glia in the microdomains is basic to synaptic integration in the cerebellum. Synaptic activity (e.g., parallel fiber activation) and transmitters or other signaling molecules (e.g., ­glutamate, ATP, NO) released from axon terminals of neurons or glial processes in the microdomain interact with receptors on the Bergman glia resulting in an increase in intracellular Ca2+ levels, which are then propagated in waves to other Bergman glia through gap junctions of the glial network. The changes in intracellular Ca2+ produced by these waves can induce release of glial signaling molecules that influence synaptic transmission at multiple synapses, alter astrocyte gene expression (e.g., expression of glutamate transporters, which remove glutamate from the synapse), alter biochemical state of the glia, and alter the structure and function of microdomains, all of which will affect Purkinje neuronal/Bergman glial communication and, consequently, information processing in the cerebellum (Müller and Kettenmann 1995; Metea and Newman 2006; Hoogland et al. 2009).

45.2 Membrane Proteins that Mediate Ca2+ Influx to the Cytosol Several molecules located in the plasma membrane enable Ca2+ to transverse the otherwise impermeable cell membrane and enter the cytosol of neurons (Fig. 45.1). Of these, voltage-­gated Ca2+ channels (VGCCs) and ligand-gated channels play a primary role. In general, VGCCs are expressed in neurons, whereas ligand-gated channels are

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expressed by both neurons and glia (Metea and Newman 2006). Both VGCCs and ligand-gated channels require stimulation to be functionally active and enable Ca2+ flux. VGCCs are activated by changes in resting membrane potential, whereas ligand-gate channels are activated by neurochemicals such as neurotransmitters. In the unstimulated state, VGCCs and ligand gated channels are closed and impermeable to Ca2+. When activated, the channels open and Ca2+ influx occurs due to the large driving force for Ca2+ resulting from the prominent concentration difference for Ca2+ between the outside (mM range) and inside (nM range) of the neuron. In the case of ligand-gated channels, other ions may also flux through the channel in addition to Ca2+ (e.g., Na+, K+). VGCCs are divided into three gene subfamilies (Cav1, Cav2, and Cav3), which are further subdivided into six classes (L, N, P, Q, R, and T) based on the physiological and pharmacological properties of the Ca2+ current mediated by the channel. The properties of the currents mediated by the different Ca2+ channel types, such as voltage-sensitivity and kinetics, the location of the channel on the neuronal surface (e.g., axon, soma, dendrite), and the number and type of Ca2+ channels expressed by the neuron play key roles in defining the physiological properties of the neuron. For example, P-type channels, which were first identified in Purkinje neurons, are highly expressed in the large dendritic tree of the Purkinje neurons (Lin et al. 1990). Excitatory synaptic input to the Purkinje neuron dendrites, particularly from climbing fibers, can activate these P-type channels resulting in prominent dendritic Ca2+ spikes. The functioning of dendritic P-type Ca2+ channels is critical to the unique physiological properties and functional role of Purkinje neurons in cerebellar function (Llinas and Sugimori 1980; Hartmann and Konnerth 2005; Kitamura and Kano 2013). Depolarizing or hyperpolarizing the membrane potential can result in Ca2+ channel activation depending on Ca2+ channel type. For example, T-type Ca2+ channels are activated by depolarization from a hyperpolarized membrane potential, whereas P-type channels are activated by depolarization from resting membrane potential (~ −60 mV). In neurons, VGCCs that contribute to action potential generation are activated by a membrane depolarization sufficient to reach the threshold voltage for channel activation, which can vary for different Ca2+ channel types. Such membrane depolarizations include pacemaker potentials (or other types of membrane oscillations), the initial phase of the action potential that is mediated by Na+ influx through voltage-­gated Na+ channels, and synaptic depolarizations produced by excitatory neurotransmitters such as glutamate. Both the influx of Ca2+ and membrane depolarization due to Ca2+ influx can result in activation of other membrane ion channels (e.g., Ca2+ activated K+ channels), which mediate

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membrane repolarizations) and thereby regulate the excitability of the neuron. The most prominent ligand-gated Ca2+ permeable channels in the cerebellum are NMDA receptor (NMDAR) channels and some subtypes of AMPA receptor channels, which when activated produce a membrane depolarization. These ligand-gated channels are activated by the neurotransmitter glutamate, although NMDA receptors also have a voltage requirement for activation. In addition to Ca2+, these channels are permeable to Na+ and K+, a property that is relevant to the degree of depolarization that can be produced when the receptor is activated. Another type of glutamate receptor, the metabotropic glutamate receptor (mGluR), and in particular mGluR subtypes 1 and 5 (mGluR1/5), also plays a key role in Ca2+ signaling in the cerebellum. mGluR1/5 are G-protein coupled receptors and do not contain an ion channel in their structure. However, when activated they induce an increase in cytosolic Ca2+ through the actions of phospholipase C (PLC), a downstream signaling partner of mGluR1 (Fig. 45.1). PLC activation results in the production of two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to its receptor, IP3R, which is located on the endoplasmic reticulum and contains a Ca2+ permeable channel (Mikoshiba 2015). IP3R activation results in efflux of Ca2+ through the receptor channel from Ca2+ stores in the endoplasmic reticulum to the cytosol, thereby increasing cytosolic Ca2+ levels. IP3R activation also requires Ca2+ as a co-agonist. Thus, IP3 and Ca2+ act cooperatively to induce Ca2+ release from intracellular stores via IP3Rs. In Purkinje neurons (but not in granule neurons), IP3Rs are also present on the inner nuclear membrane where they appear to function in nuclear Ca2+ signaling (Marchenko and Thomas 2006; Gruol et al. 2010). The nuclear membrane is contiguous with endoplasmic reticulum. Nuclear Ca2+ signaling can also occur by Ca2+ influx from the cytosol through nuclear pores. In addition to IP3Rs, a second receptor that contains a Ca2+ channel, the ryanodine receptor (RyR), is located on the endoplasmic reticulum and plays an important role in Ca2+ signaling. RyRs are activated by Ca2+ and, when activated, Ca2+ efflux from Ca2+ stores within the endoplasmic reticulum occurs through the receptor channel thereby increasing cytosolic Ca2+. Thus, RyRs act as Ca2+ amplifiers that enhance cytosolic Ca2+ signals produced by other mechanisms such as VGCCs, NMDARs, or IP3Rs. mGluR1 and downstream signaling molecules, PLC, IP3R, and RyR are highly expressed in the Purkinje neurons (Furuichi et  al. 1989; Shigemoto et al. 1992; Nakamura et al. 2004). mGluR1 activation can also result in Ca2+ signaling through another pathway, activation of plasma membrane cationic channels called transient receptor potential canonical (TRPC) channels (Sun et al. 2014). TRPC channels are

D. L. Gruol

permeable to Ca2+, Na+, and K+ and when activated produce a membrane depolarization and Ca2+ influx.

45.3 Cytosolic and Membrane Proteins that Regulate Ca2+ Levels in the Cytosol Increases in intracellular Ca2+ levels during Ca2+ signaling are typically transient in nature. Ca2+ levels recover through a variety of mechanisms including Ca2+-binding proteins and membrane transport systems. A variety of cell proteins bind Ca2+ and act as Ca2+ buffers including calbindin, parvalbumin, calmodulin, and calretinin, which differ in their Ca2+ buffering properties (Schwaller et  al. 2002). These Ca2+binding proteins play a central role in the regulation of cellular Ca2+ levels and vary in the level of expression across cell types, species, and age (Bastianelli 2003). Although most neurons express multiple types of Ca2+-binding proteins, certain cells types show more prominent expression of one or more Ca2+-binding proteins. For example, Purkinje neurons are noted for expression of calbindin and parvalbumin, basket, stellate, and Golgi cells are noted for expression of parvalbumin, and granule neurons and unipolar bush cells are noted for expression of calretinin (Bastianelli 2003). All cerebellar neurons express calmodulin. In addition to Ca2+ buffers, Ca2+ transport mechanisms on the plasma membrane (plasma membrane Ca2+-ATPase (PMCA); Na+-Ca2+ exchanger) remove Ca2+ from the cytosol to the extracellular fluid, whereas transport mechanisms located on the endoplasmic reticulum (sarco-endoplasmic Ca2+-ATPase (SERCA)) and mitochondria (mitochondrial Ca2+ uniporter and the H+/Ca2+ exchanger) import cytosolic Ca2+ into these organelles for storage (Wu et al. 2021). The actions of the intracellular Ca2+ buffers and membrane transport systems are critical for the control of cytosolic Ca2+ levels, which is highly regulated, and the maintenance of conditions necessary for normal cell function (Cheron et al. 2008).

45.4 Ca2+ and Disease Proper functioning of cellular mechanisms mediating Ca2+ signaling and homeostasis is essential for normal brain function (Brini et  al. 2014). A variety of conditions have been identified that involve altered Ca2+ signaling and altered cerebellar function, typically identified by deficits in motor function. A majority of these conditions are classified into two groups, Spinocerebellar ataxias (SCAs) or Episodic ataxias (Mark et al. 2017). SCAs are a heterogenous group of genetic and neurodegenerative diseases that have been exten-

45  Regulation of Calcium in the Cerebellum

sively studied in animal models and are characterized by ataxia and cerebellar atrophy. Disruption of Ca2+ signaling in Purkinje cells is thought to be central to the pathogenesis of several forms of these diseases (Brown and Loew 2012; Meera et al. 2016; Prestori et al. 2019). For example, mutations in the gene for P-type Ca2+ channel, which is abundantly expressed in the Purkinje neurons, is thought to play a key role in SCA6 and Episodic ataxia type 2 (EA2), whereas mutations in the gene for the T-type Ca2+ channel are implicated in SCA42. Mutations in the gene for PKC-γ, which is involved Ca2+ signaling and also expressed at high levels in Purkinje neurons, is implicated in SCA14. Several other genes for proteins involved in Ca2+ signaling that highly expressed in the cerebellum are also implicated in SCAs including the gene for TRPC3, IP3R, and mGluR1 (e.g.,SCA41,SCA15/16,SCA14, respectively) (Hisatsune et al. 2018; Prestori et al. 2019). Mutations affecting other targets in Purkinje neurons that indirectly influence Ca2+ signaling can also contribute to the ataxic symptoms (Begum et al. 2016; Hoxha et al. 2018). Cerebellar dysfunction has also been noted in several forms of migraine, and altered P-type Ca2+ channel function in Purkinje neurons has been suggested as a contributor to this condition (Vincent and Hadjikhani 2007).

45.5 Summary Ca2+ signaling is essential for cerebellar function. Ca2+ signaling contributes to neuronal excitability, is essential for synaptic transmission and synaptic plasticity, and regulates important biochemical pathways and gene expression in cerebellar cells. A variety of cellular proteins participate in Ca2+ signaling, many of which are expressed at high levels in the cerebellum, and particularly in the Purkinje neurons, which are noted for their large dendrites that exhibit prominent Ca2+-mediated action potentials, an abundance of Ca2+ signaling components, and large Ca2+ signals. The cerebellum participates in a variety of motor and non-motor behaviors, including processing of sensory, cognitive, and emotional information (Schmahmann 2019). Appropriate Ca2+ signaling in cerebellar circuits is essential for these functions. Dysregulation of Ca2+ signaling results in abnormal cellular function and possible cell death, and consequently, altered cerebellar function, which can impact the function of other brain regions that are targets of synaptic pathways originating in the cerebellum.

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297 Begum R, Bakiri Y, Volynski KE, Kullmann DM (2016) Action potential broadening in a presynaptic channelopathy. Nat Commun 7:12102 Brini M, Calì T, Ottolini D, Carafoli E (2014) Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci 71:2787–2814 Brown SA, Loew LM (2012) Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia. BMC Syst Biol 6:70 Cheron G, Servais L, Dan B (2008) Cerebellar network plasticity: from genes to fast oscillation. Neuroscience 153:1–19 Fiacco TA, McCarthy KD (2006) Astrocyte calcium elevations: properties, propagation, and effects on brain signaling. Glia 54:676–690 Furuichi T, Yoshikawa S, Miyawaki A, Wada K, Maeda N, Mikoshiba K (1989) Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400. Nature 342:32–38 Gruol DL, Netzeband JG, Nelson TE (2010) Somatic Ca2+ signaling in cerebellar Purkinje neurons. J Neurosci Res 88:275–289 Hartmann J, Konnerth A (2005) Determinants of postsynaptic Ca2+ signaling in Purkinje neurons. Cell Calcium 37:459–466 Hisatsune C, Hamada K, Mikoshiba K (2018) Ca(2+) signaling and spinocerebellar ataxia. Biochim Biophys Acta, Mol Cell Res 1865:1733–1744 Hoogland TM, Kuhn B, Göbel W, Huang W, Nakai J, Helmchen F, Flint J, Wang SS (2009) Radially expanding transglial calcium waves in the intact cerebellum. Proc Natl Acad Sci U S A 106:3496–3501 Hoxha E, Balbo I, Miniaci MC, Tempia F (2018) Purkinje cell signaling deficits in animal models of ataxia. Front Synaptic Neurosci 10:6 Kitamura K, Kano M (2013) Dendritic calcium signaling in cerebellar Purkinje cell. Neural Netw 47:11–17 Ignarro LJ, Napoli C, Loscalzo J (2002) Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide - an overview. Circ Res 90:21–28 Lalo U, Pankratov Y, Parpura V, Verkhratsky A (2011) Ionotropic receptors in neuronal–astroglial signalling: what is the role of “excitable” molecules in non-excitable cells. Biochim Biophys Acta 1813:992–1002 Lamont MG, Weber JT (2012) The role of calcium in synaptic plasticity and motor learning in the cerebellar cortex. Neurosci Biobehav Rev 36:1153–1162 Lin JW, Rudy B, Llinas R (1990) Funnel-web spider venom and a toxin fraction block calcium current expressed from rat brain mRNA in xenopus oocytes. Proc Natl Acad Sci U S A 87:4538–4542 Llinas R, Sugimori M (1980) Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices. J Physiol 305:197–213 Marchenko SM, Thomas RC (2006) Nuclear Ca2+ signalling in cerebellar Purkinje neurons. Cerebellum (London, England) 5:36–42 Mark MD, Schwitalla JC, Groemmke M, Herlitze S (2017) Keeping our calcium in balance to maintain our balance. Biochem Biophys Res Commun 483:1040–1050 Meera P, Pulst SM, Otis TS (2016) Cellular and circuit mechanisms underlying spinocerebellar ataxias. J Physiol 594:4653–4660 Metea MR, Newman EA (2006) Calcium signaling in specialized glial cells. Glia 54:650–655 Mikoshiba K (2015) Role of IP3 receptor signaling in cell functions and diseases. Adv Biol Regul 57:217–227 Müller T, Kettenmann H (1995) Physiology of Bergmann glial cells. Int Rev Neurobiol 38:341–359 Nakamura M, Sato K, Fukaya M, Araishi K, Aiba A, Kano M, Watanabe M (2004) Signaling complex formation of phospholipase Cbeta4 with metabotropic glutamate receptor type 1alpha and 1,4,5-­trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain. Eur J Neurosci 20:2929–2944 Prestori F, Moccia F, D’Angelo E (2019) Disrupted calcium signaling in animal models of human spinocerebellar ataxia (SCA). Int J Mol Sci 21:216

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Neurotrophic Factors in Cerebellar Development and Function

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Juan Pablo Zanin and Wilma J. Friedman

Abstract

Neurotrophic factors regulate numerous aspects of brain development, including the proliferation of neuronal precursors, neuronal migration, differentiation, and formation of circuitry. In the cerebellum, specific trophic factors influence different aspects of these cellular functions, both during development and in adult. In this chapter, we will provide an overview of the neurotrophin family of trophic factors in regulating different aspects of cerebellar development and function, and discuss the role of each factor in influencing the different cell types in the cerebellum. Keywords

Neurotrophin · BDNF · NT3 · Trk · p75NTR

46.1 Introduction Numerous growth factors are present in the CNS to regulate different aspects of neuronal development and function, including survival, migration, differentiation, and synaptic activity. In this chapter, we will focus on the neurotrophin family of growth factors, which includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT4). The neurotrophins are key regulators of nervous system development and maintenance. These factors elicit their functions by activating two different types of receptors; the Trk (tropomyosin receptor kinase) family of receptors, which show a specific affinity for each neurotrophin, with NGF binding to TrkA, BDNF, and NT4 to TrkB, and NT3 to TrkC; as well as the p75 neurotrophin receptor (p75NTR), which can bind with J. P. Zanin · W. J. Friedman (*) Department of Biological Sciences, Rutgers University, Newark, NJ, USA e-mail: [email protected]; [email protected]

similar affinity to all the neurotrophins. Interestingly, p75NTR can form receptor complexes with different co-­ receptors to bind different ligands and regulate a variety of cellular functions, depending on the cell context. p75NTR can associate with each of the Trk receptors, increasing the binding affinity for the corresponding neurotrophin to promote neuronal survival and differentiation. Originally, neurotrophins were identified as neuronal survival factors; however, the uncleaved neurotrophin precursors, the proneurotrophins, can be secreted and can bind to a p75NTR-­ sortilin receptor complex with high affinity and promote apoptosis (Lee et al. 2001). Thus, depending on the cellular context, neurotrophins have been involved in multiple and sometimes antagonistic cellular mechanisms including survival and apoptosis, stimulation or prevention of neuronal migration, proliferation, and differentiation. These different functions depend on whether the neurotrophin precursor protein is cleaved, which receptor complex the factor binds to, and the signaling pathway activated by the different receptor complexes. Similar to other areas in the nervous system, cerebellar development is mainly driven by three major cellular mechanisms: (1) proliferation and survival of the neural progenitors, (2) migration to the final location, and (3) differentiation into adult neurons and establishment of circuitry. These mechanisms are all influenced by neurotrophins. During development, NT-3 and BDNF are expressed in the cerebellum, (Rocamora et al. 1993; Borghesani et al. 2002), as well as their receptors, TrkB, TrkC, and p75NTR (Segal et  al. 1995).

46.1.1 Neurotrophin Effects on Proliferation of Cerebellar Granule Cell Progenitors The granule cell precursors (GCP) migrate tangentially from the rhombic lip to a sub-pial location in the cerebellar primordium, where they form the external granule layer (EGL),

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_46

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a transient secondary proliferative layer. In the EGL, the GCPs clonally expand to give rise to the most abundant neuronal population in brain, the cerebellar granule neurons (CGN). The proliferation of GCPs takes place from late embryonic stages through the first two to three postnatal weeks in rodents, with waves of GCPs exiting the cell cycle and starting their radial migration to the internal granule layer (IGL), while others continue proliferating in the EGL. Sonic hedgehog (Shh) is critical to promote GCP proliferation, while different factors have been identified to promote cell cycle exit of GCPs, including Wnt3 (Anne et al. 2013), BMP2 (Bone Morphogenetic Protein 2) (Rios et al. 2004), and PACAP (Pituitary adenylate-cyclase-activating polypeptide) (Nicot et al. 2002). In addition to these factors, several neurotrophins and their receptors are present in the cerebellum during this period and are involved in different aspects of cell cycle control and survival of cerebellar neurons. In particular, BDNF and NT-3 regulate different aspects of granule cell development. It remains unclear as to which cells synthesize and secrete NT-3 in the cerebellum, since NT-3 mRNA has been detected in granule cells (Lindholm et al. 1993a; Rocamora et al. 1993), yet the NT-3 protein has only been detected in Purkinje cells (Zhou and Rush 1994; Zanin et  al. 2016). NT-3 expression peaks around postnatal day (P) 5 in mice, the period of maximal GCP proliferation, suggesting that this neurotrophin might regulate GCP proliferation. The precursor of NT-3, proNT-3, can be detected in Purkinje cells and can be secreted to induce cell cycle exit of GCPs, requiring activation of p75NTR (Zanin et al. 2016). Thus, in addition to the factors mentioned above, proNT3 can also induce GCP cell cycle exit. p75NTR is expressed in cerebellar GCPs as well as in Purkinje neurons (Fig. 46.1) (Carter et al. 2003; Zanin et al. 2016). In Purkinje neurons, p75NTR expression starts dur-

Fig. 46.1  Postnatal day 7 cerebellum showing p75NTR (green) in the Purkinje cell layer (PCL) and in proliferating GCPs in the External Granule Layer (EGL) labeled with the proliferation marker Ki67 (magenta)

J. P. Zanin and W. J. Friedman

ing development and is maintained throughout adulthood. In contrast, p75NTR expression in granule cells is high in proliferating progenitors and is downregulated as the GCPs differentiate, with a complete absence in postmitotic granule cells, suggesting a role for p75NTR in cell cycle regulation. Deletion of p75NTR in mice elicited an acceleration of the cell cycle, with increased GCP proliferation, an elevated number of granule cells, and a larger cerebellum (Zanin et al. 2016, 2019).

46.1.2 Neurotrophins Promote Survival of Different Cerebellar Neurons 46.1.2.1 Granule Cells In addition to p75NTR, the NT-3 receptor TrkC, is expressed by both Purkinje and granule cells (Minichiello and Klein 1996). An extensive literature has demonstrated that NT-3 is important for granule cell survival. NT-3−/− animals do not survive past the first postnatal day due to severe defects in the peripheral nervous system; however, a CNS-specific deletion of NT-3 caused significant granule cell apoptosis, without affecting GCP proliferation or Purkinje cell survival (Bates et al. 1999). Moreover, animal models that either prevent the expression (Li et  al. 2004) or reduce the release (Sadakata et al. 2007) of NT-3 or BDNF in the cerebellum had reduced neuronal survival, and exhibited defects in differentiation and migration of the granule cells. Furthermore, in  vivo injections of a function-blocking antibody against NT-3 demonstrated increased apoptosis of granule cells (Katoh-Semba et  al. 2000), supporting a critical role for NT-3 in promoting survival of these neurons. BDNF is also present in the developing cerebellum, with expression in Purkinje and granule cells (Schwartz et  al. 1997) peaking after the first postnatal week (Rocamora et al. 1993). Deletion of BDNF evoked increased granule cell apoptosis, and deletion of both TrkB and TrkC showed greater granule cell loss than deletion of the individual receptors, suggesting some compensatory signaling mechanism between these two receptors (Minichiello and Klein 1996). In addition, BDNF induced the survival of granule cells in culture (Lindholm et al. 1993b; Gao et al. 1995). BDNF and TrkB expression remain elevated in the IGL of adult mice, suggesting the importance of this neurotrophin in the continued survival and function of the mature granule cells (Rocamora et al. 1993; Chen et al. 2016). 46.1.2.2 Purkinje Cells Early studies investigating the role of trophic factors on Purkinje cell survival were very challenging due to the complications of growing these cells in dissociated culture. One of the first trophic factors identified to promote Purkinje cell survival was NGF, although the effect required the application of NGF in combination with glutamate receptor agonists

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or muscarinic acetylcholine agonists (Cohen-Cory et  al. 1991). The effect of NGF on Purkinje cell survival was associated with the activation of p75NTR (Mount et  al. 1998), which remains expressed in these cells in adult animals. In further studies on the effects of neurotrophins, NT-3 promoted the survival of Purkinje cells in vitro (Lärkfors et al. 1996). The role of BDNF in Purkinje cell survival is less clear, with conflicting data using Purkinje cell cultures (Lärkfors et al. 1996; Morrison and Mason 1998), likely due to the difficulty in maintaining Purkinje cells and promoting their complex differentiation in culture. Using organotypic cerebellar explants, neurotrophin treatment showed no increase in Purkinje cell survival (Seil 1999). Moreover, in  vivo studies using knockout mice showed that deleting TrkB, TrkC, or both had little effect on Purkinje cell survival, but negatively impacted the maturation of the dendritic arbor (Minichiello and Klein 1996).

rather than a direct effect on migration. Therefore, further studies are required to establish the role of NT-3  in CGN migration.

46.1.3 Neuronal Migration As development progresses, increasing numbers of postmitotic granule cells leave the EGL and migrate to form the internal granule layer (IGL), with a peak of GCP migration in rodents during the second postnatal week. Expression of BDNF and TrkB correlates with the increase in CGN migration, suggesting that BDNF signaling might influence the onset of migration. In vivo studies showed abnormal granule cell migration in BDNF−/− mice (Borghesani et al. 2002). In vitro studies showed that cultured CGNs from BDNF−/− mice have deficits in migration, and that exogenous BDNF can stimulate migration of both wild-type and BDNF−/− CGNs (Borghesani et al. 2002). Moreover, defects in BDNF synthesis in the granule cells impaired the onset of GCP migration (Kokubo et al. 2009). BDNF can also control the directionality of migration, this chemotactic effect was blocked by the addition of K252, an inhibitor of Trk receptor activation (Kobayashi et al. 1995; Zhou et al. 2007). An elegant study demonstrated that TrkB is activated in the leading edge of the migrating granule neuron to induce directionality of migration (Zhou et al. 2007). Consistent with the antagonistic roles of neurotrophins and proneurotrophins, proBDNF can prevent the onset of granule cell migration. The anti-migratory effect was abolished in p75NTR−/− mice (Xu et al. 2011). Although some evidence suggests an involvement of NT-3  in granule cell migration, direct evidence is still required. In vivo application of NT-3 in the P6 rat cerebellum significantly reduced the thickness of the EGL at P10 (Doughty et al. 1998). Moreover, defects in the synthesis or release of NT-3 have been associated with aberrant granule cell migration (Li et al. 2004; Sadakata et al. 2007), although this seems to correspond to the decreased survival of CGNs

46.1.4 Effects of Neurotrophins on Differentiation of Cerebellar Neurons Granule cells and Purkinje cells critically influence the development of each other, alterations to survival, maturation, or electrical activity in either of these cell populations have a major impact on the other cell type, making it extremely challenging to identify cell-specific effects in each neuronal population.

46.1.4.1 Purkinje Cell Differentiation BDNF and NT-3, as well as their receptors TrkB, TrkC, and p75NTR, are present in Purkinje cells throughout development and maturity, suggesting a role for these neurotrophins in Purkinje cell survival, differentiation, and/or function. One of the most consistent phenotypes described in BDNF or NT-3-deficient mice is the aberrant arborization of Purkinje cell dendrites, although findings have been inconsistent. BDNF−/− mice show normal numbers of Purkinje cells; however, the dendritic phenotype in these animals was significantly affected, with a thinner molecular layer compared to wild-type mice and abnormal dendritic arborization (Schwartz et  al. 1997; Borghesani et  al. 2002). Mice with deletion of CAPS2 (calcium-dependent activator protein for secretion 2) have reduced secretion of NT-3 and BDNF, and showed defects in Purkinje cell dendritogenesis (Sadakata et  al. 2007). In cell culture studies, BDNF/TrkB signaling increased the density of dendritic spines in Purkinje cells, but had no effect on dendritic complexity (Morrison and Mason 1998; Shimada et  al. 1998). Although no apparent differences in the number or the morphology of Purkinje cells were observed in mice with a specific deletion of TrkB in the cerebellum (Rico et al. 2002), double-mutant mice lacking TrkB and TrkC showed a greater deficit with reduced Purkinje cell arborization compared to deletion of either receptor alone (Minichiello and Klein 1996). In contrast, in organotypic cultures, exposure to BDNF or blockade of Trk-­ activation with the tyrosine kinase inhibitor K252a did not affect Purkinje cell dendritic morphology or the number of dendrites, and organotypic cultures from wild-type and BDNF−/− animals showed no differences in dendritic morphology, even after the addition of exogenous BDNF (Adcock et al. 2004). Part of this controversy might be explained due to effects of neurotrophins on other cerebellar cell populations. For instance, BDNF−/− and TrkB/TrkC double mutant mice

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where the NR2B subunit is switched for NR2C. This receptor modification plays an important role in the establishment of functional granule cell-mossy fiber synaptic transmission in the adult cerebellum. BDNF can upregulate NR2C mRNA via TrkB activation of the ERK 1/2 (extracellular signal-­ regulated kinase) signaling pathway, promoting the maturation of the cerebellar network (Suzuki et al. 2005).

46.1.5 Effects of Neurotrophins in Cerebellar Circuit Establishment and Maintenance

Fig. 46.2  P14 Purkinje cells expressing calbindin (red) and NT3 (green)

both showed increased granule cell death. The reduced number of CGNs would likely decrease the trophic support available to the Purkinje cells, including the secretion of neurotrophins. Additionally, the electrical stimulation provided by the parallel fibers of the CGN has proven to be ­crucial for Purkinje cell dendritic development (Morrison and Mason 1998; Hirai and Launey 2000). Therefore, in a situation with reduced granule cell survival, a decrease in electrical stimulation of Purkinje cells would be expected, with a consequent effect on dendritic maturation. NT-3 also plays an important role in the morphological development of Purkinje cells. NT-3 can promote Purkinje cell differentiation in culture and in  vivo (Lindholm et  al. 1993a). Moreover, in  vivo studies using sparse deletion of TrkC from Purkinje cells in combination with NT-3 deletion from granule cells demonstrated that Purkinje cells compete for a limiting amount of NT-3 produced by the granule cells to induce Purkinje dendritic morphogenesis in a TrkC-­ dependent manner (Joo et al. 2014) (Fig. 46.2).

46.1.4.2 BDNF/TrkB in Granule Cell Differentiation Although BDNF and TrkB remain expressed in the internal granule layer of adult animals, understanding of the specific function of this signaling complex is very limited. BDNF and NT-4, but not NT-3 or NGF, promoted neurite extension in the granule cells, and this effect was blocked by the tyrosine kinase inhibitor, K-252a. Interestingly, no additive effects with the combination of BDNF and NT-4 were observed, confirming that both neurotrophins act via TrkB (Gao et al. 1995). In the developing cerebellum, granule cell maturation depends on changes in the composition of NMDA receptors,

46.1.5.1 BDNF/TrkB in Climbing Fiber Maturation Early in cerebellar development, Purkinje cells are initially innervated by multiple climbing fibers which is then refined such that one of these synapses is strengthened, while the rest are eliminated to assume the mature final ratio of one climbing fiber per Purkinje cell. Unlike what has been observed in other synapses, TrkB is necessary for the pruning of the excess climbing fibers (Johnson et  al. 2007). Moreover, BDNF produced by the Purkinje cell facilitates the elimination of the excess synapses in a mechanism that involves retrograde TrkB signaling in the climbing fibers (Choo et al. 2017). 46.1.5.2 p75NTR in Adult Cerebellum p75NTR is highly expressed in proliferating granule cell progenitors and is absent from postmitotic, mature granule cells. However, p75NTR is also expressed in Purkinje cells, where it remains present through adulthood (Carter et  al. 2003; Zanin et al. 2016). In addition to the effects of TrkB and TrkC, p75NTR has also been linked to the maturation of the Purkinje cell dendritic tree, with aberrant arborization in the absence of p75NTR. However, in adult animals, the role of p75NTR in Purkinje neurons remains largely undetermined. Purkinje cell spontaneous activity can be divided into tonic firing (with a relatively constant rate) or phasic firing (intermittent activity with variable length pauses). Spontaneous activity of Purkinje cells from p75NTR−/− exhibits an increased mean firing rate in the tonic phase. Purkinje cells from p75NTR −/− animals showed reduced activation of Rac1, which reduced SK (Ca2+-activated potassium) channel function, which is important to maintain synaptic activity and regulate the spontaneous activity of Purkinje cells (Tian et al. 2014). Thus, in contrast to granule cells, p75NTR has a continuing role in the function of mature Purkinje cells. 46.1.5.3 Cerebellar Interneurons Few studies have investigated the trophic requirements of the inhibitory interneurons of the cerebellum. Deletion of TrkB

46  Neurotrophic Factors in Cerebellar Development and Function

from the CNS did not affect Purkinje cell development; however, these animals had a reduction of GABAergic markers and reduced GABAergic boutons in inhibitory interneurons (Rico et al. 2002). Moreover, treatment of cerebellar explants with BDNF and NT-4 promoted the development of inhibitory synapses onto Purkinje cells (Seil 1999; Seil and Drake-­ baumann 2000). Additionally, chronic BDNF treatment of cerebellar slices resulted in a drastic decrease in the numbers of parvalbumin-positive cells (Koscheck et al. 2003). In cultures of postnatal cerebellar granule cells, BDNF significantly accelerated the expression of GABA receptor a6 mRNA, suggesting that BDNF might modulate the maturation of GABAergic synapses in the cerebellum (Bao et al. 1999). Using conditional KO mice for BDNF, mossy fibers (from cells outside of the cerebellum) were identified as one of the sources of BDNF in the IGL.  Although deletion of BDNF from the cerebellum itself did not affect the maturation of GABAergic synapses in the IGL, specific deletion of BDNF from mossy fibers resulted in deficits in the Golgi-­Granule cell connectivity affecting the establishment of inhibitory circuits in adult mice (Chen et al. 2016).

References Adcock K, Metzger F, Kapfhammer J (2004) Purkinje cell dendritic tree development in the absence of excitatory neurotransmission and of brain-derived neurotrophic factor in organotypic slice cultures. Neuroscience 127:137–145 Anne SL, Govek E-E, Ayrault O, Kim JH, Zhu X, Murphy DA, Van Aelst L, Roussel MF, Hatten ME (2013) WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation. PLoS One 8:e81769 Bao S, Chen L, Qiao X, Thompson RF (1999) Transgenic brain-derived neurotrophic factor modulates a developing cerebellar inhibitory synapse. Learn Mem 6:276–283 Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R (1999) Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci 2:115–117 Borghesani PR, Peyrin JM, Klein R, Rubin J, Carter AR, Schwartz PM, Luster A, Corfas G, Segal RA (2002) BDNF stimulates migration of cerebellar granule cells. Development 129:1435–1442 Carter AR, Berry EM, Segal RA (2003) Regional expression of p75NTR contributes to neurotrophin regulation of cerebellar patterning. Mol Cell Neurosci 22:1–13 Chen AI, Zang K, Masliah E, Reichardt LF (2016) Glutamatergic axon-­ derived BDNF controls GABAergic synaptic differentiation in the cerebellum. Sci Rep 6:1–13 Choo M, Miyazaki T, Yamazaki M, Kawamura M, Nakazawa T, Zhang J, Tanimura A, Uesaka N, Watanabe M, Sakimura K, Kano M (2017) Retrograde BDNF to TrkB signaling promotes synapse elimination in the developing cerebellum. Nat Commun 8:1–13 Cohen-Cory S, Dreyfus CF, Black IB (1991) NGF and excitatory neurotransmitters regulate survival and morphogenesis of cultured cerebellar Purkinje cells. J Neurosci 11:462–471 Doughty ML, Lohof A, Campana A, Delhaye-Bouchaud N, Mariani J (1998) Neurotrophin-3 promotes cerebellar granule cell exit from the EGL. Eur J Neurosci 10:3007–3011

303 Gao W, Zheng JL, Karihaloo M (1995) Neurotrophic (BDNF) act at later stages of cerebellar granule cell differentiation. J Neurosci 15:2656–2667 Hirai H, Launey T (2000) The regulatory connection between the activity of granule cell NMDA receptors and dendritic differentiation of cerebellar Purkinje cells. J Neurosci 20:5217–5224 Johnson EM, Craig ET, Yeh HH (2007) TrkB is necessary for pruning at the climbing fibre-Purkinje cell synapse in the developing murine cerebellum. J Physiol 582:629–646 Joo W, Hippenmeyer S, Luo L (2014) Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling. Science 80- ) 346:626–629 Katoh-Semba R, Takeuchi IK, Semba R, Kato K (2000) Neurotrophin-3 controls proliferation of granular precursors as well as survival of mature granule neurons in the developing rat cerebellum. J Neurochem 74(5):1923–1930 Kobayashi S, Isa K, Hayashi K, Inoue H, Uyemura K, Shirao T (1995) K252a, a potent inhibitor of protein kinases, inhibits the migration of cerebellar granule cells in vitro. Dev Brain Res 90:122–128 Kokubo M, Nishio M, Ribar TJ, Anderson KA, West AE, Means AR (2009) BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV.  J Neurosci 29:8901–8913 Koscheck T, Weyer A, Schilling RL, Schilling K (2003) Morphological development and neurochemical differentiation of cerebellar inhibitory interneurons in microexplant cultures. Neuroscience 116:973–984 Lärkfors L, Lindsay R, Alderson R (1996) Characterization of the responses of Purkinje cells to Neurotrophin treatment. J Neurochem 66:1362–1376 Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science (80- ) 294:1945–1948 Li S, Qiu F, Xu A, Price SM, Xiang M (2004) Barhl1 regulates migration and survival of cerebellar granule cells by controlling expression of the neurotrophin-3 gene. J Neurosci 24:3104–3114 Lindholm D, Castren E, Tsoulfas P, Kolbeck R, Berzaghi MD, Leingartner A, Heisenberg C-P, Tesarollo L, Parada LF, Thoenen H (1993a) Neurotrophin-3 induced by tri-iodothyronine in cerebellar granule cells promotes Purkinje cell differentiation. J Cell Biol 122:443–450 Lindholm D, Dechant G, Heisenberg C-P, Thoenen H (1993b) Brain-­ derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity. Eur J Neurosci 5:1455–1464 Minichiello L, Klein R (1996) TrkB and TrkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons. Genes Dev 10:2849–2858 Morrison ME, Mason CA (1998) Granule neuron regulation of Purkinje cell development: striking a balance between neurotrophin and glutamate signaling. J Neurosci 18:3563–3573 Mount HTJ, Elkabes S, Dreyfus CF, Black IB (1998) Differential involvement of metabotropic and p75 neurotrophin receptors in effects of nerve growth factor and neurotrophin-3 on cultured Purkinje cell survival. J Neurochem 70:1045–1053 Nicot A, Lelievre V, Tam J, Waschek JA, DiCicco-Bloom E (2002) Pituitary adenylate cyclase-activating polypeptide and sonic hedgehog interact to control cerebellar granule precursor cell proliferation. J Neurosci 22:9244–9254 Rico B, Xu B, Reichardt LF (2002) TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 5:225–233 Rios I, Alvarez-Rodríguez R, Martí E, Pons S (2004) Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development 131:3159–3168

304 Rocamora N, García-Ladona FJ, Palacios JM, Mengod G (1993) Differential expression of brain-derived neurotrophic factor, neurotrophin-­3, and low-affinity nerve growth factor receptor during the postnatal development of the rat cerebellar system. Mol Brain Res 17:1–8 Sadakata T, Kakegawa W, Mizoguchi A, Washida M, Katoh-Semba R, Shutoh F, Okamoto T, Nakashima H, Kimura K, Tanaka M, Sekine Y, Itohara S, Yuzaki M, Nagao S, Furuichi T (2007) Impaired cerebellar development and function in mice lacking CAPS2, a protein involved in neurotrophin release. J Neurosci 27:2472–2482 Schwartz PM, Borghesani PR, Levy RL, Pomeroy SL, Segal RA (1997) Abnormal cerebellar development and foliation in BDNF−/− mice. Neuron 19:269–281 Segal RA, Pomeroy SL, Stiles CD (1995) Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. J Neurosci 15:4970–4981 Seil F (1999) BDNF and NT-4, but not NT-3, promote development of inhibitory synapses in the absence of neuronal activity. Brain Res 818:561–564 Seil FJ, Drake-baumann R (2000) TrkB receptor ligands promote activity-­ dependent inhibitory synaptogenesis. J Neurosci 20:5367–5373 Shimada A, Mason CA, Morrison ME (1998) TrkB signaling modulates spine density and morphology independent of dendrite structure in cultured neonatal Purkinje cells. J Neurosci 18:8559–8570

J. P. Zanin and W. J. Friedman Suzuki K, Sato M, Morishima Y, Nakanishi S (2005) Neuronal depolarization controls brain-derived neurotrophic factor-induced upregulation of NR2C NMDA receptor via calcineurin signaling. J Neurosci 25:9535–9543 Tian J, Tep C, Benedick A, Saidi N, Ryu JC, Kim ML, Sadasivan S, Oberdick J, Smeyne R, Zhu MX, Yoon SO (2014) p75 regulates Purkinje cell firing by modulating SK Channel activity through Rac1*, vol 289, pp 31458–31472 Xu Z-Q, Sun Y, Li H-Y, Lim Y, Zhong J-H, Zhou X-F (2011) Endogenous proBDNF is a negative regulator of migration of cerebellar granule cells in neonatal mice. Eur J Neurosci 33:1376–1384 Zanin JP, Abercrombie E, Friedman WJ (2016) Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor. elife 5:1–21 Zanin JP, Verpeut JL, Li Y, Shiflett MW, Wang SS-HSH, Santhakumar V, Friedman WJ (2019) The p75NTR influences cerebellar circuit development and adult behavior via regulation of cell cycle duration of granule cell progenitors. J Neurosci 39:9119–9129 Zhou X-F, Rush RA (1994) Localization of neurotrophin-3-like immunoreactivity in the rat central nervous system. Brain Res 643:162–172 Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA (2007) Article polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53–68

The Cerebellar Neuroimmune System

47

Donna L. Gruol

Abstract

Emerging research has revealed that glial cells of the brain can produce many of the same signaling factors as cells of the peripheral immune system and, as such, can function as a brain immune system, referred to as the neuroimmune system. Both neurons and glial cells of the brain express receptors and intracellular signaling pathways that can interpret the signals communicated by these factors, which are called neuroimmune factors when produced by brain cells, and in response adjust their function. The neuroimmune system serves many roles both in normal brain biology and in brain pathology. To date, the majority of studies on the characteristics and function of the neuroimmune system comes from brain regions outside of the cerebellum, but recent studies of the cerebellum have shown that the neuroimmune system plays an important role in cerebellar development, function, and disease. This new and expanding area of research will likely bring greater understanding to the cellular and molecular mechanisms that mediate cerebellar function. Keywords

system of the brain. The neuroimmune system is not only a critical homeostatic regulator of brain development and function, contributes to repair and recovery processes during pathological conditions, but can also be an active player in pathology by contributing to cell damage and impaired brain function. Astrocytes and microglia are the primary cell types that comprise the neuroimmune system of the brain and are distributed throughout the brain. However, in the cerebellum, microglia are more populous in gray matter than white matter, whereas the opposite is the case for other brain regions (Lawson et al. 1990). Also, the density of microglia in the cerebellum is lower than for other brain regions that have been studied (e.g., the cortex), and lower than the mean level for the brain in general (Lawson et al. 1990; Stowell et al. 2018). Recent studies show that astrocytes and microglia in different brain regions have many characteristics and functions in common, but they also have properties that are unique to the brain region and local microenvironment that they are associated with (Araujo et  al. 2019; Kana et  al. 2019; Stoessel and Majewska 2021). Several types of astrocytes populate the cerebellum (Fig. 47.1) (Cerrato 2020). The Bergmann glia are considered

Neuroimmune factor · Cytokine · Chemokine · Astrocyte Microglia · Signal transduction · Neuroinflammation Development

47.1 The Neuroimmune System of the Cerebellum As in other brain regions, glial cells of the cerebellum play many roles essential for normal cerebellar development and function, including as key components of the neuroimmune D. L. Gruol (*) Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA e-mail: [email protected]

Fig. 47.1  Diagram illustrating glial cell types of the cerebellar neuroimmune system

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_47

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a specialized type of astrocyte and are unique to the cerebellum. Bergmann glia are large cells with cell bodies situated between the Purkinje neuron and molecular layers and prominent processes that extend into the molecular layer. The processes of the Bergman glia have a close functional relationship with Purkinje neuron dendrites, especially at synaptic sites, and play an important regulatory role in synaptic function (Bellamy 2006). Astrocytes located in the granule neuron layer and cortical region are considered velate protoplasmic astrocytes and have highly branched bushy processes. Velate astrocyte processes are in close contact with mossy fiber to granule neuron synapses where they play an important role in defining the structure of the synapses and controlling the diffusion of neurotransmitters and other signaling factors (Araujo et  al. 2019). Fibrous astrocytes are present in the cerebellar white matter and are characterized by straight long processes. Microglia are commonly viewed as resident macrophages of the brain. They serve important surveillance and phagocytic functions that maintain the brain pathogen and debris-­free, consistent with immune function (Hickman et  al. 2018). Microglia are mobile, constantly survey the brain parenchyma, and provide the first line of defense against pathogens and other detrimental conditions (e.g., injury). In contrast, astrocytes are often considered to be supportive in nature, as evidenced by their role in providing structural and nutritional support for neurons and glia, and as regulators of the blood– brain barrier and the extracellular environment. However, it is now evident that both microglia and astrocytes act as brain immune cells, both have a role in normal and pathological conditions, and both contribute to many aspects of normal brain function and development often with o­verlapping or complementary actions. For example, in the healthy brain, both cell types have essential roles in synaptogenesis, refinement of synaptic structure, establishment of brain architecture,

Fig. 47.2  Contrasting actions of neuroimmune factors in the brain

D. L. Gruol

regulation of synaptic transmission and plasticity, and as engineers in the recovery processes after injury or other adverse conditions (Nedergaard et  al. 2003; Colonna and Butovsky 2017; Verkhratsky and Nedergaard 2018; Cunningham et al. 2019; Wright-Jin and Gutmann 2019; Vainchtein and Molofsky 2020). Many of these actions reflect the neuroimmune functions of glial cells in that they are accomplish through the production and action of neuroimmune factors, which are a large group of signaling factors that are identical to many of the immune factors produced by the peripheral immune system. Both astrocytes and microglia can produce similar neuroimmune factors, although the conditions under which the factors are produced, and the amount produced varies. Bidirectional regulation of function occurs between astrocytes and microglia through various intercellular signaling molecules and is fundamental to the function of the brain neuroimmune system (Jha et al. 2019; Vainchtein and Molofsky 2020). Under some conditions, neurons also produce neuroimmune factors (e.g., (Bacher et al. 1998; Banisadr et al. 2005; Park et al. 2012; Balzano et al. 2020)). In the healthy brain, astrocyte and microglia production of neuroimmune factors typically occurs constitutively at low levels, with production being upregulated in response to important environmental signals as part of normal brain homeostasis and function. However, adverse conditions that cause glial activation can result in upregulated production of neuroimmune factors, a condition referred to as neuroinflammation, which is initially designed for protection, repair, and recovery (Kempuraj et al. 2016). However, if excessive glial activation occurs, dysregulated production of neuroimmune factors can occur and result in levels sufficient to produce detrimental effects on the brain, a condition characteristic of neurodegenerative diseases, brain injury or infection, and other pathological conditions (Fig. 47.2). A large number of neuroimmune factors can be pro-

47  The Cerebellar Neuroimmune System

duced under pathological conditions, a challenging situation in terms of understanding cellular and molecular actions of neuroimmune factors, which are complex and interactive.

47.2 Neuroimmune Factors A majority of neuroimmune factors are small secreted peptides (~5–20 kD) that are members of a large cytokine superfamily of proteins, which includes chemokine, interleukin (IL), interferon (IFN), colony-stimulating factor (CSF), transforming growth factor (TGF), and tumor necrosis factor (TNF) superfamilies (Dinarello 2007). These superfamilies are comprised of multiple families, each consisting of a group of related members. The superfamilies differ structurally and functionally, although there is often redundancy in function. For example, chemokines are a family of chemotactic cytokines that play an important role in cell migration. They are classified structurally into four groups, C, CC, CXC, and CX3C, based on the positions of key cysteine residues, with each group containing multiple members (Bajetto et al. 2001). The interleukins consists of at least 33 families, including the IL-6 and IL-1 families. Within the IL-6 family, there are several members including IL-6, leukemia inhibi-

Fig. 47.3  Simplified diagrams showing signal transduction pathways and partners utilized by chemokines and IL-6. The IL-6 receptor (IL-6ra) does not have signal transduction capabilities but when com-

307

tory factor (LIF), IL-11, oncostatin, ciliary neurotropic factor and cardiotropic-1. The IL-1 family has 11 members including IL-1α, IL-1β, IL-18, and IL-33. One member of the IL-1 family is a natural antagonist (e.g., IL-1R antagonist, IL-1Ra) and can block the action of other interleukins, a situation that also occurs in other neuroimmune families (Palomo et al. 2015). Neuroimmune factors produce their biological actions through the intervention of specific membrane receptors. Binding of a neuroimmune factor to its cognate receptor on target cells typically results in activation of signal transduction pathways, which vary for different neuroimmune factors. For example, members of the chemokine superfamily utilize receptors linked to G-protein-coupled pathways, whereas members of the IL-6 family utilize receptors link to tyrosine kinase pathways (Fig. 47.3). Members of the transforming growth factor-beta (TGF-β) family link to receptors coupled to the Smad signaling pathway. Activation of the signal transduction pathways and the production of second messengers induce biochemical changes and/or gene expression resulting in diverse cellular responses (Bajetto et  al. 2001). For instance, most chemokines can utilize a Gi-­ protein-­coupled pathway involving activation of phospholipase C (PLC) resulting in the production of second

bined with gp130 signal transduction proteins forms a receptor complex capable of signal transduction

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messengers diacylglycerol (DAG) and inositol 1,4,5-­trisphosphate (IP3). IP3 produces an increase in intracellular Ca2+, another important second messenger, by activating IP3 receptors (IP3R) on the endoplasmic reticulum, an intracellular organelle that serves as a storage vessel for intracellular Ca2+ among other functions, resulting in efflux of Ca2+ to the cytosol. As a second messenger, Ca2+ has a wide range of activities extending from gene expression to regulation of ion channel function and, consequently, cell excitability. Other signal transduction partners utilized by chemokines include adenylate cyclase (Acyc), mitogen-­ activated protein kinase (MAPK) (e.g., p44/42 MAPK, p38 MAPK), phosphoinositide 3-kinase (PI3-K), and JAK/STAT (Janus kinase–signal transducer of activators of transcription) (Bajetto et al. 2001). Chemokines are noted for their promiscuity relative to receptor activation in that some chemokines can act through both specific and shared receptors. For example, the chemokine CCL5, also known as RANTES, can act at three chemokine receptors, CCR1, CCR2, and CCR5, whereas the chemokine CXCL12 (also known as stromal cell-derived factor-1; SDF-1) primarily acts at the chemokine receptor CXCR4. CXCL12 acting at CXCR4 plays an important role in granule neuron migration during cerebellar development, which is critical for establishing cerebellar circuitry and structure (Tiveron and Cremer 2008). Other chemokines are also thought to be involved in cerebellar development based on the expression of the chemokine and/or its receptor during cerebellar development.

47.3 Evidence for Expression of Neuroimmune Factors and their Receptors in the Cerebellum The neuroimmune system of the cerebellum is a relatively unexplored area and little is known about the roles it plays in cerebellar function or the dysfunction that occurs in pathological conditions. Much work is needed on this issue, which is complicated by the difficulty in measuring the low in vivo levels of neuroimmune factors, limited information on the conditions that induce release of the factors from cerebellar glial cells, and the short half-life of most factors, which are small proteins and very susceptible to proteases that abound in the extracellular environment. One of the first lines of evidence that neuroimmune factors played a role in cerebellar function was the demonstration of cerebellar expression of specific neuroimmune factors or their receptors at the protein or mRNA level. Several types of studies in developing and adult cerebellum of experimental animals or humans contributed to this area. For example, studies using reverse transcriptase polymerase chain reaction (RT-PCR) showed that mRNA for tumor necrosis factor

D. L. Gruol

alpha (TNF-α) and its receptors, TNFR1 and TNFR2, were expressed in the developing mouse cerebellum during the postnatal period (P) from day P1 to P8 (other ages not studied) (Oldreive and Doherty 2010). RT-PCR analyses also identified expression of CXCL14 in the developing and adult mouse cerebellum, but CXCL14 protein was observed only during development (from day P1 to P8) and primarily localized to the dendrites of Purkinje neurons (Park et al. 2012). CCR1 mRNA was detected by RT-PCR and immunohistochemistry in postnatal and adult rat cerebellum with cellular expression showing developmental changes (Cowell and Silverstein 2003). A variety of cell types showed CCR1-­ immunoreactivity including neurons and glia (granule neurons, Purkinje cells, Golgi cells, molecular layer interneurons, Bergmann glia, astrocytes, and resting microglia) depending on developmental age, but in the adult expression was limited to granule neurons (Cowell and Silverstein 2003). In the same study, immunoreactivity for MIP-1α (also known as CCL3), which binds to CCR1, was also observed during cerebellar development (Cowell and Silverstein 2003). Expression of CXCR2 mRNA in the cerebellum was demonstrated by RT-PCR and expression of CXCR2 protein was demonstrated by Western blot and immunohistochemistry (immunostaining observed in Purkinje neurons and granule neurons) (Giovannelli et  al. 1998). Monocyte chemoattractant protein-1 (MCP-1; also known as CCL2) expression, detected by immunohistochemistry, was observed transiently in the fetal human cerebellum but disappeared by 1–2 years of age (Meng et al. 1999). In this study, MCP-1 expression was primarily in Purkinje neurons, dentate nucleus neurons and inferior olive neurons (Meng et al. 1999). The expression of neuroimmune factors or their receptors in the developing cerebellum suggested a role in cerebellar development. Consistent with this idea, a number of studies have shown that chemokines are critical to the establishment of normal cerebellar architecture during development (Ragozzino 2002; Vilz et  al. 2005; Yu et  al. 2010; Araujo et al. 2016, 2019; Ozawa et al. 2016). High expression of IL-1 receptor mRNA was observed in the cerebellum of adult rats by RNase protection assay (Gayle et  al. 1997) and in the Purkinje neurons of the rat cerebellum by in situ hybridization (Wong and Licinio 1994). Expression of IL-6 and IL-6 receptor mRNA was demonstrated (RT-PCR, in situ hybridization and Northern blot) in the developing and adult rat cerebellum (Schobitz et al. 1993, 1994; Gadient and Otten 1997). In situ hybridization showed high levels of IL-1β RNA in the granule layer of the cerebellum (Bandtlow et al. 1990). IL-15 expression has been identified by both ELISA and immunohistochemistry in the developing and adult mouse cerebellum, with the highest level of expression on the plasma membrane of the soma and processes of cerebellar neurons, although expression was also identified in astrocytes (Gómez-Nicola et  al. 2008).

47  The Cerebellar Neuroimmune System

Prominent IL-33 immunoreactivity was observed in the mouse cerebellum at postnatal day 9 but not at other ages (Wicher et al. 2013). Expression of TGF-β family members and receptors in the cerebellum during development and in the adult was demonstrated by RT-PCR and immunohistochemistry. (Araujo et al. 2016).

47.4 Neuroimmune Factors and Cerebellum Function While the expression of genes and proteins suggest a role for neuroimmune factors in the cerebellum, evidence for a functional consequence to receptor activation is critical to establishing such a role. Pharmacological and developmental studies using exogenous application of neuroimmune factors or selective antagonists have started to provide this evidence. However, with respect to pharmacological studies, it is often difficult to discern if results reflect normal physiology (i.e., baseline or non-inflammatory stimulatory conditions) or pathological conditions. In general, when tested at low levels (e.g., pico-molar), the actions of neuroimmune factors may be more relevant to physiological processes, whereas at higher levels the actions may be more relevant to adverse or pathological conditions. A number of pharmacological studies have demonstrated that neuroimmune factors can alter neuronal function in the cerebellum, consistent with a physiological or pathological role. Several examples are noted below. Both acute application and chronic exposure have been studied. In some cases, chronic exposure was accomplished by construction of transgenic mice that persistently expressed elevated levels of a specific neuroimmune factor in the brain. Knockout mice have also been useful, although the deficit occurs in both the brain and periphery complicating interpretation. Most of the pharmacological studies involved rodent cerebellar neurons in an in vitro preparation such as cultured neurons or ex vivo slices of cerebellum. In one of the few in  vivo studies, direct application of IL-1β to Purkinje neurons of rat cerebellum by microiontophoresis increased the firing rate suggesting that IL-1β can regulate Purkinje neuron excitability (Motoki et al. 2009). In mouse cerebellar slices, application of IL-1β enhanced spontaneous excitatory synaptic responses in Purkinje neurons, whereas similar application of TNFα had no effect, indicating a potential role for IL-1β as a regulator of synaptic transmission (Mandolesi et  al. 2013). Stimulus-evoked GABA receptor-mediated inhibitory responses recorded in Purkinje neurons in rat cerebellar slices were reduced by exposure to IL-1, consistent with a role for IL-1 as a regulator of synaptic transmission (Pringle et al. 1996). Chronic treatment of primary cultures of rat cerebellum with IL-6 during neuronal development resulted in altered

309

active (i.e., action potential generation) and passive (membrane resistance) electrophysiological properties and Ca2+ signaling of the cultured Purkinje neurons (Nelson et  al. 2002, 2004). In cultures of rat granule neuron, chronic exposure to IL-6 enhanced NMDA receptor-mediated membrane depolarizations and associated Ca2+ responses (Qiu et  al. 1998) and reduced L-type Ca2+ currents (Ma et  al. 2012). Chronic exposure to IL-6 during granule neuron development in culture affected neuronal viability and sensitivity to NMDA induced toxicity (Conroy et al. 2004). Exposure to TGF-beta 1 enhance K+ currents in cultures of rat granule neurons, increased expression of the GABAA receptor alpha 6 subunit, which is a key subunit in GABA receptors that mediate tonic inhibition, and increased the number of excitatory synapses (Zhuang et al. 2012; Araujo et al. 2016). In transgenic mice where genetic modification of astrocytes resulted in elevated expression of IL-6  in the brain, Purkinje neurons exhibited altered electrophysiological properties (spike firing, response to synaptic activation), expression of synaptic proteins and expression of IL-6 signal transduction partners (Nelson et al. 1999; Gruol et al. 2020). In transgenic mice in which genetic modification of astrocytes resulted in elevated expression of IL-3, deficits in cerebellar-­mediated motor functions (e.g., gait characteristics, performance in the rotorod test) were observed along with pathological changes in the cerebellum (Chiang et al. 1996). Genetic deletion of CSF-1 in mice resulted in loss of cerebellar microglia and Purkinje neurons, alterations in cerebellar structure, and defects in motor learning (Kana et al. 2019). Genetic deletion of CSF-1 receptor severely impaired climbing fiber elimination during cerebellar development, an effect attributed to microglial enhancement of GABAergic synaptic transmission to Purkinje neurons (Nakayama et al. 2018). A number of in vitro studies using rodent cerebellar slices showed that chemokines could alter synaptic transmission, suggesting a role as a synaptic modulator. For example, exposure of mouse cerebellar slices to the chemokine GRO-β (growth-related gene product beta) enhanced excitatory post-­ synaptic responses evoked by stimulation of parallel fibers and recorded in Purkinje neurons (Ragozzino et  al. 1998). Spontaneous synaptic responses recorded in Purkinje neurons in mouse cerebellar slices were also increased by exposure to GRO-α as well as the chemokine IL-8 (Giovannelli et al. 1998). In a similar study, exposure to SDF-1α depressed synaptic transmission at the parallel fiber to Purkinje neuron synapse in mouse cerebellar slices, an effect that involved reduced transmitter release (Ragozzino 2002). Several studies showed that application of chemokines to cerebellar neurons increased intracellular Ca2+ levels, consistent with activation of a receptor coupled to a G-protein signal transduction pathway. For instance, GRO-α and IL-8 increased intracellular Ca2+ levels in Purkinje neurons in

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mouse cerebellar slices and GRO-α increased intracellular Ca2+ levels in cultured Purkinje neurons (IL-8 not tested in cultures) (Giovannelli et  al. 1998). MCP-1 also increased resting Ca2+ levels in cultured Purkinje neurons, enhanced the Ca2+ response evoked by activation of metabotropic glutamate receptor 1 (mGluR1; a G-protein coupled receptor), and depressed action potential generation (van Gassen et al. 2005).

affect the physiology of Purkinje neurons underlie many types of spinocerebellar ataxias (Marcián et al. 2016; Meera et al. 2016; Hoxha et al. 2018) but emerging research indicate that astrocytes and microglia can also play a role in these and other diseases associated with ataxia (Ferro et al. 2019; Cerrato 2020; Revuelta et al. 2020). Much is left to be learned about the cerebellar neuroimmune system and its function in health and disease.

47.5 The Neuroimmune System and Cerebellum and Disease

References

Much of our knowledge about the neuroimmune system in the brain comes from studies involving conditions where neuroimmune factors are produced at elevated levels by activated glial cells and, therefore, are more easily detected. The state of increased glial activation, referred to as neuroinflammation, has been shown to occur in the cerebellum in a number of conditions associated with detrimental effects (Ferro et al. 2019; Revuelta et al. 2020). For example, pre- and neonatal exposure of rat pups to lead produced a significant increase in levels of IL-1β, IL-6, and TGF-β in the cerebellum and other brain regions (Chibowska et al. 2020). In studies of the brain from deceased human autistic patients, TGF-β and MCP-1 were found to be significantly elevated in the cerebellum, the main site of neuroinflammation in autism (Vargas et  al. 2005). Immunohistochemical staining of the cerebellum in this study indicated that MCP-1 was produced by activated astrocytes, whereas both astrocytes and neurons produced TGF-β (Vargas et  al. 2005). In neonatal mouse, conditions of hypoxia induced prominent increases in TNF-α and IL-1β in microglia and their receptors in Purkinje neurons (Kaur et al. 2014). Activated microglia and astrocytes and elevated levels of neuroimmune factors are expressed in the cerebellum in several experimental models of neurological conditions associated with ataxia (e.g., spinocerebellar ataxia, multiple sclerosis, and experimental autoimmune encephalomyelitis) (Cvetanovic et  al. 2015; Ferro et  al. 2019; Revuelta et  al. 2020). For instance, depending on age, increased levels of IL-6, IFN gamma, IL-1β, and IL-10 were observed in the cerebellum of MRL-lpr/lpr mice, an experimental model for the autoimmune disease Lupus Erythematosus (SLE) (Tomita et al. 2001). Spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disorder that affects the cerebellum, is characterized by pathogenic polyglutamine expansion in the coding region of gene for ATXN1 (ataxin-1), which results in a toxic protein. In a mouse model for this disease, transgenic ATXN1[82Q] mice, the toxic protein is expressed in Purkinje neurons and is associated with microglial and astrocyte activation and increased levels of cerebellar TNF-α, MCP-1, and IL-6 (Cvetanovic et  al. 2015). Detrimental mutations that

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311 Nakayama H, Abe M, Morimoto C, Iida T, Okabe S, Sakimura K, Hashimoto K (2018) Microglia permit climbing fiber elimination by promoting GABAergic inhibition in the developing cerebellum. Nat Commun 9:2830 Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530 Nelson TE, Campbell IL, Gruol DL (1999) Altered physiology of Purkinje neurons in cerebellar slices from transgenic mice with chronic central nervous system expression of interleukin-6. Neuroscience 89:127–136 Nelson TE, Ur CL, Gruol DL (2002) Chronic interleukin-6 exposure alters electrophysiological properties and calcium signaling in developing cerebellar Purkinje neurons in culture. J Neurophysiol 88:475–486 Nelson TE, Netzeband JG, Gruol DL (2004) Chronic interleukin-6 exposure alters metabotropic glutamate receptor-activated calcium signalling in cerebellar Purkinje neurons. Eur J Neurosci 20:2387–2400 Oldreive CE, Doherty GH (2010) Effects of tumour necrosis factor-­ alpha on developing cerebellar granule and Purkinje neurons in vitro. J Mol Neurosci 42:44–52 Ozawa PM, Ariza CB, Ishibashi CM, Fujita TC, Banin-Hirata BK, Oda JM, Watanabe MA (2016) Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma. Int J Cancer 138:10–13 Palomo J, Dietrich D, Martin P, Palmer G, Gabay C (2015) The interleukin (IL)-1 cytokine family—Balance between agonists and antagonists in inflammatory diseases. Cytokine 76:25–37 Park CR, Kim DK, Cho EB, You DJ, do Rego JL, Vaudry D, Sun W, Kim H, Seong JY, Hwang JI (2012) Spatiotemporal expression and functional implication of CXCL14 in the developing mice cerebellum. Mol Cells 34:289–293 Pringle AK, Gardner CR, Walker RJ (1996) Reduction of cerebellar GABAA responses by interleukin-1 (IL-1) through an indomethacin insensitive mechanism. Neuropharmacology 35:147–152 Qiu Z, Sweeney DD, Netzeband JG, Gruol DL (1998) Chronic interleukin-­6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J Neurosci 18:10445–10456 Ragozzino D (2002) CXC chemokine receptors in the central nervous system: role in cerebellar neuromodulation and development. J Neurovirol 8:559–572 Ragozzino D, Giovannelli A, Mileo AM, Limatola C, Santoni A, Eusebi F (1998) Modulation of the neurotransmitter release in rat cerebellar neurons by GRO beta. Neuroreport 9:3601–3606 Revuelta M, Scheuer T, Chew LJ, Schmitz T (2020) Glial factors regulating white matter development and pathologies of the cerebellum. Neurochem Res 45:643–655 Schobitz B, de Kloet ER, Sutanto W, Holsboer F (1993) Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain. Eur J Neurosci 5:1426–1435 Schobitz B, De Kloet ER, Holsboer F (1994) Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain. Prog Neurobiol 44:397–432 Stoessel MB, Majewska AK (2021) Little cells of the little brain: microglia in cerebellar development and function. Trends Neurosci 44:564–578 Stowell RD, Wong EL, Batchelor HN, Mendes MS, Lamantia CE, Whitelaw BS, Majewska AK (2018) Cerebellar microglia are dynamically unique and survey Purkinje neurons in  vivo. Dev Neurobiol 78:627–644 Tiveron MC, Cremer H (2008) CXCL12/CXCR4 signalling in neuronal cell migration. Curr Opin Neurobiol 18:237–244 Tomita M, Holman BJ, Williams LS, Pang KC, Santoro TJ (2001) Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus. J Neurosci Res 64:26–33

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Restoring a Loss of Mossy Fiber Plasticity in a Model of Fragile X Syndrome

48

Xiaoqin Zhan and Ray W. Turner

Abstract

Fragile X Syndrome is a monogenic disorder that reflects a loss of Fragile X Mental Retardation Protein (FMRP) that is needed to regulate translation of proteins important to circuit development and plasticity. A complete loss of FMRP is the leading monogenic cause of Autism Spectrum Disorders (ASD). Mossy fiber inputs to cerebellar granule cells exhibit long-term potentiation (LTP) to process sensory information to the cerebellum. Here we find that LTP of mossy fiber input is lost in FMRP KO mice. To counter this loss, we reintroduced an FMRP N-terminal fragment conjugated to a tat peptide (FMRP-­N-­tat) by tail vein injection. This action promoted transport of FMRP(1–297) across the blood–brain barrier to distribute widely across the brain within 30 min and rescued LTP at the mossy fibergranule cell synapse. These findings are important in revealing that tat-conjugated FMRP fragments can be used as a therapeutic tool to restore synaptic plasticity and reduce symptoms of Fragile X Syndrome. Keywords

Fragile X syndrome · FMRP · Mossy fiber · LTP · tat peptide · Cerebellum

48.1 Introduction Fragile X Syndrome (FXS) results from a CGG repeat expansion in the 5′-untranslated region (UTR) of the Fmr1 gene that disrupts transcription of Fragile X Mental Retardation Protein (FMRP). This has widespread consequences given that FMRP is involved in circuit development and functions that span from protein translation to synaptic X. Zhan · R. W. Turner (*) Alberta Children’s Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada e-mail: [email protected]; [email protected]

output (Bear et al. 2004; Darnell et al. 2011; Contractor et al. 2015). FMRP is almost ubiquitously expressed in cells of the brain, such that disorders in FXS arise from across the cortico-­ cerebellar axis (Zangenehpour et  al. 2009; Wang et al. 2014; Gholizadeh et al. 2015; Hampson and Blatt 2015; Stoodley et al. 2017), leading to its recognition as the leading monogenic cause of Autism Spectrum Disorders (ASD). Circuit dysfunction in ASD can reflect an aberrant processing of sensory information and synaptic plasticity. The cerebellum receives mossy fiber projections that convey sensory information to a granule cell layer across 10 lobules to form one of the largest arrays of sensory input in the CNS.  The mossy fiber-granule cell synapse normally exhibits long-term potentiation (LTP), an activity-dependent enhancement in synaptic transmission (D’Angelo et  al. 2005; Rizwan et  al. 2016; Sgritta et al. 2017) that we found is lost in FMRP knockout (KO) mice (Zhan et al. 2020). This is important in that a loss of FMRP could disrupt sensory processing at the first stage of information transfer to the cerebellar cortex. The current study explored the potential to reverse the loss of mossy fiber LTP in FMRP KO mice by reintroducing an N-terminal fragment of FMRP as a conjugate of the HIV-1 trans-activator of transcription (tat) (FMRP-N-tat) to facilitate its transfer across the blood–brain barrier. These studies were critical in revealing that FMRP-N-tat introduced by tail vein injection rapidly distributed throughout the brain and rescued mossy fiber LTP within 2 h of injection. This result suggests that FMRP-N-tat could be a novel potential therapeutic approach to treating cerebellar and other disorders inherent to FXS.

48.2 Results 48.2.1 FMRP Expression in Wild-Type Mice and a Fragile X Model We first compared the expression of FMRP in adult wild type (WT) mice and an FMRP KO mouse model. Immunocytochemistry on WT sections confirmed FMRP

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_48

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Fig. 48.1  FMRP is widely expressed in the cerebellum but lost in FMRP KO mice. (a, b) Low power montage images of sagittal cerebellar sections from WT mice labeled with an FMRP C terminal antibody (a) and dual labeled with MAP-2 as a structural marker (b). (c, d) Expanded views of the granule and Purkinje cell layers from Lobule 9

indicates strong FMRP labeling of granule cells as well as Purkinje cells. (e, f) Montage images of FMRP and MAP-2 labeling of sagittal cerebellar sections from FMRP KO mice indicates a lack of FMRP labeling. Dashed lines in (c, d) demark cell layer boundaries

labeling throughout the cerebellum and the granule cell body layer (Fig. 48.1a–d). By comparison, an FMRP antibody detected no label in the FMRP KO mouse (Fig. 48.1e, f). Since FXS reflects a loss of FMRP expression, we attempted to reintroduce a part of the molecule as a tat-

conjugated peptide in the FMRP KO mouse. We used an 11 aa segment of the HIV-1 trans-activator of transcription protein (tat) that facilitates protein transfer across cell membranes (Leibrand et  al. 2017) fused to an N-terminal fragment (1–297 aa) of FMRP (Fig.  48.2a).

48  Restoring a Loss of Mossy Fiber Plasticity in a Model of Fragile X Syndrome

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Fig. 48.2 FMRP-N-tat rapidly crosses the BBB to enter CNS neurons. (a) Schematic of the FMRP-N-tat construct with an HA tag delivered by tail vein injection. (b) Nissl stained sagittal section of a mouse brain highlighting regions of interest expanded in (c–e). (c–e) High-­ magnification images from tissue sections from FMRP KO mice after tail vein injection of vehicle alone or FMRP-N-tat. Sections reflect labeling with an N-terminal FMRP antibody (c) or an HA antibody (d, e). Cerebellar neurons exhibit no significant background immunolabel in vehicle-injected mice (c) but somatic uptake in Purkinje and granule

cells within 2  h of injecting 0.2  mg/kg FMRP-N-tat (c). Neocortical neurons in Layer 5 exhibit immunolabel within 30 min, with cell structures identified using a MAP-2 counter label (d). Hippocampal CA3 pyramidal cells retain immunolabel 12 h post injection, with cytoplasmic uptake evident in the magnified right panel. Dashed lines in (c) delineate major cell layer boundaries and arrowheads in (e) the boundary of pyramidal cell membranes. Image credit for (b): Allen Institute. All other frames are modified from Zhan et al. (2020)

We introduced FMRP-N-tat by tail vein injection and processed brains for immunocytochemistry up to 48  h after injection. No immunolabel was detected in the cerebellum of FMRP KO mice injected with vehicle, but an extensive distribution of immunolabel was detected 2 h after injecting FMRP-N-tat (Fig. 48.2c). Neocortical cells positioned in Layer 5 exhibited at least somatic labeling 30 min post FMRP-N-tat injection (Fig. 48.2d), and immunolabel was retained in hippocampal CA3 pyramidal cells 12  h later (Fig. 48.2e).

this form of plasticity between WT and FMRP KO mice in physiological studies of synaptic function in  vitro using a cerebellar slice preparation. High-frequency stimulation using a theta burst (TBS) pattern delivered to mossy fibers in lobule 9 of cerebellum evoked LTP of the excitatory ­postsynaptic potential (EPSP) amplitude and an increase in spike firing probability in granule cells (Fig. 48.3b). However, FMRP KO mice completely lacked the ability to demonstrate LTP of the EPSP or spike output (Fig.  48.3b) (Zhan et al. 2020). We therefore tail vein injected 1.0 mg/kg FMRP-­ N-­tat and 2 h later prepared cerebellar tissue slices to conduct whole-cell recordings in  vitro. This step proved to rescue mossy fiber LTP that persisted for at least 20 min after the TBS stimulus (Fig.  48.3b). These effects were dose-­ dependent in that injecting 0.2 mg/kg FMRP-N-tat did not rescue mossy fiber LTP, even though FMRP immunolabel was detectable in cerebellum 2  h after tail vein injection. Finally, tail vein injection of the tat epitope alone did not rescue LTP tested in  vitro, indicating that the effects of FMRP-N-tat on synaptic plasticity did not result from the tat moiety.

48.2.2 An FMRP-Tat Conjugate Peptide Delivered In Vivo Restores LTP of Mossy Fiber Inputs FMRP has been shown to influence long-term plasticity at several synaptic inputs (Telias 2019) and can regulate the expression of Kv4 channels that are involved in LTP at the mossy fiber synapse (Rizwan et al. 2016). To determine the potential for FMRP to affect mossy fiber LTP, we compared

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Fig. 48.3  A loss of mossy fiber-granule LTP in FMRP KO mice is restored upon tail vein injection of FMRP-N-tat. (a) Representative recordings from a granule cell in the in vitro slice preparation showing the subthreshold mossy fiber-evoked EPSP (top) and evoked spike (bottom) following delivery of TBS (arrow). (b) Mean values of mossy fiber EPSP amplitude (top row) and probability of spike discharge (bot-

tom row) in WT mice, FMRP KO mice, and FMRP KO mice 2 h after tail vein injection of FMRP-N-tat or the tat epitope alone. An initial control period of 5 min is followed by delivery of TBS (arrows) and 5 min later recorded at 0.1 Hz. Average values are mean ± SEM with sample values shown at the base of EPSP plots. Modified from Zhan et al. (2020)

48.3 Discussion

least 24  h after tail vein injection (Zhan et  al. 2020). All together these findings emphasize the potential value of FMRP-tat conjugate peptides as a therapeutic strategy that could be developed to reduce the symptoms of FXS.

48.3.1 Restoring FMRP in Fragile X Syndrome A great deal of work has been conducted to understand how translation of FMRP is disrupted and the myriad of cellular and behavioral disorders it gives rise to in FXS. Several attempts have been made to restore FMRP translation or mitigate the loss of circuit function through pharmacological approaches (Gholizadeh et  al. 2014; Park et  al. 2015; Liu et al. 2018; Protic et al. 2019; Telias 2019; Graef et al. 2019). A previous attempt at using a tat-conjugate approach used the full-length FMRP. Unfortunately, a protein of this length led to problems in preparation, blood–brain barrier access, and toxicity in cultured fibroblasts (Reis et  al. 2004). We used a 1–297 aa N-terminal fragment of FMRP, which proved to cross the blood–brain barrier and distribute across the cortico-cerebellar axis within 30 min. The effects of this compound on cell function were very fast, with rescue of mossy fiber LTP when tested at 2 h post injection. The short-­ time course was even more dramatic in vitro, where internal infusion of FMRP(1–297) through an electrode rescued LTP in the FMRP KO mouse within 10 min. Remarkably, direct application of FMRP-N-tat onto dissociated cerebellar granule cells at levels far higher than we expect it to reach following transport across the blood–brain barrier showed no toxicity tested with a live-dead cell kit up to 5 days later. The levels of three different proteins known to be disrupted in FXS were also stabilized by FMRP-N-tat injection for at

48.3.2 Role of FMRP in Synaptic Plasticity Recent work has shown that the actions of FMRP extend beyond control of protein translation as an RNA-binding molecule to modifying ion channels that control membrane excitability (Contractor et al. 2015; Ferron 2016; Yang et al. 2018; Ferron et al. 2020; Zhan et al. 2020). Indeed, FMRP proves to be an integral component of a Cav3-Kv4 channel complex that can modify biophysical properties of Kv4 current inherent to invoking LTP at the mossy fiber-granule cell synapse (Zhan et  al. 2020). The number of other forms of plasticity that rely on FMRP regulation of ion channels that could benefit from FMRP-N-tat is not yet known. For instance, we have not determined the influence of FMRP-N-­ tat on long-term depression at the mossy fiber synapse (Sgritta et al. 2017), or other forms of plasticity inherent to parallel fibers in the cerebellar cortex, the output axons of granule cells (Koekkoek et  al. 2005; Jorntell and Hansel 2006; Piochon et  al. 2014). However, a loss of FMRP has been shown to invoke excess GABA release from cerebellar basket cells when a downregulation of Kv1.2 channels increases presynaptic terminal excitability (Yang et al. 2018). By infusing FMRP(1–297) through a patch recording elec-

48  Restoring a Loss of Mossy Fiber Plasticity in a Model of Fragile X Syndrome

trode, these authors were able to rebalance excitability and GABA release from these interneurons, identifying a second potential target for FMRP-N-tat injections. Given the growing list of functions for FMRP in regulating synaptic function, plasticity, and now ion channel activities, we expect delivery of FMRP-N-tat to have widespread effects on circuit function and signal processing. Yet much work remains to evaluate this novel potential therapeutic approach to treating cerebellar and other disorders expressed in patients with FXS.

References Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370–377 Contractor A, Klyachko VA, Portera-Cailliau C (2015) Altered neuronal and circuit excitability in Fragile X syndrome. Neuron 87:699–715 D’Angelo E, Rossi P, Gall D et  al (2005) Long-term potentiation of synaptic transmission at the mossy fiber-granule cell relay of cerebellum. Prog Brain Res 148:69–80 Darnell JC, Van Driesche SJ, Zhang C et al (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–261 Ferron L (2016) Fragile X mental retardation protein controls ion channel expression and activity. J Physiol 594:5861–5867 Ferron L, Novazzi CG, Pilch KS et  al (2020) FMRP regulates presynaptic localization of neuronal voltage gated calcium channels. Neurobiol Dis 138:104779 Gholizadeh S, Arsenault J, Xuan IC et  al (2014) Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice. Neuropsychopharmacology 39:3100–3111 Gholizadeh S, Halder SK, Hampson DR (2015) Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain. Brain Res 1596:22–30 Graef JD, Wu H, Ng C et al (2019) Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons. Eur J Neurosci. https://doi.org/10.1111/ejn.14660 Hampson DR, Blatt GJ (2015) Autism spectrum disorders and neuropathology of the cerebellum. Front Neurosci 9:420 Jorntell H, Hansel C (2006) Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses. Neuron 52:227–238

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Koekkoek SK, Yamaguchi K, Milojkovic BA et  al (2005) Deletion of FMR1  in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome. Neuron 47:339–352 Leibrand CR, Paris JJ, Ghandour MS et al (2017) HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice. Neurosci Lett 640:136–143 Liu XS, Wu H, Krzisch M et al (2018) Rescue of Fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172:979–992.e6 Park CY, Halevy T, Lee DR et al (2015) Reversion of FMR1 methylation and silencing by editing the triplet repeats in fragile X iPSC-­ derived neurons. Cell Rep 13:234–241 Piochon C, Kloth AD, Grasselli G et al (2014) Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun 5:5586 Protic D, Salcedo-Arellano MJ, Dy JB et al (2019) New targeted treatments for fragile X syndrome. Curr Pediatr Rev 15:251–258 Reis SA, Willemsen R, van Unen L et  al (2004) Prospects of TAT-­ mediated protein therapy for fragile X syndrome. J Mol Histol 35:389–395 Rizwan AP, Zhan X, Zamponi GW, Turner RW (2016) Long-term potentiation at the mossy fiber-granule cell relay invokes postsynaptic second-messenger regulation of Kv4 channels. J Neurosci 36:11196–11207 Sgritta M, Locatelli F, Soda T et al (2017) Hebbian spike-timing dependent plasticity at the cerebellar input stage. J Neurosci 37:2809–2823 Stoodley CJ, D’Mello AM, Ellegood J et al (2017) Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-­ related behaviors in mice. Nat Neurosci 20:1744–1751 Telias M (2019) Molecular mechanisms of synaptic dysregulation in fragile X syndrome and autism Spectrum disorders. Front Mol Neurosci 12:51 Wang SS, Kloth AD, Badura A (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518–532 Yang Y-M, Arsenault J, Bah A et al (2018) Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the fragile X brain. Mol Psychiatry. https://doi.org/10.1038/ s41380-­018-­0240-­0 Zangenehpour S, Cornish KM, Chaudhuri A (2009) Whole-brain expression analysis of FMRP in adult monkey and its relationship to cognitive deficits in fragile X syndrome. Brain Res 1264:76–84 Zhan X, Asmara H, Cheng N et al (2020) FMRP(1-297)-tat restores ion channel and synaptic function in a model of fragile X syndrome. Nat Commun 11:2755

Part VI Neuroimaging of the Cerebellum

Cerebellar Closed Loops

49

Christophe Habas

Abstract

Data from histological tracing studies in non-human primate strongly support the view that the cerebellar system is organized into distinct, motor and non-motor, and parallel closed-loop circuits interconnecting the cerebellum and the cerebral cortex. Functional imaging data in human seem to confirm this specific network organization in human, and to extend the role of the cerebellum from motor control to regulation of cognition and emotion. Keywords

Cerebellum · Closed-loops · Tracing · Fmri Resting-state

49.1 Histological Tracing in Animal Models In the cerebellar system, cerebral cortex projects via pontine nuclei within the basis pontis to contralateral cerebellum (deep nuclei and cortex), which, in turn, sends it back projections via the thalamus. The closed-loop architecture of the cerebellar system relies on three main results. First, separate and non-overlapping territories of the dentate nuclei (DN), the main output source of the primate cerebellum, specifically target distinct thalamic and associated motor, premotor and associative cortical areas (Strick et al. 2009). In particular, cerebellar projections to prefrontal and pre-­supplementary motor cortices originate in the ventral part of DN, whereas cerebellar projections to (pre-)motor cortex arise from the dorsal part of DN (Middleton and Strick 2001). Second, viral transneuronal tracing investigations in the macaque have demonstrated two closed-loops interconnecting via the denC. Habas (*) Service de NeuroImagerie, Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France

tate nucleus, motor cortex and lobules III–VI/VIII, and prefrontal cortex (BA 46) and lobule VII (crus II) (Kelly and Strick 2003). Third, except primary visual cortex and some ventrolateral prefrontal and orbitofrontal cortices, the rest of the cerebral cortex innervates the cerebellum via pontine nuclei (Schmahmann and Pandya 1997). Therefore, the cerebellum would take part in several closed-loops whose cortico-­ponto-cerebellar afferents remain to be firmly established, for major part of them, but whose efferents are successively (Clower et  al. 2001; Middleton and Strick 2001; Dum and Strick 2003): 1. Dorsal DN, caudal ventrolateral thalamus, motor cortex (BA 4). 2. Lateral DN, X thalamus, lateral, and medial premotor cortex (BA 6, supplementary motor area). 3. Caudal DN, X thalamus, prefrontal eye field cortex (BA 8). 4. Ventromedial DN, caudal ventrolateral and mediodorsal thalamus, dorsolateral prefrontal cortex (BA 9 medial and lateral). 5. Ventrolateral DN, caudal ventrolateral and mediodorsal thalamus, dorsolateral prefrontal cortex (BA 46 dorsal). 6. Lateral DN, caudal ventrolateral thalamus, inferior parietal cortex (BA 7b). In addition to cerebello-cortical loops, cerebello-­ subcortical loops may exist as well, especially through reticular, red, and bulbar olivary nuclei. Recently, potential motor and associative striato-cerebellar loops have been also traced: DN projects to the external pallidum via intralaminar and anterior/lateral ventral thalamus in rat (Hoshi et al. 2005) and striatum in monkey, while subthalamic nucleus projects topographically back to cerebellar cortex (crus II and lobule VIIb) via pontine nuclei in monkey (Bostan et al. 2010).

Université Versailles-Saint-Quentin, Versailles, France e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_49

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49.2 Functional Neuroimaging Data Has this closed-loop organization of the cerebellar system been observed in human? Up to now, only partial arguments can be put forth in favor of such network architecture since no histological tracing data are available. Resting state functional connectivity and diffusion tensor imaging have provided some in vivo results in support of cerebellar closed-loops.

49.2.1 Cerebellar Subregional Connectivity

C. Habas

cerebellar outputs, implicates prefrontal, temporal, cingulate and parietal cortices and thalamus and striatum (Allen et al. 2005; Bernard et al. 2014), in accordance with tractographic data (Habas and Cabanis 2007; Jissendi et al. 2008; Salmi et al. 2010; Pelzer et al. 2013; Palesi et al. 2015) and partly reciprocating cortical inputs. It is also noteworthy that DN also sends direct efferents to the ventral tegmental area in mouse (Carta et  al. 2019) and that reward-related activity has been detected in granule cells and climbing fibers within the cerebellum (Wagner and Luo 2020). Functional coherence has also been demonstrated between cerebellum and: accumbens nucleus, substantia nigra, and amygdala. Therefore, there also exists direct subcortical cerebello-striatal loops allowing combination of rewardbased (ventral striatum) and error-based (cerebellum) learning process.

Cerebellar cortex can be parcellated into separate and nonor very narrow overlapping regions encompassing mainly sensorimotor (anterior lobe and lobule VIII), executive (lobules VI caudal, VII with crus I and II and IX), and limbic (lobule VI/VII especially the vermis) (Habas et  al. 2009; Krienen and Buckner 2009; O’Reilly et  al. 2009; Buckner et al. 2011). It is noteworthy however that the oculomotor cerebellum must overlap part of the executive/limbic cerebellum (Voogd et al. 2012). These regions are in functional coherence with specific zones of the cerebral cortex which may represent cortico-ponto-cerebellar connections. For instance, motor and premotor cortex are linked to the sensorimotor cerebellum, and prefrontal, cingulate, temporal, and parietal cortices to the executive cerebellum. Moreover, functional connectivity of DN that may reflect

1. The sensorimotor network (motor and premotor cortex, cerebellar lobules V–VI and VIII). 2. The right and left executive networks (dorsolateral prefrontal and parietal prefrontal cortices, crus I and II).

Fig. 49.1  The main cerebro-cerebellar networks determined by independent component analysis (ICA) applied to brain resting-state data. Abbreviations: DLPFC dorsolateral prefrontal cortex, DMPFC dorsomedian prefrontal cortex, FEF frontal eye field, INS insula, IPC inferior

parietal cortex, IPS intraparietal sulcus, MPFC medial prefrontal cortex, RSC/PCC retrosplenial cortex/posterior cingulate cortex, SMA supplementary motor area, SPC superior parietal cortex, THAL thalamus

49.2.2 Cerebellar Circuits Independent component analysis-based functional connectivity has delineated specific parallel cerebro-cerebello-­ cortical networks including Habas et al. (2009) (Fig. 49.1):

49  Cerebellar Closed Loops

3. The limbic “salience” network (frontal and insular cortices, lobules VI/VII) involved in interoception, emotional, and autonomic regulation. 4. The “default-mode network” (dorsomedian prefrontal, posterior cingulate, retrosplenial and parahippocampal cortices, precuneus, lobules IX and VII) devoted to consciousness, self-agency, memory, and mental imagery. 5. The dorsal attentional network (precentral sulcus, intraparietal sulcus, MT+, lobules VIIb/VIIIa) implicated in top-down attention and visual working memory (Brissenden et al. 2016). These cognitive and emotional circuits are represented thrice at the cerebello-cortical surface according to a spatially oriented, gradient-based organization (Guell and Schmahmann 2020). We can also add a language-dedicated network including Broca and Wernicke areas and right crus 1–2 (Tomasi and Volkow 2012). It is noteworthy that the dentate nucleus, which constitutes the main target of the overlying Purkinje cells and the main output channel of the cerebellar cortex, encompasses during the brain resting-state of three functional territories in relation with the default-mode, the salience-motor and visual cortical networks (Guell et al. 2020). All these genetically prewired and epigenetically modulated circuits correspond to cerebellar closed-loops first identified in animals.

49.3 Conclusion Altogether, available data from animal and human studies agree with the existence of anatomical and functional well-­segregated parallel ­ cerebro-ponto-cerebello-thalamo-cortical circuits which may function as distinct modules applying a common type of computation (putatively internal models or timing function) to different mental activities from motor coordination and automation to cognition and emotion (Schmahmann 1991, 1996; Ramnani 2006; Schmahmann et  al. 2019). Subcortical loops also enable direct coordination between the cerebellum and the striatum, including the ventral (limbic) basal ganglia.

References Allen G, McColl R, Holly B, Ringe WK, Fleckenstein J, Cullum CM (2005) Magnetic resonance imaging of cerebellar-prefrontal and cerebellar-parietal functional connectivity. NeuroImage 28:39–48 Bernard JA, Peltier SJ, Benson BI, Wiggins JL, Jaeggi SM, Buschkuehl M, Jonides J, Monk CS, Seidler RD (2014) Dissociable networks of the human dentate nucleus. Cereb Cortex 24:2151–2159

323 Bostan AC, Dum RP, Strick PL (2010) The basal ganglia communicates with the cerebellum. PNAS USA 107:8452–8456 Brissenden JA, Levin EJ, Osher DE, Halko MA, Somers DC (2016) Functional evidence for a cerebellar node of the dorsal attention network. J Neurosci 36(22):6083–6096 Buckner RL, Krienen FM, Castellanos A et al (2011) The organization of the human cerebellum estimated by intrinsic functional connectivity. J Neurophysiol 106:1125–1165 Carta I, Chen CH, Schott AL, Dorizan S, Khodakhah K (2019) Cerebellar modulation of the reward circuitry and social behavior. Science 363(6424):eaav0581 Clower DM, West RA, Lynch JC et al (2001) The inferior parietal lobule is the target of output from superior colliculus, hippocampus, and cerebellum. J Neurosci 21:6283–6291 Dum RP, Strick PL (2003) An unfolded map of the cerebellar dentate nucleus and its projection to the cerebral cortex. J Neurophysiol 89:634–639 Guell X, Schmahmann J (2020) Cerebellar functional anatomy: a didactic summary based on human fMRI evidence. Cerebellum 19(1):1–5 Guell X, D’Mello AM, Hubbard NA et al (2020) Functional territories of human dentate nucleus. Cereb Cortex 30(4):2401–2417. https:// doi.org/10.1093/cercor/bhz247 Habas C, Cabanis EA (2007) Anatomical parcellation of the brainstem and cerebellar white matter: a preliminary probabilistic tractography study at 3 T. Neuroradiology 49:849–863 Habas C, Kamdar N, Nguyen D, Prater K, Beckmann CF, Menon V, Greicius MD (2009) Distinct cerebellar contributions to intrinsic connectivity networks. J Neurosci 29:8586–8594 Hoshi E, Tremblay L, Féger J, Carras PL, Strick PL (2005) The cerebellum communicates with the basal ganglia. Nat Neurosci 8:1491–1493 Jissendi P, Baudry S, Balériaux D (2008) Diffusion tensor imaging (DTI) and tractography of the cerebellar projections to prefrontal and posterior parietal cortices: a study at 3 T. J Neuroradiol 35:42–50 Kelly RM, Strick PL (2003) Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J Neurosci 23:8432–8444 Krienen FM, Buckner RL (2009) Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. Cerebr Cortex 19:2485–2497 Middleton FA, Strick PL (2001) Cerebellar projections to the prefrontal cortex of the primate. J Neurosci 15:700–712 O’Reilly JX, Beckmann CF, Tomassini V, Ramnani N, Johansen-Berg H (2009) Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb Cortex 20:953–965 Palesi F, Tournier J-D, Calamante F et al (2015) Contralateral cerebello-­ thalamo-­cortical pathways with prominent involvement of associative areas in humans in vivo. Brain Struct Funct 220:3369–3384 Pelzer EA, Hintzen A, Goldau M, von Cramon DY, Timmermann L, Tittgemeyer M (2013) Cerebellar networks with basal ganglia: feasibility for tracking cerebello-pallidal and subthalamo-cerebellar projections in the human brain. Eur J Neurosci 38(8):3106–3114 Ramnani N (2006) The primate cortico-cerebellar system: anatomy and function. Nat Rev Neurosci 7:511–522 Salmi J, Pallesen KJ, Neuvonen T, Brattico E, Korvenoja A, Salonen CS (2010) Cognitive and motor loops of the human cerebro-cerebellar system. J Cogn Neurosci 22:2663–2676 Schmahmann JD (1991) An emerging concept. The cerebellar contribution to higher function. Arch Neurol 48(11):1178–1187 Schmahmann JD (1996) From movement to thought: anatomic substrates of the cerebellar contribution to cognitive processing. Hum Brain Mapp 4(3):174–198 Schmahmann JD, Pandya DN (1997) The cerebrocerebellar system. Int Rev Neurobiol 41:31–60

324 Schmahmann JD, Guell X, Stoodley CJ, Halko MA (2019) The theory and neuroscience of cerebellar cognition. Annu Rev Neurosci 42:337–364 Strick PL, Dum RP, Fiez JA (2009) Cerebellum and nonmotor function. Annu Rev Neurosci 32:413–434 Tomasi D, Volkow N (2012) Resting functional connectivity of language networks: characterization and reproductibility. Mol Psychiatry 17:841–854

C. Habas Voogd J, Schraa-Tam CKL, van der Geest JN et al (2012) Visuomotor cerebellum in human and non human primates. Cerebellum 11:392–410 Wagner MJ, Luo L (2020) Neocortex-cerebellum circuits for cognitive processing. Trends Neurosci 43(1):42–54

MRI Aspects: Conventional, SWI, and DTI

50

Thomas M. Ernst, Andreas Deistung, Marc Schlamann, and Dagmar Timmann

Abstract

This chapter will focus on structural magnetic resonance imaging (MRI) in degenerative cerebellar ataxias. First, we will briefly introduce MRI pulse sequences, which are routinely used for brain imaging in clinical practice and biomedical research. Next, we will describe characteristic MRI findings in the most common forms of degenerative ataxias. Many of the degenerative cerebellar ataxias are disorders of the gray matter, and much of the pathology is seen on T1-weighted MRI images. Three main patterns of cerebellar degeneration are distinguished: (i) “pure” cerebellar degeneration (e.g., in spinocerebellar ataxia type 6 (SCA6)), (ii) olivopontocerebellar atrophy (e.g., in the cerebellar type of multiple system atrophy (MSA-C)), and (iii) predominant atrophy of the spinal cord (e.g., in Friedreich’s ataxia). There is a subset of cerebellar ataxias, which are accompanied by white matter abnormalities. White matter abnormalities are seen as hyperintensities in T2-weighted, proton density-weighted (PD), and fluid-attenuated inversion recovery (FLAIR) images. Some patterns of white matter disease are suggestive of certain types of ataxias, e.g., hyperintensities in the pons (“hot cross bun” sign) and the middle cerebellar peduncles in MSA-C.  Susceptibility-weighted imaging T. M. Ernst (*) · D. Timmann Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University of Duisburg-Essen, Essen, Germany e-mail: [email protected]; [email protected] A. Deistung Department of Radiation Medicine, University Clinic and Outpatient Clinic for Radiology, University Hospital Halle (Saale), Halle (Saale), Germany e-mail: [email protected] M. Schlamann Neuroradiology, Department of Diagnostic and Interventional Radiology, University Hospital of Cologne, Cologne, Germany e-mail: [email protected]

(SWI) and quantitative susceptibility mapping (QSM) are not only helpful to show abnormal brain iron deposition (e.g., in superficial siderosis), but also accompanying atrophy of the iron-rich cerebellar nuclei (e.g., in SCA6). Diffusion tensor imaging (DTI) is helpful to show changes in the integrity of cerebellar white matter and cerebellar peduncles. Keywords

Structural MRI · Cerebellar degeneration · White matter Gray matter

50.1 Introduction Despite the good quality of new-generation computerized tomography (CT), magnetic resonance imaging (MRI) is the method of choice for visualization of structures within the posterior fossa and spinal canal. Unlike CT, bone artefacts are not a problem with MRI, and individual soft tissue contrast is better captured. Thus, the cerebellum, the brainstem, and the spinal cord are shown in much more detail with MRI.  Consequently, structural MRI is typically used for characterizing degenerative cerebellar ataxias. These slowly progressive degenerative disorders involve the cerebellum and cerebellar pathways to varying extents. Structural MRI is also important in the diagnostic work-up for focal cerebellar diseases, such as stroke, tumors, or multiple sclerosis, but this is beyond the scope of this chapter. T1-weighted MRI images exhibit the best gray matter/white matter contrast. Therefore, T1-weighted MRI images are commonly used to reveal atrophy of the cerebellar cortex, the brainstem, and the spinal cord (Fig.  50.1). A subset of cerebellar ataxias is accompanied with white matter disease. Proton density (PD)-weighted, T2-weighted, and fluid attenuated inversion recovery (FLAIR) MRI images are sensitive to show white matter lesions (Fig.  50.2). MRI contrast enhancement is

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_50

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Fig. 50.2  Characteristic MRI abnormalities in degenerative cerebellar ataxias based on T2-weighted images and SWI images. In (a–d), sagittal views of T2-weighted images are shown in the upper row and axial views in the lower row. In (e), axial views of T2-weighted images are presented in the upper row, and of SWI images in the lower row. (a) Healthy control subject; (b) olivopontocerebellar atrophy (OPCA) in a patient with the cerebellar type of multiple system atrophy (MSA-C), note the “hot cross bun” sign in the pons (black arrow); (c) cerebellar atrophy and white matter hyperintensities in the cerebellum and cerebellar peduncles (axial view), spinal cord (dorsal column, see lower

black arrow in sagittal view) and brainstem (pyramidal tract, see upper black arrow in sagittal view) in a patient with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL); (d) cerebellar atrophy and hyperintensities in cerebellar peduncles (white arrow in axial view) in 4H leukodystrophy, see also diffuse hypomyelination of the cerebral cortex (white arrows in sagittal view); (e) Axial T2-weighted (a) and SWI (b) images in a patient with superficial siderosis. See marked hypointensities (black signal) covering the surface of the cerebellum and brainstem (e.g., black arrow in b)

uncommon in cerebellar degeneration. Susceptibility-­ 50.2 Brief Description of Magnetic weighted imaging (SWI), quantitative susceptibility mapResonance Imaging (MRI) Sequences ping (QSM), and diffusion-weighted imaging (DWI), more specifically diffusion tensor imaging (DTI), are newer devel- In almost all modern clinical MRI scanners, the atomic opments. SWI and QSM images show not only abnormal nucleus of hydrogen 1H, the most abundant nuclide in the brain iron deposition but also accompanying atrophy of the human body, is used as a probe. In a strong external magnetic iron-rich cerebellar nuclei. DTI is beneficial in revealing field, hydrogen displays a small nuclear magnetization that changes of the integrity of cerebellar white matter and cere- can be specifically manipulated by an application of alternatbellar peduncles. ing electromagnetic fields at a specific frequency (usually

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50  MRI Aspects: Conventional, SWI, and DTI

radio frequency, RF). Information about the sample is usually deduced from the (hydrogen) nuclei’s very small RF response following a very strong and short (that is, pulsed) RF excitation. Additional magnetic fields (gradients) are applied to localize the signal’s source, allowing to subsequently scan through the sample to obtain complete three-­ dimensional information, where each point in the image represents the signal of a volume element of a given size (“voxel”) (McRobbie 2007). The decisive attribute of each image is the contrast between the relevant features displayed. In human tissues, the local density of hydrogen atoms (“proton density”) and the electric environment of the individual atoms varies. By well-chosen sequential applications of RF pulses and magnetic gradient fields (that is, MRI sequences), a variety of different contrasts can be generated that in combination yield a broad spectrum of information about a given biological sample. As a number of physical properties of the sample tissue influence the contrast, it is common practice to set up a sequence in such a way, that for the tissue of interest the influence of one of these properties is prominent (that is, weighting). A range of MRI methods allows to optimize image acquisition for specific questions or to reduce the acquisition time. We will focus on the most common contrasts in clinical neuroradiology practice: PD, T1, T2, susceptibility (SWI), and diffusion (DWI) weighting. Diffusion tensor imaging (DTI) constitutes a special case of DWI that provides unique insight into the anatomy of brain connectivity and serves as valuable tool in research.

In PD-weighted images, the influence of relaxation effects is reduced and the contrast is dominated by the local density of hydrogen nuclei (“protons”). PD-weighted images usually display a good gray matter/white matter contrast, but gray matter and cerebrospinal fluid (CSF) cannot be differentiated. Especially, in the posterior fossa PD-weighted images are less prone to artifacts than, e.g., FLAIR images (see below). The T1 relaxation (spin-lattice relaxation) time is the time constant that describes the return of the magnetization after an RF excitation to the equilibrium. In T1-weighted images, tissues with long T1 times (e.g., CSF) are displayed dark, while the ones with short T1 (e.g., fat) appear bright (Table 50.1). As T1 in gray and white matter differs strongly and T1 in CSF is much longer, T1-weighted images experience an excellent gray matter/white matter contrast. T1 can be artificially shortened by intravenous application of Gadolinium-based contrast agents. This approach is typically used to characterize brain lesions. The detectable macroscopic signal depends on the coherence of the microscopic magnetizations within each voxel. The loss of this spin coherence over time is another relaxation process, and can for example be caused by molecular collisions (spin-spin relaxation, T2). Typical tissue T2 times of white matter are shorter than in gray matter, and white matter is displayed darker than gray matter in T2-weighted images. In most brain lesions, the local extracellular water content is increased resulting in a higher T2 and, thus, brighter contrast in T2-weighted images. Hence, these lesions show up most

Table 50.1  Simplified MR image appearance of a selection of human tissues. Note that this table only describes a simplified interpretation. Image appearance might deviate, for instance, according to the applied sequence or gray value scaling in the viewer Image appearance in weighted images PD Bright (++)

T1 Dark (--)

Cortical gray matter Deep gray matter White matter Fat

Bright (++)

Dark (--)

Bright (++)

Bone

Very dark (---)

Dark (--) to bright (++)c Bright (++) Very bright (+++) Very dark (---)

Calcification Edema Iron

Dark (--) Bright (++) Insensitive

Dark (--)a Dark (--) Light bright (+)

Tissue CSF

Dark (--) Bright (++)

T2 Very bright (+++) Bright (++)

FLAIR Dark (--)

T2*/SWI Bright (++)

QSM Light bright (+)

Bright (++)

Bright (++)

Bright (++)

Dark gray (--) Dark (--) Bright (++)

Bright (++) to dark (--)c Dark gray (--) Bright (++) b

Dark (--) to very dark (---)c Bright (++) Bright (++)

Bright (++) to very bright (+++)c Light dark (-) Bright (++)d

Very dark (---) Dark (--) Bright (++) Dark (--)

Very dark (---)

Very dark (---)

No informatione

Dark (--) Bright (++) Dark (--)

Dark (--) Bright (++) Very dark (---)

Very dark (---) Light bright (-) Very bright (+++)

CSF cerebrospinal fluid, PD proton density weighted, FLAIR fluid attenuated inversion recovery, SWI susceptibility-weighted imaging, QSM quantitative susceptibility-weighted imaging a  Under certain conditions bright b  In clinical practice often used with additional fat saturation. In this case: dark c  Depending on the specific gray matter nucleus d  While fat increases the magnetic susceptibility in particular in liver tissue, its effect on brain tissue seems to be negligible e  Most QSM approaches produce valid information for the brain tissue only. Thus, the skull is usually removed on these images

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prominently in white matter regions, where they appear hyperintense (bright) (Table  50.1). However, the dominant bright feature in the T2-weighted image is usually the CSF. To compensate for the bright CSF, the FLAIR sequence is set up in such a way that signal from tissue with a T1 time close to the T1 time of CSF is efficiently suppressed. The result is a T2-like contrast, where CSF is displayed dark instead of bright, allowing to clearly distinguish hyperintense edema, gliosis, or plaques from the CSF (Wattjes et al. 2006). If local magnetic field inhomogeneities are not compensated by the sequence applied, the spin coherence is lost faster than T2 and is characterized by the effective spin-spin relaxation time (T2*  20 mM), in many brain regions, impacts of low concentrations of EtOH ([EtOH]  ≤  10  mM) are minimal or lacking. Thus, it is unlikely that low [EtOH] has such widespread action in the brain and on behavior by direct actions. Instead, it is likely that low [EtOH] has more localized actions that are then transmitted more widely, and the cerebellum is clearly involved in this process. In vivo studies of humans and animals indicate that low [EtOH] alters cerebellar processing and associated behaviors (Volkow et  al. 2008; Gallaher et  al. 1996; Schuckit 1985; Schuckit et al. 2003). Importantly, studies of cerebellar brain slices have shown that 9–10  mM EtOH can powerfully enhance or suppress (depending on genotype) GABAA receptor (GABAAR)-mediated inhibition of rat cerebellar GCs (Carta et al. 2004; Kaplan et al. 2013), which are the primary integrators of afferent information to the cerebellar cortex (Fig. 68.1). Such actions are effectively transmitted to modulate excitation of PCs (Kaplan et al. 2016a), which are the sole output of the cerebellar cortex to the cerebellar nuclei (Fig. 68.1). The Inferior Olivary neurons that supply the climbing fiber input to, and powerfully excite output PCs are also inhibited by 10 mM EtOH (Welsh et al. 2011), as is the N-methyl-D-aspartate receptor (NMDAR)-mediated component of their synaptic input to PCs and associated plasticity (He et al. 2013), providing another clear pathway for cerebellar sensitivity to low [EtOH]. Finally, 10  mM EtOH also increases mixed GABAergic/glycinergic inhibition of Unipolar Brush cells, the only other non-GC excitatory interneuron in the GC layer (not shown in Fig.  68.1, given restricted expression in specific cerebellar regions) (Richardson and Rossi 2017). Importantly, in rodent studies of EtOH-induced motor impairment, specific modulation of cerebellar processing with locally infused modulatory drugs (including nicotine) can effectively reduce or even eliminate motor impairing effects of systemic EtOH, verifying that EtOH-induced motor incoordination is primarily specifically mediated by actions in the cerebellum (Dar 2015). Given that low [EtOH] clearly modulates cerebellar output, and enough to influence known cerebellar-dependent behaviors, it is reasonable to consider such altered output will then similarly indirectly influence all other brain regions that the cerebellum communicates with (Fig.  68.1), which includes most regions that are activated in vivo by low [EtOH], as described above. Thus, in addition to mediating motor discoordination, the observed widespread changes in brain activity and associated behavioral responses to consumption of a unit or two of EtOH (leading to BACs of ~10 mM) are likely driven in part by altered cerebellar output. As the concentration of EtOH increases above 10  mM, but still in the survivable recreational/clinical range

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(20–50 mM), progressively at least some aspect of most of the cells and synapses within the cerebellar cortex are affected, including enhancement of molecular layer interneuron inhibition of PCs (25 mM EtOH) (Ming et al. 2006), direct excitation of PCs (50 mM EtOH) (Ming et al. 2006), and direct inhibition of input layer GCs (35 mM) (Lewohl et al. 1999). Thus, starting at 10 mM, progressively increasing components of the cerebellar cortical circuit are affected by EtOH, with almost all components affected by survivable BACs (50 mM). Such high sensitivity, and progressive incorporation of cerebellar components underlies increasingly impaired motor performance starting at 1–2  units of EtOH. And, as suggested above, the cerebellum likely contributes, via projections throughout the brain, to many behavioral aspects of EtOH consumption.

68.2.2 The Cerebellum Is a Common and Dominant Site of Brain Damage in People with Alcohol Use Disorder (AUD) Brain damage is commonly observed in humans with AUD, and in addition to the specific deleterious behavioral impacts of such brain damage, such as impaired memory formation and ataxia, alterations in various cognitive functions, such as impaired judgement, likely contribute to the maintenance of AUD (Bates et al. 2013; Segobin et al. 2014; Le Berre et al. 2013), creating a devastating vicious cycle. The cerebellum is a common and prominent site of AUD-associated brain damage, as reflected by overall shrinkage (Fig. 68.2) as well as PC loss (Sullivan et  al. 2003), although damage occurs preferentially in subsections of the cerebellum, notably the anterior vermis (Sullivan et al. 2003). Moreover, there is considerable heterogeneity across individuals in the extent of cerebellar damage. In this regard, a major ongoing quandary is whether AUD-associated brain damage generally and cerebellar damage specifically is primarily due to chronic excessive EtOH exposure per se, due to malnutrition (in particular thiamine deficiency) which often accompanies AUD, or both. Anatomical studies indicate that cerebellar damage is more common and severe in patients that also experienced thiamine deficiency, and the cerebellum is notably sensitive to damage by thiamine deficiency, but it is difficult to disentangle the presence of thiamine deficiency from increased EtOH exposure levels in the uncontrolled clinical scenario. However, detailed statistical analysis of various behavioral patterns in patients with AUD suggest that brain structures subserving motor control and executive function can be doubly dissociated in terms of etiology from memory impairments, with motor control/executive function impairments being most correlated with the level of EtOH exposure but not thiamine deficiency, and memory impairment being most

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Fig. 68.2  Representative MRI images of the brains from a control subject (left) and a subject with AUD (right), showing shrunken cerebellum in subject with AUD. The cerebellum is circled in both images. Adapted

with permission from original images provided by Dr. Edith Sullivan, used in Sullivan et al. (2003) ACER, 27:301

correlated with the level of EtOH exposure and thiamine deficiency (Fama et al. 2019). Thus, it is likely that much of the reported cerebellar damage in AUD is in fact due to levels of EtOH exposure, which is in keeping with its unusual sensitivity to EtOH, as described above. This conclusion is supported by animal studies in which prominent cerebellar damage occurs upon forced exposure to EtOH despite maintaining optimal nutrition (Jaatinen and Rintala 2008). Adding to the face validity of such animal models, the extent of cerebellar damage varies across subregions (Jaatinen and Rintala 2008). The statistical analysis of behavioral correlates of regional brain damage also clearly associates both motor and cognitive impairment with EtOH-induced cerebellar damage (Sullivan et al. 2020; Pinner et al. 2020), making it likely that cerebellar damage contributes to poor decision making that sustains AUD (Bates et  al. 2013; Segobin et  al. 2014; Le Berre et al. 2013). The mechanisms by which EtOH damages the cerebellum are not particularly well understood, but likely involve excitotoxicity, oxidative damage and inflammatory responses (Jaatinen and Rintala 2008). The concept of EtOH exposure causing excitotoxicity is on its face curious, given that in general EtOH dampens excitation, both through enhancing GABAergic inhibition and suppressing glutamatergic excitation. However, this apparent paradox can be reconciled by considering that excitotoxicity likely occurs during withdrawal from chronic EtOH, when the brain’s homeostatic adaptations to EtOH dampening of excitability leads to a rebound hyperexcitable state (Jaatinen and Rintala 2008).

68.2.3 The Cerebellum Is a Dominant Site of Brain Damage Underlying Fetal Alcohol Spectrum Disorder (FASD) Fetal alcohol spectrum disorder (FASD) is a spectrum of lifelong physical and neurological symptoms resulting from fetal exposure to EtOH. The range and degree of damage and consequent symptoms vary depending on the duration and level of exposure to EtOH (Sullivan et al. 2020; Pinner et al. 2020). The developing cerebellum is particularly sensitive to EtOH, and its damage and consequent malfunction is a key substrate of many of the neurological manifestations of FASD, including reduced balance, fine motor skill, broad motor coordination, and likely via its non-motor roles, language, emotional regulation and cognitive function (Sullivan et al. 2020; Pinner et al. 2020; Gill and Sillitoe 2019). Similar to the adult cerebellum, damage to the developing cerebellum manifests as overall shrinkage and involves damage to PCs (Nirgudkar et  al. 2016). Moreover, the damage is not uniform, but rather some sub-regions, particularly the anterior vermis are more commonly damaged (Nirgudkar et al. 2016), and this may have to do with molecular and physiological differences across sub-regions, despite the otherwise uniform cellular makeup of the cerebellar cortex (Pinner et al. 2020; Gill and Sillitoe 2019). In addition to spatial heterogeneity in EtOH-induced cerebellar damage, the developing cerebellum has critical developmental time points when susceptibility to damage is greatest. Since it is difficult to accurately ascertain when and to what degree a human fetus is exposed to EtOH, such infor-

68  Alcohol and the Cerebellum

mation comes largely from rodent models, in which evidence indicates that the developing cerebellum has two distinct phases of sensitivity to the damaging effects of EtOH exposure, equivalent to the second and third trimester of gestation in humans (Nirgudkar et al. 2016) (and references therein). In particular, EtOH exposure during rodent gestational age 10–19 (neurodevelopmentally equivalent to the second trimester in humans) results in cerebellar shrinkage without notable PC loss. In contrast, EtOH exposure in newborn pups, in particular, postnatal days 4–9 (neurodevelopmentally equivalent to the third trimester in humans), results in loss of PCs without dramatic cerebellar shrinkage. Thus, the overall phenotype of humans with FASD (cerebellar shrinkage and PC loss) likely reflects exposure during the second and third trimesters respectively. Similar to the adult cerebellum, EtOH-induced damage is induced in animal models with a controlled diet, suggesting at least some of the damage is induced by EtOH itself, although damage is likely exacerbated by concomitant thiamine deficiency. Likewise, although specific mechanisms of damage are not yet well understood, EtOH-induced fetal cerebellar damage likely involves some combination of excitotoxicity, oxidative damage and inflammatory responses (Jaatinen and Rintala 2008). Also, like the adult cerebellum, EtOH-induced excitotoxic damage may occur during the hyperexcitable withdrawal phase of chronic alcohol abuse (Jaatinen and Rintala 2008). In the context of excitotoxicity being a likely contributing factor in EtOH-induced cerebellar damage during this transient period of development, but also in adult cerebellum (Sect. 68.2.2), it is noteworthy that PCs, which are damaged in both contexts, have an atypical temporal expression pattern of functional NMDARs, exhibiting a transient expression in newborn rodents, which disappear at about postnatal day 8, and then re-emerge in fully adult PCs (Piochon et  al. 2007). Given the well-known role of Ca2+ influx through NMDARs in triggering excitotoxic neuronal damage, it is possible that the developmental pattern of PC NMDARs contributes to the developmental profile of their damage in the context of FASD and AUD.

68.3 The Cerebellum and Genetic Risk for Developing AUD Adoption and twin studies suggest that predilection for developing AUD is 50–60% genetically determined (Hasin et al. 2007; Hill 2010), and both clinical and preclinical studies suggest that the cerebellum plays a significant role in mediating such genetic predilection. In particular, clinical studies of humans with a family history of AUD (FH+), and thus elevated risk for developing AUD, indicate that cerebellar anatomy, physiology and sensitivity to EtOH in FH+ individuals differs from individuals without a family history of

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AUD (FH−). And preclinical animal studies suggest that genetic differences in cerebellar response to EtOH influence how much EtOH a given rodent genotype will consume.

68.3.1 Cerebellar Anatomy and Physiology in Humans with Genetic Risk for AUD MRI studies indicate that the cerebellum of FH+ offspring is significantly larger than in trait-matched FH− offspring, due primarily to increased grey matter, potentially due to reduced synaptic pruning during development (Hill 2010; Hill et al. 2007, 2011, 2016). Importantly, this difference is separable from effects related to prenatal exposure to EtOH, which also affects the size of the cerebellum, but in the opposite direction and in distinct lobes (Sharma and Hill 2017). While it is not clear how such anatomical differences influence predilection for AUD, increased cerebellar volume in FH+ individuals is associated with an allelic variation in the GABAAR α2 subunit (Hill et  al. 2011), which when knocked out in mice results in reduced EtOH consumption in females (Boehm et al. 2004). In addition to these anatomical differences, there are also considerable individual differences in cerebellar processing and communication with other brain regions that correlate with FH status. In functional MRI studies, relative to FH− individuals, alcohol naïve FH+ offspring show less functional connectivity between the cerebellum and two brain regions known to be involved in addictive behaviors, the prefrontal cortex (PFC) and nucleus accumbens (Cservenka et  al. 2014; Herting et  al. 2011). Further, FH+ individuals show reduced cerebellar activity during cognitive tasks (risky decision making and spatial working memory), despite not exhibiting any deficits in task performance (Cservenka and Nagel 2012; Mackiewicz Seghete et al. 2013). Thus, in addition to exhibiting reduced communication with addiction associated brain regions, alcohol naïve, FH+ individuals exhibit altered cerebellar processing of behavioral tasks that likely play a role in addiction. Collectively, while specific mechanisms remain unclear, genetic risk for developing an AUD is associated with altered cerebellar anatomy, communication with known reward centers of the brain, and altered activity during behaviors likely to influence development of AUD.

68.3.2 A Low Level of Response to Alcohol-­ Induced Cerebellar-Dependent Motor Impairment Is a Risk Factor for Excessive Alcohol Consumption in Rodent Models and AUD in Humans As with many addictive drugs, an endophenotypic component to genetic risk for developing an AUD is increased sen-

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sitivity to the rewarding aspects of EtOH and reduced 68.3.3 Genetic Differences in Cerebellar sensitivity to the aversive aspects of EtOH.  One well-­ Cellular Responses to Alcohol Correlate established cerebellar-associated behavioral measure of senwith, and likely Contribute to the Level sitivity to EtOH in humans is alcohol-induced static ataxia, of Alcohol Consumption in Animal which manifests as body sway, resulting from impaired vesModels tibular and ocular feedback control of balance. Such studies consistently find that a low level of sensitivity to EtOH-­ As introduced above, a primary component of the cerebelinduced body sway is heritably associated with FH+ family lum’s sensitivity to EtOH is via EtOH actions at the Golgi history status and predictive of development of AUD cell to GC inhibitory GABAergic synapse. Inhibition at this (Schuckit et  al. 2005, 2011). A similar covariation also synapse is mediated by two forms of GABAA receptor occurs in preclinical rodent models. In particular, sensitivity (GABAAR)-mediated inhibition: traditional phasic spontaneto EtOH-induced ataxia shows an inverse relationship with ous inhibitory postsynaptic currents (sIPSCs) generated by EtOH consumption in several inbred strains of mice (e.g. postsynaptic GABAARs responding to the vesicular release DBA/2  J (D2) and C57BL/6  J (B6) mice), and lines of of GABA (Fig.  68.3a), and a powerful form of tonic rodents selected for differences in alcohol consumption (e.g. ­ inhibitory current generated by high affinity, non-­ Alko, Alcohol/Alko, Non-Alcohol rats, and alcohol-­ desensitizing extrasynaptic GABAARs responding to the preferring (P)/alcohol non-preferring (NP) rats) (Rossi and ambient extracellular concentration of GABA (Fig.  68.3a) Richardson 2018). Thus, there is substantial evidence that in (Hamann et al. 2002). Early studies of the cerebellum in low both humans and rodents, genetically determined insensitiv- EtOH consuming Sprague Dawley rats (SDRs) demonstrated ity to the motor impairing effects of EtOH is a risk factor for that low [EtOH] (starting at ~10 mM) enhances Golgi cell AUD in humans and excessive EtOH consumption in rodents. inhibition of GCs (Carta et al. 2004), via both an increase in a

Golgi cell to GC synapse

b

c

SDR granule cell response to EtOH

1-2g/kg/day SDR

52mM Cl-

d

11-22g/kg/day

D2 mouse

Prairie Vole

B6 mouse

52mM

52mM EtOH

52mM

ClCl-

Cl-

Cl-

βx

γ2

δ α 4 βx ,6 α4, β x

α1

α1 βx

Cl-

6

Cl-

e

f

g

NHP

1-2

1-4 11-22

PV PV

D2

1-2

B6

SDR

Phasic GABAAR IPSC Tonic GABAAR current

~12g/kg ~12

Typical g/kg/day EtOH consumed

Fig. 68.3 (a) Top: Schematic diagram showing GABAARs in the synaptic cleft (blue) and outside of the synaptic cleft (green). Bottom: Phasic IPSCs (left) are mediated by synaptic GABAARs (as evidenced by their sensitivity to the GABAAR antagonist, GABAzine) that are rapidly activated by the high concentrations of vesicular GABA released into the synaptic cleft. Tonic GABAAR-mediated currents (right) blocked by GABAzine. Note: because GABA released into the synaptic cleft diffuses out of the cleft where it can activate extrasynaptic GABAARs, the magnitude of the tonic GABAAR current increases or decreases in parallel with changes in vesicle release rate, either from the presynaptic neuron or from neighboring synapses not directly connected to the recorded cell. (b) Example recording (left) showing that EtOH (52 mM) increases sIPSC frequency and tonic GABAAR current magnitude in a GC in a slice of cerebellum from a low EtOH consuming Sprague Dawley rat (SDR). (c and d) Example recordings showing that EtOH (52 mM) enhances the tonic GABAAR current in low EtOH

consuming rodent genotypes (SDRs and D2 mice; c), but suppresses the tonic GABAAR current in high EtOH consuming rodent genotypes (Prairie Voles and B6J mice; c). (e) Plot of mean EtOH-induced change in magnitude of GC tonic GABAAR current across mammalian genotypes with divergent EtOH consumption phenotypes. Note, EtOH consumption values are rough estimates of average amount consumed across a 24 h period for each mammalian genotype, without consideration for consumption pattern across the day. (f) Example recordings and bar chart of mean responses to varying doses of EtOH in SDRs and B6J mice showing that opposite action of EtOH is preserved at low to high [EtOH]. (g) Mean amount of EtOH consumed by B6J mice during a 2hr., 2 bottle choice (water and 10% EtOH) session, under control conditions and after a local injection of the GABAAR agonist, THIP, into lobe 3 of the cerebellum. Images adapted with permission from Mohr et al. 2013 and Kaplan et al. 2013, 2016a, b

68  Alcohol and the Cerebellum

the frequency of sIPSCs and an increase in the magnitude of the tonic GABAAR current (Fig.  68.3b), which in GCs is mediated by extrasynaptic α6 and δ subunit-containing GABAARs (Fig. 68.3a) (Hamann et al. 2002). The primary mechanism for both components is EtOH-induced increased action potential firing by Golgi cells, with the resultant increase in vesicular GABA release increasing both sIPSC frequency and tonic GABAAR current magnitude, due to the associated elevation of ambient extracellular [GABA] (Carta et al. 2004; Kaplan et al. 2013). The notably high sensitivity of the Golgi cell to GC GABAAR system to EtOH, combined with the clear role of this response in mediating at least one behavioral response to EtOH (motor impairment) makes it a potential mediator of genetic differences in response to low [EtOH] that influences initial subjective reactions to consumption of EtOH, and thus predilection for developing an AUD (as in Sect. 68.3.2). Indeed, more recent studies of different rodent genotypes with divergent EtOH consumption phenotypes determined that a general pattern exists, in which the impact of EtOH on GC tonic GABAAR currents varies in polarity and magnitude in parallel with the EtOH consumption phenotype of the mammal, with high and low EtOH consumption associated with suppression and enhancement of tonic GABAAR currents respectively (Fig.  68.3b–e). This relationship persists across the dose-response range of EtOH concentrations tested, including 9 mM (Fig. 68.3f), indicating that EtOH has opposite actions on GC tonic GABAAR currents in high and low EtOH-consuming genotypes at all levels of consumption. Importantly, even at 10 mM, EtOH suppression of the GC tonic GABAAR current observed in high EtOH consuming genotypes is strong enough to increase excitation of output PCs (Kaplan et  al. 2016a), providing a plausible mechanism by which EtOH could affect activity in the VTA reward center of the brain, via recently discovered direct excitatory connections (Carta et al. 2019). Further studies suggest that the striking genetically-­ determined correlation between GC tonic GABAAR current response to EtOH and consumption phenotype plays a causative role. Specifically, the GABAAR agonist THIP, which has an order of magnitude higher affinity for δ-subunit containing GABAARs, was focally injected into the cerebellum of B6J mice in  vivo. This would effectively increase GC tonic GABAAR currents similar to what EtOH does in low EtOH-­ consuming genotypes (Kaplan et  al. 2013). Such injections effectively reduced EtOH consumption by normally high EtOH-consuming B6J mice (Fig. 68.3g), without affecting water consumption or overall locomotion (Kaplan et  al. 2016a). While more selective manipulations of the tonic GABAAR current will need to be tested, and ideally it should be determined if EtOH consumption can be increased or decreased based on the direction of manipulation, these studies suggest that either EtOH-induced suppression of GC

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tonic GABAAR currents promotes EtOH consumption, or EtOH-induced enhancement of GC tonic GABAAR currents deters consumption or both. The molecular mechanisms that mediate the response polarity of GC tonic GABAAR currents to EtOH have been partially determined. Specifically, enhancement of tonic GABAAR currents is mediated by EtOH inhibition of neuronal nitric oxide synthase (nNOS), which excites Golgi cells enough to increase their action potential firing (Kaplan et al. 2013). Genetic control of this process appears to be implemented by expression of nNOS, with low levels of expression in high EtOH-consuming B6J mice and PVs, high levels of expression in low EtOH-consuming SDRs and D2 mice, and intermediate and variable levels of expression across individual non-human primates (NHPs) which also show variable levels of EtOH consumption (Kaplan et  al. 2013, 2016b; Mohr et al. 2013). Conversely, the suppression of GC tonic GABAAR currents observed in B6J mice and PVs is mediated solely by postsynaptic actions on the GABAARs, which is genetically determined by the level of postsynaptic PKC activity. In particular, PKC activity appears to prevent EtOH from suppressing GC tonic GABAAR currents (Kaplan et al. 2013). Collectively, the data indicate that there are two genetically controlled molecular switches (presynaptic nNOS expression and postsynaptic PKC activity), and that the balance of the two processes dictates the polarity and magnitude of the effect of EtOH on GC tonic GABAAR currents. High post synaptic PKC activity and high nNOS expression results in EtOH enhancing GC tonic GABAAR currents, and low post synaptic PKC activity and low nNOS expression results in EtOH suppressing tonic GABAAR currents. Importantly, the resultant direction of EtOH effects correlates with and influences EtOH consumption phenotype, wherein suppression and enhancement are associated with high and low EtOH consumption, respectively.

68.4 Summary The cerebellum is uniquely sensitive to EtOH, responding physiologically and behaviorally to concentrations of EtOH achieved by an adult consuming 1–2  units of alcohol (10 mM), and having nearly its entire cortical circuit affected by higher, but survivable, concentrations ( semantic), as well as metalinguistic deficits—problems with metaphor, inference, ambiguity, and verbal expression of complex thoughts; (Guell et  al. 2015) and apathy, disinhibition, and impaired emotional intelligence. Impaired focused and sustained attention, delayed recall of verbal or visual information, facial agnosia, amusia, and temporal disorientation, and limb kinetic apraxia are also reported (Schmahmann and Sherman 1998; Malm et al. 1998; Leggio et al. 2000; Neau et al. 2000; Exner et al. 2004; Gottwald et  al. 2004; Hoffmann and Schmitt 2004; Kalashnikova et  al. 2005; Hokkanen et  al. 2006; Ravizza

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et al. 2006; Richter et al. 2007; Ziemus et al. 2007; Hoffmann and Cases 2008; Manes et  al. 2009; Stoodley and Schmahmann 2009a; Schweizer et al. 2010; Alexander et al. 2012; Tedesco et al. 2011). The CCAS has been replicated in multiple studies of patients with different neurological disorders, and its essential features were confirmed (Adamaszek et al. 2017; Ahmadian et al. 2019; Argyropoulos et al. 2020; Van Overwalle et al. 2020), and used to develop the CCAS/ Schmahmann scale for the detection and determination of severity of involvement of cognition and emotional modulation in patients with cerebellar injury (Hoche et al. 2018).

75.3 The Cerebellar Cognitive Affective Syndrome in Children Levisohn et al. (2000) first studied cognition in children who underwent resection of cerebellar tumors without receiving radiation therapy or methotrexate which can lead to poor cognitive outcome. The cohort consisted of 19 children, ages 3–14 with medulloblastoma, astrocytoma, and ependymoma. Problems were noted with attention and executive function as evidenced by deficits in digit span (57% of the 14 tested), sequencing, and planning. Establishing and maintaining set was hampered by perseveration. Deficits in expressive language, present in 58% of the cohort, included brief responses, lack of elaboration, reluctance to engage in conversation, long response latencies, and word finding difficulties. Language initiation and word finding difficulties occurred in the context of average scores on verbal tests. Confrontation naming deficits were ameliorated with phonemic cues. Many demonstrated difficulty with initiation of responses and problem-solving strategies. Visual–spatial difficulties were present in 37%, characterized by impaired planning and organizational aspects of tasks (Fig. 75.1, right panel). Verbal memory was impaired in 33% of 15 children tested, particularly for unstructured recall of information. Story retrieval improved with multiple-choice prompts. There was failure to organize verbal or visual–spatial material for encoding, which impacted retrieval of information. Impaired regulation of affect was particularly evident when cerebellar damage included the vermis, manifesting as irritability, impulsivity, disinhibition, and lability of affect with poor attentional and behavioral modulation. The CCAS in children was confirmed by others. Deficits include executive dysfunction with impaired planning, sequencing, mental flexibility and hypothesis generation and testing, visual–spatial function, expressive language, and verbal memory ​(Karatekin et  al. 2000; Grill et  al. 2004; Turkel et al. 2004; Berger et al. 2005; Ronning et al. 2005; Vaquero et  al. 2008). Impairments in verbal intelligence, auditory sequential memory, and language follow right-sided tumors; deficient non-verbal tasks including spatial and

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visual sequential memory and impaired prosody after left cerebellar hemisphere tumors (Riva and Giorgi 2000). The affective component of the CCAS in children includes mood disturbances, pathologic laughing and crying (Kossorotoff et al. 2010); disinhibition, impulsivity, and irritability (Maryniak and Roszkowski 2005); dysphoria, inattention, and irritability (Turkel et al. 2004); anxiety and aggression (Richter et al. 2005); hyperspontaneous and ­disinhibited behavior, and flattened affect with apathy and poverty of spontaneous movement (Aarsen et al. 2004). Emotional lability may be marked, with rapid fluctuation of emotional expression gravitating between irritability with inconsolable crying and agitation, to giggling and easy distractibility. Surgically induced vermal lesions may result in autistic features such as avoidance of physical and eye contact, complex repetitive and rhythmic rocking movements, stereotyped linguistic utterances, and lack of empathy (Riva and Giorgi 2000). Attention-deficit disorder, addiction, anorexia, uncontrolled temper tantrums, and phobias are also reported (Steinlin et al. 2003).

75.4 Postoperative Pediatric Cerebellar Mutism Syndrome (CMS) More than half the children in Levisohn et  al. (2000) with surgical damage to the vermis developed mutism or markedly reduced speech 1–2 days after the surgery, often with hypotonia and oropharyngeal dysfunction/dysphagia. The CMS is frequently accompanied by the cerebellar motor syndrome, cerebellar cognitive affective syndrome and brain stem dysfunction including long tract signs and cranial neuropathies. The mutism is transient, but recovery from CMS may be prolonged, speech and language may not return to

normal, and the motor dysfunction and CCAS often persist (Gudrunardottir et  al. 2016). CMS has had other names, including posterior fossa syndrome (Daly and Love 1958; Wisoff and Epstein 1984; Rekate et al. 1985; Dietze Jr and Mickle 1990; Catsman-Berrevoets et al. 1992; van Dongen et  al. 1994; Kingma et  al. 1994; Kirk et  al. 1995; Pollack et  al. 1995; Schmahmann and Sherman 1997, 1998; Schmahmann 1998; Levisohn et al. 2000; Sadeh and Cohen 2001; see Schmahmann 2020). Both the CCAS and the CMS have been shown to arise in this pediatric postoperative patient population following damage to the deep cerebellar nuclei and the cerebellar outflow system in the superior cerebellar peduncles (Albazron et al. 2019).

75.5 Neuropsychiatry of the Cerebellum; The Affective Component of the CCAS Emotional dysregulation occurs when lesions involve the limbic cerebellum—the vermis and fastigial nucleus (Schmahmann 1991; Schmahmann and Sherman 1998; Richter et al. 2007), with altered regulation of mood and personality, psychotic thinking, and behaviors that meet criteria for diagnoses of attention-deficit hyperactivity disorder, obsessive–compulsive disorder, depression, bipolar disorder, disorders on the autism spectrum, atypical psychosis, and anxiety and panic disorder (Schmahmann et al. 2007). These manifestations segregate into five neuropsychiatric domains—attentional control, emotional control, social skill set, autism spectrum disorders, and psychosis spectrum disorders (Table 75.2) (Schmahmann et al. 2007). The behaviors are conceptualized as either excessive (hypermetric) or

Table 75.2  Neuropsychiatric manifestations in patients with cerebellar disorders, arranged according to major domains, each with positive and negative symptoms Attentional control

Emotional control

Autism spectrum Psychosis spectrum

Social skill set

Positive (exaggerated) symptoms Inattentiveness Distractibility Hyperactivity Compulsive and ritualistic behaviors Impulsiveness, disinhibition Lability, unpredictability Incongruous feelings, pathological laughing/crying Anxiety, agitation, panic Stereotypical behaviors Self-stimulation behaviors Illogical thought Paranoia Hallucinations Anger, aggression Irritability Overly territorial Oppositional behavior

From Schmahmann et al. (2007)

Negative (diminished) symptoms Ruminativeness Perseveration Difficulty shifting focus of attention Obsessional thoughts Anergy, anhedonia Sadness, hopelessness Dysphoria Depression Avoidant behaviors, tactile defensiveness Easy sensory overload Lack of empathy Muted affect, emotional blunting Apathy Passivity, immaturity, childishness Difficulty with social cues and interactions Unawareness of social boundaries Overly gullible and trusting

75  The Cerebellar Cognitive Affective Syndrome and the Neuropsychiatry of the Cerebellum

reduced (hypometric) responses to the external or internal environment. Deficits in social skill set likely reflect altered social cognition, defined as the set of mental processes required to understand, generate, and regulate social behavior (Garrard et  al. 2008; Sokolovsky et  al. 2010; D’Agata et al. 2011; Hoche et al. 2016; Adamaszek et al. 2017). Loss of empathy is reported in patients with cerebellar neurodegenerative disorders as well as in those following focal cerebellar injury involving the posterior lobes (Annoni et  al. 2003; Schmahmann et  al. 2007; Heilman et  al. 2014). Prominent affective changes are seen, for example, in opsoclonus-­ myoclonus syndrome which produces mood changes and inconsolable irritability with lability, aggression and night terrors, dysphoric mood, disinhibition and poor affect regulation, disruptive behaviors and temper tantrums as well as cognitive and language impairments (Turkel et al. 2006; Gorman 2010). Pathological laughing and crying occurs after stroke in the pontocerebellar circuit (Tei and Sakamoto 1997; Gondim et  al. 2001; Parvizi et  al. 2001; Schmahmann et  al. 2004; Jawaid et  al. 2008), in post-­ infectious cerebellitis (Dimova et al. 2009), and in the cerebellar form of multiple system atrophy (Parvizi et al. 2007).

75.6 Cognition in Ataxic Disorders Cognitive changes occur in most of the spinocerebellar ataxias (SCAs) (Geschwind 1999; Orsi et al. 2011; Roeske et al. 2013; Hoche et  al. 2018). Neuropathology in many SCAs involves brainstem, basal ganglia, thalamus, and sometimes the cerebral cortex, so the cerebellar lesion may not be solely responsible for the cognitive deficits. CCAS features include mild generalized cognitive impairment, impaired executive functions, deficits in verbal short-term memory (Kish et al. 1988; Burk et al. 2001; Tedesco et al. 2011), visual and verbal attention, verbal fluency, planning and strategy (Zawacki et al. 2002; Braga-Neto et al. 2011), concentration problems, impaired conceptual reasoning, and emotional instability and impulsivity (Gambardella et al. 1998; Storey et al. 1999; Lilja et  al. 2005; Suenaga et  al. 2008; Cooper et  al. 2010; Sokolovsky et al. 2010; Horton et al. 2011). Developmental cognitive impairment occurs in SCA 13 (Herman-Bert et al. 2000), and dementia in SCA 17 (Koide et al. 1999; Nakamura et al. 2001) and SCA 21 (White et al. 2000). The cognitive profile in Friedreich’s Ataxia is variable—some report normal cognition (Botez-Marquard and Botez 1993), whereas others describe impaired visual-perceptual and visual-­ constructive abilities, slowed information processing, decreased attention, reduced verbal span, deficits in letter fluency, and impaired acquisition and consolidation of verbal

489

information (Devos et  al. 2001; Wollmann et  al. 2002), as well as irritability, poor impulsive control, or blunting of affect (Mantovan et al. 2006).

75.7 Cerebellar Lesions Impair Cognition in the Developing Brain The cerebellum has a protracted developmental trajectory, and is vulnerable to environmental influences (Limperopoulos et al. 2005). Adolescents born very pre-term (0.8 being considered reliable. Internal consistency corresponds to the score consistency across the various items of a scale: all items that are thought to refer to the same theoretical construct should not differ significantly in their scoring. The quality of internal consistency is expressed as Cronbach’s α. It is assessed by comparing the scores referring to the same theoretical construct. Numerical values of 0.8 or above correspond to a good internal consistency. Validity describes the extent to which a scale actually measures what it claims to measure: Internal construct validity of a scale is determined by a principal component analysis that evaluates whether the number of factors and the loadings of the variables measured on them correspond to what is expected on the basis of the proposed theoretical concept. Furthermore, the factor analysis assesses the variability of observed variables with respect to unobserved variables (the so-called ‘factors’) by investigating whether these factors mainly account for associated variations in a series of observed variables. Linearity of a scale and particularly of the differences between ratings is essential to capture a wide spectrum of clinical severity. A scale should also not have significant floor (when data cannot take a value lower than some particular number) or ceiling effects (all scores are localized in the high end of the distribution). Last, but not least, the acquisition of a scale should not be complicated and time-consuming. The most common clinical rating scales are the International Cooperative Ataxia Rating Scale (ICARS), the Friedreich Ataxia Rating Scale (FARS), the Scale for the Assessment and Rating of Ataxia (SARA), the Brief Ataxia Rating Scale (BARS), and the Unified Multiple System Atrophy Rating Scale (UMSARS). Each scale has its strength and weaknesses, and the selection of the clinical scale to use depends on the respective clinical trial’s focus. In

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_76

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the following, each scale will be shortly introduced and its psychometric properties will be presented.

76.2 International Cooperative Ataxia Rating Scale (ICARS) ICARS hypothesizes that all of its 19 items are grouped into four multi-item subscales reflecting core cerebellar features (see Table  76.1) (Trouillas et  al. 1997). A maximum total score of 100 indicates most severe symptoms. ICARS rating takes about 20 min (Schmitz-Hübsch et al. 2006b). Cano first established reliability and validity of total ICARS scores and the subscale ‘posture and gait’ in FA (Cano et al. 2005). Video-based ICARS rating in patients with spinocerebellar ataxia (SCA), FA and controls yielded high interrater reliability for ICARS sum and subscores as well as a good test–retest (live vs. videotaped rating) reliability (Storey et al. 2004). In a large cohort of SCA patients, ICARS interrater reliability, test–retest reliability and internal consistency were found to be good (Schmitz-Hübsch et al. 2006b). Testing for validity (with ataxia disease stages or Barthel indices serving as external criteria) yielded that several ICARS items were redundant and overlapping. Furthermore, rating scores appeared determined by four different factors that did not coincide with ICARS subscales. Therefore, ICARS subscore structure has to be questioned. Schoch evaluated reliability, criterion-related validity, and internal construct validity in focal cerebellar lesions and degenerative ataxia (Schoch et  al. 2007). Test–retest reliability for total

K. Bürk

ICARS scores was good while it was highly variable for ICARS subscores. Internal consistency for all 19 ICARS items and criterion-related validity were good. However, progression over time was only captured by subscore analysis in focal cerebellar lesions, but not in degenerative ataxia. A cross-sectional analysis of internal consistency, factor structure, and correlation with UPDRS-III scores in multiple system atrophy (MSA), Parkinson’s Disease, and controls (Tison et al. 2002; Goetz et al. 2008) questioned the applicability of ICARS in MSA due to interference of basal ganglia symptoms. To date, ICARS has been applied in a number of clinical and therapeutic trials (Ristori et al. 2010; Di Prospero et  al. 2007). In 2018, a Brazilian Portuguese version of ICARS has been validated in SCA patients (Maggi et  al. 2018).

76.3 Friedreich Ataxia Rating Scale (FARS) The original FARS scale had been developed in a small cohort of 14 FA patients in 2005 (Subramony et al. 2005). The scale has four parts including a neurological examination, a disability staging, patient-reported activities of daily living (ADL), and timed performance measures (25feet walk, 9-hole peg test, and PATA rate) (see Tables 76.2 and 76.3). In the initial validation study, ADL measures and timed activities were significantly correlated with the FARS examination total scores and most of its subscores (Subramony et al. 2005). Interrater reliability was excellent for the FARS neurological examination total and its

Table 76.1  International Cooperative Ataxia Rating Scale (ICARS) (Trouillas et al. 1997) Total maximum score: 100 I.  Posture and gait disturbances (maximum score 34)  1.  Walking capacities (maximum score 8)  2.  Gait speed (maximum score 4)  3.  Standing capacities and eyes open (maximum score 6)  4.  Spread of feet in natural position without support, eyes open (maximum score 4)  5.  Body sway with feet together, eyes open (maximum score 4)  6.  Body sway with feet together, eyes closed (maximum score 4)  7.  Quality of sitting position (maximum score 4) II.  Kinetic functions (maximum score 52)  8.  Knee-tibia test for each side (decomposition of movement and intention tremor) for each side (maximum score 4)a  9.  Action tremor in the heel-to-knee test for each side (maximum score 4)a  10.  Finger-to-nose test: decomposition and dysmetria for each side (maximum score 4)a  11.  Finger-to-nose test: intention tremor of the finger for each side (maximum score 4)a  12.  Finger–finger test (action tremor and/or instability) for each side (maximum score 4)a  13.  Pronation–supination alternating movements for each side (maximum score 4)a  14.  Drawing of the Archimedes’ spiral on a predrawn pattern fir the dominant hand (maximum score 4)a III.  Speech disorders (maximum score 8)  15.  Dysarthria: fluency of speech (maximum score 4)  16.  Dysarthria: clarity of speech (maximum score 4) IV.  Oculomotor disorders (maximum score 6)  17.  Gaze-evoked nystagmus (maximum score 3)  18.  Abnormalities of the ocular pursuit (maximum score 2)  19.  Dysmetria of the saccade (maximum score 1) a

Each side of the body is assessed separately. The sum of both sides is added to the total score

76  Ataxia Scales for the Clinical Evaluation

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subsccores with the exception of bulbar and peripheral scores that were less consistent between examiners. FARS timed performance tests actually showed less rater bias and good interrater reliability (Subramony et al. 2005). In 2006, two items related to stance without visual control were added to the FARS examination protocol (FARSn). FARSn has five subscales A to E with a maximum score of 125 points indicating most severe symptomatology (see Table  76.2) (Lynch et  al. 2006). The administration of FARSn takes about 30  min. To further improve FARS Table 76.2 Friedreich Ataxia Rating Scale (FARS). A detailed description of the two FARS examination scales is depicted in Table 76.3

scale properties, the overall number of items of FARSn was reduced by deleting the two bulbar items facial and tongue atrophy (subscale A) as well as the complete subscore peripheral nervous system (subscale D) thereby creating the novel modified FARS (mFARS) with a maximum total score of 93 points (Patel et al. 2016) (see Table 76.3). FARSn and mFARS scale properties have been compared in a cross-sectional analysis of baseline data from Friedreich Ataxia Clinical Outcome Measures (FACOMS) (clinicaltrials.gov NCT03090789), a registry of

Part 1. FARS neurological examination  •  Two versions FARSn (maximum score 125) and mFARS (maximum score 93) Part 2. FARS Disability Staging (FDS) (maximum score 5)  •  0 no  •  1 minimal  •  2 mild  •  3 moderate  •  4 severe  •  5 total disability Part 3. Patient-reported activities of daily living (ADL) (maximum score 36)  •  9 items with a maximum score of 4 per item Part 4. Timed performance measures  •  25-feet walk  •  9-hole peg test  •  PATA rate

Table 76.3  FARS part 1 neurological examination FARSn (maximum total score 125) A: Bulbar (maximum score 11)  •  A1 Facial atrophy (maximum score 3)  •  A2 Tongue atrophy (maximum score 3)  •  A3 cough (maximum score 2)  •  A4 speech (maximum score 3) B: Upper limb coordination (maximum score 36)  •  B1 finger–finger (maximum score 3)a  •  B2 nose–finger (maximum score 3)a  •  B3 dysmetria (maximum score 4)a  •  B4 rapid movements (maximum score 3)a  •  B5 finger taps (maximum score 4)a C: Lower limb coordination (maximum score 16)  •  C1 heel–shin slide (maximum score 4)a  •  C2 heel–shin tap (maximum score 4)a D: Peripheral nervous system (maximum score 26)  •  D1 Muscle atrophy (maximum score 2)a  •  D2 Muscle weakness (maximum score 5)a  •  D3 Vibratory sense (maximum score 2)a  •  D4 Position sense (maximum score 2)a  •  D5 Deep tendon reflexes (maximum score 2)a E: Upright stability (maximum score 36)  •  E1 sitting position (maximum score 4)  •  E2A stance, feet apart with eyes open (maximum score 4)  •  E2B stance, feet apart with eyes closed (maximum score 4)  •  E3A stance, feet together with eyes open (maximum score 4)  •  E3B stance, feet together with eyes closed (maximum score 4)  •  E4 tandem stance (maximum score 4)  •  E5 stance dominant foot (maximum score 4)  •  E6 tandem walk (maximum score 3)  •  E7 gait (maximum score 5) a

mFARS (maximum total score 93) A: Bulbar (maximum score 5)  •  A3 cough (maximum score 2)  •  A4 speech (maximum score 3)

B: Upper limb coordination (maximum score 36)  •  B1 finger–finger (maximum score 3)a  •  B2 nose–finger (maximum score 3)a  •  B3 dysmetria (maximum score 4)a  •  B4 rapid movements (maximum score 3)a  •  B5 finger taps (maximum score 4)a C: Lower limb coordination (maximum score 16)  •  C1 heel–shin slide (maximum score 4)a  •  C2 heel–shin tap (maximum score 4)a

E: Upright stability (maximum score 36)  •  E1 sitting position (maximum score 4)  •  E2A stance, feet apart with eyes open (maximum score 4)  •  E2B stance, feet apart with eyes closed (maximum score 4)  •  E3A stance, feet together with eyes open (maximum score 4)  •  E3B stance, feet together with eyes closed (maximum score 4)  •  E4 tandem stance (maximum score 4)  •  E5 stance dominant foot (maximum score 4)  •  E6 tandem walk (maximum score 3)  •  E7 gait (maximum score 5)

Each side is assessed separately. The sum of both sides is added to the total score

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1011 FA patients representing a broad range of FA stages (Rummey et al. 2019). Mean-corrected item-total correlations were 0.58 for subscale mA (mFARS), 0.67 for subscale B, 0.84 for subscale C, 0.60 for subscale E, and 0.40 for subscale A (FARSn) and 0.42 for D (FARSn). Internal consistency and robustness against random errors for subscales B, C, and E were good (Cronbach’s α 0.87-0.91). With respect to the bulbar subscale, the deletion of items A1 and A2 improved Cronbach’s α moderately from 0.53 for A (FARSn) to 0.65 for mA (mFARS)). For both total scales, FARSn and mFARS, Cronbach’s α was excellent (0.92 both). Subscale intercorrelations were within 0.49 and 0.93 for both mFARS and FARSn. Validity of mFARS was demonstrated by single-­item-­own subscale correlations (all coefficients >0.31). It is to note that lowest coefficients were found for items E3B (stance, feet together, eyes closed), E4 (tandem stance), and E5 (stance on the dominant foot) (Rummey et al. 2019). With respect to the items deleted from the bulbar subscore in mFARS, weak single-item-own subscale correlations were evident (A1 0.22, and A2 0.35). For subscale D, the correlation coefficients were highly variable (0.2–0.73) thereby questioning the underlying construct for the subscale peripheral nervous system. There was evidence for ceiling effects in subscales C and E (reflecting non- of ambulatory patients). The deletion of A1 and A2 from FARSn reduced ceiling effects for subscale mA, but they are still apparent for mFARS. Principal component analysis for mFARS yielded three components with eigenvalues >1 and one additional with an eigenvalue of 0.83. Factor analysis using four factors resulted in a separation of independent, clinically meaningful factors. These four factors explained 70% of the variance in the overall construct of mFARS thereby supporting the four subscale structure of mFARS (Rummey et al. 2019). Test–retest reliability was good to excellent for mFARS total and subscales B, C, and E (ICC all >0.95), while subscale A was less robust (ICC 0.38) (Tai et al. 2021). Subscale and total scores for FARSn and mFARS correlated with FDS and disease duration (Rummey et al. 2019). With respect to the monitoring of progression, FARS and mFARS scores increased by 2.11 and 1.91, respectively, in the first year of follow-up. Reproducibility of progression was found to improve with increasing observational intervals (Patel et  al. 2016). FARSn has been successfully applied in large o­ bservational studies such as FA-COMS or European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) (clinicaltrials.gov NCT02069509). Many clinical trials have successfully used FARSn (Di Prospero et  al. 2007; Lynch et al. 2012). Meanwhile, mFARS has been approved by the US Food and Drug Administration (FDA) as outcome measure in clinical trials.

76.4 Scale for the Assessment and Rating of Ataxia (SARA) SARA has eight items with a total score of up to 40 points (most severe ataxia) (Schmitz-Hübsch et  al. 2006a) (Table 76.4). The time needed to complete varies between 4 and 40 min (Schmitz-Hübsch et al. 2006a; Yabe et al. 2008). SARA has primarily been validated in SCA (Schmitz-­ Hübsch et al. 2006a, 2010). In SCA, it did not show major ceiling effects. Interrater variability was significant and better than for ICARS with significant ICCs for all single items. Test–retest reliability and internal consistency were excellent (Cronbach’s α 0.94). Factorial analysis yielded a single factor that determined all items and accounted for 80% of the variance. So, in contrast to ICARS and FARS), SARA appears to assess a common underlying construct—namely ataxia. Linearity was demonstrated by the linear relation between SARA total ratings and the differences between individual ratings. When comparing SARA to ICARS scores, ‘disease stages,’ ‘Barthel indices,’ and part IV of the Unified Huntington’s Disease Rating Scale (UHDRS-IV), scores were found to be correlated to UHDRS-IV and Barthel indices and to increase with disease stages (Huntington-Study-­ Group 1996; Schmitz-Hübsch et  al. 2008a). A weak correlation between SARA scores and disease duration was attributed to differences in the individual progression rate of various SCA genotypes. However, SARA does not reliably capture all symptoms at onset and SARA does not assess oculomotor movements. Concerning longitudinal assessment, SARA clearly displays decline after 12  months. Standardized response means were good: A 2-arm trial that aims to decrease progression by 50% would require a sample size of 250 patients with various SCAs, 57 with SCA2, 70 with SCA1, and 75 with SCA3 per group (Schmitz-Hübsch et al. 2008b; Tezenas du Montcel et al. 2012). SARA has also been validated in a variety of cerebellar disorders including sporadic ataxia, FA, MSA, focal cerebellar lesions and multiple sclerosis (Weyer et  al. 2007; Yabe et  al. 2008; Bürk et al. 2009; Winser et al. 2017). In young children with early onset ataxia, for SARA items gait/posture interrater reliabilTable 76.4  Scale for the Assessment and Rating of Ataxia (SARA) Total maximum score: 40  •  Gait (maximum score 8)  •  Stance (maximum score 6)  •  Sitting (maximum score 4)  •  Speech disturbance (maximum score 6)  •  Finger chase (maximum score 4)a  •  Nose–finger test (maximum score 4)a  •  Fast alternating hand movements (maximum score 4)a  •  Heel–shin slide (maximum score 4)a As rated independently for both sides; mean of both sides is considered for total scores a

76  Ataxia Scales for the Clinical Evaluation

ity and external convergent validity were good. Due to the influence of myopathy on SARA gait/posture scores, discriminant validity was considered incomplete in this specific cohort (Brandsma et al. 2017). SARA has also served as outcome measure in clinical trials and longitudinal observational registries such as the Prospective Study of individuals at Risk for SCA1, SCA2, SCA3, SCA6, and SCA7 (RISCA) (Clinical Trials.gov #NCT01037777).

76.5 Brief Ataxia Rating Scale (BARS) The Brief Ataxia Rating Scale (BARS) was developed by a multistep process starting with a supplemented version of ICARS, the ‘Modified ICARS’ (MICARS). However, this augmented complexity weakened not only the practicability but also the quality of the novel scale. Five MICARS items that correlated best with the overall MICARS scores (r 0.92– 0.952) and corresponded to the clinical domains of ataxia of gait, upper and lower limbs, as well as speech and oculomotor dysfunction were finally selected to form the novel Brief Ataxia Rating Scale (BARS) (Table  76.5). The time to administer BARS is with 3–5 min slightly shorter than for SARA (Camargos et  al. 2016). The maximum score of 30 points reflects most severe ataxia. Internal consistency (Cronbach’s α 0.86–0.90 as tested in three cohorts) and interrater reliability (ICC 0.91) of BARS were excellent (Schmahmann et al. 2009). In the original validation study, though construct validity and interrater reliability were found to be slightly superior for SARA as compared to BARS (Cronbach’s α 0.89-0.92, ICC 0.93) despite the fact that SARA scores had retrospectively been derived from MICARS subscores (Schmahmann et al. 2009). Subsequent validation of the Brazilian Portuguese BARS in 35 adult patients with cerebellar disorders of various etiologies yielded good correlation with SARA scores (r = 0.91); internal consistency and interrater reliability measures for the Brazilian Portuguese version were in the same range or even superior to the original version (Cronbach’s α 0.972, ICC 0.94) (Camargos et al. 2016). Excellent external validity was Table 76.5  Brief Ataxia Rating Scale (BARS) Maximum score: 30  •  Walking capacity (maximum score 8)  •  Heel-to-shin test for decomposition of movement (maximum score 4)a  •  Finger-to-nose test for decomposition and dysmetria (maximum score 4)a  •  Dysarthria assessed by clarity of speech (maximum score 4)  •  Abnormalities of the ocular pursuit (maximum score 2) Each side of the body is assessed separately. The sum of both sides is added to the total score a

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also established for BARS in SCA7 subjects by demonstrating significant correlation of BARS and SARA scores (r = 0.9714, p 100

>100 5

NF

Kuehlewein et al. (2019) Zanni and Bertini (2011)

Liu et al. (2017) Owczarek-Lipska et al. (2019)

Bourque et al. (2017) Bansagi et al. (2016) Feyma et al. (2016) Khalifa and Naffaa (2015) Parisi and Glass (2003)

Isidor et al. (2010) Pehlke et al. (2013) Heimer et al. (2017)

Hobson and Kamholz (1999) Margari et al. (2013) Masurel-Paulet et al. (2016) Tonduti et al. (2013) Maruyama et al. (2016) Siskind et al. (2009)

Leonard et al. (2017)

Kong et al. (2017) Zhao et al. (2020) Bekri et al. (2006) Caramins et al. (2013) Vicario et al. (2017, 2018) Barnerias et al. (2010) Kang et al. (2014)

Reference

AP ataxia phenotype, CD cerebellar dysgenesis, CMT1X X-linked Charcot–Marie–Tooth (CMT1X) disease, DA ataxia dominates the phenotype, DD developmental delay, FXTAS Fragile X tremor ataxia syndrome, HA hypoacusis, H-SMD hypomyelinating leukodystrophy and spondylometaphyseal dysplasia, ID intellectual disability, LPD lymphoproliferative disorder, MC manifesting carriers, MTS Mohr–Tranebjaerg syndrome (deafness dystonia, optic neuropathy syndrome), NDA ataxia is a non-dominant feature, NF number of affected families reported, NP neuropathy, PA pure ataxia, PCARP posterior column ataxia and retinitis pigmentosa, PH pulmonary hypertension, PMD Pelizaeus–Merzbacher disease, PMLD Pelizaeus-Merzbacher-like disease, PS parkinsonism, SCA spinocerebellar ataxia, uk unknown, UMNS upper motor neuron signs, XLSA/A X-linked sideroblastic anemia with ataxia, XL X-linked a Lethal in males

NDA NDA

NDA NDA

NDA NDA NDA NDA NDA

NDA NDA NDA

NDA NDA NDA NDA NDA NDA

AP

Gene

Type of XL ataxia Ataxia dominates FXTAS

Table 84.1  X-linked ataxias

556 J. Finsterer

84  X-Linked Ataxias

T2-hyperintensities in the middle cerebellar peduncles and adjacent peridentate white matter or non-specific symmetric signal changes in the cerebral white matter (Finsterer 2011). Usually, the cerebellar volume is decreased and the ventricular volume is increased. Female carriers manifest clinically in 20% of the cases with premature ovarian insufficiency, resulting in premature onset of menopause or fertility problems (Sandford and Burmeister 2014). FXTAS is caused by an intronic CGG-repeat expansion in the 5′ untranslated region of the FMR1 gene on chromosome Xq27.3 (Sandford and Burmeister 2014). Rarely, FXTAS is due to point mutations. Patients with FXTAS carry a repeat number of 55–200 (FMR1 premutation) (Sandford and Burmeister 2014). If the expansion size exceeds 200, males present with Fragile-X syndrome, a severe disorder completely different from FXTAS (Sandford and Burmeister 2014). The normal length of the CGG-repeat is 5–40 (Finsterer 2011) and transmitted in a stable fashion without increase or decrease in the repeat number between generations (Finsterer 2011). In normal alleles, every ninth or tenth CGG-repeat is interrupted by an AGG triplet repeat, which is assumed to maintain repeat integrity by preventing DNA strand slipping during replication (Finsterer 2011). In intermediate alleles (41–54 repeats), the likelihood to become unstable in successive generations increases with the number of uninterrupted CGG-repeats (Finsterer 2011). Retraction of the CGG-repeat expansion between generations is rare (Finsterer 2011).

84.1.2 X-Linked Sideroblastic Anemia with Ataxia (XLSA) XLSA is a rare mitochondrial disorder (MID), characterized by mild, non-symptomatic, early-onset sideroblastic anemia with hypochromia, microcytosis, marked poikilocytosis, reticulocytosis, and heavy stippling. Bone marrow examination in affected males and occasionally in female carriers may show ring siderocytes (Finsterer 2011). In addition to anemia, cerebellar ataxia predominates the phenotype (Finsterer 2011). Ataxia is either non-progressive (Kang et  al. 2014) or slowly progressive from the fifth decade (Finsterer 2011). In addition to gait and trunk ataxia, patients present with dysmetria, dysdiadochokinesia, dysarthria, nystagmus, hypometric saccades, strabism, or kinetic tremor (Finsterer 2011). Single patients develop lower limb spasticity. Cerebral imaging may show cerebellar atrophy or hypoplasia (Finsterer 2011). Female carriers are neurologically normal but may show a dimorphic blood smear with both hypochrome, microcytic and normal red blood cells. XLSA is caused by mutations in the mitochondrial ATP-­ binding cassette transporter ABCB7 gene (Finsterer 2011). Point mutations have been detected in exons 5–16 and at the intron/exon boundaries (Finsterer 2011). The gene product,

557

ABCB7, is like frataxin, involved in the biosynthesis of iron-­ sulfur clusters. There are indications that ABCD7 transports components required for the maturation of cytosolic iron-­ sulfur clusters from the mitochondrion to the cytosol (Finsterer 2011).

84.1.3 X-Linked Ataxia Due to GJB1 Mutations X-linked ataxia due to GJB1 mutations is a recently identified disorder with not only predominant ataxia but also the involvement of peripheral nerves (wasting, sensory, and motor nerve abnormalities) (Caramins et al. 2013). Patients additionally present with scoliosis, foot deformity, or spasticity (Caramins et al. 2013). The phenotype is due to missense mutations in the GJB1 gene and has been described in two families so far (Caramins et al. 2013).

84.1.4 Spinocerebellar Ataxia Due to PMCA3 Mutations Spinocerebellar ataxia (SCA) due to PMCA3 mutations is one of the X-linked ataxias with a pure cerebellar phenotype and characterized by congenital-onset ataxia, cerebellar atrophy, dysarthria, hypotonia, nystagmus, and slow eye movements (Zanni et al. 2012; Bertini et al. 2000). This type of SCA was reported in two Italian families so far. The exact consequence of PMCA3 mutations is unknown but they seem to disrupt the intracellular calcium metabolism (Bertini et al. 2000; Caramins et al. 2013).

84.1.5 X-Linked Adrenoleukodystrophy X-linked adrenoleukodystrophy (X-ALD) is clinically characterized by dysarthria, cerebellar and sensory ataxia, and mild spastic paraparesis. Additionally, adrenal and gonadal impairment (hypogonadism) may be part of the phenotype (Finsterer 2011). Cerebral and spinal cord imaging may show atrophy of the cerebellum and upper cervical spinal cord (Finsterer 2011) or cerebral demyelination (Finsterer 2011). Rarely, X-ALD may manifest as a pure cerebellar syndrome with demyelination of the dentate nucleus or the cerebellum (Kang et al. 2014). Adrenal insufficiency occurs in 80% of males and 20% of female carriers (Rattay et al. 2020). Thus, there are patients without adrenal involvement. X-ALD is due to point mutations or deletions in the ABCD1 gene (Table 84.1) resulting in the accumulation of very long-­ chain fatty acids (Finsterer 2011). X-ALD is the most common peroxisomal disorder in adults (Rattay et al. 2020). The unfolding disease in children can be stopped with allogenic or more recently autologous hematopoietic bone marrow transplantation (Kesserwani 2020).

J. Finsterer

558

84.1.6 X-Linked Pyruvate Dehydrogenase (PDH) Deficiency X-linked PDH deficiency manifests clinically with a wide range of presentations from neonatal lactic acidosis to severe leukoencephalopathy (Leigh syndrome) (Finsterer 2011). Some patients present with dystonia and epilepsy. Less severe cases may present with intermittent ataxia exclusively (Finsterer 2011). X-linked PDH deficiency is due to missense mutations, deletions, or duplications in the PDHA1 gene encoding the E1-subunit of the PDH complex (Finsterer 2011). The genotype-phenotype correlation is poor.

testing of fetuses at risk is possible on DNA from amnion cells. Preimplantation diagnosis is available in families with a known mutation.

84.3 Conclusion

X-linked ataxias are clinically and genetically heterogeneous. Clinically, ataxia may be the dominant or a non-­ dominant phenotypic feature. Ataxia is most commonly of the cerebellar type. Other manifestations in addition to ataxia may be neurological or non-neurological in nature. X-linked ataxias, in which ataxia dominates the phenotype include FXTAS, XLSA, X-linked ataxia due to GJB1 mutations, X-linked ataxia due to PMCA3 mutations, X-ALD, 84.1.7 X-Linked Ataxias with Ataxia as a Non-­ and X-linked PDH-deficiency. The number of X-linked dominant Feature ataxias is steadily increasing and it is quite likely that their A number of X-linked disorders present with ataxia as a non-­ number will further increase in the future. Therapy of dominant phenotypic feature (Table 84.1). Most of them are X-linked ataxias is symptomatic. Bone marrow transplantarare and have been described only in a few families tion can be beneficial in children with X-ALD.  Genetic (Table  84.1). The most frequent of these disorders is Rett counseling not only depends on the X-linked trait of inheritance but also on the presence or absence of germline syndrome. mosaicism or if X-linked ataxia is due to a trinucleotide expansion. Early recognition of X-linked ataxias is warranted to prevent long-term misdiagnosis and to avoid 84.2 Management application of ineffective treatment. X-linked ataxias are usually diagnosed upon the clinical presentation and genetic studies. Supportive information may derive from blood chemical investigations, cerebral imaging, References and nerve conduction studies (Finsterer 2011). Imaging of the Bansagi B, Lewis-Smith D, Pal E, Duff J, Griffin H, Pyle A, Müller JS, central nervous system may show white matter lesions, basal Rudas G, Aranyi Z, Lochmüller H, Chinnery PF, Horvath R (2016) ganglia abnormalities, or cerebellar atrophy. Most frequently, Phenotypic convergence of Menkes and Wilson disease. Neurol Genet 2:e119 only symptomatic treatment, such as physiotherapy, speech therapy, occupational therapy, or computed devices to manage Barnerias C, Saudubray JM, Touati G, De Lonlay P, Dulac O, Ponsot G, Marsac C, Brivet M, Desguerre I (2010) Pyruvate dehydrogenase difficulties with handwriting can be offered. In X-linked PDH complex deficiency: four neurological phenotypes with differing deficiency carbohydrate-free diet together with thiamine, carpathogenesis. Dev Med Child Neurol 52:e1–e9 nitine, and vitamin-E may have a beneficial effect with an Bekri S, D’Hooghe M, Vermeersch P (2006) X-linked sideroblastic anemia and ataxia [updated 2014 Apr 3]. In: Adam MP, Ardinger excellent outcome in single patients. X-ADL in children can HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens be stopped by allogenic or more recently autologous hematoK, Amemiya A, Ledbetter N (eds) GeneReviews®. University of poietic bone marrow transplantation (Kesserwani 2020). Washington, Seattle, WA, 1993–2017. Available from http://www. ncbi.nlm.nih.gov/books/NBK1321/ Genetic counseling relies on the X-chromosomal transmission of the disorders. Affected males pass the mutation to Bertini E, des Portes V, Zanni G, Santorelli F, Dionisi-Vici C, Vicari S, Fariello G, Chelly J (2000) X-linked congenital ataxia: a clinical all their daughters but not to their sons. The father of an and genetic study. Am J Med Genet 92:53–56 affected male will neither be affected nor a carrier. Female Bourque DK, Hartley T, Nikkel SM, Pohl D, Tétreault M, Kernohan KD, Care4Rare Canada Consortium, Dyment DA (2017) A de carriers are clinically unaffected and have a 50% chance to novo mutation in RPL10 causes a rare X-linked ribosomopatransmit the mutation to their offspring. If the mother of an thy characterized by syndromic intellectual disability and epiaffected male does not carry the mutation, the mutation has lepsy: a new case and review of the literature. Eur J Med to be classified as de-novo. If a mother has two affected sons Genet. pii: S1769-­ 7212(17)30696-1. https://doi.org/10.1016/j. ejmg.2017.10.011 but does not carry the mutation, germline mosaicism has to be considered. The risk of the sibs of a proband depends on Caramins M, Colebatch JG, Bainbridge MN, Scherer SS, Abrams CK, Hackett EL, Freidin MM, Jhangiani SN, Wang M, Wu Y, Muzny the carrier status of the mother. Male sibs carrying the mutaDM, Lindeman R, Gibbs RA (2013) Exome sequencing identification will be affected, and female sibs carrying the mutation tion of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Hum Mol Genet 22:4329–4338 will be mildly affected or asymptomatic carriers. Prenatal

84  X-Linked Ataxias Feyma T, Ramsey K, C4RCD Research Group, Huentelman MJ, Craig DW, Padilla-Lopez S, Narayanan V, Kruer MC (2016) Dystonia in ATP2B3-associated X-linked spinocerebellar ataxia. Mov Disord 31:1752–1753 Finsterer J (2011) X-linked ataxias. In: Manto M, Gruol D, Rossi F, Schmahmann J, Koibuchi N (eds) Handbook of cerebellum and cerebellar disorders. Springer, Cham Heimer G, Eyal E, Zhu X, Ruzzo EK, Marek-Yagel D, Sagiv D, Anikster Y, Reznik-Wolf H, Pras E, Oz Levi D, Lancet D, Ben-Zeev B, Nissenkorn A (2017. pii: S1090-3798(17)31647-1) Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin. Eur J Paediatr Neurol. https://doi. org/10.1016/j.ejpn.2017.09.004 Hobson GM, Kamholz J (1999) PLP1-related disorders [updated 2013 Feb 28]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N (eds) GeneReviews®. University of Washington, Seattle, WA, 1993–2017. Available from http://www.ncbi.nlm.nih.gov/books/ NBK1182/ Isidor B, Pichon O, Baron S, David A, Le Caignec C (2010) Deletion of the CUL4B gene in a boy with mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia. Am J Med Genet A 152A:175–180 Kang JW, Lee SM, Koo KY, Lee YM, Nam HS, Quan Z, Kang HC (2014) Isolated cerebellar variant of adrenoleukodystrophy with a de novo adenosine triphosphate-binding cassette D1 (ABCD1) gene mutation. Yonsei Med J:1157–1160 Kesserwani H (2020) Chronic progressive spastic paraparesis: think of peroxisomal disorders—a case report of X-linked adult onset ­adrenoleukodystrophy with an update on the latest treatment strategies. Cureus 12:e9626. https://doi.org/10.7759/ cureus.9626 Khalifa M, Naffaa L (2015) Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings. Eur J Med Genet 58:381–386 Kong HE, Zhao J, Xu S, Jin P, Jin Y (2017) Fragile X-associated tremor/ ataxia syndrome: from molecular pathogenesis to development of therapeutics. Front Cell Neurosci 11:128. https://doi.org/10.3389/ fncel.2017.00128 Kuehlewein L, Schöls L, Llavona P, Grimm A, Biskup S, Zrenner E, Kohl S (2019) Phenotypic spectrum of autosomal recessive retinitis pigmentosa without posterior column ataxia caused by mutations in the FLVCR1 gene. Graefes Arch Clin Exp Ophthalmol 257:629– 638. https://doi.org/10.1007/s00417-­018-­04233-­7 Leonard H, Cobb S, Downs J (2017) Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol 13:37–51 Liu X, Zhou K, Yu D, Cai X, Hua Y, Zhou H, Wang C (2017) A delayed diagnosis of X-linked hyper IgM syndrome complicated with toxoplasmic encephalitis in a child: a case report and literature review. Medicine (Baltimore) 96:e8989. https://doi.org/10.1097/ MD.0000000000008989 Margari L, Lamanna AL, Buttiglione M, Craig F, Petruzzelli MG, Terenzio V (2013) Long-term follow-up of neurological manifestations in a boy with incontinentia pigmenti. Eur J Pediatr 172:1259–1262 Maruyama K, Ogaya S, Kurahashi N, Umemura A, Yamada K, Hashiguchi A, Takashima H, Torres RJ, Aso K (2016) Arts syndrome with a novel missense mutation in the PRPS1 gene: a case report. Brain and Development 38:954–958

559 Masurel-Paulet A, Piton A, Chancenotte S, Redin C, Thauvin-Robinet C, Henrenger Y, Minot D, Creppy A, Ruffier-Bourdet M, Thevenon J, Kuentz P, Lehalle D, Curie A, Blanchard G, Ghosn E, Bonnet M, Archimbaud-Devilliers M, Huet F, Perret O, Philip N, Mandel JL, Faivre L (2016) A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome. Am J Med Genet A 170:2103–2110 Owczarek-Lipska M, Mulahasanovic L, Obermaier CD, Hörtnagel K, Neubauer BA, Korenke GC, Biskup S, Neidhardt J (2019) Novel mutations in the GJC2 gene associated with Pelizaeus-Merzbacher-­ like disease. Mol Biol Rep 46:4507–4516. https://doi.org/10.1007/ s11033-­019-­04906-­4 Parisi M, Glass I (2003) Joubert syndrome [updated 2017 Jun 29]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K Amemiya A, Ledbetter N (eds) GeneReviews. University of Washington, Seattle, WA, 1993–2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK132 Pehlke JR, Venkataramani V, Emmert S, Mohr A, Zoll B, Nau R (2013) X-linked recessive ichthyosis (XRI), cerebellar ataxia and neuropsychiatric symptoms. Fortschr Neurol Psychiatr 81:40–43 Rattay TW, Rautenberg M, Söhn AS, Hengel H, Traschütz A, Röben B, Hayer SN, Schüle R, Wiethoff S, Zeltner L, Haack TB, Cegan A, Schöls L, Schleicher E, Peter A (2020) Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy. Sci Rep 10:15093. https://doi.org/10.1038/s41598-­020-­71248-­8 Sandford E, Burmeister M (2014) Genes and genetic testing in hereditary ataxias. Genes (Basel) 5:586–603 Siskind C, Feely SM, Bernes S, Shy ME, Garbern JY (2009) Persistent CNS dysfunction in a boy with CMT1X. J Neurol Sci 279:109–113 Tonduti D, Vanderver A, Berardinelli A, Schmidt JL, Collins CD, Novara F, Genni AD, Mita A, Triulzi F, Brunstrom-Hernandez JE, Zuffardi O, Balottin U, Orcesi S (2013) MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. J Child Neurol 28:795–800 Vicario M, Calì T, Cieri D, Vallese F, Bortolotto R, Lopreiato R, Zonta F, Nardella M, Micalizzi A, Lefeber DJ, Valente EM, Bertini E, Zanotti G, Zanni G, Brini M, Carafoli E (2017) A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: biochemical characterization of the pump defect. Biochim Biophys Acta 1863:3303–3312 Vicario M, Zanni G, Vallese F, Santorelli F, Grinzato A, Cieri D, Berto P, Frizzarin M, Lopreiato R, Zonta F, Ferro S, Sandre M, Marin O, Ruzzene M, Bertini E, Zanotti G, Brini M, Calì T, Carafoli E (2018) A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia. Neurobiol Dis 115:157–166. https://doi.org/10.1016/j.nbd.2018.04.009 Zanni G, Bertini ES (2011) X-linked disorders with cerebellar dysgenesis. Orphanet J Rare Dis 6:24. https://doi. org/10.1186/1750-­1172-­6-­24 Zanni G, Calì T, Kalscheuer VM, Ottolini D, Barresi S, Lebrun N, Montecchi-Palazzi L, Hu H, Chelly J, Bertini E, Brini M, Carafoli E (2012) Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proc Natl Acad Sci U S A 109:14514–14519 Zhao C, Liu Y, Wang Y, Li H, Zhang B, Yue Y, Zhang J (2020) A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor: case report and literature review on tremor in FXTAS.  BMC Neurol 20(1):145. https://doi.org/10.1186/ s12883-­020-­01726-­z

Imaging of Malformations of the Hindbrain and Craniocervical Junction

85

Christian Herweh

Abstract

Primary hindbrain malformations are much less frequent than those of the cerebrum or combined anomalies. Cerebellar malformations may affect both hemispheres such as rhombencephalosynapsis or molar tooth malformations, whereas dysplastic gangliocytoma in Lhermitte–Duclos–Cowden syndrome is a typical unilateral malformation. Unilateral hypoplasia usually represents cerebellar disruption, i.e., an impact during intrauterine development. The Dandy–Walker complex (DWC) as well as the Chiari malformations are often accompanied by hydrocephalus, either infra- or supratentorial. DWC is a malformation of the fourth ventricle and its CSF outflow with hydrocephalus is the major complication. In Chiari I malformation, CSF hydrodynamics are disturbed and frequently lead to syringomyelia, whereas Chiari malformations II and III are associated with spinal dysraphism which significantly affects the prognosis. Keywords

Blake’s pouch cyst · Dandy-Walker malformation · Megacisterna magna · Rhombencephalosynapsis · Molar tooth malformations · Dysplastic gangliocytoma · Cerebellar disruption

Abbreviations BPC Blake’s pouch cyst CSF Cerebrospinal fluid DWC Dandy–Walker complex DWM Dandy–Walker malformation MCM Mega cisterna magna MMC Myelomeningocele PF Posterior fossa

85.1 Introduction Malformations of the hindbrain and craniocervical junction can be separated into those restricted to the cerebellum and brainstem and those which are associated with other malformations, i.e., of the supratentorial brain. These associated anomalies largely determine the clinical presentation, while isolated infratentorial anomalies result in less impairment (Barkovich 2005). Primary malformations can be further separated into those affecting neuronal structures only and those associated with mesenchymal anomalies such as the Dandy–Walker complex and the Chiari malformations. According to Patel and Barkovich (2002), generalized cerebellar dysplasia as a result of abnormal neuronal migration is typically seen together with other malformations of the supratentorial brain, concerning either grey or white matter or both. Focal cerebellar dysplasias either affect the vermis, such as rhombencephalosynapsis and molar tooth malformations, or one hemisphere, such as Lhermitte– Duclos–Cowden syndrome.

C. Herweh (*) Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_85

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85.2 Cerebellar Hypoplasia Cerebellar hypoplasia may affect the vermis, one or both hemispheres or the entire cerebellum. If not associated with other malformations, pure cerebellar hypoplasia may cause only little or no symptoms at all (Bolduc and Limperopoulos 2009). MRI is the method of choice to evaluate cerebellar hypoplasia with sagittal orientation for the vermis and coronal images to check the cerebellar hemispheres and their foliae. In case of true cerebellar hypoplasia, the pons often is hypoplastic as well and should be inspected thoroughly. In contrast to genetically determined forms of cerebellar hypoplasia, i.e., small cerebellum with normal shape, cerebellar disruption indicates a presumably vascular insult to the developing cerebellum. This is predominantly if not exclusively the cause for the unilateral small cerebellum (Boltshauser 2004). Due to the underlying etiology, it typically seen in preterm children with low birth weight and is therefore often accompanied by other cerebral sequelae such as periventricular leukomalacia and therefore neurodevelopmental deficits are common to these children (Messerschmidt et al. 2005).

85.3 Rhombencephalosynapsis Rhombencephalosynapsis occurs as a consequence of partial or complete absence of the cerebellar vermis resulting in fusion of the cerebellar hemispheres and dentate nuclei in the midline. Ishak et al. (2012) report remnant structures such as a nodulus in 9 of 42 patients. Clinical signs may vary from

C. Herweh

mild ataxia to severe mental retardation, especially if associated with other CNS malformations (Fig. 85.1).

85.4 Molar Tooth Malformations First described in Joubert syndrome which is defined clinically by episodic hyperpnea, abnormal eye movements, ataxia and mental retardation (Joubert et al. 1969), the molar tooth sign has meanwhile been described in several other syndromes comprising cerebral malformations and even anomalies in other organ systems. It is best observed on axial sectional images and is constituted by an absent or hypoplastic vermis, a tegmental cleft causing the superior cerebellar peduncles to run parallel to one another in the antero-­ posterior direction. This is due to the fact that their axons do not cross the midline (Poretti et al. 2007) which seems to be a general feature of all midbrain-hindbrain nerve fibers in these syndromes (Fig. 85.1).

85.5 Lhermitte–Duclos–Cowden Syndrome Originally described by Lhermitte and Duclos in 1920, the cerebellar feature of this syndrome is a dysplastic cerebellar gangliocytoma, a hemisphere cerebellar dysgenesis. It typically appears as a mass of thickened cerebellar cortex with disturbance of cortical organization within one hemisphere. The T1 signal is low and T2 signal is increased, contrast enhancement is rare, and CT may show calcifications. It may be found in patients with Cowden syndrome, otherwise it can be discovered incidentally (Fig. 85.1).

85  Imaging of Malformations of the Hindbrain and Craniocervical Junction

a

b

c

d

Fig. 85.1  Different forms of cerebellar dysplasia. Rhomben­ cephalosynapsis with absence of the vermis and medial fusion of the cerebellar hemispheres (a). Note that this was an incidental finding in the present case of an adult male referred due to embolic stroke. Molar tooth

563

malformation in Joubert syndrome, note the stretched aspect of the superior cerebellar peduncles and absent vermis (b). Dysplastic cerebellar gangliocytoma of the right hemisphere, note T2 hyperintense mass with irregular architecture and calcifications (c, d)

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C. Herweh

a

c

e

b

d

f

Fig. 85.2  Comparison of a case of Dandy–Walker malformation (DWM; a, b), Blake’s pouch cyst (BPC; c, d) and a posterior fossa arachnoidal cyst (PFAC; e, f). Note that the two patients with DWM and PFAC, respectively, were already treated with placement of a CSF shunt (not shown). In DWM, the hypoplastic vermis together with the tentorium is rotated upward and the fourth ventricle shows a wide communication with a large CSF collection in the posterior fossa (PF). In BPC, the vermis is as well tilted upward against the tegmentum but to a lesser

degree than in DWM and the tentorium is configured regular. There is no communication between the enlarged fourth ventricle and the outer CSF space due to the persisting membrane forming the cyst. In case of the PFAC, there is a large cyst lying adjacent to the fourth ventricle which is compressed as the medial portions of the cerebellar hemispheres. Note the hypointense flow void within the mesencephalic aqueduct which does not continue into the cyst, proving it is not the fourth ventricle

85.6 Dandy–Walker Complex

BPC can be difficult to be distinguished from MCM because the cyst which communicates with the fourth ventricle protrudes into the cisterna magna and the separating septum may be overlooked. The MCM in contrast to the aforementioned entities does not communicate with fourth ventricle, is not regularly associated with vermian hypoplasia, and most often discovered incidentally (Fig. 85.2).

The Dandy Walker–Complex comprises a spectrum ranging from clinically relevant malformations such as the actual Dandy Walker malformation (DWM) to Blake’s pouch cyst (BPC), or to asymptomatic variants such as the mega cisterna magna (MCM). Hypoplasia (primarily of the vermis) is the common feature of all variants (Barkovich et  al. 1989). DWM features are (1) a hypoplastic or absent vermis, which is rotated upward in a counter-clockwise direction; (2) an enlarged fourth ventricle and (3) an elevated tentorium and torcular. Furthermore, it is regularly associated with a supratentorial hydrocephalus. Again, intellectual outcome may be poor, if the DWM is associated with other CNS anomalies (Klein et al. 2003).

85.7 Chiari Malformations In the outgoing nineteenth-century Hans Chiari, an Austrian physician, described three different malformations of the hindbrain and craniocervical junction, respectively, which will be discussed below (Fig. 85.3).

85  Imaging of Malformations of the Hindbrain and Craniocervical Junction

a

565

lesion. Symptoms can either be unspecific such as headache or be attributed to the affected structures, i.e., brainstem (nystagmus, vertigo) or cranial nerves (otoneurologic deficits). Furthermore, syringohydromyelia with consecutive senso-motoric deficits can develop. There is often association with bony malformations of the cranio-cervical junction such as platybasia or basilar invagination. A steep configuration of the tentorium is frequently encountered.

85.7.2 Chiari II Malformation

b

Chiari II malformations are regularly associated with spinal meningomyeloceles (MMC) and are therefore more and more often detected prenatally by ultrasound. The posterior fossa is typically small also due to a steep tentorium and the cerebellar hemispheres and vermis, not only the tonsils as in Chiari I malformation, but are also “squeezed” out downward leading to stretching and compression of the brainstem. Bony malformations of the craniocervical junction are also common. Another feature differing from Chiari I malformation is the variable occurrence of supratentorial anomalies. These are different degrees of callosal dysplasia as well as a large massa intermedia. Mesenchymal abnormalities besides a dysplastic tentorium comprise fenestration of the falx leading to gyral interdigitation between hemispheres (Miller et  al. 2008). Hydrocephalus is found in all patients, sometimes by prenatal ultrasound but at the latest after surgical closure of the neural tube defect. Recently, a randomized controlled clinical trial has shown convincingly that Chiari II patients may benefit from antenatal MMC repair at many aspects. The necessity of shunt placement as well as the degree of hindbrain herniation was reduced and consecutively the ability to walk was improved (Adzick et al. 2011).

85.7.3 Chiari III Malformation

Fig. 85.3  Chiari I and II malformation. In Chiari I malformation (a), cerebellar tonsils herniate downwards through the foramen magnum pushing the brainstem forward towards the clivus. In Chiari II malformation (b), larger parts of the caudal hemispheres herniate outward a small posterior fossa (PF) with a steep tentorium. Note the basilar invagination as well as the hypoplastic corpus callosum with a lesion from former shunt placement in the rostral portion

In Chiari III malformation, a MMC is located at the upper cervical spine leading to herniation of contents of the posterior fossa. A common feature of all Chiari malformations is the development of hydro- or syringomyelia which typically responds well to decompressive surgery at the craniocervical junction.

85.7.1 Chiari I Malformation

References

In Chiari I malformation, the cerebellar tonsils herniate through the foramen magnum which may lead to compression of the brainstem as well as the lower cranial nerves. This type may be discovered incidentally, especially in adults. In childhood it is more often discovered as a symptomatic

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566 Barkovich AJ, Kjos BO, Norman D, Edwards MS (1989) Revised classification of posterior fossa cysts and cystlike malformations based on the results of multiplanar MR imaging. AJR Am J Roentgenol 153(6):1289–1300. https://doi.org/10.2214/ajr.153.6.1289 Bolduc ME, Limperopoulos C (2009) Neurodevelopmental outcomes in children with cerebellar malformations: a systematic review. Dev Med Child Neurol 51(4):256–267. https://doi. org/10.1111/j.1469-­8749.2008.03224.x Boltshauser E (2004) Cerebellum-small brain but large confusion: a review of selected cerebellar malformations and disruptions. Am J Med Genet A 126A(4):376–385. https://doi.org/10.1002/ ajmg.a.20662 Ishak GE, Dempsey JC, Shaw DWW, Tully H, Adam MP, Sanchez-Lara PA et  al (2012) Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity. Brain 135(Pt 5):1370–1386. https://doi.org/10.1093/brain/aws065 Joubert M, Eisenring JJ, Robb JP, Andermann F (1969) Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea,

C. Herweh abnormal eye movements, ataxia, and retardation. Neurology 19(9):813–825 Klein O, Pierre-Kahn A, Boddaert N, Parisot D, Brunelle F (2003) Dandy-Walker malformation: prenatal diagnosis and prognosis. Childs Nerv Syst 19(7–8):484–489. https://doi.org/10.1007/ s00381-­003-­0782-­5 Messerschmidt A, Brugger PC, Boltshauser E, Zoder G, Sterniste W, Birnbacher R et  al (2005) Disruption of cerebellar development: potential complication of extreme prematurity. AJNR Am J Neuroradiol 26(7):1659–1667 Miller E, Widjaja E, Blaser S, Dennis M, Raybaud C (2008) The old and the new: supratentorial MR findings in Chiari II malformation. Childs Nerv Syst 24(5):563–575 Patel S, Barkovich AJ (2002) Analysis and classification of cerebellar malformations. AJNR Am J Neuroradiol 23(7):1074–1087 Poretti A, Boltshauser E, Loenneker T, Valente EM, Brancati F, Il’yasov K et al (2007) Diffusion tensor imaging in Joubert syndrome. AJNR Am J Neuroradiol 28(10):1929–1933. https://doi.org/10.3174/ajnr. A0703

86

Cerebellar Stroke Keun-Hwa Jung and Jae-Kyu Roh

Abstract

Cerebellar stroke consists of cerebellar infarction and hemorrhage. The two entities have similar symptoms and signs depending on structures involved. Vertebrobasilar atherosclerosis and cardioembolism cause the cerebellar infarction, while hypertensive microangiopathy and arteriovenous malformation generate cerebellar hemorrhage. The increasing availability of new imaging techniques helps better identify the etiology of cerebellar stroke and predict the risk of progression and recurrence. Special attention should be paid to the patients with cerebellar stroke because of potential complications including brainstem compression, acute hydrocephalus, and brainstem infarction. Optimal medical therapy, endovascular procedures, or surgical interventions improve patients’ outcomes. This chapter summarizes current understanding of cerebellar stroke, and clinical features, diagnosis, and treatment of patients. Keywords

Cerebellar · Stroke · Infarction · Hemorrhage · Superior cerebellar artery · Posterior inferior cerebellar artery Anterior inferior cerebellar artery · Vertigo · Dysmetria Gait disturbance · Nystagmus · Dysarthria · Hearing loss Mechanism · Cardioembolism · Artery to artery embolism · In situ branch atheromatous disease · Dissection Venous thrombosis · CT · MRI · Diffusion-­weighted imaging · Conventional angiography · CT angiography Doppler · Coma · Edema · Brainstem compression K.-H. Jung Department of Neurology, Seoul National University Hospital, Seoul, South Korea J.-K. Roh (*) Department of Neurology, Seoul National University Hospital, Seoul, South Korea Department of Neurology, The Armed Forces Capital Hospital, Seongnam, Gyeunggido, South Korea

Hydrocephalus · Hemorrhagic transformation Extraventricular drainage · Craniotomy · Prognosis

86.1 Introduction This part includes the essentials of clinical aspects of cerebellar stroke. The readers can refer to an extended version for more details (Jung and Roh 2013). Cerebellar stroke includes infarction (Fig.  86.1a) and hemorrhage (Fig. 86.1b). Cerebellar infarction accounts for 2–10% of cases in clinical series of cerebral infarction (Tohgi et al. 1993; Amarenco et al. 1994). The mean age of patients is 60–70 years and about two-thirds of patients are men (Tohgi et al. 1993). Along with the population aging, the incidence of cerebellar infarction is rising. Overall, the infarction in posterior inferior cerebellar arteries (PICA) territory is more common than that in the superior cerebellar artery (SCA) and anterior inferior cerebellar artery (AICA) territories (Tohgi et al. 1993). Bilateral cerebellar infarcts are not rare, constituting 31% of all cerebellar infarcts (Tohgi et al. 1993). While the relative contribution of the different etiologies depends on ethnic origin, age, and sex, the common etiologies of cerebellar infarction are cardioembolism and large artery atherosclerosis (Amarenco et  al. 1990; Bogousslavsky et  al. 1993). Cerebellar infarction may occur in association with vertebral artery dissection, especially in younger patients (Schievink 2001). Rare causes include vasculitis (McLean et  al. 1993), hypercoagulable states (Amarenco et  al. 1994), acute drug intoxication (Aggarwal and Byrne 1991), and migraine (Reid et al. 2006). Cerebellar hemorrhage is the rarest type of intracerebral hemorrhage (ICH) constituting 10% of all ICH cases (Flaherty et  al. 2005). The mortality rate of cerebellar hemorrhage is relatively high ranging from 20% to 75% because of possible swelling in the restricted posterior fossa (Salvati et  al. 2001). Hypertension is the major risk factor of cerebellar hemor-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_86

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K.-H. Jung and J.-K. Roh

b

Fig. 86.1  Type of cerebellar stroke. Cerebellar stroke consists of cerebellar infarction and hemorrhage. Diffusion-weighted magnetic resonance image demonstrates cerebellar infarction in the left PICA territory (a). Brain CT (b) shows hemorrhage in the left cerebellar hemisphere

rhage (60–89% of all cases). Other causes include vascular malformations, aneurysms, coagulopathy, and amyloid angiopathy (St Louis et al. 1998).

86.2 Clinical Features Cerebellar stroke syndromes depend on the vascular territory, infarct size, and concurrent lesions in the brainstem (Lee 2009). The main clinical features include vertigo/dizziness, nausea and vomiting, headache, and gait instability. Vertigo/dizziness occurs in nearly three quarters of patients with cerebellar stroke (Tohgi et al. 1993; Kumral et al. 2005a, b). The territory of cerebellar infarction associated with dizziness frequently involves the medial PICA (medPICA) (Norrving and Magnusson 1995). Over half of patients with cerebellar strokes have nausea and vomiting in association with vertigo/dizziness (Tohgi et al. 1993). About 10–20% of patients with cerebellar infarction presented as isolated vertigo/dizziness (Kim et al. 2016). Additionally, about 40% of patients with cerebellar infarction suffer from headache (Kumral et  al. 2005a, b). Cerebellar infarctions with headache presentation frequently involve left hemispheric and PICA territory (Altiparmak et al. 2021). Limb ataxia is present in about 40% of patients with cerebellar stroke and is a sign of infarction in the lateral SCA and PICA territories (Ye et  al. 2010). About half of patients with cerebellar stroke complain of gait instability (Tohgi et al. 1993). While most patients with unilateral cerebellar lesions fall toward the side

of the lesion, some patients fall to the contralateral side of the lesion or bilaterally (Lee et  al. 2006; Ye et  al. 2010). Truncal ataxia is more severe in infarctions in the medial superior cerebellar artery branch (medSCA) and medPICA territories compared to lateral SCA (latSCA) and lateral PICA (latPICA) (Sohn et al. 2006). Dysarthria is also a common sign (50%) among patients with cerebellar stroke (Tohgi et al. 1993; Kumral et al. 2005a, b). Cerebellar-type dysarthria is characterized by ataxic and slurred speech, explosive staccato scanning vocalization, and wavering modulation and occurs in the medSCA lesion (Urban et  al. 2003). Oculomotor signs include nystagmus, impaired smooth pursuit, and ocular tilt reaction (OTR). Half of patients with cerebellar infarction have nystagmus, which is more common in medPICA compared to latPICA and SCA infarction (Barth et al. 1994; Ye et al. 2010). Horizontal smooth pursuit eye movements are impaired in patients with lesions in the uvula and the pyramid of the vermis (Baier et al. 2009). The symptoms of cerebellar infarction often begin simultaneously with brainstem symptoms or signs, e.g., Horner’s syndrome, weakness, paresthesia, hearing loss, tinnitus, dysphagia, or mental clouding. Specifically, a classical syndrome of AICA territory infarction includes vestibular and acoustic dysfunction, hearing loss, tinnitus, facial weakness, trigeminal sensory loss, and sensory dissociation in the face (Amarenco and Hauw 1990). A localized cerebellar infarction may lead to a specific affect deficit (Schmahmann and Sherman 1998) and executive functioning abilities (Manes et al. 2009). The crossed cerebello-cerebral diaschisis phenomenon may sup-

86  Cerebellar Stroke

port the nature of cerebellar cognitive dysfunction. Although the majority of cerebellar infarcts have a benign clinical course, acute hydrocephalus and brainstem compression by evolving edema are often associated with a high morbidity and mortality.

86.3 Cerebellar Infarction 86.3.1 Mechanism Cerebellar infarctions can be divided into territorial infarcts and nonterritorial infarcts, which are either unilateral or bilateral. The leading cause of cerebellar infarcts is emboli arising from cardiac or intra-arterial sources at the orifice of the vertebral artery (Caplan et al. 2004). In unilateral PICA infarction, cardioembolism is found in one-fifth of the cases (Kumral et al. 2005b). More than one-third of patients have steno-occlusive subclavian-vertebral atherosclerotic disease, which may cause multiple artery to artery embolisms or hemodynamic compromise (Min et  al. 1999; Shin et  al. 1999). In situ branch disease is present in one-fifth of PICA infarction. In situ branch disease often induces PICA territorial or nonterritorial lesions. However, Kim et al. (1998) have found that cerebellar involvement is rare in patients with isolated PICA disease, supporting the concept that the collateral circulation system is effective within the cerebellum through the AICA or the SCA. In more than two-thirds of cases, the main cause of AICA infarction is the thrombotic occlusion of AICA itself or the progression of vertebrobasilar system atherosclerosis into the AICA (Tohgi et al. 1993; Kumral et al. 2006). In one-fifth of patients, the causes of cardioembolism are detectable, but more than three-fourths of these patients also have a concomitant vertebrobasilar atherosclerosis (Kumral et al. 2006). The most common mechanism of SCA infarction is embolic, resulting from either cardioembolism or artery-to-artery embolism. Cardioembolic source can be detected in one-third of the patients with the SCA infarction (Kumral et al. 2005a) and atherosclerotic disease of the vertebrobasilar system in one-third of cases (Amarenco et  al. 1994). Small cerebellar infarcts are frequently associated with large artery disease involving the basilar or vertebral arteries and cardioembolism (Amarenco et al. 1993, 1994). Small cerebellar infarcts are usually located in cortical areas, not within well-defined arterial regions and thus are regarded as border zone infarcts (Amarenco et al. 1993). Border zone infarction can be explained by a combination of hemodynamic mechanism and embolism (Caplan and Hennerici 1998). Alternatively, small cerebellar infarcts may be end artery area infarcts from the small artery disease in patients with no embolic source from the heart or large arteries (Canaple and Bogousslavsky 1999). A previous pathologic report showed that the deep cerebellum is one of the predi-

569

lection sites of lacunar infarction (Fisher 1965). Bilateral cerebellar infarctions have similar characteristics in the territory involved as compared to unilateral cerebellar infarction, but they are more likely to have a stroke mechanism of large artery atherosclerosis, and have a higher rate of stroke recurrence (Hong et al. 2008).

86.3.2 Diagnosis The widely used brain imaging technique is CT, which provides images very quickly and accurately excludes acute hemorrhage. However, this technique is hampered by a low sensitivity for acute ischemic stroke within the first few hours, especially for infarctions in the posterior fossa (Chalela et  al. 2007). MRI is a more sensitive method for visualization of affected cerebellar structures within the posterior fossa (Schmahmann et  al. 2000) and thus enables to establish various types of stroke, including small and large territorial infarcts, hemorrhages, and venous infarcts, and to correlate them with the clinical findings and outcome (Barth et al. 1993; Canaple and Bogousslavsky 1999). MRI becomes more sensitive when diffusion-weighted imaging (DWI) is added, having 80–95% sensitivity in the first 24 h (Chalela et  al. 2007). DWI can detect small ischemic lesions in the very early time window after the onset of symptoms, in contrast to the CT and conventional MRI (Roh et al. 2000; Kang et al. 2000). The methods to evaluate cerebrovascular status include Doppler ultrasound, CT angiography (CTA), MRA, and conventional angiography. Doppler ultrasound has advantages of early availability, monitoring, and low cost, whereas it is limited by a relatively poor accuracy in the posterior circulation as compared to the anterior circulation. CTA is known to be more sensitive than Doppler ultrasound and MRA in patients with vertebral artery pathology (Bash et al. 2005). However, the exposure of a potentially toxic dye and radiation limits the use of this technique. MRA overcomes this limitation, but it is less available and requires more time to acquire images compared with CTA. Conventional angiography can demonstrate the exact pathology of cerebellar vessels but this technique has procedure-­ related complications, in addition to all the disadvantages of CTA. As in cases of other strokes, cardiac evaluations, such as echocardiography and Holter monitoring, are useful to identify a potential cardioembolic source.

86.3.3 Space-Occupying Infarction Subsequent edema formation from the initial infarct often becomes space occupying within the posterior fossa, leading to brainstem compression, hydrocephalus, cardiorespiratory distress, altered consciousness, and death (Koh et al. 2000).

570

This complication occurs in 10–25% of patients, peaking on the third day after the infarction (Hornig et  al. 1994; Koh et al. 2000). The critical factors for this process include the infarct size, vasculopathy type, association with hemorrhagic transformation, and lack of collateral flow. Figure 86.2 shows a representative large PICA infarction with hydrocephalus and brainstem compression. A progressive decline in level of consciousness and secondary brain stem signs are common clinical manifestations (Hornig et  al. 1994). The outcome after sizeable cerebellar infarction depends mainly on the level of consciousness (Hornig et al. 1994). Therefore, close monitoring for signs of mental alteration is crucial. If deterioration occurs, the progression from the original vascular lesion with or without brainstem ischemia must be differentiated from brainstem compression or hydrocephalus, because the treatments for each status might be different. Hemorrhagic transformation also increases the likelihood of mass effect (Koh et  al. 2000). Hemorrhagic transformation usually occurs within the first week of stroke onset, but sometimes in the second and third weeks after stroke onset (Chaves et al. 1996). The main mechanism of cerebellar hemorrhagic infarction is embolic, from cardiac or proximal artery sources, similar to the mechanism in the anterior circulation (Chaves et al. 1996). The recent guideline recommends surgical decompression to improve functional outcome and to reduce the fatality in patients aged ≤60 years and who can treated 70% (high-risk antibodies); ++ = 30–70% (intermediate-risk antibodies); + = 70% (high-risk antibodies); ++ = 30–70% (intermediate-risk antibodies); + = 113 months) and Ri (>69 months) antibodies (Shams’ili et al. 2003). It has been demonstrated that the Scale for the assessment and rating of ataxia (SARA) can

R. Iorio and L. Campetella

be a valuable tool to evaluate the neurologic disability in patients with PCS (Damato et al. 2022). Survival is mostly influenced by the accompanying cancer and the concurrent oncological prognosis.

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89

Essential Tremor Elan D. Louis

Abstract

Essential tremor (ET) is a chronic, progressive neurologic disease. Its central feature is a 4–12-Hz kinetic tremor (i.e., tremor occurring during voluntary movement). Along with an emerging appreciation of the presence of etiological, clinical, and pathological heterogeneity, there is growing support for the notion that ET itself may be a family of diseases whose central defining feature is kinetic tremor of the arms, and which might more accurately be referred to as “the essential tremors.” Clinical and scientific advances have increasingly placed the seat of the disease in the cerebellum and cerebellar system. Keyword

Tremor

89.1 Introduction Essential tremor (ET) is a chronic, progressive neurologic disease. Its central feature is a 4–12-Hz kinetic tremor (i.e., tremor occurring during voluntary movement) (Fig.  89.1) (Louis 2001). Along with an emerging appreciation of the presence of etiological, clinical, and pathological heterogeneity, there is growing support for the notion that ET itself may be a family of diseases whose central defining feature is kinetic tremor of the arms, and which might more accurately be referred to as “the essential tremors” (Louis 2014a). Clinical and scientific advances have increasingly placed the seat of the disease in the cerebellum and cerebellar system.

Fig. 89.1  Spiral drawn by a patient with ET who has moderate arm and hand tremor

89.2 Epidemiology ET is among the most prevalent movement disorders. Its pooled population prevalence across all ages is 0.9% (Louis and Ferreira 2010). Prevalence increases markedly with age, and among individuals age 95 and older, it has been reported to reach values in excess of 20% (Louis and Ferreira 2010). The incidence rate is 619/100,000 person-years among persons age 65 and older (Benito-León et al. 2005). Its prevalence and incidence are similar in males and females. Older age and family history of ET are both established risk factors for ET.

E. D. Louis (*) Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_89

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89.3 Etiology The precise causes of ET are unclear, yet genetic and environmental factors are contributors. There are numerous large kindreds, with an autosomal dominant pattern of inheritance, and in a large familial aggregation study, first-degree relatives of ET patients were nearly five times more likely to develop ET than members of the population (Louis et  al. 2001). A variant in the Lingo-1 gene has been most consistently associated with ET (Stefansson et al. 2009); however, there has been a lack of consistent association across genome-wide association studies (Müller et al. 2016). Recent whole exome sequencing studies have identified private causal mutations in some ET families, but no major causal genes have been identified to date, and this is likely due to a variety of issues including phenocopies, incomplete penetrance, bilineal inheritance, or possibly other modes of inheritance (Ma et  al. 2006). The existence of cases without apparent family history and lack of complete disease concordance in monozygotic twins (Tanner et al. 2001) argue for nongenetic (i.e., environmental) causes as well. A number of environmental toxins are under investigation, including β-carboline alkaloids (e.g., harmane, a dietary toxin) and lead (Louis 2008; Louis et  al. 2020). One epidemiological study indicated a possible protective role of cigarette smoking and another indicated that higher levels of pre-morbid ethanol consumption raise the risk of developing ET, with the presumed mechanism being Purkinje cell toxicity (Louis et al. 2008, 2009).

89.4 Pathobiology The olivary model of ET, initially proposed in the early 1970s, posited that a tremor pacemaker in the inferior olivary nucleus was driving the tremor in ET.  However, there has been trend to move on to other more plausible mechanisms (Louis 2014b; Lenka and Louis 2017). Recent research on ET has focused on the cerebellum and the role it seems to play in the biology of ET. Interest in the cerebellum was initially motivated by neuroimaging studies, which strongly implicate the importance of this brain region in ET, and clinical studies, which frequently note the presence of a range of “cerebellar signs” (e.g., intention tremor, gait ataxia) in patients with ET. More recently, controlled postmortem studies have revealed a broad array of degenerative changes in the cerebellar cortex, primarily involving the Purkinje cells and surrounding neuronal populations, in the majority of ET cases (Louis and Faust 2020). In several studies, there is Purkinje cell loss (Louis et  al. 2007; Choe et  al. 2016). A smaller group of ET cases demonstrate a Lewy body pathology. Given these data, there is growing support for the notion

E. D. Louis

that the cerebellum may be central to a disease pathobiology that is neurodegenerative. How these changes lead to an altered cerebellar and cerebellar outflow physiology, and eventually tremor, is an area of active investigation.

89.5 Clinical Features The cardinal clinical feature of ET is kinetic tremor, evidenced during a variety of activities on neurological examination (e.g., finger-nose-finger maneuver, spiral drawing, drinking from a cup, pouring water). In approximately 50% of patients, the tremor has an intentional component, worsening on finger-nose-finger maneuver as the patient approaches the target. Postural tremor also occurs in patients with ET and is generally greatest in amplitude at the wrist or elbow joints and generally involves wrist flexion extension rather than wrist rotation–supination. As a rule, the amplitude of kinetic tremor exceeds that of postural tremor, and the converse pattern should raise questions about the diagnosis. Tremor at rest, without other cardinal features of parkinsonism, occurs in approximately 2–46% of ET patients, depending on the ascertainment setting (Louis et al. 2015), but in contrast to that of Parkinson disease (PD), it is a late feature. Another motor feature of ET is gait ataxia, with tandem gait difficulty that is in excess of that seen in similarly aged control subjects. Although in most patients, this is mild, in some ET patients, it may be of moderate severity. There is some evidence that such gait ataxia is more pronounced in patients who have midline cranial tremors (e.g., neck, jaw, voice). Saccadic eye movement abnormalities have also been detected in ET patients in several physiological studies, but these are of a subclinical nature. Recent years have also witnessed a growing awareness of the presence of nonmotor features in ET patients, which may broadly be divided into cognitive, psychiatric, sensory (e.g., hearing loss), and others (e.g., sleep disturbance). The extent to which the cognitive features are cerebellar or cerebral based is not clear. Initially the tremor may be mild and asymptomatic, and it may not worsen for years, but in most individuals, the tremor worsens over time. There are few prospective, longitudinal natural history studies, yet the best estimates indicate that arm tremor worsens by 2–5% per year. With the passage of time, there is a tendency for the spread of tremor beyond the arms, with patients developing cranial tremors (neck, voice, jaw). While in the past, ET was often viewed as a “benign” problem, the term “benign essential tremor” is no longer considered an appropriate term. In fact, the majority of patients have tremor-related disability, and 15–25% are sufficiently disabled by high-amplitude shaking that they cannot continue to work.

89  Essential Tremor

Essential tremor patients have about a fourfold increased risk of developing incident PD, thus developing what is commonly referred to as ET-PD (Benito-León et al. 2009). The pathobiology of this particular connection is not fully understood, although it may relate to the presence of Lewy body pathology in some ET cases.

89.6 Treatment The tremor of ET may be severe enough to result in embarrassment and functional disability, and these are the main motivations for treatment. β-Blockers (esp. propranolol) and primidone, alone or in combination, are the most effective pharmacologic therapies, although many patients chose to discontinue these medications due to their limited efficacy (Zesiewicz et al. 2011). Other agents that have been used include topiramate, which is sometimes listed as a front-line agent, gabapentin, and benzodiazepines (alprazolam or clonazepam). Most of these agents enhanced GABAergic tone. Many patients note that tremor is temporarily suppressed by drinking ethanol. Botulinum toxin injections into selected hand muscles may be beneficial for some patients. High-­frequency thalamic stimulation markedly reduces the severity of the tremor and has replaced stereotactic thalamotomy as the treatment of choice for severe pharmacologically refractory tremor. Several other emerging surgical therapies exist as alternatives, including focused ultrasound (Halpern et al. 2019), which creates a lesion in the thalamus.

89.7 Conclusions Essential tremor is an extraordinarily common neurological disorder that is both chronic and progressive. Patients exhibit a variety of features on examination that suggest a cerebellar dysfunction, and new science is linking the disease to the cerebellum. As such, this progressive disease (or diseases) seems to involve a slow form of cerebellar degeneration, making it the most common form of cerebellar degeneration. This presumed pathobiology raises real challenges for the development of effective pharmacotherapies.

References Benito-León J, Bermejo-Pareja F, Louis ED (2005) Incidence of essential tremor in three elderly populations of central Spain. Neurology 64(10):1721–1725 Benito-León J, Louis ED, Bermejo-Pareja F (2009) Risk of incident Parkinson’s disease and parkinsonism in essential tremor: a population based study. J Neurol Neurosurg Psychiatry 80(4):423–425

597 Choe M, Cortés E, Vonsattel JPG, Kuo SH, Faust PL, Louis ED (2016) Purkinje cell loss in essential tremor: random sampling quantification and nearest neighbor analysis. Mov Disord 31:393–401 Halpern CH, Santini V, Lipsman N, Lozano AM, Schwartz ML, Shah BB et al (2019) Three-year follow-up of prospective trial of focused ultrasound thalamotomy for essential tremor. Neurology 93(24):e2284–e2293 Lenka A, Louis ED (2017) The olivary model of essential tremor: time to lay this model to rest? Tremor Other Hyperkinet Mov 7:473. https://doi.org/10.7916/D8FF40RX Louis ED (2001) Clinical practice. Essential tremor. N Engl J Med 345(12):887–891 Louis ED (2008) Environmental epidemiology of essential tremor. Neuroepidemiology 31(3):139–149 Louis ED (2014a) ‘Essential tremor’ or ‘the essential tremors’: is this one disease or a family of diseases? Neuroepidemiology 42(2):81–89 Louis E (2014b) Re-thinking the biology of essential tremor: from models to morphology. Parkinsonism Relat Disord 20(Suppl 1):S88–S93 Louis ED, Faust PL (2020) Essential tremor pathology: neurodegeneration and reorganization of neuronal connections. Nat Rev Neurol 16:69–83 Louis ED, Ferreira JJ (2010) How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord 25(5):534–541 Louis ED, Ford B, Frucht S, Barnes LF, X-Tang M, Ottman R (2001) Risk of tremor and impairment from tremor in relatives of patients with essential tremor: a community-based family study. Ann Neurol 49(6):761–769 Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Robinson CA et al (2007) Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 130(Pt 12):3297–3307 Louis ED, Benito-León J, Bermejo-Pareja F (2008) Population-based prospective study of cigarette smoking and risk of incident essential tremor. Neurology 70(19):1682–1687 Louis ED, Benito-León J, Bermejo-Pareja F (2009) Population-based study of baseline ethanol consumption and risk of incident essential tremor. J Neurol Neurosurg Psychiatry 80(5):494–497 Louis ED, Hernandez N, Michalec M (2015) Prevalence and correlates of rest tremor in essential tremor: cross-sectional survey of 831 patients across four distinct cohorts. Eur J Neurol 22:927–932 Louis ED, Eliasen EH, Ferrer M, Iglesias Hernandez D, Gaini S, Jiang W et al (2020) Blood harmane (1-methyl-9H-pyrido[3,4-b]índole) and mercury in essential tremor: a population-based, environmental epidemiology study in the Faroe Islands. Neuroepidemiology 54(3):272–280 Ma S, Davis TL, Blair MA, Fang JY, Bradford Y, Haines JL et  al (2006) Familial essential tremor with apparent autosomal dominant inheritance: should we also consider other inheritance modes? Mov Disord 21(9):1368–1374 Müller SH, Girard SL, Hopfner F, Merner ND, Clark LN, Lorenz D et  al (2016) Genome-wide association study in essential tremor identifies three new loci. Brain 139:3163–3169 Stefansson H, Steinberg S, Petursson H, Gustafsson O, Gudjonsdottir IH, Jonsdottir GA et al (2009) Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat Genet 41(3):277–279 Tanner CM, Goldman SM, Lyons KE, Aston DA, Tetrud JW, Welsh MD et  al (2001) Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology 57(8):1389–1391 Zesiewicz TA, Elble RJ, Louis ED, Gronseth GS, Ondo WG, Dewey RB Jr et al (2011) Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology. Neurology 77(19):1752–1755

90

Toxic Agents Alexandra Bakolas and Mario Manto

Abstract

Cerebellum is vulnerable to intoxication and poisoning, especially in elderly patients and in patients with structural lesions. Purkinje neurons are the main target of cerebellotoxic agents. The most common toxic agent is ethanol. Cerebellotoxic drugs include antiepileptics, antineoplastics, lithium salts, and heroin. Regarding environmental factors, chronic exposure to heavy metals, benzene derivatives, and hyperthermia cause a cerebellar syndrome. Recently, deposits of gadolinium (Gd), a heavy metal of the lanthanide group, have been described mainly in dentate nuclei and globus pallidus following repeated administration of linear Gd-based contrast agents (GBCAs). Both the mechanism of these deposits and their clinical consequences are unknown. Cerebellotoxicity should be listed in the differential diagnosis of cerebellar ataxia of unknown origin. Keywords

Ataxia · Intoxication · Ethanol · Antiepileptics · Antineoplastics · Lithium · Heroin · Gadolinium

Cerebellar ataxias of toxic origin are often overlooked, especially because the symptoms may be mild or part of a more complex syndrome where ataxic signs are included in a large set of neurological manifestations (Manto 2010). The most common causes are ethanol intake, drug ingestion, and enviA. Bakolas Unité des Ataxies Cérébelleuses, CHU-Charleroi, Charleroi, Belgium M. Manto (*) Unité des Ataxies Cérébelleuses, CHU-Charleroi, Charleroi, Belgium Service des Neurosciences, Université de Mons, Mons, Belgium e-mail: [email protected]

Table 90.1  Cerebellar ataxia induced by toxic agents (A) Ethanol ingestion (B) Drugs Anticonvulsants (phenytoin, carbamazepine, phenobarbital, vigabatrin) Antineoplastics (5-FU, capecitabine, Ara-C, methotrexate, cisplatin, immune checkpoint inhibitors) Lithium salts Amiodarone Calcineurin inhibitors Mefloquine Isoniazid Metronidazole Statins Drug abuse and addiction (cocaine, heroin, phencyclidine, methadone) (C) Environmental causes Metals (mercury, lead, manganese, copper, gadolinium, thallium) Benzene derivatives Hyperthermia Carbon monoxide Chemical weapons Insecticides/herbicides (chlordecone, paraquat, phosphine, carbon disulfide) Dimethylamine borane Saxitoxin Scorpion sting Adapted from Manto (2013)

ronmental sources (Table 90.1). Elderly patients are particularly susceptible, but people of all ages can be affected. Because the cerebellar syndrome may be irreversible and in some cases is life threatening, early identification is mandatory.

90.1 Ethanol Intake The prevalence of ethanol dependence has been estimated around 0.5–3% of the population in Europe and the USA. There is a complex interaction between genetic contri-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_90

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butions, environment, and alcohol dependence. For instance, an increased thickness of lobule I of the cerebellum is associated with a greater consumption of drugs and hard liquor in young adults (Anderson et al. 2010). Recent animal studies highlight the role of epigenetic mechanisms in the regulation of ethanol intake (Qiang et al. 2014). Neurological complications are multiple. Cerebellar ataxia is a clinical hallmark of acute ethanol intoxication (Gilman et al. 1981). Patients show a loss of balance, lack of coordination in lower limbs, and walking difficulties. Gaze-­ evoked nystagmus is common, as well as slurred speech. The association of mental confusion, oculomotor deficits, and ataxic gait raises the diagnosis of Wernicke’s encephalopathy. In Korsakoff’s syndrome, memory deficits and confabulation are at the forefront. Chronic ethanol ingestion causes a progressive cerebellar syndrome evolving over a few months. The ataxia is usually most severe in case of malnutrition. Pontine or extrapontine myelinolysis may occur, affecting cerebellum, midbrain, thalamus, basal ganglia, and periventricular white matter (Kim et al. 2007). Laboratory findings (macrocytic anemia, platelet reduction, impaired liver function tests, sideropenia, decreased levels of blood transketolase) do not predict the development or the severity of cerebellar ataxia. Cerebellar atrophy is detected in about 30% of patients with a daily intake of 150 g of ethanol over a period of 10 years (Haubek and Lee 1979). Cerebral cortex often shows variable degrees of atrophy. Brain MRI demonstrates a pattern of cerebellar atrophy predominating in the anterior lobe. In addition, it shows widening of cerebral sulci, dilatation of ventricles, symmetric lesions in the periventricular areas and dorsal thalamus, atrophy of mammillary bodies, or enhancement with gadolinium injection (Gallucci et  al. 1990). A pattern of global cerebral atrophy may develop (“chronic brain atrophy”). Fetal alcohol syndrome is ­associated with atrophy of the anterior region of the vermis (lobules I–V) and relative sparing of lobules VI–X (Sowell et al. 1996). Neuropathological studies show lesions in the mammillary bodies, in diencephalon/mesencephalon, temporal lobes, and frontal lobes. Cerebellar lesions are conspicuous in the anterior lobe. The mechanisms of ethanol-induced cerebellar toxicity are multiple. In particular, ethanol affects neurotransmission and brain metabolism (Manto 2013; Volkow et  al. 2013). Neurons containing GABA-A/benzodiazepine receptors in the superior vermis are vulnerable and cerebellar glucose metabolic rates are impaired (Gilman et al. 1996). Acetate, a metabolite of ethanol, has a primary role in ethanol-induced impairments by modulating GABA synthesis. Cerebellum acetate production is mediated by astrocytic aldehyde dehydrogenase 2 (ALDH2). Through this central metabolic path-

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way, ALDH2 regulates the cellular and behavioral effects related to ethanol consumption. This astrocytic enzyme is also expressed in other brain areas, such as the hippocampus, central nucleus of the amygdala, ventral tegmental area (VTA), and possibly in other types of glial cells and neurons. Impacts on behavior are region specific (Jin et al. 2021). Nutritional deficits contribute to the degeneration of neurons. Indeed, thiamine is a cofactor of enzymes of energy metabolism, and chronic alcoholics have a low intake of thiamine. Moreover, ethanol blocks its conversion into the active form (Laforenza et al. 1990). Glia are also affected (de la Monte and Kril 2014). Oxidative stress and endoplasmic reticulum (ER) stress are the main pro-apoptotic mechanisms in alcohol abuse (Mitoma et al. 2021). Patients developing Wernicke encephalopathy should be treated immediately with thiamine 50–100 mg IV, with correction of electrolyte deficits. Ataxia of stance and gait may subside in case of abstinence (Diener et al. 1984); otherwise, an irreversible syndrome dominated by gait difficulties develops.

90.2 Drugs 90.2.1 Anticonvulsants 90.2.1.1 Phenytoin Cerebellar ataxia induced by phenytoin intake can manifest with a minor cerebellar syndrome characterized by nystagmus and lack of balance (Selhorst et al. 1972). However, a severe pancerebellar syndrome may be observed. The deficits are either transient or permanent. Cerebellar ataxia is more common in case of silent cerebellar disease and myoclonic epilepsy is considered a predisposing factor. Phenytoin has been incriminated as a teratogenic agent causing pontocerebellar hypoplasia (Squier et al. 1990). Cerebellar atrophy has been documented following an acute overdose and following chronic treatment (Kuruvilla and Bharucha 1997). Purkinje cells and granule cells are particularly vulnerable. 90.2.1.2 Carbamazepine Carbamazepine causes a cerebellar syndrome which is dose dependent. Dizziness is the commonest symptom. Patients show gaze-evoked nystagmus, action tremor, and ataxia of stance/gait (Masland 1982). The cerebellar syndrome is overlooked in case of impaired consciousness. The association of carbamazepine and lithium salts necessitates close clinical and biological monitoring. Severe intoxication requires monitoring in an intensive care unit.

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90.2.1.3 Other Anticonvulsants Phenobarbital may cause gaze-evoked nystagmus, kinetic tremor, and ataxia of stance and gait. Most patients show drowsiness. Vigabatrin (an inhibitor of GABA transaminase) triggers a mild ataxic posture in about 5–10% of adults with poorly controlled epilepsy. Gabapentin enhances GABAergic inhibition and is currently administered for neuropathic pain. Although about 8% of patients exhibit ataxia, the drug may improve the ataxia in patients with isolated cerebellar atrophy (paradoxical effect).

The mechanism of the autoimmune toxicity also remains unclear. Management is based upon corticotherapy (1  mg/kg of prednisolone). In some conditions, immunotherapy should be discontinued or even definitively stopped (Tan et  al. 2019). Prompt recognition is essential to prevent hydrocephalus (Zurko and Mehta 2018). The majority of the patients recover, although some may develop sequelae.

90.2.2 Antineoplastics

90.2.3.1 Lithium Salts Lithium salts have a narrow therapeutic range (0.6–1.2 mM). Cerebellar ataxia develops either after an acute intoxication or during chronic therapy. Side effects include hypothyroidism and also affect the cardiovascular, renal, gastrointestinal, and/or nervous system (Simard et al. 1989). Enhanced physiological tremor affecting the hands is a common observation. Dehydration and hyperthermia are risk factors for neurotoxicity. Neurological signs are multiple: coma, seizures, extrapyramidal syndrome, pyramidal deficits, and cerebellar ataxia. Cerebellar syndrome is reversible or associated with permanent sequelae.

90.2.2.1 5-FU and Capecitabine High doses of 5-FU cause a disabling pancerebellar syndrome (Moertel et al. 1964). Cerebellar ataxia may be part of a global encephalopathy. Capecitabine is an oral prodrug of 5-FU which can induce a diffuse toxic encephalopathy with seizure-like symptoms and disseminated white matter alterations affecting supraand infratentorial structures (Niemann et al. 2004). 90.2.2.2 Ara-C (Cytarabine) Cerebellar toxicity is dose dependent. In many cases, ataxia develops for cumulative doses greater than 24  g. In some cases, cerebellar deficits are irreversible (Herzig et al. 1987). Other neurological signs include somnolence and pyramidal deficits. 90.2.2.3 Methotrexate Methotrexate is cerebellotoxic, especially with intrathecal administration. A leukoencephalopathy affecting the cerebellum may occur with oral doses (González-Suárez et  al. 2014). The drug inhibits dihydrofolate reductase. Part of the toxicity is mediated by folate deficiency. 90.2.2.4 Immune Checkpoint Inhibitors Immune checkpoint inhibitors (ICI) include anti-CTLA4 and anti-PD1/PDL1 inhibitors. Neurologic immune-related adverse events (irAEs) have been described recently with this novel drug category, occurring in about 1–5% of the patients. The most reported neurological disorders are peripheral neuropathy, meningoencephalitis, and myasthenia gravis (Haugh et al. 2020). Some cases of cerebellar ataxia secondary to anti-PDL1 use have been described, for example, after administration of pembrolizumab or nivolumab (Vitt et al. 2018; Kawamura et al. 2017). In particular, immune-mediated cerebellitis carries the risk of cerebellar edema with tonsillar herniation (Zurko and Mehta 2018). The percentage of irAEs increases if bitherapy (anti-CTLA4 combined with anti-PD1) is administered (Kao et al. 2017). Timing of side effects is currently unpredictable.

90.2.3 Other Drugs

90.2.3.2 Amiodarone Amiodarone is a lipophilic antiarrhythmic drug. Side effects include respiratory failure, liver toxicity, thyroid dysfunction, corneal deposits, as well as neurological side effects. Postural tremor, peripheral neuropathy, and cerebellar deficits are the most common (Orr and Ahlskog 2009). There is a striking relationship between the long-term amiodarone maintenance dose and the frequency of neurotoxic effects, especially in the elderly. Cerebellar ataxia may subside very slowly following drug discontinuation. 90.2.3.3 Calcineurin Inhibitors Classical neurological side effects of the calcineurin inhibitors (cyclosporine, tacrolimus, and pimecrolimus) are behavioral disorders, aphasia, seizures, cerebellar ataxia, vestibular deficits, motor spinal cord syndrome, and paresthesia (Palmer and Toto 1991; Belli et al. 1993). The ataxia may be triggered by hypomagnesemia (Thompson et  al. 1984). Posterior reversible leukoencephalopathy syndrome is characterized by white matter lesions predominating in the posterior regions of cerebral hemispheres (Hinchey et  al. 1996). Patients present with impaired mental status, headache, seizures, visual disturbances, and cerebellar ataxia (Wong et al. 2003). Brain MRI is particularly useful to establish the diagnosis, especially FLAIR sequence. Acute cerebellar edema requires brainstem decompression.

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90.2.3.4 Metronidazole Cerebellar toxicity affects nuclei. MRI demonstrates bilateral edema with increased diffusion coefficients in cerebellar nuclei (Chatzkel and Vossough 2010). Patients often recover clinically and radiologically after interruption of therapy. Patients with extracerebellar symptoms usually show a slower recovery. A mechanism of vasogenic edema has been suggested. 90.2.3.5 Statins The most common side effects of statins are myopathies due to rhabdomyolysis. Cerebellar ataxia is rare, affecting elderly patients with cardiovascular comorbidities. Patients show in particular tandem gait ataxia (Teive et  al. 2016). Statins inhibit the HMGCoA reductase that is also involved in Coenzyme Q10 synthesis. There is probably a link between ataxia and coenzyme Q10 deficiency, familial or statin induced (Saha and Whayne 2016). Ataxia is reversible after stopping the administration of statins.

90.2.4 Drug Abuse and Addiction 90.2.4.1 Cocaine Seizures, drowsiness, delirium, and cerebellar ataxia are among the clinical presentation of cocaine intoxication. Cerebellar infarction is a complication of cocaine intake (Aggarwal and Byrne 1991). Other toxic agents, such as phenytoin, may be added to “crack” cocaine and contribute to the neurological deficits. 90.2.4.2 Heroin Heroin ingestion causes a toxic spongiform leukoencephalopathy (Weber et al. 1998). Cerebellar ataxia may be prominent. Lesions are typically symmetrical, usually predominating in white matter. Intoxication may be fatal (Ryan et al. 2005). 90.2.4.3 Herbs Ceremonial herbs are used during social events. Kava causes postural ataxia and limb tremor, probably via disruption of GABAergic pathways (Singh and Singh 2002). Ingestion of Peganum harmala seed extract (containing beta-carboline alkaloids) triggers a reversible neurological syndrome characterized by psychomotor agitation, hallucinations, postural and kinetic tremor, limbs dysmetria, ataxia, and vomiting (Frison et al. 2008). 90.2.4.4 Methadone Accidental ingestion causes an acute toxic encephalopathy presenting with impaired consciousness. Patients develop obstructive hydrocephalus due to severe cerebellar edema (Anselmo et  al. 2006). A delayed syndrome has been

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described (Zanin et al. 2010). Administration of methylprednisolone and external drainage of cerebrospinal fluid are recommended, but urgent decompressive occipital craniotomy may be necessary.

90.3 Environment 90.3.1 Metals 90.3.1.1 Mercury Patients exhibit a very suggestive association of constricted visual fields (tunnel vision), hearing deficits, sensory deficits in the extremities caused by a peripheral neuropathy, and cerebellar deficits (Korogi et al. 1998). The calcarine region, the post- and precentral gyri, and the temporal gyri are particularly affected, as well as the inferior and middle parts of the vermis and cerebellar hemispheres. 90.3.1.2 Lead The main causes of lead intoxication are ingestion of paints, sniffing of leaded gasoline, flour contamination, exposure to lead stearate, and contamination from automobile batteries. Toxicity is greater in children. Patients often complain of abdominal pain and anemia is common. Lead is toxic for the central (especially frontal cortex, hippocampus, and cerebellum) and the peripheral nervous system (peripheral motor neuropathy). Extreme lead exposure causes convulsions and coma. Cerebellar ataxia may be prominent in adults (Mani et al. 1998). Cerebellar intoxication may present as a pseudotumor with obstructive hydrocephalus due to edema (Johnson et al. 1993). Cerebral calcifications and hyperintense lesions on brain MRI are common. Chelation therapy is required when lead intoxication is confirmed. 90.3.1.3 Gadolinium Gadolinium (Gd) deposits have been identified in cerebellar nuclei following repeated administration of Gd-based contrast agents (GBCAs) (Kanda et al. 2014). Gd deposits are also detected in the inner segment of the frontal lobe, cerebellar white matter, globus pallidus, and frontal lobe white matter, but the globus pallidus and the dentate nucleus are the regions with the highest levels of deposits. Macrocyclic GBCAs (gadoterate meglumine; gadoteridol; gadobutrol) are more stable than linear chelates (gadodiamide, gadopentetate dimeglumine; gadobenate dimeglumine, gadoxetic acid disodium) which have higher dissociation rates. GBCAs are characterized by the ionic charge of the complex. With a concentration up to 30-fold higher than macrocyclic agent, the linear form is most commonly found in tissues. Deposits might thus be related to the

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stability of GBCAs and the capacity of free Gd3+ releasing by a process of transmetallation. Gd3+ is produced by dechelation of GBCA, and is a competitor of Ca2+ in some metabolic pathways because of its high binding affinity with calcium channels. At a cellular level, GBCAs might also disturb intracellular signaling. Experimental studies suggest that GBCAs deposits impair the action of thyroid hormone (TH) in cerebellum especially by impacting on the dendritic arborization of Purkinje cells (Khairinisa et  al. 2021). TH effect is mainly exerted by binding to the nuclear TH receptor (TR), although recent studies indicate that a part of TH action is exerted though membrane receptor. TR transcription is augmented with gadodiamide but not with gadoterate. GBCAs would inhibit the Ca2+ channel, and in this manner modulate TR action (Khairinisa et al. 2021). GBCAs likely spread in the cerebral spinal fluid via the choroid plexus and are cleared by the glymphatic system. Age and sex do not impact total Gd retention. GBCAs pass through the placenta and are possibly associated with deposits in the fetal cerebellum (Fretellier et al. 2019). However, impact of GBCAs on pregnancy remains unclear. A recent study indicates that low to moderate renal impairment does not influence brain deposits of gadobutrol (Dogra et  al. 2021). In humans, it should be emphasized that the long-term clinical consequences of Gd deposits in cerebellar nuclei or basal ganglia remain uncertain, both in terms of motor control and cognitive operations.

90.3.1.4 Thallium Thallium is a colorless and odorless heavy metal found in some pyrites. Thallium ions are absorbed through the skin and mucous membranes. The clinical symptoms of acute intoxication are nonspecific. Early diagnosis of intoxication is thus challenging. Gastrointestinal symptoms are often the earliest manifestations of poisoning. Peripheral neuropathy and hair loss are common but occur at a later stage. Ataxia can be a serious consequence of thallium intoxication. The major neurotoxic mechanism involved in brain damage is the inhibition of the Na+/ K+  ATPase, an increase of oxidative stress and secondary excitotoxicity (Osorio-Rico et al. 2017). Thallium poisoning treatment is based on administration of Prussian blue combined with blood purification (Lin et al. 2019).

90.3.2 Toluene/Benzene Derivatives Intoxication is common in glue-sniffing and following chronic exposure in poorly ventilated working areas. An

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acute encephalopathy with coma, seizures, behavioral abnormalities, and cerebellar ataxia occurs in children (King 1982). In adults, the intoxication presents with headache, hyperactivity, memory impairment, and cerebellar ataxia. Cerebellar ataxia may be prominent and irreversible (Damasceno and de Capitani 1994). Teenagers and young adults who develop cerebellar ataxia and decreased visual acuity should be suspected of a thinner intoxication (Uchino et al. 2002).

90.3.3 Hyperthermia Cerebellum is vulnerable to hyperthermia (above 40.5 °C). Heat stroke and neuroleptic malignant syndrome are causes of disabling ataxia. Although symptoms may resolve within 3–10  days, cerebellar atrophy often develops after a few months, probably because of a peculiar vulnerability of Purkinje cells to high fever (Bazille et al. 2005). Treatment includes cooling of the body and monitoring of vital functions.

90.3.4 Chemical Weapons Marked brainstem–cerebellar symptoms have been described in patients exposed to diphenylarsinic acid poisoning (Ishii et al. 2004). Symptoms include ataxia, diplopia, myoclonus, as well as symptoms related to hemokinetic dysfunction.

90.3.5 Insecticides/Herbicides/Pesticides Deliberate self-harm by ingestion of organophosphate insecticides, such as dimethoate, is common in Sri Lanka (Fonseka et al. 2003). A cholinergic crisis is followed by various neurological and psychiatric manifestations. Cerebellar signs may appear about a week after ingestion or start 5–6 weeks after intoxication.

90.3.6 Others 90.3.6.1 Saxitoxin (Shellfish Poisoning) Saxitoxin is a neurotoxin contaminating a mollusc and binding to voltage-sensitive sodium channels found at high densities in cerebellar cortex (Purkinje cells, parallel fibers, basket cells) (Mourre et al. 1990). Patients develop gastrointestinal and neurological symptoms, especially a cerebellar syndrome of benign course (Rhodes et  al. 1975). Paresthesias are common.

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90.4 Animal-Related Cerebellar Toxicity 90.4.1 Scorpions Myoclonus and cerebellar ataxia are the main neurological deficits in some series. Complications can be severe (Gadwalkar et al. 2006). Cerebellar stroke is a potential complication. Treatment includes supportive care and antivenom serum administration.

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605 Sowell ER, Jernigan TL, Mattson SN et al (1996) Abnormal development of the cerebellar vermis in children prenatally exposed to alcohol: size reduction in lobules I-V. Alcohol Clin Exp Res 20:31–34 Squier W, Hope PL, Lindenbaum RH (1990) Neocerebellar hypoplasia in a neonate following intra-uterine exposure to anti-convulsants. Dev Med Child Neurol 32:737–742 Tan YY, Rannikmäe K, Steele N (2019) Case report: immune-mediated cerebellar ataxia secondary to anti-PD-L1 treatment for lung cancer. Int J Neurosci 129(12):1223–1225 Teive HA, Moro A, Moscovich M, Arruda WO, Munhoz RP (2016) Statin-associated cerebellar ataxia. A Brazilian case series. Parkinsonism Relat Disord 25:97–99 Thompson CB, June CH, Sullivan KM, Thomas ED (1984) Association between cyclosporin neurotoxicity and hypomagnesemia. Lancet ii:1116–1120 Uchino A, Kato A, Yuzuriha T, Takashima Y, Hiejima S, Murakami M, Endoh K, Yoshikai T, Kudo S (2002) Comparison between patient characteristics and cranial MR findings in chronic thinner intoxication. Eur Radiol 12:1338–1341 Vitt JR, Kreple C, Mahmood N, Dickerson E, Lopez GY, Richie MB (2018) Autoimmune pancerebellitis associated with pembrolizumab therapy. Neurology 91(2):91–93 Volkow ND, Kim SW, Wang GJ, Alexoff D, Logan J, Muench L, Shea C, Telang F, Fowler JS, Wong C, Benveniste H, Tomasi D (2013) Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain. NeuroImage 64:277–283 Weber W, Henkes H, Moller P, Bade K, Kuhne D (1998) Toxic spongiform leucoencephalopathy after inhaling heroin vapour. Eur Radiol 8:749–755 Wong R, Beguelin GZ, de Lima M, Giralt SA, Hosing C, Ippoliti C, Forman AD, Kumar AJ, Champlin R, Couriel D (2003) Tacrolimus-­ associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol 122(1):128–134 Zanin A, Masiero S, Severino MS, Calderone M, Da Dalt L, Laverda AM (2010) A delayed methadone encephalopathy: clinical and neuroradiological findings. J Child Neurol 25(6):748–751 Zurko J, Mehta A (2018) Association of immune-mediated cerebellitis with immune checkpoint inhibitor therapy. Mayo Clin Proc Innov Qual Outcomes 2(1):74–77

91

Endocrine Disorders Mario Manto and Christiane S. Hampe

Abstract

Keywords

This chapter discusses the links between hormonal disorders and cerebellar symptoms. Cerebellar development depends on thyroid hormone (TH) which crosses both the blood–brain barrier and the blood–CSF barrier using specific transporters, including monocarboxylate transporter 8 (MCT8) and the organic anion transporting polypeptide 1C1 (OATP1C1). Growth and dendritic arborization of Purkinje neurons, synaptogenesis, and myelination are dependent on TH. Hormonal disorders impact cerebellar functions and may cause cerebellar ataxia both in children and in adults. In particular, thyroid and parathyroid disorders, diabetes mellitus and diabetes insipidus may be associated with cerebellar deficits. Deficit in TH may decompensate or worsen a preexisting cerebellar disorder. In the case of hypothyroidism, cerebellar deficits are usually reversible with hormonal replacement. The main disorders combining diabetes and cerebellar ataxia are Friedreich ataxia (FRDA), ataxia associated with anti-­GAD antibodies, autoimmune polyglandular syndromes (APSs), aceruloplasminemia, and cerebellar ataxia associated with hypogonadism (in particular Holmes ataxia/BoucherNeuhäuser syndrome) Hormonal investigations should be included in the general workup of cerebellar ataxias of undetermined origin.

Cerebellum · Endocrine · Hormones · Thyroid

The endocrine and nervous systems are closely interrelated and dysfunctions in one system can impact the other (Manto and Hampe 2018). Hormonal disorders may cause or worsen preexisting cerebellar syndromes, from development to the elderly (Manto 2013). The classical example is a dysfunction of the thyroid gland, which worsens a chronic cerebellar ataxia of other origin, such as a genetic ataxia evolving slowly. Ataxia may be decompensated by hormonal dysfunction. From the historical standpoint, Söderbergh was the first to underline the occurrence of cerebellar symptoms in hypothyroidism (Söderbergh 1912). In particular, he reported clumsiness, tremor, and adiadochokinesia that disappeared with the treatment of myxedema. He also described a gelatinous aspect of the cerebellum in a postmortem assessment. Other authors reported that the ataxic symptoms may be the presenting symptoms of hypothyroidism (Jellinek and Kelly 1960). In reported cases, gait ataxia was more striking, sometimes leading to falls, and all patients displayed delayed tendon reflexes (Manto and Hampe 2018). Table 91.1 lists the main endocrine disorders associated with cerebellar ataxia in daily practice. This chapter summarizes the main links between endocrine disorders and cerebellar ataxia from a clinical standpoint.

M. Manto (*) Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU-­ Charleroi, Charleroi, Belgium Service des Neurosciences, Université de Mons, Mons, Belgium e-mail: [email protected] C. S. Hampe University of Washington, Seattle, WA, USA © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_91

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608 Table 91.1  Main endocrine disorders associated with cerebellar ataxia A. Thyroid disorders Hypothyroidism Hyperthyroidism Hashimoto ataxia Drug induced (amiodarone, lithium salts) B. Parathyroid disorders Hypoparathyroidism Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Hyperparathyroidism C. Cerebellar ataxia and diabetes mellitus Friedreich ataxia Mitochondrial diseases Anti-GAD antibodiesa APS syndromesb Aceruloplasminemia Von Hippel-Lindau disease Wolfram disease (DIDMOAD syndrome) Infections (CMV) D. Cerebellar ataxia and diabetes insipidus Erdheim-Chester disease Langerhans histiocytosis Wolfram disease (DIDMOAD syndrome) Septo-optic dysplasia E. Cerebellar ataxia and hypogonadism Holmes ataxia Boucher-Neuhäuser syndrome Marinesco-Sjögren syndrome Septo-optic dysplasia Kallmann syndrome Congenital disorders of glycosylation 4H syndrome Oliver-McFarlane syndrome Laurence-Moon syndrome Usher syndrome Adapted from Manto (2013) a Anti-glutamic acid decarboxylase b Autoimmune polyendocrine syndromes

91.1 Thyroid Disorders Thyroid hormone (TH) plays a critical role in cerebellar circuitry (Koibuchi 2013) and modulates many aspects of cerebellar neurons (Manto 2010; Ahmed et al. 2010; Pasquini and Adamo 1994). TH exerts trophic actions during development of the cerebellum and regulates migration and maturation of both neurons and glia (Manto 2010). In particular, the growth and branching of the dendritic tree of Purkinje neurons is greatly affected by perinatal hypothyroidism (Koibuchi 2008). TH is generated in the thyroid from thyroglobulin (TG) and iodide. TH is converted by deiodinases (Schweizer and Steegborn 2015). In tanycytes and astrocytes T4 is converted into T3 (active form) by the enzyme type 2 iodothyro-

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nine deiodinase (DIO2) (Koibuchi 2008), but this reaction is carried out by type 1 iodothyronine deiodinase (DIO1) in the thyroid and peripheral tissues. T3 is subsequently transferred to neurons and oligodendrocytes and is converted by type 3 deiodinase (D3) into the inactive form T2. Thyroid hormone crosses the blood–brain barrier (BBB) and the blood–CSF barrier by binding to specific transporters, especially the monocarboxylate transporter 8 (MCT8; SLC16A2 gene on chromosome Xq13.2) and the organic anion transporting polypeptide 1C1 (OATP1C1) (Bernal 2005; Groeneweg et  al. 2017). MCT8 is particularly expressed in the brain, heart, liver, adrenal glands, kidney, and thyroid gland (Price et al. 1998). Patients with hemizygous mutations in MCT8 show a psychomotor syndrome characterized by severe intellectual and locomotor disability (Allan-Herndon-Dudley syndrome—AHDS). The MCT8-­ deficient fetus exhibits a lack of development of cerebellar folia, delayed maturation of Purkinje neurons, and a less folded dentate nucleus (López-Espíndola et al. 2014). In the human brain, OATP1C1 facilitates T4 uptake by astrocytes, and up to now only one case of dysfunctional OATP1C1 has been described (Strømme et  al. 2018). The patient showed normal development during the first year of life, but subsequently developed dementia with spasticity and intolerance to cold. Exome sequencing revealed a homozygous variant in the gene resulting in an amino acid substitution from aspartic acid to asparagine at position 252. The patient responded well to treatment with the T3 analog Triac, showing some improvement and stabilization in her condition. Within the cell, TH interacts with thyroid hormone receptors (TRs; gene products: TRa and TRb) which belong to the steroid family of nuclear receptors. TRs form heterodimers and regulate their target gene expression even in the absence of ligand, because of a rapid exchange of coactivator/corepressor complexes by ligand-bound or -free TRs (Feng et al. 2001). Expression of TRs isoforms TRa and TRb is tissue-­ specific and levels vary during development (Cheng et  al. 2010). Expression in the cerebellum persists both during development and later in life (Bradley et  al. 1992), but declines to lower levels after birth (Keijzer et  al. 2007). Major cerebellar genes affected by TH include Reln (encoding Reelin, an extracellular matrix protein involved in neuronal migration, expressed in granule cells), Shh (encoding Sonic Hedgehog, a key morphogen produced in Purkinje cells), Laminin (encoding Laminin, an extracellular matrix protein with functions in neuronal migration), and Bdnf (encoding brain-derived neurotrophic factor expressed in granule cells, involved in synaptic structure) (Salazar et al. 2019). Dysregulation of expression of these proteins can interfere with neuronal development and function. Mutations of either receptor isoform can cause resistance to thyroid hormones (RTH), characterized by reduced sensi-

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tivity to TH, with the majority cases of RTH being caused by mutations in TRb (RTHβ). Most patients with RTHβ are heterozygous for dominant negative TRb mutations, with the mutant receptor inhibiting the function of the wild-type receptor (Refetoff and Dumitrescu 2007). To date only four patients with homozygous mutations in TRb have been described (Ferrara et al. 2012). These patients exhibit a more severe phenotype than patients with heterozygous mutations in this gene. Patients show elevated TH levels (principally free T4). Symptoms include sinus tachycardia, attention deficit disorders/hyperactivity/learning disabilities, delayed bone age, short stature, hearing impairments, and goiter. However, the clinical presentation of RTHβ is highly heterogeneous (Dumitrescu and Refetoff 2013). This variability can be partly explained by the character and position of the genetic defect (Pappa and Refetoff 2021). To date, only seven patients with RTHα have been described; these individuals have near-normal levels of TH but display hypothyroidism, delayed growth, and constipation (van Mullem et al. 2012). Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and not only controls the production of TSH (thyrotropin stimulating hormone) in the thyroid but also activates noradrenergic cerebellar neurons (Shibusawa et al. 2008), which may have an anti-ataxia effect in animal models (Muroga et  al. 1982). Treatment with the TRH analog taltirelin in a mouse model of spinocerebellar ataxia improved ataxic behavior (Nakamura et  al. 2005). TRH treatment of patients with spinocerebellar degeneration improved ataxia in these patients (Sobue et  al. 1980) and taltirelin is approved for the treatment of spinocerebellar degeneration in Japan (the drug is still awaiting FDA approval for use in the USA). It remains unclear whether the treatment effect is due to direct activation of TRH receptors expressed in the cerebellum’s granule cells and molecular layer interneurons (Heuer et  al. 2000) with subsequent increase in cerebellar cGMP concentrations (Mailman et al. 1979) or by upregulation of TH levels. The neurological effect of abnormally high (hyper) or low (hypo) levels of thyroid hormones are discussed in the following sections.

91.1.1 Hypothyroidism The three forms of hypothyroidism are congenital hypothyroidism, endemic cretinism, and adult-onset hypothyroidism. General signs are common (Van Vliet and Deladoëy 2014). Congenital hypothyroidism is associated with a growth deficit and impaired neurological functions. Endemic cretinism is caused by dietary iodine deficiency and is characterized by delayed skeletal maturation, and neuronal dysfunctions, including cerebellar ataxia. Perinatal hypothyroidism has major consequences on the ontogeny of the cerebellum and

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can be associated with structural and intellectual deficiencies in the child (Manto and Hampe 2018). Major neurological symptoms in adult-onset hypothyroidism are myoclonus, peripheral and entrapment neuropathy, and cerebellar ataxia (Manto 2013). It is noteworthy that cerebellar ataxia may be the first manifestation of hypothyroidism, although this is a rare presentation (Gilman et  al. 1981). Neurological deficits have usually a slowly progressive presentation and stance/gait difficulties are the commonest complaints (Harayama et  al. 1983; Pinelli et al. 1990). The ataxia has both a central and a peripheral component (Barnard et al. 1971; Manto 2010). Rodent models of hypothyroidism have shown deficiencies in cerebellar development, particularly affecting the Purkinje cells (Bernal 2005), and similar findings were reported in children with severe congenital hypothyroidism (Cooper et al. 2019). The effects of acute subclinical hypothyroidism on brain function and structure were studied in individuals with hypothyroidism, whose TH treatment was reduced by 30% to induce subclinical hypothyroidism (Göbel et  al. 2020). Subjects showed slower reactions in the working memory task, with no changes in attention tasks. Structural changes included increased gray matter volumes in the right cerebellum. Brain activation changes after medication withdrawal were observed in several brain regions, including the cerebellum (Göbel et al. 2020). The successful reversal of cerebellar symptoms by hormone replacement suggests that the pathogenesis is due to endocrine dysfunction of the cerebellum. In rodents, the impaired cerebellar development can be rescued only if TH is administered within the first 14  days of postnatal life (Koibuchi and Chin 2000), suggesting a critical period. Similarly, TH administration in human newborns with congenital hypothyroidism has to commence immediately after birth to rescue intellectual development (LaFranchi 1999). However, some cases of hypothyroidism-associated cerebellar ataxia do not benefit from thyroid hormone replacement (Selim and Drachman 2001), suggesting nonendocrine pathogenic factors, such as autoimmune attack (Laurberg 2006).

91.1.2 Hyperthyroidism In adults, neurological symptoms of hyperthyroidism include physiological tremor, which may show a kinetic component highly suggestive of cerebellar dysfunction, seizures, and pyramidal deficits. Ocular flutter, myoclonus and truncal ataxia have been reported in Graves’ disease (Kuwahara et al. 2013). Hyperthyroidism can be caused by Grave’s disease, an autoimmune disease overstimulating the thyroid, thyroid nodules, or thyroiditis. Autoantibodies in Grave’s disease target and activate the thyrotropin receptor, causing overproduction of TH.

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Treatment is based on antithyroid drugs aimed at the reduction of thyroid hormones, radioactive iodine therapy (especially in the elderly and in those with active toxic multinodular goiter) and surgical ablation of the hyperactive tissue. Beta-blockers are valuable to decrease cardiac symptoms and reduce tremor. Ophthalmopathy is managed with symptomatic therapies, including corticosteroids and immunosuppression. Cessation of smoking is recommended in Graves’ disease, as smoking is a major risk factor for the development of Graves’ ophthalmopathy (Hägg and Asplund 1987). The effect of acute subclinical hyperthyroidism was studied in healthy men administered TH for 8 weeks (Göbel et al. 2020). TH treatment had a beneficial effect on cognition. Gray matter volumes in the right posterior cerebellum were increased, while a decrease was observed for the anterior cerebellum.

91.1.3 Hashimoto Thyroiditis and Ataxia Hashimoto Thyroiditis is an autoimmune disorder more commonly affecting women. The neurological presentation is either an encephalopathy with a fluctuating course (dementia, psychotic behavior, seizures, impaired consciousness) or a vascular-like syndrome, which may affect the cerebellum (Kothbauer-Margreiter et al. 1996; Aydin-Ozemir et al. 2006; Hoffmann et al. 2007). Some of the neurological findings of Hashimoto Thyroiditis are similar to Creutzfeldt-Jakob disease; however, the characteristic absence of protein 14-3-3 in the CSF rules out the latter (Seipelt et al. 1999). A slowing of background activity is common on EEG recordings, suggestive of preceding seizures. Indeed, epileptic discharges may be observed (Lin and Liao 2009). However, periodic sharp waves, as often observed in epilepsy, are absent. Brain MRI shows focal hyperintense areas, diffuse subcortical lesions, and atrophy of the gray matter (Bohnen et al. 1997). The pattern of brain perfusion on SPECT is often diffuse with patchy defects. Autoantibodies against TG, thyroid peroxidase (TPO) enzyme, TSH receptor, and the amino terminal of the alpha-enolase (anti-NAE antibodies) are found in patients’ blood (Yoneda et al. 2007). The latter are useful diagnostic biomarkers of Hashimoto encephalopathy (Nakagawa et al. 2009). Ultrasonography of the thyroid gland shows a hypoechoic structure (Seipelt et al. 1999), suggestive of thyroid autoimmunity (Schiemann et  al. 1999) and hypothyroidism. Hashimoto Thyroiditis with hypothyroidism is treated with TH replacement (Jonklaas et  al. 2014). Other symptoms, such as myoclonus, may be responsive to clonazepam or piracetam. Immunosuppressants, plasmapheresis, and administration of immunoglobulins are used in refractory cases (Boers and Colebatch 2001), while thyroidectomy is an option in poorly controlled relapses (Yuceyar et al. 2007).

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Cerebellar ataxia associated with Hashimoto thyroiditis may have a subacute onset or may even be recurrent. Ataxia is thought to result from autoimmune attack against cerebellar neurons, rather than a result of the hormonal instability (Ott et al. 2011), as ataxia may occur in the euthyroid state or persist despite TH replacement therapy (Selim and Drachman 2001; Shneyder et  al. 2012; Leyhe and Mussig 2014). Because many patients respond well to steroid treatment (Shaw et al. 1991; Bohnen et al. 1997), the name “Steroid-­ Responsive Encephalopathy with Autoimmune Thyroiditis (SREAT)” was suggested to replace the term “Hashimoto encephalopathy” (Laurent et  al. 2016; Groenewegen et  al. 2021). It remains unclear whether antithyroid autoantibodies cross-react with targets in the cerebellum, or whether the cerebellar defects are the results of a widespread autoimmune response and/or inflammatory response. Notably, autoantibody levels in the CSF are absent, or very low (Ilias et al. 2015), supporting the latter argument.

91.1.4 Drug-Induced Thyroid Dysfunction Amiodarone and lithium salts are potential causes of hormonal disturbances and cerebellar ataxia. Amiodarone is an antiarrhythmic drug causing both hypothyroidism and thyrotoxicosis. This effect is in part due to the drugs high iodine content, which elevates the daily intake of iodine and stimulates TH production (thyrotoxicosis). Continuous Amiodarone treatment can eventually injure the thyroid tissue and lead to hypothyroidism. About 5% of patients develop cerebellar toxicity (Garretto et al. 1994). Lithium salts are mainly used to treat bipolar disorders (Lazarus 2009). The thyroid concentrates lithium (Berens et  al. 1970), where lithium inhibits thyroid hormone release (Spaulding et al. 1972). This inhibition causes an increase in TSH concentration, which together with lithium-induced cell proliferation (Rao et al. 2005) leads to an enlargement of the thyroid. Indeed, goiter develops in up to 40% and hypothyroidism in up to 20% of lithium-treated patients (Lazarus 2009). Thus, lithium salts can cause hyperthyroidism and exacerbate a preexisting autoimmune thyroid disease. Patients treated with these medications should be monitored for development of thyroid disorders and ataxia. Cessation of treatment is recommended when ataxia develops.

91.2 Parathyroid Disorders The parathyroid glands are located posterior to the thyroid gland and produce parathyroid hormones (PTHs). The major function of PTH is the regulation of blood calcium levels. At low blood calcium levels, PTH is released and mobilizes calcium release. As blood calcium levels increase, the release of PTH is inhibited in a negative feedback loop.

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91.2.1 Hypoparathyroidism Hypoparathyroidism is idiopathic or acquired (gland resection, thalassemia, autoimmune polyglandular syndrome (APS), 22q11.2 deletion syndrome) (Cao et al. 2011) and is characterized by abnormally low levels of parathyroid hormones (PTH), resulting in hypocalcemia and hyperphosphatemia. Hypocalcemia reduces the threshold potential of neuronal axons, resulting in increased excitability of the neuromuscular system, manifesting with tetany and muscle cramps. Patients may also exhibit seizures, dystonic posturing, and parkinsonism. Cerebellar syndrome is characterized by dysarthria, dysmetria, dysdiadochokinesia, and ataxia of gait (Ertaş et al. 1997). In chronic hypoparathyroidism, deposits of calcium occur in the cerebellum. These are easily detected with a brain CT scan. Cerebellar deficits may subside with calcium administration and vitamin D supplements.

91.2.2 Pseudohypoparathyroidism and Pseudopseudohypoparathyroidism Pseudohypoparathyroidism is due to a resistance to PTH.  Patients have mutations in the alpha-subunit of the stimulatory G protein, a signaling protein essential for the actions of PTH (Bastepe 2008), and show increased PTH levels. The resulting hypocalcemia and hyperphosphatemia are associated with extensive symmetrical calcifications in the brain, especially in cerebral sulci, basal ganglia, and dentate nuclei (Nyland and Skre 1977; Araki et al. 1990). Patients with type Ia (Albright osteodystrophy) show short stature, brachydactyly, heterotopic calcifications, and cognitive deficits, while in type Ib the hormone resistance occurs in the absence of the above phenotypic manifestations, and patients with pseudopseudohypoparathyroidism show Albright’s phenotype without hormone resistance. Neurological symptoms are variable: extrapyramidal ­syndrome, syndrome of raised intracranial pressure with papilledema, and paroxysmal kinesigenic dyskinesias (Thomas et al. 2010). A bilateral cerebellar syndrome has been reported (Nyland and Skre 1977).

91.2.3 Hyperparathyroidism In hyperparathyroidism an excess of PTH is secreted. This endocrine disorder is either primary (adenoma), secondary (vitamin D deficiency, malabsorption), or tertiary (renal failure). It may also be part of the Von Hippel-Lindau disease, which typically includes cerebellar hemangioblastomas.

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Cerebellar syndrome associated with hyperparathyroidism is subtle. Rarely, hyperparathyroidism surgery may improve the cognitive status in patients with encephalopathy masking the endocrine disorder (Voci 2020).

91.3 Cerebellar Ataxia and Diabetes The brain is especially sensitive to hypoglycemia and neurological manifestations include confusion, behavioral change, seizures, and coma. These temporary functional brain failures can be corrected by normalization of blood glucose levels. Severe hypoglycemia due to an overdose in insulin (Berz and Orlander 2008) or pancreatic insulinoma may cause prolonged cerebellar ataxia and lesions of the middle cerebellar peduncle and the anterior limb of the internal capsule, consistent with extrapontine myelinolysis (Schwaninger et al. 2002). In some rare genetic disorders concomitant diabetes can further exacerbate the neurological symptoms.

91.3.1 Friedreich Ataxia Friedreich ataxia is an autosomal recessive disease caused by mutations of the frataxin gene. Frataxin is a mitochondrial protein and mutations result in inefficient energy production and production of reactive oxygen species (Armstrong et al. 2010). While this in itself leads to neuronal degeneration, the presence of diabetes mellitus in 10–12% of patients is an additional factor contributing to the development of ataxia (Manto 2010).

91.3.2 Anti-GAD Antibodies Autoantibodies directed against glutamate decarboxylase (GADA) are associated with type 1 diabetes mellitus (T1D), stiff-person syndrome, and cerebellar ataxia (Saiz et  al. 1997). GADA inhibits the function of GAD and may thereby impair GABAergic neurotransmission (Manto et  al. 2011; Hampe et al. 2013). The severity of GADA-associated cerebellar ataxia ranges from mild to severe. The cerebellar syndrome may be restricted to ocular movements (vestibulocerebellar syndrome) or extend to limbs and gait. Brain MRI shows cerebellar atrophy after several years of disease (Ishida et al. 1999). Intracerebellar administration of GADA induces hyperexcitatory motor cortex activity (Manto et  al. 2007, 2011). Cerebellar syndrome may respond to intravenous immunoglobulins, plasma exchange, and immunosuppressive therapy (Abele et al. 1999; Ishida et al. 1999).

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Rituximab is a novel option, associated with temporal reduction in antibody levels (Planche et al. 2014). Derivatives of GABA, such as baclofen and gabapentin, are recommended for oculomotor disturbances.

91.3.3 Autoimmune Polyglandular Syndromes These syndromes are divided in three forms (Kahaly 2009): (a) type I (APECED syndrome) is a juvenile form characterized by a mucocutaneous candidiasis and various autoimmune disorders (hypoparathyroidism, Addison’s disease, thyroiditis, alopecia universalis); (b) type 2 (Schmidt syndrome) is characterized by the association of Addison’s disease with thyroiditis and T1D, and (c) type 3 is associated with T1D, autoimmune gastritis, vitiligo, alopecia, pernicious anemia, and myasthenia gravis. The neurological deficits are caused by multiple autoantibodies, endocrinopathies (discussed above for diabetes mellitus, hypoparathyroidism, hypothyroidism), vitamin deficits (especially vitamin B12 and vitamin E), and sprue. Cerebellar ataxia may be prominent in APS type I and type II. In APS type II, the ataxic syndrome may have a subacute course (Manto and Jissendi 2012). Brain MRI discloses pancerebellar atrophy.

91.3.4 Aceruloplasminemia This autosomal recessive disease is characterized by mutations in the ceruloplasmin gene, resulting in defective iron metabolism. Serum levels of iron and copper are decreased, whereas ferritin concentrations are increased in the context of microcytic anemia. Brain imaging shows iron accumulation in dentate nuclei, thalamus, striatum. Neurons are especially susceptible to iron overload and iron accumulation causes neurodegeneration (Zecca et al. 2004), probably through reactive oxygen species. The retinal pigmented epithelium is atrophied. Isolated cerebellar atrophy may occur in heterozygous cases. The disease is characterized by a triad in adults between 25 and 60 years: diabetes mellitus, retinal degeneration, and neurological deficits. Movement disorders include cerebellar ataxia and extrapyramidal signs (blepharospasm, torticollis, chorea) (Miyajima et al. 1987, 2003). Treatment may include iron-chelating agents (desferrioxamine; deferiprone) (Miyajima et al. 2003). Alternative therapies include fresh-frozen plasma and oral administration of zinc sulfate (Kuhn et al. 2007).

M. Manto and C. S. Hampe

91.4 Cerebellar Ataxia and Hypogonadism Holmes ataxia and Boucher-Neuhäuser syndrome are disorders characterized by the triad of early-onset autosomal-­ recessive cerebellar ataxia (ARCA), hypogonadism, and chorioretinal dystrophy. Hypogonadism presents with primary amenorrhea, insufficient development of sexual organs, and impaired growth of secondary sexual hair. Gait ataxia usually starts at 6–7 years of age (Manto and Hampe 2018). Holmes ataxia is characterized by nystagmus, dysarthria, tendon hyperreflexia, and mental deficits (Manto 2010). Boucher-Neuhäuser syndrome presents with a spinocerebellar syndrome, chorioretinal dystrophy, and hypogonadotropic hypogonadism (Tarnutzer et al. 2015). Atrophy of the retinal pigment epithelium and degeneration of fundi are common. Neuronal defects may be caused by mutations of the PNPLA6 (patatin-like phospholipase domain containing 6) gene. PNPLA6 encodes the neuropathy target esterase (NTE) protein, involved in membrane stability, particularly in neurons with effects on neuronal development and axon maintenance (Deik et al. 2014). The majority of mutations affect the C-terminal phospholipid esterase domain and likely impair the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of acetylcholine (Synofzik et  al. 2014). Mutations of the PNPLA6 gene induce a wide spectrum of neurodegenerative diseases, including spastic ataxias/paraplegias and mild peripheral neuropathy. Suboptimal neuronal development (caused by mutations of PNPLA6) may also result in reduced secretion of LHRH in the hypothalamus, leading to the observed low blood levels of LH and FSH hormones. However, the lack of a robust response to LHRH suggests additional pituitary involvement (Seminara et al. 2002). Thus, the association between hypogonadism and ataxia is not mediated by a direct effect of hormones on the cerebellum, but by mutations of the PNPLA6 gene, causing defects in neuronal development and hormone release. Additional mutations associated with Holmes ataxia and dementia involve genes with roles in ubiquitination (Heimdal et  al. 2014; Margolin et  al. 2013). Three of the mutations involve the ring finger protein 216 (RNF216) gene, the STIP1 homology and U-Box containing protein 1 (STUB1) (E3 ubiquitin protein ligases), and OTU Deubiquitinase 4 (OTUD4). RNF216 catalyzed ubiquitination of proteins marks them for degradation. One such substrate is the activity-­regulated cytoskeletal-associated protein (Arc/Arg 3.1), critical for synaptic plasticity and memory. Dysfunctional regulation of Arc due to RNF216 mutations cause synaptic deficits and may contribute to dementia and cognitive impairments (Husain et al. 2017).

91  Endocrine Disorders

To which degree the different mutations contribute to cerebellar atrophy observed in patients with Holmes ataxia and Boucher-Neuhäuser syndrome is unclear. A mild axonal neuropathy is found in some patients with Holmes ataxia (Manto 2010). A deficiency in cytochrome c oxidase in Holmes ataxia may be discovered in some patients; however, the pathogenesis and the impact on the disease manifestations remain unclear (De Michele et al. 1993).

91.5 Cerebellum and Steroid Hormones Like other steroid hormones, estrogen crosses the BBB by transmembrane diffusion. Additionally, estrogen is synthesized by Purkinje cells (Azcoitia et al. 2011). The cerebellum was initially regarded as insensitive to estrogen. This assumption was based on the relative sparsity of estrogen receptors in the cerebellum. More recently, the effect of estrogen on the cerebellum has been reevaluated and it is now understood that estrogen guides cerebellar development and modulates glutamatergic transmission (Mitra et al. 2003; Price and Handa 2000; Andreescu et al. 2007). In the developing cerebellum, estrogen promotes dendritic growth and spine formation and development of synapses (Sasahara et al. 2007). Mechanistically, it has been proposed that estrogen stimulates the expression of the neurotrophin BDNF (Tsutsui 2008). In the adult brain, estrogens may augment glutamatergic neurotransmission between the granule cell parallel fibers and Purkinje cells (Smith et al. 1988). Decreased estrogen levels in postmenopausal women are associated with a reduction of cerebellar volume and a decrease in balance performance. This is prevented by estrogen therapy, and postmenopausal women with estrogen treatment exhibit an increase in the gray matter of the cerebellum (Boccardi et al. 2006; Ghidoni et al. 2006; Robertson et al. 2009). Glucocorticoids (GCs) are another group of steroid hormones and are secreted from the adrenal gland. GC treatment is an effective therapy used in prematurely born infants to accelerate lung maturation (Halliday and Ehrenkranz 2000). However, GC therapy has been linked to adverse neurological outcomes, including neuromotor deficits and cerebellar hypoplasia (Yeh et  al. 2004; Cheong et al. 2014). Treatment of neonatal mice with GC-induced rapid and selective apoptosis of neural progenitor cells (NPC) in the external granule layer of the developing cerebellum (Noguchi et  al. 2008), which may point to the involved pathomechanism.

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91.6 Conclusions Cerebellar development and function are in part regulated by the endocrine system. Hormones can affect cerebellar development and function directly (e.g., THs and estrogen). In other instances, hormone dysfunction can exacerbate cerebellar disorders (diabetes). Finally, certain mutations can cause cerebellar disorders and endocrine diseases via independent pathways (PNPLA6 mutations in Holmes ataxia). A deep understanding of the underlying pathomechanisms is needed to dissect the etiology of the disease and to design appropriate treatment. Conflicts of Interest None. Writing and Editing  MM, CSH.

References Abele M, Weller M, Mescheriakov S, Bürk K, Dichgans J, Klockgether T (1999) Cerebellar ataxia with glutamic acid decarboxylase autoantibodies. Neurology 52(4):857–859 Ahmed OM, Abd El-Tawab SM, Ahmed RG (2010) Effects of experimentally induced maternal hypothyroidism and hyperthyroidism on the development of rat offspring: I. The development of the thyroid hormones-neurotransmitters and adenosinergic system interactions. Int J Dev Neurosci 28(6):437–454 Andreescu CE, Milojkovic BA, Haasdijk ED, Kramer P, De Jong FH, Krust A, De Zeeuw CI, De Jeu MT (2007) Estradiol improves cerebellar memory formation by activating estrogen receptor beta. J Neurosci 27(40):10832–10839 Araki Y, Furukawa T, Tsuda K, Yamamoto T, Tsukaguchi I (1990) High field MR imaging of the brain in pseudohypoparathyroidism. Neuroradiology 32(4):325–327 Armstrong JS, Khdour O, Hecht SM (2010) Does oxidative stress contribute to the pathology of Friedreich’s ataxia? A radical question. FASEB J 24(7):2152–2163 Aydin-Ozemir Z, Tüzün E, Baykan B, Akman-Demir G, Ozbey N, Gürses C, Christadoss P, Gökyiğit A (2006) Autoimmune thyroid encephalopathy presenting with epilepsia partialis continua. Clin EEG Neurosci 37(3):204–209 Azcoitia I, Yague JG, Garcia-Segura LM (2011) Estradiol synthesis within the human brain. Neuroscience 191:139–147 Barnard RO, Campbell MJ, McDonald WI (1971) Pathological findings in a case of hypothyroidism with ataxia. J Neurol Neurosurg Psychiatry 34(6):755–760 Bastepe M (2008) The GNAS locus and pseudohypoparathyroidism. Adv Exp Med Biol 626:27–40 Berens SC, Wolff J, Murphy DI (1970) Lithium concentration by the thyroid. Endocrinology 87:1085–1087 Bernal J (2005) The significance of thyroid hormone transporters in the brain. Endocrinology 146(4):1698–1700 Berz JP, Orlander JD (2008) Prolonged cerebellar ataxia: an unusual complication of hypoglycemia. J Gen Intern Med 23(1):103–105

614 Boccardi M, Ghidoni R, Govoni S, Testa C, Benussi L, Bonetti M, Binetti G, Frisoni GB (2006) Effects of hormone therapy on brain morphology of healthy postmenopausal women: a Voxel-based morphometry study. Menopause 13(4):584–591 Boers PM, Colebatch JG (2001) Hashimoto’s encephalopathy responding to plasmapheresis. J Neurol Neurosurg Psychiatry 70(1):132 Bohnen NI, Parnell KJ, Harper CM (1997) Reversible MRI findings in a patient with Hashimoto’s encephalopathy. Neurology 49(1):246–247 Bradley DJ, Towle HC, Young WS 3rd (1992) Spatial and temporal expression of alpha- and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the developing mammalian nervous system. J Neurosci 12(6):2288–2302 Cao Z, Yu R, Dun K, Burke J, Caplin N, Greenaway T (2011) 22q11.2 deletion presenting with severe hypocalcaemia, seizure and basal ganglia calcification in an adult man. Intern Med J 41(1a):63–66 Cheng SY, Leonard JL, Davis PJ (2010) Molecular aspects of thyroid hormone actions. Endocr Rev 31(2):139–170 Cheong JL, Burnett AC, Lee KJ, Roberts G, Thompson DK, Wood SJ, Connelly A, Anderson PJ, Doyle LW, Victorian Infant Collaborative Study Group (2014) Association between postnatal dexamethasone for treatment of bronchopulmonary dysplasia and brain volumes at adolescence in infants born very preterm. J Pediatr 164(4):737–743.e1 Cooper HE, Kaden E, Halliday LF, Bamiou DE, Mankad K, Peters C, Clark CA (2019) White matter microstructural abnormalities in children with severe congenital hypothyroidism. Neuroimage Clin 24:101980 De Michele G, Filla A, Striano S, Rimoldi M, Campanella G (1993) Heterogeneous findings in four cases of cerebellar ataxia associated with hypogonadism (Holmes’ type ataxia). Clin Neurol Neurosurg 95(1):23–28 Deik A, Johannes B, Rucker JC, Sánchez E, Brodie SE, Deegan E, Landy K, Kajiwara Y, Scelsa S, Saunders-Pullman R, Paisán-Ruiz C (2014) Compound heterozygous PNPLA6 mutations cause Boucher–Neuhäuser syndrome with late-onset ataxia. J Neurol 261(12):2411–2423 Dumitrescu AM, Refetoff S (2013) The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 1830(7):3987–4003 Ertaş NK, Hanoğlu L, Kirbaş D, Hatemi H (1997) Cerebellar syndrome due to hypoparathyroidism. J Neurol 244(5):338–339 Feng X, Jiang Y, Meltzer P, Yen PM (2001) Transgenic targeting of a dominant negative corepressor to liver blocks basal repression by thyroid hormone receptor and increases cell proliferation. J Biol Chem 276(18):15066–15072 Ferrara AM, Onigata K, Ercan O, Woodhead H, Weiss RE, Refetoff SJ (2012) Homozygous thyroid hormone receptor beta-gene mutations in resistance to thyroid hormone: three new cases and review of the literature. Clin Endocrinol Metab 97(4):1328–1336 Garretto NS, Rey RD, Kohler G et  al (1994) Cerebellar syndrome caused by amiodarone. Arq Neuropsiquiatr 52:575–577 Ghidoni R, Boccardi M, Benussi L, Testa C, Villa A, Pievani M, Gigola L, Sabattoli F, Barbiero L, Frisoni GB, Binetti G (2006) Effects of estrogens on cognition and brain morphology: involvement of the cerebellum. Maturitas 54(3):222–228 Gilman S, Bloedel JR, Lechtenberg R (1981) Disorders of the cerebellum, Contemporary neurology series. F.A. Davis, Philadelphia Göbel A, Göttlich M, Reinwald J, Rogge B, Uter JC, Heldmann M, Münte TF (2020) The influence of thyroid hormones on brain structure and function in humans. Exp Clin Endocrinol Diabetes 128(6-07):432–436 Groenewegen KL, Mooij CF, van Trotsenburg PAS (2021) Persisting symptoms in patients with Hashimoto’s disease despite normal thyroid hormone levels: does thyroid autoimmunity play a role? A systematic review. J Transl Autoimmun 4:100101

M. Manto and C. S. Hampe Groeneweg S, Visser WE, Visser TJ (2017) Disorder of thyroid hormone transport into the tissues. Best Pract Res Clin Endocrinol Metab 31(2):241–253 Hägg E, Asplund K (1987) Is endocrine ophthalmopathy related to smoking? Br Med J (Clin Res Ed) 295(6599):634–635 Halliday HL, Ehrenkranz RA (2000) Early postnatal (500 are associated with a more severe phenotype characterized by early-onset ataxia and increased incidence of extra-neurological symptoms (Filla et al. 1996).

92.6 Biochemistry Frataxin is a mitochondrial protein which is highly conserved during evolution. Mutations cause an inefficient energy production and production of reactive oxygen species (Armstrong et al. 2010). FA is considered as a mitochondriopathy. There is a reduction in the biosynthesis of iron–sulfur clusters and iron overload in mitochondria, leading to oxidative stress.

92.7 Neuropathology and Pathology of the Heart Dentate nuclei are characterized by a loss of neurons. A thinning of the superior cerebellar peduncles may be observed. Spinal cord is characterized by reduced antero-posterior and transverse diameters. A thinning of the posterior column is commonly found. The size of the dorsal root ganglia is decreased with a paucity of nerve cells. By contrast, the ante-

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92  Friedreich Ataxia

rior roots are relatively preserved. Peripheral sensory nerves show a loss of large myelinated fibers. The gross features of the cardiomyopathy are a thickening of ventricular wall and increased connective tissue. Iron-­ positive granules are observed, adjacent to or within necrotic cardiomyocytes.

no approved treatment. Research strategies aim to augment FXN production and modulate the downstream processes related to mitochondrial dysfunction, including the production of reactive oxygen species, ferroptosis, and Nrf2 activation (Rodden and Lynch 2021). Declaration

92.8 Differential Diagnosis

Funding  No specific funding is related to this chapter.

Friedreich ataxia should be distinguished from other recessive ataxias, especially ataxia with deficit in vitamin E (AVED), abetalipoproteinemia, adrenoleukodystrophy, mitochondrial disorders, and Refsum disease.

Conflict of Interests  The author declares no conflict of interest.

92.9 Treatment The ultimate goal of FA therapies is to counter the effects of FXN deficiency or to increase its expression (Tsou et  al. 2009). The possible role of iron in the pathogenesis of the disease has led to chelation therapies, such as administration of desferrioxamine or deferiprone. However, there is no iron overload globally in the body. Antioxidants, such as idebenone, have also been proposed. Human recombinant erythropoietin increases the levels of FXN in  vitro, with possible neuroprotective effects in  vivo. So far, clinical trials have failed to demonstrate a clear benefit of iron chelators, antioxidants, and erythropoietin on neurological functions. Omaveloxolone is an Nrf2 activator which restores redox balance and inflammation in animal models of FA. A recent double-blind randomized placebo-controlled phase 2 trial has shown a favorable effect upon neurological function (Lynch et al. 2021). Histone deacetylase inhibitors aim to revert silent heterochromatin to active chromatin. Studies are ongoing. Regarding extra-cerebellar manifestations, beta-blockers are administered in patients presenting palpitations. A cardiological follow-up is required for the monitoring of arrhythmias. Glucose intolerance/diabetes mellitus are treated according to guidelines (diet, oral hypoglycemic drugs, insulin). Rehabilitation therapies and occupational therapies are recommended. Severe scoliosis may require surgery (Rummey et al. 2021).

92.10 Conclusion and Future Directions FA is a disabling progressive neurodegenerative disorder with both neurological and extra-neurological manifestations. It is considered as a multisystem disease. FXN is an essential mitochondrial protein involved in iron sulfur cluster biogenesis and oxidative phosphorylation. There is still

Ethical Committee Request  Not applicable. Consent to Participate  This is a review article that does not involve patients. No consent is needed. Data Availability  The concept reported in this article is not based on raw data. Code Availability  There is no software application or custom code associated with this article.

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620 Friedreich N (1863c) Uber degenerative Atrophie der spinalen Hinterstrange. Arch Pathol Anat Phys Klin Med 27:1–26 Gentil M (1990) Dysarthria in Friedreich disease. Brain Lang 38(3):438–448 Giroud M, Septien L, Pelletier JL, Dueret N, Dumas R (1994) Decrease in cerebellar blood flow in patients with Friedreich’s ataxia: a TC-HMPAO SPECT study of three cases. Neurol Res 16(5):342–344 Harding AE (1981) Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 104(3):589–620 Hernández-Torres A, Montón F, Hess Medler S, de Nóbrega E, Nieto A (2021) Longitudinal study of cognitive functioning in Friedreich’s ataxia. J Int Neuropsychol Soc 27(4):343–350 Hirayama K, Takayanagi K, Nakamura R, Yanagisawa N, Hattori T, Kita K, Yanagimoto S, Fujita M, Nagaoka M, Satomura Y (1994) Spinocerebellar degenerations in Japan: a nationwide epidemiological and clinical study. Acta Neurol Scand 89(Suppl. 153):1–22 Junck L, Gilman S, Gebarski SS, Koeppe RA, Kluin KJ, Markel DS (1994) Structural and functional brain imaging in Friedreich’s ataxia. Arch Neurol 51(4):349–355 Klockgether T, Chamberlain S, Wüllner U, Fetter M, Dittmann H, Petersen D, Dichgans J (1993) Late-onset Friedreich’s ataxia. Molecular genetics, clinical neurophysiology, and magnetic resonance imaging. Arch Neurol 50(8):803–806 Koenig M (1998) Friedreich’s ataxia. In: Rubinsztein D, Hayden M (eds) Analysis of triplet repeat disorders. BIOS Scientific Publishers Ltd., Oxford, pp 219–238 Labuda M, Labuda D, Miranda C, Poirier J, Soong BW, Barucha NE et  al (2000) Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion. Neurology 54(12):2322–2324 Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O’Grady M, Meyer CJ (2021) Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol 89(2):212–225 Manto M (2010) Cerebellar disorders. A practical approach to diagnosis and management. Cambridge University Press, Cambridge McLeod JG (1971) An electrophysiological and pathological study of peripheral nerves in Friedreich’s ataxia. J Neurol Sci 12(3):333–349

M. Manto Morvan D, Komajda M, Doan LD, Brice A, Isnard R, Seck A, Lechat P, Agid Y, Grosgogeat Y (1992) Cardiomyopathy in Friedreich’s ataxia: a Doppler-echocardiographic study. Eur Heart J 13(10):1393–1398 Pandolfo M (2002) Friedreich’s ataxia. In: Manto M, Pandolfo M (eds) The cerebellum and its disorders. Cambridge University Press, Cambridge, pp 505–518 Rabiah PK, Bateman JB, Demer JL, Perlman S (1997) Ophthalmologic findings in patients with ataxia. Am J Ophthalmol 123(1):108–117 Reetz K, Dogan I, Hilgers RD, Giunti P, Parkinson MH, Mariotti C, Nanetti L, Durr A, Ewenczyk C, Boesch S, Nachbauer W, Klopstock T, Stendel C, Rodríguez de Rivera Garrido FJ, Rummey C, Schöls L, Hayer SN, Klockgether T, Giordano I, Didszun C, Rai M, Pandolfo M, Schulz JB, EFACTS Study Group (2021) Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study. Lancet Neurol 20(5):362–372 Riva A, Bradac GB (1995) Primary cerebellar and spino-cerebellar ataxia an MRI study on 63 cases. J Neuroradiol 22(2):71–76 Rodden LN, Lynch DR (2021) Designing phase II clinical trials in Friedreich ataxia. Expert Opin Emerg Drugs 26(4):415–423 Rummey C, Flynn JM, Corben LA, Delatycki MB, Wilmot G, Subramony SH, Bushara K, Duquette A, Gomez CM, Hoyle JC, Roxburgh R, Seeberger L, Yoon G, Mathews KD, Zesiewicz T, Perlman S, Lynch DR (2021) Scoliosis in Friedreich’s ataxia: longitudinal characterization in a large heterogeneous cohort. Ann Clin Transl Neurol 8(6):1239–1250 Santoro L, De Michele G, Perretti A, Crisci C, Cocozza S, Cavalcanti F, Ragno M, Monticelli A, Filla A, Caruso G (1999) Relation between trinucleotide GAA repeat length and sensory neuropathy in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 66(1):93–96 Spieker S, Schulz JB, Petersen D, Fetter M, Klockgether T, Dichgans J (1995) Fixation instability and oculomotor abnormalities in Friedreich’s ataxia. J Neurol 242(8):517–521 Tsou AY, Friedman LS, Wilson RB, Lynch DR (2009) Pharmacotherapy for Friedreich ataxia. CNS Drugs 23(3):213–223 Zeng J, Wang J, Zeng S, He M, Zeng X, Zhou Y, Liu Z, Jiang H, Tang B (2015) Friedreich’s ataxia (FRDA) is an extremely rare cause of autosomal recessive ataxia in Chinese Han population. J Neurol Sci 351(1–2):124–126

Ataxia Telangiectasia

93

Rob A. Dineen and William P. Whitehouse

Abstract

Ataxia Telangiectasia (A-T) is a rare autosomal recessive disorder associated with early onset cerebellar neurodegeneration, respiratory disease, immunodeficiency, radiosensitivity and cancer predisposition. Severe (“classic”) and milder (“variant”) forms of the disease exist, depending on whether the mutation in the A-T Mutated (ATM) gene results in complete absence or reduced levels of functioning ATM protein, respectively. Onset of neurological features in classic A-T usually occurs in the preschool years. While cerebellar ataxia is usually present, other extrapyramidal motor features are sometimes dominant. Eye movements are universally affected, and speech, swallowing, and motor power are usually affected as the disease progresses during childhood. A number of therapeutic options are currently being tested, with early promising results warranting larger trials. Keywords

Ataxia Telangiectasia (A-T) · Ataxia Telangiectasia Mutated (ATM) gene · Cerebellar neurodegeneration Extrapyramidal motor features · Magnetic resonance imaging

R. A. Dineen (*) Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK NIHR Nottingham Biomedical Research Centre, Nottingham, UK e-mail: [email protected]

93.1 Introduction Ataxia Telangiectasia (A-T; OMIM #208900) is an autosomal recessive multisystem disorder characterized by cerebellar neurodegeneration, immunodeficiency, respiratory problems, oculocutaneous telangiectasia, and predisposition to cancer (Crawford 1998; Rothblum-Oviatt et al. 2016). As well as these major features, a number of other associations are recognized, including endocrine abnormalities, nutritional deficiencies due to problems with feeding and swallowing, scoliosis, and premature senescence. Ataxia Telangiectasia arises due to biallelic mutations in the A-T Mutated (ATM) gene at 11q22-23 which codes for the 370 kDa ATM protein kinase (Savitsky et al. 1995; Taylor et al. 2015) which is known to have a number of important roles in maintaining cellular health. People with A-T who have no ATM protein production, or production of residual ATM protein with no detectable kinase activity, have the severe form of the disease referred to as “Classic A-T,” with onset of clinical manifestations during early childhood, progressive accumulation of disability through childhood, and death typically occurring from complications of A-T during the second to fourth decades (Crawford et al. 2006). Classic A-T has an estimated birth incidence of between 1:100,000 and 1:300,000 (Woods et al. 1990; Swift et al. 1986). People with A-T who have some retained ATM kinase function, either due to reduced production of normal ATM protein or due to expression of mutant ATM protein with reduced function (Taylor et  al. 2015), have a milder and more variable form referred to as ‘Variant A-T’ which is characterized by later onset, longer survival, and different profiles of neurological dysfunction and cancer occurrence (Schon et al. 2019).

W. P. Whitehouse Paediatric Neurology, Nottingham Children’s Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK Division of Child Health, School of Medicine, University of Nottingham, Nottingham, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_93

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93.2 Genetics and Molecular Biology

93.3 Neuropathology

The ATM gene is large, comprising 66 exons (62 of which are coding) spanning over 150  kb at 11q22-23. A-T can occur with homozygous and compound heterozygous biallelic mutations, and over 400 pathological mutations have been identified. Heterozygote frequency of ATM gene mutations is estimated at 2.8% (Woods et  al. 1990; Swift et  al. 1986). Biallelic truncating mutations leading to unstable, nonfunctioning ATM protein fragments or ATM null mutations leading to expression of nonfunctioning ATM protein are found in classic A-T (Taylor et  al. 2015). Variant A-T with a milder course can result from splice site mutations (either homozygous or heterozygous with a typical truncating ATM mutation) leading to low levels of normal functioning ATM kinase, or from missense mutations leading to expression of ATM protein with reduced kinase activity (Stewart et al. 2001; van Os et al. 2019). The ATM serine/threonine protein kinase is now appreciated to play a number of roles in maintaining cellular homeostasis, genome stability, and cell cycle regulation (Shiloh 2020; Yang and Herrup 2005), and full discussion of these is beyond the scope of this chapter. ATM kinase becomes activated in response to double-stranded DNA breaks, which is dependent on the MRE11-RAD50-NBS sensor complex. Notably mutations in the MRE11 gene lead to the “A-T like disorder” (ATLD) with phenotypic overlap with A-T (Stewart et  al. 1999). The role of ATM in the DNA repair response accounts for the radiation sensitivity and cancer predisposition in people with A-T, and carriers of ATM mutations have an increased risk of solid cancers (Lesueur et al. 2021). ATM kinase is also activated in response to oxidative stress (Chen et al. 2012), and animal models have shown that absence of functioning ATM leads to increased steady-state levels of reactive oxygen species in the brain (Kamsler et  al. 2001) which may be an important mechanism contributing to the observed neurodegeneration.

The neuropathology of A-T is characterized by cerebellar cortical atrophy involving both the vermis and hemispheres, with loss of Purkinje cells, thinning of the molecular layer, and depletion of granular neurons (Clark 2015). Macroscopically the cerebellar hemispheres and vermis are atrophic (Fig. 93.1) (Tavani et al. 2003); in vivo imaging studies have shown that in classic A-T the cerebellar atrophy progresses throughout childhood (Fig.  93.2a) (Dineen et  al. 2020), while adults with variant A-T show a spectrum of cerebellar hemispheric and vermian atrophy ranging from none to severe (Schon et al. 2019). Chronic neuronal degeneration is also observed in the dentate and inferior olivary nuclei (Aguilar et  al. 1968). Axonal degeneration with demyelination is commonly found in the posterior columns of the spinal cord, and degeneration with ballooning in the anterior horn cells is also described (Aguilar et al. 1968). Pathological changes are also seen in the substantia nigra, including neuronal loss, neurons with little or no melanin pigmentation, astrocytic hypertrophy, and occasional eosinophilic cytoplasmic inclusions in the substantia nigra (De León et al. 1976); loss of ­pigmented substantia nigra neurons and early spongiosis (Centerwall and Miller 1958); and presence of Lewy bodies in the substantia nigra (Agamanolis and Greenstein 1979). In stark contrast to the dominant neurodegeneration seen in the cerebellum, cerebral neurodegeneration does not appear to be a feature of A-T.  However, pathological studies have shown a distinctive vascular abnormality in the cerebrum consisting of dilated capillary loops, often containing fibrin thrombi around which there is perivascular hemorrhage and associated demyelination and astrocytic gliosis, referred to as “gliovascular nodules” (Boder 1987; Amromin et  al. 1979; Agamanolis and Greenstein 1979). These lesions may correspond to hypointense foci seen on susceptibility-­weighted magnetic resonance imaging, which increase in number during adolescence in classic A-T (Dineen et al. 2021).

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Fig. 93.1  Axial (top row) and sagittal (bottom row) T1-weighted MRI images from a child with A-T (left column) and a comparable aged child without A-T (right column) to show the striking atrophy of the cerebellar vermis and cerebellar hemispheres

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Fig. 93.2 (a) Progressive reduction in cerebellar volume (relative to the total intracranial volume) across a similar age range in children with classic A-T (blue dots) compared to children without A-T (green dots). (From Dineen et al. 2020). (b) Neurological decline (measured using the Crawford Quantitative Neurologic A-T Scale) in children and young

people with classic A-T.  After a relatively stable period during early childhood (Circle) there is then a relatively rapid decline between the ages of around 6 and 12 years, after which neurological function plateaus (large square). (From Crawford 2015)

93.4 Neurological Features

drink from a cup, rather than an action tremor per se. The lower limbs, upper limbs, and trunk can all be variably affected at this age. At school, children will learn to write but their writing will become increasingly ataxic and slow, affected by involuntary jerks and tremor. Most will find using a wheelchair, when exhausted or outdoors helpful by 10–12  years of age. With increasing motor and locomotor impairment aids such as a posterior walker and a standing frame are helpful. Bradykinesia is usual by this time, but in addition to the hyperkinetic adventitious movements mentioned above. Eye movements are universally affected, and characteristically complex. The earliest sign is loss of cancellation of the Vestibulo-Ocular Reflex (VOR), followed by an overcompensated VOR (Fig. 93.3). Saccades are hypometric and delayed but variable within the same child on the same day, leading to the development of occasional and later frequent oculomotor apraxia with head jerks when looking left or right. Off-foveal gaze becomes increasingly evident as saccades become more impaired with age: the child will be attending to a task, but the eyes will be pointing slightly off target, e.g., when performing the finger-nose test for cerebellar ataxia. Pursuits become choppy, and with age are lost altogether. Convergence is impaired, and involuntary conjugate eye jerks, and in some, slow conjugate eye deviation, and intermittent nystagmus, in lateral and less often in primary gaze, can be seen.

Although the name suggests ataxia is the predominant neurological feature, and while cerebellar ataxia is seen, dystonia and movement disorder are usually more striking. The neurological features are characterized by their complexity, variability between affected people and within a person from time to time, and progression during childhood leading to severe neurodisability in classic A-T by late adolescence (Fig. 93.2b). Classic A-T presents after infancy with symptoms in the preschool years. Early child development is normal and children usually start walking and utter their first words at the usual age around 13 months on average. During the second year many families will notice the child remains unstable walking, rather like they were when they first started to walk independently, and while “a narrow based ataxic gait” is sometimes seen, it is by no means characteristic. The evolution of neurological features in the preschool years is variable. In addition to a clumsy or ataxic gait, which improves at a slower than typical rate, dystonia affecting the limbs and trunk can be seen, and young children often find running easier than walking. The combination of cerebellar ataxia, dystonia and chorea, ballismus, and sometimes intermittent tremor can make the child look wildly unsteady although they rarely fall. Tremor is often task specific, e.g., when trying to

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Fig. 93.3 (a) Vestibulo-Ocular Reflex (VOR) Test. Upper schematic: plan view of patient seated opposite examiner, with their eyes fixed on a target above and behind the examiners head. Lower schematic: examiner’s view of patient’s eyes and nose. After explanation, when the patient is seen to be fixed on the target, the examiner briskly rotates the patient’s head to their left, then to their right. In a normal response, the patient’s eyes remain fixed on the target: by moving to right and left respectively, relative to the patient’s head. In an abnormal response, the patient’s eyes deviate off target while the head is rotated. (b) VOR Cancellation Test. Upper schematic: plan view of patient seated oppo-

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site examiner, with their eyes fixed on a target they are holding at eye level at arm’s length. Lower schematic: examiner’s view of patients eyes and nose. After explanation, when the patient is seen to be fixed on the target, the examiner briskly rotates the patient’s head and arms to their left, then to their right. In a normal response, the patient’s eyes remain fixed on the target: by not moving, relative to the patient’s head. In an abnormal response, the patient’s eyes deviate off target while the head is rotated. This is a very sensitive test of cerebellar function, in young, mildly affected patients with A-T this is often the first abnormality seen

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Speech will be age appropriate early on, but most will have dysarthria during their early school years. Articulation becomes increasingly impaired due to cerebellar dysarthria, and there is a characteristic increase in response time, so children need more time to make their answer to a question, often several seconds. This pause in conversation can feel uncomfortable for parents and especially teachers, who will be tempted to keep on repeating the question. However, this repeating the question seems to only make matters worse, as if the child then had to start over with trying to get their answer out. This in turn can lead to the child giving up, on that question, or in some cases exhibiting situational mutism. With increasing age, some become particularly self-conscious about their speaking and will become reluctant to talk especially with strangers. Their maximum phonation time is reduced, as is their loudness in ordinary conversation and the rate of speech, which can become staccato like, often with a nasal quality and impaired prosody. Tongue movements become slow and stiff/dystonic, relying more and more on mandible movements as the child gets older. Feeding becomes slower and more difficult with age, although dribbling/drooling seen in young school children generally improves thereafter. Many will have an unsafe swallow with the risk of silent aspiration and faltering growth in the early teens, making an early discussion about the merits of tube feeding important. Muscle power is maintained usually into late teens in spite of a slowly progressive sensory–motor neuropathy; however, joint position and vibration sense are slowly lost through the teenage years, as are the tendon reflexes and distal muscle bulk. Cognitive function appears unaffected early on, and if a young school age child with A-T seems to have global developmental delay or intellectual disability an additional diagnosis should be sought, especially in consanguineous families. The progressive impairment in speech, reading (because of the eye movement impairment), writing, and typing causes significant educational difficulties in children and young people with A-T, making cognitive assessment challenging. However, studies have documented mild-to-­ moderate/severe cognitive deficits involving the domains of attention, nonverbal memory, and verbal fluency (Vinck et al. 2011) and features consistent with a cerebellar cognitive affective syndrome (Hoche et al. 2014, 2019). Fatigue becomes an increasingly important issue in older children, affecting their abilities and sense of agency and mood. While mental state is generally normal, the increasing disabilities, especially communication and locomotor difficulties, make the child more and more dependent for activities of daily living on carers. The lack of effective disease modifying therapy and the universally bleak prognosis make this a very challenging disease for people and their families to live with. Variant A-T which typically has a milder phenotype than classic A-T can also present in young school aged children, but often presents later in adult life as a predominantly dystonic, or

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a predominantly ataxic, or a mixed syndrome (Schon et  al. 2019). It can also present with mild neurological symptoms recognized when the person presents with a malignancy.

93.5 Monitoring Neurological Status In clinical trials validated ataxia scales have generally been used, particularly the ICARS (Trouillas et al. 1997), the shorter version the Brief Ataxia Rating Scale (BARS) (Schmahmann et al. 2009), and the Scale for the Assessment and Rating of Ataxia (SARA) (Schmitz-Hübsch et al. 2006). However, these were designed and validated in cerebellar ataxias and are not ideal for A-T.  The A-TNEST is a systematic neurological assessment that has been developed by several international A-T clinics to cover all the neurological domains affected in A-T. It evolved from the less detailed Crawford score (Crawford et al. 2000), and although not systematically validated it has been in clinical use for almost 20 years (Jackson et al. 2016). Clinical Global Impression scales specific to A-T have also been proposed for use in assessment of A-T patients longitudinally and in interventional studies (Nissenkorn et al. 2016). There is now growing interest in using wearable sensors to monitor free-living motor activity in neurological disorders, including ataxias, to provide ecologically valid biomarkers for motor function (Ilg et al. 2020). Initial testing of wearable sensors in A-T show that these provide accurate and reliable data reflecting neurological disease severity and motor performance (Khan et al. 2021). Recent work has shown elevation of serum neurofilament light chain (NfL) levels in A-T, with correlation to clinical phenotype (Veenhuis et  al. 2021a) and neurological status (Donath et al. 2021). Although NfL is not specific for A-T, it has potential for use as a serum biomarker for neurodegeneration in A-T, following further validation studies. Quantitative magnetic resonance imaging also shows potential for monitoring neurodegeneration. Volumetric MRI allows direct measurement and tracking of cerebellar atrophy, and other MRI-based metrics that index neuronal health and cell density also show differences between people with A-T and healthy controls (Dineen et  al. 2020). Like NfL measurement, quantitative MRI requires further validation as a biomarker for neurodegeneration in A-T, and the responsiveness of both NfL and quantitative MRI to interventions targeting neurodegeneration in A-T is currently untested.

93.6 Non-neurological Features It is important for practitioners caring for people with A-T to have an understanding of the spectrum of problems associated with the condition, although detailed discussion of the many nonneurological facets of A-T is beyond the scope of this chapter.

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Respiratory involvement in A-T includes recurrent respiratory tract infections and interstitial lung disease/pulmonary fibrosis. The recurrent infections are multifactorial and factors, such as immunodeficiency, dysfunctional swallowing due to neurodegeneration leading to episodes of aspiration, an inefficient cough, and scoliosis if present (Bhatt et  al. 2015). Patients with classic A-T have a higher rate of recurrent respiratory infections and prophylactic antibiotic use than those with variant A-T (Staples et  al. 2008). The increased radiosensitivity seen in people with A-T means that use of X-rays and CT scans for monitoring lung disease should be carefully considered, and ongoing studies are investigating the role of MRI as a nonionizing lung imaging technique in A-T. In classic A-T the immunocompromised state is characterized by undetectable/low immunoglobulin A (IgA) levels and both T cell lymphopenia and B cell lymphopenia (Staples et al. 2008). Low IgG2 subclass levels and low levels of antibodies to pneumococcal polysaccharide are also seen. Some people with classic A-T require Ig replacement therapy, but immunodeficiency and requirement for Ig replacement therapy is much less common in people with variant A-T. Risk of developing cancer is significantly increased in people with A-T, with several large cohorts reporting cancer in around 20–25% of included individuals (Suarez et  al. 2015; Reiman et al. 2011). In classic A-T there is a high incidence in those aged 16 years and under, and lymphoid cancers occur four times more commonly than solid tumors. In people with variant A-T the occurrence of cancer during childhood is rare, and solid tumors are approximately twice as common as lymphoid tumors, with breast cancer being the most frequently seen cancer (Reiman et al. 2011). Other clinical features of A-T, such as the cutaneous, endocrine, and nutritional manifestations, are not discussed here, but readers are directed to the article by Rothblum-­ Oviatt and colleagues for coverage of these areas (Rothblum-­ Oviatt et al. 2016).

93.7 Therapeutic Approaches Therapeutic approaches in A-T fall into three categories: symptomatic and palliative treatments to mitigate the progressive disability and discomfort; treatments aimed at preventing complications; and treatments that aim to slow or reverse the progression of the disease itself. As a long-term neurodegenerative condition with immune deficiency and progressive lung disease a multidisciplinary and multiagency approach is needed to support affected children and adults and their families (van Os et  al. 2017; Whitehouse 2017; Ataxia-telangiectasia in children: Guidance on diagnosis and clinical care 2014). Physiotherapy and occupational therapy, mobility, and communication assessments are key to minimizing disability

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and maximizing participation in education, and family and leisure activities. Symptomatic treatment is best tailored to individual patients, given the wide variation in ataxia and movement disorder symptoms. Some will benefit from L-Dopa, or trihexyphenidyl (e.g., for dystonia and bradykinesia), or baclofen or diazepam (e.g., at night for painful muscle spasms). One small open-label trial found encouraging results with amantadine (Nissenkorn et al. 2013). Deep Brain Stimulation with bilateral globus pallidus pars interna electrodes has also shown benefit in a patient with variant A-T (Georgiev et al. 2016) but has not been widely reported. It is important to maintain lung health with chest physiotherapy, cough assist when required, and prophylactic antibiotics and subcutaneous or intravenous immunoglobulin replacement when needed. Lung infections are best treated early and aggressively. Standing frames and measures to avoid contractures will not only help maintain mobility but may slow the development of scoliosis which will eventually impact on lung health and comfort. Likewise maintaining nutrition is important and most older children with classic A-T will benefit from tube feed supplementation. Bone marrow transplantation can improve the associated immunodeficiency and reduce the risk of cancer (Sabino Pinho de Oliveira et al. 2020) but is unlikely to improve neurological degeneration.

93.8 Ongoing Trials and Future Directions Although there are no proven curative treatments, the past 5years has seen the initiation of a number of innovative therapeutic trials aiming to slow or reverse the neurological decline in people with A-T. Although definitive results from large randomized controlled trials are not yet available, we review the promising interventions here in the expectation that the field will move rapidly over the coming years. Nicotinamide riboside, a pyridine nucleotide similar to vitamin B3, is an NAD+ precursor. Supplementation has potential in several areas of therapeutics (Mehmel et  al. 2020). A clinical trial of nicotinamide riboside in patients with A-T has recently been reported (Veenhuis et al. 2021b). This was an uncontrolled open-label proof-of-concept study, including 18 patients with classic and 6 with variant A-T, treated for only 4 months with nicotinamide riboside 25 mg/ kg/day, after which it was discontinued. They were reassessed 2 months after stopping treatment. There was no placebo and no blinding, so the modest improvement in ataxia scale scores and IgG levels could be misleading. No adverse effects were noted. A longer, blinded, placebo-controlled study will be needed to validate the results. Several small trials showed some improvement in ataxia scores with corticosteroid treatments including oral betamethasone (Zannolli et al. 2012), and dexamethasone delivered by regular autologous intraerythrocyte dexamethasone

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phosphate (the “EryDex system”) which seemed effective with fewer adverse effects (Chessa et  al. 2014). A larger, multinational, pivotal randomized placebo-controlled trial of the EryDex System has just closed with planned reporting in 2022. The mechanism of action is unclear and a role in promoting alternative gene splicing (Menotta et  al. 2012) has recently been contested (Pozzi et  al. 2020). There is also some evidence that the dexamethasone improves the redox state in A-T cells by promoting an NRF2-mediated antioxidant response (Biagiotti et al. 2016). N-Acetyl-l-Leucine has been used for many years to treat vestibular symptoms, and more recently cerebellar ataxia (Schniepp et al. 2016). In mice it has been shown to attenuate cortical cell death after traumatic brain injury (Hegdekar et al. 2021). This provided the rationale for a clinical trial in patients with A-T which is currently underway (Fields et al. 2021). An AntiSense Oligonucleotide (ASO) was designed by Dr. Tim Yu at Boston Children’s Hospital to silence one 18-month-old girl’s mutations with good evidence of restored function in vitro. She has been receiving regular CSF doses for over a year, although the results from this N-of-1 trial have not been published yet. This gene therapy technique has the potential to effectively cure A-T, and has been applied to other neurodegenerative diseases with some success (Evers et al. 2015).

93.9 Conclusion In summary, A-T is a complex multisystem disease which, in the classic form, is associated with relentless progression during childhood. Prognosis remains poor death commonly occurring in the second to fourth decades due to cancer or respiratory complication. Exploration of genotype–phenotype associations has potential to identify A-T subtypes that show different disease behaviors, particularly in those with variant A-T.  Early results from a number of therapeutic approaches show promise and offer the potential for effective treatments in the coming years, with larger trials warranted.

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Neuroimmune Mechanisms of Cerebellar Ataxias

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Hiroshi Mitoma and Mario Manto

Abstract

This chapter discusses cell- and autoantibody-mediated immune mechanisms impairing cerebellar neurons and circuits. Various autoimmune processes induce cerebellar tissue injury, which culminate in the development of immune-mediated cerebellar ataxias (IMCAs), a subgroup of cerebellar ataxias (CAs). The intracellular presence of Yo (cdr2) and Hu onconeural antigens in cancer and neuronal cells suggests cell-mediated and molecular mimicry mechanisms in paraneoplastic cerebellar degeneration (PCD), which develops mainly through CD8+ T-cellmediated autoimmunity against an autoantigen recognized by the onconeural antibody (Ab). The killing of cancer cells releases additional oncoantigens, a mechanism which enhances the perpetuation of the cancer-­immunity cycle. In contrast, autoantibodies play pathogenic roles in some patients: anti-GAD Ab suppresses GABA release, while anti-voltage-gated Ca2+ channel Ab, anti-metabotropic glutamate receptor type 1 Ab, and anti-glutamate receptor-δ Ab cause a dysregulation of long-term depression (LTD), resulting in impairment of synaptic plasticitymediated functions (LTDpathies). Keywords

Immune-mediated cerebellar ataxias · Autoimmune ataxia · Paraneoplastic cerebellar degenerations Anti-GAD ataxia · LTDpathies

H. Mitoma (*) Department of Medical Education, Tokyo Medical University, Tokyo, Japan e-mail: [email protected] M. Manto Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, Charleroi, Belgium Service des Neurosciences, University of Mons, Mons, Belgium e-mail: [email protected]

94.1 Introduction Disorders of the immune system can result in cerebellar tissue injury and the development of immune-mediated cerebellar ataxia (IMCA) (Hadjivassiliou 2012; Mitoma et  al. 2016, 2021a). The etiologies of IMCAs are diverse (Hadjivassiliou 2012; Mitoma et  al. 2016, 2021a). Autoimmunity can be triggered by another pathology in some patients, such as infection (postinfectious cerebellitis: PIC), neoplasm (paraneoplastic cerebellar degeneration: PCD), and gluten sensitivity (GA), although the triggering factor is some patients remains obscure (primary autoimmune cerebellar ataxia: PACA) (Hadjivassiliou 2012; Mitoma et al. 2016, 2021a). One systemic study surveyed the etiology of CA in 1500 patients in the UK and demonstrated a high (more than expected) prevalence of IMCAs among ataxic patients (Hadjivassiliou et al. 2017). It is unclear how CNS tolerance is broken and how the immune system attacks the cerebellum. However, recent studies have elucidated some mechanisms by which the immune system can induce damage of the cerebellar neurons (Mitoma et al. 2020a, 2021a). This chapter reviews cell- and antibody (Ab)-mediated pathomechanisms of various types of IMCAs.

94.2 Neural Damage Induced by Cell-­Mediated Autoimmunity 94.2.1 Clinical Profile and Treatment of Paraneoplastic Syndrome PCD is characterized by acute or subacute onset. Patients sometimes show prodromal clinical symptoms, such as nausea, vomiting, and dizziness, resembling viral infection-­ related disease (Dalmau and Rosenfeld 2008). Subsequently, patients develop gait ataxia, followed by signs of pancerebellar involvement (Dalmau and Rosenfeld 2008). Cerebrospinal

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_94

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fluid (CSF) examination shows elements of inflammation, including moderate lymphocytic pleocytosis, high protein concentrations, high IgG index, and oligoclonal bands (Dalmau and Rosenfeld 2008). Identification of the characteristic autoantibodies is a key step to reach diagnosis, although seronegative cases have been described (Dalmau and Rosenfeld 2008; Ducray et  al. 2014). Based on the “Recommended Diagnostic Criteria in 2004” (Graus et  al. 2004), a definite diagnosis of PCD is established by: (1) confirmation of the presence of cancer, which develops within 5 years of diagnosis of CA, or (2) appearance of well-­ characterized onconeural antibodies (anti-Yo, anti-Hu, anti­CV2, anti-Ri, and anti-Ma2). On the other hand, a possible diagnosis of PCD is based on the appearance of the partially characterized onconeural autoantibody (anti-Tr/DNER) (Graus et  al. 2004). Antibodies are associated with given cancers (Dalmau and Rosenfeld 2008; Ducray et  al. 2014; Graus et al. 2004): breast and gynecological cancers in case of anti-Yo Ab, lung (especially small-cell) cancer in anti-Hu Ab, lung (especially small cell) cancer and malignant thymoma in anti-CV2 Ab, breast and lung cancers in anti-Ri Ab, testicular and (mostly non-small cell) lung cancer in anti­Ma2 Ab, and Hodgkin lymphoma in anti-Tr/DNER Ab. The first line of therapy is fast removal of the cancer by surgery, radiotherapy, and/or chemotherapy to diminish triggering and driving factors of autoimmunity against the cerebellum (Dalmau and Rosenfeld 2008; Ducray et  al. 2014; Graus et al. 2004). In addition to the selected cancer treatment modality, various types of immunotherapies (single or combinations of corticosteroids, intravenous immunoglobulins (IVIg), plasmapheresis, immunosuppressants, and rituximab) are used (Dalmau and Rosenfeld 2008; Ducray et al. 2014; Graus et al. 2004). Unfortunately, prognosis is often poor since the majority of patients fail to respond to the anti-­ cancer therapy and immunotherapy (Keime-Guibert et  al. 2000; Demarquay and Honnorat 2011). Nevertheless, the cerebellar syndrome may remain stable over years as in patients showing anti-Tr/DNER Ab.

94.2.2 Cell-Mediated Mechanisms of Paraneoplastic Syndrome Various inflammatory changes develop in the early stages of PCD, including perivascular cuffing by lymphocytes, infiltration of lymphocytes within the PC layer, and microglial activation (Verschnuren et al. 1996). The infiltrates consist of T and B cells, plasma cells, microglia/macrophage lineages, and reactive Bergmann cell gliosis (Storstein et al. 2009). There is still debate on whether the autoantibodies that target intracellular antigens Yo (cdr2) and Hu proteins play pathogenic roles in the development of inflammatory cerebellar lesions. Anti-Yo Ab toward Cdr2 is internalized and

H. Mitoma and M. Manto

interferes with c-Myc (the nuclear transcription factor)-associated cell cycle signaling, resulting in cell apoptosis (Sakai et  al. 2004). In addition, anti-Yo Ab toward Cdr2 impairs also the interaction with mortality factor-like proteins MRGX and/or NFκβ, leading to changes in transcriptional activity (Sakai et al. 2004). However, lack of IgG deposits and B cells infiltration has been reported (Lancaster and Dalmau 2012). Notably, many studies using passive transfer of onconeural antibodies have shown that targeted intracellular antigens and immunization using protein or DNA fail to induce ataxic symptoms in animals (Tanaka et  al. 1995). Thus, many researchers believe that antibody-mediated mechanisms are not the main autoimmune mechanisms underlying PCDs associated with anti-Yo and anti-Hu Abs (Lancaster and Dalmau 2012). Yo (cdr2) and Hu onconeural antigens are intracellularly located in tumor and neuronal cells (Zaborowski and Michalak 2013), suggesting cell-mediated and molecular mimicry mechanisms. Consistently, PCD patients are positive for anti-Yo (cdr2) or anti-Hu antibody, and cdr2- or Hu-specific T cells in blood and CSF (Rousseau et al. 2005), and the T cells found in tumors, peripheral blood, and affected nervous tissue originate from the same clone population (Plonquet et al. 2002). The infiltrated lymphocytes in the cerebellum are mainly CD3+ and CD8+ T cells, and only a few are CD4+ lymphocytes (Plonquet et al. 2002). CD4+ and CD8+ T-cell interaction is required to induce inflammation in a mouse model of paraneoplastic neurological disease, where CD4+ T cells exhibit Th1 phenotype and secrete IFN-γ and TNF-α (Gebauer et  al. 2017). These studies suggest that the main etiology of PCD involves CD8+ T-cell-mediated autoimmunity toward an autoantigen recognized by the onconeural Ab (Albert et al. 1998). On the other hand, cytotoxic lymphocytes appear to be aggressive toward cells presenting cdr2 or Hu antigens and induce cell death possibly through one or more of the following mechanisms: (1) activation of TNF and FasL receptors, which triggers apoptotic cell death cascade, and (2) excretion of granules that destroy cells through the actions of granzyme B, perforin, and T-cell restricted intracellular antigen 1 (Zaborowski and Michalak 2013).

94.2.3 Augmented Cancer-Immunity Cycle in Paraneoplastic Syndrome Chen and Mellman have proposed the notion of the cancer-­ immunity cycle (Chen and Mellman 2013) (Fig.  94.1): (1) release of neoantigens created by oncogenesis, (2) presentation of these oncoantigens on MHCI and MHCII molecules by dendritic cells (DCs), (3) priming and activation of effector T cells, (4) trafficking of cytotoxic T cells (CTLs) to cancer sites, (5) infiltration of CTLs into cancer tissues, (6)

94  Neuroimmune Mechanisms of Cerebellar Ataxias

633 Lymph node

Dendritic cell

Cancer

MHC II / TCR-CD4, CD28

CD4+

ThFH

PD-L1

MHC I/ TCR-CD8, CD28

MHC I / TCR-CD8, CD28

CD8+

PD-1

Th1

IL-4

IL-2 CD8+

Cancer-immunity cycle

Cerebellum

BBB

CD8+

CD8+ B cell

??

Intracellular antigen; cdr2

Anti-Yo (cdr2) Ab

Anti-Yo (cdr2) Ab

Fig. 94.1  The cancer-immunity cycle. The cycle includes following stages: release of neoantigens created by oncogenesis, presentation of these oncoantigens on MHCI and MHCII molecules by dendritic cells, priming and activation of effector T cells, trafficking of cytotoxic T

cells (CTL) to cancer sites, infiltration of CTLs into cancer tissues, recognition of cancer cells by CTLs through the interaction between the T cell receptor and the cognate antigens bound to MHC, and finally killing of cancer cells

recognition of cancer cells by CTLs through the interaction between the T-cell receptor (TCR) and the cognate antigens bound to MHC, and finally (7) killing of cancer cells. The killing of tumor cells releases additional cancer antigens, resulting in perpetuation of the cancer-immunity cycle. The cancer-immunity cycle is controlled through divergent stimulatory and inhibitory factors. The cytokine-­mediated signaling pathways control the status of the cycle (Chen and Mellman 2013; Qiu et al. 2021). For example, the priming and activation of T cells is enhanced by a wide range of cytokines [e.g., IL-12 secreted by M1 macrophages, interferon (IFN)-γ secreted by Th1 and natural killer (NK) cells, and IL-2 secreted by CD8+ T cells] and co-stimulating signals (through the binding of CD137 on T cells/CD137L on DCs, OX40/OX40L, and CD27/CD70) (Chen and Mellman 2013; Qiu et al. 2021). In contrast, the priming and activation are inhibited by coinhibitory signals through the PD-1/PDL-1 and regulatory T cells (Treg) (Chen and Mellman 2013; Qiu et al. 2021). Thus, stimulating factors promote immunity, whereas inhibitory factors keep the process in check, reduce immunity, and prevent autoimmunity (Chen and Mellman 2013).

In PCD, autoimmunity might reflect augmentation of the cancer-immunity cycle, and poor prognosis seems to correlate with the amount of remnant tumor tissue and metastasis, which could also cause persistent activation of the immune system and robust autoimmune response (Mitoma et al. 2021b). Consistent with this assumption, the effects of PCD therapies using immune check point inhibitors have been examined recently (Graus and Dalmau 2019). Immune check point inhibitors, such as a PD-1 inhibitor, are currently ­considered effective for the treatment of several cancers, such as melanoma, lung, urogenital and gastrointestinal cancers (Graus and Dalmau 2019). However, discrete neurological complications have been reported in up to 12% of the patients, including those with myasthenia, GuillainBarré syndrome, and encephalitis (Touat et  al. 2017). Notably, PCD has also been reported recently, in which amplified autoimmune responses to cancer proteins resembled healthy cerebellar cells at a molecular level (Segal et al. 2021). Thus, PD-1/PDL-1 seems to suppress the cancer-immunity cycle, thus serving as the immunological cycle offswitch.

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94.3 Neural Dysfunction Induced by Autoantibody-Mediated Autoimmunity 94.3.1 Significance of Associated Autoantibodies Autoantibodies are linked to the pathophysiology of IMCAs (Mitoma et al. 2021a) (Table 94.1). Therefore, identification of autoantibodies can provide a lead to the diagnosis of IMCAs. There are two types of autoantibodies: (1) autoantibodies suggestive of specific etiologies and (2) nonspecific autoantibodies found in other neurological and systemic

Table 94.1  Classification of autoantibodies in immune-mediated cerebellar ataxias Characterized autoantibodies, suggestive of a specific etiology in IMCAs Well characterized Anti-gliadin, TG2, 6 Gluten ataxia Anti-Yo PCDs; Breast, uterus and ovarian cancers Anti-Hu PCDs; Small cell lung carcinoma Anti-CV2 PCDs; Small cell lung carcinoma, thymoma Anti-Ri PCDs; Paraneoplastic OMS; Breast cancer Anti-Ma2 PCDs; Testicular and lung cancers Partially characterized Anti-Tr PCDs; Hodgkin’s lymphoma Autoantibodies detected in various neurological conditions (e.g., CAs), suggestive of autoimmune pathomechanisms Autoantibodies assumed to have pathogenic roles in the development of CAs Anti-VGCC (P/Q type) Ca channel dysfunction: anti-VGCC ataxia, PCD, Lambert-Eaton syndrome Anti-DPPX K channel dysfunction: antiDPPX ataxia, limbic encephalitis Anti-LGI1 K channel dysfunction and AMPA-R: anti-LGI1 ataxia, limbic encephalitis Anti-CASPR2 K channel dysfunction: antiCaspr2 ataxia, limbic encephalitis, Morvan syndrome Anti-mGluR1 mGluR dysfunction: anti-mGluR ataxia, PCD Anti-GAD65 (high titer) Low GABA release: anti-GAD ataxia, PCD, SPS Anti-MAG Although pathogenic for neuropathy, mechanism still uncertain: anti-MAG ataxia Autoantibodies with unreported pathogenic actions Anti-thyroid PACA, thyroid autoimmune diseases Anti-SSA(Ro), SSB PACA, Sjögren syndrome

H. Mitoma and M. Manto Table 94.1 (continued) Autoantibodies reported only in a few CA patients, with less characterized significance in ataxia Anti-ZIC4 Paraneoplastic (rare) Anti-PCA2 Paraneoplastic (rare) Anti-glycine R Paraneoplastic OMS (rare) PIC, Unknown Anti-GluRδ2 Reported in a few patients with Anti-PKCγ neoplasm Anti-Ca/ARHGAP26 Reported in a few patients with neoplasm. Unknown Anti-SOX1 Reported in a few patients with neoplasm. Unknown Anti-CARP VIII Reported in a few patients with neoplasm. Unknown Anti-Homer3 Reported in a few patients with neoplasm. Unknown Anti-Sj/ITPR-1 Unknown Anti-Septin-5 Unknown Anti-neurochondrin Unknown Anti-Nb/AP3B2 Unknown Unknown conditions might be PACA PCD paraneoplastic cerebellar degeneration, PIC postinfectious cerebellitis, OMS opsoclonus myoclonus syndrome, PACA primary autoimmune cerebellar ataxia, TG transglutaminase, VGCC voltage-gated calcium channel, DPPX dipeptidyl-peptidase-like protein 6, LGI1 leucine-­rich glioma-inactivated protein 1, CASPR2 contactin-­associated protein-like 2, mGluR1; metabotropic glutamate receptor, GAD65 glutamic acid decarboxylase 65, MAG myelin associated glycoprotein, ZIC4 zinc finger protein of the cerebellum 4, PCA2 Purkinje cell antibody 2, GluRδ2 glutamate receptor delta 2, PKCγ protein kinase C gamma, Ca/ARHGAP26 Ca/Rho GTPase-activating protein 26, SOX1 sex determining region Y-related high-mobility group box 1, CARP VIII carbonic anhydrase-related protein VIII, Sj/ITPR-1 Sj/inositol 1,4,5-­trisphosphate receptor 1, Nb/AP3B2 Nb/adaptor complex 3 B2 Modified from Mitoma et al. (2021a)

conditions, including CAs. These provide only possible explanations for an autoimmune pathophysiology. The former types of autoantibodies include antigliadin and TG6 Abs in GA, and anti-Yo, Hu, CV2, Ri, and Ma2 Abs for PCD (Mitoma et al. 2021a). Whether these autoantibodies play pathogenic roles in CAs remain to be clarified in several cases. In autoimmune limbic encephalitis, autoantibodies toward glutamate and GABA receptors and potassium channel-related proteins cause basal synaptic transmission dysfunction (Dalmau et al. 2017). Dalmau et  al. (2017) classified the actions of these autoantibodies into three categories: (1) surface dynamics impairment of the target receptor through elimination of the receptor from synapses (e.g., NMDA receptor), (2) receptor blockade without density changes (e.g., GABA receptors), and (3) impairment of synaptic protein–protein interactions (e.g., LGl1, Caspr2) (Dalmau et  al. 2017). Interestingly, autoantibodies toward glutamate receptors, GABA receptors, and K+ channel-related proteins are preferentially found in autoimmune limbic encephalitis but not in IMCAs

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94  Neuroimmune Mechanisms of Cerebellar Ataxias

(Mitoma et al. 2020a). In IMCAs, autoantibodies toward glutamic acid decarboxylase 65 (GAD65), voltage-gated Ca2+ channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR-δ) are thought to play pathogenic roles in synaptic transmission and plasticity (Mitoma et al. 2020a).

94.3.2 Anti-GAD Antibody and Anti-GAD Ataxia GAD is an enzyme that catalyzes the conversion of glutamate to GABA (Mitoma et al. 2017; Graus et al. 2020). GAD exists in two isoforms: GAD65 and GAD67. In 2001, Honnorat and colleagues reported the first series of 14 CA patients associated with high titer of anti-GAD65 Ab (Honnorat et al. 2001). The levels of serum anti-GAD65 Ab titers usually exceed 2000 U/mL, or 10–100-fold those found in patients with type 1 diabetes mellitus (T1DM) (Mitoma et al. 2017; Graus et al. 2020; Honnorat et al. 2001; Arińo et al. 2014). Although the triggering condition(s) of GAD65 are unknown, autoimmunity is often triggered by paraneoplastic or gluten sensitivity conditions (Graus et al. 2020). The condition mainly affects women in their 60s, with subacute or chronic/insidious course (Mitoma et  al. 2017; Graus et al. 2020; Honnorat et al. 2001; Arińo et al. 2014). Anti-GAD ataxia is sometimes associated with extracerebellar features, including epilepsy, ophthalmoplegia, and Stiff-­ Person syndrome (Mitoma et  al. 2017; Graus et  al. 2020; Honnorat et al. 2001; Arińo et al. 2014). Gait ataxia is the most prominent ataxic clinical sign (Mitoma et  al. 2017). Induction and maintenance therapies include corticosteroids, IVIg, immunosuppressants, plasmapheresis, and rituximab, either alone or in combination (Mitoma et  al. 2017; Graus et al. 2020; Honnorat et al. 2001; Arińo et al. 2014). Some patients, especially those with chronic course, exhibit poor response to these immunotherapies (Arińo et al. 2014). The significance of anti-GAD65 has been a matter of debate (Mitoma et  al. 2017). Some researchers argue that anti-GAD65 Ab has no pathogenic roles in the development of CAs based on the following reasons (Graus et al. 2020): (1) anti-GAD65 Ab is associated with other conditions, such as T1DM and Stiff-Person syndrome, (2) GAD65 is intracellularly located together with GABA transported with the cytosolic phase of GABA-containing vesicles, implying that autoantibodies may not have access to GAD65, and (3) the correlation between anti-GAD65 Ab titers and clinical features is lacking. Nevertheless, recent physiological studies clearly have showed that intracerebellar administration of patients’ CSF and monoclonal Abs elicits cerebellar control impairment and ataxic symptoms (Mitoma et  al. 2017; Manto et  al. 2015). Furthermore, slice preparation studies demonstrate that patients’ CSF IgGs depress GABA release,

and these effects are abolished after the absorption of anti-­ GAD Ab, while anti-GAD65 Ab elicit no actions in slices from GAD65 knockout mice, where inhibitory transmission is mediated compensatorily by GAD67 (Mitoma et al. 2017; Manto et  al. 2015). Notably, anti-GAD Ab obtained from patients with TIDM have no effects (Mitoma et  al. 2017; Manto et  al. 2015). These studies show that anti-GAD Ab acts on terminals of GABA neurons with an epitope specificity, resulting GABA release depression, which culminates in the development of CAs (Fig. 94.2). There are still no experimental data on how anti-GAD Ab accesses GAD65 (Graus et al. 2020), although anti-GAD Ab can be internalized impairs the association of GAD65 with the synaptic vesicles (Manto et al. 2015). It was established that Purkinje cells internalize proteins from the blood and CSF (Fishman et al. 1990). It should be acknowledged that the above studies did not rule out secondary involvement of cell-mediated mechanisms.

94.3.3 Anti-VGCC, mGluR1, and GluR Delta Antibodies and LTDpathy The action potential at the presynaptic terminal activates VGCCs, such as P/Q-type and/or N-type Ca2+ channels. Anti-VGCC Ab was initially found in Lambert-Eaton syndrome (LEMS) (Clouston et  al. 1992). Subsequently, CA associated with autoantibodies toward the P/Q-type VGCC was also described in patients with PCD with or without LEMS (Clouston et al. 1992). The most frequent cancer is small cell lung cancer (SCLC) (Mason et al. 1997). The prevalence of anti-VGCC Ab in PCD patients is 2% (Shams’ili et  al. 2003). Patients exhibit common symptoms found in PCD (Mason et al. 1997). On the other hand, anti-VGCC has also been reported in non-paraneoplastic conditions (Clouston et al. 1992). The association of malignancy determines the therapeutic response to immunotherapies. One study of 16 anti-VGCC Ab-positive PCD patients with SCLC reported no recovery after immunotherapy in half of the patients, with a median survival time of 12 months (Graus et  al. 2002). In contrast, a good prognosis was reported in patients with non-paraneoplastic conditions. The mGluR1 is coupled to the G-protein Gq family, which mediates inositol trisphosphate (IP3)-induced Ca2+ mobilization and activation of protein kinase C (PKC). CA associated with anti-mGluR Ab is found in paraneoplastic conditions (Hodgkin’s lymphoma, cutaneous T lymphoma, and prostate adenocarcinoma) (Sillevis Smitt et al. 2000; Iorio et al. 2013; Spatola et al. 2020) as well as in non-paraneoplastic conditions (Spatola et al. 2020). Patients with this type of CA present with gait and limb ataxia and often exhibit a subacute clinical course, which is characteristically associated with extracerebellar clinical features, including behavioral

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H. Mitoma and M. Manto

Dysregulated LTD by anti-VGCC, mGluR1, and GluR delta Abs PF GABAergic IN Golgi PC

GC

Decrease in GABA release by anti-GAD Ab

Impairments in internal forward model -Disorganized online predictive controls -Disorganized updates to pathologies

CN

CF

Motor control centers Excitatory neurons

MF .Thalamo-cortical tracts .Brainstem nuclei .Spinal cord

Inhibitory neurons

Fig. 94.2  A schematic diagram of Ab-induced cerebellar dysfunctions. MF mossy fiber, CF climbing fiber, GC granule cell, Golgi Golgi cell, PF parallel fiber, GABAergic In GABAergic interneurons, CN cerebel-

lar nucleus neurons, LTD long-term depression, VGCC voltage-gated Ca2+ channel, mGluR1 metabotropic glutamate receptor type 1 Ab, GluR delta glutamate receptor-δ

changes (irritability, apathy, mood, personality changes, psychosis with hallucinations, and catatonia), cognitive changes (memory deficit, and deficits in executive functions and spatial orientation) or dysgeusia (Spatola et  al. 2020). Most patients benefit from immunotherapy (e.g., IVIg, corticosteroids, mycophenolate mofetil, cyclophosphamide, and rituximab, alone or in combinations) (Spatola et  al. 2020). However, a few exhibit progressive worsening of CAs (Spatola et al. 2020). The GluR-δ is a postsynaptic transmembrane protein localized at the PF–PC synapse. Infection or vaccination triggers CA associated with anti-GluR-δ Ab in children (Shimokaze et al. 2007; Shiihara et al. 2007). Children with this type of CA characteristically show good prognosis following immunotherapy (e.g., IVIg and intravenous methylprednisolone). VGCC, mGluR1, and GluR delta are involved in the induction of long-term depression (LTD) at parallel fiber (PF)–Purkinje cell (PC) synapses (Fig.  94.2). Conjunctive activation of PF and climbing fiber (CF) induces PF–PC

LTD (Ito 2002), where [Ca2+]i increases through two pathways: (1) PF activates mGluR1-phospholipase C β(PLCβ)-IP3 signaling pathway, leading to Ca release from the Ca2+ stores in the endoplasmic reticulum, and (2) CF activates VGCC, leading to Ca entry (Ito 2002). The increase in [Ca2+]i, more than the addictive level, activates PKCα, which phosphorylates GluA2-C-terminus, ultimately leading to the internalization of AMPA receptors in AP2- and clathrin-dependent manners (Wang et al. 2000; Wang and Linden 2000). GluR delta serves to gate the induction of PF–PC LTD (Kohda et  al. 2013). On the other hand, previous studies demonstrated impairment of induction of PF–PC LTD by anti-­ mGluR1 Ab from patients (Coesmans et  al. 2003) and Ab against H2 ligand binding site of GluR delta (Hirai et  al. 2003), respectively. Thus, dysregulated PF–PC LTD might be the core pathogenic mechanism of CA with anti-VGCC Ab, anti-mGluR1 Ab, and anti-GluR delta Ab. In this regard, we have recently proposed the concept of “LTDpathies” to stress the roles of disorganized PF–PC LTD-mediated pathophysiological mechanisms (Mitoma et al. 2021b).

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94.3.4 Autoantibodies-Induced Dysfunction of Online Predictive Controls and Cerebellar Reserve The cerebellum executes predictive calculations for timing and muscle synergies using an internal forward model (Cabaraux et al. 2020). This model solves the dynamics forward in time by combining the former state of the body from peripheral sensory organs and the efference copy from the motor area in the brain (Cabaraux et al. 2020). The cerebellar output signals for timing and synergy controls are generated through a chain of inhibitory neurons: the Basket cells (inhibitory interneurons) and PCs (Cabaraux et  al. 2020), where a pause in PC activities releases the activation of dentate nucleus neurons leading to “on” signals toward the motor cortex (disinhibition mode). On the other hand, the internal forward model is acquired and updated through multiple forms of synaptic plasticity (Cabaraux et  al. 2020). Thus, if the cerebellum is insulted by pathological injury, the lost internal forward model is reorganized through synaptic plasticity. This ability for compensation and restoration is termed cerebellar reserve (Mitoma et al. 2020b). The disinhibition mode, formed through chains of inhibitory neurons, is impaired by anti-GAD Ab-induced reduction in GABA release and, presumably, dysregulation of the PF– PC LTD (Cabaraux et al. 2020). In addition, the overall functions of various synaptic plasticities in the cerebellar cortex are affected by dysregulation of the PF–PC LTD or impairments of plasticity at the GABA synapses (rebound potentiation) (De Zeeuw et al. 2020). In conclusion, impairments in online predictive controls and cerebellar reserve are critical pathomechanisms in anti-GAD ataxia and LTDpathies.

94.4 Cooperation of Cell- and Antibody-­ Mediated Mechanisms Cell death and cerebellar dysfunctions are not triggered only by cell- and Ab-mediated mechanisms but also by cooperative pathology by cell- and Ab-mediated immunity. For example, in multiple sclerosis, myelin antigen-specific Th1 and Th17 are activated by perivascular macrophages and play a pathological role in demyelination (Kira and Isobe 2019). Furthermore, immunoglobulins and complement deposits are also observed in lesions in half of the autopsied MS patients, suggesting that Ab and complement-mediated myelin phagocytosis is probably a critical step in established MS lesions (Breij et al. 2008). In anti-GAD ataxia, the Ab-mediated damage is amplified by local neuroinflammation induced by activated microglia and astrocytes. Any decrease in GABA release attenuates

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GABA-mediated suppression of glutamate release, resulting in acute excitotoxicity (Mitoma et al. 2017). In this regard, total loss of PCs is consistently observed on autopsy examination (Mitoma et al. 2017). Excessive levels of glutamate activate microglia, which in turn releases of excessive amount of glutamate (Suzumura 2013) and TNF-α (Mandolesi et al. 2013). TNF-α inhibits the re-uptake of glutamate through excitatory amino acid transporters (EAATs) on astrocytes (Anderson and Swanson 2000). Thus, once the increase in glutamate release is achieved, it is further enhanced through positive feedback through activated microglia and astrocytes. Thus, various types of cross talk between cell- and Ab-mediated autoimmune mechanisms can potentially occur in IMCAs.

94.5 Conclusion Recent advances have clarified how various cell- and Ab-mediated immune mechanisms impair cerebellar neurons and circuits. The diversity of autoimmunity seems to reflect the diverse etiologies of IMCAs. On the other hand, common mechanisms can amplify autoimmunity, including the cancer-immunity cycle and the amplification of glutamate excitotoxicity by neuroinflammation. It remains unclear how the balance between inflammatory and regulatory mechanisms are broken to cause autoimmunity and how autoreactive lymphocytes can penetrate the blood–brain barrier. Further molecular studies about these mechanisms are needed to control autoimmunity toward the cerebellum.

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H. Mitoma and M. Manto Keime-Guibert F, Graus F, Fleury A, Renė R, Honnorat J, Broet P, Delattre JY (2000) Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, Anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 68:479–482 Kira J, Isobe N (2019) Multiple sclerosis. In: Mitoma H, Manto M (eds) Neuroimmune diseases: from cells to the living brain. Springer Nature, Cham, pp 487–521 Kohda K, Kakegawa W, Matsuda S, Yamamoto T, Hirano H, Yuzaki M (2013) The δ glutamate receptor gates long-term depression by coordinating interactions between two AMPA receptor phosphorylation sites. Proc Natl Acad Sci U S A 110:E948–E957 Lancaster E, Dalmau L (2012) Neuronal autoantigens-­pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8:380–390 Mandolesi G, Musella A, Gentile A, Grasselli G, Haji N, Sepman H, Fresegna D, Bullitta S, De Vito F, Musumeci G, Di Sanza C, Strata P, Centonze D (2013) Interleukin-1β alters glutamate transmission at purkinje cell synapses in a mouse model of multiple sclerosis. J Neurosci 33:12105–12121 Manto M, Honnorat J, Hampe CS, Guerra-Narbona R, López-Ramos JC, Delgado-García JM, Saitow F, Suzuki H, Yanagawa Y, Mizusawa H, Mitoma H (2015) Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission. Front Behav Neurosci 9:78 Mason WP, Graus F, Lang B, Honnorat J, Delattre JY, Valldeoriola F, Antoine JC, Rosenblum MK, Rosenfeld MR, Newsom-Davis J, Posner JB, Dalmau J (1997) Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain 120(Pt 8):1279–1300 Mitoma H, Adhikari K, Aeschlimann D, Chattopadhyay P, Hadjivassiliou M, Hampe CS, Honnorat J, Joubert B, Kakei S, Lee J, Manto M, Matsunaga A, Mizusawa H, Nanri K, Shanmugarajah P, Yoneda M, Yuki N (2016) Consensus paper: Neuroimmune mechanisms of cerebellar ataxias. Cerebellum 15:213–232 Mitoma H, Manto M, Hampe CS (2017) Pathogenic roles of glutamate decarboxylase 65 autoantibodies in cerebellar ataxias. J Immunol Res 2017:2913297 Mitoma H, Honnorat J, Yanaguchi K, Manto M (2020a) Fundamental mechanisms of autoantibody-induced impairments on ion channels and synapses in immune-mediated cerebellar ataxias. Int J Mol Sci 21:4936 Mitoma H, Buffo A, Gelfo F, Guell X, Fucà E, Kakei S, Lee J, Manto M, Petrosini L, Shaikh AG, Schmahmann JD (2020b) Consensus paper. Cerebellar reserve: from cerebellar physiology to cerebellar disorders. Cerebellum 19:131–153 Mitoma H, Manto M, Hadjivassiliou M (2021a) Immune-mediated cerebellar ataxias: clinical diagnosis and treatment based on immunological and physiological mechanisms. J Mov Disord 14:10–28 Mitoma H, Honnorat J, Yanaguchi K, Manto M (2021b) LTDpathies: a novel clinical concept. Cerebellum. https://doi.org/10.1007/ s12311-­021-­01259-­2 Plonquet A, Gherardi RK, Cr’eange A, Antoine JC, Benyahia B, Grisold W, Drlicek M, Dreyfus P, Honnorat J, Khouatra C, Rouard H, Authier FJ, Farcet JP, Delattre JY, Delfau-Larue MH (2002) Oligoclonal T-cells in blood and target tissues of patients with anti­Hu syndrome. J Neuroimmunol 122:100–105 Qiu Y, Su M, Liu L, Tang Y, Pan Y, Sun J (2021) Clinical application of cytokines in cancer immunotherapy. Drug Des Dev Ther 15:2269–2287 Rousseau A, Benyahia B, Dalmau J, Connan F, Guillet JG, Delattre JY, Choppin J (2005) T cell response to Hu-D peptides in patients with anti-Hu syndrome. J Neuro-Oncol 71:231–236

94  Neuroimmune Mechanisms of Cerebellar Ataxias Sakai K, Kitagawa Y, Saiki S, Saiki M, Hirose G (2004) Effect of a paraneoplastic cerebellar degeneration-associated neural protein on B-myb promoter activity. Neurobiol Dis 15:529–533 Segal Y, Bukstein F, Raz M, Aizenstein O, Alcalay Y, Gadoth A (2021) PD-1-inhibitor-induced PCA-2 (MAP1B) autoimmunity in a patient with renal cell carcinoma. Cerebellum. https://doi.org/10.1007/ s12311-­021-­01298-­9 Shams’ili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, Vecht C, Sillevis Smitt P (2003) Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 126(Pt 6):1409–1418 Shiihara T, Kato M, Konno A, Takahashi Y, Hayasaka K (2007) Acute cerebellar ataxia and consecutive cerebellitis produced by glutamate receptor delta2 autoantibody. Brain Dev 29:254–256 Shimokaze T, Kato M, Yoshimura Y, Takahashi Y, Hayasaka K (2007) A case of acute cerebellitis accompanied by autoantibodies against glutamate receptor delta2. Brain Dev 29:224–226 Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, Coesmans M, Jaarsma D, Henzen-Logmans S, Vecht C, De Zeeuw C, Sekiyama N, Nakanishi S, Shigemoto R (2000) Paraneoplastic cerebellar ataxia due to antibodies toward against a glutamate receptor. N Engl J Med 342:21–27 Spatola M, Pedrol MP, Maudes E, Simabukuro M, Muñiz-Castrillo S, Pinto AL, Wandinger KP, Spiegler J, Schramm P, Dutra LA, Iorio R, Kornblum C, Bien CG, Höftberger R, Leypoldt F, Titulaer MJ, Sillevis Smitt P, Honnorat J, Rosenfeld MR, Graus F, Dalmau J (2020) Clinical features prognostic factors, and antibody effects in anti-mGlur1 encephalitis. Neurology 95:e3012–e3025

639 Storstein A, Krossnes BK, Vedeler CA (2009) Morphological and immunohistochemical characterization of paraneoplastic cerebellar degeneration associated with Yo antibodies. Acta Neurol Scand 120:64–67 Suzumura A (2013) Neuron-microglia interaction in neuroinflammation. Curr Protein Peptide Sci 14:16–20 Tanaka K, Tanaka M, Igarashi S, Onodera O, Miyatake T, Tsuji S (1995) Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody. 2. Passive transfer of murine mononuclear cells activated with recombinant Yo protein to paraneoplastic cerebellar degeneration lymphocytes in severe combined immunodeficiency mice. Clin Neurol Neurosurg 97:101–105 Touat M, Talmasov D, Ricard D, Psimaras D (2017) Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol 30:659–668 Verschnuren J, Chuang L, Rosenblum MK, Lieberman F, Pryor A, Posner JB, Dalmau J (1996) Inflammatory infiltrates and complete absence of Purkinje cells in anti- Yo–associated paraneoplastic cerebellar degeneration. Acta Neuropathol 91:519–525 Wang YT, Linden DJ (2000) Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron 25:635–647 Wang SS, Denk W, Hausser M (2000) Coincidence detection in single dendritic spines mediated by calcium release. Nat Neurosci 3:1266–1273 Zaborowski MP, Michalak S (2013) Cell-mediated immune response in paraneoplastic neurological syndromes. Clin Dev Immunol 2013:630602

Primary Autoimmune Cerebellar Ataxia (PACA)

95

Marios Hadjivassiliou and Hiroshi Mitoma

Abstract

Immune-mediated ataxias are likely to account for a large number of progressive ataxias. Advances in the field of immune-mediated ataxias meant that a number of novel antibodies directly linked to the pathogenesis of ataxia can now be used to diagnose immune ataxias. Primary Autoimmune Cerebellar Ataxia (PACA), however, refers to those ataxias that are suspected as being autoimmune but lack any specific well-characterized pathogenic antibody markers. The recent publication of proposed diagnostic criteria for PACA means that there are now better ways of suspecting and diagnosing PACA. This is important because immune-mediated ataxias are potentially treatable. Early diagnosis and treatment result in better outcomes and less disability. Keywords

Primary Autoimmune Cerebellar Ataxia Immune-­mediated ataxias · Mycophenolate

95.1 Introduction Primary Autoimmune Cerebellar Ataxia (PACA) refers to those ataxias where there is a strong suspicion of an autoimmune etiology but the absence of any well-characterized pathogenic antibodies linked to autoimmune ataxias (Hadjivassiliou 2010). The evidence in support of this entity comes from a number of observations. First, the Human

M. Hadjivassiliou (*) Academic Department of Neurosciences, Royal Hallamshire Hospital, Sheffield, UK e-mail: [email protected] H. Mitoma Department of Medical Education, Tokyo Medical University, Tokyo, Japan e-mail: [email protected]

Lymphocyte Antigen (HLA) type DQ2 is significantly overrepresented in patients with idiopathic sporadic ataxia. This HLA type has been shown to have a strong association with autoimmune diseases. Secondly, it has been shown that there is a significantly higher prevalence of one or more autoimmune diseases in patients with idiopathic sporadic ataxia when compared to patients with genetic ataxias, 47%, and 6% respectively (Hadjivassiliou et  al. 2008). Thirdly, antibodies against cerebellar neurons are present in at least 60% of patients with idiopathic sporadic ataxia in contrast to 5% in patients with genetic ataxias (Hadjivassiliou et al. 2008).

95.2 Diagnosis The diagnosis of PACA has so far been problematic. This is because there is no single serological or other markers to confirm this diagnosis. Even if the HLA DQ2 is overrepresented in this group, given that this HLA marker is found in up to 35% of healthy individuals, this test cannot serve as a marker for PACA. The presence of additional autoimmune diseases in either the patient or their first-degree relatives may raise suspicion of PACA. To address this problem, an International Task Force consisting of neurologists with an interest in immune ataxias, produced diagnostic criteria for PACA in an attempt to aid diagnosis and more importantly enable the initiation of treatment for such patients (Hadjivassiliou et al. 2020a). In this publication, it was suggested that PACA should encompass all ataxias that fulfill the proposed criteria: Predominantly, subacute or acute pure cerebellar syndrome, primarily with vermian involvement in addition to having two out of three of the following criteria: (a) CSF pleocytosis and/or positive oligoclonal bands (b) History of other autoimmune disorders or family history of autoimmune disorders in first-degree relatives (c) Presence of antibodies that support autoimmunity but not yet shown to be directly involved in ataxia pathogenesis or be markers of ataxia with a known trigger

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_95

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PACA may be associated with neuronal antibodies but these antibodies would have not been shown to be involved in the pathogenesis of cerebellar ataxia. Therefore, those patients with positive antibodies that are well characterized and are known to be associated with autoimmune ataxias (e.g., DPPX, mGluR1, and anti-GAD) should not come under the category of PACA. It is possible that a patient with PACA may, in the future, be identified as having a novel pathogenic antibody that directly links to the ataxia. In such cases, the ataxia will be named after the pathogenic antibody that defines it (e.g., anti-GAD ataxia). It is likely therefore that the term PACA encompasses a heterogeneous group of autoimmune ataxias. Immunohistochemical studies using sera from patients with idiopathic sporadic ataxia have shown a variety of staining patterns in 60% (Hadjivassiliou et al. 2008). This heterogenicity, however, is not a problem because the principal aim of the development of these criteria was to allow the clinician to suspect PACA and consider treatment. A recent report showed that a commercially available immunofluorescence assay (primarily used for screening for paraneoplastic antibodies) can be used to provide additional diagnostic aid for suspected immune-mediated ataxias and particularly PACA (Hadjivassiliou et al. 2021). In this study, a total of 300 patients that had undergone testing using this assay were divided into three groups: immune ataxias, genetic ataxias, and patients with a cerebellar variant of multiple system atrophy (MSA-C). The prevalence of positive immunofluorescence was 91% in the immune ataxia group, 5% in the genetic ataxia, and 4% in the MSA-C groups. This technique may prove helpful in adding support to the suspicion of PACA.

95.3 Prevalence In a large prospective evaluation of 1500 patients with progressive ataxia, immune-mediated ataxias accounted for 26% of all ataxias with gluten ataxia being by far the most common (Hadjivassiliou et  al. 2016). This study was published prior to the development of diagnostic criteria for PACA. Of interest is the fact that 20% of the ataxias in this same study were labeled as having idiopathic sporadic ataxia. While geneticists may argue that the majority of these patients have a genetic cause for their ataxia, the reality of the matter is different. The introduction of next-generation sequencing and the use of whole-genome sequencing has enabled clinicians to investigate a genetic cause in all of these idiopathic sporadic ataxia cases. Applying these genetic techniques to a large group of patients with adult-onset idiopathic sporadic ataxia has shown that the identification of a genetic cause ranged between 7% (when applying a large panel of ataxia genes) to 16% (using whole genome sequenc-

M. Hadjivassiliou and H. Mitoma

ing). This means that the vast majority of these patients are unlikely to have a genetic ataxia and may well have an immune mediated ataxia.

95.4 Clinical Characteristics and Treatment Patients with PACA tend to develop ataxia in their mid-50s. The onset may be acute/subacute and the progression can be slow. They exhibit pure ataxia with particular involvement of gait. Depending on the duration of their ataxia, they may have cerebellar atrophy on MRI with predilection for the vermis. MR spectroscopy of the cerebellum shows clear involvement of the vermis with or without involvement of the hemispheres. As per the diagnostic criteria, these patients often have additional autoimmune diseases. In a recent report on the treatment of 30 patients with PACA, the authors found that all of their patients had an additional autoimmune disease: 10 had thyroid disease, 5 had type 1 Diabetes, 4 had pernicious anemia, 3 had Sjogren’s, 2 had stiff person syndrome, 1 had lupus, 1 had scleroderma, 1 had rheumatoid arthritis, 1 had Crohn’s disease, 1 had myositis, and 1 had vitiligo (Hadjivassiliou et  al. 2020b). The same study reported outcomes in 30 patients with PACA.  Of these 22 received mycophenolate, the remaining 8 were not on any treatment. Out of the 22 treated patients, 4 underwent serial MR spectroscopy prior to starting treatment and thus were used as controls, making the total number of patients in the control group 12. The mean change of the MRS within the vermis (NAA/Cr ratio) in the treatment group was +0.144  ±  0.09 (improved) and in the untreated group −0.155 ± 0.06 (deteriorated). The difference was significant. The authors also showed a strong correlation between MR spectroscopy and the SARA score. The results suggested that PACA is potentially treatable. Like with any immune ataxia, early recognition and treatment are associated with a better outcome. There are also a small number or case reports or series reporting improvement of the ataxia with immune treatments such as intravenous immunoglobulins (Takeguchi et al. 2006).

95.5 Conclusions PACA is proving to be a common cause of otherwise idiopathic late-onset ataxias. The creation of diagnostic criteria for PACA means that clinicians have the opportunity to suspect and diagnose PACA in order to consider immunosuppressive treatment. While PACA is likely to prove to be a heterogeneous entity (in terms of different types of autoimmune ataxias), the treatment approach remains common among autoimmune ataxias.

95  Primary Autoimmune Cerebellar Ataxia (PACA)

References Hadjivassiliou M (2010) Primary autoimmune cerebellar ataxia (PACA). Adv Clin Neurol Rehab 9(6):9–11 Hadjivassiliou M, Boscolo S, Tongiorgi E, Grunewald RA, Sharrack B, Sanders DS, Woodroofe N, Davies-Jones GAB (2008) Cerebellar ataxia as a possible organ specific autoimmune disease. Mov Disord 23(10):1270–1377 Hadjivassiliou M, Martindale J, Shanmugarajah P, Grunewald RA, Sarrigiannis PG, Beauchamp N, Garrard K, Warburton R, Sanders DS, Friend D, Duty S, Taylor J, Hoggard N (2016) Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/ jnnp-­2016-­314863 Hadjivassiliou M, Graus F, Honnorat J, Jarius S, Titulaer M, Manto M, Hoggard N, Sarrigiannis PG, Mitoma H (2020a) Diagnsotic cri-

643 teria for primary autoimmune cerebellar ataxia-guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias. Cerebellum. https://doi.org/10.1007/s12311-­020-­01132-­8 Hadjivassiliou M, Grunewald RA, Shanmugarajah PD, Sarrigiannis PG, Zis P, Skarlatou V, Hoggard N (2020b) Treatment of primary autoimmune cerebellar ataxia with mycophenolate. Cerebellum. https://doi.org/10.1007/s12311-­020-­01152-­4 Hadjivassiliou M, Wild G, Shanmugarajah P, Grunewald RA, Akil M (2021) Indirect immunofluoresent assay as an aid in the diagnosis of suspected immune mediated ataxias. Cerebellum Ataxias. https:// doi.org/10.1186/s40673-­021-­00129-­1 Takeguchi M, Nanri K, Okita M (2006) Efficacy of intravenous immunoglobulin for slowly progressive cerebellar atrophy. Rinsho Shinkeigaku (Japanese) 46:467–474

96

Gluten Ataxia Marios Hadjivassiliou

Abstract

Gluten ataxia (GA) is defined as sporadic ataxia with positive serological markers for gluten sensitivity and in the absence of an alternative etiology for the ataxia. It is the commonest immune-mediated ataxia and part of the spectrum of gluten-related disorders. GA may be associated with coeliac disease (gluten-sensitive enteropathy) but the presence of enteropathy is not a prerequisite for the diagnosis. A range of serological markers for gluten sensitivity and coeliac disease (CD) is available but it is important to appreciate the correct utility in the context of diagnosing GA.  Some markers are specific to the presence of enteropathy, while others are sensitive to the whole spectrum of gluten-related disorders. GA responds well to a strict gluten-free diet with the best outcomes observed in patients where the diagnosis and treatment have been made early, before the loss of cerebellar reserve and permanent ataxia. The pathophysiology is closely linked to transglutaminases, a group of enzymes that are involved not only in tissue repair but also interact with gliadin, forming immunogenic peptides that trigger an autoimmune reaction leading to gut, skin, and neural tissue injury. Keywords

Gluten ataxia · Gluten-free diet · Gluten-related disorders Transglutaminases · Coeliac disease · Antigliadin antibodies

96.1 Introduction Coeliac disease (also known as gluten-sensitive enteropathy) affects 1% of the population and classically presents at gastroenterology clinics with a combination of diarrhea, abdominal pain, bloating, weight loss, anemia, and symptoms and signs of malabsorption. The development of cerebellar ataxia in the context of CD was originally attributed to vitamin deficiencies such as B12 or vitamin E, due to malabsorption. Many such, mainly single case reports or small series, have been published over the years. Perhaps the most comprehensive case series that included neuropathological data was published as far back as 1966 (Cooke and Thomas-Smith 1966). In 1996, our group approached the subject from a neurological perspective by examining the prevalence of antigliadin antibodies (at the time the only marker of gluten sensitivity) in a cohort of patients presenting with neurological dysfunction of unknown cause. The majority of these patients had idiopathic sporadic ataxia. The study demonstrated a greater than 50% prevalence of antigliadin antibodies in this cohort as compared to 12.5% in the healthy population and 5% in the neurology control group (Hadjivassiliou et  al. 1996). This finding led to a renewed interest in the field of neurological manifestations of gluten sensitivity (beyond the presence of enteropathy) and led to the introduction of the disease entity of gluten ataxia (Hadjivassiliou et al. 1998).

96.2 Diagnosis and Prevalence

M. Hadjivassiliou (*) Royal Hallamshire Hospital, Sheffield, UK e-mail: [email protected]

GA is the commonest immune-mediated ataxia and forms part of the spectrum of gluten-related disorders. Among 1500 consecutive patients with progressive ataxia assessed at a single center, GA accounted for 25% of all ataxias and just over 50% of all sporadic ataxias (Hadjivassiliou et al. 2016). The diagnosis of GA was based on the presence of antigliadin antibodies in the absence of any alternative etiology for the ataxia. A sys-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_96

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tematic review of serum antigliadin antibodies in cerebellar ataxias concluded that there is an association between antigliadin antibodies and idiopathic cerebellar ataxia across different geographic regions (Lin et al. 2018). There is a range of serological tests that are used in the context of diagnosing glutenrelated disorders. The type of test has to be selected on the basis of the type of manifestation. For example, antibodies against transglutaminase type 2 (TG2, the autoantigen in CD) are very helpful in making a diagnosis of CD. The same is true for endomysium antibodies (EMA). EMA is in fact an immunofluorescence assay that uses a monkey esophagus to detect TG2 antibodies. Native gliadin antibodies (IgG and IgA) are sensitive markers for the whole spectrum of gluten sensitivity and have been utilized as the diagnostic marker for GA irrespective of the presence of enteropathy (Hadjivassiliou et al. 2010). More specific markers, depending on the type of manifestation, have been developed. For example, TG3 antibodies have been shown to be prevalent in patients with Dermatitis Herpetiformis, the skin manifestation of gluten sensitivity, and TG6 antibodies have been found to be prevalent in GA (Sárdy et al. 2002; Hadjivassiliou et al. 2013). TG3 is an epidermal transglutaminase and TG6 is a brain-expressed transglutaminase. Availability of the above serological tests may be problematic and most immunology labs will only cater to tests that are specific to CD (i.e., TG2 and EMA antibodies). This is problematic as many patients with GA remain undiagnosed and untreated.

M. Hadjivassiliou

The response to treatment with a gluten-free diet depends on the duration of the ataxia prior to the diagnosis. While the benefits of a gluten-free diet in the treatment of patients with coeliac disease have long been established, there are very few studies, mainly case reports, of the effect of a gluten-free diet on ataxia and on other neurological manifestations. These studies suggest variable but overall favorable responsiveness to a gluten-free diet. Only one large systematic study of the effect of a glutenfree diet on a cohort of patients presenting with ataxia, with or without enteropathy, has been published (Hadjivassiliou et al. 2003). This showed significant improvement in the performance of ataxia test scores and in the subjective global clinical impression scale in the treatment group when compared to the control group. A small, uncontrolled study showed improvement with intravenous immunoglobulins in four patients with GA without enteropathy (Bürk et al. 2001). The current recommendations are that patients presenting with progressive idiopathic cerebellar ataxia, where all other causes have been ruled out, should be screened for gluten sensitivity using antigliadin IgG and IgA, anti-TG2 antibodies, endomysium and if available anti-TG6 antibodies (IgG and IgA). Patients positive for any of these antibodies and no alternative cause for their ataxia should undergo gastroscopy and duodenal biopsy to establish the presence of enteropathy. To some degree, this can be predicted on the basis of the presence of TG2 and/or EMA antibodies. Irrespective of the presence of enteropathy, all patients should be offered dietary advice for a strict gluten-free diet, with regular follow-up to ensure that the antibodies are 96.3 Clinical Characteristics and Treatment eliminated (can take up to a year assuming the diet is strict). Stabilization or improvement of the ataxia at 1 year, often GA usually presents with pure cerebellar ataxia, sometimes associated with improvement of the spectroscopic measureassociated with peripheral neuropathy (both length-­ ment on MR spectroscopy of the vermis (increased NAA/Cr dependent axonal sensorimotor neuropathy but also sensory ratio), would be a strong indicator that the patient should ganglionopathy). Rarely, it can present with ataxia in continue on a gluten-free diet for life (Hadjivassiliou et al. ­combination with myoclonus (Sarrigiannis et al. 2014). The 2017). The commonest reason for the lack of response is myoclonus has been shown to be of cortical origin. GA is poor compliance with the gluten-free diet. If patients are usually of insidious onset with a mean age at an onset of indeed strict with their gluten-­free diet yet continue to prog53 years. However, it can present acutely and follow a rap- ress the use of immunosuppressive medication should be idly progressive course mimicking paraneoplastic cerebellar considered (usually mycophenolate). degeneration (Newrick et  al. 2021). All patients with GA have gait ataxia and the majority have limb ataxia. The universal presence of gait ataxia reflects the fact that cerebellar 96.4 Pathophysiology vermian involvement is the norm both in GA but also in other immune-mediated ataxias. Gastrointestinal symptoms are The pathophysiology of GA has an autoimmune basis. In not very prominent even in those patients who are found to 1997, TG2 was identified as the autoantigen in CD (Dieterich have an enteropathy after duodenal biopsy (representing et al. 1997). TG2 belongs to a family of enzymes involved in about a third of all GA patients). tissue repair. They have the ability to cross-link or modify Up to 60% of patients (depending on the time of diagnosis proteins, particularly those that are glutamine-rich. The and duration of ataxia) have evidence of cerebellar atrophy deamidation of gluten peptides results in the production of on MR imaging and all of them have abnormal MR spectros- immunogenic peptides that enhance binding with disease-­ copy of the vermis with low NAA/Cr ratio (Hadjivassiliou relevant human leukocyte antigens leading to the developet al. 2017). ment of gluten-specific T cells. During the process of

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deamidation, TG2 may bind onto gluten peptides and induce an immunological response that involves B cells and the production of self-antibodies such as TG2 antibodies. The role of B cells is more than the production of antibodies and includes antigen presentation to T cells. Variations in the specificity of antibodies produced in individual patients may explain the wide spectrum of manifestations seen in gluten-­related disorders. For example TG3, an epidermal transglutaminase has been shown to be the autoantigen in dermatitis herpetiformis (Sárdy et al. 2002). More relevant to GA is the identification of TG6, a brain expressed transglutaminase as the autoantigen in GA (Hadjivassiliou et al. 2008). An immune response directed against transglutaminase TG6 may be responsible for cerebellar damage. The IgA deposition in brain vessels and the pathological finding of perivascular cuffing with inflammatory cells (postmortem tissue from patients with GA) implies a vasculature-centered inflammation that can compromise blood–brain barrier allowing the exposure to pathogenic antibodies that trigger neural injury (Hadjivassiliou et al. 2006; Rouvroye et al. 2020). Indeed, there is evidence of cross-reactivity of TG6 and other gluten-related antibodies with neural tissue as well as evidence of induction of ataxia in mice using serum from patients with GA (Boscolo et  al. 2010).

96.5 Conclusions Gluten ataxia is the commonest immune ataxia and the one most often underdiagnosed. The presence of enteropathy (Coeliac Disease) is not a prerequisite for the diagnosis of GA. Serological screening has to include native antigliadin antibodies and if available TG6 antibodies. Serological tests that are specific to CD are not sufficient to exclude GA. Making an early diagnosis is essential as this condition is treatable with strict gluten-free diet. Close monitoring is, however, also essential to ensure that the adherence to gluten-­ free diet is indeed very strict. This can be confirmed with repeat serological testing.

References Boscolo S, Lorenzon A, Sblattero D, Florian F, Stabel M, Marzari R, Not T, Aeschlimann D, Ventura A, Hadjivassiliou M, Tongiorgi E (2010) Anti transglutaminase antibodies cause ataxia in mice. PLoS One 5(3):e9698

647 Bürk K, Melms A, Schulz JB, Dichgans J (2001) Effectiveness of intravenous immunoglobulin therapy in cerebellar ataxia associated with gluten sensitivity. Ann Neurol 50:827–828 Cooke WT, Thomas-Smith W (1966) Neurological disorders associated with adult coeliac disease. Brain 89:683–722 Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D (1997) Identification of tissue transglutaminase as the autoantigen of coeliac disease. Nat Med 3(7):797–801 Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo AJ, Stephenson TJ, Milford-Ward A (1996) Does cryptic gluten sensitivity play a part in neurological illness? Lancet 347:369–371 Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, Davies-Jones GAB, Gibson A, Jarratt JA, Kandler RH, Lobo A, Powell T, Smith CML (1998) Clinical, radiological, neurophysiological and neuropathological characteristics of gluten ataxia. Lancet 352:1582–1585 Hadjivassiliou M, Davies-Jones GAB, Sanders DS, Grünewald RAG (2003) Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry 74(9):1221–1224 Hadjivassiliou M, Maki M, Sanders DS, Williamson C, Grunewald RA, Woodroofe N, Korponay-Szabo I (2006) Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology 66:373–377 Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D (2008) Autoantibodies in gluten ataxia recognise a novel neuronal transglutaminase. Ann Neurol 64:332–343 Hadjivassiliou M, Sanders DS, Grunewald RA, Woodroofe N, Boscolo S, Aeschlimann D (2010) Gluten sensitivity: from gut to brain. Lancet Neurol 9:318–330 Hadjivassiliou M, Aeschlimann P, Sanders DS, Maki M, Kaukinen K, Grunewlad RA, Bandmann O, Woodroofe N, Haddock G, Aeschlimann DP (2013) Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology 80:1–6 Hadjivassiliou M, Martindale J, Shanmugarajah P, Grunewald RA, Sarrigiannis PG, Beauchamp N, Garrard K, Warburton R, Sanders DS, Friend D, Duty S, Taylor J, Hoggard N (2016) Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/ jnnp-­2016-­314863 Hadjivassiliou M, Grunewald RA, Sanders DS, Shanmugarajah P, Hoggard N (2017) Effect of gluten-free diet on MR spectroscopy in gluten ataxia. Neurology 89:1–5 Lin C, Wang M, Tse W, Pinotti R, Alaedini A, Green PHR, Kuo S (2018) Serum antigliadin antibodies in cerebellar ataxias: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-­2018-­318215 Newrick L, Hoggard N, Hadjivassiliou M (2021) Recognition and management of rapid-onset gluten ataxias: case series. Cerebellum Ataxias. https://doi.org/10.1186/s40673-­021-­00139-­z Rouvroye MD, Zis P, Van-Dam A, Rozemuller AJM, Bouma G, Hadjivassiliou M (2020) The neuropathology of gluten-related neurological disorders: a systematic review. Nutrients 12:822 Sárdy M, Kárpáti S, Merkl B, Paulsson M, Smyth N (2002) Epidermal transglutaminase (TGase3) is the autoantigen of dermatitis herpetiformis. J Exp Med 195:747–757 Sarrigiannis PG, Hoggard N, Aeschlimann D, Sandres DS, Grunewlad RA, Unwin ZC, Hadjivassiliou M (2014) Myoclonus ataxia and refractory coeliac disease. Cerebellum Ataxias. https://doi. org/10.1186/2053-­8871-­1-­11

Cerebrotendinous Xanthomatosis

97

Evelien Hendriks, Bianca M. L. Stelten, and Aad Verrips

Abstract

Cerebrotendinous xanthomatosis (CTX) is a treatable, rare autosomal recessively inherited inborn error of the bile acid metabolism, with more than 300 described patients worldwide. Sterol 27-hydroxylase (CYP27) deficiency, caused by mutations in the CYP27A1 gene, leads to cholestanol accumulation in multiple tissues of the body, including the nervous system. Main clinical features include chronic diarrhea, tendon xanthomas, premature cataracts, and neuropsychiatric impairment. The degree of disability ranges from nearly asymptomatic in early childhood to severe disability at older age. Due to clinical heterogeneity, diagnosing CTX can be challenging. Diagnostic delay and initial misdiagnosis are of frequent occurrence, particularly in the absence of tendon xanthomas. Early treatment and therefore early diagnosis are essential, for cholestanol levels to be normalized with chenodeoxycholic acid (CDCA) and disease progression to be stabilized, preventing progression of the disease and disability. Therapy initiation in adults with more advanced impairment seems to have lower favorable impact. In patients with neurological symptoms as ataxia, spasticity, parkinsonism, and early-onset dementia, and in patients with premature cataract, CTX needs to be considered. Serum cholestanol levels of untreated CTX patients are raised, and urine examination reveals abnormal bile alcohols. Brain MR imaging of CTX patients show a broad variety of findings, of which cerebellar signal abnormalities, specifically at the dentate nucleus, are the most characteristic. Furthermore, genetic analysis can detect E. Hendriks · A. Verrips (*) Department of Neurology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands e-mail: [email protected]; [email protected] B. M. L. Stelten Department of Neurology, Catharina Hospital, Eindhoven, The Netherlands e-mail: [email protected]

pathogenic mutations in the CYP27A1 gene. There is no genotype-phenotype correlation; on the contrary, there is a broad intrafamilial phenotypic diversity in most affected families. Neonatal screening is a promising diagnostic tool in the near future. Keywords

Cerebrotendinous xanthomatosis · CYP27A1 · Bile acid synthesis · Chenodeoxycholic acid · Diagnosis and management

97.1 Introduction Worldwide, over 300 CTX patients have been reported since Van Bogaert et  al. described the first patient in 1937 (Van Bogaert et al. 1937). The estimated prevalence of CTX is 3–5 per 100,000 (Lorincz et al. 2005). Early diagnosis is essential because by early initiation of treatment severe neurological deterioration can be prevented.

97.2 Clinical Description in Children During neonatal age, cholestasis can be the first clinical manifestation of CTX. In a Dutch cohort including 26 families with a total of 50 CTX patients, six of nine well-described neonatal cases showed an extended period of self-limiting (cholestatic) neonatal jaundice (Clayton et  al. 2002). However, some neonatal patients develop severe cholestasis (giant cell hepatitis). Cholestatic CTX is usually underestimated, but it could be severe or even fatal in infancy (Zhang et al. 2021). Chronic diarrhea is one of the earliest and main symptoms of CTX (Brass et al. 2020). Premature cataracts can be present in the first decade of life (Cruysberg et  al. 1995). Pediatricians should be aware of the diagnostic possibility of cerebrotendinous xanthomatosis in children presenting with chronic diarrhea and juvenile cataracts (Berginer

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_97

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et  al. 2009). During early school age, children with CTX may develop learning difficulties and behavioral abnormalities. Autism spectrum disorder is an early and probably underestimated frequent feature in CTX (Stelten et al. 2018). During the second decade, other neurological symptoms and signs become apparent (van Heijst et  al. 1998). Newborn screening for CTX is probably the solution for early identification and treatment (DeBarber et al. 2018; Vaz et al. 2017). Because it is still not known what the relationship is between the biochemical profile, variants in the CYP27A1 gene and the natural disease course, the timing of therapeutic intervention is difficult (Hollak 2021).

97.3 Clinical Description in Adults The development of a neuropsychiatric disorder is the clinical hallmark in adults with CTX. Possible neurological findings include cerebellar and pyramidal signs, epilepsy, cognitive impairment, and axonal polyneuropathy (Verrips et al. 2000a, b). Hallucinations, mood disorders, dementia, agitation, and aggression are possible occurring psychiatric findings (Berginer et al. 1988b; Guyant-Maréchal et al. 2005). Tendon xanthomas were absent in nearly two-thirds of the investigated Dutch adult group (Verrips et al. 2000a). Particularly in the absence of tendon xanthomas, misdiagnosis is not uncommon due to the abovementioned non-specific clinical features (Fig. 97.1). Spinal xanthomatosis is both a clinical and radiological CTX variant in which a (primarily) spinal cord syndrome is the only clinical sign for many years, with a slowly progressive course (Bartholdi et  al. 2004; Verrips et  al. 1999a). Tachylalia, meaning an increased velocity of speech, is reported in CTX patients aged 20–40 years. The pathophysiology of tachylalia is unknown (Verrips et  al. 1998). If premature cataracts and neurological disorders such as ataxia, spasticity, parkinsonism, and early-onset dementia are present, CTX should be taken into consideration (Su et al. 2010). Complaints of chronic diarrhea should be checked during history taking. Accurate inspection, especially of the Achilles tendons, in order to detect the presence of xanthomas is essential during the examination. If untreated, the progression of symptoms occurs in most patients resulting in further deterioration. Increase of neuropsychiatric symptoms can lead to acute decompensation with acute psychosis and even attempted suicide. Furthermore, premature atherosclerosis is more common and patients have an increased risk of acute myocardial infarction (Passaseo et al. 2012).

Fig. 97.1  Large tendon xanthoma in a 50-year-old male patient with CTX

97.4 Normal Bile Acid Synthesis Figure 97.2 shows the normal hepatic bile acid synthesis in black. The rate of bile acid synthesis is limited by the enzyme 7α-hydroxylase. Inside the hepatic mitochondria, the 27- hydroxylation of cholesterol is accomplished by two main pathways (Javitt 1994). The first is the auxiliary (classic) pathway: in this exclusive hepatic pathway, sterol 27-­ hydroxylase (CYP27) metabolizes ­5β-cholestane-3α,7α-­diol into cholic and chenodeoxycholic acid. The second is the acidic (alternative) pathway in which CYP27 metabolizes both extrahepatic and hepatic cholesterol immediately into 27-hydroxycholesterol (Javitt 1994). Because 27-hydroxycholesterol downregulates the activity of β-HMG CoA by inducing negative feedback on the activity of this rating enzyme in the synthesis of cholesterol and because of the great quantity of extrahepatic metabolization, the acidic pathway probably is the most significant pathway concerning bile acid synthesis. In the elimination of human intracellular cholestanol, the acidic pathway is considered as a crucial oxidative mechanism (Duane and Javitt 1999).

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97  Cerebrotendinous Xanthomatosis

AUXILIARY PATHWAY

3-hydroxy-3-methyl-glutaryl-CoA 3-hydroxy-3-methylglutaryl-CoA reductase

CEREBROTENDINOUS XANTHOMATOSIS Mevalonic acid

ACIDIC PATHWAY

CHOLESTANOL Cholesterol 7α-hydroxylase

ABNORMAL BILE ACIDS

7α-hydroxycholesterol

23-nor cholic acid 23-hydroxy cholic acid

7α-hydroxy-4-cholesten-3-one

7α, 12α-dihydroxy-4-cholesten-3-one

5β -cholestane-3α,7α,12α-23 (R) 25-pentol 5β -cholestane-3α,7α,12α-24 (R) 25-pentol

BILE ALCOHOLS 5β -cholestane-3α,7α,12α-triol

BILE ALCOHOL EXCRETION IN URINE

5β -cholestane-3α,7α,12α-25-tetrol

5β -cholestane-3α,7α,12α-24 (S) 25-pentol

5 -cholestane-3α,7α-diol 27-hydroxylase

7α,27-dihydroxy-4-cholesten-3-one

COLESTANOL ACCUMULATION IN TISSUE

27-hydroxylase

5β -cholestane-3α,7α,27-triol

5β -cholestane-3α,7α,12α,27-tetrol

27-hydroxycholesterol 3α-7α-dihydroxy-5β -cholestanoic acid3α,7α.12α-trihydroxy -5β - cholestanoic acid

Chenodeoxycholic acid

Cholic acid

PRIMARY BILE ACIDS

Fig. 97.2  Metabolic pathway

97.5 Bile Acid Synthesis in CTX Figure 97.2 shows the biochemical disorders in CTX in red. Usually cholestanol production, via cholesterol and 4-­cholesten-3-one, provides only small amounts of cholestanol. In patients with CTX, excessive amounts of cholestanol are produced due to deficiency of CYP27. The absence of chenodeoxycholic acid causes a lack of feedback on 7α-hydroxylase, resulting in the conversion of cholesterol into cholestanol (Björkhem et al. 2001). In patients with CTX, the conversion of cholesterol into cholestanol, primarily through the 7α-hydroxycholesterol pathway, takes place in the liver. Approximately, 80% of the surplus of cholestanol is synthesized by a series of conversions of different metabolites (7α-hydroxycholesterol into 7α-hydroxy-4-­cholesten-3-one, into cholesta-4,6-dien-3-one and eventually via 4-cholesten3-one into cholestanol). The absence of negative feedback caused by a lack of 27-hydroxylated products leads to an increased activity of β-HMG CoA reductase, resulting in increased cholesterol synthesis (Björkhem et al. 2001). In CTX, bile alcohols are produced: 5β-cholestane-­3α,7α,12α,25-tetrol (foremost), 5β-cholestane-3α,7α,12α,24-­tetrol,23,25-pentol, 5β-cholestane-3α,7α,12α and 5β-cholestane-3α,7α,12α,24,25-

pentol. Small amounts of cholic acid and abnormal bile acids (23-hydroxycholic acid, 23-norcholic acid) are produced via the 24- and 25-­hydroxylation pathways. Cholestanol enters the circulation via the entero-hepatic-loop through excretion in bile and resorption in the terminal ileum. An unknown mechanism is responsible for the accumulation of cholestanol and cholesterol in various tissues, particularly in the central nervous system, muscle tendons, and the eye lenses (Panzenboeck et al. 2007). Not only cholestanol but also bile alcohols follow the enterohepatic-loop. These bile alcohols are excreted in urine after glucuronidation.

97.6 Investigations 97.6.1 Diagnostic Tests To diagnose CTX, the following tests can be used: increased serum cholestanol levels can be demonstrated using gas chromatography–mass spectrometry, and mass spectrometry can detect elevated urinary excretion and increased serum levels of bile alcohols. The most specific test is the genetic analysis which can identify pathogenic mutations in the CYP27A1 gene.

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97.6.2 Other Investigations In brain magnetic resonance imaging (MRI), cerebellar and cerebral atrophy are common non-specific findings in the early stages of the disease. Typical findings in more advanced stages contain symmetrical high signal lesions in the deep cerebellar white matter and in the globus pallidus on T2-weighted MRI, with low signal dentate nucleus lesions (Fig. 97.3) (Barkhof et al. 2000). The most constant radiological characteristics are the cerebellar white matter lesions in and around the dentate nuclei (De Stefano et  al. 2001). The lesions are frequently stable over time (Berginer et al. 1994). Signs and symptoms, biochemical findings, and MRI findings are not correlated to each other (Dotti et al. 1994). Extensive, vague described bands of increased T2-weighted signal limited to the dorsal and lateral columns of the spinal cord can be found on MRI concerning patients with spinal xanthomatosis (Verrips et al. 1999a). Depicting tendon xanthomas on T1-weighted MRI images may reveal an intermediate intensity similar to muscle tissue. T2-weighted MRI images show an intermediate to high intensity with an irregu-

E. Hendriks et al.

lar aspect (Barkhof et  al. 2000). Electroencephalography (EEG) before initiation of therapy in patients with CTX shows abnormalities that indicate a metabolic encephalopathy. This may be accompanied with or without epileptic seizures (Van Heijst et al. 1998). Electromyography (EMG) can detect a neuropathy which is mainly axonal in patients with CTX (Verrips et al. 2000c).

97.7 Management If untreated, CTX is progressive. CTX can be treated with oral chenodeoxycholic acid (CDCA) in a dosage of 250 mg three times daily in adult patients (Berginer et al. 1984). A statine can be added to reduce the serum cholestanol level even further (Verrips et al. 1999b). In children, CDCA dose is 5–15 mg/kg/day. Treatment is less beneficial if it is initiated during the more severe stages of CTX.  Patients diagnosed and treated before the age of 24  years have a significantly better outcome at follow-up. The majority of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symptoms, with parkinsonism as a treatment-resistant feature (Stelten et al. 2019a, b; Verrips et al. 2020). Monitoring of serum creatine kinase and transaminases is required once every 2 months during the first 6 months of treatment. Monitoring of serum cholestanol and bile alcohol excretion in urine is required once every 6 months during the first 2 years of treatment, and afterward once a year. In patients with CTX ursodeoxycholic acid is contra-indicated, because the negative feedback on 7α-hydroxylase remains unrecovered causing uninhibited production of deleterious metabolites including cholestanol (Koopman et al. 1984; Koopman et al. 1985; Verrips et al. 2009).

97.7.1 Pregnancy

Fig. 97.3  T2-weighted MRI of a 53-year-old male patient with CTX showing the typical symmetrical low signal lesions in the dentate nucleus, and the high signal lesions in the deep cerebellar white matter on T2-weighted MRI

It is unknown to date whether or not pregnancy in CTX patients brings an increased risk for the (unborn) child. Berginer et  al. investigated children of CTX patients. Eighteen children born of nine females with CTX were described. Twelve of these children seemed unaffected. Mental retardation was found in 2 out of 18 children. There was no available information on the remaining four children. Eleven children of seven males with CTX seemed unaffected (Berginer et al. 1988a). Clayton et al. studied the histories of 44 affected families and found four cases of fetal death in siblings of CTX patients (Clayton et al. 2002). During pregnancy, CDCA treatment is contraindicated due to potential teratogenicity (Iser and Sali 1981).

97  Cerebrotendinous Xanthomatosis

97.7.2 Neonatal Period In infants with CTX with CDCA supplementation at a dosage of 5  mg/kg/day is well tolerated. CDCA supplementation at 15  mg/kg/day seems hepatotoxic in infants (Huidekoper et al. 2016).

97.7.3 Recommendations Since CTX is treatable and early initiation of therapy is crucial, all patients with two of four characteristic findings of CTX (tendon xanthomas, persistent diarrhea, premature cataracts, and progressive neurological symptoms) should rapidly undergo thorough metabolic examination, which can easily and accurately determine the biochemical diagnosis. Metabolic screening of all siblings is recommended since affected relatives are possibly asymptomatic and because CTX has a broad phenotypic heterogeneity occurring within families.

References Barkhof F, Verrips A, Wesseling P, van Der Knaap MS, van Engelen BG, Gabreëls FJ, Keyser A, Wevers RA, Valk J (2000) Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 217(3):869–876 Bartholdi D, Zumsteg D, Verrips A, Wevers RA, Sistermans E, Hess K, Jung HH (2004) Spinal phenotype of cerebrotendinous xanthomatosis—a pitfall in the diagnosis of multiple sclerosis. J Neurol 251(1):105–107 Berginer VM, Salen G, Shefer S (1984) Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 311(26):1649–1652 Berginer VM, Carmi R, Salen G (1988a) Pregnancy in women with cerebrotendinous xanthomatosis (CTX): high risk condition for fetus and newborn infant? Am J Med Genet 31(1):11–16 Berginer VM, Foster NL, Sadowsky M, Townsend JA 3rd, Siegel GJ, Salen G (1988b) Psychiatric disorders in patients with cerebrotendinous xanthomatosis. Am J Psychiatry 145(3):354–357 Berginer VM, Berginer J, Korczyn AD, Tadmor R (1994) Magnetic resonance imaging in cerebrotendinous xanthomatosis: a prospective clinical and neuroradiological study. J Neurol Sci 122(1):102–108 Berginer VM, Gross B, Morad K, Kfir N, Morkos S, Aaref S, Falik-­ Zaccai TC (2009) Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat. Pediatrics 123(1):143–147 Björkhem I, Boberg KM, Leitersdorf E (2001) In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2961–2988 Brass EP, Stelten BML, Verrips A (2020) Cerebrotendinous xanthomatosis-­associated diarrhea and response to chenodeoxycholic acid treatment. JIMD Rep 56(1):105–111 Clayton PT, Verrips A, Sistermans E, Mann A, Mieli-Vergani G, Wevers R (2002) Mutations in the sterol 27-hydroxylase gene (CYP27A) cause hepatitis of infancy as well as cerebrotendinous xanthomatosis. J Inherit Metab Dis 25(6):501–513 Cruysberg JR, Wevers RA, van Engelen BG, Pinckers A, van Spreeken A, Tolboom JJ (1995) Ocular and systemic manifes-

653 tations of cerebrotendinous xanthomatosis. Am J Ophthalmol 120(5):597–604 De Stefano N, Dotti MT, Mortilla M, Federico A (2001) Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis. Brain 24(1):121–131 DeBarber AE, Kalfon L, Fedida A, Fleisher Sheffer V, Ben Haroush S, Chasnyk N, Shuster Biton E, Mandel H, Jeffries K, Shinwell ES, Falik-Zaccai TC (2018) Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment. J Lipid Res 59(11):2214–2222 Dotti MT, Federico A, Signorini E, Caputo N, Venturi C, Filosomi G, Guazzi GC (1994) Cerebrotendinous xanthomatosis (van Bogaert-­ Scherer-­ Epstein disease): CT and MR findings. AJNR Am J Neuroradiol 15(9):1721–1726 Duane WC, Javitt NB (1999) 27-hydroxycholesterol: production rates in normal human subjects. J Lipid Res 40(7):1194–1199 Guyant-Maréchal L, Verrips A, Girard C, Wevers RA, Zijlstra F, Sistermans E, Vera P, Campion D, Hannequin D (2005) Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype. Am J Med Genet A 139A(2):114–117 Hollak CEM (2021) Expanding the clinical spectrum of cerebrotendinous xanthomatosis: implications for newborn screening, follow-up and treatment. J Intern Med. https://doi.org/10.1111/joim.13276. Epub ahead of print Huidekoper HH, Vaz FM, Verrips A, Bosch AM (2016) Hepatotoxicity due to chenodeoxycholic acid supplementation in an infant with cerebrotendinous xanthomatosis: implications for treatment. Eur J Pediatr 175(1):143–146 Iser JH, Sali A (1981) Chenodeoxycholic acid: a review of its pharmacological properties and therapeutic use. Drugs 21(2):90–119 Javitt NB (1994) Bile acid synthesis from cholesterol: regulatory and auxiliary pathways. FASEB J 8(15):1308–1311 Koopman BJ, Wolthers BG, van der Molen JC, Nagel GT, Waterreus RJ, Oosterhuis HJ (1984) Capillary gas chromatographic determinations of urinary bile acids and bile alcohols in CTX patients proving the ineffectivity of ursodeoxycholic acid treatment. Clin Chim Acta 142(1):103–111 Koopman BJ, Wolthers BG, van der Molen JC, Waterreus RJ. Bile acid therapies applied to patients suffering from cerebrotendinous xanthomatosis. Clin Chim Acta 1985;152(1–2):115–122 Lorincz MT, Rainier S, Thomas D, Fink JK (2005) Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized. Arch Neurol 62(9):1459–1463 Panzenboeck U, Andersson U, Hansson M, Sattler W, Meaney S, Björkhem I (2007) On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis. J Lipid Res 48(5):1167–1174 Passaseo I, Cacciotti L, Pauselli L, Ansalone G (2012) Acute myocardial infarction in patient with cerebrotendinous xanthomatosis: should these patients undergo stress tests during screening? J Cardiovasc Med (Hagerstown) 13(4):281–283 Stelten BML, Bonnot O, Huidekoper HH, van Spronsen J, van Hasselt PM, Kluijtmans LAJ, Wevers RA, Verrips A (2018) Autism spectrum disorder: an early and frequent feature in cerebrotendinous xanthomatosis. J Inherit Metab Dis 41:641–646 Stelten BML, Huidekoper HH, van de Warrenburg BPC, Brilstra EH, Hollak CEM, Haak HR, Kluijtmans LAJ, Wevers RA, Verrips A (2019a) Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start. Neurology 92(2):e83–e95 Stelten BML, van de Warrenburg BPC, Wevers RA, Verrips A (2019b) Movement disorders in cerebrotendinous xanthomatosis. Parkinsonism Relat Disord 58:12–16 Su CS, Chang WN, Huang SH, Lui CC, Pan TL, Lu CH, Chuang YC, Huang CR, Tsai NW, Hsieh MJ, Chang CC (2010) Cerebrotendinous xanthomatosis patients with and without parkinsonism: clinical characteristics and neuroimaging findings. Mov Disord 25(4):452–458

654 Van Bogaert L, Scherer H, Epstein E (1937) Une Forme Cérébrale de la Cholestérinose Généralisée. Masson et Cie, Paris Van Heijst AF, Verrips A, Wevers RA, Cruysberg JR, Renier WO, Tolboom JJ (1998) Treatment and follow-up of children with cerebrotendinous xanthomatosis. Eur J Pediatr 157(4):313–316 Vaz FM, Bootsma AH, Kulik W, Verrips A, Wevers RA, Schielen PC, DeBarber AE, Huidekoper HH (2017) A newborn screening method for cerebrotendinous xanthomatosis using bile alcohol glucuronides and metabolite ratios. J Lipid Res 58(5):1002–1007 Verrips A, Van Engelen B, de Swart B (1998) Increased speech rate (tachylalia) in cerebrotendinous xanthomatosis: a new sign. J Med Speech Lang Pathol 6:161–164 Verrips A, Nijeholt GJ, Barkhof F, Van Engelen BG, Wesseling P, Luyten JA, Wevers RA, Stam J, Wokke JH, van den Heuvel LP, Keyser A, Gabreëls FJ (1999a) Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis. Brain 122(8):1589–1595 Verrips A, Wevers RA, Van Engelen BG, Keyser A, Wolthers BG, Barkhof F, Stalenhoef A, De Graaf R, Janssen-Zijlstra F, Van Spreeken A, Gabreëls FJ (1999b) Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. Metabolism 48(2):233–238 Verrips A, van Engelen BG, Wevers RA, van Geel BM, Cruysberg JR, van den Heuvel LP, Keyser A, Gabreëls FJ (2000a) Presence of diar-

E. Hendriks et al. rhea and absence of tendon xanthomas in patients with cerebrotendinous xanthomatosis. Arch Neurol 57(4):520–524 Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreëls FJ, van Engelen BG, van den Heuvel LP (2000b) Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 123(5):908–919 Verrips A, van Engelen BG, ter Laak H, Gabreëls-Festen A, Janssen A, Zwarts M, Wevers RA, Gabreëls FJ (2000c) Cerebrotendinous xanthomatosis. Controversies about nerve and muscle: observations in ten patients. Neuromuscul Disord 10(6):407–414 Verrips A, Wevers RA, van Spronsen FJ, Sikkens H (2009) [The right medicine for cerebrotendinous xanthomatosis]. Ned Tijdschr Geneeskd 153(15):726–727 (Dutch) Verrips A, Dotti MT, Mignarri A, Stelten BML, Verma S, Federico A (2020) The safety and effectiveness of chenodeoxycholic acid treatment in patients with cerebrotendinous xanthomatosis: two retrospective cohort studies. Neurol Sci 41:943–949 Zhang P, Zhao J, Peng XM, Qian YY, Zhao XM, Zhou WH, Wang JS, Wu BB, Wang HJ (2021) Cholestasis as a dominating symptom of patients with CYP27A1 mutations: an analysis of 17 Chinese infants. J Clin Lipidol 15(1):116–123

Cerebellar Variant of Multiple System Atrophy (MSA-C)

98

Marios Hadjivassiliou

Abstract

Neurodegeneration refers to the progressive loss of structure and function including neuronal cell death. Neurodegenerative diseases are usually incurable and often present late in life because the greatest risk factor for neurodegeneration is aging. Neurodegeneration in the context of cerebellar ataxias is best exemplified by the cerebellar variant of multiple system atrophy (MSA-C). This is a rare but progressive disease, usually presenting in the early 50s with a combination of cerebellar ataxia and autonomic dysfunction. It is responsible for 8.5% of all ataxias. By definition, MSA-C presents with cerebellar symptoms and signs but in some cases, there is overlap with the Parkinsonian variant of MSA (MSA-P) where rigidity, bradykinesia, and other Parkinsonian features predominate. Although the pathology of MSA has been delineated, the etiology remains obscure and the disease remains untreatable leading to severe disability and premature death. Symptomatic support by a multidisciplinary team is important in the management of these patients.

mind: the term sporadic Olivo-Ponto-Cerebellar Atrophy (OPCA) was first introduced in 1900 (Dejerine and Thomas 1900) to describe the pathological features at PM of atrophy of the olives, pons, and cerebellum (which is the case in MSA-C). When similar clinical features were observed in some familial cases, the term familial OPCA was introduced. However, much later, it would be shown that, in fact, these familial OPCA cases were genetic ataxias due to mutations causing spinocerebellar ataxias type 1, 2, or 3 (SCA1,2,3). In 1960 another publication (Shy and Drager 1960) described two patients with progressive autonomic dysfunction causing orthostatic hypotension, and urinary and sexual dysfunction who also developed Parkinsonian features. Such cases were labeled as having Shy–Drager syndrome. In 1972, the term multiple system atrophy was introduced to describe these patients (Bannister and Oppenheimer 1972). The discovery of oligodendroglial cytoplasmic inclusion bodies in both the cerebellar and the Parkinsonian types of MSA provided conclusive evidence that OPCA and striatonigral degeneration (Shy-Drager Syndrome) are in fact the same disease entity. The terms MSA-C and MSA-P were then introduced to describe the two main phenotypes.

Keywords

Multiple system atrophy · Neurodegeneration · Cerebellar ataxia · Autonomic dysfunction

98.1 Introduction Among progressive cerebellar ataxias, MSA-C stands out because of the rapidity of progression, early speech involvement, autonomic dysfunction, and significant disability. The historical evolution of this disease entity is worth bearing in M. Hadjivassiliou (*) Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust and University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK e-mail: [email protected]

98.2 Prevalence Among a cohort of 1500 patients with progressive ataxias studied in Sheffield, UK, MSA-C accounted for 8.5% of all ataxias and 10% of sporadic ataxias (Hadjivassiliou et  al. 2016). Epidemiological studies have shown a point prevalence ranging of 3.4–4.9 per 100,000 population, increasing to 7.8 among the over 40 years of age (Schrag et al. 1999). While MSA-P cases are said to outnumber MSA-C cases by between 2:1 and 4:1, one has to be cautious about such calculations because of the way that these groups of patients are followed up. Patients with MSA-P tend to be followed up in well-established movement disorders clinics at regional neurology centers, at least in the UK. In such clinics, the majority of patients will have mainly idiopathic Parkinson’s

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_98

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disease and similar conditions including MSA-P.  MSA-C patients who present with ataxia are less likely to be seen in such clinics and are often diagnosed with progressive ataxia and discharged to the local services. Of interest is the observation that MSA-C is by far commoner than MSA-P in Japan. Such a difference may be down to the way the neurological services are configured in Japan or may be genuine.

98.3 Clinical Characteristics Patients with MSA-C, by definition, present with cerebellar ataxia. At the time of presentation, such patients may already have features suggestive of autonomic involvement including orthostatic hypotension, urinary frequency, urgency or incontinence, constipation, erectile dysfunction, and sleep disorders (e.g., REM sleep disorder). One or more of these additional autonomic features may develop at a later date or may even precede the development of cerebellar dysfunction, sometimes by years. Early speech involvement in the form of cerebellar dysarthria is characteristic. Some degree of Parkinsonian features may also be present including rigidity and bradykinesia with stooping and slowness in walking. Subtle myoclonus affecting the fingers may also be present, sometimes referred to as poly-mini myoclonus. Broken pursuit on examination of eye movements is common but gaze evoked nystagmus much less so. Generalized hyperreflexia and even extensor plantars may be present. Aside the broad-­based gait and falls due to gait ataxia, patients with MSA-C may also develop anterocollis and less likely other forms of dystonia. Respiratory disturbance is also common and takes the form of inspiratory stridor, sleep apnea, and REM sleep disorder. While patients with MSA-C do not develop cognitive decline and dementia, emotional incontinence can be seen and manifests with inappropriate laughing or crying (Fanciulli and Wenning 2015).

98.4 Diagnosis For the experienced clinician and ataxologist, the diagnosis of MSA-C is usually suspected by the additional presence of autonomic features, early speech involvement, and rapidity of progression. The diagnosis can also be supported by brain imaging that may demonstrate the characteristic pattern of brainstem involvement resulting in the hot-cross bun sign. This sign is not pathognomonic of MSA-C and can be seen in SCA2 and paraneoplastic cerebellar degeneration. However, in the correct clinical context, it can be very helpful in consolidating the suspected diagnosis. It is also worth mentioning that this sign tends to develop later on in the disease course and may not be present at the presentation. MR spectroscopy of the cerebellum can be a very useful tool in the diagnosis of MSA-C at presentation. The NAA/Cr ratio

measured from the vermis and the hemisphere tends to show very low values even at the early stages of the disease (Kadodwala et  al. 2019). Attempts to devise neuroimaging criteria for the diagnosis of MSA have been made (Brooks et al. 2009). Along the same lines, based on the clinical features, diagnostic criteria have been developed and attempt to define three degrees of certainty for the diagnosis: definite, probable, and possible MSA.  Definite diagnosis requires post-mortem evidence of widespread alpha-synuclein positive glial cytoplasmic inclusions with concomitant olivopontocerebellar atrophy (Trojanowski et  al. 2007). The first clinical criteria for the diagnosis of MSA were published in 1989 (Quinn 1989) followed by consensus criteria in 1998 and a revision of the consensus criteria in 2008. Of interest is the validity of these diagnostic criteria as assessed by a clinicopathological study (Osaki et al. 2009). In this study, it was shown that after the first visit, the sensitivity for possible and probable MSA was 41% and 18%, respectively, increasing to 92% and 63% at the last visit. This is entirely expected given the progressive nature of the condition and the accumulation of more clinical features that allow a more accurate clinical diagnosis. Some have argued that the division of MSA into MSA-P and MSA-C is somewhat artificial because of a substantial overlap between the 2. It was argued that approximately half of the MSA-P patients show additional cerebellar signs and as many as 75% of the MSA-C patients develop Parkinsonian features during the disease course (Stankovic et al. 2019). While this is true later on in the disease course, as far as patients are concerned, it is the correct diagnosis at presentation that counts. Making the correct diagnosis early is helpful in outlining the prognosis and the need to address the rapidly changing circumstances (inability to work, increasing disability, etc.), something that is best addressed by a multidisciplinary team.

98.5 Progression and Prognosis MSA-C is characterized by relentless worsening, sometimes with a rapid pace at the onset. The rapid progression may sometimes lead to investigations specifically looking for paraneoplastic or other immune-mediated ataxias which also tend to follow an acute/subacute course. Up to 50% of patients require walking aid within 3 years of symptom onset and 60% are wheelchair bound for 5  years (Fanciulli and Wenning 2015). The median time before the patient is bedridden is 6–8 years. Death is usually due to cardiac arrhythmia or disruption of the brain-stem cardiorespiratory drive (sudden death), pneumonia, and other sources of sepsis, ­particularly urinary sepsis leading to a more systemic infection. The early presence of autonomic failure is a negative prognostic factor. The course of the disease is very different from what is seen in other late-onset ataxias. For example, spinocerebellar ataxia type 6 (SCA6) is a relatively common

98  Cerebellar Variant of Multiple System Atrophy (MSA-C) Fig. 98.1  NAA/Cr ratio from the cerebellar vermis using MR spectroscopy is depicted on the vertical axis. The graph shows the decline of the NAA/Cr over time and compares MSA-C with spinocerebellar ataxia type 6. Note the very low NAA/Cr at baseline in the MSA-C group when compared to SCA6 and the rapid decline over time for the MSA-C group when compared to SCA6. There is a very good correlation between NA/Cr and the SARA (Scale for the Assessment and Rating of Ataxia) score

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late-­onset pure ataxia that, by comparison to MSA-C, follows a much more benign course and does not usually lead to early death. Figure 98.1 compares the changes in MR spectroscopy of the vermis in patients with SCA6 and patients with MSA-C over time. Apart of demonstrating the significantly lower NAA/Cr ratio from the cerebellum in MSA-C when compared to SCA6 at the time of presentation (a useful diagnostic tool), it also shows the rapid progression when comparing the two groups.

98.6 Pathogenesis

A linkage analysis study looking at some of the very rare cases of familial MSA in Japan identified mutations in the COQ2 gene. The enzyme encoded by the COQ2 gene is essential for the biosynthesis of Coenzyme Q10. Similar findings were reported in some sporadic cases of MSA. While the proportion of such mutation-positive patients is very small, this finding raised the possibility of a role of impaired COQ2 in the pathogenesis of MSA (Tsuji et al. 2013). It also opens the possibility of a potential treatment approach by using CoQ10 supplementation. There are ongoing studies looking at this approach. Several other treatment studies have been published using various different agents, none of which has reported any benefits.

As mentioned above, a definite diagnosis of MSA requires postmortem evidence of widespread alpha-synuclein-­ positive glial cytoplasmic inclusions with concomitant olivo- 98.7 Management pontocerebellar atrophy (Trojanowski et  al. 2007). The pathology, therefore, is well described. Relocalization of an As there is no treatment for this condition, the clinical manimportant stabilizer of myelin integrity called p25alpha into agement of patients with MSA-C is down to symptomatic the oligodendroglial precedes alpha-synuclein aggregation. treatment and support. This is best done in dedicated This seems to result in oligodendrocyte swelling and the MSA-C clinics with a multidisciplinary team of specialist overexpression of alpha-synuclein. The formation of glial ataxia/MSA nurses, physiotherapists, and occupational cytoplasmic inclusions interferes with neuronal support and therapists. Medication can be used for orthostatic hypotenactivates microglial cells. This, in turn, results in the release sion (fludrocortisone, midodrine, ephedrine), urinary of misfolded alpha-synuclein into the extracellular space. urgency and frequency (anticholinergics), sometimes Misfolded alpha-synuclein is taken up by neighboring neu- requiring intermittent self-catheterization, and emotional rons to form neuronal cytoplasmic inclusions (Fanciulli and lability (citalopram). For Parkinsonian symptoms (particuWenning 2015). The spreading of this process to other areas larly rigidity), levodopa may offer temporary benefit but of the brain ultimately leads to neuronal death in multiple this is not usually sustained. Botox injections can be used areas leading to the multisystem neuronal involvement. What for anterocollis particularly if this is associated with pain. leads to such pathology remains unclear. Equally unclear is The rapidity of progression means that these patients the reason as to why the same pathology can affect different require regular review and support because of their rapidly parts of the brain and thus result in two distinct (at least at the changing needs. This is why an early diagnosis is important for planning for the future. onset) clinical presentations of MSA-C or MSA-P.

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98.8 Conclusions MSA-C is a common cause of late-onset progressive cerebellar ataxia. The diagnosis is based on a combination of clinical and radiological findings. MSA-C should be considered as a fatal neurodegenerative ataxia associated with significant disability and as yet without any effective treatment. Despite this, close review and monitoring by a multidisciplinary team are essential in addressing the rapidly progressive needs of these patients. Symptomatic medication can be extremely helpful for issues like bladder instability and postural hypotension.

References Bannister R, Oppenheimer DR (1972) Degenerative diseases of the nervous system associated with autonomic failure. Brain 95:457–474 Brooks DJ, Seppi K, On behalf of the Neuroimaging Working Group on MSA (2009) Proposed neuroimaging criteria for the diagnosis of MSA. Mov Disord 24:949–964 Dejerine L, Thomas A (1900) L’atrophie olivo-ponto-cérébelleuse. Nouv iconog de la Salpêtrière 13:330 Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372:249–262 Hadjivassiliou M, Martindale J, Shanmugarajah P, Grunewald RA, Sarrigiannis PG, Beauchamp N, Garrard K, Warburton R, Sanders

M. Hadjivassiliou DS, Friend D, Duty S, Taylor J, Hoggard N (2016) Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/ jnnp-­2016-­314863 Kadodwala VH, Hadjivassiliou M, Currie S, Skipper N, Hoggard N (2019) Is H-MR spectroscopy useful as a diagnostic aid in MSA-C? Cerebellum Ataxias. https://doi.org/10.1186/s40673-­019-­0099-­0 Osaki Y, Ben-Shlomo Y, Lees A, Wenning G, Quinn N (2009) A validation exercise on the new consensus criteria for multiple system atrophy. Mov Disord 71:670–676 Quinn N (1989) Multiple system atrophy-the nature of the beast. J Neurol Neurosurg Psychiatry 52(Suppl):78–89 Schrag A, Ben-Shlomo Y, Quin NP (1999) Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 354:1771–1775 Shy GM, Drager GA (1960) A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. Arch Neurol 2:511–527 Stankovic I, Quinn N, Vignatelli L, Antonini A, Berg D, Coon E, et al, On behalf of the Movement Disorder Society Multi System Atrophy Study Group (2019) A critique of the second consensus criteria for multiple system atrophy. Mov Disord. https://doi.org/10.1002/ mds.27701 Trojanowski JQ, Revesz T, On behalf of the Neuropathology Working Group on MSA (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33:615 Tsuji S, On behalf of the Multiple-System Atrophy Research Collaboration (2013) Mutations in COQ@ in familial and sporadic Multiple-System Atrophy. N Engl J Med 369:233–244

99

Cerebellar Tumors Thomas Beez

Abstract

Cerebellar tumors can occur in the cerebellar parenchyma, mainly in the hemispheres, and in the fourth ventricle. It is the predominant location of brain tumors in children, but less common in adults. Typical signs and symptoms arise from raised intracranial pressure due to hydrocephalus, functional disruption of the cerebellum, and involvement of the brainstem. Conventional contrast-­ enhanced MRI is the gold standard of initial imaging. Tumor entities vary according to age: in children medulloblastoma, pilocytic astrocytoma and ependymoma are the most common tumors, whereas in adults, metastasis and hemangioblastoma are often found. Treatment is adjusted to the individual risk profile and modalities comprise neurosurgical resection, chemotherapy, and radiotherapy. The treatment-associated morbidity especially of neurosurgical approaches depends on tumor location: large midline tumors involving the fourth ventricle are associated with a higher rate of postoperative cerebellar mutism syndrome, one of the most severe neurological sequelae of cerebellar tumors. Keywords

Posterior fossa · Medulloblastoma · Pilocytic astrocytoma · Ependymoma · Metastasis Hemangioblastoma · Postoperative cerebellar mutism syndrome · Telovelar approach

T. Beez (*) Department of Neurosurgery, Medical Faculty, Heinrich-Heine-­University, Düsseldorf, Germany e-mail: [email protected]

99.1 Introduction Cerebellar tumors are a subgroup of posterior fossa tumors. They can be defined as intra-axial lesions, as they occur within the cerebellar parenchyma and/or the fourth ventricle, as opposed to extra-axial posterior fossa tumors located outside the cerebellum, for example, in the cerebellopontine angle. Signs and symptoms of cerebellar tumors can arise through several pathophysiological mechanisms: (1) local disruption of the cerebellar structure can lead to typical cerebellar symptoms, such as ataxia, gait disturbance, and dysmetria; (2) hydrocephalus can result from occlusion of the cerebrospinal fluid (CSF) pathways, mainly the cerebral aqueduct, fourth ventricle, and its outlets, leading to the typical hydrocephalic symptoms of headache, nausea, and vomiting; (3) compression or invasion of the brainstem can cause cranial nerve dysfunction or motor weakness. The diagnosis of a cerebellar tumor is established through neuroimaging, with conventional cranial magnetic resonance imaging (MRI) being the current gold standard (Poretti et al. 2012; Ramsewak et  al. 2013). The basic imaging protocol should include contrast-enhanced sequences, diffusion-­ weighted imaging (DWI), and fluid-attenuated inversion recovery (FLAIR) images. This protocol will provide anatomical and morphological information (tumor localization, infiltration versus displacement of surrounding structures, cystic versus solid tumor components) as well as information on tumor biology (surrogates of cellularity, pattern of contrast enhancement). MR spectroscopy can provide information on the presence and concentration of metabolites within tumor tissue, such as lactate, choline, creatine, N-acetylaspartate, and myoinositol. By identifying consistent patterns of tumor entities, an increase in diagnostic accuracy can be achieved when combined with basic MRI (Shiroishi et  al. 2015). Positron emission tomography (PET) can provide metabolic information by measuring the uptake of a radioactive tracer. In general, higher tracer uptake correlates with more aggres-

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sive disease (Zukotynski et al. 2014). This technique is also helpful in assessing adjuvant treatment response (Dunkl et al. 2015). Cranial computed tomography offers limited diagnostic value, exposes to ionizing radiation, and should thus be reserved for emergencies or specific additional questions, such as the presence of intratumoral calcification.

99.2 Cerebellar Tumors in Children Cerebellar tumors are the most common brain tumors in childhood, with the exception of a supratentorial predominance in infants. Overall, 60% of pediatric brain tumors are found in the cerebellum. In addition to the symptoms described above, it is noteworthy that, especially in cases of benign, slow-growing cerebellar tumors, there is a significant capacity for functional compensation, with only mild and unspecific symptoms being present for a prolonged period of time. Therefore, the duration of symptoms prior to diagnosis of a cerebellar tumor can be up to 3–5 months in children. The three most common tumor entities among pediatric cerebellar tumors are medulloblastoma, pilocytic astrocytoma, and ependymoma (Fig. 99.1). In addition to depicting tumor localization, morphology, and surrounding anatomy, the preoperative MRI can allow preoperative prediction of tumor type for these, three most common pediatric brain tumor entities mainly by analyzing signal intensity on DWI and apparent diffusion coefficient (ADC) maps (Rumboldt et al. 2006). For medulloblastoma, even the prediction of the molecular subgroup is possible to a certain degree by incorporating further radiological features into radiomics approaches (Perreault et al. 2014). Medulloblastomas (Fig. 99.1a) are malignant tumors considered as grade 4 tumors according to the four-tier World

T. Beez

Health Organization (WHO) classification of brain tumors (Louis et al. 2021). Molecular biology subdivides medulloblastoma into at least four molecular subtypes with distinct features, age peaks, and prognoses (Taylor et  al. 2012). These tumors typically arise from the roof of the fourth ventricle, although sonic hedgehog-activated medulloblastomas are tumors of the cerebellar hemispheres (Ramsewak et al. 2013). They present with heterogeneous contrast enhancement and can have cystic areas. Low-signal intensity on ADC maps discriminates medulloblastoma from pilocytic astrocytoma and ependymoma (Rumboldt et  al. 2006). Medulloblastoma can disseminate within the central nervous system, and cranio-spinal MRI as well as CSF cytology are recommended. Pilocytic astrocytomas (Fig.  99.1b) are benign tumors (WHO grade 1) and usually develop from the cerebellar hemispheres with often large cysts and focal areas of solid tumor tissue with contrast enhancement (Ramsewak et  al. 2013). High-signal intensity on ADC maps is typical for the solid tumor areas (Rumboldt et al. 2006). Ependymomas (Fig. 99.1c) can present as WHO grade 2 or 3 tumors, or as subependymoma (WHO grade I). The commonly arise from the fourth ventricle and extend through the lateral or median apertures into the extra-axial compartment (Ramsewak et al. 2013). On MRI, they appear as heterogeneous tumors with contrast enhancement, cystic areas, calcifications, and hemorrhage. Signal intensity on ADC maps is intermediate between the two previously mentioned tumor types (Rumboldt et al. 2006). Similar to medulloblastoma, these tumors are currently not only classified solely based on histopathology, but also based on molecular characteristics for improved risk stratification (Pajtler et al. 2015). Another similarity to medulloblastoma is the risk of CSF dissemination, making cranio-spinal imaging and CSF cytology mandatory.

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a

b

c

Fig. 99.1  Axial MRI images of the most common pediatric cerebellar tumor, with the following sequences: T1 without contrast (left), T1 with contrast (middle) and ADC (right). (a) Medulloblastoma located in the fourth ventricle, showing contrast enhancement and low ADC value (0.9  ×  103  mm2/s). (b) Pilocytic astrocytoma of the right cerebellar

hemisphere, showing contrast enhancement of the solid tumor and high ADC value (1.6 × 103 mm2/s). (c) Ependymoma WHO grade II extending through the left lateral aperture, showing focal contrast enhancement and intermediate ADC value (1.1 × 103 mm2/s)

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99.3 Cerebellar Tumors in Adults Posterior fossa tumors are rare in adults compared to children and account for only 15% of adult brain tumors, with a significant proportion of extra-axial lesions such as meningioma and vestibular schwannoma (Ramsewak et al. 2013). The most common cerebellar tumors in adults are metastases and hemangioblastomas (Fig.  99.2). Most of these tumors are located in the cerebellar hemispheres; genuine midline/ fourth ventricular tumors are rare in adults and are mainly ependymomas. Cerebellar metastasis (Fig. 99.2a) occurs predominantly in patients with breast, pulmonary, and gastrointestinal can-

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cer (Schroeder et al. 2020). These lesions have a very heterogeneous pattern on MRI, ranging from solid tumors to mainly cystic lesions, often with evident focal hemorrhage and avid contrast enhancement. Multiple lesions are a typical sign of metastatic disease. Within the posterior fossa, both intra- as well as extra-axial localization is possible. In contrast, hemangioblastomas (Fig. 99.2b) are usually singular, well-circumscribed lesions with a large cyst and a small contrast-enhancing nodule (Kim et  al. 2020). These tumors are benign (WHO grade 1) and can occur sporadically or associated with von Hippel-Lindau disease, a neurocutaneous syndrome. Hemangioblastoma is typically found within the cerebellar hemisphere.

a

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Fig. 99.2  MRI images of the most common adult cerebellar tumors. (a) Metastasis of the left cerebellar hemisphere, comparison of axial T1 sequences without (left) and with (middle) contrast reveals contrast enhancement of the wall, an additional metastasis is found in the right

frontal lobe (right). (b) Hemangioblastoma of the right cerebellar hemisphere, comparison of sagittal T1 sequences without (left) and with (middle) contrast reveals contrast enhancement only of the nodule, which is better visualized in the magnified axial image (right)

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99.4 Treatment of Cerebellar Tumors: An Overview The three pillars of treatment for cerebellar tumors are neurosurgical resection, radiotherapy, and chemotherapy (Pollack et  al. 2019). Which treatment modality or which combination is indicated in the individual patient depends on several factors. In general, neurosurgical removal of the tumor is performed in most cases, combined with temporary or permanent CSF diversion if hydrocephalus is present. Adjuvant therapy is risk-adjusted and thus the spectrum ranges from none (for example in completely resected pilocytic astrocytoma or hemangioblastoma) to cranio-spinal radiotherapy and chemotherapy (for example, in WHO grade III ependymoma or high-risk medulloblastoma subgroups). The neurosurgical approaches to cerebellar tumors are tailored according to the tumor localization and comprise median, paramedian, or lateral suboccipital as well as retromastoid craniotomies. As an illustrative example, a typical median suboccipital craniotomy and intradural telovelar approach are outlined (Mussi and Rhoton 2000): This approach is used for resection of fourth ventricular tumors involving the cerebellar midline. After median skin incision, the musculature is divided into the median avascular plane, and the suboccipital bone and posterior arch of the first ­vertebral body (C1) are exposed. A craniotomy extending into the foramen magnum is performed and, depending on tumor extension, the C1 arch is removed. The dura is opened and the inferior cerebellar surface is visualized. The arachnoid planes between uvula, cerebellar tonsils and brainstem are carefully dissected, allowing gentle retraction and access to the tela choroidea and inferior medullary velum (Fig. 99.3). These structures do not contain functional tracts and can thus be divided to expose the fourth ventricle, without sacrificing the cerebellar vermis. The intradural procedure is performed under magnification with an operating microscope. The tumor is dissected with microsurgical instruments and removed with surgical suction and ultrasonic aspiration.

a

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Fig. 99.4  Steps of a fourth ventricular tumor resection (child with medulloblastoma). (a) After opening of the dura, the tumor (double asterisk) is seen protruding through the median aperture between the

Large tumors can protrude through the apertures of the fourth ventricle and are usually debulked before dissection (Fig. 99.4). The complication rate after cerebellar tumor resection is approximately 30% and includes morbidity related to the disease itself (such as hydrocephalus-related problems), general surgical complications (such as wound breakdown), as well as neurological sequelae (Campbell et  al. 2017). The latter group comprises cerebellar motor syndrome, cerebellar cognitive affective syndrome, neuropsychological deficits, and brainstem dysfunction (long tract signs, motor weakness, cranial nerve dysfunction) (Levisohn et al. 2000; Neervoort et al. 2010). A specific complication after surgery of the cerebellum/fourth ventricle is postoperative cerebellar mutism syndrome (CMS), which is defined as postoperative delayed onset mutism and emotional lability, often accompa-

Fig. 99.3  Intraoperative microscopic photograph of the anatomy for the telovelar approach. The green arrow visualizes the direction of the approach, which requires incision of the tela choroidea (and deeper into the inferior medullary velum) along the dotted line

c

cerebellar tonsils (single asterisks), still covered by arachnoid. (b) The tumor is debulked (asterisk). (c) After tumor resection the floor of the fourth ventricle (asterisk) and the cerebral aqueduct (arrow) are exposed

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nied by hypotonia and oropharyngeal dysfunction or dysphagia as well as the neurological sequelae mentioned before (Gudrunardottir et al. 2016). It is most often seen in children after resection of large cerebellar midline tumors, correlating with medulloblastoma (Robertson et  al. 2006). Damage to the vermis, dentate nuclei, median, and superior cerebellar peduncles as well as brainstem is typically observed in affected patients (Wells et  al. 2010; Liu et  al. 2018; Beez et al. 2021). The telovelar approach as described above may mitigate postsurgical damage mainly to the vermis, and the occurrence of postoperative cerebellar mutism syndrome appears to be reduced, although not completely avoided (Cobourn et al. 2020). Therefore, a multifactorial pathophysiology is assumed and ongoing research aims to improve risk prediction and prevention (Gudrunardottir et  al. 2016; Wibroe et al. 2017).

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Mussi ACM, Rhoton AL (2000) Telovelar approach to the fourth ventricle: microsurgical anatomy. J Neurosurg 92:812–823. https://doi. org/10.3171/jns.2000.92.5.0812 Neervoort FW, Van Ouwerkerk WJR, Folkersma H et al (2010) Surgical morbidity and mortality of pediatric brain tumors: a single center audit. Childs Nerv Syst 26:1583–1592. https://doi.org/10.1007/ s00381-­010-­1086-­1 Pajtler KW, Witt H, Sill M et  al (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27:728–743. https://doi. org/10.1016/j.ccell.2015.04.002 Perreault S, Ramaswamy V, Achrol AS et  al (2014) MRI surrogates for molecular subgroups of medulloblastoma. Am J Neuroradiol 35:1263–1269. https://doi.org/10.3174/ajnr.A3990 Pollack IF, Agnihotri S, Broniscer A (2019) Childhood brain tumors: current management, biological insights, and future directions. J Neurosurg Pediatr 23:261–273. https://doi.org/10.3171/2018.10. PEDS18377 Poretti A, Meoded A, Huisman TAGM (2012) Neuroimaging of pediatric posterior fossa tumors including review of the literature. J Magn Reson Imaging 35:32–47. https://doi.org/10.1002/jmri.22722 Ramsewak DW, Thomas A, Patel SR et  al (2013) Pictorial review of pediatric and adult primary posterior fossa masses. Neurographics References 3:70–86. https://doi.org/10.3174/ng.2130057 Robertson PL, Muraszko KM, Holmes EJ et  al (2006) Incidence Beez T, Munoz-Bendix C, Steiger H-J, Hänggi D (2021) Functional and severity of postoperative cerebellar mutism syndrome in tracts of the cerebellum-essentials for the neurosurgeon. Neurosurg children with medulloblastoma: a prospective study by the Rev 44:273–278. https://doi.org/10.1007/s10143-­020-­01242-­1 Children’s Oncology Group. J Neurosurg 105:444–451. https://doi. Campbell E, Beez T, Todd L (2017) Prospective review of 30-day mororg/10.3171/ped.2006.105.6.444 bidity and mortality in a paediatric neurosurgical unit. Childs Nerv Rumboldt Z, Camacho DLA, Lake D et  al (2006) Apparent diffuSyst 33. https://doi.org/10.1007/s00381-­017-­3358-­5 sion coefficients for differentiation of cerebellar tumors in chilCobourn K, Marayati F, Tsering D et al (2020) Cerebellar mutism syndren. Am J Neuroradiol 27:1362–1369. https://doi.org/10.1016/ drome: current approaches to minimize risk for CMS. Childs Nerv s0513-­5117(08)70144-­3 Syst 36:1171–1179. https://doi.org/10.1007/s00381-­019-­04240-­x Schroeder T, Bittrich P, Kuhne JF et al (2020) Mapping distribution of Dunkl V, Cleff C, Stoffels G et  al (2015) The usefulness of dynamic brain metastases: does the primary tumor matter? J Neuro-Oncol O-(2–18F-Fluoroethyl)-l-tyrosine PET in the clinical evaluation of 147:229–235. https://doi.org/10.1007/s11060-­020-­03419-­6 brain tumors in children and adolescents. J Nucl Med 56:88–92. Shiroishi MS, Panigrahy A, Moore KR et  al (2015) Combined MRI https://doi.org/10.2967/jnumed.114.148734 and MRS improves pre-therapeutic diagnoses of pediatric brain Gudrunardottir T, Morgan AT, Lux AL et  al (2016) Consensus paper tumors over MRI alone. Neuroradiology 57:951–956. https://doi. on post-operative pediatric cerebellar mutism syndrome: the Iceland org/10.1007/s00234-­015-­1553-­1 Delphi results. Childs Nerv Syst 32:1195–1203 Taylor MD, Northcott PA, Korshunov A et  al (2012) Molecular subKim EH, Moon JH, Kang SG et  al (2020) Diagnostic challenges of groups of medulloblastoma: the current consensus. Acta Neuropathol posterior fossa hemangioblastomas: refining current radiological 123:465–472. https://doi.org/10.1007/s00401-­011-­0922-­z classification scheme. Sci Rep 10:1–8. https://doi.org/10.1038/ Wells EM, Khademian ZP, Walsh KS et  al (2010) Postoperative cers41598-­020-­63207-­0 ebellar mutism syndrome following treatment of medulloblastoma: Levisohn L, Cronin-Golomb A, Schmahmann JD (2000) neuroradiographic features and origin. J Neurosurg Pediatr 5:329– Neuropsychological consequences of cerebellar tumour resection 334. https://doi.org/10.3171/2009.11.PEDS09131 in children. Cerebellar cognitive affective syndrome in a paedi- Wibroe M, Cappelen J, Castor C et al (2017) Cerebellar mutism synatric population. Brain 123:1041–1050. https://doi.org/10.1093/ drome in children with brain tumours of the posterior fossa. BMC brain/123.5.1041 Cancer 17:439. https://doi.org/10.1186/s12885-­017-­3416-­0 Liu J-F, Dineen RA, Avula S et  al (2018) Development of a pre-­ Zukotynski K, Fahey F, Kocak M et al (2014) 18 F-FDG PET and MR operative scoring system for predicting risk of post-operative paediimaging associations across a spectrum of pediatric brain tumors: atric cerebellar mutism syndrome. Br J Neurosurg 32:18–27. https:// a report from the Pediatric Brain Tumor Consortium. J Nucl Med doi.org/10.1080/02688697.2018.1431204 55:1473–1480. https://doi.org/10.2967/jnumed.114.139626 Louis DN, Perry A, Wesseling P et al (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-­ Oncology 23:1231–1251. https://doi.org/10.1093/neuonc/noab106

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Jordi Gandini and Mario Manto

Abstract

Traumatic brain injuries (TBI) are an important cause of mortality and morbidity worldwide. Although most cranial traumatic injuries involve the supratentorial regions, the injured patients often show several cerebellar symptoms immediately after the trauma or later: nystagmus, dysarthria, tremor, postural instability, loss of coordination of fine movements, and also cognitive/affective impairments. In addition, due to the proximity and anatomical connectivity with the brainstem, cerebellar symptoms are often combined with brainstem symptoms. Cerebellar ataxia may result from lesions of the afferent tracts, the cerebellar parenchyma, and/or the efferent tracts. We discuss the pathogenesis of cerebellar deficits following TBI and highlight the need for close clinical and radiological follow-up of patients. Keywords

Cerebellum · Trauma · Injury · Ataxia · MRI · DTI

100.1 Introduction 100.1.1 Clinical Presentation Traumatic brain injuries (TBI) are an important cause of mortality and morbidity worldwide (Hyder et  al. 2007). Although most cranial traumatic injuries involve the supratentorial regions (Tsai et  al. 1980), injured patients often J. Gandini Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU Hôpital Civil Marie Curie, Charleroi, Belgium M. Manto (*) Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU Hôpital Civil Marie Curie, Charleroi, Belgium

show a variety of cerebellar symptoms after the trauma. Ataxia involves not only motor control but also cognitive/ affective domains. Indeed, patients show various combinations of nystagmus, dysarthria, tremor, postural instability, loss of coordination of fine movements, and cognitive/affective impairment (Braga et  al. 2007; Basford et  al. 2003; Kuhtz-Buschbeck et al. 2003; Louis et al. 1996; Mysiw et al. 1990; Wober et al. 1993). As a result of the anatomical proximity of structures within the posterior fossa, the cerebellum and brainstem are often damaged simultaneously. This contributes to the gravity of TBI, with a potential risk of death. Different clinical presentations are observed. Symptoms usually appear immediately after the trauma, but injured individuals can also develop delayed cerebellar signs and symptoms appearing from 3  weeks to 2  years after injury (Louis et al. 1996). This delayed cerebellar syndrome may show a progressive course, with a worsening over a few months. In some patients, tremor presents with a rest component and a kinetic component (midbrain tremor). Post-­ traumatic palatal myoclonus results from lesions of the Guillain–Mollaret triangle. Olivary hypertrophy develops over a period of months to years after the trauma. The repetitive contractions of the soft palate may be associated with the myoclonus of the neck and shoulder. Mood disorders and neuropsychological deficits are commonly observed, although they can be mild. Unfortunately, they are often overlooked or may be interpreted as a search for financial compensation. In children with severe TBI, there is an association between cerebellar lesions and deficits in visual recognition, dyscalculia, and IQ (Braga et al. 2007). Some patients show clear evidence of Schmahmann’s syndrome (cerebellar cognitive affective syndrome; Schmahmann and Sherman 1998; see also Stoodley and Schmahmann 2009) but we currently lack detailed reports regarding the onset and the evolution of this important syndrome in the course of a TBI.

Université de Mons, Mons, Belgium e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_100

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100.1.2 Type of Traumas In severe TBI, penetrating injuries or fractures cause liquorrhea in open head injuries, with possible involvement of the vertebrobasilar system, so that patients may present with dissection of neck vessels and secondary infarction (Manto 2010). Nevertheless, the head trauma leading to a dissection may be minor, so the complication is neglected or even ignored. Arterial occlusion within the vertebrobasilar system may lead to cerebellar ischemia by a sudden drop of perfusion or by a mechanism of arterioarterial embolism. Cervico-­ occipital pain followed by combinations of brainstem/ cerebellar deficits is very suggestive of a dissection. Rarely, the trauma causes an aneurysm of cerebellar arteries. Severe trauma is often associated with subarachnoid hemorrhage and may lead to secondary vasospasm triggering ischemia with worsening of the initial clinical status. Secondary ischemia should thus be considered in patients showing secondary deterioration. Ischemia may worsen edema and vice versa, causing a vicious circle within the posterior fossa and leading to intracranial hypertension. Cerebellar concussion is characterized by cerebellar symptoms occurring just after the trauma and resolving gradually with complete disappearance (Fumeya and Hideshima 1994). Patients may show impaired consciousness with amnesia of the trauma. Patients are at risk to develop post-traumatic concussion disorder with various combinations of headache, anxiety, fatigue, and lack of balance. These symptoms may be disabling and block the return to regular professional activities, with social consequences. Cerebellar contusion is characterized by microbleeds causing a local hematoma, with a tendency of microbleeds to merge into a larger hematoma after a few hours (Gudeman et al. 1979). Contusion is often associated with a mechanism of diffuse axonal injury (see below). The risk of tonsillar herniation should not be overlooked. Secondary brainstem ­hemorrhage (Duret hemorrhage) may develop as a consequence of elongation of penetrating brainstem vessels. Subdural hematoma corresponds to blood accumulation between the dura and the arachnoid. Brain MRI is highly suggestive: the sedimentation of erythrocytes gives a “hematocrit effect” (Manto 2010). Epidural hematoma is due to bleeding of meningeal vessels, diploic veins or sinuses, as a result of a skull fracture. It is most common in children, often presenting with a lucid interval of a few hours between the trauma and the cerebellar deficits. Blast exposure in absence of head impact is mainly observed in soldiers during war (Mac Donald et  al. 2013). Cerebellar white matter is particularly vulnerable, along with the brainstem and orbitofrontal cortex, but patients do not exhibit clear-cut ataxic signs. Superficial siderosis is a late complication characterized by a slowly progressive cerebellar syndrome associated with

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progressive bilateral hearing loss and possibly cognitive symptoms combined with pyramidal tract symptoms. Other causes include surgery for a primary cerebellar tumor and vascular malformations. The source of the bleeding may remain occult.

100.1.3 Localization of Lesions In terms of localization of the primary lesion, lesions target the afferent pathways (mainly the corticopontocerebellar tract and also the olivo-cerebellar tract), the cerebellar parenchyma (cerebellar cortex, white matter, cerebellar nuclei) and/or the efferent pathways (mainly the dentatorubrothalamic tract). Lesions are documented using brain CT scan, brain MRI, and SPECT studies. Conventional MRI is very useful early after the trauma and as a follow-up tool to show late complications such as delayed cerebellar atrophy, olivary hypertrophy, or superficial siderosis. Conventional MRI is complemented by DTI studies allowing the assessment of the afferent and efferent tracts of the cerebellum, showing lesions even in mild TBI (Jang and Kwon 2015, 2017). Crossed atrophy evolves months to years after the TBI as a result of anterograde or retrograde degeneration. In delayed cerebellar ataxia, the post-traumatic lesions are located in thalamus and in brainstem, suggesting a retrograde mechanism of degeneration involving cerebro-­ cerebellum connections (Louis et  al. 1996; Iwadate et  al. 1989). Wang et  al. demonstrated anomalies in cerebellar middle peduncles and in pontine crossing tracts in patients with mild TBI using DTI-weighted images (Wang et  al. 2016).

100.2 Direct Cerebellar Injuries 100.2.1 Axotomy Animal models of injuries targeting climbing fibers, the cerebellar white matter or cerebellar peduncles (pedunculotomy) have been developed (Sherrard 1997; Dusart and Sotelo 1994; Potts et al. 2009). Axotomy has attracted scientists to assess neuronal repair and plasticity in the cerebellar circuitry (Potts et  al. 2009). Climbing fibers and Purkinje cells react differently to injury (Carulli et al. 2004): climbing fibers initially fall into axonal regression, but then, in the presence of favorable conditions, they can regenerate. In contrast, Purkinje cells are more resistant to axotomy, but they show a low level of recovery after injury (Carulli et al. 2004; Rossi et al. 2006). It is presumed that this model recapitulates acute sections occurring in the cerebellum as a result of a TBI.

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100.2.2 Stab Injury

100.3.2 Metabolic Changes

Stab injuries are characterized by penetration of the surface of the cerebellum by a pointy object (Culic et al. 2005). In this kind of cerebellar trauma, anatomo-pathologic studies show dendritic degeneration and reduction of dimensions of Purkinje cells located in the traumatized area (Chen and Aston-Jones 1994). A similar phenomenon has been demonstrated in the inferior olivary nucleus.

Metabolic changes are the result of deafferentation of cerebellar hemispheres after a cerebral lesion (Liu et al. 2007). Several authors have observed depressed activity in the contralateral cerebellar hemisphere and metabolic reorganization in the ipsilateral cerebellar hemisphere (crossed cerebellar diaschisis) (Niimura et al. 1999).

100.2.3 Stretch Injury This traumatic model has been described only in  vitro, in particular in several types of cerebellar neurons cultivated on a silastic membrane, that is warped by nitrogen pulse to obtain the stretching of cultured cells (Ellis et al. 1995). The injured culture showed a loss of all cell types (Purkinje and non-Purkinje neurons and glial cells) and an increased level of S-100ẞ receptor, that is known to mediate Purkinje neuron degeneration (Slemmer et al. 2004).

100.2.4 Blast Injury DTI studies show evidence of cerebellar white matter lesions in case of TBI, despite absence of motor or neuropsychological deficits (Mac Donald et al. 2013). Shear stress has been incriminated.

100.3 Indirect Cerebellar Injuries

100.3.3 Presynaptic Hyperexcitability This mechanism is characterized by increased neurotransmission from mossy fibers to Purkinje cells via granule cells (Ai and Baker 2002) or from inferior olivary nucleus to Purkinje cells via climbing fibers (Xu et al. 2000; O’Hearn et al. 1993; O’Hearn and Molliver 1997).

100.4 Common Cellular Mechanisms At the cellular level, four pathophysiologic mechanisms are implicated in cerebellar damage regardless the mechanism of injury: excitotoxicity, differential gene expression, inflammatory response, and axonal degeneration (Ai and Baker 2002; Allen and Chase 2001; Chen and Aston-Jones 1994).

100.4.1 Excitotoxicity and Differential Gene Expression

Genetic and toxic models have confirmed that Purkinje cells are very sensitive to excitotoxicity likely because of the hyperconIn extra-cerebellar brain injuries, patients may also show cer- nected histological architecture of the cerebellar cortex and the ebellar anomalies. This phenomenon is due to three mecha- importance of glutamatergic transmission (Sarna and Hawkes nism of damage transmission: mechanical forces, metabolic 2003; Slemmer et al. 2005; Potts et al. 2009). This sensitivity is changes, and presynaptic hyperexcitability. also attributable to the high expression of AMPA receptors in this population of neurons. These receptors mediate the excitotoxic effect of glutamate and reduce the synthesis of aldolase C, a gly100.3.1 Mechanical Forces colytic enzyme, that can prevent excitotoxic damage (Slemmer et al. 2007; Welsh et al. 2002). In addition, after traumatic injuThis mechanism of injury is due to the impact between the ries, a downregulation of glial glutamate transporters, and alteracerebellum and the internal face of the skull by a “counter-­ tion of glutamate reuptake system and of glutamate metabotropic coup” injury (Potts et  al. 2009). This mechanical stress receptors have been described (Rao et al. 1998; Ai and Baker involves Purkinje cells especially. These neurons show axo- 2004). They all contribute to the excitotoxic cascade. nal cleaving, depletion of cytoskeletal proteins, neurofilament compaction, and perturbation of permeability of axolemma (Shaw 2002; Povlishock et  al. 1997; Taft et  al. 100.4.2 Inflammatory Response 1992). The anomalies start initially in the dendrites and often are not restricted to the traumatized zone (Posmantur et al. After TBI an important hyperactivation of microglia is 1996a, b). observed in cerebellar cortex. After neuronal death microglia

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cells behave like scavengers and healing promotors (Mautes et al. 1996; Kim and de Vellis 2005). However, inhibition of microglia does not impact Purkinje cell death, suggesting that activation of microglial cells is a consequence, and not the cause, of cellular death of Purkinje neurons (Sato and Noble 1998).

100.4.3 Axonal Degeneration Traumatic axonal injury is a degenerative process that evolves from injured axons to cellular soma leading potentially to a complete disconnection (Buki and Povlishock 2006). In animal models, several authors have observed extensive bilateral axonal degeneration in cerebellar parenchyma, neurofilament degeneration, or redistribution from the axon to the cellular soma and ẞ-amyloid accumulation in neurons (Hoshino et  al. 2003; Hamberger et  al. 2003; Lighthall et al. 1990; Matthews et al. 1998; Park et al. 2007; Graham and Gennarelli 1997). Dysfunction at the level of middle and posterior cerebellum up to 14 days after trauma has been demonstrated using neurophysiological techniques (Park et al. 2007).

100.5 Cerebro-Cerebellar Connections Several studies showed fluid anisotropy (FA) in DTI-­ weighted images after TBI (Wang et al. 2016). The increased FA in middle cerebellar peduncles and in pontine crossing tracts after mild TBI is likely due to axonal swelling and oedema (Wang et  al. 2016). Lesions of the cortico-ponto-­ cerebellar tract and lesions of the dentatorubrothalamic tract have both been demonstrated using advanced tractographic tools. Lesions of the efferent pathways are associated with cerebellar ataxia and tremors (Kitamura et  al. 2008; Min et  al. 2012; Jang et  al. 2016; Schulz et  al. 2017; Jang and Kwon 2015).

100.6 Management At the acute stage, the patient should be carefully examined, mobilized cautiously, and monitored for vital functions. A brain CT scan or preferentially a brain MRI should be performed immediately. Severe TBI may require monitoring of intracranial pressure and drainage of obstructive hydrocephalus, keeping in mind the risk of tonsillar herniation. Cerebellar stroke is best managed within a stroke unit. Subarachnoid hemorrhage and vasospasm require intensive care monitoring. Some teams systematically perform transcranial doppler sonography assessments to look for vasospasm.

At the chronic stage, patients may benefit from drugs against ataxia, intensive rehabilitation (speech rehabilitation, physical therapy, assistive devices) and non-invasive stimulation techniques. Drugs such as propranolol, clonazepam, and primidone may reduce the kinetic tremor in some patients. We currently lack specific therapies for the Schmahmann’s syndrome occurring post-TBI.  Studies are warranted.

100.7 Conclusion Cerebellar traumatic injuries can explain a consistent portion of the symptomatology of TBI. DTI is a promising technique to characterize the structural integrity of cerebellar tracts and complements the conventional MRI.  The anatomical proximity of the cerebellum and brainstem may lead to serious complications leading to death. Close clinical/radiological follow-up is mandatory. Declaration  The authors declare no conflict of interest. Funding  This work was conducted without any funding from public or private sources. Ethical Committee Request  Not applicable. Consent to Participate  Not applicable. Data Availability  The chapter is not associated with raw data. Code Availability There is no software application or custom code used in this paper. Authors’ Contribution Chapter preparation: JG.  Editing: MM.  All authors have read and agreed to the publication.

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669 M, Brody DL (2013) Cerebellar white matter abnormalities following primary blast injury in US military personnel. PLoS One 8(2):e55823 Manto M (2010) Trauma of the posterior fossa. In: Cerebellar disorders. A practical approach to diagnosis and management. Cambridge University Press, Cambridge, pp 149–156 Matthews MA, Carey ME, Soblosky JS, Davidson JF, Tabor SL (1998) Focal brain injury and its effects on cerebral mantle, neurons, and fiber tracks. Brain Res 794(1):1–18 Mautes AE, Fukuda K, Noble LJ (1996) Cellular response in the cerebellum after midline traumatic brain injury in the rat. Neurosci Lett 214(2–3):95–98 Min Y, Park SH, Hwang SB (2012) Corticospinal tract and pontocerebellar fiber of central pontine myelinolysis. Ann Rehabil Med 36:887–892 Mysiw WJ, Corrigan JD, Gribble MW (1990) The ataxic subgroup: a discrete outcome after traumatic brain injury. Brain Inj 4(3):247–255 Niimura K, Chugani DC, Muzik O, Chugani HT (1999) Cerebellar reorganization following cortical injury in humans: effects of lesion size and age. Neurology 52(4):792–797 O’Hearn E, Molliver ME (1997) The olivocerebellar projection mediates ibogaine-induced degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity. J Neurosci 17(22):8828–8841 O’Hearn E, Long DB, Molliver ME (1993) Ibogaine induces glial activation in parasagittal zones of the cerebellum. Neuroreport 4(3):299–302 Park E, Liu E, Shek M, Park A, Baker AJ (2007) Heavy neurofilament accumulation and alpha-spectrin degradation accompany cerebellar white matter functional deficits following forebrain fluid percussion injury. Exp Neurol 204(1):49–57 Posmantur RM, Kampfl A, Liu SJ, Heck K, Taft WC, Clifton GL et al (1996a) Cytoskeletal derangements of cortical neuronal processes three hours after traumatic brain injury in rats: an immunofluorescence study. J Neuropathol Exp Neurol 55(1):68–80 Posmantur RM, Kampfl A, Taft WC, Bhattacharjee M, Dixon CE, Bao J et  al (1996b) Diminished microtubule-associated protein 2 (MAP2) immunoreactivity following cortical impact brain injury. J Neurotrauma 13(3):125–137 Potts MB, Advanikar H, Noble-Haeusslein LJ (2009) Models of traumatic brain injury. Cerebellum 8:211–221 Povlishock JT, Marmarou A, McIntosh T, Trojanowski JQ, Moroi J (1997) Impact acceleration injury in the rat: evidence for focal axolemmal change and related neurofilament sidearm alteration. J Neuropathol Exp Neurol 56(4):347–359 Rao VL, Baskaya MK, Dogan A, Rothstein JD, Dempsey RJ (1998) Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain. J Neurochem 70(5):2020–2027 Rossi F, Gianola S, Corvetti L (2006) The strange case of Purkinje axon regeneration and plasticity. Cerebellum 5(2):174–182 Sarna JR, Hawkes R (2003) Patterned Purkinje cell death in the cerebellum. Prog Neurobiol 70(6):473–507 Sato M, Noble LJ (1998) Involvement of the endothelin receptor subtype A in neuronal pathogenesis after traumatic brain injury. Brain Res 809(1):39–49 Schmahmann JD, Sherman JC (1998) The cerebellar cognitive affective syndrome. Brain 21(Pt 4):561–579. PMID: 9577385 Schulz R, Frey BM, Koch P et al (2017) Cortico-cerebellar structural, connectivity is related to residual motor output in chronic stroke. Cereb Cortex 27:635–645 Shaw NA (2002) The neurophysiology of concussion. Prog Neurobiol 67(4):281–344 Sherrard RM (1997) Insulin-like growth factor 1 induces climbing fibre re-innervation of the rat cerebellum. Neuroreport 8(15):3225–3228

670 Slemmer JE, Weber JT, De Zeeuw CI (2004) Cell death, glial protein alterations and elevated S-100 beta release in cerebellar cell cultures following mechanically induced trauma. Neurobiol Dis 15(3):563–572 Slemmer JE, De Zeeuw CI, Weber JT (2005) Don’t get too excited: mechanisms of glutamate-mediated Purkinje cell death. Prog Brain Res 148:367–390 Slemmer JE, Haasdijk ED, Engel DC, Plesnila N, Weber JT (2007) Aldolase C-positive cerebellar Purkinje cells are resistant to delayed death after cerebral trauma and AMPA-mediated excitotoxicity. Eur J Neurosci 26(3):649–656 Stoodley CJ, Schmahmann JD (2009) Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. NeuroImage 44(2):489–501. https://doi.org/10.1016/j. ­ neuroimage.2008.08.039 Taft WC, Yang K, Dixon CE, Hayes RL (1992) Microtubule-associated protein 2 levels decrease in hippocampus following traumatic brain injury. J Neurotrauma 9(3):281–290

J. Gandini and M. Manto Tsai FY, Teal JS, Itabashi HH, Huprich JE, Hieshima GB, Segall HD (1980) Computed tomography of posterior fossa trauma. J Comput Assist Tomogr 4(3):291–305 Wang Z, Wu W, Liu Y, Wang T, Chen X, Zhang J et al (2016) Altered cerebellar white matter integrity in patients with mild traumatic brain injury in the acute stage. PLoS One 11(3):e0151489 Welsh JP, Yuen G, Placantonakis DG, Vu TQ, Haiss F, O’Hearn E et al (2002) Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv Neurol 89:331–359 Wober C, Oder W, Kollegger H, Prayer L, Baumgartner C, Wober-­ Bingol C et  al (1993) Posturographic measurement of body sway in survivors of severe closed head injury. Arch Phys Med Rehabil 74(11):1151–1156 Xu Z, Chang LW, Slikker W Jr, Ali SF, Rountree RL, Scallet AC (2000) A dose–response study of ibogaine-induced neuropathology in the rat cerebellum. Toxicol Sci 57(1):95–101

Superficial Siderosis

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Hiroyuki Katoh and Masahiko Watanabe

Abstract

Superficial siderosis (SS) is an uncommon and often underdiagnosed disorder caused by chronic or repeated hemorrhage in the subarachnoid space that deposits hemosiderin in the subpial layers of the central nervous system, leading to impaired nerve function. The progression of SS is insidious, often requiring patients to experience advanced symptoms until a clinician with a high level of suspicion for the condition orders magnetic resonance imaging (MRI) of the brain or spine and diagnoses the condition by confirming the characteristic image findings. Conditions that can cause repeated bleeding episodes into the subarachnoid space are wide-ranging, so the diagnosis of SS in some cases may be the beginning of an arduous journey searching for the ailment that led to SS development. This chapter will review the fundamentals of SS and focus on spinal dural defects, which have recently become a topic of interest as the precipitating condition that brings about SS. Keywords

Hemosiderin · Dural defect · Hemosiderosis · Cerebral amyloid angiopathy · Flow dynamics

101.1 Introduction Superficial siderosis (SS) is a progressively disabling disease caused by recurrent subarachnoid hemorrhage that disseminates heme into the circulating cerebrospinal fluid, leading to accumulation of hemosiderin and other iron breakdown products in the surface of the central nervous system and cranial nerves (Koeppen et al. 1992). While the precise mechaH. Katoh (*) · M. Watanabe Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan e-mail: [email protected]; [email protected]

nisms that bring about neurological impairment are not sufficiently understood, the deposited processed iron products generate free radicals that induce neuronal cell loss and impair the function of the affected area. SS was recognized in autopsies and experimentally confirmed in animal studies, but it was a rare condition until the widespread adoption of magnetic resonance imaging (MRI) made it possible to visualize hemosiderin accumulation on the surface of neural structures. SS is now increasingly recognized, and a focal variant termed cortical SS has also been determined with distinct clinical characteristics (Linn et al. 2008).

101.2 Classification and Etiology Superficial siderosis was historically a condition only identified through postmortem autopsies. However, the recent advances in iron-sensitive or other susceptibility-weighted MRI sequences have made it possible to diagnose SS in vivo by its characteristic low-signal intensity rim around the outer surfaces of the brain and spinal cord. There are two types of siderosis with distinct underlying pathology and clinical presentation.

101.2.1 Infratentorial SS (iSS) This is the classical presentation of SS, first described in 1908 by Hamill, in which the infratentorial regions of the brain and the spinal cord are affected (Hamill 1908). Patients with iSS typically present with slowly progressive hearing impairment, cerebellar ataxia, and myelopathy. Chronic intermittent or continuous minor bleeding into the subarachnoid space is the cause of iSS, but the source of hemorrhage is historically reported to be identifiable only in approximately 50% of cases (Fearnley et al. 1995). Cases in which the precipitating pathology is unknown are termed classical iSS (referred to also as type 1 iSS) and are differentiated

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_101

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from secondary iSS (or type 2 iSS) in which surgery, trauma, vascular lesions or tumors of the brain or spinal cord have been identified as the cause for subarachnoid hemorrhage. In 2012, Kumar proposed the term “duropathies” to describe dural defects or tears in the ventral dura mater of the spinal canal that cause chronic bleeding and lead to the development of SS (Kumar 2012). Several theories have been put forth to describe how duropathies could cause hemorrhage into the subarachnoid space, such as bleeding from the epidural veins around the dural defect (Kumar 2012) as well as bleeding from the bridging veins on the surface of the cerebellum that rupture due to brain sagging brought about by intracranial hypotension (Schievink et al. 2013). In iSS, repetitive or chronic hemorrhage into the subdural space increases heme within the cerebrospinal fluid, where heme oxygenase degrades heme into ferrous ions and biliverdin. The increase of heme and iron within the cerebrospinal fluid induces the production of ferritin, which is incorporated into lysosomes of macrophages and stored as hemosiderin. Iron can induce cell death by generating free radicals, so free iron is quickly sequestered along with ferritin within the central nervous system. This protects cells in the short-term, but long-term accumulation of ferritin and hemosiderin damages cells. An important factor that decides the distribution of hemosiderin is the difference in the ferritin-­producing capacity of myelin in the central nervous system compared to myelin of the peripheral nerves. With myelin of the central nervous system known to produce higher levels of ferritin compared to peripheral myelin, the auditory nerve which is associated with higher levels of central myelin compared to other cranial nerves accumulates greater hemosiderin and thus more often becomes symptomatic in SS. The olfactory nerve as well as the optical nerve also contain high levels of central myelin, and are also often affected in SS. The fact that the cerebellum is also susceptible to hemosiderin accumulation can also be attributed to the fact that cerebellar Bergmann glia have a high capacity to produce ferritin. Neural structures that have high surface area contact with cerebral spinal fluid are also at risk for hemosiderin accumulation, and myelopathy can ensue when the pyramidal tract accumulates hemosiderin at the cerebral crus, medullary pyramid, and spinal cord conus where its fibers traverse near the subarachnoid space. Other susceptible areas are the sylvian fissure, inferior frontal cortex, hippocampus, and insular cortex (Koeppen et al. 1992).

101.2.2 Cortical SS (cSS) Cortical SS has different potential causes and clinical presentation compared to classical siderosis, and the siderosis is generally restricted to the supratentorial compartment and

H. Katoh and M. Watanabe

the convexities of the cerebral hemispheres, thus the name “cortical” SS (Linn et al. 2008). It is often associated with cerebral amyloid angiopathy (CAA), a common cerebral small vessel disorder found in older individuals (Linn et al. 2010; Viswanathan and Greenberg 2011). The clinical symptoms of cSS can include a characteristic transient focal neurological episode (Greenberg et al. 1993), which is important because it may be a predictor of future intracerebral hemorrhage risk in patients with CAA (Charidimou et  al. 2012; Linn et al. 2013). CAA is relatively common among elderly people, and is characterized by deposition of beta-amyloid within the walls of small cortical and leptomeningeal arteries. It can be a major cause of spontaneous intracerebral hemorrhage thus leading to the development of cSS, but it is also believed to contribute to the cognitive decline seen in elderly people and can also accompany Alzheimer’s disease (Charidimou et al. 2017). The vessels affected by CAA become brittle and fragile and are susceptible to repeated bleeding episodes into the subarachnoid space which may cause symptoms. The development of cSS can trigger transient focal neurological symptoms sometimes referred to as “amyloid spells” and has been shown to be a risk factor for future intracranial hemorrhage and subsequent dementia, independent of and more significantly than coincident microbleeds (Biffi et al. 2010). When cSS is observed in patients under 60 years, it may be indicative of trauma or brain vascular malformations, but may more likely be cause by a rare condition called reversible cerebral vasoconstriction syndrome (RCVS) which is characterized by transient “thunderclap” headaches associated with reversible segmental constriction of cerebral arteries (Kumar et al. 2010).

101.3 Symptoms 101.3.1 Infratentorial SS (iSS) Symptoms The cerebellum, brain stem, eighth cranial nerve, and spinal cord are the areas known to be susceptible to hemosiderin deposits due to their anatomical characteristics, and therefore SS patients suffer from impairment of these systems. Cerebellar ataxia and hearing impairment are the most frequent symptoms, followed by a multitude of symptoms such as spinal pyramidal tract disorder, cognitive impairment, olfactory disturbance, and impaired vision (Fearnley et  al. 1995). In their literature review of 270 cases, Levy, et  al. reported that hearing impairment and cerebellar ataxia were seen in 81% of patients, followed by myelopathy (53%), urinary difficulty (14%), headache (14%), and impaired smell (14%) (Levy et al. 2007). Cognitive impairment is another well-known symptom associated with SS, believed to be

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brought about by supratentorial hemosiderin accumulation, but cerebellar dysfunction has also been proposed to affect execution of cognitive routines (Uttner et al. 2009). Olfactory impairment is also often seen in SS patients but is believed to be underdiagnosed due to lack of sufficient testing (Bürk et al. 2001; Kumar et al. 2006). Other cranial nerves are similarly at risk of being affected, but reports of their involvement are rare except for some visual impairment (Fearnley et al. 1995; Bürk et al. 2001; Kumar et al. 2006).

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optimal compared to other iron-sensitive MRI techniques. The hypointense lesions representing hemosiderin deposits are most pronounced in T2*-gradient recalled echo (T2*GRE) sequences, followed in order of intensity by susceptibility-­weighted imaging (SWI) sequences and standard T2-weighted sequences, with increased magnetic field strength leading to increased visualization of the areas of signal loss (Gregoire et al. 2011). The presence of siderosis warrants contrast-enhanced MRI of the entire brain and spinal cord in order to define the extent of SS and to diagnose the potential bleeding source. 101.3.2 Cortical SS (cSS) Symptoms In cSS, subpial deposits of hemosiderin are usually observed in the cerebral convexities. The deposits are usually Patients suffering from cSS may experience headaches or focal, but may be disseminated over multiple sulci. The most seizures stemming from focal subarachnoid hemorrhage, but commonly affected areas with cSS are the occipital lobes, can often be asymptomatic (Linn et al. 2008; Kumar et al. followed by the parietal, frontal, and temporal lobes (Shams 2010). By incorporating cSS into the radiological diagnosis et  al. 2016). When signs of cSS are observed, the MRI of CAA, the sensitivity of the modified Boston criteria for images need to be assessed for other image markers of CAA CAA increased from 90 to 95% with only a modest decrease including lobar microbleeds, white matter hyperintensities, in specificity (Feldman et  al. 2008). CAA often exhibits perivascular spaces in the cerebral white matter, cortical symptoms similar to transient ischemic attacks (TIAs), in microinfarcts, and cortical thinning (Charidimou et al. 2017). which case cSS may be observed in the cerebral cortex. A Vascular CAA has been reported to be detectable by molecufocal motor and/or sensory disturbance occurs and may lar amyloid imaging (Gurol et al. 2016), but the diagnostic spread, but the symptoms are transient and usually resolves utility of amyloid PET remains to be established. in a period of up to 30 min. A patient may experience multiIn classical iSS, the surfaces of posterior fossa structures ple similar stereotypical episodes, referred to as transient such as the cerebellum and brainstem display diffuse hypoinfocal neurological episodes (CAA-TFNEs). The differential tense signals on T2*-GRE sequences, with the cerebellar diagnosis of such symptoms include TIAs, epileptic seizures, lesions more pronounced on the upper surface and vermis and migraine auras, and the involvement of spreading depo- areas. Hypointense lesions are also often observed on the larization similar to migraine auras have also been proposed. surface of the vestibulocochlear nerve, correlating to the It is important to note that if the patient suffering from CAA-­ clinical symptom of hearing impairment. Continuing from TFNE is diagnosed with TIA and treated with antithrombotic the brainstem, the surface of the spinal cord is also layered agents, there is a high possibility that would exacerbate with a hypointense signal on T2*-GRE sequences and the cerebral or subarachnoid hemorrhaging. Therefore, it is spinal cord may display signs of atrophy. The cervical spinal ­ imperative that imaging for hemosiderin deposits be carried cord is often the most intensely affected, but SS can be seen to exclude the possibility of CAA-TFNEs before antithrom- more caudally from the thoracic area down to the conus of botic treatments are administered. the spinal cord. In addition to the evaluation of hemosiderin deposits, another objective of performing the MRI scan of the spine is to search for a possible cause of iSS, including 101.4 Imaging dural defects. Dural defects are often accompanied by ventral epidural fluid collection, and they be associated with The diagnosis of SS is made through MRI. The high levels of osteophytes, herniated discs, or even spinal cord hernias iron deposits can be visualized as low intensity lesions using (Fig. 101.1) (Sugimoto et al. 2005; Kumar et al. 2009; Toro standard T2-weighted MR images, but the sensitivity is sub- et al. 2014).

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Fig. 101.1  T2-weighted magnetic resonance imaging (MRI) of the cervical to upper thoracic spine reveals hypointensity in the superficial areas of the central nervous system which is characteristic of superficial siderosis. An anterior epidural fluid collection spanning the C7 to T10 levels is also visible. Source: Katoh et  al. (2020) published under CCBY 4.0 licenses

101.5 Dural Defects as a Cause of SS While the spinal epidural fluid collection spanning multiple vertebral levels indicates the range within which the dural defect is present, further imaging is required to pinpoint the exact location of the dural defect because it would be unpractical to perform multilevel laminectomy and durotomy in search of a possible dural defect. However, a consensus has not been reached regarding the method to reliably localize the dural defect, and therefore each hospital must improvise according to the available facilities and faculty of the radiological department. There are multiple reports utilizing digital subtraction myelography with a relatively high success rate of identifying the lesion site (Hoxworth et  al. 2012; Schievink et  al. 2019), but the immediate diffusion of the injected contrast medium up and down the epidural cavity

H. Katoh and M. Watanabe

often makes confident identification of the dural defect difficult with myelography. With the development of MRI techniques with high resolution and the capacity for CSF-cisternography, MRI is now the diagnostic tool of choice to visualize dural defects. The different nomenclature for gradient echo sequences by each MR manufacturer makes it difficult to understand the various techniques, but the basic premise is to utilize balanced steady-state free precession (SSFP) sequences that offer high spatial resolution along with a very high signal-to-noise ratio and a T2/ T1-weighted image contrast (Tsuchiya et  al. 2004; Sumi et al. 2007). Even with the relatively high spatial resolution and contrast of modern MRI techniques, the surgeon may not feel sufficiently confident to perform surgery in search of a defect with only this one MRI exam. Therefore, we suggest combining SSFP sequences with kinematic MRI (cine-MRI) sequences that can visualize the motion of CSF through a dural defect into a spinal extradural arachnoid cyst as a pulsating turbulent flow. Recently, Ishibe et  al. used a time-resolved three-­ directional phase-contrast MRI sequence termed time-spatial labeling inversion pulse magnetic resonance imaging (Time-­ SLIP MRI) to detect the communicating hole in cases of spinal extradural arachnoid cysts (Ishibe et al. 2016). Time-SLIP MRI can detect abnormal flow in a designated area, but the process is complicated as well as time consuming. Its merit as well as demerit rise from the fact that it can selectively label and visualize the CSF motion of a targeted area, but it would be unsuitable to search for abnormal flow in a nonspecific and wide area. Instead, we propose a novel sequence developed at our institution termed dynamic iMSDE SSFP, which visualizes the CSF motion of the entire acquired image in a relatively short period of time (Horie et al. 2017, 2021). In a recent case of infratentorial SS, we utilized a balanced turbo field echo (BTFE) MRI sequence to acquire a rapid and high-resolution image of the spinal anatomical structures including the dura mater (Fig.  101.2 as well as Supplemental Video S1 in (Katoh et al. 2020)), followed by dynamic iMSDE SSFP MRI to visualize irregular flow of CSF through the dura defect to localize a dural defect at the T5–T6 level (Fig. 101.3 as well as Supplemental Video S2 in (Katoh et al. 2020)). The dural defect was repaired through a minimal laminectomy and durotomy, leading to the resolution of the anterior fluid collection and most probably the chronic subdural hemorrhaging (Figs. 101.4 and 101.5). The progression of symptoms was not seen after surgery, but improvement in symptoms was limited.

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a

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b

Fig. 101.2  A balanced turbo field echo (BTFE) MRI sequence, which produces images with high spatial resolution and contrast to visualize anatomical structures, reveals a gap in the anterior dura mater at the

T5–T6 level. (a) Sagittal-, and (b): axial-oriented images. Source: Katoh et al. (2020) published under CCBY 4.0 licenses

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Fig. 101.3  A dynamic improved motion-sensitized driven-equilibrium steady-state free precession (dynamic iMSDE SSFP) MRI sequence, which visualizes CSF motion, reveals an irregular flow of CSF through

a

H. Katoh and M. Watanabe

the dura at the T5–T6 level in the middle panel. Source: Katoh et al. (2020) published under CCBY 4.0 licenses

b

Fig. 101.4  Intraoperative images of the T5–T6 dural defect before (a) and after (b) primary suture. In both images, caudal is on the left side of the image and the spinal cord is retracted superiorly. Source: Katoh et al. (2020) published under CCBY 4.0 licenses

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barrier and reach the hemosiderin in the central nervous system, unlike other iron chelators (Fredenburg et al. 1996). There have been reports from multiple countries demonstrating a decrease in the CNS hemosiderin deposits and improvement of symptoms (Levy et  al. 2007; Levy and Llinas 2011, 2012; Kessler et al. 2018), with greater benefits being seen with earlier initiation of treatment (Nose et al. 2022). The side effects of deferiprone are gastrointestinal symptoms, dark urine or stool, increase in hepatic enzymes, and neutropenia, requiring strict monitoring. Furthermore, deferiprone is not covered by health insurance for the treatment of SS in many countries, making it difficult for patients to gain access this treatment. The unfortunate reality for most patients is that most symptoms of SS cannot be effectively reversed with treatment unless diagnosed and treated at an extremely early stage before the irreversible neurodegenerative cascade runs its course. Therefore, most treatments are implemented to help patients accommodate their symptoms and minimize further neurological decline. Physical and occupation therapies support the motor function of patients suffering from gait ataxia, weakness, or myelopathy. SS patients with hearing impairment may benefit from a cochlear implantation.

101.7 Conclusion

Fig. 101.5  T2-weighted MRI of upper spine taken 3 months after surgery confirms the resolution of the anterior epidural fluid collection. Source: Katoh et al. (2020) published under CCBY 4.0 licenses

101.6 Treatment The primary treatment of SS is to achieve hemostasis most often through surgical means, such as repair of the dural defect, resection of tumors, and management of vascular malformations. However, progression of symptoms is often seen in patients even after surgery due to the residual buildup of hemosiderin which cannot be reversed by surgery. The benefits seen from medical treatment for SS remain mixed with some improvement reported after administering steroids (Scheid et al. 2009) and antioxidants (Leussink et al. 2003), but some promising results have been reported by administering iron chelation agents. Deferiprone, an FDA-approved drug for thalassemia, is a lipid-soluble iron chelator that can penetrate the blood–brain

While MRI has made the diagnosis of SS relatively straight-­ forward, the fact of the matter is that many of the symptoms of SS become irreversible when the hemosiderin deposits become apparent on MRI.  This leads to an uncomfortable dilemma for the clinician because an ideal treatment needs to begin before the detrimental effects of hemosiderin deposits become apparent, but that would avert the development of the signature MRI characteristics that leads to a definite diagnosis. However, the unfortunate reality for many patients eventually diagnosed with SS is that their illness remained undiagnosed until the signature MRI characteristics materialized, at which time they were informed of their limited treatment options. Therefore, it is with the wish that this chapter advances the understanding of SS to the point that it becomes diagnosed, or at least suspected, at an earlier time point that would allow medical or surgical interventions to avert the detrimental symptoms of SS.

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H. Katoh and M. Watanabe Kumar S, Goddeau RP Jr, Selim MH, Thomas A, Schlaug G, Alhazzani A, Searls DE, Caplan LR (2010) Atraumatic convexal subarachnoid hemorrhage: clinical presentation, imaging patterns, and etiologies. Neurology 74(11):893–899 Leussink VI, Flachenecker P, Brechtelsbauer D, Bendszus M, Sliwka U, Gold R, Becker G (2003) Superficial siderosis of the central nervous system: pathogenetic heterogeneity and therapeutic approaches. Acta Neurol Scand 107(1):54–61 Levy M, Llinas RH (2011) Deferiprone reduces hemosiderin deposits in the brain of a patient with superficial siderosis. AJNR Am J Neuroradiol 32(1):E1–E2 Levy M, Llinas RH (2012) Update on a patient with superficial siderosis on deferiprone. AJNR Am J Neuroradiol 33(6):E99–E100 Levy M, Turtzo C, Llinas RH (2007) Superficial siderosis: a case report and review of the literature. Nat Clin Pract Neurol 3(1):54–58; quiz 59 Linn J, Herms J, Dichgans M, Brückmann H, Fesl G, Freilinger T, Wiesmann M (2008) Subarachnoid hemosiderosis and superficial cortical hemosiderosis in cerebral amyloid angiopathy. AJNR Am J Neuroradiol 29(1):184–186 Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, van Buchem MA, Bruckmann H, Greenberg SM (2010) Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 74(17):1346–1350 Linn J, Wollenweber FA, Lummel N, Bochmann K, Pfefferkorn T, Gschwendtner A, Bruckmann H, Dichgans M, Opherk C (2013) Superficial siderosis is a warning sign for future intracranial hemorrhage. J Neurol 260(1):176–181 Nose Y, Uwano I, Tateishi U, Sasaki M, Yokota T, Sanjo N (2022) Quantitative clinical and radiological recovery in post-operative patients with superficial siderosis by an iron chelator. J Neurol 269(5):2539–2548 Scheid R, Frisch S, Schroeter ML (2009) Superficial siderosis of the central nervous system—treatment with steroids? J Clin Pharm Ther 34(5):603–605 Schievink WI, Chu RM, Maya MM, Johnson JP, Cohen HC (2013) Spinal manifestations of spontaneous intracranial hypotension. J Neurosurg Spine 18(1):96–101 Schievink WI, Maya MM, Moser FG, Prasad RS, Cruz RB, Nuño M, Farb RI (2019) Lateral decubitus digital subtraction myelography to identify spinal CSF-venous fistulas in spontaneous intracranial hypotension. J Neurosurg Spine 1–4 Shams S, Martola J, Charidimou A, Cavallin L, Granberg T, Shams M, Forslin Y, Aspelin P, Kristoffersen-Wiberg M, Wahlund LO (2016) Cortical superficial siderosis: prevalence and biomarker profile in a memory clinic population. Neurology 87(11):1110–1117 Sugimoto T, Kasai Y, Takegami K, Morimoto R, Maeda M, Uchida A (2005) A case of idiopathic spinal cord herniation with duplicated dura mater. J Spinal Disord Tech 18(1):106–111 Sumi T, Sumi M, Van Cauteren M, Kimura Y, Nakamura T (2007) Parallel imaging technique for the external carotid artery and its branches: comparison of balanced turbo field echo, phase contrast, and time-of-flight sequences. J Magn Reson Imaging 25(5):1028–1034 Toro J, Díaz C, Reyes S, Jeanneret V, Burbano LE (2014) Superficial siderosis related to a thoracic disc herniation with associated dural injury. CNS Neurosci Ther 20(5):469–472 Tsuchiya K, Aoki C, Hachiya J (2004) Evaluation of MR cisternography of the cerebellopontine angle using a balanced fast-field-echo sequence: preliminary findings. Eur Radiol 14(2):239–242 Uttner I, Tumani H, Arnim C, Brettschneider J (2009) Cognitive impairment in superficial siderosis of the central nervous system: a case report. Cerebellum 8(1):61–63 Viswanathan A, Greenberg SM (2011) Cerebral amyloid angiopathy in the elderly. Ann Neurol 70(6):871–880

Ataxia in Multiple Sclerosis

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Giacomo Koch and Danny Adrian Spampinato

Abstract

Keywords

It is well known that the cerebellum is commonly affected in patients with multiple sclerosis (MS), thus making everyday life activities such as walking or picking up objects extremely difficult for patients with advanced stages. Previous reports have discovered that as many as four out of five MS patients experience cerebellar ataxia, which is characterized by the inability to coordinate movements and maintain balance. Unfortunately, no treatment is currently available to effectively treat patient’s symptoms. What makes ataxia particularly challenging for rehabilitation experts is that it can cause widespread damage to both motor and sensory mechanisms of the central nervous system, thus the symptoms that patients exhibit vary tremendously from person to person. As a result of cerebellar damage, MS patients are also incapable of adjusting movements to the ever-changing environment, reflecting a damaged error-based motor learning mechanism that can impede rehabilitation interventions for gait, posture, and upper-limb movements. Here, we will provide a general overview of human cerebellar function and pathophysiology of ataxia and describe how this affects specific features of motor control and motor learning. Moreover, we will discuss clinical assessments of ataxia and detail how non-invasive brain stimulation can improve the symptoms of MS patients with concurrent rehabilitation therapy.

Ataxia · Multiple sclerosis · Cerebellum · Non-invasive brain stimulation · Motor control · Motor recovery

G. Koch (*) Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy e-mail: [email protected] D. A. Spampinato Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy e-mail: [email protected]

102.1 Introduction The cerebellum and its afferent and efferent connections in the central nervous system are often affected in patients with multiple sclerosis (MS). Imaging studies have echoed this notion by demonstrating abnormal cerebellar activation and function in MS patients when compared to matched healthy controls (Saini et al. 2004; Rocca et al. 2007). As the cerebellum is a region that integrates a tremendous amount of neural information (sensory, visual, proprioceptive, and even cognitive) necessary for conducting and coordinating movements in a smooth and timely fashion, damage to this region can make daily activities like getting dressed and walking extremely difficult for patients. It is reported that the vast majority of patients display cerebellar symptoms of ataxia and tremor at some point in their life (Wilkins 2017). This can also be accompanied by weakness, spasticity, or reduced somatosensory or visual input (Wilkins 2017). Besides the physical aspects, patients can also suffer from fatigue, depression, and sleep disorders, in part, due to the taxing effects of limited daily life function and the important role the cerebellum plays in cognition (Mariotti et  al. 2005; Rodríguez-Labrada et  al. 2011). For instance, recent work found that selective atrophy of particular cerebellar lobules was associated with fatigue at the clinical onset of MS (Lazzarotto et al. 2020). This is important to consider since fatigue is a debilitating symptom for patients as they have the perception that they are unable to perform physical and mental tasks, which represents a major obstacle for rehabilitation strategies. On the other hand, of all the motor issues associated with MS, ataxia is the most visible and potentially most damaging symptom since it causes unsteadiness or incoordination, which ultimately affects posture, gait, arm-reaching, and eye movements.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_102

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To understand how ataxia affects daily life activities, it is first critical to consider how different cerebellar regions contribute to the control of various motor and cognitive behaviors. Functionally, the cerebellum can be divided into three denominations: vestibulocerebellum (flocculonodular lobe), spinocerebellum (vermis and intermediate parts of the hemisphere), and cerebrocerebellum (lateral hemisphere) (Voogd and Glickstein 1998). Appreciation for these zones becomes clear with animal lesion studies. For instance, lesions to the vestibulocerebellum result in gait and balance dysfunction, as well as the inability to control eye movements (Leiner et al. 1987). In support of this, patients with vestibulocerebellar ataxia have postural instability (including the upper limbs), nystagmus, and tinnitus in some of them (Dichgans 1984). Lesions to the intermediate and lateral cortex are of particular interest to upper-limb function. “Knocking out” the interpositus nucleus (intermediate zone of the spinocerebellum) in monkeys causes tremors and skews the balance of agonist-antagonist muscle activity of the limb as it moves (Thach et al. 1992). Spinocerebellar ataxia can produce incoordination of gait, while also degrading the overall function of the hands and eye movements. Furthermore, functional ablation of the dentate nucleus (lateral hemisphere) impairs the coordination of multi-jointed movements (Topka et  al. 1998). This is evident in monkey studies, where inactivation of the dentate nucleus resulted in impaired and abnormally resonating reaching movements (Thach et  al. 1992). Diminished finger dexterity was also noted in this study and human patient examination. Overall, it is clear that damage to specific cerebellar regions can impede specific aspects of movement control.

102.2 Ataxia in Motor Control From neural recording and lesion studies, it is also clear the cerebellum exerts control over the flexibility of these behaviors since it receives information about motor commands and sensory consequences of movement. Because of this, the cerebellum has been suggested to act as a comparator that detects the difference (i.e., motor error) between an intended movement and the actual movement and then uses this error to make appropriate corrections throughout the continuous movement (Leiner et al. 1987). This is evident, for example, in the reaching movements that often have hand paths that are highly curved and tend to be quite variable from reach to reach. Indeed, MS patients with ataxia may have difficulty in accurately controlling the force, direction, velocity, and pattern of muscle contractions, leading to highly uncoordinated movements. An underlying inability to account for complex limb mechanics may cause this abnormal curvature (Bastian et al. 1996). Consistent with this idea, patients show greater

G. Koch and D. A. Spampinato

deficits when they reach quickly and move many joints or body parts simultaneously. Patients compensate by moving more slowly and breaking movements down into simpler components, a phenomenon originally characterized as the decomposition of movement (Holmes 1939). During arm reaching, it is also common for patients to display dysmetria, a form of ataxia that leads to the overshooting or undershooting of movements. As a result, this requires patients to make several corrective movements to reach the desired location or target. As a result, patients display reaching trajectories that are highly erratic and have prolonged movement paths compared to neurologically healthy individuals. Animal and human studies have suggested that ataxia-related dysmetria may be due to a lack of agonist-antagonist muscle control (Vilis and Hore 1977; Hore et al. 1991). This is evident in the scenario of initiating a movement: an agonist muscle will burst to help accelerate the upper limb; however, there is an extended agonist response and a delayed response from the antagonist muscle (which helps decelerate the limb), thus causing an overshoot in this situation (Brown et al. 1990; Hallett and Massaquoi 1993). This is seen commonly in diagnostic tests where patients are asked to repeatedly move the tip of their finger from their nose to set position (i.e., to the finger of the clinician testing the patient). During this test, it is common to see several submovements to both final positions with either under-shooting (hypometria) or over-shooting (hypermetria) (Manto 2009). Another aspect of ataxia that leads to erroneous movements is dyssynergia, which is the incorrect ordering or co-­ activation of muscle contractions for agonist-antagonist muscles. Dyssynergia is an interesting consideration for rehabilitation because this phenomenon, to a degree, results from an inability of the damaged cerebellum to compensate for movement-induced interaction torques (Bastian et  al. 2000). As a result, patients display slow reaction times and adjust their movements by making simple, single-jointed movements. This is also marked by another common symptom seen in patients (Day et al. 1998) termed dysdiadochokinesia, or the inability to perform rapidly alternating movements is regularly tested for by having patients move their hand alternatively palm up and palm down as fast as possible. Patients struggle to initiate movements and make the required alternating motions. Moreover, decreased intra-­ limb coordination is evident between both upper limbs at high movement velocities (Vilis and Hore 1977). This is likely due to a combination of dyssynergia and a mass input– output computation for the cerebellum to execute a planned voluntary movement. Overall, several motor issues can arise from ataxia, which is important to consider when developing potentially useful rehabilitation strategies. Several of these symptoms can occur simultaneously, and with age, many of

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these dysfunctions worsen. Understanding how patients with cerebellar damage, along with these symptoms, can learn (or re-learn) new motor tasks is critical for helping design novel and scientifically based rehabilitation interventions.

102.3 Ataxia and Motor Learning Evidence from several lines of work has implicated the cerebellum as a critical structure involved in error-based learning tasks such as motor adaptation (Martin et  al. 1996; Diedrichsen et al. 2005). Error-based learning refers to the process of developing forward internal models (i.e., a model capable of predicting the consequences of a motor command) by reducing errors that relay the difference between predicted sensory consequences of a motor command and the resulting sensory feedback. The presence of this error, known as sensory prediction error, is important because the motor system uses this discrepancy to immediately adjust the subsequent motor output, resulting in errors that are corrected on a trial-by-trial basis. This process of error-based learning is vital to performing daily activities such as walking on two different surfaces (i.e., concrete vs. sand), which will require different motor outputs from the cerebellum. Animal and human physiological studies have demonstrated that error-based learning leads to plastic change within the cerebellum (Medina and Lisberger 2008; Jayaram et  al. 2011; Schlerf et al. 2012). Moreover, works in patients with cerebellar damage have shown that patients display deficits in reducing their sensory prediction errors, which ultimately leads to patients not fully adapting to novel environmental settings (Tseng et  al. 2007). In clinical settings, physical therapists attempt to stimulate error-based learning by giving patients detailed sensory feedback; however, patients with severe ataxia are unable to use this feedback to correct movements. Fortunately, the brain uses other learning mechanisms that are not entirely reliant on the cerebellum, which can aid patient rehabilitation. Reinforcement learning is another mechanism of learning that relies simply on an outcome measure that is based on either success or failure. This mechanism requires individuals to explore motor actions to determine which movement maximizes successful outcomes. Similar to error-based learning, reinforcement learning is driven by comparing an expected and observed outcome, however, learning in this mechanism is driven by a reward prediction error that relates to the probability of an action resulting in a success (Sutton and Barto 1999), thought to rely on circuits involving the basal ganglia (Schultz 2006). Interestingly, recent work has shown that cerebellar ataxia patients’ reinforcement learning is intact and could be used to improve a feature of their reaching ataxia (Therrien et al. 2016). Indeed, reinforcement

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training was capable of reducing the prolonged path lengths that characterize reaching ataxia, which could not be achieved with error-based learning. Overall, these findings suggest that MS patients with ataxia may learn better when less movement feedback is given and suggest that future rehabilitation strategies should integrate reinforcement learning to improve patients’ motor output.

102.4 Assessment of Ataxia There are a handful of assessment tools that clinicians used to determine the degree of upper-and lower-limb function in ataxic patients. To date, one of the most commonly used assessment tools is the International Cooperative Ataxia Rating Scale (ICARS), due to being one of the most reliable tests available (Yelnik and Bonan 2008). This measure includes an assessment of 19 different times that include subscales scored for postural/gait, dysarthria, oculomotor disorders, and limb dysfunction. The scale is scored out of 100 with each subscale section having an ordinal scale from 0 to 4. A score of 0 indicates normal function, whereas a higher score reflects greater impairment or inability to complete the task. Additionally, clinicians often use the Scale for the Assessment and Rating of Ataxia (SARA), an eight-item performance based scale that includes the aforementioned finger-nose test and the tapping test (Yabe et al. 2008), along assessments of gait, stance, sitting, and speech disturbance. Examination of ocular movements is missing. Of note, while these clinical exams incorporate several elements of ataxic symptoms, they fail to provide details regarding the overall quality of movement, such as an analysis of patient arm reaching trajectory curves. Nevertheless, the ICARS and SARA examinations have been recently found to be reliable in MS patients with ataxia (Salcı et al. 2017), in particular for discriminating mild and moderate ataxia. Since the cerebellum is highly involved in continuously monitoring and adjusting motor movements, it receives constant sensory feedback from multiple modalities (i.e., vision and proprioception). Therefore, an assessment of sensory consequences of self-generated movements should be assessed. The current clinical scales do not provide meaningful information about perceptual deficits even though the cerebellum plays a critical role in active proprioception (Bhanpuri et al. 2012). Given the importance of the cerebellum for these movements, we highly suggest that current assessment scales should also include an active perception task. For example, a clinician could ask a patient to lift a liquid-filled mug. If the patient has good active proprioception, then they will lift the cup without spilling. Adding a proprioceptive component to current scales will provide a more efficient upper-limb assessment and would be a simple

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addition that would not prolong the time of the current analysis, and it could be scored similarly to the ICARS. Nonetheless, current assessment scales need to include a proprioceptive component to more accurately interpret ataxic deficits.

G. Koch and D. A. Spampinato

On the other hand, when plasticity protocols like repetitive (r)TMS and tDCS are applied over the cerebellum, stimulation can be used to make causal inferences about brain function by enhancing neuronal processing. When applied over the cerebellum in healthy individuals, rTMS and tDCS have been demonstrated to affect CBI (Galea et  al. 2009; Koch 2010) and improve error-based learning mechanisms 102.5 Non-invasive Brain Stimulation in motor adaptation tasks (Galea et  al. 2011; Koch et  al. Studies to Assess Ataxia or Improve 2020). On this basis, several studies have attempted to inteSymptoms grate plasticity protocols in rehabilitation regimes and/or clinical assessments of cerebellar ataxia to improve motor Two common non-invasive techniques to stimulate the cere- function in patients. Of the plasticity protocols, rTMS has bellum non-invasively include transcranial magnetic stimu- been the most successful for improving MS symptoms that lation (TMS), and transcranial direct current stimulation relate to cerebellar dysfunction (Koch et al. 2008; Elzamarany (tDCS). Single and paired-pulse TMS techniques can assess et al. 2016), spasticity (Centonze et al. 2007; Kateva et al. the integrity of the corticospinal tract and the connectivity 2018; Şan et  al. 2019), cognitive dysfunction, and fatigue between the cerebellum and primary motor cortex (M1). (Korzhova et al. 2019; Şan et al. 2019). These techniques can detect changes in cerebellar and cortiConcerning MS patients, Koch et  al. investigated how cal excitability following an intervention, thus providing a 5-Hz rTMS over the left M1 improved manual dexterity in manner to quantify the effects of plasticity on these brain patients with cerebellar symptoms (dysmetria, dysarthria, regions. dysdiadochokinesia, gait, and balance disorders). Relative to When applied over M1, TMS causes a contralateral mus- sham and healthy controls, 5-Hz stimulation significantly cle twitch that can be recorded with electromyography. This reduced the time patients needed to complete the nine-hole amplitude of this response, termed the motor evoked poten- pegboard tasks that assess manual dexterity. The authors tial (MEP), is commonly used to measure the excitability of argued that the recovery of cerebellar function due to M1 the corticospinal tract. Interestingly, if a conditioning stimu- rTMS could be due to two separate ideas. One possibility is lation is delivered to the cerebellum 5 ms before a pulse is that stimulation may directly influence Cerebropontine-­ applied over M1, the MEP amplitude is modified. Since the cerebellar projections. Alternatively, stimulation may have cerebellar cortex is inhibitory, stimulation of the cerebellum modulated the activity of M1 interneurons that receive proresults in a smaller MEP, a phenomenon known as Cerebellar-­ jections from the cerebellum, thereby counteracting the Brain Inhibition (CBI) (Ugawa et al. 1995). Indeed, CBI has reduced drive from the cerebellum in patients. Importantly, it been interpreted as the result of the conditioning pulse acti- is critical to note that the positive effects on manual dexterity vating Purkinje cells of the cerebellum inhibiting the deep were seen up to 10 min following stimulation, but not after cerebellar nuclei which in turn has a disynaptic excitatory 20  min. This indicates that the observed improvements are connection through the thalamus to the motor cortex only transient and suggests that multiple sessions of rTMS (Spampinato and Celnik 2021). Of note, the strength of CBI are likely needed to have a more lasting effect on patients’ in healthy individuals is associated with movement variabil- movement quality. Interestingly, Elzamarany et  al. tested ity (Schlerf et al. 2015) and is modulated with error-based whether having MS patients with dysmetria undergo two conmotor learning (Spampinato and Celnik 2018). Moreover, a secutive sessions of rTMS provided long-term improvement recent report has shown that CBI has low measurement error on the nine-hole pegboard test. Here, patients either real 5-Hz for tracking intra- and interday changes in cerebellar con- rTMS on 2 consecutive days or a single session of real 5-Hz nectivity, thus it can be considered a reliable measure to rTMS followed by a session of sham rTMS and were comassess the modulation of this pathway with interventions or pared to healthy controls who received two real sessions. disease progression (Mooney et al. 2021). Although CBI has Relative to single session patient group and controls, patients not been measured previously in MS patients, individuals receiving real rTMS con consecutive days showed significant with cerebellar ataxia due to lesions in the cerebellar efferent improvement of manual dexterity immediately following the pathway have a CBI response that is either significantly second session and in a 1-month follow-­up session. Overall, reduced or absent (Ugawa et al. 1997). Thus, CBI is a reli- these results suggest that targeting M1 administering this able tool to measure cerebellar-M1 connectivity and should technique may be particularly useful in treating cerebellar be considered for future studies with MS patients, in particu- functional impairment in patients with MS. lar, to track whether changes in connectivity are found folApplying plasticity protocols directly over the cerebellum lowing an intervention or pharmacological treatment. to prove ataxia symptoms, on the other hand, has only

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recently received more attention in MS patients. For instance, one study demonstrated that another form of repetitive TMS, termed intermittent theta-burst (iTBS), improved MS patients’ gait, and balance abilities (Tramontano et al. 2020). Here, a group of 20 patients received cerebellar iTBS, while undergoing a vestibular rehabilitation exercise that aimed to improve gaze stability and balance. The authors found that the combination of stimulation and rehabilitation greatly improved various clinical scores evaluating gait and balance when compared to sham stimulation. One important implication of these findings is that directly stimulating the cerebellum of MS patients can enhance motor control function, thus the potential for targeting this brain region to ameliorate ataxic symptoms in patients is promising. Along these lines, a recent study conducted in patients with neurodegenerative ataxia found promising results for the long-term application of a tDCS montage that stimulates the cerebellum and spinal cord simultaneously (tDCS for 5  days/week for 2  weeks) (Benussi et  al. 2021). This double-blind, sham-controlled study evaluated clinical and neurophysiological outcome measures before and following the treatment. The authors found that real tDCS compared to sham showed improved SARA and ICARS scores, which were visible both immediately and at a 12-week follow-up. Importantly, at the 12-week follow-up, all patients (sham and real tDCS) received a second treatment of tDCS and their SARA and ICARS were evaluated at 24-, 36-, and 52-weeks following the initial treatment. Here, the authors found an add-on effect after two repeated treatments with real tDCS compared to a single treatment, which was found still prominent at the 52-week follow-up. Interestingly, the authors also found that the improvements in SARA and ICARS were linked to the amount of restored cerebellar activity, measured with paired-­ pulse TMS technique CBI. In conclusion, these novel studies specifically aiming to ameliorate ataxia symptoms in MS, provide a solid foundation for future studies to apply stimulation directly over the cerebellum.

102.6 Suggestions and Concluding Remarks Providing an effective rehabilitation intervention to improve motor control is critical for increasing the quality of life for MS patients. In this chapter, we have covered the roles of the cerebellum in the control of voluntary movements and highlighted some of the current assessment measures for ataxia and how brain stimulation can be used in rehabilitation settings. As noted, current assessment scales need to be improved by adding more elements that can better characterize certain features of ataxia. For example, ocular motor analyses via eye-tracking technology can reveal subtle cerebellar symptoms such as saccadic dysmetria and discrete nystagmus, as well as cognitive deficits early in the disease

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course (Moroso et  al. 2017, 2018). Accurately identifying how severe the ataxia is in MS patients is a critical first step to providing the correct treatment to improve their motor and cognitive function. Currently, there are several rehabilitation techniques available that use either compensatory or restorative approaches. Using one of these approaches each have their advantages depending on the severity and situation of the patient. In this regard, incorporating reinforcement learning provides a promising future for therapy, as this learning process predominately involves other brain areas that help compensate for the malfunctioning cerebellum. Furthermore, we suggest implementing non-invasive brain stimulation like rTMS and tDCS for future restorative approaches, since these plasticity protocols have been shown to improve clinical scores of ataxia.

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684 Holmes G (1939) The cerebellum of man. Brain 62(1):1–30 Hore J, Wild B, Diener HC (1991) Cerebellar dysmetria at the elbow, wrist, and fingers. J Neurophysiol 65(3):563–571 Jayaram G, Galea JM, Bastian AJ, Celnik P (2011) Human locomotor adaptive learning is proportional to depression of cerebellar excitability. Cereb Cortex (New York, N.Y.: 1991) 21(8):1901–1909 Kateva V, Kmetska K, Milushev E, Milanov I (2018) Muscle spasticity and the effects of repetitive transcranial magnetic stimulation in patients with multiple sclerosis. J Neurol Neurosci 9:39 Koch G (2010) Repetitive transcranial magnetic stimulation: a tool for human cerebellar plasticity. Funct Neurol 25(3):159–163 Koch G, Rossi S, Prosperetti C, Codecà C, Monteleone F, Petrosini L, Bernardi G, Centonze D (2008) Improvement of hand dexterity following motor cortex rTMS in multiple sclerosis patients with cerebellar impairment. Mult Scler (Houndmills, Basingstoke, England) 14(7):995–998 Koch G, Esposito R, Motta C, Casula EP, Di Lorenzo F, Bonnì S, Cinnera AM, Ponzo V, Maiella M, Picazio S, Assogna M, Sallustio F, Caltagirone C, Pellicciari MC (2020) Improving visuo-motor learning with cerebellar theta burst stimulation: behavioral and neurophysiological evidence. NeuroImage 208:116424 Korzhova J, Bakulin I, Sinitsyn D, Poydasheva A, Suponeva N, Zakharova M, Piradov M (2019) High-frequency repetitive transcranial magnetic stimulation and intermittent theta-burst stimulation for spasticity management in secondary progressive multiple sclerosis. Eur J Neurol 26(4):680–e44 Lazzarotto A, Margoni M, Franciotta S, Zywicki S, Riccardi A, Poggiali D, Anglani M, Gallo P (2020) Selective cerebellar atrophy associates with depression and fatigue in the early phases of relapse-onset multiple sclerosis. Cerebellum (London, England) 19(2):192–200 Leiner HC, Leiner AL, Dow RS (1987) Cerebro-cerebellar learning loops in apes and humans. Ital J Neurol Sci 8(5):425–436 Manto M (2009) Mechanisms of human cerebellar dysmetria: experimental evidence and current conceptual bases. J Neuroeng Rehabil 6:10 Mariotti C, Fancellu R, Di Donato S (2005) An overview of the patient with ataxia. J Neurol 252(5):511–518 Martin TA, Keating JG, Goodkin HP, Bastian AJ, Thach WT (1996) Throwing while looking through prisms. I.  Focal olivocerebellar lesions impair adaptation. Brain 119(Pt 4):1183–1198 Medina JF, Lisberger SG (2008) Links from complex spikes to local plasticity and motor learning in the cerebellum of awake-behaving monkeys. Nat Neurosci 11(10):1185–1192 Mooney RA, Casamento-Moran A, Celnik PA (2021) The reliability of cerebellar brain inhibition. Clin Neurophysiol 132(10):2365–2370 Moroso A, Ruet A, Deloire M, Lamargue-Hamel D, Cubizolle S, Charré-Morin J, Saubusse A, Brochet B (2017) Cerebellar assessment in early multiple sclerosis. Cerebellum (London, England) 16(2):607–611 Moroso A, Ruet A, Lamargue-Hamel D, Munsch F, Deloire M, Ouallet JC, Cubizolle S, Charré-Morin J, Saubusse A, Tourdias T, Dousset V, Brochet B (2018) Preliminary evidence of the cerebellar role on cognitive performances in clinically isolated syndrome. J Neurol Sci 385:1–6 Rocca MA, Pagani E, Absinta M, Valsasina P, Falini A, Scotti G, Comi G, Filippi M (2007) Altered functional and structural connectivities in patients with MS: a 3-T study. Neurology 69(23):2136–2145 Rodríguez-Labrada R, Velázquez-Perez L, Ochoa NC, Polo LG, Valencia RH, Cruz GS, Montero JM, Laffita-Mesa JM, Mederos LE, Zaldívar YG, Parra CT, Acosta AP, Mariño TC (2011) Subtle rapid eye movement sleep abnormalities in presymptomatic spinocerebellar ataxia type 2 gene carriers. Mov Disord 26(2):347–350

G. Koch and D. A. Spampinato Saini S, DeStefano N, Smith S, Guidi L, Amato MP, Federico A, Matthews PM (2004) Altered cerebellar functional connectivity mediates potential adaptive plasticity in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 75(6):840–846 Salcı Y, Fil A, Keklicek H, Çetin B, Armutlu K, Dolgun A, Tuncer A, Karabudak R (2017) Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia. Mult Scler Relat Disord 18:135–140 Şan AU, Yılmaz B, Kesikburun S (2019) The effect of repetitive transcranial magnetic stimulation on spasticity in patients with multiple sclerosis. J Clin Neurol (Seoul, Korea) 15(4):461–467 Schlerf JE, Galea JM, Bastian AJ, Celnik PA (2012) Dynamic modulation of cerebellar excitability for abrupt, but not gradual, visuomotor adaptation. J Neurosci 32(34):11610–11617 Schlerf JE, Galea JM, Spampinato D, Celnik PA (2015) Laterality differences in cerebellar-motor cortex connectivity. Cereb Cortex (New York, N.Y.: 1991) 25(7):1827–1834 Schultz W (2006) Behavioral theories and the neurophysiology of reward. Annu Rev Psychol 57:87–115 Spampinato D, Celnik P (2018) Deconstructing skill learning and its physiological mechanisms. Cortex 104:90–102 Spampinato D, Celnik P (2021) Multiple motor learning processes in humans: defining their neurophysiological bases. Neuroscientist 27(3):246–267 Sutton R, Barto A (1999) Reinforcement learning. MIT Press Thach WT, Goodkin HP, Keating JG (1992) The cerebellum and the adaptive coordination of movement. Annu Rev Neurosci 15:403–442 Therrien AS, Wolpert DM, Bastian AJ (2016) Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise. Brain 139(Pt 1):101–114 Topka H, Konczak J, Dichgans J (1998) Coordination of multi-joint arm movements in cerebellar ataxia: analysis of hand and angular kinematics. Exp Brain Res 119(4):483–492 Tramontano M, Grasso MG, Soldi S, Casula EP, Bonnì S, Mastrogiacomo S, D’Acunto A, Porrazzini F, Caltagirone C, Koch G (2020) Cerebellar intermittent theta-burst stimulation combined with vestibular rehabilitation improves gait and balance in patients with multiple sclerosis: a preliminary double-blind randomized controlled trial. Cerebellum (London, England) 19(6):897–901 Tseng YW, Diedrichsen J, Krakauer JW, Shadmehr R, Bastian AJ (2007) Sensory prediction errors drive cerebellum-dependent adaptation of reaching. J Neurophysiol 98(1):54–62 Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I (1995) Magnetic stimulation over the cerebellum in humans. Ann Neurol 37(6):703–713 Ugawa Y, Terao Y, Hanajima R, Sakai K, Furubayashi T, Machii K, Kanazawa I (1997) Magnetic stimulation over the cerebellum in patients with ataxia. Electroencephalogr Clin Neurophysiol 104(5):453–458 Vilis T, Hore J (1977) Effects of changes in mechanical state of limb on cerebellar intention tremor. J Neurophysiol 40(5):1214–1224 Voogd J, Glickstein M (1998) The anatomy of the cerebellum. Trends Neurosci 21(9):370–375 Wilkins A (2017) Cerebellar dysfunction in multiple sclerosis. Front Neurol 8:312 Yabe I, Matsushima M, Soma H, Basri R, Sasaki H (2008) Usefulness of the scale for assessment and rating of ataxia (SARA). J Neurol Sci 266(1–2):164–166 Yelnik A, Bonan I (2008) Clinical tools for assessing balance disorders. Neurophysiol Clin 38(6):439–445

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CANVAS Mario Manto and Joao Lemos

Abstract

CANVAS designates a disorder characterized by a complex phenotype combining cerebellar ataxia, sensory axonal neuropathy, and bilateral vestibular areflexia. Chronic cough and dysautonomia are common. The sensory neuropathy and vestibular areflexia are the consequences of ganglionopathy. The genetic defect is a biallelic expansion in the second intron of replication factor C subunit 1 (RFC1) gene. The pentanucleotide AAAAG is normally repeated 11 times. In patients, the sequence is changed to AAGGG and is expanded from hundreds to thousands of times. The pathogenic repeat expansion is inherited in a recessive manner, suggesting a loss of gene function. There is currently no effective therapy. Keywords

Cerebellar ataxia · Peripheral neuropathy · Vestibular areflexia · RFC1 gene

103.1 Introduction In the 1990s, neurotologists have reported patients showing a pattern of slowly progressive vestibular dysfunction associated with cerebellar ataxia. One peculiar feature was the presence of an abnormal visuo-vestibular ocular reflex (VVOR) (Waterston et al. 1992). The pattern of slowly progressive late-onset ataxia associated with bilateral vestibuM. Manto (*) Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU-­Charleroi, Charleroi, Belgium Service des Neurosciences, Université de Mons, Mons, Belgium e-mail: [email protected] J. Lemos Department of Neurology, Coimbra University Hospital Centre, Coimbra, Portugal Faculty of Medicine, Coimbra University, Coimbra, Portugal

lopathy emerged as a possible distinct syndrome in 2004 (Migliaccio et  al. 2004). Axonal sensory neuropathy was subsequently reported in association with cerebellar ataxia and vestibulopathy (Zingler et al. 2007). The terminology of CANVAS (cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome) was coined in 2011 from a cohort study gathering 18 patients (Szmulewicz et al. 2011a, b). The estimated disease prevalence at birth ranges from 1:10,000 to 1:650 individuals (Cortese et al. 2020).

103.2 Clinical Presentation The mean age of onset is just over 50  years. The disease may present either sporadically or may occur in siblings. Patients complain of progressive unsteadiness, often worsening in darkness. Postural and limb ataxia results from a combination of cerebellar, proprioceptive, and vestibular deficits (Dupré et al. 2021). Cerebellar involvement further manifests clinically with spontaneous (often downbeat) and gaze-­evoked nystagmus, dysmetric saccades, broken ocular pursuit, dysarthria, and dysphagia. Patients frequently report oscillopsia, which may be static due to the presence of spontaneous downbeat nystagmus, or more commonly, dynamic (i.e., elicited during head movements), due to a profound bilateral impairment of the vestibulo-ocular reflex (VOR). The latter can be confirmed at the bedside by the detection of overt refixation saccades (catch-up saccades) after rapid head movements to either side (i.e., head impulse), while patients fixate on a stationary target. Characteristically in CANVAS, even slower head movements from side to side will also lead to catch-up saccades (i.e., abnormal VVOR), due to additional involvement of ocular pursuit and optokinetic eye movements. Other cerebellar-related ocular motor disorders including saccadic intrusions or oscillations, periodic alternating nystagmus, central positional nystagmus, skew deviation, or esotropia have not been described so far (Dupré et al. 2021). Patients report symptoms suggestive of a peripheral neuropathy such as loss of feeling, “pins and

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_103

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needles” (paresthesia) and unpleasant sensation in response to touch (dysesthesia) (Dominik et al. 2021). The disorder may manifest as an isolated sensory neuropathy. Chronic dry cough is common. Cough may appear up to 30  years before neurological onset (Cortese et al. 2020). About onethird of patients present dysautonomic symptoms. Some patients show signs of motor neuron disease and others parkinsonism. There is often intrafamilial variability in age at onset and severity of clinical features (Dominik et al. 2021). The clinical progression of the disorder is mainly slow, with a small handicap for decades (Dupré et al. 2021).

103.3 Neurophysiological Investigations Nerve conduction studies demonstrate non-length dependent sensory neuropathy in all patients, contrasting with normal motor nerve conduction testing (Cortese et al. 2019). A slight

M. Manto and J. Lemos

alteration of motor conduction testing is sometimes observed. H-reflexes are reduced or abolished, whereas latencies of F-waves are spared. Vestibular impairment is shown by bilaterally abnormal video head impulse test (vHIT) (Fig.  103.1), bilaterally reduced caloric response, or reduced VOR gain assessed using a rotatory chair. The VOR is absent or severely reduced (Dupré et al. 2021). VVOR laboratory evaluation still needs standardized assessment, but VVOR gain seems to be significantly lower in CANVAS patients than in patients with isolated bilateral vestibular failure (ReyMartinez et al. 2018). Dysautonomia is common and may be demonstrated by specialized techniques assessing the autonomous nervous system. Patients develop orthostatic hypotension (Szmulewicz et al. 2014).

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Fig. 103.1  Video head impulse test (vHIT) of the two horizontal semicircular canals (SCCs) in a CANVAS patient. To evaluate each SCC vestibulo-ocular reflex (VOR), the patient’s head is briskly moved in the maximally excitatory direction for each SCC plane (i.e., rightward rotation for the right horizontal SCC, and leftward rotation for the left horizontal SCC) while the patient keeps fixating a visual target at 1.5-m distance. In a normal individual, the eyes will move in the opposite direction at equal velocity, giving rise to a gain of eye velocity/head

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velocity of approximately 1. Note the abnormally low VOR gains at 60 ms (0.69, 0.64) for the right and left SCCs, respectively (the peak of gray curves—head velocity—markedly surpasses the peak of black curves—eye velocity—at ∼60 ms). To compensate for such low gain, the eyes drift back at the end of the head impulse (overt corrective saccades). CANVAS Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

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103.4 Neuroimaging Cerebellar atrophy is found at the level of the vermis (lobules VI, VIIa, VIIb) and hemispheric Crus I (Dupré et al. 2021). MRI spinal cord abnormalities (related to posterior cord injury) have been reported in 42 patients genetically determined, under the form of posterior cord atrophy and T2 hypersignals (Cortese et al. 2020).

103.5 Genetics In a healthy subject, the second intronic region of the RFC1 gene shows a pentanucleotide AAAAG which is present 11 times in most cases. In patients, the sequence is AAGGG and is expanded from less than several hundred to more than 2000 times (Dominik et  al. 2021). The mutation is pathogenic when both alleles are affected. The pathogenic alleles are fully penetrant. The biallelic mutant AAGGG expansion is the only conformation causing the disease. The following repeats are non-pathogenic: AAAAG, AAAGG, AAGAG, and AGAGG (Cortese et  al. 2019; Akcimen et  al. 2019). Genetic testing is based on RP-PCR and flanking PCR. Southern blotting is used to confirm the PCR results and remains the gold standard. There is no correlation between the size of the repeat and the age of onset.

assess in MSA as a result of the frequent cold and swollen feet with edema (Sullivan et  al. 2021). Vestibular deficit is relatively common in chronic inflammatory demyelinating polyneuropathy, but it is relatively mild.

103.8 Treatment There is still no cure. Combinations of motor, vestibular, and sensory rehabilitation are proposed, with limited benefits.

103.9 Conclusion and Future Directions CANVAS is likely underdiagnosed or misdiagnosed due to the complex phenotype resulting in a challenging diagnosis. The involvement of the cerebellum or peripheral nerves might be subtle in some patients. Because the timing of involvement of the three components (vestibular, cerebellar, peripheral nerves) may differ, the patient has to be retested clinically/electrophysiologically on a regular basis (Dupré et al. 2021). The pathogenic mechanism is not established. The recessive inheritance point toward a loss of gene function but there is no clear reduction in the expression of the canonical RFC1 transcript or protein (Cortese et al. 2019). Declaration Funding  No specific funding related to this chapter.

103.6 Neuropathology Nerve biopsy reveals a severe axonal neuropathy predominantly in myelinated fibers (Cortese et  al. 2019). A severe neuronal loss of the sensory nerve ganglia, the vestibular/ facial/trigeminal nerves and of the dorsal root of spinal cord is found (Szmulewicz et al. 2014). The spinal cord specimen shows a severe atrophy of dorsal root and posterior column. Purkinje cell loss predominates in the anterior/superior level and VIIa vermal part.

103.7 Differential Diagnosis CANVAS is a differential diagnosis of late-onset ataxia. In particular, CANVAS should be distinguished from Friedreich ataxia (FA), spinocerebellar ataxias (SCAs, especially SCA1 and SCA3), mitochondrial disorders (especially POLG disorders), and multiple system atrophy (MSA). Atypical presentations of MSA should be screened for RFC1 expansion, taking into account that sensory neuropathy is difficult to

Conflict of Interests  The author declares no conflict of interest. Ethical Committee Request  Not applicable.

References Akcimen F, Ross JP, Bourassa CV, Liao C, Rochefort D, Gama MTD, Dicaire MJ, Barsottini OG, Brais B, Pedroso JL, Dion PA, Rouleau GA (2019) Investigation of the RFC1 repeat expansion in a Canadian and a Brazilian ataxia cohort: identification of novel conformations. Front Genet 10:1219 Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Zuchner S, Reilly MM, Houlden H (2019) Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet 51:649–658 Cortese A, Tozza S, Yau WY, Rossi S, Beecroft SJ, Jaunmuktane Z, Dyer Z, Ravenscroft G, Lamont PJ, Mossman S, Chancellor A, Maisonobe T, Pereon Y, Cauquil C, Colnaghi S, Mallucci G, Curro R, Tomaselli PJ, Thomas-Black G, Sullivan R, Efthymiou S, Rossor

103 CANVAS AM, Laura M, Pipis M, Horga A, Polke J, Kaski D, Horvath R, Chinnery PF, Marques W, Tassorelli C, Devigili G, Leonardis L, Wood NW, Bronstein A, Giunti P, Zuchner S, Stojkovic T, Laing N, Roxburgh RH, Houlden H, Reilly MM (2020) Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. Brain 143:480–490 Dominik N, Galassi Deforie V, Cortese A, Houlden H (2021) CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions. J Neurol 268(3):1119–1126 Dupré M, Hermann R, Froment Tilikete C (2021) Update on cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Cerebellum 20(5):687–700 Migliaccio AA, Halmagyi GM, McGarvie LA, Cremer PD (2004) Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign. Brain 127(Pt 2):280–293 Rey-Martinez J, Batuecas-Caletrio A, Matiño E, Trinidad-Ruiz G, Altuna X, Perez-Fernandez N (2018) Mathematical methods for measuring the visually enhanced vestibulo-ocular reflex and preliminary results from healthy subjects and patient groups. Front Neurol 9:69 Sullivan R, Yau WY, Chelban V, Rossi S, Dominik N, O’Connor E, Hardy J, Wood N, Cortese A, Houlden H (2021) RFC1-related ataxia

689 is a mimic of early multiple system atrophy. J Neurol Neurosurg Psychiatry 92(4):444–446 Szmulewicz DJ, Waterston JA, MacDougall HG, Mossman S, Chancellor AM, McLean CA et al (2011a) Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis. Ann N Y Acad Sci 1233:139–147 Szmulewicz DJ, Waterston JA, Halmagyi GM, Mossman S, Chancellor AM, McLean CA, Storey E (2011b) Sensory neuropathy as part of the cerebellar ataxia neuropathy vestibular areflexia syndrome. Neurology 76:1903–1910 Szmulewicz DJ, McLean CA, Rodriguez ML, Chancellor AM, Mossman S, Lamont D et al (2014) Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS.  Neurology 82(16):1410–1415 Waterston JA, Barnes GR, Grealy MA, Luxon LM (1992) Coordination of eye and head movements during smooth pursuit in patients with vestibular failure. J Neurol Neurosurg Psychiatry 55(12):1125–1131 Zingler VC, Cnyrim C, Jahn K, Weintz E, Fernbacher J, Frenzel C et al (2007) Causative factors and epidemiology of bilateral vestibulopathy in 255 patients. Ann Neurol 61(6):524–532

Spastic Paraplegia Type 7 (SPG7)

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Gorka Fernández-Eulate, Aurora Pujol, and Adolfo López de Munain

Abstract

Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous disorders associated with different modes of inheritance and multiple loci and disease genes. HSP is classified as pure when circumscribed to the spinal cord, or complex when other neural systems are involved. Biallelic variants in the SPG7 gene generally cause a complex HSP phenotype-associated ataxia and should be searched for in the context of adult-onset undiagnosed ataxia. Furthermore, the SPG7 gene product is targeted to mitochondria and to the endoplasmic reticulum, and a subset of patients may present with classical mitochondrial disease, including progressive external ophthalmoplegia (PEO), with multiple deletions of mitochondrial DNA (mtDNA). Cerebellar atrophy on MRI is common and a subset of patients may present with extrapyramidal G. Fernández-Eulate Reference Center for Lysosomal Diseases, Neurology Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France Nord/Est/Ile-de-France Neuromuscular Reference Center, Neuro-myology Department, Pitié-Salpêtrière University Hospital, APHP, Paris, France A. Pujol Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain A. L. de Munain (*) Department of Neurology, Hospital Universitario Donostia, San Sebastián, Spain Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain CIBERNED, Institute Carlos III, Madrid, Spain Department of Neurosciences, School of Medicine and Nursery, University of the Basque Country, San Sebastián, Spain e-mail: [email protected]

signs, possible nigrostriatal denervation, and a partial response to levodopa. An axonal neuropathy on nerve conduction studies may also be possible. Current therapeutic options remain symptomatic. Keywords

Hereditary spastic paraplegia · Ataxia · SPG7 gene Mitochondria

104.1 Introduction Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by upper motor neuron involvement, with lower limb pyramidal weakness and spasticity as the main clinical features. The overall prevalence of HSPs in multisource population-based studies is estimated at 4.8–13.9 cases/100,000 (Ruano et  al. 2014), manifesting from early childhood to late adulthood. According to Harding’s classification (Harding 1983), HSPs are divided into pure and complex forms depending on the presence of additional features such as ataxia, intellectual disability, optic atrophy, deafness, dementia, peripheral neuropathy, and epilepsy (Salinas et al. 2008). HSPs can be inherited in an autosomal dominant (AD), autosomal recessive (AR), or X-linked manner and there are more than 80 genes or loci associated with HSP. SPG7 was the first autosomal recessive HSP gene to be characterized (Casari et al. 1998) and a frequent cause of complex HSPs, frequently associated marked cerebellar ataxia.

104.2 The SPG7 Gene and Transcript The SPG7 gene is composed of 17 exons, spans approximately 52 kb and localizes in chromosome 16q24.4 (OMIM 602783) (Settasatian et  al. 1999). Mutations in this gene account for around 4% of ARHSP cases, although there is a

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large number of heterozygous missense variants which have alternatively described as causative mutations or susceptibility polymorphisms (Arnoldi et al. 2008; Elleuch et al. 2006). To date, 272 exonic variants have been described, most of them of uncertain significance; however, the c.1529C>T (p. Ala510Val) missense variant represents 44–60% of mutations in the widest series (De la Casa-Fages et  al. 2019; Choquet et  al. 2016; Pfeffer et  al. 2015; Roxburgh et  al. 2013; Sánchez-Ferrero et al. 2013). Although a dominant effect for some mutations was suggested (Sánchez-Ferrero et al. 2013), the recent finding of pathogenic intronic variants questions the former finding and invites whole-genome analysis when only one allele carries a mutation (Verdura et al. 2020). A pseudodominant mode of inheritance, meaning subjects presenting clinical disease in two consecutive generations, while carrying two pathologic variants each, may also be found given the fact that the Ala510Val variant shows a minor allele frequency in the general population of almost 1% in public databases such as the 1000 genomes and in the NHLBI exome-sequencing projects (McDermott et  al. 2001). The presence of intronic variants and the possible pseudodominancy further complicates the genetic counselling in SPG7 disease.

G. Fernández-Eulate et al.

The SPG7 gene encodes paraplegin, a mitochondrial protein which has been found to have a dual role: a metalloprotease responsible for assembling ribosomes and eliminating non-functional proteins in the mitochondria (Koppen et  al. 2007) and a regulator of the mitochondrial permeability transition pore (PTP) (Bernardi and Forte 2015; Shanmughapriya et al. 2015). Paraplegin assembles with the AFG3L2 protein to form this oligomeric mAAA proteolytic complex, a regulatory enzyme in (Patron et  al. 2018), and interestingly, mutations in the AFG3L2 gene are responsible for the autosomal-­ dominant spinocerebellar ataxia 28 (Cagnoli et al. 2006; Mariotti et al. 2008). SPG7 was first implicated in mtDNA metabolism by those cases that presented with multiple mtDNA deletions and PEO (Pfeffer et  al. 2014). This finding was later supported by the observation of accumulated mitochondrial DNA (mtDNA) damage, leading to multiple mtDNA deletions in muscle (Wedding et  al. 2014) and low levels of mtDNA in blood compared to controls (De la Casa-Fages et al. 2019). SPG7 is produced as an endoplasmic reticulum (ER)-specific isoform (Mancuso et  al. 2012) and mtDNA replication occurs at ER-mitochondrial contact sites (Lewis et al. 2016) further correlating with the mtDNA alterations observed (Fig. 104.1).

104  Spastic Paraplegia Type 7 (SPG7)

693

[Ca2+]cyt

MCU

mPTP

EMRE

OMM Mitochondrial Respiratory Chain

IMM I

Modulated by [Ca2+]mt

[Ca2+]mt

Regulation of the MCU complex assembly

CALCIUM HOMEOSTASIS

AFG3L2

Matrix

AFG3L2

CypD

SPG7

II

III

IV

OXPHOS ACTIVITY

Regulation of the respiratory chain synthesis

m-AAA proteases AFG3L2/SPG7 Hetero-Oligomers Regulation of the protein degradation process

Regulation of the ribosome assembly

Misfolded protein

54S

37S PROTEIN DEGRADATION

PROTEIN ACTIVATION

Other functions: Mithochondrial dynamics?

mtDNA stability?

Mithochondrial ROS?

OH-

mtDNA

H2O2

ROS

O 2-

Fig. 104.1  Paraplegin (SPG7) cellular functions. (Courtesy of Neia Naldaiz)

104.3 Clinical Presentation Spastic paraplegia type 7 generally has an adult onset (35– 40 years) (Coarelli et al. 2019; De la Casa-Fages et al. 2019; Klebe et  al. 2012), frequently manifesting as a cerebellar ataxia syndrome with different degrees of pyramidalism (complex HSP). Mutations in the SPG7 gene may result in

both pure or complex HSP phenotypes, showing a wide phenotypic heterogeneity, however, in a recently published large cohort of patients harboring SPG7 mutations, patients with loss-of-function variants showed a spasticity-predominant phenotype, while cerebellar ataxia was associated with a later onset of disease and the Ala510Val variant (Coarelli et al. 2019).

694

Indeed, recent studies indicate that pathogenic variants in this gene are one of the most common causes of recessive adult-onset undiagnosed cerebellar ataxia (Choquet et  al. 2016; Pfeffer et  al. 2015). The frequent SPG7 Ala510Val variant accounted for 2.3% of cerebellar ataxia cases in Italy, and the authors suggested that this variant should be considered as a priority candidate to test in the presence of late onset pure ataxia (Mancini et  al. 2019). In adult cases of unexplained ataxia, 18.6% of patients carried SPG7 variants (Pfeffer et al. 2015). Furthermore, SPG7 patients may show a wide variety of mitochondrial disease-associated signs and symptoms, including ptosis, progressive external ophthalmoplegia (PEO), and optical or peripheral neuropathy (Arnoldi et al. 2008; Casari et  al. 1998; Van Gassen et  al. 2012; Klebe et al. 2012). The clinical spectrum of SPG7 disease continues to expand and extrapyramidal signs and symptoms (Bradykinesia, rigidity, and rest tremor) in the form of parkinsonism (sometimes levodopa-responsive) may be present in up to 21% of patients, and even in some rare cases as the sole clinical finding (De la Casa-Fages et al. 2019; Pedroso et al. 2018).

104.4 Diagnosis and Management The diagnosis is based on the clinical examination supported by other additional explorations to exclude alternative diseases (electromyogram, imaging techniques, electroencephalogram, cerebrospinal fluid, and blood analysis). Typically, cerebellar involvement and/or mild cerebellar atrophy is observed on 58–70% of MRI scans (Coarelli et al. 2019; De la Casa-Fages et al. 2019). However, these imaging findings may not always translate into clinical cerebellar signs in patients (Casari et al. 1998; Elleuch et  al. 2006; Warnecke et  al. 2010; Brugman et al. 2008). Electromyography may reveal an axonal sensory motor neuropathy and ioflupane SPECT may show different degrees of unilateral or bilateral nigrostriatal denervation in patients with parkinsonism, although may also be essentially normal (De la Casa-Fages et al. 2019). The muscle biopsy may reveal changes associated with denervation and reinnervation as well as atrophic fibers and changes associated with mitochondrial pathology such as ragged-red fibers, succinate dehydrogenase positive and cytochrome c oxidase negative fibers, and an increased number of subsarcolemmal and perinuclear mitochondria of abnormal size (Casari et  al. 1998; De la Casa-Fages et  al. 2019). Neuropathologic examination of nerve tissue revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons (Coarelli et al. 2019).

G. Fernández-Eulate et al.

Treatment is symptomatic including muscle relaxants and anti-spasticity medication such as baclofen, tizanidine, dantrolene, and diazepam. If extrapyramidal signs and symptoms are clinically present, a Levodopa trial may be considered, given that patients have been found to respond at least partially to this drug. Functional rehabilitation is equally important as physiotherapy can help reduce contractures and improve stability. Furthermore, occupational therapy and assistive devices help patients retain autonomy and speech and orthoptic therapy to treat dysarthria and the oculomotor disarrangements may also be considered. Acknowledgements We are indebted to our patients and the AS-L HSP (Association Strümpell-Lorrain, Hereditary Spastic Paraplegias, France). To Neia Naldaiz for her essential contribution to the SPG7 functions figure.

References Arnoldi A, Tonelli A, Crippa F et  al (2008) A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat 29(4):522–531 Bernardi P, Forte M (2015) Commentary: SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Front Physiol 6:320. Switzerland Brugman F, Scheffer H, Wokke JH et al (2008) Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes. Neurology 71:1500–1505 Cagnoli C, Mariotti C, Taroni F et al (2006) SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22­q11.2. Brain 129:235–242 Casari G, De Fusco M, Ciarmatori S et al (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-­ encoded mitochondrial metalloprotease. Cell 93(6):973–983 Choquet K, Tetreault M, Yang S et al (2016) SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases. Eur J Hum Genet 24(7):1016–1021 Coarelli G, Schule R, van der Warrenburg BPC et  al (2019) Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. Neurology 92(23):e2679–e2690 De la Casa-Fages B, Fernández-Eulate G, Gamez J et  al (2019) Parkinsonism and spastic paraplegia type 7: expanding the spectrum of mitochondrial Parkinsonism. Mov Disord 34:1547–1561 Elleuch N, Depienne C, Benomar A et al (2006) Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 66(5):654–659 Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1(8334):1151–1155 Klebe S, Depienne C, Gerber S et  al (2012) Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain 135(Pt 10):2980–2993 Koppen M, Metodiev MD, Casari G, Rugarli EI, Langer T (2007) Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia. Mol Cell Biol 27(2):758–767

104  Spastic Paraplegia Type 7 (SPG7) Lewis SC, Uchiyama LF, Nunnari J (2016) ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353(6296):aaf5549 Mancini C, Giorgio E, Rubegni A, Rugarli EI (2019) Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy. Eur J Neurol 26(1):80–86 Mancuso G, Barth E, Crivello P et  al (2012) Alternative splicing of Spg7, a gene involved in hereditary spastic paraplegia, encodes a variant of paraplegin targeted to the endoplasmic reticulum. PLoS One 7(5):e36337 Mariotti C, Brusco A, Di Bella D et al (2008) Spinocerebellar ataxia type 28: a novel autosomal dominant cerebellar ataxia characterized by slow progression and ophthalmoparesis. Cerebellum 7:184–188 McDermott CJ, Dayaratne RK, Tomkins J et al (2001) Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England. Neurology 56(4):467–471 Patron M, Sprenger H-G, Langer T (2018) m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration. Cell Res 28(3):296–306 Pedroso JL, Vale TC, Bueno FL, Marussi VHR, do Amaral LLF, Franca MC Jr, Barsottini OG (2018) SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit. Parkinsonism Relat Disord 47:88–90 Pfeffer G, Gorman GS, Griffin H et al (2014) Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 137(Pt 5):1323–1336 Pfeffer G, Pyle A, Griffin H et al (2015) SPG7 mutations are a common cause of undiagnosed ataxia. Neurology 84(11):1174–1176 Roxburgh RH, Marquis-Nicholson R, Ashton F et  al (2013) The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most

695 common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol 260(5):1286–1294 Ruano L, Melo C, Silva MC, Coutinho P (2014) The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 42:174–183 Salinas S, Proukakis C, Crosby A, Warner TT (2008) Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol 7(12):1127–1138 Sánchez-Ferrero E, Coto E, Beetz C et  al (2013) SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p. A510V. Clin Genet 83:257–262 Settasatian C, Whitmore SA, Crawford J, Bilton RL, Cleton-Jansen AM, Sutherland GR, Callen DF (1999) Genomic structure and expression analysis of the spastic paraplegia gene, SPG7. Hum Genet 105(1–2):139–144. Germany Shanmughapriya S, Rajan S, Hoffman NE et  al (2015) SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Mol Cell 60(1):47–62 Van Gassen KLI, van der Heijden CDCC, de Bot ST et  al (2012) Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. Brain 135(Pt 10):2994–3004 Verdura E, Schlüter A, Fernández-Eulate G, Ramos-Martín R et  al (2020) A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases. Ann Clin Transl Neurol 7(1):105–111 Warnecke T, Duning T, Schirmacher A et al (2010) A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects. Mov Disord 25:413–420 Wedding IM, Koht J, Tran GT et al (2014) Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions. PLoS One 9(1):e86340

Part XI Therapies of Cerebellar Ataxias

Drugs in Selected Ataxias

105

Dagmar Timmann and Winfried Ilg

Abstract

In this chapter, drug treatment in the few treatable causes of degenerative ataxias will first be presented including vitamin deficiency, metabolic disorders, and autoimmune disorders. Next, older and more recent drug trials will be discussed which have been performed in Friedreich’s ataxia and may lead to effective drug treatments in the future. Finally, it will be shown that, as yet, symptomatic treatments of most degenerative ataxias are lacking, that is, there is still no “anti-ataxic drug.” The only exceptions are aminopyridines and acetazolamide which can be beneficial in the treatment of downbeat nystagmus and episodic ataxias. Keywords

Aminopyridine · Causative therapy · Idebenone Medication · Symptomatic treatment

2015). Despite the huge increase in knowledge of the underlying genetics and pathophysiology, however, causal treatments are currently not available for the large majority of hereditary and non-hereditary degenerative ataxias. Genetic treatments are within reach for a subset of hereditary ataxias but are unlikely to cure the disease in the near future (Scoles and Pulst 2019; Vázquez-Mojena et al. 2021) Furthermore, no symptomatic drug treatment is available that ameliorates the clinical signs and symptoms of ataxia. Pharmacological interventions using a number of “anti-ataxic drugs” have been found to be largely ineffective (Ilg et  al. 2014). The only exceptions are aminopyridines for the treatment of downbeat nystagmus, and acetazolamide and aminopyridines for the treatment of episodic ataxias. Most preclinical and clinical drug studies have been done on Friedreich’s ataxia, and the findings will be briefly summarized.

105.2 Treatable Causes of Ataxia 105.1 Introduction

105.2.1 Vitamin Deficiency

Options for drug treatment are very limited in patients with degenerative forms of ataxias. Drug treatments are available for a few metabolic disorders and vitamin deficiencies that can cause ataxia. These diseases have to be excluded in all cases of ataxias of unknown origin (Ramirez-Zamora et al.

Vitamin B12 deficiency is a cause of sensory ataxia. Sensory ataxia is also characteristic of vitamin E deficiency. Vitamin E deficiency can be due to malnutrition or metabolic disorders (that is, abetalipoproteinemia, and ataxia with vitamin E deficiency, AVED). It is mandatory to exclude vitamin B1 deficiency in chronic alcoholics with cerebellar ataxia to prevent the occurrence of a Korsakoff’s syndrome.

D. Timmann (*) Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University of Duisburg-Essen, Essen, Germany e-mail: [email protected] W. Ilg Section Computational Sensomotorics, Department of Cognitive Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany e-mail: [email protected]

105.2.2 Metabolic Disorders There are a couple of metabolic disorders which can cause ataxia and are potentially treatable with drugs: abetalipoproteinemia, AVED, cerebrotendinous xanthomatosis, Niemann Pick disease type C, Refsum disease, and Wilson disease (Ramirez-Zamora et al. 2015). Similar to abetalipoprotein-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_105

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Table 105.1  Metabolic disorders which can cause ataxia and are potentially treatable with drugs. These are autosomal-recessive diseases. Diagnosis is confirmed by genetic testing Metabolic disorder Abetalipoproteinemia

AVED

Laboratory test Acanthocytes in blood smear; low serum level of vitamin E; low low-density lipoproteins (LDL) in cholesterol tests; absent betalipoproteins in lipoprotein electrophoresis Reduced serum vitamin E

Genetic mutation MTP (microsomal triglyceride transfer protein) gene

Treatment option Low-fat diet; high doses of vitamin E; vitamin A, D and K High doses of vitamin E

Cerebrotendinous xanthomatosis Niemann Pick disease type C Refsum disease

Increased serum cholestanol

TTPA (α-tocopherol transfer protein) gene CYP27A1 gene

Increased serum chitotriosidase and oxysterols

NPC1 and NPC2 genes

Increased serum phytanic acid

Wilson disease

Low serum ceruloplasmin; low serum copper; elevated urine copper (collected for 24 h) Low coenzyme Q10 in muscle tissue

PHYH (phytanoyl-CoA hydroxylase) gene ATP7B gene

Primary coenzyme Q10 deficiencies

emia and AVED, sensory ataxia is typical in Refsum disease. Ataxia in the three other disorders is of the cerebellar type. Metabolic testing and drug treatment options are summarized in Table  105.1. Primary coenzyme Q10 deficiency is another potentially treatable cause of ataxia.

105.2.3 Endocrine Disorders Hypothyroidism can be accompanied by cerebellar ataxia.

105.2.4 Autoimmune Disorders Whether autoimmune disease can lead to cerebellar ataxia is a matter of ongoing discussion. Likewise, it is an open question whether corticoids or intravenous immunoglobulin are advantageous. Evidence is best for anti-glutamic acid decarboxylase (GAD)-associated cerebellar ataxia in patients with a polyglandular autoimmune disorder (Saiz et al. 2008). One has to be aware, however, that antibody titers are already high in diabetes mellitus type 1 and have to be significantly higher in anti-GAD associated cerebellar ataxias (typically >10.000 IU/mL) (Tsiortou et al. 2021). They should also be present in CSF. Whether gluten- and thyroid-related antibodies in coeliac and Hashimoto’s disease can cause cerebellar ataxia is unclear.

105.3 Friedreich’s Ataxia Friedreich’s ataxia is the most common hereditary ataxia. Since the discovery of the genetic mutation in 1996, much has been learned about the underlying pathophysiology

Various genes: COQ2; PDSS1; PDSS2; COQ8; COQ9; COQ6

Chenodeoxycholic acid; statins Miglustat Phytanic acid-restricted diet; plasmapheresis Copper chelators (penicillamine); zinc High-dose coenzyme Q10

(Pandolfo 2012). Friedreich’s ataxia is a mitochondriopathy. Frataxin levels are abnormally low. Frataxin is involved in the regulation of the mitochondrial iron metabolism. There is reduced biosynthesis of iron-sulfur clusters leading to disordered cell respiration, and there is iron overload within the mitochondria. As a consequence, oxidative stress is increased which results in subsequent cell death (apoptosis). Based on this known pathophysiology, a number of preclinical and clinical drug trials have been initiated. Firstly, antioxidant drugs have been tested, in particular idebenone, but also vitamin E and coenzyme Q10. Idebenone is a derivative of coenzyme Q10. Initial studies suggested that idebenone reduces the degree of accompanying cardiomyopathy based on echocardiographic measures. Although subsequent studies indicated additional effects on some neurological signs, more recent placebo-controlled trials in large patient populations were unable to show significant effects on cardiac or neurological outcome parameters (Lagedrost et al. 2011). To date, idebenone cannot generally be recommended in the treatment of Friedreich’s ataxia. Secondly, iron chelators have been tested to reduce the iron content of the mitochondria. Deferiprone is preferred to deferoxamine because it can penetrate cellular membranes and is thought to redistribute iron out of the mitochondria and into the extracellular environment. Iron chelators have the problem of major side effects, in particular iron-deficient anemia, and close monitoring of blood parameters is needed. Agranulocytosis is a major risk factor of deferiprone. In a placebo-controlled study, deferiprone showed no significant effects on neurological outcome parameters in Friedreich’s ataxia at a low and medium dose, at higher doses ataxia became even worse (Pandolfo et  al. 2014). At low and medium doses, the degree of accompanying cardiomyopathy based on echocardiographic measures improved, but it was

105  Drugs in Selected Ataxias

unclear whether this had an impact on cardiac function. As yet, the intake of deferiprone cannot be recommended in the treatment of Friedreich’s ataxia. Thirdly, treatments are tested which increase the frataxin level. In preclinical studies and clinical pilot studies, erythropoietin led to increased frataxin levels. In subsequent placebo-­controlled studies, however, no significant effects on frataxin levels or neurological outcome parameters could be observed (Mariotti et al. 2012). Potential side effects, in particular increases in hematocrit requiring phlebotomies, are another limitation. To date, treatment with erythropoietin cannot be recommended for Friedreich’s ataxia. A more recent development is clinical pilot trials with histone deacetylase inhibitors (HDACi). The idea of this epigenetic treatment is to reactivate the frataxin gene and therefore to increase the expression of frataxin mRNA and frataxin levels. HDACi have been shown to increase frataxin levels in various human cell models as well as buccal cells of Friedreich’s ataxia patients. An exploratory study was able to show that high doses of nicotinamide (that is, niacin or vitamin B3) increase frataxin levels in blood samples in patients with Friedreich’s ataxia (Libri et  al. 2014). The main side effect was nausea. Nicotinamide was given for up to 8 weeks and no effects on neurological scores could be observed. Future studies are needed to evaluate the effects of prolonged treatment on cardiac and neurological parameters, as well as the side effects of long-term treatment with high doses of nicotinamide (Reetz et al. 2019). Most recently, omaveloxolone has been shown to improve neurological function in Friedreich’s ataxia (MOXIe trial; Lynch et  al. 2021). Omaveloxone is a master transcription factor (Nrf2) that regulates genes involved in mitochondrial, antioxidative, and anti-inflammatory functions (Reisman et al. 2019). These promising initial findings await confirmation in future trials.

701

cant effects were found in patients with SCA2 (Coarelli et al. 2022). Likewise, the experience of many ataxia clinics is negative. Varenicline was assessed in a randomized controlled trial in SCA3 patients (Zesiewicz et  al. 2012). Although positive effects on neurological outcomes were reported, the drop-out rate was high and results need to be treated cautiously. Furthermore, side effects are common. Positive effects of acetyl-dl-leucine on neurological outcome parameters have been reported in a case series (Strupp et  al. 2013), but were not confirmed in a double-blind, placebo-­controlled trial (Feil et al. 2021).

105.5 Aminopyridines

Aminopyridines are of help in a significant subset of patients with downbeat nystagmus (DBN) and episodic ataxia type 2 (EA2) (Ilg et al. 2014). Downbeat nystagmus is a common accompanying sign in degenerative ataxias. Initial studies have been performed using 3,4-diaminopyridine (Strupp et al. 2003). In subsequent studies, 4-aminopyridine (4-AP) was used. Because 4-AP appears to cross the blood–brain barrier more easily, to date 4-AP is usually recommended. Most recent studies are performed with the slow release form of 4-AP (fampridine or dalfampridine). The therapeutic effect of aminopyridines has been demonstrated in placebo-controlled studies in DBN and EA2 (Strupp et al. 2011). Whether aminopyridines have a beneficial effect on other symptoms of ataxia, for example ataxia of stance and gait, is unclear. Experience of many ataxia clinics, however, is not convincing. Results of a placebo-controlled study have to be awaited. In EA2, as yet, acetazolamide is the treatment of choice, which has originally been used to treat arterial hypertension. Acetazolamide has a number of side-effects including the development of kidney stones, and aminopyridines are a useful alternative. A recent double-blind, placebo-controlled trial confirmed that fampridine is effective in EA2, and has 105.4 Symptomatic Treatment of Ataxias fewer side effects than acetazolamide (Muth et al. 2021). Common side effects of aminopyridines are vertigo, To date, symptomatic drug treatment of ataxia is basically not available. Several drugs and food supplements have been headache, and nausea. Life-threatening cardiac arrhythmias used, including 5-hydroxytryptophane, buspirone, creatine, are a rare but a severe side effect. Seizures are reported in l-carnitine, vitamin E, coenzyme Q10, idebenone, and high doses. Patients with prolonged QTc intervals on electroamantadine with no convincing effects. In a placebo-­ cardiogram or known epilepsy should not receive aminopyricontrolled trial, positive effects of daily zinc supplementa- dines. Tests of kidney function should be performed in tion together with neurorehabilitation therapy was found in particular in patients older than 50 years. SCA2 patients with reduced zinc concentrations in serum and CSF (Velázquez-Pérez et  al. 2011). In a placebo-­ controlled trial, riluzole was found to be beneficial in patients 105.6 Conclusions with various forms of ataxias (Ristori et al. 2010). In a subsequent study of the same group, effects were variable and As yet, causal or symptomatic drug treatment is available significant only after 1  year of drug intake (Romano et  al. only in a very small subset of patients with ataxia. Given the 2015). In a more recent study of another group, no signifi- increased knowledge about the genetics and pathophysiol-

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Crossman SL, Rummey C, Meier T, Lynch DR (2011) Idebenone in Ref PubMed Friedreich ataxia cardiomyopathy-results from a 6-month phase III Scoles DR, Pulst SM (2019) Antisense therapies for movement disstudy (IONIA). Am Heart J 161:639–645. CrossRef PubMed orders. Mov Disord 34:1112–1119. https://doi.org/10.1002/ Libri V, Yandim C, Athanasopoulos S, Loyse N, Natisvili T, Law mds.27782. Epub 2019 Jul 8 PMID: 31283857 PP, Chan PK, Mohammad T, Mauri M, Tam KT, Leiper J, Piper Strupp M, Schüler O, Krafczyk S, Jahn K, Schautzer F, Büttner S, Ramesh A, Parkinson MH, Huson L, Giunti P, Festenstein R U, Brandt T (2003) Treatment of downbeat nystagmus with (2014) Epigenetic and neurological effects and safety of high-dose 3,4-­ diaminopyridine: a placebo-controlled study. Neurology nicotinamide in patients with Friedreich’s ataxia: an exploratory, 61:165–170. CrossRef PubMed open-label, dose-escalation study. Lancet 384:504–513. 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CrossRef PubMed PubMedCentral Mariotti C, Fancellu R, Caldarazzo S, Nanetti L, Di Bella D, Plumari M, Tsiortou P, Alexopoulos H, Dalakas MC (2021) GAD antibody-­ Lauria G, Cappellini MD, Duca L, Solari A, Taroni F (2012) Erythspectrum disorders: progress in clinical phenotypes, immunopathoropoietin in Friedreich ataxia: no effect on frataxin in a randomized genesis and therapeutic interventions. Ther Adv Neurol Disord controlled trial. Mov Disord 27:446–449. CrossRef PubMed 14:17562864211003486 Muth C, Teufel J, Schöls L, Synofzik M, Franke C, Timmann D, Vázquez-Mojena Y, León-Arcia K, González-Zaldivar Y, Rodríguez-­ Mansmann U, Strupp M (2021) Fampridine and acetazolamide in Labrada R, Velázquez-Pérez L (2021) Gene therapy for polyEA2 and related familial EA: a prospective randomized placebo-­ glutamine spinocerebellar ataxias: advances, challenges, and

ogy of many ataxias, this may well change in the future with genetic treatments holding promise for a subset of hereditary ataxias. Patients should be evaluated for downbeat nystagmus because aminopyridines can be helpful. In patients with episodic ataxia type 2 aminopyridines are a useful alternative for acetazolamide. SCA2 patients should be checked for lack of zinc concentration and Zn supplementation may be started. Ataxia is frequently accompanied by extracerebellar symptoms, such as restless legs syndrome, depression, spasticity, neuropathic pain, bladder dysfunction, sleeping disorders, dystonia and parkinsonism, which should be treated according to standard medications.

105  Drugs in Selected Ataxias perspectives. Mov Disord 36:2731–2744. https://doi.org/10.1002/ mds.28819. Epub 2021 Oct 10 PMID: 34628681 Velázquez-Pérez L, Rodríguez-Chanfrau J, García-Rodríguez JC, Sánchez-Cruz G, Aguilera-Rodríguez R, Rodríguez-Labrada R, Rodríguez-Díaz JC, Canales-Ochoa N, Gotay DA, Almaguer Mederos LE, Laffita Mesa JM, Porto-Verdecia M, Triana CG, Pupo NR, Batista IH, López-Hernandez OD, Polanco ID, Novas AJ (2011) Oral zinc

703 sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial. Neurochem Res 36:1793–1800. CrossRef PubMed Zesiewicz TA, Greenstein PE, Sullivan KL, Wecker L, Miller A, Jahan I, Chen R, Perlman SL (2012) A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 78:545–550. CrossRef PubMed

106

Cerebellar Stimulation Giuliana Grimaldi

Abstract

Non-invasive brain stimulation (NIBS), encompassing Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), is becoming more and more promising as a novel procedure to modulate cerebellar functions and as therapy for cerebellar patients. This chapter provides the elementary concept of this therapeutic approach, which is based on the modulation of cerebellar brain inhibition (CBI), and reports a brief overview of the studies focusing on the therapeutic potentials and effectiveness of these techniques. Evidences of the effectiveness of this appealing therapeutic approach are growing, but many issues remain to be clarified to include these treatments in the standard management of cerebellar patients.

Motor cortex +

Sensory cortex

Motor thalamus +

Pons

Dentate nucleus

Keywords

Modulation of the cerebellar brain inhibition (CBI) Non-invasive brain stimulation (NIBS) · Transcranial magnetic stimulation (TMS) · Transcranial direct current stimulation (tDCS)

106.1 Introduction There is a consensus that both Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) can effectively influence cerebellar functions, not only in the motor domain but also for the cognitive and affective operations handled by the cerebrocerebellar circuits (Grimaldi et al. 2014a). The cerebellum plays important roles in movement execution and motor control by modulation of the activity of the primary motor cortex (M1) through cerebello-thalamo-cortical connections (Fig. 106.1)

-

afferent pathway

efferent pathway

Cerebellar cortex + Anodal tDCS

– Cathodal tDCS

Fig. 106.1  Simplified scheme of the fronto-ponto-cerebello-thalamocortical loop. Solid lines indicate the cerebellar efferent pathways and dotted lines the cerebellar afferent pathways. The sign plus (+) indicates facilitatory effect. The sign minus (−) indicates inhibitory effect. Anodal tDCS increases cerebellar cortical exitability (arrow +), while cathodal decreases it (arrow −) (Adapted from Grimaldi et al. 2014a)

G. Grimaldi (*) U.O.C. Unità Spinale, Villa delle Ginestre, ASP Palermo, Palermo, Italy © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_106

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(Ito 1984). The dentato-thalamo-cortical pathway itself is facilitatory. However, Purkinje cells of the cerebellar cortex inhibit cerebellar nuclei. Therefore, activation of Purkinje cells results in disfacilitation of the motor cortex (i.e., decreased excitability of the motor cortex: cerebellar brain inhibition—CBI). Both TMS and tDCS—non-invasive brain stimulation (NIBS) through electromagnetic induction and direct electrical current, respectively—modulate the electrical properties of the networks between the cerebellum and M1, tuning cerebellar excitability (Grimaldi et  al. 2014a). This is the basic concept for therapeutic applications of neuromodulation techniques in cerebellar patients. Studies show that the normal effects of CBI are reduced or absent in patients with degeneration or lesions of the efferent system from the cerebellum, confirming the clinical potential of NIBS to manage motor deficits in cerebellar ataxias (Pope and Miall 2014).

106.2 Transcranial Magnetic Stimulation (TMS) TMS is based on electromagnetic induction by means of a magnetic field generator (the coil) which is placed over the scalp and produces small electric currents. This technique has been used in the last decades to investigate neural networks in human by stimulating/inhibiting neural structures non-invasively. Single-pulse TMS on the M1 and the recording of the motor evoked potential (MEP, generated in response to the TMS pulse: test stimulus) are used to measure motor cortical excitability. Applying a conditioning stimulus over the cerebellum before the test stimulus over the contralateral M1 allows to study the CBI (i.e., the cerebellar regulatory effects on M1) (Grimaldi et  al. 2014a). Low-frequency repetitive TMS (rTMS) has an inhibitory effect on the cerebellar cortex thus decreasing CBI, high-­frequency rTMS has an excitatory effect (Pope and Miall 2014). Safety and feasibility of repetitive transcranial magnetic stimulation (rTMS, 1  Hz) over the cerebellum in ataxic patients with posterior circulation stroke have been demonstrated (Kim et al. 2014). rTMS, more specifically the iTBS protocol (intermittent theta burst stimulation, interstimulus interval of 15 ms), applied over the injured cerebellar hemisphere of stroke patients induces both neurophysiological changes (a decrease in CBI and an increase in intracortical facilitation) and a clinical improvement, thus suggesting that cerebellar iTBS could be a promising tool to promote recovery of cerebellar stroke patients (Bonnì et al. 2014). Improved cognition has been demonstrated using TMS (21 daily sessions of TMS over the cerebellum) in an ataxic patient (affected by idiopathic late-onset cerebellar atrophy) presenting speech and gait difficulties. The TMS-induced reduc-

G. Grimaldi

tion in CBI resulted in the improvements in the patients’ functional mobility (postural control and walking) and dual-­ tasking (naming supermarket items while walking) after treatment (Farzan et al. 2013). Decreasing cortical excitability by administrating 1 Hz rTMS for 10 min over the right (unaffected) cerebellum in a patient with a left cerebellar lesion and a selective deficit in procedural learning induces recovery of the deficit and an improvement of the task performance (Torriero et al. 2007).

106.3 Transcranial Direct Current Stimulation (tDCS) tDCS is based on the application of a steady current of small intensity (usually between 0.5 and 2 mAmp; anodal or cathodal) between two large electrodes fixed on the scalp (Tomlinson et  al. 2013). The current causes a polarity-­ dependent modulation of brain activity which is site-specific (Nitsche et  al. 2003). When applied over the cerebellum, tDCS can effectively modulate CBI by changing tonic Purkinje cell activity and thus resulting in modulation of cerebral cortical excitability (Fig.  106.1). Cathodal tDCS over the cerebellum reduces cortical excitability and leads to a lasting inhibition of CBI for up to 30 min after stimulation. On the other hand, anodal cerebellar tDCS, which increases cortical excitability, increases the magnitude of CBI (Galea et  al. 2009). Anodal ctDCS causes walking adaptation to occur more rapidly, whereas cathodal ctDCS slowed it down relative to sham stimulation (Jayaram et al. 2012). Recently, Pozzi et al. showed that anodal tDCS over the motor cortex in ataxic patients induced an improvement of the symmetry of step execution and reduction of base-width. This was associated with patients’ perception of improvement, lasting 30 days after stimulation (Pozzi et al. 2014). A study on the effect of anodal tDCS applied over the cerebellum in ataxic patients showed that tDCS exerts a favorable effect on upper limb stretch reflexes, reducing significantly the amplitudes of long-latency stretch reflexes (Grimaldi and Manto 2013). The effectiveness of tDCS on cerebellar patients improves when combining tDCS over the cerebellum and tDCS over the motor/premotor cerebral cortex (transcranial cerebello-cerebral DCS—tCCDCS). tCCDCS reduces both postural and action tremor, cancels hypermetria, and restores EMG activity associated with fast goal-­ directed movements (decrease of the onset latency of the antagonist EMG activity) (Grimaldi et  al. 2014b). These findings suggest that tCCDCS impacts on the distorted timing of muscle discharges which is considered as a signature of a cerebellar lesion involving the cerebello-thalamo-­ cortical pathway. tDCS is now considered a potential therapeutic tool as well as a valuable clinical tool for neurorehabilitation inter-

106  Cerebellar Stimulation

ventions. tDCS also raises researchers’ interest as a technique to provide novel information on cerebellar functions and to promote neuroplasticity (Grimaldi et  al. 2014a). Moreover, this technique (similarly to TMS) is non-invasive, well-tolerated and safe, provided an appropriate current intensity is used, and interstimulation intervals are applied. However, important questions about therapeutic application of tDCS still remains open (Grimaldi et al. 2016): what is the optimal intensity? Are there any differences in responsiveness among cerebellar patients? How long the effects last? Is the effectiveness influenced by the extent of cerebellum volume loss in patients with cerebellar atrophy? Should tDCS be applied on a daily basis? Which are the optimal sites of stimulation and how to combine them? Could we consider a combination of stimulation of the cerebellum and the spinal cord (Priori et al. 2014)?

References Bonnì S, Ponzo V, Caltagirone C, Koch G (2014) Cerebellar theta burst stimulation in stroke patients with ataxia. Funct Neurol 7:1–5 Farzan F, Wu Y, Manor B, Anastasio EM, Lough M, Novak V et  al (2013) Cerebellar TMS in treatment of a patient with cerebellar ataxia: evidence from clinical, biomechanics and neurophysiological assessments. Cerebellum 12:707–712. CrossRef PubMed PubMedCentral Galea JM, Jayaram G, Ajagbe L, Celnik P (2009) Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation. J Neurosci 29(28):9115–9122. CrossRef PubMed PubMedCentral Grimaldi G, Manto M (2013) Anodal Transcranial Direct Current Stimulation (tDCS) decreases the amplitudes of long-latency stretch reflexes in cerebellar ataxia. Ann Biomed Eng 41:2437–2447. CrossRef PubMed Grimaldi G, Argyropoulos GP, Boehringer A, Celnik P, Edwards MJ, Ferrucci R, Galea JM, Groiss SJ, Hiraoka K, Kassavetis P, Lesage E, Manto M, Miall RC, Priori A, Sadnicka A, Ugawa Y, Ziemann U (2014a) Non-invasive cerebellar stimulation—a consensus paper. Cerebellum 13(1):121–138. CrossRef PubMed

707 Grimaldi G, Oulad Ben Taib N, Manto M, Bodranghien F (2014b) Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation: tremor reduction and re-programming of the timing of antagonist commands. Front Syst Neurosci 8:9. CrossRef PubMed PubMedCentral Grimaldi G, Argyropoulos GP, Bastian A, Cortes M, Davis NJ, Edwards DJ, Ferrucci R, Fregni F, Galea JM, Hamada M, Manto M, Miall RC, Morales-Quezada L, Pope PA, Priori A, Rothwell J, Tomlinson SP, Celnik P (2016) Cerebellar Transcranial Direct Current Stimulation (ctDCS): a novel approach to understanding cerebellar function in health and disease. Neuroscientist 22(1):83–97. CrossRef PubMed PubMedCentral Ito M (1984) Cerebellum and neural control. Raven, New York Jayaram G, Tang B, Pallegadda R, Vasudevan EV, Celnik P, Bastian A (2012) Modulating locomotor adaptation with cerebellar stimulation. J Neurophysiol 107(11):2950–2957. CrossRef PubMed PubMedCentral Kim WS, Jung SH, Oh MK, Min YS, Lim JY, Paik NJ (2014) Effect of repetitive transcranial magnetic stimulation over the cerebellum on patients with ataxia after posterior circulation stroke: a pilot study. J Rehabil Med 46(5):418–423. CrossRef PubMed Nitsche MA, Schauenburg A, Lang N, Liebetanz D, Exner C, Paulus W, Tergau F (2003) Facilitation of implicit motor learning by weak transcranial direct current stimulation of the primary motor cortex in the human. J Cogn Neurosci 15:619–626. CrossRef PubMed Pope PA, Miall RC (2014) Restoring cognitive functions using non-­ invasive brain stimulation techniques in patients with cerebellar disorders. Front Psychiatry 5:33. CrossRef PubMed PubMedCentral Pozzi NG, Minafra B, Zangaglia R, De Marzi R, Sandrini G, Priori A, Pacchetti C (2014) Transcranial direct current stimulation (tDCS) of the cortical motor areas in three cases of cerebellar ataxia. Cerebellum 13(1):109–112. CrossRef PubMed Priori A, Ciocca M, Parazzini M, Vergari M, Ferrucci R (2014) Transcranial cerebellar direct current stimulation and transcutaneous spinal cord direct current stimulation as innovative tools for neuroscientists. J Physiol 592(Pt 16):3345–3369. CrossRef PubMed PubMedCentral Tomlinson S, Davis N, Bracewell R (2013) Brain stimulation studies of non-motor cerebellar function: a systematic review. Neurosci Biobehav Rev 37:766–789. CrossRef PubMed Torriero S, Oliveri M, Koch G, Lo Gerfo E, Salerno S, Petrosini L et al (2007) Cortical networks of procedural learning: evidence from cerebellar damage. Neuropsychologia 45:1208–1214. CrossRef PubMed

Motor Rehabilitation of Cerebellar Disorders

107

Winfried Ilg and Dagmar Timmann

Abstract

Keywords

Disorders of the cerebellum affect motor functions in a variety of ways and can lead to significant and severe limitations in activities of daily living. Possibilities for medical interventions are still rare and limited to specific diseases and symptoms. Furthermore, motor rehabilitation for patients suffering from cerebellar damage—in particular by degenerative cerebellar disease—is challenging, since the cerebellum is known to play an important role in the execution as well as for adaptation and (re)-learning of movements. This chapter briefly reviews the state-of-the-art on motor rehabilitation in cerebellar disease. Recent studies indicate that even in the case of degenerative cerebellar diseases intensive and continuous motor training can reduce ataxia symptoms and increase motor performance relevant to daily living. In addition, current studies in the area of motor control and motor learning—in combination with modern imaging techniques—in cerebellar disease are described. These results offer promising perspectives for a deeper understanding of remaining motor learning capacities in cerebellar disease, and thus might help in the future to optimize motor rehabilitation for individual patients.

Neurorehabilitation · Motor training · Cerebellar ataxia Dynamic stability · Coordination

107.1 Introduction Cerebellar dysfunction can induce a variety of motor impairments including limb ataxia, dysarthria, oculomotor dysfunction, imbalance, and ataxia of gait (Diener and Dichgans 1996). Causes for cerebellar impairments can be various, including stroke, tumors, multiple sclerosis, and degenerative disease. Motor rehabilitation is challenging for this patient population since the cerebellum is known to play an important role in motor learning (Bastian 2011; Ilg et  al. 2014). However, recent results deliver evidence that patients with degenerative cerebellar diseases can benefit from motor training. This chapter will review briefly the state-of-the-art of motor rehabilitation in cerebellar ataxia, focusing on gait and posture. More reviews can be found in (Cassidy et al. 2009; Bastian 2011; Marsden and Harris 2011; Ilg et  al. 2014; Synofzik and Ilg 2014; Milne et al. 2017).

107.2 General Predictions of Functional Recovery

W. Ilg (*) Section Computational Sensomotorics, Hertie Institute for Clinical Brain Research and Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany e-mail: [email protected] D. Timmann Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University of Duisburg-Essen, Essen, Germany e-mail: [email protected]

The cause, site, and extent of brain lesions are generally thought to be important predictors of the degree of functional recovery. For example, functional deficits seem more marked following a hemorrhage compared to an ischemic infarct, but have better chances of recovery if survived. In focal cerebellar lesions, either due to tumor surgery or stroke, lesion site appears to be more important than extent. For example, functional recovery is worse in lesions affecting the deep cerebellar nuclei (e.g., Konczak et al. 2005).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_107

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In many degenerative cerebellar ataxias, neuronal loss is caused by genetic factors with autosomal dominant inheritance as in the spinocerebellar ataxias (SCA) (Schöls et al. 2004) or a recessive trait like in Friedreich’s ataxia. Many sporadic cases of cerebellar degeneration escape the detection of causative factors and are currently classified as sporadic adult onset ataxia of unknown etiology (SAOA). In general, degenerative ataxias are the most difficult group to treat, due to their progressive nature. In addition, virtually all parts of the cerebellum are affected although degeneration is frequently most prominent in the midline. In contrast, ataxia following stroke, neurosurgery or trauma affects only circumscribed regions of the cerebellum, but leaves other regions intact. These regions may compensate for the defective parts. Thus, in patients with progressive degenerative diseases it would be a major achievement to stay on the current status of motor function as long as possible or to slow down progression of functional impairment.

107.3 Ataxia-Specific Impairments and Rehabilitation Strategies

W. Ilg and D. Timmann Table 107.1  Overview of studies examining motor rehabilitation in cerebellar disease Reference Balliet et al. (1987)

Patient group Five patients after traumatic brain injury with cerebellar involvement

Gill-Body et al. (1997)

Two patients with different cerebellar etiologies

Cernak et al. (2008)

One child after cerebellar/ brainstem infarct

Ilg et al. (2009)

16 patients (10 cerebellar, 6 afferent degeneration)

Miyai et al. (2012)

42 patients with pure cerebellar degeneration

Ilg et al. (2012)

10 children with cerebellar degeneration

Keller and Bastian (2014)

14 patients with cerebellar ataxia

Burciu et al. (2013)

19 patients with pure cerebellar degeneration

Bunn et al. (2015)

12 patients with spinocerebellar ataxia type 6

107.3.1 Motor Impairments Cerebellar damage does not cause loss of movement, but instead leads to increased movement variability and poor accuracy (Bastian 2006). In the case of limb movements typical ataxia symptoms are dysmetria, cerebellar tremor, and dyssynergia (Bastian et al. 1996). Cerebellar ataxic gait is typically characterized by increased step width, irregular foot trajectories, and a resulting instable walking path (Morton and Bastian 2004; Ilg and Timmann 2013) with a high risk of falling.

107.3.2 Motor Rehabilitation Since the cerebellum plays an important role in motor learning, benefits from motor rehabilitation for patients with cerebellar damage were under debate for a long time and only few studies have evaluated interventions for these patients (Table 107.1). More recently, rehabilitation in cerebellar disease has been examined more systematically. In an intra-individual case–control design, the benefits of intensive coordination training have been tested in 16 patients suffering from cerebellar degeneration or degeneration of afferent pathways (Ilg et  al. 2009, 2010). The strategy of the physiotherapeutical intervention was to activate and demand control mechanisms for balance control and multi-joint coordination. Furthermore,

Main result Using increasingly demanding balance and gait tasks, improvements were reached for increased postural stability in clinical measures and less dependency on walking aids in everyday life Individualized treatment programs to train balance. The outcomes suggest that patients with cerebellar lesions, acute or chronic, may be able to learn to improve their postural stability Locomotion training on treadmill with weight support in conjunction with physical therapy can be an effective way to improve ambulatory function in individuals with severe cerebellar ataxia 4 weeks intensive coordination training improves gait in terms of velocity, lateral sway and variability of intralimb coordination pattern, improvements in subjective important movements in daily life 4 weeks physiotherapy in combination with occupational therapy improves gait speed and fall frequency 6 weeks video-gamed based coordination training in children improves velocity, step length variability, dynamic balance Improvement in locomotor performance observed after a 6-week home balance exercise program. Exercises are individually designed to provide a significant challenge to the person’s balance 2 weeks training on a balance task increased balance performance in cerebellar patients. In contrast to controls, patients revealed significantly more post-training gray matter volume in the dorsal premotor cortex Participants undertook balance exercises in front of optokinetic stimuli during weeks 4–8, training intervention was feasible, outcome measures reveal trends towards balance improvements

107  Motor Rehabilitation of Cerebellar Disorders Table 107.1 (continued) Reference Fonteyn et al. (2014)

Patient group 10 patients with cerebellar ataxia

Kaut et al. (2014)

17 patients with spinocerebellar ataxia types 1, 2, 3, and 6

Schatton et al. (2017)

10 children with advanced cerebellar degeneration

Milne et al. (2018)

19 patients with Friedreich’s ataxia

Wang et al. (2018)

9 patients spinocerebellar ataxia type 3

Draganova et al. (2021)

40 patients with pure cerebellar degeneration

Main result Training gait adaptability training on a treadmill with virtual obstacles projected on the belt’s surface can lead to increased obstacle avoidance capacity and dynamic stability Whole body vibrations (WBV) can lead to improvements of gait and posture. The use of stochastic WBV could provide a supplementation to treat ataxia and can be combined with physiotherapeutical training 12-week home-based training with body-controlled videogames in 10 young subjects with advanced degenerative ataxia. After intervention, ataxia symptoms were reduced (SARA −2.5 points, with benefits correlating to the amount of training) 6-week outpatient rehabilitation program followed by a 6-week home exercise program, a significant improvement in health and well-being in the intervention group 4-week exergaming training on cerebellar ataxia. Significant decrease in the SARA score and the gait-posture subscore 5-days of single-joint, goal-­ directed forearm movements. Cerebellar patients improved performance during visuomotor practice, but a training focusing on either proprioceptive feedback, or explicit verbal feedback and instruction did not show additional benefits

711

the intervention trained the patients’ ability to select and use visual, somatosensory and vestibular inputs to preserve and re-train patients’ capability for reacting to unforeseen situations and for avoiding falls as much as possible. Important principles in the motor training are (1) to train a small amount of exercises with a high amount of repetitions (2) to include movements with relevance in all day living and (3) to train increasingly demanding movements (from static to dynamic balance; from slow to fast movements; from single joint movements to complex multi-joint coordination). These are common principles in neurorehabilitation (e.g., Taub et  al. 1999; Platz et al. 2001). Results indicated that patients’ benefits can be meaningful for their everyday life and persisted after 1 year. The specificity of motor improvements is shown by measures reflecting intra-limb coordination (see Fig.  107.1c, d). Furthermore, continuous training has been shown to be crucial in patients with degenerative diseases: Importantly, the degree of longterm retention depends on training intensity. A similar study combining physiotherapy with occupational therapy in 42 patients with degenerative cerebellar ataxia revealed improvements of ataxia, gait speed, fall frequency, and activities of daily living (Miyai et al. 2012). Inspired by these positive results, further studies have been performed recently, examining the effects of different training strategies (Table 107.1) and the relationship between functional improvements and changes in neural substrate (Burciu et al. 2013; Draganova et al. 2021).

712

W. Ilg and D. Timmann

a

20

b

SARA score

15

10

5 (BT)

(AT)

(F1J)

(BT)

(AT)

(F1J)

0

d c

600 500

Body sway (mm)

400 300 200 100 0

Fig. 107.1 (a) Snapshot of a demanding exercise: training of dynamic balance and multijoint coordination. (b) Group data of the clinical ataxia score SARA before training intervention (BT), after the 4 week’s training intervention (AT) and for follow-up assessment after 1 year. (c) Illustration of an experiment testing dynamic balance capacities. Patients have to compensate the perturbation of the accelerating tread-

mill (accelerating phase 1 s) by anterior directed steps The red and the blue characters show one and the same patient before (red) and after (blue) the intervention period. After intervention patients were able to compensate the perturbation more efficient and in a more secure way. (d) Quantitative measurement for the body sway in the perturbation experiment for the three assessment points (Ilg et al. 2009, 2010)

107.4 Discussion

Best evidence for beneficial interventions exists for coordination training, which is (1) adapted on the severity of the ataxia and (2) consists in increasingly demanding exercises for multijoint coordination and balance. These approaches, to activate the remaining coordination capabilities should be used as long as possible, in order to potentially decelerate the process of degeneration of motor capabilities (which has yet shown only in animal studies (Fryer et al. 2011)). However, these types of exercise might be limited to stages of disease in which the patients are able to stand without help and have some gait capabilities. In more severe cases, in which free standing and walking is not possible anymore, treadmill training with potential weight support may be helpful to increase walking capabilities and to preserve general fitness as far as possible. In such stages, compensatory techniques like replacing rapid multi-­ joint arm movements with slower movements with sequential single joint movements (Bastian 1997) might be useful.

107.4.1 Current Praxis of Motor Rehabilitation Recent studies give evidence that intensive motor training can reduce ataxia symptoms in patients suffering from degenerative cerebellar disease equivalent to gaining back functional performance of 2 or more years of disease progression (Ilg et al. 2010). However, motor rehabilitation in degenerative cerebellar disease remains a challenge and requires a careful analysis of the patient’s current motor capacities and condition in everyday life. In general, a combination of restorative and compensatory techniques may be utilized; the relative emphasis depend on the severity of cerebellar ataxia and its pattern of progression (Bastian 1997; Cassidy et al. 2009; Marsden and Harris 2011).

107  Motor Rehabilitation of Cerebellar Disorders

The use of mobility aids is dependent on disease stage and individual preferences. Furthermore, in severe cases of upper limb ataxia, when basic activities of daily living like eating are impaired, the use of orthotics can help to improve functional performance (Cassidy et al. 2009).

107.4.2 Open Questions There is common agreement that continuous motor training is necessary for patients with degenerative ataxia (Ilg et al. 2014). This should include physiotherapeutic treatments as well as training at home, e.g., by exergame-based coordination training (Ilg et al. 2012; Schatton et al. 2017). There is a need of long-term studies to evaluate the benefits of rehabilitation strategies in patients’ everyday life (Milne et al. 2020). When performing long-term studies with patients suffering from degenerative disease, one has to keep in mind that progression in degeneration is different for specific types of diseases (Jacobi et al. 2011). There is also need to examine (1) whether patients with more severe impairments would also benefit from physiotherapeutical training and (2) whether motor training in very early stage and preclinical stages of the disease (Ilg et al. 2016) could slow down degeneration. Animal studies indicate that degeneration processes in the cerebellum could be decelerated by motor training (e.g., Fryer et al. 2011 SCA 1, mouse model).

107.4.2.1 Motor Rehabilitation for Upper Extremities and Speech There is still a lack of rehabilitation studies for upper limb movements in ataxia. It has been shown, however, that patients with cerebellar degeneration improve performance of single-joint, goal-directed forearm movements with practice (Draganova et  al. 2021). In principle, the concept of training with increasingly demanding coordination exercises could also be transferred to goal-directed upper limb movements. Another promising approach (Bhanpuri et al. 2014) tries to model the dysmetria reaching behavior to develop individualized robotic training interventions. First piloting studies show the feasibility and efficacy of speech training specifically tailored to cerebellar dysarthria (Vogel et  al. 2019) (Sonoda et al. 2021). 107.4.2.2 Studies on Mechanisms of Motor Learning and Rehabilitation Until today, it is not fully understood in how far functional improvements are related to motor learning. Further studies including modern brain imaging and modeling techniques are needed in order to clarify (1) in which way functional improvements are related to motor learning and (2) whether associated changes in neural substrates could be identified either within the cerebellum and its connections or in other

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brain structures compensating the cerebellar deficit. Premotor cortex appears to be important in compensatory remodeling following damage of the cerebro-cerebellar motor system (Burciu et al. 2013; Draganova et al. 2021). Recent studies delivered evidence that cerebellar patients might be less impaired in reinforcement learning (Therrien et  al. 2016) in comparison to sensory error-based learning (Therrien and Bastian 2015). Reinforcement learning is commonly thought to be less cerebellar-dependent than sensory error-based learning. Based on this work, current projects work on the use of reinforcement signals to improve arm movements in cerebellar patients (Therrien et al. 2021). Another direction of research is use of augmented feedback to facilitate learning. Draganova et al. (2021), however, were unable to show additional benefit of proprioceptive training or additional external verbal feedback and instructions in patients with cerebellar degeneration (Draganova et al. 2021). In contrast, using augmented feedback for the compensation of the impaired predictive control mechanisms of cerebellar patients delivers first promising results (Zimmet et al. 2020). Further studies in these directions will help to get a more detailed understanding of potentials of motor rehabilitation in degenerative ataxia and will enable individualized training concepts, which could involve different training modalities (dual task training) and potentially rehabilitation technology such as biofeedback (Cakrt et al. 2012; Fleszar et al. 2019) and non-invasive stimulation (Galea et  al. 2009; Miterko et al. 2019).

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714 tile biofeedback in patients with degenerative cerebellar disease. NeuroRehabilitation 31:429–434 Cassidy E, Kilbridge C, Holland A (2009) Management of the Ataxias: towards best Clinical Practice—Physiotherapy Supplement. In: Ataxia UK Cernak K, Stevens V, Price R, Shumway-Cook A (2008) Locomotor training using body-weight support on a treadmill in conjunction with ongoing physical therapy in a child with severe cerebellar ataxia. Phys Ther 88:88–97 Diener HC, Dichgans J (1996) Cerebellar and spinocerebellar gait disorders. In: Bronstein AM, Brandt T, Woollacott (eds) Clinical disorders of posture and gait, 1st edn. Arnold, London, pp 147–155 Draganova R, Konietschke F, Steiner KM, Elangovan N, Gumus M, Goricke SM, Ernst TM, Deistung A, van Eimeren T, Konczak J, Timmann D (2021) Motor training-related brain reorganization in patients with cerebellar degeneration. Hum Brain Mapp 43:1611 Fleszar Z, Mellone S, Giese M, Tacconi C, Becker C, Schöls L, Synofzik M, Ilg W (2019) Real-time use of audio-biofeedback can improve postural sway in patients with degenerative ataxia. Ann Clin Transl Neurol 6:285–294 Fonteyn EM, Heeren A, Engels JJ, Boer JJ, van de Warrenburg BP, Weerdesteyn V (2014) Gait adaptability training improves obstacle avoidance and dynamic stability in patients with cerebellar degeneration. Gait Posture 40:247–251 Fryer JD, Yu P, Kang H, Mandel-Brehm C, Carter AN, Crespo-Barreto J, Gao Y, Flora A, Shaw C, Orr HT, Zoghbi HY (2011) Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science 334:690–693 Galea JM, Jayaram G, Ajagbe L, Celnik P (2009) Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation. J Neurosci 29:9115–9122 Gill-Body KM, Popat RA, Parker SW, Krebs DE (1997) Rehabilitation of balance in two patients with cerebellar dysfunction. Phys Ther 77:534–552 Ilg W, Timmann D (2013) Gait ataxia-specific cerebellar influences and their rehabilitation. Mov Disord 28:1566–1575 Ilg W, Synofzik M, Brötz D, Burkard S, Giese MA, Schöls L (2009) Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology 73:1823–1830 Ilg W, Brötz D, Burkard S, Giese MA, Schöls L, Synofzik M (2010) Long-term effects of coordinative training in degenerative cerebellar disease. Mov Disord 25:2239–2246 Ilg W, Schatton C, Schicks J, Giese MA, Schols L, Synofzik M (2012) Video game-based coordinative training improves ataxia in children with degenerative ataxia. Neurology 79:2056–2060 Ilg W, Bastian AJ, Boesch S, Burciu RG, Celnik P, Claassen J, Feil K, Kalla R, Miyai I, Nachbauer W, Schols L, Strupp M, Synofzik M, Teufel J, Timmann D (2014) Consensus paper: management of degenerative cerebellar disorders. Cerebellum 13:248–268 Ilg W, Fleszar Z, Schatton C, Hengel H, Harmuth F, Bauer P, Timmann D, Giese M, Schols L, Synofzik M (2016) Individual changes in preclinical spinocerebellar ataxia identified via increased motor complexity. Mov Disord 31:1891–1900 Jacobi H et al (2011) The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology 77:1035–1041 Kaut O, Jacobi H, Coch C, Prochnicki A, Minnerop M, Klockgether T, Wullner U (2014) A randomized pilot study of stochastic vibration therapy in spinocerebellar ataxia. Cerebellum 13:237–242 Keller JL, Bastian AJ (2014) A home balance exercise program improves walking in people with cerebellar ataxia. Neurorehabil Neural Repair 28:770 Konczak J, Schoch B, Dimitrova A, Gizewski E, Timmann D (2005) Functional recovery of children and adolescents after cerebellar tumour resection. Brain 128:1428–1441

W. Ilg and D. Timmann Marsden J, Harris C (2011) Cerebellar ataxia: pathophysiology and rehabilitation. Clin Rehabil 25:195–216 Milne SC, Corben LA, Georgiou-Karistianis N, Delatycki MB, Yiu EM (2017) Rehabilitation for individuals with genetic degenerative ataxia: a systematic review. Neurorehabil Neural Repair 31:609–622 Milne SC, Corben LA, Roberts M, Murphy A, Tai G, Georgiou-­ Karistianis N, Yiu EM, Delatycki MB (2018) Can rehabilitation improve the health and well-being in Friedreich’s ataxia: a randomized controlled trial? Clin Rehabil 32:630–643 Milne SC, Corben LA, Roberts M, Szmulewicz D, Burns J, Grobler AC, Williams S, Chua J, Liang C, Lamont PJ, Grootendorst AC, Massey L, Sue C, Dalziel K, LaGrappe D, Willis L, Freijah A, Gerken P, Delatycki MB (2020) Rehabilitation for ataxia study: protocol for a randomised controlled trial of an outpatient and supported home-­ based physiotherapy programme for people with hereditary cerebellar ataxia. BMJ Open 10:e040230 Miterko LN et al (2019) Consensus paper: experimental neurostimulation of the cerebellum. Cerebellum 18:1064–1097 Miyai I, Ito M, Hattori N, Mihara M, Hatakenaka M, Yagura H, Sobue G, Nishizawa M (2012) Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair 26:515–522 Morton SM, Bastian AJ (2004) Cerebellar control of balance and locomotion. Neuroscientist 10:247–259 Platz T, Winter T, Muller N, Pinkowski C, Eickhof C, Mauritz KH (2001) Arm ability training for stroke and traumatic brain injury patients with mild arm paresis: a single-blind, randomized, controlled trial. Arch Phys Med Rehabil 82:961–968 Schatton C, Synofzik M, Fleszar Z, Giese MA, Schols L, Ilg W (2017) Individualized exergame training improves postural control in advanced degenerative spinocerebellar ataxia: a rater-blinded, intra-­ individually controlled trial. Parkinsonism Relat Disord 39:80–84 Schöls L, Bauer P, Schmidt T, Schulte T, Riess O (2004) Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3:291–304 Sonoda Y, Yoshida N, Kawami K, Kitamura A, Ogawa N, Yamakawa I, Kim H, Sanada M, Imai S, Urushitani M (2021) Short-term effect of intensive speech therapy on dysarthria in patients with sporadic spinocerebellar degeneration. J Speech Lang Hear Res 64:725–733 Synofzik M, Ilg W (2014) Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames. Biomed Res Int 2014:583507 Taub E, Uswatte G, Pidikiti R (1999) Constraint-Induced Movement Therapy: a new family of techniques with broad application to physical rehabilitation—a clinical review. J Rehabil Res Dev 36:237–251 Therrien AS, Bastian AJ (2015) Cerebellar damage impairs internal predictions for sensory and motor function. Curr Opin Neurobiol 33:127–133 Therrien AS, Wolpert DM, Bastian AJ (2016) Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise. Brain 139:101–114 Therrien AS, Statton MA, Bastian AJ (2021) Reinforcement signaling can be used to reduce elements of cerebellar reaching ataxia. Cerebellum 20:62–73 Vogel AP, Stoll LH, Oettinger A, Rommel N, Kraus EM, Timmann D, Scott D, Atay C, Storey E, Schols L, Synofzik M (2019) Speech treatment improves dysarthria in multisystemic ataxia: a rater-blinded, controlled pilot-study in ARSACS. J Neurol 266:1260–1266 Wang RY, Huang FY, Soong BW, Huang SF, Yang YR (2018) A randomized controlled pilot trial of game-based training in individuals with spinocerebellar ataxia type 3. Sci Rep 8:7816 Zimmet AM, Cao D, Bastian AJ, Cowan NJ (2020) Cerebellar patients have intact feedback control that can be leveraged to improve reaching. Elife 9:e53246

Editing the Genome

108

Jordi Gandini and Mario Manto

Abstract

Cerebellar ataxias (CAs) represent a heterogeneous group of sporadic or inherited disorders, including the genetic group of nucleotide repeat disorders. The mechanisms leading to the clinical deficits have been greatly clarified with the advent of genetic studies, novel neuroimaging tools, and the development of cellular/animal models recapitulating neuronal defects in humans. Targeting the DNA and the RNA represents a highly promising approach in so-called degenerative ataxias, previously considered as untreatable disorders. Disease-modifying treatments of CAs have become a reality and will likely be administered on a regular basis in selected CAs during this decade. Keywords

Cerebellum · Genome · Editing · RNA · DNA

108.1 Introduction: Definition of Cerebellar Ataxias and Their Mechanisms with an Emphasis on Polyglutaminopathies Cerebellar ataxias (Cas) are a group of highly heterogeneous disorders in terms of phenotypes and genotypes, often compromising the quality of life and even lifespan in some cases (Kuo 2019). Patients exhibit a variety of phenotypes, ranging from pure cerebellar deficits to complex combinations of J. Gandini Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU Hôpital Civil Marie Curie, Charleroi, Belgium M. Manto (*) Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU Hôpital Civil Marie Curie, Charleroi, Belgium Université de Mons, Mons, Belgium e-mail: [email protected]

neurological signs related to the central nervous system and/ or peripheral nervous system involvement (this volume). In terms of cerebellar symptoms, patients exhibit oculomotor deficits, speech deficits, motor symptoms affecting limbs and gait, as well as a wide range of cognitive/affective impairments and social difficulties. Cas affect all ages and are represented worldwide, although founder effects cause an increased prevalence in some geographically isolated areas. Multiples mechanisms underlie Cas. We focus here on genetic Cas, in particular on a subgroup of diseases caused by expansion of trinucleotide’s sequences, known as nucleotide repeat disorders (NRDs). These disorders represent debilitating genetic Cas, with repeat expansions in one or both alleles and repeat instability (Zain and Smith 2019). Anticipation (earlier onset of symptoms with an increasing severity of disease in successive generations) is very suggestive. Indeed, genetic instability and correlation between the size of expanded repeats and age of onset/severity of the disease are key features. Expanded sequences affect both coding and non-coding regions. The most common NRDs are related to not only expanded trinucleotide repeat sequences but include also disorders characterized by tetra-, penta-, or hexanucleotide repeats. Several NRDs such as spinocerebellar ataxia (SCA) type 1/2/3/6/7/17 show an expansion of CAG repeats resulting in toxic RNA and polyglutamine tracts, hence the terminology of polyglutaminopathies (we will not discuss here Huntington’s disease and spinobulbar muscular atrophy) (Klockgether et al. 2019). The expanded CAG repeats result in gain-of-function disorders with pathological proteins (ataxins). By comparison, Friedreich ataxia (FRDA) and Fragile X syndrome (FXS) represent exemplative cases of NRDs with a loss-of-function pathogenesis. Most FRDA patients show an expansion of the GAA*TCC repeat in the frataxin gene, causing deficits in frataxin by a mechanism of FXN silencing (Gottesfeld 2019). FXS is due to a CGG*CCG of the FMR1 gene. When the expansion overpasses 200 repeats (full mutation), the gene is silent and

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_108

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the expression of the protein FMRP is markedly reduced. A number of copies between 55 and 200 (premutated alleles) correspond to premutations, causing the Fragile X tremor ataxia syndrome (FXTAS) which affects mainly adult men. Noteworthy, these patients have an increased transcription of FMR1 mRNA. However, FMRP translation is impaired. Unfortunately, most of the symptomatic therapies such as conventional oral medications or rehabilitation currently administered have failed to reverse the fatal evolution of NRDs (Perlman and Boltshauser 2018). Currently, we are also missing an effective approach to achieve a real prevention of clinical deficits.

108.2 Definition of Genome Editing The multimodal development of next-generation sequencing (NGS), novel neuroimaging tools such as tractography and fMRI, relevant cellular models, and dedicated animal models have not only extended our understanding of cerebellar disorders but have also improved significantly the identification of the molecular/cellular mechanisms leading to CAs encountered in daily practice (Synofzik et al. 2019). There is also a substantial progress in the field of biomarkers: volumetry of the cerebellum and spinal cord, fMRI assessment of brain networks, neurophysiological biomarkers such as oculomotor biomarkers or markers for gait deterioration, fluid biomarkers such as neurofilament light chain –Nfl– in the serum or CSF (Deelchand et al. 2019. Shirai et al. 2019). The advancement in knowledge of the molecular pathophysiology of CAs has opened the way for therapies acting directly on the nucleic acids, allowing the manipulation of the genome. Therapies targeting DNA and RNA represent a revolution in ataxiology.

108.3 Experimental Studies of Genome Editing in Cerebellar Ataxias (In Vitro Studies, In Vivo Studies) Three technologies are very promising: antisense oligonucleotides (ASOs), RNA interference (RNAi) and clustered regularly interspaced short palindromic repeats (CRISPR).

108.3.1 ASOs Antisense oligonucleotides (ASOs) have an RNA-like structure. In gain-of-function disorders, the main goal is to decrease the mRNA contents by use of single-stranded ASOs, by blocking translation or by a direct silencing effect (Moore et al. 2017). In particular, ASOs bind complementary mRNA using Watson–Crick hybridization. This process

leads to RNase H enzyme recruitment (Sullivan et al. 2019). In SCA3 fibroblasts, ASOs remove the central 88 amino-acid region of the ataxin-3 protein (Sullivan et  al. 2019). It has been demonstrated in the mouse model of SCA2 that intrathecal administration of ASOs decreases the levels of the mutated protein and improve the firing of Purkinje neurons as well as motor tasks (Scoles et al. 2017). Administration of ASOs is associated with a slower progression of motor deficits and a longer survival (Becker et al. 2017). Similar findings have been reported in the SCA3 mouse model with intracerebroventricular injection of ATXN3-targeting ASO (McLoughlin et al. 2018). A reduction of 50% of pathological ataxin-3 has been demonstrated in the cerebellum, diencephalon, forebrain, and cervical spinal cord without signs of microgliosis or astrogliosis (Moore et  al. 2017; Toonen et al. 2017).

108.3.2 RNAi The aim of RNA interference (RNAi) is to block the expression of mutated polyglutamine-proteins. Synthetic small interfering RNA (siRNAs) and short hairpin RNA (shRNAs) regulate the RNAi process of target mRNA enzymatic cleavage. RNAi decreases the levels of ataxin-7  in the mouse model of SCA7 (Ramachandran et al. 2014). One of the effects of polyQ proteins is to impair transcription regulation and therefore attempts are ongoing to revert this mechanism using histone deacetylases (HDACs) such as valproic acid (Lin et  al. 2014). In FRDA, delivering the mRNA is also currently investigated. Another approach is via dsRNA which activates the FXN gene expression (Shen et al. 2018).

108.3.3 CRISPR Clustered regularly interspaced short palindromic repeats (CRISPR) is a naturally prokaryotic immune system that protects bacteria from invading virus (Mojica et  al. 2000; Barrangou et al. 2007). CRISPR-associated (Cas) enzymes target and cleave specific nucleic acid sequences, currently CRISPR-based applications use the enzyme Cas9 from Streptococcus pyogenes (spCas9) (Sternberg and Doudna 2015). To target specific DNA sequences, Cas9 utilizes two types of nucleic acids: CRISPR RNA (crRNA), composed by 20-nucleotides sequence, that bind the targeted DNA, and a platform of RNA, called trans-activating crRNA (tracrRNA), that is anchored to Cas9 (Mali et al. 2013; Cong et al. 2013; Wiedenheft et al. 2012). CrRNA and tracrRNA can be fused to form a single-guide RNA (sgRNA) chimera that has both the ability to target and cleave the chosen DNA sequences (Jinek et al. 2012).

108  Editing the Genome

For the time being, this technology is studied ex vivo and in  vivo for the therapy of HIV infection, several types of solid neoplasms, leukemia, and β-thalassemia (Hirakawa et al. 2020). A limit of this technique is the development of immune response anti-Cas9 enzymes (Chew 2018). Moreover, side effects of the DNA cleavage are not well known, and potential mutagenic effects must be considered (Zhang et al. 2015; Florea and Busselberg 2011).

108.3.4 Other Technologies in Development In 2019, Shen et al. demonstrated that nascent polypeptide associated complex (NAC), a ribosome-associated protein biogenesis factor (particularly his N-terminal peptide) which exerts chaperone activity toward structurally diverse model substrates including PolyQ proteins, suppresses the aggregation of polyglutamine expanded proteins associated with several types of SCAs (Shen et  al. 2019). Therefore, this molecule might represent a promising therapy to target proteotoxicity of mutant PolyQ-expanded proteins. Recently, the role of nuclease FAN1 in the modulation of the expression of triplets in several diseases has been emphasized (Deshmukh et  al. 2021). In particular, FAN1 activity might delay the onset of HD. Variants of this enzyme might have a beneficial effect upon the age of onset of SCA1, SCA2, SCA3, SCA6, SCA7, and SCA 17 (Bettencourt et al. 2016; Ciosi et al. 2019; Mergener et al. 2020).

108.4 Conclusion and Perspectives In conclusion, gene therapy has a huge potential in particular for triplet expansion diseases. The genetic advances and identification of molecular mechanisms of ataxias have opened the possibility of a direct repair of the pathological DNA–RNA machinery. These novel therapeutic strategies will likely be used to block the onset of symptoms in CAs at the premanifest stage or at a very early stage when the neuronal reserve is high. Effective preventive therapies for dominant ataxias are thus envisioned. Genome engineering methods including excision or modification of the repeats have become a reality. Declaration  The authors declare no conflict of interest. Funding  This work was conducted without any funding from public or private sources. Ethical Committee Request  Not applicable. Consent to Participate  Not applicable.

717 Data Availability  The chapter is not associated with raw data. Code Availability There is no software application or custom code used in this paper. Authors’ Contribution Chapter preparation: JG.  Editing: MM.  All authors have read and agreed to the publication.

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Grafting Jan Cendelin and Zdenka Purkartova

vascular disorders, tumors, and their surgical treatment lead to irreversible damage to the cerebellar tissue occurring sudNeurotransplantation is as a potential therapeutic method denly or when in an advanced stage at the time of diagnosis. for diseases of the nervous system, including the cerebelOther cases are the slowly progressive cerebellar degeneralum. Experiments on laboratory animals have shown many tive diseases, for which, however, usually no causal therapy promising results, but also potential risks and limitations, capable of substantial slowing down of the process is curwith many questions remaining unanswered. We discuss the rently available in the clinic, although animal studies have main goals of neurotransplantation as a treatment of cereopened novel perspectives (see Chap. 108). bellar disorders, potential graft effect mechanisms, types of These pathologies lead to the loss of all types of cerebellar grafts with their advantages and disadvantages, and probneurons focally (e.g., traumas, cerebrovascular diseases, and lems of graft development and functional integration. tumors), or to the rather diffuse extinction of specific neuronal population (e.g., degenerative processes, untreated immuneKeywords mediated cerebellitis). Thereby they reduce cerebellar reserve, Cell rescue · Cerebellum · Cerebellar ataxia · Mouse induce a non-restorable state, and may lead to irreversible detemodels · Neurotransplantation · Stem cells rioration of cerebellar functions (Mitoma and Manto 2016). Because of the problematic treatment of many of the cerebellar diseases and their severe functional consequences, new thera109.1 Introduction peutic approaches are being investigated. These include, first of all, new or repurposed neuroprotective medicaments, pharmaCerebellar pathologies are manifested by motor, cognitive, cotherapy or genetic therapy, targeting specifically the pathobehavioral, and emotional disorders. In severe cases, they genesis of the disease, or non-invasive cerebellar stimulation lead to complete disability of the patient or even premature (see Chap. 106) promoting residual cerebellar functions death. For some cerebellar diseases, such as immune-­ (Mitoma and Manto 2016; Gandini et al. 2020). mediated cerebellar ataxias, effective therapy is available, Neurotransplantation also belongs among the experimental particularly if administered early upon correct and timely therapies for cerebellar damage. It has been investigated as a diagnosis at a stage when the cerebellar reserve is sufficient. promising and hopeful approach for decades. Despite intensive On the other hand, some pathologies, e.g., trauma, cerebro- research and the quantity of new knowledge, there are still many questions and doubts. Neurotransplantation is not yet a safe, effective, and routine therapy, but remains mostly in the stage of experiments on laboratory animals (Cendelin et al. 2019). J. Cendelin (*) Abstract

Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, Plzen, Czech Republic Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Plzen, Czech Republic e-mail: [email protected] Z. Purkartova Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, Plzen, Czech Republic e-mail: [email protected]

109.2 Goal of Neurotransplantation Therapy Cerebellar transplantation goals include (1) substitution of lost cells, (2) promotion of function of residual cerebellar tissue via plasticity stimulation, and (3) prevention (or delay)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_109

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of degeneration of intrinsic cerebellar neurons. The problem is that proper cerebellar function is dependent on specific cerebellar circuitries, consisting of projection Purkinje neurons, many types of cerebellar cortex interneurons, deep cerebellar nuclei, as well as on multiple afferent and efferent connections with many neural structures. Effective restoration of these complex circuitries by grafted neurons would be extremely difficult since it requires survival and appropriate differentiation, and adequate synaptic integration of a sufficient number of grafted cells. Nevertheless, it would be the only solution if most of the intrinsic neurons of a certain type or a substantial part of the cerebellar tissue is damaged. In the case of cerebellar function support, the sufficient cerebellar reserve (see Chap. 110) must still be preserved to maintain a restorable state (Mitoma and Manto 2016; Cendelin et al. 2018a). If a small amount of tissue (neurons of a certain type) remains, it is not capable of compensating for the loss of function of extinct cells and to maintain cerebellar function on an acceptable level. Analogously, prevention of neuronal degeneration can have a substantial effect only if started before the massive neuronal loss has developed. From this point of view, different goals and mechanisms of graft effect are of importance in slowly developing early-stage diseases, fully developed mild damage and in fully developed massive damage to cerebellar tissue, or advanced stages of progressive uncontrollable cerebellar degeneration (Cendelin et al. 2018a, 2019).

109.3 Graft Types and Mechanisms of Their Effect Because grafting mature neural tissue is not possible, immature cerebellar cells, neural precursors or stem cells are used. Individual types of grafts have their advantages and can act via different, in some cases multiple mechanisms to meet one or more of the transplantation goals as described above. Indeed, they also have disadvantages and serious limitations that are of a biological, technical, and, in some cases, ethical nature. Fetal (embryonic) cerebellar tissue transplantation is a classic approach that has been used in many mouse models of cerebellar degenerations since the 1980s (Sotelo and Alvarado-Mallart 1987; Kohsaka et al. 1988; Triarhou et al. 1996; Kaemmerer and Low 1999; Fuca et  al. 2017; Purkartova et al. 2019) (Fig. 109.1). The graft can be injected either as a solid piece of tissue or as a cell suspension, surviving for many weeks or months in both healthy and mutant cerebellum (Kaemmerer and Low 1999; Fuca et  al. 2017; Cendelin et al. 2018b; Purkartova et al. 2019). Fetal cerebellar tissue is a good source of Purkinje cells (Fig. 109.1b) and thus could potentially be used to replenish a deficient population of these projection neurons of the cerebellar cortex

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(Sotelo et al. 1990; Carletti and Rossi 2005; Fuca et al. 2017; Cendelin et al. 2018b; Purkartova et al. 2019). It could also be effective in the substitution of granule cells (Kohsaka et al. 1988). Nevertheless, there are controversial results regarding the integration of fetal cerebellar grafts into the host’s cerebellum (Kohsaka et al. 1988; Sotelo et al. 1990; Carletti et al. 2008; Cendelin et al. 2018b; Purkartova et al. 2019). There may be differences in intensity of colonization of the host’s cerebellum by grafted Purkinje cells and axons sprouting from the graft into the host’s tissue not only between healthy and mutant mice but also between different types of cerebellar mutants (Purkartova et  al. 2019). Alleviation of motor deficits after fetal cerebellar cell transplantation has been found only in some cerebellar mutants (Triarhou et al. 1996; Kaemmerer and Low 1999), while other studies reported no or only weak effects (Fuca et al. 2017; Cendelin et al. 2018b; Purkartova et al. 2019). As in the neurotransplantation treatment of Parkinson’s disease by fetal dopaminergic neurons, the only available source of fetal cerebellum would be aborted human fetuses. This is a problematic source, because of difficult quality standardization, risk of infection transmission, and also from an ethical point of view. Neural stem cells can be isolated from donor brain, particularly from its neurogenic zones (e.g., subventricular zone) and immature (fetal) brain. The advantage is the possibility of in  vitro expansion of these stem cells, which is, however, limited. Therefore, the source is dependent on donor brain availability. There are similar technical and ethical problems, as in fetal cerebellar tissue. Neural stem cells do not show a strong tendency to differentiate into cerebellar-­ specific neuronal phenotypes (Chintawar et al. 2009; Rolando et al. 2010; Mendonca et al. 2015); in particular, differentiation into Purkinje cells is rare (Rosario et al. 1997; Lee et al. 2005). On the other hand, grafted neural stem cells have been shown to contribute to the survival of degenerating intrinsic cells by metabolic support via gap junctions (Jaderstad et al. 2010). Embryonic stem cells can be maintained and expanded effectively in vitro and show a capacity to differentiate into various cell types or cerebellar organoids (Muguruma et al. 2015). Nevertheless, human embryonic cells are ethically problematic and their manipulation is strictly regulated by national legislation. Carcinoma stem cells are derived from carcinoma (teratocarcinoma) and, as such, they are easy to maintain and expand in vitro. Neural progenitors derived from carcinoma stem cells grafted into the cerebellum of normal and cerebellar mutant mice did not differentiate into local specific neuronal phenotypes and overall morphology of the graft did not promise any positive effect (Houdek et al. 2012). On the other hand, these cells had a therapeutic effect in animal

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b

Fig. 109.1  A fluorescent graft (donor tissue expressing enhanced green fluorescent protein, EGFP) in the host mouse cerebellum (a). A detail of Purkinje cells in the graft, showing no laminar arrangement (b)

models of amyotrophic lateral sclerosis (Garbuzova-Davis Huda et al. 2016). These activities are mediated by the proet  al. 2002), spinal cord injury (Saporta et  al. 2002), or duction of various bioactive compounds, such as neurostroke (Hara et  al. 2007). Nevertheless, carcinoma stem trophic factors and other substances contained in extracellular cells are considered dangerous for human use, although vesicles (Jones et al. 2010; Nakano and Fujimiya 2021). Cell their tumorigenic capacity might be reduced by advanced rescue can also be achieved by fusion (Bae et al. 2007; Diaz neurodifferentiation (Pleasure et al. 1992; Garbuzova-Davis et  al. 2012; Huda et  al. 2016; Kemp et  al. 2018). Cell et al. 2002). ­pathology seems to increase the frequency of fusion events Adult stem cells can be isolated from various tissues compared to healthy tissue (Diaz et  al. 2012; Huda et  al. without any significant damage to the donor. Advanced tech- 2016; Kemp et al. 2018). Fusion between grafted MSCs and nologies even allow the generation of induced pluripotent degenerating Purkinje cells generated functioning Purkinje stem cells from somatic cells (iPSCs) (Takahashi and cells, whereas the MSCs provide a normal nucleus that is Yamanaka 2006). Their features and therapeutic potential are reprogrammed to maintain Purkinje neuron phenotype of the not yet fully explored. Nevertheless, Purkinje cells and cer- heterokaryon cell (Bae et  al. 2007; Kemp et  al. 2018). ebellar organoids have already been generated from iPSCs Intravenous, i.e., systemic administration of MSCs is also (Wang et al. 2015; Watson et al. 2018; Nayler et al. 2021), possible. In SCA2 mice, it has been shown to be even more suggesting that they can become an effective tool for cere- effective than local intracerebellar injection (Chang et  al. bellar cell therapy. This type of graft would be available for 2011). In aggressive cerebellar degeneration, repeated sysautotransplantation as well (considering in  vitro gene ther- temic injection of bone marrow cells might be necessary apy in the case of hereditary cerebellar degeneration). (Díaz et al. 2019). Mesenchymal stem cells (MSCs) can be isolated from, e.g., bone marrow, umbilical cord, or adipose tissue, without injuring the donor substantially. Autotransplantation is also 109.4 Host Tissue Factors Determining Graft possible. MSCs have been grafted in many mouse models of Survival, Development cerebellar diseases, showing mostly positive results. They and Functional Integration usually do not differentiate intensively into cerebellar-­ specific neurons (Bae et al. 2007; Jones et al. 2010; Chang Survival, appropriate differentiation, migration, and synaptic et al. 2011; Matsuura et al. 2014) and thus do not appear to integration of grafted cells would be essential, namely if be an optimum graft for cell replacement therapy. their specific therapeutic effect based on lost cell substitution Effects are rather based on degenerating cell rescue, ame- is required. These processes depend not only on the properlioration of neuropathology in the cerebellum, anti-­ ties of the grafted cells (graft type, differentiation stage, inflammatory effects, and support of residual cerebellar in  vitro pre-treatment), but also on signals from the host’s tissue plasticity (Jones et  al. 2010; Matsuura et  al. 2014; tissue milieu. The cerebellum, however, belongs to less neu-

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rogenic structures that do not stimulate differentiation of neural stem cells into local specific neurons (Suhonen et al. 1996). Another obstacle can be the granular layer of adult mice that acts as a barrier preventing grafted Purkinje cell axons to grow from the molecular layer toward the deep cerebellar nuclei (Keep et  al. 1992; Carletti et  al. 2008). Therefore, establishing corticonuclear projections is problematic if grafted Purkinje cells occupy the molecular layer. From the point of view of the clinical use of cerebellar transplantation, it is important to consider grafting into a pathologically changed tissue providing potentially different signals from the healthy one. These signals can either be of a positive or a negative nature. For instance, the Purkinje cell deficient cortex of Purkinje cell degeneration (pcd) mice has been reported to exert a selective neurotrophic effect on grafted Purkinje cells that colonized the molecular layer (Sotelo and Alvarado-Mallart 1987). In addition, the cerebellum of these mice provides stronger signals that promote the survival of grafted Purkinje cells, compared to the healthy cerebellum (Carletti and Rossi 2005). In contrast, in the cerebellum of Lurcher mice, embryonic cerebellar grafts maintain a rather delimited structure, with a low tendency for cell migration and fiber sprouting, unlike in healthy and pcd mice (Cendelin et al. 2018b; Purkartova et al. 2019). It is not yet clear what factors are responsible for such differences in graft integration between the normal cerebellum and various cerebellar pathologies. In cerebellar mutants, there are differences in microvascular bed (Kolinko et al. 2016), trophic factor levels (Salomova et al. 2020), distribution and activation of glial cells (Baltanas et al. 2013; Salomova et al. 2020), immune system and inflammatory parameters (Mandakova et al. 2005; Vernet-der Garabedian et al. 2013), or corticosterone level reactivity (Hilber et al. 2004) that can potentially influence the levels of cerebellar tissue neurogenicity.

109.5 Conclusion It is important to consider that neurotransplantation is an invasive method with many risks, including the classic complications of surgery or infection introduction into the cranial cavity. In addition, the potential tumorigenic capacity of grafted cells should be considered (Garbuzova-Davis et  al. 2002; Amariglio et al. 2009). Currently, there have been only a few clinical trials on cerebellar patients (Wu et  al. 1991; Tian et  al. 2009). Therefore, valid information on the efficiency, long-term persistence of the effect and the safety of neurotransplantation as a therapy of cerebellar diseases is still missing. Although many studies in animal models show the promising efficiency of cerebellar transplantation (Triarhou et  al. 1996; Kaemmerer and Low 1999; Bae et  al. 2007; Chintawar et al. 2009; Mendonca et al. 2015), other studies

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are rather pessimistic or controversial (Fuca et  al. 2017; Cendelin et al. 2018b; Purkartova et al. 2019). Furthermore, there is a wide spectrum of cerebellar pathologies. Hereditary cerebellar degenerations themselves represent a highly heterogeneous group. Each disease might determine different specific conditions in the patient’s cerebellum that could lead to a different response to grafted cells. Thus, cerebellar transplantation can present different positive as well as negative effects (cost/benefit ratio) in individual diseases and pathologies. Tailored approaches might be considered.

References Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L, Paz N, Koren-Michowitz M, Waldman D, Leider-­ Trejo L, Toren A, Constantini S, Rechavi G (2009) Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med 6(2):e1000029 Bae JS, Han HS, Youn DH, Carter JE, Modo M, Schuchman EH, Jin HK (2007) Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration. Stem Cells 25(5):1307–1316 Baltanas FC, Berciano MT, Valero J, Gomez C, Diaz D, Alonso JR, Lafarga M, Weruaga E (2013) Differential glial activation during the degeneration of Purkinje cells and mitral cells in the PCD mutant mice. Glia 61(2):254–272 Carletti B, Rossi F (2005) Selective rather than inductive mechanisms favour specific replacement of Purkinje cells by embryonic cerebellar cells transplanted to the cerebellum of adult Purkinje cell degeneration (pcd) mutant mice. Eur J Neurosci 22(5):1001–1012 Carletti B, Williams IM, Leto K, Nakajima K, Magrassi L, Rossi F (2008) Time constraints and positional cues in the developing cerebellum regulate Purkinje cell placement in the cortical architecture. Dev Biol 317(1):147–160 Cendelin J, Mitoma H, Manto M (2018a) Neurotransplantation therapy and cerebellar reserve. CNS Neurol Disord Drug Targets 17(3):172–183 Cendelin J, Purkartova Z, Kubik J, Ulbricht E, Tichanek F, Kolinko Y (2018b) Long-term development of embryonic cerebellar grafts in two strains of Lurcher mice. Cerebellum (London, England) 17(4):428–437 Cendelin J, Buffo A, Hirai H, Magrassi L, Mitoma H, Sherrard R, Vozeh F, Manto M (2019) Task force paper on cerebellar transplantation: are we ready to treat cerebellar disorders with cell therapy? Cerebellum (London, England) 18(3):575–592 Chang YK, Chen MH, Chiang YH, Chen YF, Ma WH, Tseng CY, Soong BW, Ho JH, Lee OK (2011) Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci 18:54 Chintawar S, Hourez R, Ravella A, Gall D, Orduz D, Rai M, Bishop DP, Geuna S, Schiffmann SN, Pandolfo M (2009) Grafting neural precursor cells promotes functional recovery in an SCA1 mouse model. J Neurosci 29(42):13126–13135 Diaz D, Recio JS, Weruaga E, Alonso JR (2012) Mild cerebellar neurodegeneration of aged heterozygous PCD mice increases cell fusion of Purkinje and bone marrow-derived cells. Cell Transplant 21(7):1595–1602

109 Grafting Díaz D, Del Pilar C, Carretero J, Alonso JR, Weruaga E (2019) Daily bone marrow cell transplantations for the management of fast neurodegenerative processes. J Tissue Eng Regen Med 13(9):1702–1711 Fuca E, Guglielmotto M, Boda E, Rossi F, Leto K, Buffo A (2017) Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice. Neurobiol Dis 102:49–59 Gandini J, Manto M, Bremova-Ertl T, Feil K, Strupp M (2020) The neurological update: therapies for cerebellar ataxias in 2020. J Neurol 267(4):1211–1220 Garbuzova-Davis S, Willing AE, Milliken M, Saporta S, Zigova T, Cahill DW, Sanberg PR (2002) Positive effect of transplantation of hNT neurons (NTera 2/D1 cell-line) in a model of familial amyotrophic lateral sclerosis. Exp Neurol 174(2):169–180 Hara K, Matsukawa N, Yasuhara T, Xu L, Yu G, Maki M, Kawase T, Hess DC, Kim SU, Borlongan CV (2007) Transplantation of post-­ mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in  vitro evidence of expedited neuronal differentiation and GDNF secretion. J Neurosci Res 85(6):1240–1251 Hilber P, Lorivel T, Delarue C, Caston J (2004) Stress and anxious-related behaviors in Lurcher mutant mice. Brain Res 1003(1–2):108–112 Houdek Z, Cendelin J, Kulda V, Babuska V, Cedikova M, Kralickova M, Pachernik J, Stefano GB, Vozeh F (2012) Intracerebellar application of P19-derived neuroprogenitor and naive stem cells to Lurcher mutant and wild type B6CBA mice. Med Sci Monit 18(5):Br174–Br180 Huda F, Fan Y, Suzuki M, Konno A, Matsuzaki Y, Takahashi N, Chan JK, Hirai H (2016) Fusion of human fetal mesenchymal stem cells with “degenerating” cerebellar neurons in spinocerebellar ataxia type 1 model mice. PLoS One 11(11):e0164202 Jaderstad J, Jaderstad LM, Li J, Chintawar S, Salto C, Pandolfo M, Ourednik V, Teng YD, Sidman RL, Arenas E, Snyder EY, Herlenius E (2010) Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host. Proc Natl Acad Sci U S A 107(11):5184–5189 Jones J, Jaramillo-Merchan J, Bueno C, Pastor D, Viso-Leon M, Martinez S (2010) Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia. Neurobiol Dis 40(2):415–423 Kaemmerer WF, Low WC (1999) Cerebellar allografts survive and transiently alleviate ataxia in a transgenic model of spinocerebellar ataxia type-1. Exp Neurol 158(2):301–311 Keep M, Alvarado-Mallart RM, Sotelo C (1992) New insight on the factors orienting the axonal outgrowth of grafted Purkinje cells in the pcd cerebellum. Dev Neurosci 14(2):153–165 Kemp KC, Dey R, Verhagen J, Scolding NJ, Usowicz MM, Wilkins A (2018) Aberrant cerebellar Purkinje cell function repaired in vivo by fusion with infiltrating bone marrow-derived cells. Acta Neuropathol 135(6):907–921 Kohsaka S, Takayama H, Ueda T, Toya S, Tsukada Y (1988) Reorganization of cerebellar cell suspension transplanted into the weaver mutant cerebellum and immunohistochemical detection of synaptic formation. Neurosci Res 6(2):162–166 Kolinko Y, Cendelin J, Kralickova M, Tonar Z (2016) Smaller absolute quantities but greater relative densities of microvessels are associated with cerebellar degeneration in Lurcher mice. Front Neuroanat 10:35 Lee A, Kessler JD, Read TA, Kaiser C, Corbeil D, Huttner WB, Johnson JE, Wechsler-Reya RJ (2005) Isolation of neural stem cells from the postnatal cerebellum. Nat Neurosci 8(6):723–729

723 Mandakova P, Sinkora J, Sima P, Vozeh F (2005) Reduced primary T lymphopoiesis in 3-month-old lurcher mice: sign of premature ageing of thymus? Neuroimmunomodulation 12(6):348–356 Matsuura S, Shuvaev AN, Iizuka A, Nakamura K, Hirai H (2014) Mesenchymal stem cells ameliorate cerebellar pathology in a mouse model of spinocerebellar ataxia type 1. Cerebellum (London, England) 13(3):323–330 Mendonca LS, Nobrega C, Hirai H, Kaspar BK, Pereira de Almeida L (2015) Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice. Brain 138(Pt 2):320–335 Mitoma H, Manto M (2016) The physiological basis of therapies for cerebellar ataxias. Ther Adv Neurol Disord 9(5):396–413 Muguruma K, Nishiyama A, Kawakami H, Hashimoto K, Sasai Y (2015) Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep 10(4):537–550 Nakano M, Fujimiya M (2021) Potential effects of mesenchymal stem cell derived extracellular vesicles and exosomal miRNAs in neurological disorders. Neural Regen Res 16(12):2359–2366 Nayler S, Agarwal D, Curion F, Bowden R, Becker EBE (2021) High-resolution transcriptional landscape of xeno-free human induced pluripotent stem cell-derived cerebellar organoids. Sci Rep 11(1):12959 Pleasure SJ, Page C, Lee VM (1992) Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons. J Neurosci 12(5):1802–1815 Purkartova Z, Tichanek F, Kolinko Y, Cendelin J (2019) Embryonic cerebellar graft morphology differs in two mouse models of cerebellar degeneration. Cerebellum (London, England) 18(5):855–865 Rolando C, Gribaudo S, Yoshikawa K, Leto K, De Marchis S, Rossi F (2010) Extracerebellar progenitors grafted to the neurogenic milieu of the postnatal rat cerebellum adapt to the host environment but fail to acquire cerebellar identities. Eur J Neurosci 31(8):1340–1351 Rosario CM, Yandava BD, Kosaras B, Zurakowski D, Sidman RL, Snyder EY (1997) Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action. Development 124(21):4213–4224 Salomova M, Tichanek F, Jelinkova D, Cendelin J (2020) Abnormalities in the cerebellar levels of trophic factors BDNF and GDNF in pcd and lurcher cerebellar mutant mice. Neurosci Lett 725:134870 Saporta S, Makoui AS, Willing AE, Daadi M, Cahill DW, Sanberg PR (2002) Functional recovery after complete contusion injury to the spinal cord and transplantation of human neuroteratocarcinoma neurons in rats. J Neurosurg 97(1 Suppl):63–68 Sotelo C, Alvarado-Mallart RM (1987) Embryonic and adult neurons interact to allow Purkinje cell replacement in mutant cerebellum. Nature 327(6121):421–423 Sotelo C, Alvarado-Mallart RM, Gardette R, Crepel F (1990) Fate of grafted embryonic Purkinje cells in the cerebellum of the adult “Purkinje cell degeneration” mutant mouse. I.  Development of reciprocal graft-host interactions. J Comp Neurol 295(2):165–187 Suhonen JO, Peterson DA, Ray J, Gage FH (1996) Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature 383(6601):624–627 Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676 Tian ZM, Chen T, Zhong N, Li ZC, Yin F, Liu S (2009) Clinical study of transplantation of neural stem cells in therapy of inherited cerebellar atrophy. Beijing Da Xue Xue Bao Yi Xue Ban 41(4):456–458

724 Triarhou LC, Zhang W, Lee WH (1996) Amelioration of the behavioral phenotype in genetically ataxic mice through bilateral intracerebellar grafting of fetal Purkinje cells. Cell Transplant 5(2):269–277 Vernet-der Garabedian B, Derer P, Bailly Y, Mariani J (2013) Innate immunity in the Grid2Lc/+ mouse model of cerebellar neurodegeneration: glial CD95/CD95L plays a non-apoptotic role in persistent neuron loss-associated inflammatory reactions in the cerebellum. J Neuroinflammation 10:65 Wang S, Wang B, Pan N, Fu L, Wang C, Song G, An J, Liu Z, Zhu W, Guan Y, Xu ZQ, Chan P, Chen Z, Zhang YA (2015) Differentiation

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Cerebellar Reserve Hiroshi Mitoma and Mario Manto

Abstract

Keywords

The cerebellum can self-compensate and restore tissue damage in response to pathological injury, a unique property known as cerebellar reserve. Cerebellar ataxias (CAs), induced by transient pathologies, such as stroke or trauma, can show partial and sometimes complete recovery with time. In slowly progressive but controllable pathologies, such as immune- or metabolic-mediated CA, elimination of the pathology subsequently results in partial or complete recovery. The cerebellar reserve correlates with specific cerebellar functions involved in acquiring and updating the internal forward model, a neural substrate of state prediction embedded in the cerebellum. The cerebellum integrates multimodal cerebral and peripheral inputs through multiple plastic modifications at divergent synapses to acquire/update the internal model. This capacity for dynamic reorganization is utilized in learning processes and also in pathological conditions. The aim of any therapy should be to preserve cerebellar reserve. Non-invasive cerebellar stimulation and neurotransplantation could enhance cerebellar reserve through synaptic modifications in order to improve CAs. Clinicians and neuroscientists should not miss the advantage of this unique physiological property of the cerebellum.

Cerebellar reserve · Cerebellar ataxias · Synaptic plasticity

H. Mitoma (*) Department of Medical Education, Tokyo Medical University, Tokyo, Japan e-mail: [email protected] M. Manto Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, Charleroi, Belgium Service des Neurosciences, University of Mons, Mons, Belgium e-mail: [email protected]

110.1 Definition of Cerebellar Reserve Degenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), exhibit differences in terms of patient susceptibility to these pathologies (Stern 2012, 2017; Steffener and Stern 2012). To explain the interindividual ­differences in the susceptibility to AD and PD, the concept of cognitive reserve or motor reserve has been introduced, respectively (Stern 2012, 2017; Steffener and Stern 2012). The reserve is considered as a modulator between pathology and outcome (Stern 2012) (Fig. 110.1). In PD, the loss of 50–60% of nigral dopaminergic neurons is associated with the appearance of clinical features of parkinsonism (Stern 2017), suggesting that compensatory mechanisms underlie the reserve. In a series of publications, Stern (Stern 2012, 2017; Steffener and Stern 2012) highlighted the importance of quantitative and functional aspects of such compensations in aging and pathological insults. Brain networks are reintegrated for the utilization of pre-­ existing storage during the compensatory processes. For such reorganization, quantitative aspects, such as the number of remaining intact/undamaged neurons and synapses, are critical. It is well known that cerebellar ataxias (CAs) that are induced by transient pathologies, such as stroke or trauma, can show partial improvement and sometimes complete recovery with time (Manto 2008). This unique feature of recovery, which is hardly observed in other CNS-related symptoms, was recognized more than a century ago in a classical paper by the British neurologist Gordon Holmes (Holmes 1917) who described the CA recovery process in two patients (pages 514– 515, Holmes 1917). The first patient had a limited lateral lesion and the symptoms disappeared after 58 days. The sec-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_110

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a

Manifestations of Cerebellar Ataxias (oculomotor, motor, cognitive/affective)

Pathology Cerebellar reserve -Modulator between pathologies and outcomes -Tolerance to pathologies b

Cerebellar reserve

Asymptomatic stage Recovery

Threshold

Prodromal stage Symptomatic restorable stage Ataxic stage Symptomatic non-restorable stage

Time-course Fig. 110.1  The principle of cerebellar reserve. (a) Cerebellar reserve serves as the modulator between pathologies and outcomes and the tolerance to pathologies. (b) When the etiology weakens diffuse areas of cerebellar neurons, gradually leading to cell death, the affected lesion itself can replenish vanishing cerebellar functions, termed functional cerebellar reserve. Removal of the etiology and subsequent neuromod-

ulation therapies will compensate and restore lost functions, resulting in improvements of cerebellar ataxias. Clinical courses are divided into four stages: asymptomatic stage, prodromal stage, and ataxic stage (subdivided in symptomatic restorable stage and symptomatic non-­ restorable stage)

ond patient showed a more severe CA, which was induced by a large medial and lateral cerebellar lesion. Clinical improvement occurred after 71 days. There was no difference in gait between the two patients during the recovery phase, despite the marked difference in the extent of the lesions. In this regard, we define cerebellar reserve as the capacity for compensation and restoration following pathological changes affecting the cerebellum (Mitoma et al. 2018, 2020, 2021a, b; Manto et al. 2021; Cendelin et al. 2019). Compared with the classical meaning in other diseases, the notion of cerebellar reserve characteristically implies not only resilience to pathologies but also functional recovery.

110.2.1 Structural Cerebellar Reserve

110.2 Clinical Course and Cerebellar Reserve The aim of this section is to review the effect of cerebellar reserve on the clinical course taking into consideration the nature of pathologies (Mitoma et al. 2020).

When the etiology elicits immediate structural damage in a limited area of the cerebellum (e.g., stroke or traumatic injury), the ensuing functional cerebellar deficit can be restored through compensation by other areas not affected by the structural damage. This is termed structural cerebellar reserve (Mitoma et al. 2020). Based on experimental studies on cerebellar ocular disorders, Shaikh hypothesized that the extent of the reversibility can be classified into two patterns: low-risk and high-risk cerebellar reserves (Mitoma et  al. 2020). Experimentally induced focal lesions in the flocculus/ paraflocculus induced impaired reduction in the gain of the ocular pursuit system, deficit in gaze holding and subsequent gaze-evoked nystagmus, as well as abnormal increase in the gain of the vestibulo-ocular reflex (VOR) (Zee et al. 1981). The pursuit gain increased and gaze-holding function improved several months after the lesion, whereas impairment of VOR gain persisted throughout the postoperative course (Mitoma et al. 2020). According to Shaikh, when the

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backup substitute is anatomically discrete from the primary lesion, the lesion will not affect the capacity for reserve (low-­ risk cerebellar reserve), whereas when the backup substitute is adjacent to the primary substrate, the backup will be partially involved, leading to impairment in the capacity for reserve (high-risk cerebellar reserve) (Mitoma et al. 2020).

110.2.2 Functional Cerebellar Reserve When the etiology weakens cerebellar neurons (as well as glial cells) in diffuse areas, gradually leading to cell death, the affected lesion itself can replenish vanishing cerebellar functions, which is termed functional cerebellar reserve (Mitoma et al. 2020). Such etiologies include degenerative CAs, immune-mediated CAs (IMCAc), and metabolic/ toxic CAs. The progressive clinical course is classified into different stages over the period of months to years in terms of cerebellar reserve (Fig. 110.1). The asymptomatic stage covers the period of no visible symptoms with full cerebellar reserve compensation and recovery of altered functions. With the further weakening of the cerebellar reserve by the pathology, pre-ataxic changes start to appear in the prodromal stage. In patients with degenerative CA, pre-ataxic changes in gait stability have been reported recently, which are characterized by large postural sways (Velázquez-Pérez et al. 2021) and abnormal ocular movements (de Oliveira et  al. 2021) without clinical evidence of abnormalities in the Assessment and Rating of Ataxia (SARA) scale. A recent study investigated the serial changes in patients carrying non-ataxic spinocerebellar ataxia (SCA) types 1, 2, 3, and 6 mutations up to the full manifestation of CA. The results showed a bimodal pattern of marginal progression during the prodromal stage, followed by a subsequent increase in symptomatic progression (Jacobi et  al. 2020). Thus, the prodromal symptoms seem to denote an incomplete form of CA and perhaps reflect vulnerability in cerebellar compensation and restoration. Even after the appearance of clinical manifestations of CAs, effective therapies can still improve CAs (symptomatic restorable stage). For example, in patients with early-stage IMCAs, with normal or mildly atrophied cerebellum, immunotherapies can stop the progression of the disease and rehabilitation can further diminish CAs, leading to partial or even complete recovery (Mitoma et  al. 2020). However, in the symptomatic non-restorable stage, patients with advanced stage, most of whom have evident cerebellar atrophy, show no improvement, although the CAs remain stable (Mitoma et al. 2020). These two different clinical courses suggest the existence of a threshold that differentiates the restorable stage from the non-restorable stage. This switching most likely reflects the preservation of the cerebellar reserve. In such progressive diseases, the capacity for cerebellar reserve determines also the decline rate in disease progression.

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110.3 Neural Mechanisms Underlying Cerebellar Reserve Compared with other regions, such as the cerebral cortex and basal ganglia, the cerebellum shows the capacity for compensation and restoration, which sometimes leads to the alleviation of symptoms in the case of transient pathologies. Interestingly, about 60–80% of the whole brain’s 85–100 billion neurons are located in the cerebellum, even though the cerebellum forms only about 10% of the brain mass (Colin et al. 2002; Walloe et al. 2014). These considerable numbers of neurons constitute a major feature of the cerebellar reserve. Then, what is the neural substrate in these enormous numbers of cerebellar neurons that serves this capacity for compensation and restoration? The answer might come from bioengineering and computational models which attempt to compare the cerebellum to computers. An internal forward model integrates various inputs to predict the state of the future motor apparatus for a motor command (Wolpert et al. 1995). The leading current theory is that the neural substrate of state prediction with the internal forward model is embedded in the cerebellum for rapid and stable control of movements (Popa et  al. 2013; Tanaka et  al. 2019). For the development of the internal model, multimodal cerebral and periphery inputs are integrated through multiple plastic modifications at divergent synapses. These circuit architectures have been discussed exclusively in terms of learning processes in the past. In this section, we postulate that the cerebellar-specific resilience and reversibility are attributed to the reorganization of the internal model through these two unique circuit architectures: “redundant afferents” and “multiple forms of synaptic plasticity.”.

110.3.1 Redundant Afferents to Microzone Efference Copy and Sensory Feedback  The cerebellum integrates two lines of inputs necessary for an internal forward model: (1) an efference copy (copy of a motor command) from the controller; (2) a sensory feedback signal that describes slightly past (~100 ms) state of the motor apparatus (Tanaka et al. 2019). Given that the motor command is generated in the primary motor cortex (M1), the region of the cerebro-­cerebellum that receives M1 inputs serves as the internal forward model. Therefore, the cerebro-cerebellum receives an efference copy of the motor command, which monitors the current motor command online with a minimal delay, through mossy fibers (MFs) (Tanaka et al. 2019). This assumption was confirmed in an experiment where monkeys were trained to perform a step-tracking wrist movement in eight evenly spaced directions (Kakei et  al. 1999). A majority of MFs in the hemisphere part of the lobules V and VI, strongly connected

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with M1, were active during the limb movement slightly behind the M1 neuron activities (Kakei et  al. 1999). Furthermore, MFs demonstrated a significant shift in the preferred direction for different forearm postures as observed in M1 neurons (Tomatsu et al. 2015). Sensory feedback signals from the periphery provide the current state of the body. The intermediate zone of the lobules IV and V receives strong proprioceptive and cutaneous afferents through spinocerebellar tracts-MFs (Oscarsson 1965; Cooke et al. 1971; Ekerot and Larson 1972). Granule cells (GCs) and MFs in these regions consistently respond to somatosensory stimuli (Ishikawa et al. 2014). Multimodalities  The functional unit of the cerebellar cortex is hypothesized as a microzone, a rostrocaudal strip of the cerebellar cortex (Apps et  al. 2018) (Fig.  110.2). Purkinje cells (PCs) in the microzone receive climbing fibers (CFs) from a group of neurons within a restricted area of the inferior olive nucleus, and in turn, these PCs project to a small group of neurons in the deep cerebellar nucleus. Notably, the branching patterns of individual MFs are intensively divergent, especially along the mediolateral axis (Wu et al. 1999; Jörntell et al. 2002) (Fig. 110.2). In other words, MF inputs are highly convergent to each microzone (Mitoma et  al. 2021a, b). Coincidently, individual GC receives convergent functional multimodal (somatosensory, auditory, and visual) inputs via separate MFs (Ishikawa et al. 2015). Furthermore, there is convergence on single GC from sensory signals via the external cuneate nucleus and efference copy via the basilar pontine nucleus (Huang et  al. 2013). Thus, within the microzone, the combinatorial code with redundant and multimodal MF inputs and inferior olive (IO) inputs seems to provide potential functional flexibility to generate reorganized outputs (Mitoma et al. 2021a, b).

110.3.2 Multiple Forms of Synaptic Plasticity The divergent forms of plasticity in the cerebellar cortex characteristically cooperate synergistically to ultimately create the optimal output for any behavior (Fig. 110.3) (De Zeeuw et al. 2021). In other words, the multiple forms of synaptic plasticity cooperate in the functional reorganization of the internal model after pathologies. As discussed below, a large part of cerebellar synaptic plasticity is a triggering machinery, such as intracellular Ca2+ signaling and the receptor trafficking machinery. These molecular mechanisms might serve as molecular biomarkers for cerebellar reserve or therapeutic targets for the potentiation of cerebellar reserve (see Sect. 110.4). Here main types of the plasticity are briefly summarized.

H. Mitoma and M. Manto

Spike-timing dependent plasticity at mossy fiber-granule cell synapses  Spike-timing dependent plasticity (STDP) is found between MF-GC synapses (STDP in Fig.  110.3) (Sgritta et  al. 2017). Spike timing-dependent long-term potentiation and depression (st-LTP and st-LTD) is confined to a ±25 ms time-window. Excitatory postsynaptic potentials (EPSPs) inducing action potentials (APs) cause st-LTP of EPSPs, while APs preceding to EPSPs cause st-LTD of EPSPs. Thus, a set of multimodal input converges on GC (see Sect. 110.3.2) with adequate timing, leading to the ­st-­LTP of STDP. Since this type of synaptic plasticity serves as amplifier of cerebellar inputs, a new set of multimodal sensory input and efferent copy of cerebral command may be enhanced by STDP at the input stage of cerebellar cortex, resulting in re-organization of the internal model.

Long-Term Depression at Parallel Fiber-Purkinje Cell Synapse and Rebound Potentiation of Inhibitory Inputs to Purkinje Cells  CF activation is an integral component of the process of parallel fiber (PF)-PC LTD induction and rebound potentiation (RP), although the significance of CF inputs is still controversial (Streng et al. 2018). Conjunctive activation of CF and PF elicits LTD of PF-PC synaptic transmissions (Ito et  al. 1982) (PF-PC LTD in Fig.  110.3). Simultaneous activation of voltage-gated Ca channel (VGCC) (P/Q-type) and metabotropic glutamate receptor type 1 (mGluR1) elicits an increase in [Ca2+]i to levels higher than the additive level (Wang et al. 2000), leading to PKCα activation and subsequent GluA2-C terminus phosphorylation. The latter ultimately detaches AMPA receptors from the scaffold protein and enhances their internalization with PICK1 in AP2- and clathrin-dependent manners (Wang and Linden 2000). Repetitive CF activation causes Ca2+ influx through voltage-­gated Ca2+-channels, leading to long-term potentiation of GABA-mediated synaptic transmissions on PCs (RP in Fig.  110.3) (Kano et  al. 1996). In turn, the Ca2+ influx activates Ca2+/calmodulin-dependent protein kinase II (CaMKII) to elicit structural changes in GABAARassociated protein (GABARAP) and subsequently enhances the interaction between GABARAP and GABAAR γ2 subunits, leading to an increase in GABAAR expression at the inhibitory synaptic sites (Kawaguchi and Hirano 2007). RP would be elicited in a large number of PCs belonging to the same microzone, in which PCs are innervated by the same CF (Andersson and Oscarsson 1978). Thus, RP seems to provide synaptic plasticity with more coarse spatial resolution than PF-PC LTD.

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PC

Microzone determined by CF

PF Rostro-caudal Medio-lateral GC MF Divergent projection of MF

CN CF

IO Fig. 110.2 Redundant convergence of mossy fiber-granule cell-­ parallel fiber innervations within a microzone. Peripheral and cerebellar information inputs are conveyed to a microzone, extending along the rostrocaudal axis, through mossy fiber (MF)-granule cells (GC)-parallel fibers (PF). The branching patterns of individual MFs are extensively

divergent, especially along the mediolateral axis. Thus, Purkinje cells in a microzone receive redundant MF inputs. MF mossy fiber, PF parallel fiber, IO inferior olive nucleus, CF climbing fiber, GC granule cell, PC Purkinje cell, CN deep cerebellar nucleus

Long-term Potentiation at Parallel Fiber–Purkinje Cell Synapse  PF–PC LTP (PF–PC LTP) is induced by PF activity alone through two mechanisms. The presynaptic LTP is induced by PF stimulation alone at 4–8  Hz, and cAMP-­ dependent phosphorylation of active zone protein RIM1α causes an increase in glutamate release (Lonart et al. 2003). In contrast, PF stimulation alone at 1 Hz causes postsynaptic PF-LTP, in which intracellular concentration of Ca2+ transiently increases to a level lower than that observed following the induction of PF-PC LTD. Such a lower increase in Ca2+ activates PP2B (calcineurin), which results in dephosphorylation of AMPA-receptors, with subsequent stabilization of AMPAR at the synaptic membrane through interaction with scaffold proteins (Belmeguenai and Hansel 2005; Schonewille et al. 2010). Thus, PF-LTP and PF-LTD mutually counterbalance each other (Lev-Ram et al. 2003).

LTDpathies  Recent clinical studies provide examples of how impairment of synaptic plasticity affects the internal model, resulting in the development of CAs. Anti-VGCC, mGluR1, and glutamate receptor delta (GluR delta), involved in the induction of PF-PC LTD, cause CAs (Mitoma et  al. 2021b). Coincidently, CSF or serum samples from these patients exhibit low PF-PC LTD levels (Mitoma et al. 2021b). Thus, one possible mechanism is that antibodies interfere with basal synaptic transmission, and the disordered PF-PC LTD impairs the reorganization of the internal model. Alternatively, PF-PC LTD might also play direct roles in online predictive controls by maintaining the internal model (Mitoma et al. 2021b). To stress these specific pathomechanisms, we need to collect further information on the etiologies that affect PF-PC LTD under the umbrella of LTDpathies (Mitoma et al. 2021b).

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PF-PC LTD/LTP Stc-PC LTD/LTP PF GABAergic IN Golgi

Internal Models/Predictions .Elaboration .Maintenance

GC RP

PC

STDP

MF LTP CN

CF

Regulation of motor and

MF

cognitive operations .Thalamo-cortical tracts

Motor control centers

.Brainstem nuclei .Spinal cord

Excitatory neurons

Inhibitory neurons

Fig. 110.3  Multiple forms of synaptic plasticity with special concern of spatial range. (1) STDP: spike-timing-dependent plasticity MF-GrC synapse. (2) RP: rebound potentiation at inhibitory interneuron–PC synapse. RP should be induced in PCs innervated by the same CF (microzone). (3) PF-PC LTD: LTD at PF-PC synapse. LTD should be induced at PF-PC synapse only when both PF-PC and CF-PC synapses are activated conjunctively. (4) PF-PC LTP: LTP at PF-PC synapse. The postsynaptic type of LTP should be induced PF-PC synapse along the same

PF, except when conjunctively activated by CF. (5) Stc-PC LTP/LTD: Long-term potentiation or long-term depression at StC-PC synapse. This type of plasticity should be part of PC dendrites. (6) MF-LTP: LTP at MF-DCN synapse. Cerebellum is a major site for the elaboration/ updates of internal models. Predictions are used for motor and cognitive operations of daily life. Abbreviations: MF mossy fiber, PF parallel fiber, GC granule cell, StC stellate cell, PC Purkinje cell, GABAergic IN GABAergic interneurons, CN deep cerebellar nucleus neurons

110.4 Molecular Mechanisms Underlying Cerebellar Reserve

catabolic process that plays an important role in the maintenance of cellular homeostasis and protection of cells against various insults. Interestingly, motor training applied before the appearance of symptoms in the tambaleante mouse model of ataxia is beneficial based on the associated changes in autophagy (Fucà et  al. 2017), suggesting that cellular reserve can be potentiated by environmental enrichment. A recent study using antibodies targeting amyloid-beta protein reported no beneficial effects on cognitive functions in AD (Vaz and Silvestre 2020), suggesting the importance of introduction of therapies at the pre-clinical stage. By analogy, for future etiology-based drugs that can delay cell degeneration, therapeutic effects will be limited during the early stages when cell death cascades are not accelerated and cell reserve mechanisms effectively protect against progression of the pathology.

Various pathologies, such as glutamate-mediated excitotoxicity, microglia-induced neural inflammation, and misfolded proteins and protein aggregation, cause endoplasmic reticulum (ER) stress and oxidative stress, leading to apoptosis (Matilla-Dueñas et al. 2010; Luo 2014). On the other hand, there is a crosstalk between pro-apoptotic processes and autophagy. The generation of reactive oxygen species (ROS), supplied by the mitochondria and ER, and subsequent oxidative stress activates autophagy (Kaminskyy and Zhivotovsky 2014). Accumulation of misfolded proteins in the ER lumen overflows the capacity of ER chaperon systems, resulting in ER stress wit subsequent autophagy activation (Luo 2014). Thus, one possible candidate modulator of cellular cerebellar reserve is autophagy, a conserved

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110.5 Cerebellar Reserve-Based Therapeutic Strategies 110.5.1 General Principle In general, the aim of etiology-based therapies is to halt or delay the progression of the disease, whereas that of neuromodulation therapies is to maintain or potentiate cerebellar reserve, which include rehabilitation, non-invasive cerebellar stimulation, and, in the near future, neurotransplantation (Mitoma et  al. 2018, 2020, 2021a, b; Manto et  al. 2021; Cendelin et al. 2019). These two types of therapies should be used carefully taking into consideration the type of underlying pathology. The use of etiology-based therapies can halt disease progression, while the start of use of neuromodulation therapies at the time when cerebellar reserve is preserved often improves CAs, leading to partial or full recovery (Mitoma et  al. 2018, 2020, 2021a, b, Manto et  al. 2021; Cendelin et  al. 2019). Thus, the following therapeutic strategies are assumed. 1. In case of acute and potentially expanding pathology, spatial expansion should be immediately halted to preserve the structural cerebellar reserve in the residual regions. For example, in cerebellar infarction, the extension of the infarct core to the surrounding ischemic penumbra should be prevented using intravenous injection of recombinant tissue plasminogen activator to preserve structural cerebellar reserve. For management of patients with potentially expanding pathology accompanied by local tissue edema (e.g., traumatic, hemorrhagic, and cerebellitis lesions accompanied by local tissue edema), it is crucial to protect the intact residual areas of the cerebellum and the brainstem by controlling edema. 2. In case of diffuse/progressive but controllable pathologies, disease progression should be halted to preserve the functional cerebellar reserve. Thus, abstinence of alcohol, removing toxic agents, and/or use of immunotherapies should be implemented during the restorable stage when cerebellar reserve is preserved. 3. When the pathology is diffuse/progressive, but uncontrollable and etiology-based therapies are applicable (e.g., neurodegenerative CA), neuromodulation therapies are expected to slow down the disease progression (Mitoma et al. 2018, 2020, 2021a, b, Manto et al. 2021; Cendelin et  al. 2019). Consistently, rehabilitation has therapeutic benefits in patients with degenerative CA (Ilg et al. 2010).

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110.5.2 Neuromodulation Therapies for Potentiation of Cerebellar Reserve Non-invasive cerebellar stimulation (NICS) and neurotransplantation are promising treatment modalities that could potentiate cerebellar reserve. It should be acknowledged that both these therapies potentiate the synaptic plasticity in pathological conditions. Non-invasive cerebellar stimulation  The aim of NICS, which includes transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial magnetic stimulation (TMS), is modulation of cerebellar control on the cerebral cortex and spinal cord, thereby relieving CAs (Manto et al. 2021). tDCS and tACS tune neural excitability, while TMS induces the generation of action potentials plus tuning the excitability (Manto et  al. 2021). A systematic review by Nuzzo et al. (2018) analyzed the therapeutic benefits of NICS in 170 patients with CAs described in 7 studies (in 3 of the 7 studies, the effects were examined in a sham-controlled design). The therapeutic mechanisms remain speculative. Two mechanisms are suggested. First, NICS would modulate the cerebello-cerebral pathway. Stimulation of the cerebellum using TMS delivered 5–6  ms before cerebral stimuli, reduced the excitability of M1, an action termed cerebellar brain inhibition (Manto et al. 2021). Furthermore, a recent animal experiment showed that activation of DNs induced by reduced inhibition from PCs (i.e., disinhibition) facilitated the execution of a particular movement, while suppression of the DNs by increased PC activity (i.e., inhibition) contributed to the stabilization of unnecessary movements (Ishikawa et al. 2014). Thus, NICS seems to restore the damaged PC-mediated modulation on cerebellar efferents (disinhibition/inhibition mode) to relieve CAs. Second, plasticity of cerebellar cortex synapses is assumed to be the neural basis for the long-lasting modulation (Nuzzo et al. 2018; Manto et al. 2021). Several types of synaptic plasticity in the cerebellar cortex (see Sect. 110.3.2) can be the targets of NICS. Consistently, animal experiments showed that hyperpolarization current induced long-term increase in the firing rate of Golgi neurons (Hull et al. 2013). Neurotransplantation  Due to the specific, complex, and elaborate cell-to-cell connections, it is difficult to replace the damaged CNS region with grafted cells (Cendelin et  al. 2019). Cerebellar transplantation comprises two stages: (1) rescue of neurons from extinction in order to maintain cerebellar reserve, and (2) reconstruction of damaged cerebellar circuits for potentiation of cerebellar reserve (Cendelin et al.

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2019). The latter process depends on the capacity of synaptic plasticity. One previous study reported that mesenchymal stem cells grafted into the cerebellum of newborn Lurcher mice produced neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) (Jones et al. 2010), and BDNF, in addition to the above cell-protective effects, upregulated glutamatergic vesicles at the PF-PC synapses (Carter et al. 2002) and facilitated GABAergic synaptic transmissions (Huang et al. 2012).

110.5.3 Biomarkers for Early Intervention There is a need for early therapeutic intervention and development of biomarkers for cerebellar reserve. First, pathology-­ related biomarkers that can detect early stages of the disease process are clinically important for disease assessment and treatment-decision making. In this regard, new biomarkers have been developed recently for detection of deposits of β-amyloid neuritic plaques and aggregation of tau tangles and have been assessed in asymptomatic patients and prodromal stage of AD (Cullen et al. 2021). Importantly, molecular biomarkers that can reflect the early disease-specific pathologies are preferable. Second, functional analysis that can provide an estimate of the preserved cerebellar reserve is needed. Towards this goal, cerebellar-specific functions, such as predictive controls, can be used as appropriate indexes, as discussed in our recent study (Manto et al. 2021). Another potentially useful approach is detection of changes in cerebello-cerebral networks using task-based functional MRI, as utilized in AD (Soch et al. 2021).

110.6 Conclusion Cerebellar reserve, a unique property of the cerebellar circuitry, needs to be considered in any treatment strategy in patients with cerebellar diseases. Potentiation of the inherent restoration and compensation processes provide resilience to the pathological process and helps in future improvement of CAs, respectively. Following the pathological insult, the cerebellum integrates redundant inputs through multiple forms of synaptic plasticity to reorganize the internal forward model. Current and future treatment approaches include NICS, which targets synaptic plasticity, as well as neurotransplantation, though many practical aspects of the latter need to be resolved before entering in clinical applications. For early interventions using neuromodulation therapies that can potentiate cerebellar reserve, we need to find suitable biomarkers with the goals of preservation of the cerebellar reserve as much as feasible. Tailored approaches might be required because the CAs are highly heterogeneous in terms of phenotypes and also genotypes.

H. Mitoma and M. Manto

Declaration

Funding  This project was executed without any financial support from governmental, commercial or not-for-profit organizations. Conflicts of Interest  Both authors declare no conflict of interest. Ethical Committee Request  Not applicable. Consent to Participate  This is a review article that did not include studies on subjects. Both authors consented to participate in this project. Consent for Publication Both authors consented for publication of this review. Data Availability The concept reviewed in this manuscript is not based on raw data. Code Availability  No software application or custom code is associated with this review.

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Index

A Actinopterygian fish, 399 Action prediction, 514 Action sequencing, 513, 514 Acute, 5, 16, 156, 164, 178, 181, 184, 194, 216, 239, 288, 289, 309, 334–336, 339, 341, 366–367, 459, 465, 474, 480, 482, 486, 487, 506, 521, 526, 527, 531, 532, 535, 567, 569–571, 577, 579, 600–603, 609, 610, 631, 641, 642, 650, 656, 666, 668, 710, 731 Addiction, 435, 488, 514, 599, 602 Adenosine, 225–229, 282, 415 Adult neurogenesis, 216 Affect, 8, 65, 88, 96, 108, 194, 238, 240, 251, 259, 301, 303, 310, 315, 365, 371, 372, 375, 381, 382, 389, 411, 437, 454, 474, 479, 480, 485–489, 523, 525, 527, 541, 548, 561, 575, 578, 583, 586, 601, 610, 612, 613, 657, 673, 682, 710, 715, 716, 727, 729 Aging, 205, 211, 217, 240, 330, 567, 725 Albus, 9, 287 Alcohol use disorder (AUD), 240, 433–438 Aminopyridine, 44, 410, 411, 699, 701, 702 AMPA receptors (AMPARs), 157, 163, 164, 174, 198–199, 217, 287–290, 296, 576, 589, 667, 728, 729 Anatomy, 2, 7–8, 10, 18, 23–27, 77, 277, 327, 328, 351–355, 415, 420, 469, 470, 472–473, 501, 512, 533, 660 Angiography, 569 Anterior inferior cerebellar artery (AICA), 29, 31–36, 480, 567–569 Anti-epilepticsAnti-GAD ataxia, 527, 575, 576, 578–579, 634, 635, 637, 642 Antigliadin antibodies, 645–647 Anti-GluR delta ataxia, 579 Anti-inflammatory action, 427 Anti-mGluR1 ataxia, 579 Antineoplastics, 599, 601 Anti-VGCC-ataxia, 579, 634 2-Arachidonoyl glycerol (2-AG), 282 Artery to artery embolism, 569 Articulation, 78, 376, 377, 458–460 Astrocyte, 187, 189, 190, 216, 222, 223, 226, 229, 235, 239, 295, 305, 306, 308–310, 414, 421, 425, 427, 537, 544, 608, 637 Ataxia, 211, 427 Ataxia-telangiectasia (AT), 334, 522, 523, 526, 547, 548, 551, 627 Ataxia Telangiectasia Mutated (ATM) gene, 547–549, 551, 621, 622 Ataxic dysarthria, 376, 457–461, 463 Ataxic gait, 254, 336, 409, 474, 501–508, 600, 624, 710 Ataxiology, 2, 363, 469, 470, 535, 716 AtoH1, 49, 93–95, 108, 112, 395 ATP, 225–229, 295, 405, 557 Autism, 8, 139, 159, 206, 209, 223, 229, 239, 240, 310, 335, 341, 373, 383, 415, 474, 488, 514, 537–539, 543, 552, 556 Autism spectrum disorder (ASD), 159, 313, 367, 383, 427, 488, 539, 650

Autoantibodies, 416, 575, 576, 578, 579, 583–589, 609–612, 632, 634–635, 637 Autoimmune ataxia, 641, 642 Autoimmune diseases, 576, 578, 634, 641, 642 Autosomal recessive, 413, 522–527, 531, 532, 534, 549, 550, 552, 553, 555, 611, 612, 621, 691, 700 Autosomal recessive cerebellar ataxias (ARCAs), 340, 522, 523, 547 Axon collateral, 44, 119, 124, 170, 179, 184, 201, 211 B Balance, 34, 65, 158, 202, 205, 206, 277, 344, 345, 427, 434, 436, 437, 441, 442, 444, 445, 501–503, 507, 508, 527, 543, 600, 613, 619, 666, 683, 710, 712 Basic helix-loop-helix (bHLH), 93, 108 Basilar artery (BA), 29, 31, 33, 34, 36, 37, 89, 90, 321 Basket cell (BC), 7, 101, 107, 108, 116, 118–119, 122, 123, 155, 156, 169–171, 177, 178, 191–194, 197, 209, 210, 221, 226, 259, 260, 395, 400, 404, 405, 603, 637 Behaviour, 103, 139, 222, 229, 373, 379–383, 427, 549, 551, 600, 610 Bile acid synthesis, 650–651 Bipolar disorder, 383, 488, 514, 541–544, 610 Blake’s pouch cyst (BPC), 564 Blood flow, 54, 215, 333–335, 542, 570, 618 Brain damage, 433–435, 481, 603 Brain-derived neurotrophic factor (BDNF), 119, 299–303, 608, 613, 732 Brain injury, 240, 306, 419, 482, 628, 710 Brain metabolites, 600 Brain plasticity, 419–421 Brainstem, 7–9, 32, 34–37, 51, 52, 54, 56, 61, 63–66, 79, 84, 111, 117, 127, 184, 201, 202, 206, 233, 277, 325, 326, 328, 329, 335, 343, 420, 451, 452–454, 458, 470, 474, 475, 480, 489, 502, 525, 565, 568, 569, 570, 578, 584, 587, 601, 656, 663, 664, 666, 731 compression, 565, 569–571, 659 Branching, 31, 37, 44, 119, 123, 124, 149, 201, 608, 728, 729 Brief Ataxia Rating Scale (BARS), 475, 493, 497, 504, 505, 507, 626 C Ca2+ binding proteins, 296, 443, 542 Ca2+ channels, 193, 282 CACNA1A, 409, 413–417, 532, 533 Calcitonin gene related peptide (CGRP), 232, 233, 235 Calcium channel, 157, 204, 267, 270, 272, 443, 445, 587, 603 Calcium signaling, 190, 443–445, 538, 586 Calretinin (CR), 181, 182, 184, 247, 250, 296, 411 Cancer, 549, 551, 579, 583–590, 621, 622, 627, 632–635, 662 Cannabinoid CB1 receptors, 334 Cannabinoid CB2 receptors, 222, 223

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8

735

736 CANVAS, 524, 527, 548, 549, 551, 685–688 Cardioembolism, 567, 569 Caudal lobe, 394 Causative therapy, 701 Ca v2.1 Ca2+ channel, 409 Cell rescue, 721 Cerebellar anatomy, 2, 10, 277, 393–395, 415, 435, 437–438, 470 arteries, 29, 31–40, 334, 458, 480, 567, 666 atrophy, 296, 326, 328, 329, 334, 363, 382, 388, 425, 427, 443, 461, 497, 526, 533, 534, 549, 551, 552, 557, 558, 578, 579, 589, 600, 601, 603, 611–613, 618, 622, 626, 642, 646, 666, 688, 694, 706, 707, 727 cortex, 177, 178, 210–212 degeneration, 10, 326, 328, 330, 334–336, 345, 346, 382, 403, 405, 406, 427, 479–482, 497, 527, 575, 576, 579, 583, 584, 597, 631, 634, 646, 656, 710, 711, 713, 720, 721 development, 137–143, 221–222, 233, 299, 302, 305, 308, 309, 393, 395–397, 425, 533, 587, 609, 613 disorders, 1, 2, 10, 114, 133, 137, 142, 143, 158–159, 334–336, 451, 454, 457, 464, 474, 482, 488, 489, 496, 497, 716 disruption, 532, 533, 562 function, 1, 5, 15–19, 43, 47, 118, 119, 151, 163, 190, 202, 204, 205, 221, 222, 229, 235, 277, 293–297, 308, 336, 348, 352–354, 363, 366, 371, 372, 377, 380, 381, 383, 411, 419, 422, 442, 446, 451, 458, 479, 489, 499, 531, 537, 541, 543, 625, 682, 705, 707, 719, 720, 726, 727 malformation, 140, 141, 360, 525, 531, 532 module, 43, 66, 155, 380 mutism, 459, 488, 663, 664 neurodegeneration, 425–427, 621 nuclear neurons, 55, 425 nuclei, 9, 18, 37, 43, 44, 47, 52, 62–66, 94, 95, 103, 111, 114, 138, 142, 157, 158, 191–193, 209, 211, 212, 223, 233, 235, 265, 275–277, 326, 328–330, 343, 345, 389, 432, 433, 470, 474, 480–482, 602, 603, 666, 706, 720, 722 reserve, 637, 719, 720, 726–732 syndrome, 457, 469–476, 498, 550, 557, 577, 584–587, 590, 599–601, 603, 607, 611, 632, 641, 665, 666 system, 87, 321, 322, 351, 354, 419–421, 595 tremor, 464, 465, 710 Cerebellar ataxia(s), 340–341 in adolescence, 524, 526, 622, 624 in childhood, 524, 526, 527, 531–535 in infancy, 524, 526, 527, 551 in young adulthood, 526 in young children, 496, 524, 526, 531, 532, 624 Cerebellar-cerebral networks, 367 Cerebellar cognitive affective syndrome (CCAS), 8, 10, 345, 346, 348, 360, 363, 367, 470–476, 485–489, 527, 548, 550, 626, 663, 665 Cerebellar motor syndrome (CMS), 8, 345, 348, 463, 470–476, 488, 551 Cerebellothalamic, 83, 421 Cerebellum, 209, 212, 379, 387–389, 393–397, 399–402, 404, 405, 409–411, 414–416, 419, 422, 425–427, 432–437, 441–445, 451–454, 457, 459–461, 469–476, 479–482, 485–489, 501–503, 507, 508, 511, 512, 514, 515, 531, 533, 537–539, 541–544 Cerebral amyloid angiopathy (CAA), 672, 673 Cerebrotendinous xanthomatosis (CTX), 329, 523, 525, 526, 534, 548, 552, 649, 699, 700 Channel, 66, 166, 295, 296, 409 Channelopathies, 409, 416–417 Chemokine, 307–309 Chenodeoxycholic acid, 552, 650–652, 700

Index Children, 8, 206, 341, 345, 360, 383, 459, 465, 487–489, 497, 503, 524, 531–535, 538, 543, 557, 558, 562, 577, 579, 587, 589, 602, 603, 609, 624, 626–628, 649–650, 652, 660, 662, 664–666, 710, 711 Climbing fiber (CF), 209, 211, 389 neurons, 47–49 Clinical evaluation, 466, 493, 494, 496–499 Closed-loops, 321–323, 381, 512 Coarticulation, 460 Coeliac disease, 589, 645, 646 Coeruleo-cerebellar pathway, 203 Cognition, 8–10, 85, 88, 206, 209, 211, 335, 353, 354, 363–367, 373, 375, 380–382, 402, 459, 474, 486, 487, 489, 501, 527, 537, 538, 541, 542, 610, 618, 679, 706 Cognitive affective syndrome (CCAS), 8, 10, 485–489 Coma, 415, 533, 572, 602, 603, 611 Compartments, 43, 44, 93, 103, 189, 193 Compensation, 57, 371, 422, 480, 504, 637, 660, 665, 713, 725–727, 732 Compensatory eye movements, 249, 251, 252, 254 Complex spike, 44, 57, 103, 118, 127, 156, 157, 193, 265–267, 270, 276, 277, 283, 284, 388, 389, 445, 503 Computerized tomography (CT), 37, 325, 329, 568, 569, 571, 572, 589, 611, 618, 627, 666, 668 Congenital ataxias, 523–526 Conventional angiography, 569 Coordination, 5, 8, 61, 78, 205, 293, 376, 389, 445, 460, 461, 469, 470, 474, 495, 503, 505, 507, 511, 512, 600, 665, 680, 710–713 Corpus cerebelli, 18, 19, 393, 394, 399–402 Corticocerebellar pathways, 88 Corticopontine, 7, 69, 77–80, 83, 88, 376 Corticospinal, 64, 81 Corticospinal tract, 62, 64–65, 682 Corticotropin releasing factor (CRF), 232–235, 284 Covert articulation, 459 Craniotomy, 570, 572, 602, 663 CT angiography (CTA), 569 Cyclic guanosine monophosphate (cGMP), 216, 217, 281, 282, 538, 544, 609 CYP27A1, 523, 548, 552, 650, 651, 700 Cytokine, 205, 215, 216, 307, 427, 633 D Dandy-Walker malformation (DWM), 140–142, 532, 564 Decision-making, 387–389 Decomposition of movement, 421, 463, 465, 466, 474, 494, 497, 680 Deep cerebellar nuclei (DCN), 6, 42, 71, 72, 77, 83, 84, 87, 107, 108, 115, 116, 191, 201–204, 238, 259–261, 265, 269–272, 284, 343, 345, 360, 365, 367, 394, 395, 401, 404, 415, 419, 420, 444, 451, 459, 488, 682, 709, 720, 722 Δ9-tetrahydrocannabidol, 221 Dendritic integration, 158 Dentate nucleus, 6, 8, 10, 35, 37, 83, 84, 87, 206, 277, 308, 321, 323, 344, 345, 364, 365, 453, 473, 474, 526, 557, 572, 602, 608, 637, 652, 680 Development, 6, 9, 10, 18, 19, 44, 48, 49, 93–96, 100–102, 108, 111–114, 121–124, 129, 137–143, 155, 188–190, 194, 199, 206, 210–212, 222, 232, 233, 235, 245, 261, 276, 305, 306, 308, 309, 313, 328, 351, 364, 393, 395–397, 409, 411, 421, 422, 425–427, 435, 436, 441, 446, 475, 524, 533, 537, 541, 576–578, 586, 600, 607, 608, 610–613, 624, 627, 631, 632, 634, 635, 642, 645, 646, 650, 656, 672, 701, 716, 717, 721–722, 727, 729

Index Developmental peptides, 233 Diacylglycerol lipase, 223, 287, 296, 308, 441, 443 Diagnosis and management, 694 Differential diagnosis, 504, 521–527, 531, 532, 534, 535, 589, 619, 673, 688 Diffusion tensor imaging (DTI), 88, 322, 325–330, 361, 366, 666–668 Diffusion-weighted imaging (DWI), 326–328, 480, 482, 569, 659, 660 Direct current stimulation (DCS), 360 Dissection, 9, 25, 567, 663, 666 DNA, 96, 129, 232, 240, 329, 425, 522, 523, 525, 526, 534, 548, 557, 558, 584, 622, 632, 716, 717 Doppler, 569, 668 Dorsal column nuclei, 62, 64 Dural defect, 672–674, 676, 677 Dynamic stability, 711 Dynorphin, 232, 235 Dysarthria, 8, 80, 345, 457–460, 474, 486, 494, 497, 504, 526, 549, 556, 557, 568, 589, 611, 612, 617, 626, 656, 665, 681, 682, 685, 694, 709, 713 Dysdiadochokinesia, 463, 465, 557, 611 Dysmetria, 8, 10, 17, 70, 80, 345, 360, 363, 421, 463, 465, 466, 470, 473, 474, 476, 487, 494, 495, 497, 551, 556, 557, 575, 589, 602, 611, 617, 659, 680, 682, 683, 710 Dysplastic gangliocytoma, 563 Dystonia, 10, 84, 211, 334, 409–411, 415, 498, 549, 551, 552, 556, 558, 624, 627, 656, 702 E EA2, see Episodic ataxia type 2 (EA2) Early B-cell factor 2 (Ebf2), 96, 101 Edema, 327, 328, 480, 569, 601, 602, 688, 731 Editing, 198, 199 Efferent cell, 395, 400, 401 Electrical coupling, 294 Electrical inhibition, 170 Emotion, 9, 10, 84, 85, 137, 323, 352–354, 366, 373, 382, 388, 389, 473, 474, 485 Endocannabinoid system, 221–224 Endocrine, 551, 621, 627, 700 Endopeptidases, 232 Enzyme, 51, 132, 157, 173, 194, 201, 216, 221, 223, 227, 237, 238, 294, 542, 544, 578, 600, 608, 610, 635, 646, 650, 657, 667, 677, 692, 716, 717 Ependymoma, 239, 487, 535, 660, 662, 663 Episodic ataxia type 2 (EA2), 159, 297, 341, 382, 409–411, 416, 417, 535, 701 Essential, 5, 6, 41, 44, 72, 85, 124, 137, 140–142, 158, 188, 190, 199, 217, 233, 235, 293–297, 305, 306, 334, 336, 341, 344, 360, 366, 380, 402, 451, 461, 471, 487, 493, 515, 521, 531, 548, 552, 601, 611, 647, 649, 657, 658, 721 Ethanol, 216, 334, 409, 527, 596, 597, 599, 600 Eurydendroid cell, 394, 395, 400 Evidence accumulation, 388, 389 Evolution, 101, 114, 138, 143, 181, 401, 422, 461, 522, 551, 618, 624, 665, 716 Excitability, 119, 127, 130, 151, 158, 159, 166, 171, 174, 179, 185, 210, 235, 237, 238, 240, 259, 260, 265, 267, 276, 284, 285, 294, 295, 308, 309, 316, 360, 361, 371, 414, 434, 445, 575, 611, 682, 706, 731 Excitation, 54, 57, 132, 150, 156, 158, 163, 165, 169, 184, 202, 203, 221, 234, 247, 276, 284, 327, 339, 405, 416, 433, 434, 437, 445 Exopeptidases, 232 Expansion coding, 247, 249 External cuneate nucleus (ECN), 47, 49, 54, 56, 63, 728

737 Extrapyramidal motor features, 551 Eye movements, 54, 69, 71–74, 78, 84, 119, 184, 202, 217, 249, 251, 252, 254, 289, 344, 451–454, 497, 557, 562, 568, 596, 624, 626, 656, 679, 680, 685 Eyeblink conditioning, 103, 217, 233, 249, 276 F False beliefs, 382, 512–515 Fastigial, 6, 25, 31, 37, 65, 71, 83–85, 111, 211, 343–346, 355, 451, 452, 472, 474, 487, 488 Fear conditioning, 163–165, 167, 402 Feedback inhibition, 174 Feed-forward inhibition, 115, 123, 158, 163, 164, 166, 169–171, 267 Fetal alcohol spectrum disorder (FASD), 240, 434–435, 437 Fiber connections, 399, 401–402 Fish, 101, 178, 245, 255, 394, 395, 397, 399–402 Fissure, 18, 19, 23, 24, 37, 40, 70, 71, 90, 99, 426, 482, 672 Flocculus, 23, 24, 26, 31, 34, 35, 43, 52, 53, 55, 65, 70, 74, 83, 127–132, 204, 209, 233, 244, 245, 249–254, 288, 289, 344, 394, 400, 404, 451, 453, 454, 472, 726 Flow dynamics, 674 Fluoro-2-deoxy-D-glucose (FDG), 334–336 Fmr1 KO mouse model, 538 FMRP, see Fragile X mental retardation protein (FMRP) Forward model, 72–74, 276, 471, 503, 637, 727, 732 Fragile X mental retardation protein (FMRP), 313–317, 538, 543, 544, 716 Fragile X-Associated Tremor Ataxia Syndrome ( FXTAS), 313, 316, 522, 524, 537, 538, 557, 715 Frataxin, 550, 551, 557, 611, 618, 700, 701, 715 Friedreich ataxia (FA), 329, 494–496, 522–526, 534, 535, 549, 608, 611, 617–619, 668, 688, 715 Friedreich ataxia rating scale (FARS), 493–496 Functional connectivity (FC), 9, 88–90, 322, 344, 352, 353, 360, 365–367, 380–383, 435, 485 Functional gradients, 352–354 Functional magnetic resonance imaging (fMRI), 9, 137, 206, 224, 351–355, 364–366, 381, 389, 470, 472, 512–514, 716 Functional neuroanatomy, 87, 352–354 Functional topography, 363–367, 380, 470 G GAA expansion, 618 GABA A receptors, 151, 226, 238–240, 247, 283, 309, 411, 415, 433, 436, 538, 542 GABA B receptors, 151, 247, 538, 542 GABAergic, 52, 55, 57, 94, 96, 112, 115, 116, 119, 155, 171, 179, 191–194, 203, 239, 247, 269, 275, 277, 283, 303, 309, 336, 401, 432–434, 436, 538, 542, 543, 601, 602, 611 interneurons, 95, 102, 107, 108, 113, 123, 137, 169, 171, 177, 191, 636 neurogenesis, 95–96 neuron, 41, 93, 95, 107, 108, 113, 137, 138, 178, 191, 193–194, 229, 277 Gadolinium, 327, 599, 600, 602–603 Gain control, 174 Gait disturbance, 494, 505, 506, 556, 659 Gambling, 388 Gamma-aminobutyric acid (GABA), 51, 57, 119, 151, 163–167, 170, 173, 184, 189, 191–194, 203–205, 210, 211, 222, 225–227, 231, 233, 234, 266, 303, 309, 316, 334, 336, 341, 401, 415, 436, 437, 538, 542, 576, 578, 600, 601, 612, 634, 635, 637

738 Gamma-aminobutyric acid (GABA) (cont.) receptor, 164, 166, 192–194, 203, 309, 334, 336, 538, 634, 635, 637 release, 204, 227, 316, 436, 437, 576, 578, 600, 601, 612 synapse, 118–119 Genetic counseling, 533 Genetic heterogeneity, 526, 547 Genetic model, 393 Genetics, 10, 138–140, 142, 393, 409, 521–527, 541, 553, 618, 622, 688, 699, 701 Genome, 10, 132, 138, 139, 142, 143, 199, 393, 522, 527, 547, 550, 642, 692, 716–717 Glia, 101, 119, 123, 124, 141, 170, 187, 189, 190, 199, 225, 227–229, 232, 293, 295, 305, 306, 308, 329, 336, 394–396, 421, 427, 587, 600, 672 Glial fibrillary acidic protein (GFAP), 538, 544 Gliotransmission, 190 Globular cell, 178, 179, 211 Glucose metabolism, 333–336, 618 Glutamate entrapment, 184 Glutamate receptor, 117, 170, 198, 199, 289, 296, 300, 403, 589, 729 Glutamatergic, 47, 65, 107, 108, 111–119, 138, 155, 158, 163, 164, 170, 183, 191–193, 197–199, 229, 233, 247, 340, 395, 401, 414, 416, 432, 434, 445, 613, 667, 732 Glutamatergic neurogenesis, 94–95 Glutamate synapse, 117–118 Glutamic acid decarboxylases (GADs), 538 Gluten ataxia, 334, 548, 575, 576, 579, 634, 642, 645, 647 Gluten-free diet, 579, 646 Gluten related disorders, 645–647 Glycine, 119, 173, 184, 203, 247, 414 Goldfish, 399–402 Golgi, 394, 395 Golgi cell, 7, 101, 108, 115, 116, 119, 127, 173–174, 177, 179, 183, 184, 191, 193, 194, 197, 209, 210, 235, 245, 247, 260, 283, 296, 308, 394, 395, 401, 432, 436, 437, 470 Gordon Holmes, 8, 15–19, 376, 548 G-protein-coupled receptors (GPCRs), 231, 232, 235, 296 Granular layer (GL), 7, 42, 44, 71, 94, 95, 101, 102, 117, 122, 123, 150, 151, 169, 173, 174, 187, 189, 191, 192, 245, 247, 249, 254, 255, 259–261, 283, 361, 411, 426, 588, 722 Granule cell (GCs), 6, 7, 44, 47, 52, 53, 94, 95, 101–104, 107, 108, 111–113, 115–119, 122, 127, 138, 139, 142, 149–152, 171, 173, 174, 177–179, 181, 183, 184, 191–194, 197, 199, 209–211, 216–217, 225–227, 232, 233, 238, 244–246, 251, 254, 259–261, 283, 287, 289, 299–303, 313–316, 322, 388, 389, 394–397, 400–402, 404, 405, 425, 426, 432, 445, 470, 608, 609, 720, 728, 729 Gray matter, 117, 305, 325, 327, 328, 382, 482, 537, 542, 609, 610, 613 Grid2Lc, 403, 405, 406 H Hearing loss, 184, 504, 526, 550–552, 596, 618, 666 Hemangioblastomas, 480, 611, 662 Hemisphere, 6, 8, 9, 18, 19, 23–25, 31, 34, 37, 40, 77, 81, 83–85, 87, 90, 93, 100, 289, 334, 335, 339–341, 343, 344, 346–348, 352–354, 364, 376, 377, 380, 381, 383, 419, 420, 443, 459, 488, 503, 534, 562–565, 568, 572, 601, 602, 622, 623, 642, 660, 662, 667, 672, 680, 706, 727 Hemorrhage, 142, 328, 329, 487, 489, 521, 532, 533, 567–569, 572, 660, 662, 666, 668, 671–673, 709 Hemorrhagic transformation, 570 Hemosiderin, 671–673, 677 Hemosiderosis, 673

Index Hereditary ataxias, 329, 480, 506, 521–523, 547, 699, 700, 702 Hereditary spastic paraplegias (HSPs), 691 Heroin, 599, 602 Historical background, 5–10 History of neuroscience, 15–19 Homeostasis, 216, 284, 296, 306, 416, 445, 523, 548, 584, 622, 730 Hormones, 232, 235, 237, 239, 334, 416, 608–613 5-HT3 receptor, 210, 211 Human cerebellum, 9, 10, 23–25, 83, 142, 243, 308, 351, 360, 380, 479, 481 Hydrocephalus, 480, 532, 564, 565, 569–572, 601, 602, 659, 663, 668 Hypotonia, 5, 17, 421, 422, 425, 427, 465, 488, 489, 524, 525, 532, 552, 556, 557, 664 I Idebenone, 700, 701 Identity preservation, 255 Immune ataxias, 579, 641, 642 Immune mediated ataxias, 642, 646, 656 Immune-mediated cerebellar ataxias, 576, 719 Implicit learning, 512, 514 Infarction, 31, 83, 377, 458, 474, 567–572, 602, 666, 731 Inferior olive (IO), 6, 41–44, 52–55, 61, 62, 64, 84, 101, 111–113, 115, 118, 127–129, 155, 157, 191, 192, 217, 233, 251, 260, 261, 277, 308, 343, 355, 394, 395, 401, 404, 405, 420, 421, 425, 444, 445, 470, 471, 473, 728 Inferior olivary nucleus (ION), 41, 47, 49, 728, 729 Inflammation, 142, 225, 405, 421, 427, 531, 538, 619, 632, 647, 730 Inheritance, 480, 521–526, 532, 533, 541, 558, 596, 688, 692, 710 Inhibition, 54, 57, 94, 112, 118, 119, 157, 165, 166, 169–171, 173, 191–194, 203, 204, 217, 221, 224, 227, 233, 234, 239, 247, 265, 267, 276, 277, 309, 360, 402, 406, 427, 433, 434, 436, 437, 442, 445, 453, 584, 603, 668, 682, 706, 731 Inhibitory interneurons, 95, 101, 115, 127, 157, 166, 167, 173, 177, 193, 203, 302, 637 Inhibitory transmission, 163, 164, 166, 203, 635 Injury, 5, 8, 15, 17, 142, 188, 189, 240, 306, 346, 363, 376, 397, 419–422, 465, 469, 482, 485, 487, 489, 533, 631, 637, 647, 665–668, 721, 726 Inositol triphosphate receptor type 1 (IP3R1), 443, 445 In situ branch atheromatous disease, 569 Interlimb coordination, 422 Internal model, 158, 323, 344, 379, 382, 388, 389, 452, 460, 461, 470–472, 474, 502, 503, 508, 681, 727–730 International cooperative ataxia rating scale (ICARS), 475, 493, 494, 496–498, 504, 505, 626, 681–683 Interneuron, 65, 94, 95, 101, 102, 107, 112, 119, 123, 133, 138, 149, 155, 156, 163–167, 169, 170, 174, 177, 184, 191, 193, 204, 221, 229, 259, 281, 283, 287, 302, 303, 308, 317, 395, 404, 432, 433, 543, 578, 609 Intoxication, 229, 531, 532, 535, 567, 600–603 Intracellular Ca2+ stores, 293 In vivo imaging, 393, 622 Ion channel, 123, 157, 185, 308, 317, 409, 575 Isthmic organizer, 93, 137, 138, 395, 396 J Joubert syndrome, 95, 114, 140, 141, 489, 523, 525, 532, 556, 562, 563 K Kainate receptor (KAR), 198, 199

Index L Lambert-Eaton myasthenic syndrome (LEMS), 416, 585 Language, 8, 10, 78, 137, 158, 277, 346, 352–354, 360, 364, 367, 372, 375–378, 388, 434, 457–461, 485, 487–489, 532, 537 Larsell, O., 6, 9, 15, 17–19, 23, 24, 469 Late-onset cerebellar ataxias, 522, 524, 527 Laterality effect, 364, 365 Lateral reticular nucleus (LRN), 49, 52, 53, 63 Learning, 6, 10, 103, 127, 158, 163–167, 193, 204–206, 209, 216, 217, 221, 223, 229, 233, 239, 247–249, 259–261, 267, 276, 284, 287–289, 294, 309, 322, 344, 360, 361, 365, 372, 373, 388, 402, 405, 445, 460, 486, 511, 512, 514, 544, 579, 609, 650, 681–683, 706, 713, 727 Lesion, 388, 389 deficit, 345, 479 symptom, 346, 354, 473, 479–482 Ligand-gated receptors, 295, 296 Limbic, 7, 8, 10, 80, 84, 85, 322, 323, 343, 346, 348, 359, 360, 376, 377, 380, 382, 388, 470, 472, 473, 488, 576, 580, 583–585, 589, 634 Lithium, 599–601, 608, 610 Lobules, 18, 19, 23–26, 31, 34, 37, 42, 52–57, 63, 65, 66, 83, 84, 89, 90, 99, 100, 102, 115, 119, 167, 177, 181, 182, 184, 202, 244, 245, 313, 321–323, 328, 343–346, 348, 352–354, 360, 364–367, 380, 382, 383, 388, 389, 442, 451, 469–473, 481, 482, 503, 542, 600, 679, 688, 727, 728 Localized MR spectroscopy, 340 Locomotion, 6, 8, 65, 217, 229, 405, 410, 421, 422, 437, 710 Locus coeruleus, 179, 201 Long-term depression (LTD), 57, 127, 151, 157, 164, 193, 216, 217, 239, 259, 276, 287–290, 294, 316, 361, 579, 636, 728, 730 Long-term plasticity, 151, 193, 221, 276, 285 Long-term potentiation (LTP), 103, 151, 199, 217, 259, 260, 282, 283, 288, 289, 294, 313, 315, 316, 361, 728–730 Long-term synaptic plasticity, 151, 152, 170, 587 LTDpathies, 579, 636, 637, 729 Lugaro cells, 6, 94, 95, 107, 170, 174, 177–179, 210, 211, 226, 235 M Magnetic resonance imaging (MRI), 9, 10, 24, 33, 34, 36, 37, 39, 88, 141, 325–330, 361, 380, 522, 531, 549, 622, 626, 652, 659, 671, 674 Major depression, 541–544 Malformation, 140, 141, 360, 480, 489, 525, 531–533, 561–565, 568, 666, 672, 677 Mapping, 55, 88, 94, 102, 112, 113, 259, 326, 328, 345, 346, 351–355, 365, 405, 473, 474, 479–482 Mechanism, 5, 10, 118, 141, 143, 151, 164, 184, 193, 203 Medication, 10, 206, 542, 597, 609, 646, 657, 658, 694, 702, 716 Medulloblastoma, 95, 239, 459, 487, 535, 660, 663, 664 Megacisterna magna (MCM), 564 Mentalizing network, 380–382, 512 Metabotropic glutamate receptor (mGluR), 151, 164, 197–198, 245, 247, 281, 287, 296, 336, 441, 576, 577, 586–589, 634–636 Metabotropic glutamate receptor 1 (mGluR1), 122, 123, 151, 157, 158, 198, 247–249, 281, 283, 284, 287, 289, 296, 297, 310, 425, 427, 441, 443–446, 576, 577, 579, 587–589, 634–636, 642, 728, 729 Metabotropic glutamate receptor 5 (mGluR5), 198, 336, 538, 543, 590 Metastasis, 480, 633, 662 MHB, see Mid-hindbrain-boundary Microcircuit, 173–174, 178, 179, 188, 190 Microglia, 187–188, 216, 225, 284, 305, 306, 308–310, 421, 589, 637, 667, 730

739 Microzone, 179, 249, 254, 255, 277, 470, 503, 727–730 Mid-hindbrain-boundary (MHB), 395, 396 Migraine, 297, 341, 409, 410, 415, 416, 527, 532, 673 Miller-Fisher syndrome, 527, 577, 578, 589 Mitochondria, 218, 245, 293, 294, 296, 405, 618, 650, 692, 694, 700, 730 Mitochondrial dysfunction, 552, 619 Modulation of the cerebellar brain inhibition (CBI) Molar tooth malformations, 562 Monoacylglycerol lipase, 223 Morphogenesis, 302, 393 Mossy fiber, 55, 61–63, 209 neuron, 47 Motor control, 5, 9, 10, 64, 103, 118, 137, 163, 202, 205, 206, 221, 229, 261, 359, 366, 388, 402, 433, 451, 471, 472, 476, 537, 603, 665, 680–681, 683, 705 Motor coordination, 119, 155, 158, 159, 163, 166, 177, 179, 185, 194, 204, 205, 216, 233, 235, 293, 323, 389, 405, 413, 427, 432, 434, 441, 445, 463 Motor learning, 10, 66, 72, 103, 163, 166, 193, 194, 205, 206, 217, 233, 235, 259, 267, 282, 287, 288, 294, 309, 344, 345, 361, 453, 681, 682, 709, 710, 713 Motor recovery, 365 Motor timing, 276 Motor training, 709, 711–713, 730 Mouse cerebellum, 138, 182, 202, 204, 308, 309, 405, 588, 721 Mouse models, 140, 266, 441, 445, 446, 538, 720, 721 Movement, 211, 387–389, 415, 451, 454, 460, 461, 463, 465, 466, 469, 472, 473, 488, 497, 503, 507, 508, 526 MR spectroscopy of human cerebellum, 642, 656 Multiple sclerosis (MS), 211, 237, 240, 310, 325, 458, 496, 527, 532, 548, 637, 679, 709 Multisystem disease, 556, 619, 628 Mutant, 57, 101, 115, 123, 128, 138–140, 143, 166, 171, 193–194, 216, 393, 403–406, 413–416, 427, 441–446, 609, 621, 688, 720, 722 Mutism, 8, 459, 474, 485, 486, 488, 626 Mycophenolate, 579, 636, 642, 646 N Neural circuits, 10, 399–401, 459, 472, 485 Neural integration, 252 Neural progenitor, 108, 109, 299, 613 Neuroactive, 237–240 Neurochemical profile in cerebellar ataxias, 341 in psychiatric disorders, 341 Neurochemical profile of cerebellum, 341 Neurodevelopment, 189, 223 Neuroepithelial domain, 49 Neuroimaging, 8–9, 87, 222, 322, 323, 344, 351, 353–355, 365, 375, 377, 378, 382, 383, 388, 460, 470, 472, 473, 501, 505, 507, 513–515, 522, 531–533, 535, 596, 618, 656, 659, 688, 716 Neuroimmune factors, 306–310 Neuroinflammation, 336, 427, 637 Neurological diseases, 133, 198, 341, 446, 451 Neuromodulation, 384, 507, 508, 706, 726, 731–732 Neuromodulators, 164–165, 190, 233 Neuronal degeneration, 421, 611, 622 Neuronal migration, 140, 141, 189, 299, 301, 538, 543, 544, 561, 608 Neuropeptides, 231–235 Neuroprotection, 427 Neuropsychiatry, 474, 485–489 Neurorehabilitation, 701, 706, 711 Neurosteroids, 237, 239, 240

740 Neurotransmitter, 51, 111, 112, 149, 151, 166, 189, 190, 197, 198, 209, 225, 231, 237, 295, 296, 306, 401, 402, 410, 414–416, 538, 539, 585, 587 Neurotransplantation, 719, 720, 722, 731, 732 Neurotrophin, 299–302 Nitric oxide (NO), 215–218, 281, 282, 289 Nitric oxide synthase (nNOS), 178, 215–216, 282, 411, 437 N-methyl-D-aspartate receptor (NMDAR), 151, 164, 174, 194, 198, 199, 235, 245, 281, 289, 296, 302, 309, 433, 576, 634 Nodulus, 19, 24, 25, 31, 35, 43, 52, 53, 55, 57, 193, 245, 250, 254, 344, 451, 453, 454, 472, 562 Non invasive brain stimulation (NIBS), 507, 515, 682–683, 706 Non-invasive neurostimulation, 515 Non-progressive, 489, 521, 522, 525, 531–534, 557 Noradrenaline, 165, 178 Noradrenergic, 101, 179, 201, 203–206, 609 Norepinephrine, 84, 164, 201–206 NT3, 299 Nystagmus, 344, 377, 422, 453, 454, 470, 474, 494, 504, 527, 565, 589, 600, 601, 612, 624, 656, 665, 680, 683, 685, 699, 701, 702, 726 O Oculomotor, 55, 65, 66, 70, 71, 74, 249, 251, 252, 287, 340, 344, 354, 377, 451, 452, 470, 472, 474–476, 496–498, 522, 523, 525, 526, 532, 534, 548–551, 568, 600, 612, 618, 624, 681, 694, 709, 716 Oligodendrocyte, 187, 657 Olive, see Inferior Olive, Inferior Olivary Nucleus, 7, 32, 42, 43 Orexin, 232, 233, 235 Orphan nuclear receptor, 425 Oscillations, 149, 174, 261, 295, 410, 411, 464–466, 474, 503, 507, 685 P P1 receptors, 226 P2 receptors, 226 p75NTR, 299–302 Pacemaker, 9, 157, 159, 295, 596 Pancreas transcription factor 1-a (Ptf1a), 93 Parallel fibers (PFs), 6, 7, 23, 71, 115, 116, 127, 138, 149–152, 164, 167, 170, 174, 177, 191, 193, 205, 209, 210, 217, 259, 288, 302, 309, 316, 400, 404, 470, 503, 603, 613, 729 Paraneoplastic, 506, 521, 535, 575, 576, 578, 579, 583, 584, 586–588, 590, 631–635, 642, 646, 656 Paraneoplastic cerebellar degeneration, 334–336, 527, 548 Pattern formation, 101–103 Patterning, 53, 74, 102–104, 113–114, 119, 139, 140, 247, 254, 395 Perception, 10, 66, 71–74, 184, 457, 460, 461, 473, 679, 681, 706 Peripheral neuropathy, 497, 526, 584, 586, 587, 601–603, 612, 646, 685, 691, 694 Phase control, 251 Phenotypic heterogeneity, 693 Phosphodiesterases, 216, 544 Pilocytic astrocytoma, 239, 480, 535, 660, 663 Pinceau formation, 123, 170–171 Plasticity, 44, 57, 104, 127–133, 151, 158, 167, 193, 226, 240, 259–261, 276, 281–285, 288, 294, 306, 313, 315, 316, 419–422, 433, 538, 635, 637, 666, 682, 683, 719, 721, 727, 728, 730–732 Pons, 7, 8, 29, 34, 39, 69–71, 78–81, 83, 84, 184, 326, 328, 329, 340, 526, 562 Pontine gray nucleus (PGN), 49

Index Pontocerebellar, 71, 77, 80–83, 87, 141, 329, 361, 376, 459, 472, 489, 521, 525, 533, 537, 542, 600 Positron emission tomography (PET), 333–337, 376, 578, 659, 673 Posterior cerebellum, 25, 366, 381, 383, 472, 512–514, 610, 668 Posterior fossa, 9, 141, 325, 327, 459, 480, 488, 525, 532–534, 564, 565, 567, 569, 570, 659, 662, 665, 666, 673 Posterior inferior cerebellar artery (PICA), 17, 31–34, 345, 364, 365, 367, 459, 474, 480, 487, 567–571 Posterior lobe, 6–8, 18, 19, 23, 83, 84, 202, 336, 343, 345, 346, 348, 364, 469, 470, 473, 481, 485–487, 489 Post-infectious cerebellitis (PIC), 489, 575–577, 589, 631, 634 Postoperative cerebellar mutism syndrome, 663, 664 Posture, 5, 6, 8, 202, 233, 344, 421, 469–471, 494, 496–499, 501, 504, 541, 601, 679, 709, 728 Precerebellar systems, 48 Prediction, 10, 72–74, 158, 184, 255, 260, 355, 360, 364, 371, 372, 379, 381, 470, 471, 475, 503, 513, 515, 664, 681, 727, 730 Preparatory movement, 277 Primary autoimmune cerebellar ataxia (PACA), 575, 576, 631, 634, 641 Prognosis, 354, 532, 533, 579, 590, 626, 628, 632, 633, 635, 636, 656–657 Progression, 95, 96, 330, 352, 353, 373, 493, 494, 496, 498, 499, 521, 522, 532, 551, 572, 618, 624, 628, 642, 650, 655–657, 674, 677, 682, 686, 710, 712, 713, 716, 727, 730, 731 Progressive, 115, 118, 124, 235, 249, 254, 325, 330, 373, 405, 421, 422, 433, 442, 444, 445, 460, 498, 506, 507, 521–526, 531, 532, 534–535, 549, 551, 555, 557, 575, 578, 584, 586, 587, 589, 590, 595, 597, 600, 609, 617, 619, 621, 624, 626, 627, 636, 642, 645, 646, 650, 652, 653, 655, 656, 658, 665, 666, 671, 685, 694, 710, 719, 720, 727, 731 Projections, 6, 53, 63, 69, 77, 87, 103, 111, 128, 189, 204, 313, 321, 343–345, 361, 365, 377, 389, 395, 419, 421, 433, 445, 451, 472, 682, 722 Protein kinase C (PKC), 55–57, 122, 123, 128, 131, 133, 164, 197, 281–283, 287, 288, 437, 444, 585, 586, 635, 636, 728 Psychiatric disorders, 335, 336, 341, 383, 543, 544 Purkinje cells (PCs), 6, 43, 47, 53, 61, 71, 93, 107, 111, 115, 127, 137, 163, 174, 177, 183, 191, 193, 197, 209–211, 221, 226, 233, 238, 245, 270, 275, 281–284, 296, 300–303, 308, 314, 315, 383, 388, 389, 400–402, 404, 405, 410, 415, 416, 425–427, 432, 452, 453, 469, 470, 503, 507, 542, 578, 586–588, 596, 600, 603, 608, 609, 613, 622, 635, 666, 667, 682, 694, 706, 720–722, 728, 729 Purkinje cell type specification, 96 Purkinje neuron, 142, 187–189, 203, 295, 306, 309, 667, 668, 716, 720, 721 Pursuit, 70, 451, 453, 470, 474, 494, 497, 504, 656, 685, 726 R Rating scales, 8, 475, 493, 504, 505 Rebound burst, 270, 271, 276 Rebound spiking, 275 Receptor binding, 333–337 Receptors (P1), 227 Recessive, 10, 328, 409, 413, 414, 506, 523, 526, 527, 532, 547–553, 617, 619, 688, 694, 710 Reelin, 100, 103, 104, 211, 239, 538, 543, 608 Regional cerebral blood flow (rCBF), 333–335 Reinnervation, 694 Remote degeneration, 419, 422 Resting state, 322, 351–354, 366, 380, 381 Resting state functional connectivity, 9, 352, 353, 485 Resurgent current, 149, 157

Index Reticulospinal tracts (RST), 62, 65–66, 502 Reticulotegmental nucleus (RTN), 49 RFC1 gene, 524, 551, 688 Rhombencephalosynapsis, 489, 525, 562, 563 Rhombic lip (RL), 93, 101, 102, 107, 112, 114, 137, 138, 142, 245, 299, 395, 396 Rhombomere, 48, 49 Rhombomere 1, 112, 137 RNA, 129, 198, 308, 543, 548, 577, 584, 585, 715, 716 Rolling Nagoya mouse, 414, 416–417 Rubrospinal, 64 Rubrospinal tract (RbST), 62, 64 S Saccades, 65, 70–72, 277, 451–454, 470, 474, 494, 557, 624, 685, 687 Scale(s), 72, 139, 156, 247, 335, 337, 359, 400, 401, 441, 475, 487, 493–499, 505, 590, 626, 627, 646, 681, 683, 727 Scale for the Assessment and Rating of Ataxia (SARA), 493, 496–497, 504, 505, 590, 618, 626, 642, 657, 681, 683, 711, 712, 727 Schizophrenia, 8, 159, 198, 199, 209, 212, 223, 239, 240, 341, 361, 366, 427, 446, 514, 541–544 Screening, 128, 132, 142, 393, 534, 586, 589, 642, 653 Second messenger, 197, 231, 235, 294, 296, 307–308, 441 Sensory predictions, 73, 255, 372, 681 Sequencing, 10, 360, 364, 365, 367, 371–373, 381, 382, 460, 461, 470, 487, 503, 512–515, 522, 547, 548, 550, 608, 642, 692, 716 Serotonin, 84, 178, 209–212, 235, 281, 334, 336, 341 Short-term plasticity, 221 Signal delay lines, 249, 252 Signal transduction, 55, 95, 216, 231, 235, 307–309, 589 Simple spike, 57, 103, 117, 127, 156, 157, 193, 252, 254, 265–267, 388, 410, 445 Single photon emission computed tomography (SPECT), 333–337, 377, 459, 610, 618, 666, 694 S-nitrosylation, 216, 217 Social mentalizing, 379, 380, 382, 512–515 Soluble guanylyl cyclase (sGC), 216, 281 Spatiotemporal regulation, 109 Speech, 457 perception, 457 production, 376, 458, 460, 461 Speech sound/phoneme discrimination, 460, 461 SPG7 gene, 691–693 Spinal cord, 7, 43, 47, 49, 55, 61–66, 83, 111, 117, 202, 325, 326, 328, 329, 343, 344, 360, 395, 400, 401, 432, 470, 472, 473, 475, 502, 507, 549, 557, 601, 618, 622, 650, 652, 671–673, 676, 683, 688, 707, 716, 721, 731 Spinocerebellar ataxia (SCA), 8, 10, 17, 61, 73, 159, 194, 254, 266, 296, 310, 326, 328, 334–336, 340, 341, 345, 364, 365, 382, 415, 427, 441, 443, 445, 446, 458, 460, 474, 480, 489, 494, 496, 506, 522–527, 532, 534, 555–557, 568, 569, 609, 655–657, 688, 692, 710, 711, 715, 727 Spinocerebellar ataxia type 23 (SCA23), 235 Spinocerebellar tract, 7, 41, 61–63, 470, 472, 617 Spino-cuneo-cerebellar tract, 63 Spino-olivocerebellar pathways (SOCPs), 63 Spontaneous activity, 150, 158, 166, 249, 302, 406 Stellate cell (SC), 7, 57, 95, 102, 107, 108, 113, 118, 119, 122–124, 130, 163–167, 169, 170, 177–179, 191–193, 197, 198, 203, 209, 210, 216, 221, 238, 260, 394, 395, 400, 425, 730 Stem cell, 187, 396, 397, 446, 720–722 Steroid(s), 237–240, 427, 579, 608, 610, 613, 677 Stripe, 43, 44, 95, 99–104

741 Stroke, 6, 8, 10, 78, 80, 202, 240, 325, 334, 345, 361, 364, 365, 419, 458, 474, 479, 480, 482, 487, 489, 506, 525–527, 532, 563, 603, 604, 668, 706, 709, 710, 721, 725, 726 Structural MRI, 325, 470, 480 Students, 1, 2 Superior cerebellar arteries (SCA), 29, 31, 36–40, 345, 364, 377, 458, 474, 480, 567 Symptomatic treatment, 558, 627, 657, 701 Synapse, 62, 77, 115–119, 121–124, 127, 150, 151, 155, 157, 158, 163–167, 170, 171, 174, 179, 184, 185, 188, 189, 191, 193, 194, 197, 199, 205, 211, 216, 217, 221, 226, 227, 235, 238, 239, 243–245, 249, 259–261, 266, 281–285, 287–290, 295, 302, 303, 306, 309, 316, 355, 415, 416, 421, 425, 432, 433, 436, 445, 548, 579, 613, 634, 636, 725, 727–732 Synapse elimination, 121–124, 426 Synaptic, 42, 44, 57, 62, 65, 77, 103, 116–119, 121–123, 149–151, 158, 164, 165, 167, 170, 173–174, 177, 179, 184, 188, 193, 197, 199, 221, 225, 232, 238, 245–249, 260, 265, 266, 271, 275, 276, 282–284, 287, 288, 295, 297, 299, 302, 306, 309, 313, 415, 728, 729 Synaptic plasticity, 157, 190, 193, 198, 199, 210, 211, 217, 227, 229, 239, 275, 276, 294, 297, 315, 316, 538, 543, 544, 579, 612, 637, 728–732 Synaptic specificity, 117 Synaptic transmission, 123, 150, 151, 163–165, 179, 190, 193, 194, 197, 199, 226, 227, 240, 248, 249, 288, 294, 295, 297, 302, 306, 309, 402, 410, 416, 445, 575, 634, 635, 728, 729 Synaptogenesis, 115, 118, 121–124, 190, 306, 404, 426 Synchrony, 44, 113, 277 T tat peptide, 313 Teleost, 170, 394, 395, 399–402 Telovelar approach, 663, 664 Thalamocortical, 77, 83, 705 Thalamus, 8, 29, 55, 62, 64, 77, 84, 90, 111–113, 206, 277, 321, 322, 344, 361, 376, 395, 419–421, 425, 432, 459, 470, 472, 489, 501, 597, 600, 612, 666, 682 Theory of mind, 366, 379–384, 511 Thyroid, 601, 603, 607–610, 642 Timing, 44, 102, 151, 152, 166, 194, 210, 233, 247, 249, 260, 261, 269, 276, 277, 288, 323, 360, 367, 387, 443, 460, 461, 463, 467, 471, 474, 503, 507, 508, 601, 637, 650, 688, 728 sequencing, 371 Tinnitus, 184, 504, 568, 680 Topography, 9, 42–43, 78, 101–104, 351, 355, 360, 364, 372, 472, 476 Tracer, 53, 62, 69, 70, 81, 333, 336, 337, 345 Tracing, 8, 49, 63, 77, 85, 88, 89, 101, 111, 184, 321, 345, 395, 401, 470, 481, 485 Trait inferences, 511, 513 Transcranial direct current stimulation (tDCS), 10, 360, 361, 515, 682, 683, 705–707, 731 Transcranial magnetic stimulation (TMS), 10, 260, 515, 682, 683, 705–707, 731 Transcription factor, 48, 49, 93, 94, 96, 101, 102, 108, 112, 113, 237, 395, 396, 425, 427, 585, 632, 701 Transglutaminase, 646, 647 Transient receptor potential cation channel type C3 (TRPC3), 103, 248, 249, 251, 254, 255, 441–446 Trauma, 419, 458, 665–668, 672, 710, 719, 725 Tremor, 6, 10, 17, 329, 334, 336, 341, 413, 421, 425, 427, 463–466, 494, 497–499, 507, 522, 524, 525, 527, 549, 551, 552, 555–557, 600–602, 607, 609, 610, 617, 624, 665, 668, 679, 680, 694, 706, 716

742 Tropomyosin receptor kinase (Trk), 299, 301 T-type calcium conductance, 157, 267, 270, 272, 275, 295, 297, 443, 445 U Unified Multiple System Atrophy Rating Scale (UMSARS), 493, 498–499 Unipolar brush cells (UBCs), 6, 7, 94, 101, 107, 116, 138, 142, 173, 181–185, 243–247, 249–255, 433, 442–445 Uvula, 6, 24, 25, 31, 52, 53, 83, 193, 250, 344, 451, 453, 454, 472, 568, 663 V Valvula cerebelli, 394, 399, 400, 402 Venous thrombosis, 570 Ventricular zone (VZ), 93, 96, 100–102, 107, 112–114, 137, 395, 396 Vergence, 454, 474 Vermis, 6, 8, 18, 19, 23–25, 31, 37, 41, 42, 52, 54, 62, 64, 65, 70, 71, 93, 95, 100, 101, 111, 138, 139, 177, 238, 244, 250, 334–336, 339–341, 343, 344, 346, 348, 354, 360, 367, 380, 381, 383, 399, 419, 433, 434, 442, 451, 453, 454, 459, 470, 472–474, 487, 488, 503, 523, 525, 532, 533, 538, 542, 561–565, 572, 600, 602, 618, 622, 623, 642, 646, 656, 657, 663, 664, 673, 680, 688 Vertebral artery, 31, 32, 567, 569, 570 Vertigo, 8, 410, 474, 504, 527, 565, 568, 701

Index Vestibular areflexia, 524, 527, 548, 549, 551, 685, 687 complex, 53–57, 65, 233 Vestibulospinal tract, 55, 62, 65, 502 Visual perception, 71–74, 489 Voicing Onset Time (VOT), 461 W White matter (WM), 6, 7, 9, 23, 25, 26, 37, 41, 44, 94, 102, 112, 113, 121, 123, 187–189, 201, 226, 245, 305, 306, 325–330, 339, 366, 383, 394, 395, 426, 458, 482, 532–534, 549, 557, 558, 561, 600–602, 652, 666, 667, 673 Withdrawal, 434, 435 X X-chromosomal, 555, 558 Z Zebrafish, 393–397, 401, 402 Zebrin, 42, 43, 96, 99–101, 103, 155, 157, 173, 249, 415, 442, 444 Zone, 6, 24, 32, 33, 35, 38, 62, 64–66, 80, 84, 93–94, 99–104, 112, 113, 117, 118, 123, 130–132, 137–139, 167, 232, 249, 254, 288, 322, 344, 375, 380, 394, 395, 397, 404, 459, 469, 472, 474, 667, 680, 720, 728, 729