Essentials of Cerebellum and Cerebellar Disorders: A Primer For Graduate Students

Contents
Editors and Authors
About the Editors and Authors
About the Editors
1: Introduction
Part I: Brief Historical Note
2: A Brief History of the Cerebellum
2.1 Early and Evolving Views of Cerebellar Organization and Function
2.2 Cerebellar Cortex
2.3 Connectional Anatomy
2.4 The Cerebellar Motor Syndrome
2.5 The Cerebellar Cognitive Affective Syndrome
2.6 Atlases and Functional Neuroimaging
2.7 Theories
2.8 Evolving Techniques and Therapies
References
3: Pivotal Insights: The Contributions of Gordon Holmes (1876–1965) and Olof Larsell (1886–1964) to Our Understanding of Cerebellar Function and Structure
3.1 Gordon M. Holmes
3.2 Olof Larsell
3.3 The Problem
3.4 Early Studies, 1920–1932
3.5 The Middle Period, 1932–1947
3.6 Later Studies and the Solution, 1948–1954
References
Part II: Anatomy and Histology of the Cerebellum
4: Gross Anatomy of the Cerebellum
References
5: Vascular Supply and Territories of the Cerebellum
5.1 Overview
5.2 Posterior Inferior Cerebellar Arteries (PICAs)
5.3 Anterior Inferior Cerebellar Arteries (AICAs)
5.4 Superior Cerebellar Arteries (SCAs)
5.5 Cerebellar Veins
References
6: The Olivocerebellar Tract
6.1 Introduction
6.2 Morphology of Single Olivocerebellar Axons
6.3 Topography in the Olivocerebellar Tract
6.4 Physiological Properties
6.5 Development of the Olivocerebellar Projection
6.6 Plasticity of Olivocerebellar Axons
6.7 Conclusion
References
7: Precerebellar Nuclei: Embryological Principles
7.1 Anatomy and Histology of the Precerebellar Nuclei
7.2 Specification of Precerebellar Nuclei Neurons
References
8: Vestibular Nuclei and Their Cerebellar Connections
8.1 Introduction
8.2 Vestibular Nuclei
8.3 Cerebellum
8.4 Vestibular End Organs
8.5 Vestibular Primary Afferent Cerebellar Projections
8.6 Vestibular Primary Afferents’ Projections to Vestibular Nuclei
8.7 Visual Projections to Vestibular Nuclei
8.8 Neck-Proprioceptive Afferents to Vestibular Nuclei
8.9 Autonomic Influences of the Vestibular Nuclei
8.10 Internal Connections Within the Vestibular Nuclei
8.11 Bilateral Connections Between Vestibular Nuclei
8.12 Ascending Projections of Vestibular Nuclei
8.13 Cholinergic and GABAergic Secondary Vestibular Projections
8.14 Descending Projections of Vestibular Nuclei
8.15 Cerebellar Projections to Vestibular Nuclei
8.16 Cerebellar and Vestibular Compensation
8.17 Subcellular Evidence of Cerebellar Plasticity
References
9: Spinocerebellar and Cerebellospinal Pathways
9.1 Information Routes from Spinal Cord to the Cerebellum
9.1.1 Spinocerebellar Mossy Fiber Systems
9.1.1.1 The Dorsal Spinocerebellar Tract
9.1.1.2 The Ventral Spinocerebellar Tract
9.1.1.3 The Spino-Cuneo-Cerebellar Tract
9.1.1.4 The Rostral Spinocerebellar Tract
9.1.1.5 Indirect Spinocerebellar Mossy Fiber Tracts
9.1.1.6 Cerebellar Targets of Spinocerebellar Mossy Fiber Tracts
9.1.2 Spino-Olivocerebellar Pathways
9.2 Information Routes from the Cerebellum to the Spinal Cord
9.2.1 Lateral Systems
9.2.1.1 The Crossed Corticospinal Tract
9.2.1.2 The Rubrospinal Tract
9.2.2 Medial Systems
9.2.2.1 The Uncrossed Corticospinal Tract
9.2.2.2 The Tectospinal Tract
9.2.2.3 The Vestibulospinal Tracts
9.2.2.4 The Reticulospinal Tracts
9.2.2.5 The Interstitiospinal Tract
9.2.3 Direct Cerebellospinal Projections
9.3 Conclusion
References
10: Visual Circuits
10.1 Anatomical Considerations
10.1.1 Cerebrocortical Areas Projecting to the Pons
10.1.2 Pontocerebellar Projections and Cerebellar Output
10.2 Cerebellum and Eye Movements
10.2.1 Cerebellar Lesions Impair Saccades and Smooth Pursuit Eye Movements
10.2.2 Cerebellar Adaptation of Eye Movements
10.3 Cerebellar Contributions to Visual Perception
10.3.1 A Role of the Cerebellum in Global Visual Motion Perception
10.3.2 The Cerebellum Contributes to Predictive Visual Perception
10.4 Conclusion
References
11: The Cerebrocerebellar System
11.1 The Feedforward Limb of the Cerebrocerebellar System
11.1.1 Patterns of Termination in the Pons
11.1.2 Neurons of the Basis Pontis
11.1.3 Corticopontine Projections
11.1.4 Pontocerebellar Projections
11.2 The Feedback Limb of the Cerebrocerebellar System
11.2.1 The Cerebellar Corticonuclear Microcomplex
11.2.2 Cerebellothalamic Projections
11.2.3 Thalamocortical Projections
11.2.4 Cerebrocerebellar Loops
11.3 Other Cerebral Hemisphere Connections with Cerebellum
11.3.1 Basal Ganglia
11.3.2 Inferior Olive
11.3.3 Hypothalamus
11.3.4 Mammillary Body
11.3.5 Septal Nuclei, Hippocampus, Amygdala, and Ventral Tegmental Area
References
12: Cerebello-Cerebral Feedback Projections
12.1 Introduction
12.2 Projections
12.2.1 Sensorimotor Network
12.2.2 Cognitive Networks
12.3 Conclusion
References
Part III: Embryology and Development of the Cerebellum
13: Cerebellar Neurogenesis
13.1 Introduction
13.2 Cerebellar Territory and Germinal Zones
13.3 Glutamatergic Neurogenesis
13.3.1 Primary Cilia and GCP Proliferation
13.4 GABAergic Neurogenesis
13.5 Neurogenesis and Purkinje Cell Type Specification
13.6 Concluding Remarks
References
14: Zones and Stripes
14.1 Adult Zones and Stripes
14.2 Pattern Formation
14.2.1 Pattern Formation in the Ventricular Zone (VZ)
14.2.2 Pattern Formation in the Rhombic Lip
14.3 Pattern Formation of Afferent and Efferent Projections
14.4 Functional and Clinical Implications
References
15: Specification of Cerebellar Neurons
15.1 Birthplaces and Birthdates of Cerebellar Neurons
15.2 Molecular Machinery to Specify Distinct Types of Cerebellar Neurons
References
16: Cerebellar Nucleus Development
16.1 Concepts of CN Development Have Changed Markedly in Recent Years
16.1.1 Glutamatergic Neurons are Born at the Rhombic Lip
16.1.2 GABAergic Neurons are Derived from the Ventricular Zone
16.2 Future Studies will Need to Address Fine-Grain Patterning of Different Nuclei
References
17: Development of Glutamatergic and GABAergic Synapses
17.1 Development of Glutamate Synapses
17.1.1 Mossy Fiber Synapses
17.1.2 Parallel Fiber Synapses
17.1.3 Climbing Fiber Synapses
17.2 Development of GABA Synapses
17.2.1 Stellate/Basket Cell Synapses
17.2.2 PC Axon Collaterals
17.2.3 Golgi Cell Synapses
References
18: Synaptogenesis and Synapse Elimination in Developing Cerebellum
18.1 Synaptogenesis and Refinement of CF to PC Synapses
18.1.1 Synaptogenesis of CFs to Immature PCs
18.1.2 Postnatal Refinement of CF to PC Synapses
18.2 Synaptogenesis and Refinement of PF to PC Synapses
18.2.1 Synaptogenesis of PFs to Immature PCs
18.2.2 Postnatal Refinement of PF to PC Synapses
18.3 Synaptogenesis of BCs and SCs to PCs
18.3.1 Synaptogenesis of BC Axon to Immature PCs
18.3.2 Synaptogenesis of SC Axon to Immature PCs
References
19: Cerebellar Epigenetics: Transcription of microRNAs in Purkinje Neurons as an Approach to Neuronal Plasticity
19.1 Introduction
19.2 Biological Consequences of Prolonged HOKS of a Climbing Fiber Pathway to the Flocculus
19.3 Transcription of miRNAs in Purkinje Cells
19.4 HOKS Increases miR335 Transcripts and this Increase Decays Rapidly Depending on HOKS Duration
19.5 Hybridization Histochemistry Localizes miRNA Transcripts to Purkinje Cells
19.6 Central Floccular Zone is a Homogeneous Source of Purkinje Cells Excited by HOKS
19.7 HOKS Evokes More Pri-miR335 Transcripts than miR335 Transcripts
19.8 Screens for Discovering mRNAs Targeted by microRNAs
19.9 Identification of 14-3-3 Isoforms in Mouse Flocculus
19.10 miR335 Represses 14-3-3-θ mRNA in N2a Cells
19.11 14-3-3-θ Interacts with PKC-γ in the Cerebellum
19.12 miRNAs and Cerebellar Plasticity
References
20: The Genetic Programs Behind Cerebellar Development
20.1 Introduction
20.2 Mouse Cerebellar Developmental Genetics: from Phenotypes to Genes and Back Again
20.3 Human Cerebellar Developmental Disorders and Human Cerebellar Development
20.4 The Current Age of Transcriptomics and Epigenomics
20.5 New Models and Future Perspectives
References
Part IV: Cerebellar Circuits: Biochemistry, Neurotransmitters and Neuromodulation
21: Granule Cells and Parallel Fibers
21.1 Granule Cell Structure and Electroresponsiveness
21.2 Glomerular Organization of GrCs Synaptic Inputs
21.3 Synaptic Transmission and Plasticity
21.4 Granular Layer Coding and Transmission of GrC Output to the Molecular Layer Through AA and PF
21.5 Functional Activation of GrCs In Vitro and In Vivo
References
Further Reading
22: Purkinje Cells
22.1 PC Identity
22.1.1 Morphology
22.1.2 Diversity
22.2 PC Activity
22.2.1 Two Types of Action Potentials
22.2.2 Spontaneous SS Activity
22.2.3 PC Integration of GC Inputs: Passive and Active Mechanisms
22.2.4 PC are Inhibited by MLIs
22.3 PC Roles and Cerebellar Disorders
22.3.1 Physiological Role of the Spontaneous Activity of PCs
22.3.2 Cerebellar Disorders
References
23: Stellate Cells
23.1 Introduction
23.2 Stellate Cells and Synaptic Transmission
23.2.1 Excitatory Synaptic Transmission
23.2.2 Regulation of Postsynaptic Glutamate Receptors
23.2.3 Modulation of Inhibitory Synaptic Transmission by NMDA Receptors
23.2.4 Presynaptic Regulation by Neuromodulators
23.3 Gap Junctions
23.4 Intrinsic Excitability
23.5 Stellate Cells in Motor and Non-motor Behaviors
23.5.1 Motor Behaviors
23.5.2 Motor Learning
23.5.3 Associative Learning
23.5.3.1 Classical Eye-Blink Conditioning
23.5.3.2 Associative Emotional Memory
23.5.4 Receptive Field Plasticity
References
24: Basket Cells
24.1 Introduction
24.2 Cytology
24.3 Inputs
24.4 Outputs
24.5 Pinceau Formation
References
25: Golgi Neurons
25.1 Golgi Cells Within the Cerebellar Microcircuit
25.1.1 Golgi Cell Morphology and Diversity
25.1.2 Excitatory Synaptic Inputs to Golgi Cells
