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Experimental Brain Research Aug 2020Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques... (Review)
Review
Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques which aim to induce and quantify plasticity, the mechanisms and nature of their inherent variability and use such observations to review the idea that excessive and abnormal plasticity is a pathophysiological substrate of dystonia. We have tried to define the tone of our review by a couple of Professor John Rothwell's many inspiring characteristics; his endless curiosity to refine knowledge and disease models by scientific exploration and his wise yet humble readiness to revise scientific doctrines when the evidence is supportive. We conclude that high variability of response to non-invasive brain stimulation plasticity protocols significantly clouds the interpretation of historical findings in dystonia research. There is an opportunity to wipe the slate clean of assumptions and armed with an informative literature in health, re-evaluate whether excessive plasticity has a causal role in the pathophysiology of dystonia.
Topics: Dystonia; Dystonic Disorders; Humans; Neuronal Plasticity
PubMed: 32206849
DOI: 10.1007/s00221-020-05773-3 -
Neurobiology of Disease Dec 2022During the last decades deep brain stimulation (DBS) has become an important treatment option for a variety of neurological disorders such as drug-intractable dystonia.... (Review)
Review
During the last decades deep brain stimulation (DBS) has become an important treatment option for a variety of neurological disorders such as drug-intractable dystonia. Yet, the mechanisms of action of DBS are still largely unknown. Dystonia is a heterogenous movement disorder characterized by involuntary muscle contractions causing abnormal movements, postures, or both. The underlying pathophysiological processes remain unclear, but a dysfunction of the basal ganglia circuit is critically involved as supported by the effectiveness of DBS of the globus pallidus internus (GPi) in various types of dystonia. However, the degree of clinical improvement differs among the types of dystonia, as well as from patient to patient, and the delayed response to GPi-DBS in dystonia patients hampers the adjustment and optimization of stimulation parameters. Preclinical studies in suitable animal models can contribute decisively to detect the underlying mechanisms of DBS and biomarkers, to identify new possible stimulation targets and to optimize stimulation patterns. In this review, we give an overview of previous research on DBS in animal models of dystonia. With regard to the aims of research we discuss the opportunities and limitations concerning different available animal models of dystonia and technical challenges.
Topics: Animals; Dystonia; Deep Brain Stimulation; Globus Pallidus; Dystonic Disorders; Models, Animal; Treatment Outcome
PubMed: 36307031
DOI: 10.1016/j.nbd.2022.105912 -
Journal of the Neurological Sciences Apr 2022Dystonia and tremor frequently co-occur. In some cases, they have shared biological mechanisms, while in others dystonia and tremor are two comorbid conditions. The term... (Review)
Review
Dystonia and tremor frequently co-occur. In some cases, they have shared biological mechanisms, while in others dystonia and tremor are two comorbid conditions. The term "dystonic tremor" is used to describe tremor in those who have dystonia. Two mutually exclusive definitions of "dystonic tremor" were proposed. According to one definition, dystonic tremor is the tremor in the dystonic body part. An alternate definition of dystonic tremor entails irregular and jerky oscillations that have saw tooth appearance with or without overt dystonia. This paper outlines the differences in two definitions of dystonic tremor and identifies their limitations. Given the diverse views defining "dystonic tremor", this paper will use the term "tremor in dystonia". In addition, we will outline different ways to separate the subtypes of tremor in dystonia. Then we will discuss pathophysiological mechanisms derived from the objective measures and single neuron physiology analyses of tremor in dystonia. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.
Topics: Dystonia; Dystonic Disorders; Essential Tremor; Humans; Tremor
PubMed: 35259651
DOI: 10.1016/j.jns.2022.120199 -
Toxins Nov 2022Oromandibular dystonia (OMD) induces severe motor impairments, such as masticatory disturbances, dysphagia, and dysarthria, resulting in a serious decline in quality of... (Review)
Review
Oromandibular dystonia (OMD) induces severe motor impairments, such as masticatory disturbances, dysphagia, and dysarthria, resulting in a serious decline in quality of life. Non-invasive brain-imaging techniques such as electroencephalography (EEG) and magnetoencephalography (MEG) are powerful approaches that can elucidate human cortical activity with high temporal resolution. Previous studies with EEG and MEG have revealed that movements in the stomatognathic system are regulated by the bilateral central cortex. Recently, in addition to the standard therapy of botulinum neurotoxin (BoNT) injection into the affected muscles, bilateral deep brain stimulation (DBS) has been applied for the treatment of OMD. However, some patients' OMD symptoms do not improve sufficiently after DBS, and they require additional BoNT therapy. In this review, we provide an overview of the unique central spatiotemporal processing mechanisms in these regions in the bilateral cortex using EEG and MEG, as they relate to the sensorimotor functions of the stomatognathic system. Increased knowledge regarding the neurophysiological underpinnings of the stomatognathic system will improve our understanding of OMD and other movement disorders, as well as aid the development of potential novel approaches such as combination treatment with BoNT injection and DBS or non-invasive cortical current stimulation therapies.
Topics: Humans; Botulinum Toxins; Dystonia; Deep Brain Stimulation; Quality of Life; Dystonic Disorders
PubMed: 36356002
DOI: 10.3390/toxins14110751 -
Arquivos de Neuro-psiquiatria Nov 2016The diagnosis and treatment of dystonia are challenging. This is likely due to gaps in the complete understanding of its pathophysiology, lack of animal models for... (Review)
Review
The diagnosis and treatment of dystonia are challenging. This is likely due to gaps in the complete understanding of its pathophysiology, lack of animal models for translational studies, absence of a consistent pathological substrate and highly variable phenotypes and genotypes. The aim of this review article is to provide an overview of the clinical, neurophysiological and genetic features of dystonia that can help in the identification of this movement disorder, as well as in the differential diagnosis of the main forms of genetic dystonia. The variation of penetrance, age of onset, and topographic distribution of the disease in carriers of the same genetic mutation indicates that other factors - either genetic or environmental - might be involved in the development of symptoms. The growing knowledge of cell dysfunction in mutants may give insights into more effective therapeutic targets.
Topics: Algorithms; Diagnosis, Differential; Dystonia; Dystonic Disorders; Humans; Protein Interaction Maps; Risk Factors; Tremor
PubMed: 27901258
DOI: 10.1590/0004-282X20160140 -
Movement Disorders : Official Journal... Mar 2021Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication-refractory dystonia but has largely been abandoned... (Review)
Review
Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication-refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre-and postoperative Burke-Fahn-Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty-five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median-reported follow-up was 12 months (n = 83; range: 2-180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication-refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Deep Brain Stimulation; Dystonia; Dystonic Disorders; Globus Pallidus; Humans; Movement Disorders; Pallidotomy; Treatment Outcome
PubMed: 33215750
DOI: 10.1002/mds.28384 -
Tremor and Other Hyperkinetic Movements... 2018Dystonia is a movement disorder with high heterogeneity regarding phenotypic appearance and etiology that occurs in both sporadic and familial forms. The etiology of the... (Review)
Review
BACKGROUND
Dystonia is a movement disorder with high heterogeneity regarding phenotypic appearance and etiology that occurs in both sporadic and familial forms. The etiology of the disease remains unknown. However, there is increasing evidence suggesting that a small number of gene alterations may lead to dystonia. Although pathogenic variants to the familial type of dystonia have been extensively reviewed and discussed, relatively little is known about the contribution of single-nucleotide polymorphisms (SNPs) to dystonia. This review focuses on the potential role of SNPs and other variants in dystonia susceptibility.
METHODS
We searched the PubMed database for peer-reviewed articles published in English, from its inception through January 2018, that concerned human studies of dystonia and genetic variants. The following search terms were included: "dystonia" in combination with the following terms: 1) "polymorphisms" and 2) "SNPs" as free words.
RESULTS
A total of 43 published studies regarding , , , , , , , , , , , , COMT, , , , , , , , , , , , , , and genes, were included in the current review.
DISCUSSION
To date, a few variants, which are possibly involved in several molecular pathways, have been related to dystonia. Large cohort studies are needed to determine robust associations between variants and dystonia with adjustment for other potential cofounders, in order to elucidate the pathogenic mechanisms of dystonia and the net effect of the genes.
Topics: Apoptosis Regulatory Proteins; DNA-Binding Proteins; Dystonia; Dystonic Disorders; Genetic Predisposition to Disease; Humans; Molecular Chaperones; Nuclear Proteins; Polymorphism, Single Nucleotide; Risk Factors; Sodium-Potassium-Exchanging ATPase
PubMed: 30643666
DOI: 10.7916/D8H438GS -
Neurobiology of Disease Oct 2019Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions.... (Review)
Review
Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances in both animal and cell-based models have helped clarify divergent etiologies in dystonia and have facilitated the identification of new therapeutic targets. Advances in medicinal chemistry have also made available novel compounds for testing in biochemical, physiological, and behavioral models of dystonia. Here, we briefly review motor circuit anatomy and the anatomical and functional abnormalities in dystonia. We then discuss recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics.
Topics: Animals; Basal Ganglia; Cerebellum; Disease Models, Animal; Drug Discovery; Dystonia; Dystonic Disorders; Humans
PubMed: 31279827
DOI: 10.1016/j.nbd.2019.104526 -
The Journal of Molecular Diagnostics :... Mar 2022Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this,...
Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this, we applied an integrated two-step approach that included gene dosage analysis and a next-generation sequencing panel containing 72 known genes causative for dystonia and related movement disorders to 318 Taiwanese patients with isolated or combined dystonia. Whole-genome sequencing was performed for one multiplex family with no known causative variant. The panel confirmed the genetic diagnosis in 40 probands (12.6%). A genetic diagnosis was more likely with juvenile onset compared with adult onset (24.2% vs 10.8%; P = 0.03) and those with combined features, especially with myoclonus, compared with isolated dystonia (35.3% vs 10.5%; P = 0.004). The most common causative genes were SGCE followed by GCH1, TH, CACNA1B, PRRT2, MR1, CIZ1, PLA2G6, and PRKN. Genetic causes were identified from single cases in TOR1A, TUBB4A, THAP1, ATP1A3, ANO3, GNAL, KMT2B, SLC6A3, ADCY5, CYP27A1, PANK2, C19orf12, and SPG11. The whole-genome sequencing analysis identified a novel intragenic deletion in OPHN1 in a multiplex family with X-linked dystonia and intellectual delay. Our findings delineate the genetic architecture and clinical spectrum of dystonia-causing pathogenic variants in an Asian population.
Topics: Adult; Anoctamins; Apoptosis Regulatory Proteins; DNA-Binding Proteins; Dystonia; Dystonic Disorders; Humans; Mitochondrial Proteins; Molecular Chaperones; Mutation; Nuclear Proteins; Proteins; Sodium-Potassium-Exchanging ATPase; Spastic Paraplegia, Hereditary; Taiwan; Tubulin; Whole Genome Sequencing
PubMed: 35041927
DOI: 10.1016/j.jmoldx.2021.12.003 -
Internal Medicine (Tokyo, Japan) Aug 2022KMT2B-related dystonia (DYT28, DYT-KMT2B) is an inherited dystonia that generally begins in the lower limbs during childhood and evolves into generalized dystonia. We...
KMT2B-related dystonia (DYT28, DYT-KMT2B) is an inherited dystonia that generally begins in the lower limbs during childhood and evolves into generalized dystonia. We herein report a case of adult-onset DYT28 with dystonic tremor. A 27-year-old woman initially displayed right upper limb and cervical tremors over the course of 1 year. A neurological examination also revealed cervical and lower limb dystonia. Although the disease generally develops during childhood, we diagnosed the woman with DYT28, as genetic testing revealed a mutation in KMT2B. Adult-onset patients with DYT28 might also show uncommon symptoms as well as DYT-TOR1A (DYT1).
Topics: Adult; Dystonia; Dystonic Disorders; Female; Histone-Lysine N-Methyltransferase; Humans; Molecular Chaperones; Mutation; Tremor
PubMed: 35022352
DOI: 10.2169/internalmedicine.8700-21