Temporal discrimination: Mechanisms and relevance to adult-onset dystonia

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis

Dystonia: A Leading Neurological Movement Disorder

Dystonia is the third leading movement disorder arising mainly from the damage of basal ganglia or other parts of the brain that control movements. The objective of this review is to represent the detailed profile of dystonia. A computerized literature review was conducted in authentic scientific databases including PubMed, Google Scholar, Scopus, Science Direct and National Institutes of Health (NIH) etc. Terms searched included dystonia, risk factors, etiologies, clinical features, classification, pathology, guidelines, treatment strategies, primary and secondary dystonia. Initially, 97 articles and 9 books were extracted but finally, 64 articles and 7 books were used. After analysis, we found that causes of dystonia could be acquired or inherited and dystonia can be classified based on age at onset, etiology, and distribution of the affected body parts. The risk factors of this heterogeneous disorder could be trauma, thyroid disorder, hypertension, life habits, occupation, use of drugs and genetics. A significant number of articles were found which signify the ability of brainstem and cerebellar pathology to trigger the symptoms of dystonia. Since antipsychotic drugs are the most commonly prescribed among the people with intellectual disability (ID), therefore they possess a greater risk to experience antipsychotic drugs-induced movement side effects including acute dystonia, parkinsonism, tardive dyskinesia, and akathisia. Depending on various manifestations and causes, there are several treatment options including oral medications, intramuscular injection of botulinum toxin, neurosurgical procedures and occupational therapy

Dystonia and Parkinson's disease: What is the relationship?

Dystonia and Parkinson's disease are closely linked disorders sharing many pathophysiological overlaps. Dystonia can be seen in 30% or more of the patients suffering with PD and sometimes can precede the overt parkinsonism. The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is variable; dystonia commonly occurs in PD patients following levodopa initiation. Similarly, parkinsonism is commonly seen in patients with mutations in various DYT genes including those involved in the dopamine synthesis pathway. Pharmacological blockade of dopamine receptors can cause both tardive dystonia and parkinsonism and these movement disorders syndromes can occur in many other neurodegenerative, genetic, toxic and metabolic diseases. Pallidotomy in the past and currently deep brain stimulation largely involving the GPi are effective treatment options for both dystonia and parkinsonism. However, the physiological mechanisms underlying the response of these two different movement disorder syndromes are poorly understood. Interestingly, DBS for PD can cause dystonia such as blepharospasm and bilateral pallidal DBS for dystonia can result in features of parkinsonism. Advances in our understanding of these responses may provide better explanations for the relationship between dystonia and Parkinson's disease

Imaging Studies in Focal Dystonias: A Systems Level Approach to Studying a Systems Level Disorder

Focal dystonias are dystonias that affect one part of the body, and are sometimes task-specific. Brain imaging and transcranial magnetic stimulation techniques have been valuable in defining the pathophysiology of dystonias in general, and are particularly amenable to studying focal dystonias. Over the past few years, several common themes have emerged in the imaging literature, and this review summarizes these findings and suggests some ways in which these distinct themes might all point to one common systems-level mechanism for dystonia. These themes include (1) the role of premotor regions in focal dystonia, (2) the role of the sensory system and sensorimotor integration in focal dystonia, (3) the role of decreased inhibition/increased excitation in focal dystonia, and (4) the role of brain imaging in evaluating and guiding treatment of focal dystonias. The data across these themes, together with the features of dystonia itself, are consistent with a hypothesis that all dystonias reflect excessive output of postural control/stabilization systems in the brain, and that the mechanisms for dystonia reflect amplification of an existing functional system, rather than recruitment of the wrong motor programs. Imaging is currently being used to test treatment effectiveness, and to visually guide treatment of dystonia, such as placement of deep brain stimulation electrodes. In the future, it is hoped that imaging may be used to individualize treatments across behavioral, pharmacologic, and surgical domains, thus optimizing both the speed and effectiveness of treatment for any given individual with focal dystonia

Cerebellum

A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.P40 OD010996/ODCDC CDC HHS/Office of the Director/United StatesR01 NS079750/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesP51 OD011132/ODCDC CDC HHS/Office of the Director/United StatesR25 MH086466/NIMH NIH HHS/National Institute of Mental Health/United StatesR01 NS024328/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS082296/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesP30 NS076405/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS085054/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS050808/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesU54 TR001456/NCATS NIH HHS/National Center for Advancing Translational Sciences/United StatesR01 NS069936/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesU54 NS065701/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesR01 NS088528/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United StatesK08 NS072158/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United States2018-04-01T00:00:00Z27734238PMC53365116542vault:3362

Engineering Solutions To The Characterisation Of Clinical Disorders Of Upper Eyelid Movement

This project is about improving functioning in patients with ptosis associated with poor levator palpebrae superioris (LPS) function. LPS is a highly specialised muscle responsible for raising the eyelid. Defective LPS may cause the eyelid to droop uncontrollably, thereby covering the visual axis and affecting vision. The current method of correction relies heavily on the experience of the surgeon. Rarely, the implanted materials are at risk of exposure, infection, rejection. More commonly, the ability to completely shut the eyelids is impaired, leading to the danger of corneal exposure that can lead to severe pain and sight-threatening complications. Many patients will require repeat surgeries for correction in the future. One reason for such mechanical failure includes the lack of understanding of the mechanical characteristics of the muscle involved in blinking, and the current surgical suspension material used in replacing it. This lack of a scientific basis means that ptosis is a major challenge in ophthalmic surgery. The aim of this work will include analysing and characterising LPS and blinking dynamics, in the hope of improving future clinical procedures and perhaps provide insights on surgical materials. Two separate approaches are running in parallel to investigate blinking dynamics: to define the mechanical characteristics and properties of the muscles involved in blinking, a new apparatus was designed and constructed to measure the force in eyelid closure, particularly the maximum force of contraction and natural force of closure. On another aspect, a high-speed camera was used at Moorfields Eye Hospital to record and analyse blinking in 32 patients with ptosis, thyroid eye disease and Blepharospasm. The collected and analysed data are used to investigate how eye blinking dynamics in diseased patients are different from healthy individuals and to attempt to separate them from controls using a modelling system. In addition, the blinking dynamics of dermatochalasis patients before and after blepharoplasty surgery were also compared with healthy individuals using high-speed camera and later advanced statistical analysis

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia

A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia