Mechanisms and Emerging Therapies in Tremor Disorders (Contemporary Clinical Neuroscience)

Foreword
Contents
1 Definition of Tremor
	1.1 Introduction
	1.2 Types of Tremor
		1.2.1 Differential Diagnosis Between Tremor and the Other Involuntary Disorders
		1.2.2 Sources of Tremor
	References
2 Membrane Mechanisms of Tremor
	2.1 Background
	2.2 Outline
	2.3 Membrane Mechanisms of Essential Tremor
		2.3.1 Membrane Oscillations in Thalamic Neurons
		2.3.2 Membrane Oscillations in the Inferior Olive Neurons
		2.3.3 Thalamic and Inferior Olive Oscillations and Relation to Harmaline Model of Tremor
		2.3.4 Synchronization of Isolated Neuronal Oscillations
			2.3.4.1 Neuronal Coupling in Thalamus
			2.3.4.2 Experimental and Computational Evidence of Thalamic Coupling as a Cause of Tremor
			2.3.4.3 Other Causes of Thalamic Neuronal Excitability in Essential Tremor
			2.3.4.4 Neuronal Coupling in Inferior Olive
			2.3.4.5 Influence of Cerebellum and Conditional Learning on Synchronized Inferior Olive Discharge and Tremor
		2.3.5 Membrane Electrophysiology and Essential Tremor Frequency
		2.3.6 Pharmacotherapy of Tremor Supports the Membrane Hypothesis for Essential Tremor
			2.3.6.1 Beta-Blockers and Membrane Physiology of Tremor
			2.3.6.2 Anti-Seizure Drugs and Membrane Physiology of Tremor
			2.3.6.3 Membrane Physiology of Tremor and Alcohol
	2.4 Membrane Physiology and Tremor of Parkinson's Disease
	2.5 Membrane Physiology in Drug-Induced Tremor
		2.5.1 Valproate-Induced Tremor
		2.5.2 Lithium-Induced Tremor
		2.5.3 Neuroleptic-Induced Tremor
		2.5.4 Tremor in Hyperthyroidism
		2.5.5 Caffeine-Induced Tremor
		2.5.6 Tremor Induced by Adrenergic Agonists
	2.6 Membrane Mechanisms in Pathogenesis of Acquired Pendular Nystagmus and Saccadic Oscillations
		2.6.1 Membrane Mechanisms for APN in MS
		2.6.2 Membrane Mechanisms for Pathogenesis of APN in OPT
		2.6.3 Membrane Mechanisms for Pathogenesis of Saccadic Oscillations
	2.7 Summary and Future Directions
	References
3 Advances in the Genetics of Human Tremor
	3.1 Introduction
	3.2 Genetics of Parkinson's Disease
		3.2.1 Autosomal Dominant PD
			3.2.1.1 SNCA
			3.2.1.2 LRRK2
			3.2.1.3 VPS35
		3.2.2 Autosomal Recessive PD
			3.2.2.1 PRKN
			3.2.2.2 PINK1
			3.2.2.3 PARK7
		3.2.3 Other Genes Linked to Monogenic PD Forms
		3.2.4 Susceptibility Genes
			3.2.4.1 GBA
	3.3 Genetics of Essential Tremor
		3.3.1 Linkage Studies
		3.3.2 Whole-Genome and Exome Sequencing Studies
		3.3.3 GWASs
	3.4 Tremor in Ataxias
		3.4.1 SCA2 and SCA3
		3.4.2 SCA7
		3.4.3 SCA12
		3.4.4 SCA15 and SCA16
		3.4.5 SCA20
		3.4.6 SCA27
		3.4.7 Fragile X-Associated Tremor/Ataxia Syndrome
		3.4.8 Others
	3.5 Familial Cortical Myoclonic Tremor with Epilepsy
	3.6 Dystonic Tremor
		3.6.1 Dominant Dystonias
		3.6.2 Recessive Dystonias
	3.7 Roussy–Lévy Syndrome
	3.8 Wilson's Disease
	3.9 Conclusions
	References
4 Two Origins of Tremors Related to the Guillain-Mollaret Triangle: The Forward Model-Related Tremor and the Inferior Olive Oscillation-Related Tremor
	4.1 Introduction
	4.2 Physiological Backgrounds of Two Types of Tremors
		4.2.1 Two Loop Circuitries in the Dentato-rubro-olivary (Guillain-Mollaret (G-M)) Triangle and Their Functions
			4.2.1.1 Physiology of the Short Loop
			4.2.1.2 Physiology of the Long Loop
		4.2.2 Physiological Operation of the Short Loop
			4.2.2.1 A Putative Servo-Like Mechanism to Limit the Synchrony of IO Cells
		4.2.3 Physiological Operation of the Long Loop: The Cerebrocerebellum as Loci of Forward Models
			4.2.3.1 System Identification of the Transformation in the Cerebrocerebellum: Its Similarity to the Kalman Filter
		4.2.4 Interaction Between the Two Loops
	4.3 Generation of Two Types of Tremors
		4.3.1 Failure of the Short Loop Results in Regular Oscillatory Tremors
		4.3.2 Generation of Irregular Tremor-Like Movement and Its Relevance to the Forward Model Hypothesis of the Cerebellum
	4.4 Impairments in the G-M Triangle
		4.4.1 Disruptions of the Two Loops in the G-M Triangle
		4.4.2 Disinhibition of IO as a Pathophysiological Mechanism for Regular Tremors and Its Implication for ET
		4.4.3 Reorganization and Maladaptation in the G-M Triangle
			4.4.3.1 Reorganization in the Short Loop
			4.4.3.2 Induction of Maladaptation Caused by Regular Tremors
	4.5 Consideration of Neuroimaging Studies
	4.6 Conclusion
	References
5 Physiologic Tremor
	5.1 Introduction
	5.2 Mechanical Resonant Tremor
	5.3 Mechanical-Reflex Tremor
	5.4 Central Neurogenic Tremor
	5.5 Enhanced Physiologic Tremor
	5.6 Low-Frequency Aperiodic Error
	5.7 Summary
	References
6 Rest Tremor
	6.1 Definition and Clinical Description
	6.2 Disorders Associated with Rest Tremor
	6.3 Pathophysiology of Rest Tremor
	6.4 Therapy of Rest Tremor
	References
7 Postural Tremors
	7.1 Introduction
	7.2 Postural Physiological Tremor
	7.3 Postural Enhanced Physiological Tremor
	7.4 Essential Tremor
	7.5 Relationships Between PT, EPT and ET
	7.6 Postural Parkinson's Disease Tremor
	7.7 Relationships Between ET and PD
	7.8 Conclusion
	References
8 Isometric Tremor
	8.1 Introduction
	8.2 Definition and Phenomenology of Isometric Tremor
	8.3 Diagnostic Pathways and Therapeutic Options in Isometric Tremor
		8.3.1 Isometric Tremor in Enhanced Physiological Tremor
			8.3.1.1 Pathophysiology
			8.3.1.2 Therapeutic Strategies
		8.3.2 Isometric Tremor in the Essential Tremor Syndrome
			8.3.2.1 Pathophysiology
			8.3.2.2 Therapeutic Strategies
		8.3.3 Isometric Tremor in Parkinson's Disease
			8.3.3.1 Pathophysiology
			8.3.3.2 Therapeutic Strategies
		8.3.4 Isometric Tremor in Cerebellar Disorders
			8.3.4.1 Pathophysiology
			8.3.4.2 Therapeutic Strategies
		8.3.5 Isometric Tremor in the Dystonic Tremor Syndrome
			8.3.5.1 Pathophysiology
			8.3.5.2 Therapeutic Strategies
		8.3.6 Isometric Tremor in the Holmes Tremor Syndrome
			8.3.6.1 Pathophysiology
			8.3.6.2 Therapeutic Strategies
		8.3.7 Isometric Tremor in the Orthostatic Tremor Syndrome
			8.3.7.1 Pathophysiology
			8.3.7.2 Therapeutic Strategies
	8.4 Conclusion
	References
9 Essential Tremor and Other Forms of Kinetic Tremor
	9.1 Kinetic Tremor: An Introduction
	9.2 Essential Tremor
		9.2.1 Essential Tremor or Essential Tremors?
		9.2.2 Etiology: Epidemiology and Genetics
		9.2.3 Pathophysiology
		9.2.4 Clinical Presentation and Natural History
		9.2.5 Diagnosis
	9.3 Other Kinetic Tremors
		9.3.1 Drug-Induced Kinetic Tremor
		9.3.2 Kinetic Tremor of Wilson's Disease
		9.3.3 Kinetic Tremor of Fragile X Tremor Ataxia Syndrome
		9.3.4 Kinetic Tremor in Patients with Peripheral Neuropathy
		9.3.5 Kinetic Tremor in Parkinson's Disease
		9.3.6 Primary Writing Tremor
		9.3.7 Rubral Tremor
	9.4 Kinetic Tremor: Conclusions
	References
10 Dystonic Tremor
	Abbreviations
	10.1 Introduction
	10.2 Classification of Tremors
		10.2.1 Dystonia and Tremor
			10.2.1.1 Historical Development of the Term
		10.2.2 Epidemiology
		10.2.3 Neurophysiological Assessment
	10.3 Treatment
	10.4 Conclusion and Outlook
	References
11 Cerebellar Lesions and Tremor
	11.1 Introduction
	11.2 Epidemiologic Data
	11.3 Pathophysiological Basis of Cerebellar Tremor
		11.3.1 Anatomy of the Cerebellum
		11.3.2 Role of the Cerebellum in Motor Learning
		11.3.3 Role of the Cerebellum in Various Tremor Syndromes
		11.3.4 Animal Experiments on Cerebellar Tremor
		11.3.5 Theories on Cerebellar Lesion Location and Tremor Genesis
	11.4 Neurophysiological Examination of Tremor
		11.4.1 Development of Quantitative Tremor Recording Devices: A Historical Overview
		11.4.2 Tremor Quantifying Parameters
		11.4.3 Tremor Recording and Analysis in Cerebellar Tremor
	11.5 Clinical Characteristics and Neurophysiological Aspects of Cerebellar Tremor
		11.5.1 Physiologic Tremor in Cerebellar Lesion
		11.5.2 Low Frequency Tremor in Cerebellar Lesion
		11.5.3 High Amplitude–Normal Frequency Tremor in Cerebellar Lesion
	11.6 Correlation of Imaging Data and Tremor Characteristics in Cerebellar Lesions
	11.7 Differential Diagnosis (Holmes Tremor, Cerebellar Atrophy, Toxin-Induced Cerebellar Disorders)
	11.8 Treatment and Recovery of Cerebellar Tremor
	References
12 Orthostatic Tremor
	12.1 Introduction
	12.2 Epidemiology
	12.3 Phenomenology and Clinical Features
		12.3.1 General Characteristics
		12.3.2 Clinical Examination
		12.3.3 Diagnosis
		12.3.4 Laboratory Workup
		12.3.5 Differential Diagnosis
		12.3.6 Severity Assessment and Health-Related Quality of Life in Orthostatic Tremor
	12.4 Secondary (Symptomatic) Orthostatic Tremor
	12.5 Pathophysiology
	12.6 Treatment
		12.6.1 General Considerations
		12.6.2 Pharmacological Agents
		12.6.3 Non-pharmacological Treatments
	12.7 Summary
	References
13 Posttraumatic Tremor and Other Posttraumatic Movement Disorders
	13.1 Introduction
	13.2 Classification of Posttraumatic Movement Disorders
	13.3 Trauma to the Central Nervous System
		13.3.1 Movement Disorders Following Traumatic Brain Injury
		13.3.2 Holmes and Other Tremors Following Traumatic Brain Injury
		13.3.3 Dystonia Following Traumatic Brain Injury
		13.3.4 Single Head Trauma, Parkinson's Disease, and Parkinsonism
		13.3.5 Pugilistic Parkinsonism, Dementia, and Chronic Traumatic Encephalopathy
		13.3.6 Hemiballismus, Tics, and Other Hyperkinetic Movement Disorders Following Traumatic Brain Injury
	13.4 Trauma to Peripheral Nervous System and Soft Tissues
		13.4.1 Peripherally Induced Tremor and Parkinsonism
		13.4.2 Peripherally Induced Limb Dystonia
		13.4.3 Complex Regional Pain Syndrome and Dystonia
		13.4.4 Posttraumatic Cervical and Shoulder Dystonia
		13.4.5 Other Forms of Peripherally Induced Dystonia
		13.4.6 Functional Movement Disorders Following Peripheral Trauma
		13.4.7 Pathophysiology of Peripherally Induced Tremor and Other Movement Disorders
		13.4.8 Other Peripherally Induced Movement Disorders
	13.5 Conclusions
	References
14 Tremor in Childhood
	14.1 Classification
	14.2 Examination of the Child with a Tremor
	14.3 Pathophysiology
	14.4 An Approach to the Diagnosis of Tremor in Childhood
	14.5 The Newborn
	14.6 Infants
		14.6.1 Inborn Errors of Dopamine Metabolism
		14.6.2 Vitamin B12 Deficiency
		14.6.3 Head Tremors of Infancy
		14.6.4 Shuddering Attacks
	14.7 Childhood and Beyond
		14.7.1 Enhanced Physiological Tremor
		14.7.2 Essential Tremor
		14.7.3 Drugs and Toxins
		14.7.4 Hydrocephalus
		14.7.5 Palatal Tremor
		14.7.6 Holmes Tremor Following Head Injury
		14.7.7 Wilson's Disease
		14.7.8 Hereditary Geniospasm
		14.7.9 Spinal Muscular Atrophy and Neuropathies
		14.7.10 Glut-1 Deficiency
		14.7.11 Segawa Disease
		14.7.12 Epilepsia Partialis Continua
		14.7.13 Familial Cortical Myoclonic Tremor with Epilepsy
		14.7.14 Task-Specific Tremors
		14.7.15 Gene Microdeletions and Microduplications
		14.7.16 Psychogenic Tremor
		14.7.17 Myogenic Tremor
	References
15 Metabolic Causes of Tremor
	15.1 Introduction to Metabolic Causes of Tremors
	15.2 Hypoglycemia
	15.3 Hyperthyroidism
	15.4 Pheochromocytoma
	15.5 Hepatic Encephalopathy
	15.6 Hyponatremia
	15.7 Hypomagnesemia
	15.8 Hypermanganesemia
	15.9 Primary Hyperparathyroidism and Hypoparathyroidism
	15.10 Vitamin B12 Deficiency
	15.11 Ataxia with Vitamin E Deficiency (AVED)
	15.12 Abetalipoproteinemia (Basssen-Kronzweig Syndrome)
	15.13 Cerebral Folate Deficiency (CFTD)
	15.14 Biotin-Thiamine-Responsive Basal Ganglia Disease (BTBGD)
	15.15 Niemann-Pick Type C (NP-C)
	15.16 Wilson's Disease
	15.17 Segawa Disease
	15.18 GLUT1 Deficiency Syndrome
	15.19 Cerebrotendinous Xanthomatosis (CTX)
	15.20 Arginase-1 Deficiency (ARG1D)
	15.21 Biotinidase Deficiency (BTD)
	References
16 Tremor: The Clinical Approach to Reach the Diagnosis
	16.1 Introduction
	16.2 History
	16.3 Location
	16.4 Tremor Characteristics
	16.5 Exam
	16.6 Rest Tremor
		16.6.1 PD and Other Parkinsonian Disorders
	16.7 Action Tremor
		16.7.1 ET
		16.7.2 Enhanced Physiologic Tremor
		16.7.3 Dystonic Tremor
	16.8 Mixed Tremor
		16.8.1 Drug-Induced Tremor
		16.8.2 Neuropathic Tremor
		16.8.3 Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
		16.8.4 Holmes Tremor
		16.8.5 Wilson's Disease
	16.9 Focal Tremor
		16.9.1 Voice Tremor
		16.9.2 Head Tremor
		16.9.3 Palatal Tremor
		16.9.4 Jaw Tremor
		16.9.5 Orthostatic Tremor
	16.10 Task-Specific Tremor
		16.10.1 Primary Writing Tremor
		16.10.2 Functional Tremor
	16.11 Conclusion
	References
17 Signal Processing
	17.1 Introduction
	17.2 Power Spectral Density Estimation
		17.2.1 Statistical Preliminaries
		17.2.2 Definition
		17.2.3 Relating Continuous- and Discrete-Time Representations
		17.2.4 Autocorrelation Versus Power Spectral Density (PSD)
		17.2.5 Types of PSD Estimation
		17.2.6 Periodogram
		17.2.7 Hazards of the Fast Fourier Transform (FFT)
		17.2.8 Signal Windowing
		17.2.9 PSD Smoothing
			17.2.9.1 The Welch–Bartlett Method
			17.2.9.2 The Blackman–Tukey Method
			17.2.9.3 Smoothing Spectral Peaks
		17.2.10 Interpreting the Power Spectral Density
		17.2.11 Recommendations and Tradeoffs
		17.2.12 Power Spectral Density Statistics
	17.3 Coherence Analysis
		17.3.1 Coherence Estimation
	17.4 Spectrogram
	17.5 Discussion and Summary
	References
18 Diffusion Imaging in Tremor
	18.1 Introduction
	18.2 Methodological Considerations
	18.3 Diffusion Tensor Imaging in Tremor
		18.3.1 Parkinsonian Syndromes
		18.3.2 Essential Tremor
	18.4 Diffusion Tractography in Tremor
		18.4.1 Essential Tremor
		18.4.2 Lesion Evaluation
		18.4.3 Deep Brain Stimulation
	Bibliography
19 The Role of the Noradrenergic System in Tremor Pathogenesis
	19.1 Introduction
	19.2 The Functional Anatomy of Tremor (Fig. 19.1)
	19.3 The Influence of Noradrenaline on the Motor System (Fig. 19.2)
	19.4 The Effect of Psychological Stress on Tremor
	19.5 The Role of the Noradrenergic System in Parkinson's Disease Tremor
	19.6 The Role of the Noradrenergic System in Essential Tremor
	19.7 The Role of Serotonin in Tremor
	19.8 Conclusion
	References
20 Metabolic Networks in Parkinson's Disease
	20.1 Introduction
	20.2 Metabolic Networks in Parkinson's Disease
		20.2.1 The Derivation of Metabolic Networks
		20.2.2 The PD-Related Motor Pattern
		20.2.3 The PD-Related Tremor Pattern
		20.2.4 The PD-Related Cognitive Pattern
	20.3 Atypical Parkinsonian Syndromes
	20.4 Metabolic Networks in Prodromal States and Rapid Eye Movement Disorder
	20.5 Network Changes with Treatment
	20.6 Future Research Applications
	20.7 Conclusions
	References
21 Deep Brain Stimulation for Tremor
	21.1 Introduction
	21.2 Anatomical Targets for Deep Brain Stimulation in Tremor Disorders