25.1.3 Inhibitory Synaptic Inputs to Golgi Cells
25.2 Golgi Cell Function
25.2.1 Gain Control
25.2.2 Combinatorial Pattern Enrichment
25.2.3 Temporal Windowing and Oscillations
25.3 Conclusion
References
26: Lugaro Cells
26.1 Introduction
26.2 Morphological Characteristics of Lugaro/Globular Cells
26.3 Physiological Characteristics of Lugaro/Globular Cells
26.4 Possible Physiological Meanings
References
27: Unipolar Brush Cells
27.1 Morphology and Spatial Distribution
27.2 UBC Subtypes
27.3 UBC Connectivity
27.4 Function
27.5 Cerebellar UBCs and Disease
27.5.1 Tinnitus
27.5.2 Ataxia
References
28: Glial Cells
28.1 Gliogenesis and Glial Lineages
28.2 Oligodendrocytes and Microglia
28.3 Astrocytes
28.4 Bergmann Glia
28.5 Astroglial Functions in the Cerebellum
References
29: GABA Pathways and Receptors
29.1 GABA Pathways in the Cerebellum
29.2 GABA Receptors in the Cerebellum
29.3 Regulation of GABAergic Neurons and Synapses
29.4 Mutant Mice Affected in GABAergic Neurons or GABA Receptors
29.5 GABA in Cerebellar Ataxia
References
30: Glutamatergic Pathways and Receptors
30.1 Glutamatergic Pathways and Synaptic Transmission
30.2 Glutamate Receptors
30.2.1 Metabotropic Glutamate Receptors (mGluRs)
30.2.2 Ionotropic Glutamate Receptors (iGluRs)
30.2.2.1 AMPA Receptors (AMPARs)
30.2.2.2 NMDA Receptors (NMDARs)
30.2.2.3 Kainate Receptors (KARs)
30.3 Glutamate Pathways in Glia Cells
30.4 Concluding Remarks
References
31: Norepinephrine in the Cerebellum
31.1 Anatomical Considerations
31.2 Physiology of NE in Cerebellum—Cellular Actions
31.3 Noradrenergic Receptors in Cerebellum
31.4 Functional Implications
31.5 Clinical Considerations
31.6 Summary
References
32: Serotonin in the Cerebellum
32.1 Serotonergic Innervation in the Cerebellum
32.2 Serotonergic Modulation of the Cerebellar Cortex
32.3 Serotonergic Modulation of Cerebellar Nuclei
32.4 The Role of Serotonin in the Developing and Aging Cerebellum
32.5 Altered Serotonergic Modulation of the Cerebellum in Human Patients
32.6 Concluding Remarks
References
33: Nitric Oxide
33.1 Chemical Properties and General Functions
33.2 Nitric Oxide Synthase
33.3 Signal Transduction
33.4 Physiological and Pathophysiological Functions
33.4.1 Granule Cell Neurogenesis
33.4.2 Synaptic Plasticity in the Cerebellar Cortex
33.4.3 Involvement in Cerebellar-Dependent Learning
33.4.4 Neurotoxic and Neuroprotective Roles of NO in the Cerebellum
References
34: Cannabinoids
34.1 Introduction to Cannabinergic Cerebellar Circuitry
34.2 Metabolic Control of the eCBS
34.3 Therapeutic Targeting of the eCBS in the Cerebellum
References
35: Purinergic Signaling in the Cerebellum
35.1 Introduction
35.2 Mechanisms of ATP Release from Neurons and Glia
35.3 ATP (P2) Receptors
35.4 ATP (P2) Receptors in the Cerebellum
35.5 Extracellular Metabolism of ATP
35.6 Adenosine Release from Neurons and Glia in the Brain
35.7 Adenosine (P1) Receptors in the Cerebellum
35.8 Adenosine Release in Cerebellum
35.9 Breakdown and Uptake of Adenosine
35.10 The Role of Purinergic Signaling in the Cerebellum and in Motor Control
35.11 Conclusions and Future Work
References
36: Neuropeptides in the Cerebellum
36.1 Introduction
36.2 Neuropeptides in the Cerebellum
36.3 Role of Peptides in the Cerebellum
36.4 Development of the Cerebellum
36.5 Adult Cerebellum
36.6 Neuropeptide Receptors
36.7 Conclusion and Future Directions
References
37: Neuroactive Steroids
37.1 Introduction
37.2 Physiological Effects
37.2.1 Developing Cerebellum
37.2.2 Mature Cerebellum
37.3 Roles in Cerebellar Diseases
37.3.1 Developing Cerebellum
37.3.2 Mature Cerebellum
37.4 Conclusions and Future Directions
References
38: Role of Unipolar Brush Cells in the Vestibulocerebellum
38.1 History
38.2 Cytology
38.3 Ontogeny and Distribution
38.4 Cell Physiology
38.5 A Continuum of Subtypes
38.6 Expansion Coding in the Vestibulocerebellum
38.7 Potential Role of the Typical ON-UBC
38.8 Potential Role of the Typical OFF-UBC
38.9 Preserving Identity of Input
38.10 Relevance for Disease
38.11 Conclusions
References
39: Distributed Plasticity in the Cerebellar Circuit
39.1 Introduction
39.2 Evidence for Distributed Cerebellar Plasticity during Behavior
39.3 Distributed Plasticity in Computational Models
39.4 Conclusions
References
Part V: Basic Physiology
40: Simple Spikes and Complex Spikes
40.1 Simple and Complex Spikes
40.1.1 Simple Spikes Occur at High Rates and Are Driven in Part by Intrinsic Pacemaking
40.1.2 Complex Spikes Occur in Response to Climbing Fiber Input
40.1.3 Complex Spikes Transiently Inhibit Simple Spike Firing
References
41: Rebound Depolarizations
41.1 Rebound Depolarization in Response to Purkinje Cell Input
41.1.1 Rebound Responses
41.1.2 Ionic Basis for Rebound Responses
41.2 Rebound Depolarizations Encode Purkinje Cell Input Patterns
References
42: Cerebellar Nuclei
42.1 Basic Physiology of CN Neurons
42.1.1 Cellular Physiology
42.1.2 Synaptic Physiology and Synaptic Plasticity
42.2 The Control of CN Spiking Output by Input Rates and Patterns
42.3 A View at CN Function
42.3.1 Behavioral Correlates of CN Activity Changes
42.3.2 Multiple Functional Areas in the CN and Microzonal Organization
42.3.3 Output of the CN Is Split into Distinctive Pathways
References
43: Plasticity of the Cerebellum
43.1 Parallel Fiber LTD
43.2 Parallel Fiber LTP
43.3 Climbing Fiber LTD
43.4 Interneuron-Purkinje Cell Synaptic LTP
43.5 Plasticity of Mossy Fiber-Granule Cell Synapses
43.6 Plasticity in the Deep Cerebellar Nuclei (DCN)
43.7 Plasticity of Intrinsic Excitability in Purkinje Cells
43.8 Spike–Timing-Dependent Plasticity (STDP) in the Cerebellum
43.9 Conclusions
References
44: Long-Term Depression at Parallel Fiber–Purkinje Cell Synapses
44.1 Introduction
44.2 LTD-Dependent Endocytosis of AMPA Receptors
44.3 Optogenetic Control of Cerebellar LTD
44.4 Unique Features of Cerebellar LTD
References
45: Regulation of Calcium in the Cerebellum
45.1 Ca2+ Signaling Is Essential for Cerebellar Function
45.2 Membrane Proteins that Mediate Ca2+ Influx to the Cytosol
45.3 Cytosolic and Membrane Proteins that Regulate Ca2+ Levels in the Cytosol
45.4 Ca2+ and Disease
45.5 Summary
References
46: Neurotrophic Factors in Cerebellar Development and Function
46.1 Introduction
46.1.1 Neurotrophin Effects on Proliferation of Cerebellar Granule Cell Progenitors
46.1.2 Neurotrophins Promote Survival of Different Cerebellar Neurons
46.1.2.1 Granule Cells
46.1.2.2 Purkinje Cells
46.1.3 Neuronal Migration
46.1.4 Effects of Neurotrophins on Differentiation of Cerebellar Neurons
46.1.4.1 Purkinje Cell Differentiation
46.1.4.2 BDNF/TrkB in Granule Cell Differentiation
46.1.5 Effects of Neurotrophins in Cerebellar Circuit Establishment and Maintenance
46.1.5.1 BDNF/TrkB in Climbing Fiber Maturation
46.1.5.2 p75NTR in Adult Cerebellum
46.1.5.3 Cerebellar Interneurons
References
47: The Cerebellar Neuroimmune System
47.1 The Neuroimmune System of the Cerebellum
47.2 Neuroimmune Factors
47.3 Evidence for Expression of Neuroimmune Factors and their Receptors in the Cerebellum
47.4 Neuroimmune Factors and Cerebellum Function
47.5 The Neuroimmune System and Cerebellum and Disease
References
48: Restoring a Loss of Mossy Fiber Plasticity in a Model of Fragile X Syndrome
48.1 Introduction
48.2 Results
48.2.1 FMRP Expression in Wild-Type Mice and a Fragile X Model
48.2.2 An FMRP-Tat Conjugate Peptide Delivered In Vivo Restores LTP of Mossy Fiber Inputs
48.3 Discussion
48.3.1 Restoring FMRP in Fragile X Syndrome
48.3.2 Role of FMRP in Synaptic Plasticity
References
Part VI: Neuroimaging of the Cerebellum
49: Cerebellar Closed Loops
49.1 Histological Tracing in Animal Models
49.2 Functional Neuroimaging Data
49.2.1 Cerebellar Subregional Connectivity
49.2.2 Cerebellar Circuits
49.3 Conclusion
References
50: MRI Aspects: Conventional, SWI, and DTI
50.1 Introduction
50.2 Brief Description of Magnetic Resonance Imaging (MRI) Sequences
50.3 T1-Weighted MRI Images
50.4 T2-Weighted, Proton Density (PD)-Weighted, and FLAIR MRI Images
50.5 T2*-Weighted MRI Images
50.6 DTI Images
50.7 Conclusions and Outlook
References
51: SPECT and PET
51.1 Technical Aspects of SPECT and PET
51.2 Cerebellar Regional Blood Flow (rCBF)
51.3 Cerebellar Glucose Metabolism
51.4 Cerebellar Receptor Binding
References
52: MR Spectroscopy
52.1 Introduction
52.2 Normal Metabolic Profile of Cerebellum
52.3 MR Spectroscopy in Cerebellar Ataxias
52.4 MRS of Cerebellum in Other Neurological Diseases
52.5 MRS of Cerebellum in Psychiatric Disorders
References
53: Functional Topography of the Human Cerebellum
53.1 Introduction
53.2 Neuroanatomical Connections
53.3 Vestibular Cerebellum
53.4 Sensorimotor Cerebellum
53.5 Cognitive/Affective Cerebellum
53.6 Summary
References
54: fMRI-Based Anatomy: Mapping the Cerebellum
54.1 Introduction
54.2 Three Functional Subdivisions: Motor, Attentional/Executive (Task-Positive), and Default-Mode (Task-Negative)
54.3 Anatomical Order in Cerebellar Cortex
54.4 Functional Order in Cerebellar Cortex
54.5 Special Cases: Emotion, Vestibular, Language, and Social Processing
54.6 Recent Trends and Future Directions
54.7 Conclusion
References
Part VII: Functional Properties of the Cerebellum
55: Cerebro-Cerebellar Networks
55.1 Neurophysiology of Cerebello-Cortical Circuits
55.2 Conclusions
References
56: Clinical Functional Topography in Cognition
56.1 The Cerebellar Cognitive Profile
56.2 Laterality Effects
56.3 Vascular Territory Effects
56.4 Deep Cerebellar Nuclei Effects
56.5 Lobular Distribution of Impairments in Performance
56.6 Cerebello-Cerebral Network-Based Impairments in Performance
56.7 Conclusions
References
57: Sequencing
57.1 Cerebellar Damage and Learning of Searching Sequences
References
58: Speech and Language
58.1 Introduction
58.2 Motor Speech Production: Planning and Coordination of Articulatory Movements
58.3 Verbal Fluency and Lexical/Semantic Retrieval
58.4 Syntax Impairment
58.5 Aphasia
58.6 Acquired and Developmental Dyslexia
58.7 Peripheral and Central Agraphia
58.8 Conclusion
References
59: Theory of Mind and Cerebellum
59.1 Introduction
59.2 Cerebro-Cerebellar Circuits Related to ToM Functions
59.3 Cerebrocerebellar Circuits Underpinning Social Sequencing and Prediction
59.4 Theory of Mind Impairment Driven by Cerebellar Structural and Functional Alterations: A Focus on the Clinic
59.4.1 Cerebellar Diseases
59.4.2 Insight from Neurodegenerative, Psychiatric, and Neurodevelopmental Conditions
59.5 Conclusion
References
60: Cerebellum and Decision-Making
60.1 Decision-Making
60.2 The Cerebellum Is Part of a Large Network Involved in Decision-Making
60.3 Human Data Indicates a Role for the Cerebellum in Decision-Making
60.4 Neuronal Mechanisms of Cerebellar Involvement in Decision-Making
60.5 Discussion
60.6 Conclusion
References
Part VIII: Cellular and Animal Models of Cerebellar Disorders
61: The Zebrafish Cerebellum
61.1 Introduction
61.2 The Cerebellar Anatomy and Architecture
61.3 Cerebellar Development and Neurogenesis
References
62: The Teleost Fish
62.1 Morphology, Cellular Organization, and Neural Circuits of the Teleost Cerebellum
62.2 Efferent Neurons of the Teleost Cerebellum
62.3 Afferent and Efferent Fiber Connections
62.4 Functions of the Teleost Cerebellum
References
63: Lurcher Mouse
63.1 Introduction
63.2 Morphological Changes in the Lurcher Mutant Central Nervous System
63.3 Pathogenesis of the Neurodegeneration in Lurcher Mice
63.4 Functional Impairments
63.4.1 Motor Functions
63.4.2 Cognitive and Behavioral Abnormalities
63.5 Concluding Remarks
References
64: The Tottering Mouse
64.1 Introduction
64.2 Tottering Mouse: A Calcium Channelopathy
64.3 Tottering Behavioral Phenotype
64.4 P/Q-Type Ca2+ Channel and Cerebellar Dysfunction
64.5 Beyond P/Q-Type Channels
64.6 Effectiveness of EA2 Therapies in the Tottering Mouse
64.7 Conclusion
References
65: The Rolling Nagoya Mouse
65.1 Rolling Nagoya Phenotype
65.2 The Rolling Nagoya Mutation Resides in Cacna1a-Encoded CaV2.1 Ion Channels
65.3 Rolling Nagoya Brain Morphology
65.4 Effect of the Rolling Nagoya Mutation on the Electrophysiology of CaV2.1 Channels and Neuronal Function
65.5 Relevance of the Rolling Nagoya Mouse to Human CaV2.1 Channelopathies?
References
66: Lesions of the Cerebellum
66.1 Hemicerebellectomy
66.2 Effects of Cerebellar Lesion on Precerebellar Nuclei: Inferior Olive and Pontine Nuclei
66.3 HCb and Postlesional Structural Plasticity
66.4 Effects of Cerebellar Lesion Performed at Different Developmental Stages
66.5 Conclusions
References
67: The Staggerer Mouse: RORα Deficiency Induces Cerebellar Neurodegeneration
67.1 The Staggerer Mouse
67.1.1 RORα and Spinocerebellar Ataxia
67.2 The Heterozygote Staggerer
67.3 Conclusion
References
68: Alcohol and the Cerebellum
68.1 Introduction to the Cerebellum and Alcohol
68.2 The Cerebellum is a Highly Alcohol-sensitive Brain Region
68.2.1 Human Clinical and Rodent Pre-clinical Studies Highlight the Cerebellum as a Brain Region That Is Uniquely Sensitive to the Pharmacological Effects of Alcohol That Likely Mediates Many Behavioral Effects of Moderate Recreational Alcohol Cons
68.2.2 The Cerebellum Is a Common and Dominant Site of Brain Damage in People with Alcohol Use Disorder (AUD)
68.2.3 The Cerebellum Is a Dominant Site of Brain Damage Underlying Fetal Alcohol Spectrum Disorder (FASD)
68.3 The Cerebellum and Genetic Risk for Developing AUD
68.3.1 Cerebellar Anatomy and Physiology in Humans with Genetic Risk for 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
68.3.3 Genetic Differences in Cerebellar Cellular Responses to Alcohol Correlate with, and likely Contribute to the Level of Alcohol Consumption in Animal Models
68.4 Summary
References
69: Moonwalker Mouse
69.1 Introduction
69.2 Mwk Mice Harbour a Mutation in the TRPC3 Channel
69.3 Mwk Mice Display Overt Cerebellar Ataxia
69.4 Loss of TRPC3-Expressing Neurons in the Mwk Cerebellum
69.5 The Mwk Mutation Decreases PC Dendritic Complexity and Impairs Synaptic Wiring
69.6 The Mwk Mutation Disrupts TRPC3-Mediated Synaptic Transmission and PC Spiking
69.7 The mGluR1-TRPC3 Pathway Is a Common Pathogenic Pathway Underlying Cerebellar Ataxia
69.8 Conclusion
References
Part IX: Human Cerebellar Symptoms: From Movement to Cognition
70: Cerebellum and Oculomotor Deficits
References
71: Speech Disorders
71.1 Introduction
71.2 Ataxic Dysarthria
71.3 Main Features of Ataxic Dysarthria
71.4 Different Types of Dysarthria in Different Cerebellar Pathologies
71.5 Dysprosody, Foreign Accent Syndrome and Stuttering
71.6 Cerebellar Mutism
71.7 Disorders of Covert Articulation in Cerebellar Damage
71.8 Neural Substrates of Ataxic Dysarthria
71.9 The Cerebellar “Internal Model” of Movements and the Cerebellar “Timing System” in Speech Production and Speech Sounds/Phonemes Discrimination
References
72: Deficits of Limbs Movements
72.1 Introduction
72.2 Dysmetria: Hypermetria and Hypometria
72.3 Cerebellar Tremor
72.4 Decompositions of Movement
72.5 Dysdiadochokinesia and Dysrhythmokinesia
72.6 Loss of Check and Rebound
72.7 Disorders of Muscle Tone: Hypotonia and Cerebellar Fits
72.8 Isometrataxia
72.9 Handwriting Abnormalities and Megalographia
72.10 Clinical Examination of Limbs Movements
References
73: The Three Cornerstones of the Cerebellar Syndrome
73.1 Introduction: Main Steps of the History of Cerebellar Research Leading to the Current View on Ataxiology
73.2 Neuroanatomical and Functional Basic Underpinning the Three Domains of Cerebellar Ataxiology
73.2.1 General Considerations
73.2.1.1 Cerebellar Macro-/Micro-anatomy, Internal Models and the Segregated Functional Organization
73.2.1.2 Cerebellar Microcomplexes: The Elemental Anatomo-Functional Units
73.2.1.3 How Does the Cerebellum Operate? Predictions and Internal Models
73.2.2 Three Domains for Three Specific Loops
73.2.2.1 Connectional Anatomy of the CMS
73.2.2.2 Connectional Anatomy of the VCS
73.2.2.3 Connectional Anatomy of the CCAS/SS
73.3 The Three Pillars from a Clinical Perspective in Daily Practice
73.3.1 The CMS
73.3.2 The VCS
73.3.3 The CCAS/SS
73.4 Rating Scales of Cerebellar Syndrome
73.5 Conclusion
References
74: Lesion-Symptom Mapping
74.1 Introduction
74.2 “Pure” Human Cerebellar Lesion Conditions
74.2.1 Cerebellar Stroke
74.2.2 Cerebellar Tumors
74.2.3 Cerebellar Degeneration
74.3 Lesion-Symptom Mapping in Focal Cerebellar Disease
74.3.1 Lesion Delineation
74.3.2 Lesion Normalization
74.3.3 Descriptive Statistical Analysis
74.3.4 Inferential Statistical Analysis
74.4 Lesion-Symptom Mapping in Cerebellar Degeneration
74.5 Atlases of the Cerebellum in Stereotaxic Space
74.6 Limitations
References
75: The Cerebellar Cognitive Affective Syndrome and the Neuropsychiatry of the Cerebellum
75.1 The Initial Description
75.2 Subsequent Reports
75.3 The Cerebellar Cognitive Affective Syndrome in Children
75.4 Postoperative Pediatric Cerebellar Mutism Syndrome (CMS)
75.5 Neuropsychiatry of the Cerebellum; The Affective Component of the CCAS
75.6 Cognition in Ataxic Disorders
75.7 Cerebellar Lesions Impair Cognition in the Developing Brain
75.8 Clinical Implications
References
76: Ataxia Scales for the Clinical Evaluation
76.1 Introduction
76.2 International Cooperative Ataxia Rating Scale (ICARS)
76.3 Friedreich Ataxia Rating Scale (FARS)
76.4 Scale for the Assessment and Rating of Ataxia (SARA)
76.5 Brief Ataxia Rating Scale (BARS)
76.6 Unified Multiple System Atrophy Rating Scale (UMSARS)
References
77: The Ataxic Gait
77.1 Introduction
77.2 Anatomical and Functional Substratum of Ataxic Gait
77.2.1 The Neuroanatomical Basis of Balance and Gait
77.2.2 Functional Role of Cerebellum and Its Implication in Ataxic Gait: Internal Models
77.3 Assessment of Ataxic Gait
77.3.1 Clinical Assessment
77.3.2 Paraclinical Assessment of Ataxic Gait
77.4 Ataxic Gait in Specific Disorders of the Cerebellum
77.5 Current Therapies to Compensate Ataxic Gait
77.6 Conclusions
References
78: The Social Cerebellum and Human Interactions
78.1 The Social Sequencing Function of the Posterior Cerebellar Crus 2
78.2 Clinical Implications
78.3 Non-invasive Brain Stimulation
References
Part X: Human Cerebellar Disorders: From Prenatal Period to Elderly
79: Genetics and Differential Diagnosis of Cerebellar Ataxias
79.1 Introduction
79.2 Inheritance and Genetics
79.3 Clinical Phenotypes and Age at Onset
79.4 Congenital Ataxias
79.5 Cerebellar Ataxias in Infancy and Young Children (<2 years)
79.6 Cerebellar Ataxias in Childhood, Adolescence, and Young Adulthood
79.7 Late-Onset Cerebellar Ataxias
References
80: Overview of Ataxia in Childhood
80.1 Diagnostic Work-Up
80.2 Acute Ataxia
80.3 Non-progressive Ataxia
80.4 Progressive Ataxia
80.5 Intermittent Ataxia
80.6 Episodic Ataxia
References
81: Cerebellar Pathology in Autism
References
82: Cerebellar Pathology in Schizophrenia, Bipolar Disorder, and Major Depression
References
83: Autosomal Recessive Ataxias
83.1 Introduction
83.2 Pathophysiology
83.3 Diagnostic Approach
83.4 Clinical Presentation
83.5 Rare Recessive Ataxias with Targeted Treatments
83.6 Conclusion
References
84: X-Linked Ataxias
84.1 Introduction
84.1.1 Fragile X-Associated Tremor Ataxia Syndrome (FXTAS)
84.1.2 X-Linked Sideroblastic Anemia with Ataxia (XLSA)
84.1.3 X-Linked Ataxia Due to GJB1 Mutations
84.1.4 Spinocerebellar Ataxia Due to PMCA3 Mutations
84.1.5 X-Linked Adrenoleukodystrophy
84.1.6 X-Linked Pyruvate Dehydrogenase (PDH) Deficiency
84.1.7 X-Linked Ataxias with Ataxia as a Non-dominant Feature
84.2 Management
84.3 Conclusion
References
85: Imaging of Malformations of the Hindbrain and Craniocervical Junction
85.1 Introduction
85.2 Cerebellar Hypoplasia
85.3 Rhombencephalosynapsis
85.4 Molar Tooth Malformations
85.5 Lhermitte–Duclos–Cowden Syndrome
85.6 Dandy–Walker Complex
85.7 Chiari Malformations
85.7.1 Chiari I Malformation
85.7.2 Chiari II Malformation
85.7.3 Chiari III Malformation
References
86: Cerebellar Stroke
86.1 Introduction
86.2 Clinical Features
86.3 Cerebellar Infarction
86.3.1 Mechanism
86.3.2 Diagnosis
86.3.3 Space-Occupying Infarction
86.3.4 Treatment
86.4 Cerebellar Hemorrhage
References
87: Immune-Mediated Cerebellar Ataxias
87.1 Introduction
87.2 Postinfectious Cerebellitis
87.3 Miler Fisher Syndrome
87.4 Anti-GAD Ataxia
87.5 Anti-VGCC Ataxia, Anti-mGluR1 Ataxia, Anti-GluR Delta Ataxia: LTDpathies
87.6 Anti-Caspr2 Ataxia and Anti-DPPX Ataxia
References
88: Paraneoplastic Cerebellar Syndrome
88.1 Introduction
88.2 Autoantibodies
88.2.1 Antibodies Binding to Intracellular Antigens
88.2.1.1 High-Risk Antibodies
Yo/PCA-1
Hu/ANNA-1
Ri/ANNA-2
CRMP5/CV2
Ma and Ma2
Amphiphysin
AGNA/SOX1
ANNA-3
KLHL11
88.2.1.2 Unknown-Risk Antibodies
Ca/ARHGAP26/GRAF1
CARP VIII
PKC Gamma
ZIC4
PCA-2/MAP1B
TRIM9 and TRIM67
NIF
88.2.1.3 Other Autoantibodies
88.2.2 Antibodies Binding to Plasma-Membrane Antigens
88.2.2.1 High-Risk Antibodies
Tr/DNER
88.2.2.2 Intermediate-Risk Antibodies
VGCC
88.2.2.3 Low-Risk Antibodies
mGluR1
CASPR2
88.2.2.4 Unknown-Risk Autoantibodies
88.3 Clinical Characteristics and Diagnosis
88.4 Treatment and Prognosis
References
89: Essential Tremor
89.1 Introduction
89.2 Epidemiology
89.3 Etiology
89.4 Pathobiology
89.5 Clinical Features
89.6 Treatment
89.7 Conclusions
References
90: Toxic Agents
90.1 Ethanol Intake
90.2 Drugs
90.2.1 Anticonvulsants
90.2.1.1 Phenytoin
90.2.1.2 Carbamazepine
90.2.1.3 Other Anticonvulsants
90.2.2 Antineoplastics
90.2.2.1 5-FU and Capecitabine
90.2.2.2 Ara-C (Cytarabine)
90.2.2.3 Methotrexate
90.2.2.4 Immune Checkpoint Inhibitors
90.2.3 Other Drugs
90.2.3.1 Lithium Salts
90.2.3.2 Amiodarone
90.2.3.3 Calcineurin Inhibitors
90.2.3.4 Metronidazole
90.2.3.5 Statins
90.2.4 Drug Abuse and Addiction
90.2.4.1 Cocaine
90.2.4.2 Heroin
90.2.4.3 Herbs
90.2.4.4 Methadone
90.3 Environment
90.3.1 Metals
90.3.1.1 Mercury
90.3.1.2 Lead
90.3.1.3 Gadolinium
90.3.1.4 Thallium
90.3.2 Toluene/Benzene Derivatives
90.3.3 Hyperthermia
90.3.4 Chemical Weapons
90.3.5 Insecticides/Herbicides/Pesticides
90.3.6 Others
90.3.6.1 Saxitoxin (Shellfish Poisoning)
90.4 Animal-Related Cerebellar Toxicity
90.4.1 Scorpions
References
91: Endocrine Disorders
91.1 Thyroid Disorders
91.1.1 Hypothyroidism
91.1.2 Hyperthyroidism
91.1.3 Hashimoto Thyroiditis and Ataxia
91.1.4 Drug-Induced Thyroid Dysfunction
91.2 Parathyroid Disorders
91.2.1 Hypoparathyroidism
91.2.2 Pseudohypoparathyroidism and Pseudopseudohypoparathyroidism
91.2.3 Hyperparathyroidism
91.3 Cerebellar Ataxia and Diabetes
91.3.1 Friedreich Ataxia
91.3.2 Anti-GAD Antibodies
91.3.3 Autoimmune Polyglandular Syndromes
91.3.4 Aceruloplasminemia
91.4 Cerebellar Ataxia and Hypogonadism
91.5 Cerebellum and Steroid Hormones
91.6 Conclusions
References
92: Friedreich Ataxia
92.1 Introduction
92.2 Clinical Presentation
92.3 Neurophysiological Investigations
92.4 Neuroimaging
92.5 Genetics
92.6 Biochemistry
92.7 Neuropathology and Pathology of the Heart
92.8 Differential Diagnosis
92.9 Treatment
92.10 Conclusion and Future Directions
References
93: Ataxia Telangiectasia
93.1 Introduction
93.2 Genetics and Molecular Biology
93.3 Neuropathology
93.4 Neurological Features
93.5 Monitoring Neurological Status
93.6 Non-neurological Features
93.7 Therapeutic Approaches
93.8 Ongoing Trials and Future Directions
93.9 Conclusion
References
94: Neuroimmune Mechanisms of Cerebellar Ataxias
94.1 Introduction
94.2 Neural Damage Induced by Cell-Mediated Autoimmunity
94.2.1 Clinical Profile and Treatment of Paraneoplastic Syndrome
94.2.2 Cell-Mediated Mechanisms of Paraneoplastic Syndrome
94.2.3 Augmented Cancer-Immunity Cycle in Paraneoplastic Syndrome
94.3 Neural Dysfunction Induced by Autoantibody-Mediated Autoimmunity
94.3.1 Significance of Associated Autoantibodies
94.3.2 Anti-GAD Antibody and Anti-GAD Ataxia
94.3.3 Anti-VGCC, mGluR1, and GluR Delta Antibodies and LTDpathy
94.3.4 Autoantibodies-Induced Dysfunction of Online Predictive Controls and Cerebellar Reserve
94.4 Cooperation of Cell- and Antibody-Mediated Mechanisms
94.5 Conclusion
References
95: Primary Autoimmune Cerebellar Ataxia (PACA)
95.1 Introduction
95.2 Diagnosis
95.3 Prevalence
95.4 Clinical Characteristics and Treatment
95.5 Conclusions
References
96: Gluten Ataxia
96.1 Introduction
96.2 Diagnosis and Prevalence
96.3 Clinical Characteristics and Treatment
96.4 Pathophysiology
96.5 Conclusions
References
97: Cerebrotendinous Xanthomatosis
97.1 Introduction
97.2 Clinical Description in Children
97.3 Clinical Description in Adults
97.4 Normal Bile Acid Synthesis
97.5 Bile Acid Synthesis in CTX
97.6 Investigations
97.6.1 Diagnostic Tests
97.6.2 Other Investigations
97.7 Management
97.7.1 Pregnancy
97.7.2 Neonatal Period
97.7.3 Recommendations
References
98: Cerebellar Variant of Multiple System Atrophy (MSA-C)
98.1 Introduction
98.2 Prevalence
98.3 Clinical Characteristics
98.4 Diagnosis
98.5 Progression and Prognosis
98.6 Pathogenesis
98.7 Management
98.8 Conclusions
References
99: Cerebellar Tumors
99.1 Introduction
99.2 Cerebellar Tumors in Children
99.3 Cerebellar Tumors in Adults
99.4 Treatment of Cerebellar Tumors: An Overview
References
100: Post-traumatic Cerebellar Syndromes
100.1 Introduction
100.1.1 Clinical Presentation
100.1.2 Type of Traumas
100.1.3 Localization of Lesions
100.2 Direct Cerebellar Injuries
100.2.1 Axotomy
100.2.2 Stab Injury
100.2.3 Stretch Injury
100.2.4 Blast Injury
100.3 Indirect Cerebellar Injuries
100.3.1 Mechanical Forces
100.3.2 Metabolic Changes
100.3.3 Presynaptic Hyperexcitability
100.4 Common Cellular Mechanisms
100.4.1 Excitotoxicity and Differential Gene Expression
100.4.2 Inflammatory Response
100.4.3 Axonal Degeneration
100.5 Cerebro-Cerebellar Connections
100.6 Management
100.7 Conclusion
References
101: Superficial Siderosis
101.1 Introduction
101.2 Classification and Etiology
101.2.1 Infratentorial SS (iSS)
101.2.2 Cortical SS (cSS)
101.3 Symptoms
101.3.1 Infratentorial SS (iSS) Symptoms
101.3.2 Cortical SS (cSS) Symptoms
101.4 Imaging
101.5 Dural Defects as a Cause of SS
101.6 Treatment
101.7 Conclusion
References
102: Ataxia in Multiple Sclerosis
102.1 Introduction
102.2 Ataxia in Motor Control
102.3 Ataxia and Motor Learning
102.4 Assessment of Ataxia
102.5 Non-invasive Brain Stimulation Studies to Assess Ataxia or Improve Symptoms
102.6 Suggestions and Concluding Remarks
References
103: CANVAS
103.1 Introduction
103.2 Clinical Presentation
103.3 Neurophysiological Investigations
103.4 Neuroimaging
103.5 Genetics
103.6 Neuropathology
103.7 Differential Diagnosis
103.8 Treatment
103.9 Conclusion and Future Directions
References
104: Spastic Paraplegia Type 7 (SPG7)
104.1 Introduction
104.2 The SPG7 Gene and Transcript
104.3 Clinical Presentation
104.4 Diagnosis and Management
References
Part XI: Therapies of Cerebellar Ataxias
105: Drugs in Selected Ataxias
105.1 Introduction
105.2 Treatable Causes of Ataxia
105.2.1 Vitamin Deficiency
105.2.2 Metabolic Disorders
105.2.3 Endocrine Disorders
105.2.4 Autoimmune Disorders
105.3 Friedreich’s Ataxia
105.4 Symptomatic Treatment of Ataxias
105.5 Aminopyridines
105.6 Conclusions
References
106: Cerebellar Stimulation
106.1 Introduction
106.2 Transcranial Magnetic Stimulation (TMS)
106.3 Transcranial Direct Current Stimulation (tDCS)
References
107: Motor Rehabilitation of Cerebellar Disorders
107.1 Introduction
107.2 General Predictions of Functional Recovery
107.3 Ataxia-Specific Impairments and Rehabilitation Strategies
107.3.1 Motor Impairments
107.3.2 Motor Rehabilitation
107.4 Discussion
107.4.1 Current Praxis of Motor Rehabilitation
107.4.2 Open Questions
107.4.2.1 Motor Rehabilitation for Upper Extremities and Speech
107.4.2.2 Studies on Mechanisms of Motor Learning and Rehabilitation
References
108: Editing the Genome
108.1 Introduction: Definition of Cerebellar Ataxias and Their Mechanisms with an Emphasis on Polyglutaminopathies
108.2 Definition of Genome Editing
108.3 Experimental Studies of Genome Editing in Cerebellar Ataxias (In Vitro Studies, In Vivo Studies)
108.3.1 ASOs
108.3.2 RNAi
108.3.3 CRISPR
108.3.4 Other Technologies in Development
108.4 Conclusion and Perspectives
References
109: Grafting
109.1 Introduction
109.2 Goal of Neurotransplantation Therapy
109.3 Graft Types and Mechanisms of Their Effect
109.4 Host Tissue Factors Determining Graft Survival, Development and Functional Integration
109.5 Conclusion
References
110: Cerebellar Reserve
110.1 Definition of Cerebellar Reserve
110.2 Clinical Course and Cerebellar Reserve
110.2.1 Structural Cerebellar Reserve
110.2.2 Functional Cerebellar Reserve
110.3 Neural Mechanisms Underlying Cerebellar Reserve
110.3.1 Redundant Afferents to Microzone
110.3.2 Multiple Forms of Synaptic Plasticity
110.4 Molecular Mechanisms Underlying Cerebellar Reserve
110.5 Cerebellar Reserve-Based Therapeutic Strategies
110.5.1 General Principle
110.5.2 Neuromodulation Therapies for Potentiation of Cerebellar Reserve
110.5.3 Biomarkers for Early Intervention
110.6 Conclusion
References
Index