		21.2.1 The Motor Thalamus
		21.2.2 The Posterior Subthalamic Area/Caudal Zona Incerta
		21.2.3 The Dentatorubrothalamic Tract
		21.2.4 The Subthalamic Nucleus
		21.2.5 The Internal Globus Pallidus
	21.3 Mechanism(s) of Action
	21.4 DBS as a Symptomatic Treatment for Tremor
		21.4.1 Tremor in Parkinson's Disease
		21.4.2 Essential Tremor
		21.4.3 Dystonic Tremor
		21.4.4 Tremor Secondary to Multiple Sclerosis
		21.4.5 Orthostatic Tremor
		21.4.6 Primary Writing Tremor
		21.4.7 Holmes Tremor
		21.4.8 Posttraumatic Tremor
		21.4.9 Tremor Secondary to Cerebellar Degeneration
		21.4.10 Neuropathic Tremor
	21.5 Adverse Events
		21.5.1 Surgical Adverse Events
		21.5.2 Device Complications Including Lead Replacement
		21.5.3 Stimulation-Related Adverse Events
	21.6 Future Directions: Adaptive Stimulation for Tremor
	21.7 Deep Brain Stimulation and MRI-Guided Focused Ultrasound
	21.8 Final Remarks
	References
22 Mechatronic Devices for Upper Limb Tremor
	22.1 Introduction
	22.2 Tremor Signal Sensing and Estimation
		22.2.1 Tremor Signal Sensing Technology
		22.2.2 Tremor Estimation Techniques
	22.3 Actuation
		22.3.1 Mechanical Joint Actuation
		22.3.2 Actuation of the Muscles and Sensory Nerves
	22.4 Control Systems
	22.5 State of the Art: Wearable Mechatronic Tremor Suppression Devices
	22.6 Discussion: Challenges and Opportunities
	22.7 Final Remarks
	References
23 Drug-Induced Tremors
	23.1 Introduction
	23.2 Antiarrhythmics
		23.2.1 Amiodarone
		23.2.2 Others: Procainamide and Mexiletine
	23.3 Antidepressants and Mood Stabilizers
		23.3.1 Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Norepinephrine Reuptake Inhibitors (SNRIs)
		23.3.2 Tricyclic Antidepressants (TCAs) and Tetracyclic Antidepressants
		23.3.3 Withdrawal Syndromes and Serotonin Syndrome
		23.3.4 Lithium
	23.4 Antiepileptics
		23.4.1 Valproic Acid
		23.4.2 Other Antiepileptics
	23.5 Antimicrobials
		23.5.1 Antibiotics
		23.5.2 Antifungals
		23.5.3 Antivirals
		23.5.4 Antiparasitic Agents
	23.6 Bronchodilators
	23.7 Dopamine Receptor Antagonists and Dopamine Depleting Agents
		23.7.1 Dopamine Receptor Antagonists
		23.7.2 Tardive Tremor
		23.7.3 Dopamine Depleting Agents
	23.8 Gastrointestinal Agents
		23.8.1 Metoclopramide
		23.8.2 Other Antiemetics: Promethazine and Prochlorperazine
		23.8.3 Misoprostol
		23.8.4 Cimetidine
		23.8.5 Bismuth Salts
	23.9 Immunosuppressants and Chemotherapeutics
		23.9.1 Calcineurin and Non-Calcineurin Inhibitors
		23.9.2 Interferons
		23.9.3 Antineoplastic Agents
		23.9.4 Immune Checkpoint Inhibitors
	23.10 Substances of Abuse or Misuse
		23.10.1 Alcohol
		23.10.2 Stimulants
		23.10.3 Nicotine
	23.11 Sympathomimetics, Methylxanthines, and Beta-Adrenergic Antagonists
		23.11.1 Sympathomimetics
		23.11.2 Methylxanthines
		23.11.3 Beta-Adrenergic Antagonists
	23.12 Conclusion
	References
Index