Hanieh Agharazi, H. A. Jinnah, David S. Zee, A. Shaikh
Introduction: This study explores the effects of botulinum neurotoxin (BoNT) on the relationship between dystonia and tremor, specifically focusing on cervical dystonia (CD) and its connection to head tremor.Methods: Fourteen CD patients were recruited; eight (57%) with clinically observable head oscillations were included in further analysis. A high-resolution magnetic search coil system precisely measured head movements, addressing two questions: 1) BoNT’s effects on head movement amplitude, frequency, and regularity, and 2) BoNT’s influence on the relationship between head position and head oscillations. For the first question, temporal head position measurements of three patients were analyzed before and after BoNT injection. The second question examined the effects of BoNT injections on the dependence of the oscillations on the position of the head.Results: Three distinct trends were observed: shifts from regular to irregular oscillations, transitions from irregular to regular oscillations, and an absence of change. Poincaré analysis revealed that BoNT induced changes in regularity, aligning oscillations closer to a consistent “set point” of regularity. BoNT injections reduced head oscillation amplitude, particularly in head orientations linked to high-intensity pre-injection oscillations. Oscillation frequency decreased in most cases, and overall variance in the amplitude of head position decreased post-injection.Discussion: These findings illuminate the complexity of CD but also suggest therapeutic potential for BoNT. They show that co-existing mechanisms contribute to regular and irregular head oscillations in CD, which involve proprioception and central structures like the cerebellum and basal ganglia. These insights advocate for personalized treatment to optimize outcomes that is based on individual head oscillation characteristics.
简介：本研究探讨了肉毒杆菌神经毒素（BoNT）对肌张力障碍与震颤之间关系的影响，尤其关注颈性肌张力障碍（CD）及其与头部震颤之间的关系：招募了 14 名 CD 患者，其中 8 人（57%）具有临床可观察到的头部震颤，被纳入进一步分析。高分辨率磁搜索线圈系统精确测量了头部运动，解决了两个问题：1）BoNT 对头部运动幅度、频率和规律性的影响；2）BoNT 对头部位置和头部振荡之间关系的影响。对于第一个问题，分析了三名患者在注射 BoNT 前后的颞部头部位置测量结果。第二个问题是研究注射 BoNT 对振荡与头部位置关系的影响：结果：观察到三种明显的趋势：从规则振荡到不规则振荡的转变、从不规则振荡到规则振荡的过渡以及无变化。Poincaré分析显示，BoNT诱导了规则性的变化，使振荡更接近规则性的一致 "设定点"。注射 BoNT 会降低头部振荡幅度，尤其是在与注射前高强度振荡相关的头部方向。大多数情况下，振荡频率会降低，注射后头部位置振幅的总体差异也会减小：这些发现揭示了 CD 的复杂性，同时也表明了 BoNT 的治疗潜力。这些研究结果表明，CD患者的头部有规律和无规律摆动的机制是并存的，其中涉及本体感觉以及小脑和基底节等中枢结构。这些见解主张根据个体头部振荡特征进行个性化治疗，以优化治疗效果。
{"title":"Effects of botulinum neurotoxin on regularity of head oscillations in cervical dystonia","authors":"Hanieh Agharazi, H. A. Jinnah, David S. Zee, A. Shaikh","doi":"10.3389/dyst.2024.12347","DOIUrl":"https://doi.org/10.3389/dyst.2024.12347","url":null,"abstract":"Introduction: This study explores the effects of botulinum neurotoxin (BoNT) on the relationship between dystonia and tremor, specifically focusing on cervical dystonia (CD) and its connection to head tremor.Methods: Fourteen CD patients were recruited; eight (57%) with clinically observable head oscillations were included in further analysis. A high-resolution magnetic search coil system precisely measured head movements, addressing two questions: 1) BoNT’s effects on head movement amplitude, frequency, and regularity, and 2) BoNT’s influence on the relationship between head position and head oscillations. For the first question, temporal head position measurements of three patients were analyzed before and after BoNT injection. The second question examined the effects of BoNT injections on the dependence of the oscillations on the position of the head.Results: Three distinct trends were observed: shifts from regular to irregular oscillations, transitions from irregular to regular oscillations, and an absence of change. Poincaré analysis revealed that BoNT induced changes in regularity, aligning oscillations closer to a consistent “set point” of regularity. BoNT injections reduced head oscillation amplitude, particularly in head orientations linked to high-intensity pre-injection oscillations. Oscillation frequency decreased in most cases, and overall variance in the amplitude of head position decreased post-injection.Discussion: These findings illuminate the complexity of CD but also suggest therapeutic potential for BoNT. They show that co-existing mechanisms contribute to regular and irregular head oscillations in CD, which involve proprioception and central structures like the cerebellum and basal ganglia. These insights advocate for personalized treatment to optimize outcomes that is based on individual head oscillation characteristics.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140078011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Feline Hamami, Skadi Gerkensmeier, Alexander Münchau, A. Weissbach
Myoclonus-Dystonia is a rare, neurological movement disorder, clinically characterized by myoclonic jerks and dystonic symptoms, such as cervical dystonia and writer’s cramp. Psychiatric symptoms, like anxiety, depression, and addiction, are frequently reported. Monogenic Myoclonus-Dystonia is mostly caused by pathogenic variants in the ε-sarcoglycan gene, which is among other regions highly expressed in the cerebellum. The current pharmacological treatment is not satisfactory. Neurophysiological and imaging studies in this patient population are scarce with partly heterogeneous results and sometimes important limitations. However, some studies point towards subcortical alterations, e.g., of the cerebellum and its connections. Further studies addressing previous limitations are important for a better understanding of the underlying pathology of Myoclonus-Dystonia and might build a bridge for the development of future treatment.
{"title":"ε-sarcoglycan myoclonus-dystonia—overview of neurophysiological, behavioral, and imaging characteristics","authors":"Feline Hamami, Skadi Gerkensmeier, Alexander Münchau, A. Weissbach","doi":"10.3389/dyst.2024.11693","DOIUrl":"https://doi.org/10.3389/dyst.2024.11693","url":null,"abstract":"Myoclonus-Dystonia is a rare, neurological movement disorder, clinically characterized by myoclonic jerks and dystonic symptoms, such as cervical dystonia and writer’s cramp. Psychiatric symptoms, like anxiety, depression, and addiction, are frequently reported. Monogenic Myoclonus-Dystonia is mostly caused by pathogenic variants in the ε-sarcoglycan gene, which is among other regions highly expressed in the cerebellum. The current pharmacological treatment is not satisfactory. Neurophysiological and imaging studies in this patient population are scarce with partly heterogeneous results and sometimes important limitations. However, some studies point towards subcortical alterations, e.g., of the cerebellum and its connections. Further studies addressing previous limitations are important for a better understanding of the underlying pathology of Myoclonus-Dystonia and might build a bridge for the development of future treatment.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140444739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dystonia is a network disorder presumed to result from abnormalities in multiple brain regions and in multiple cell populations. The specific pathomechanisms affecting the motor circuits in dystonia are, however, still largely unclear. Animal models for dystonia have long been used to advance our understanding on how specific brain regions and cell populations are involved in dystonia symptomatogenesis. Lesioning, pharmacological modulation and electrical stimulation paradigms were able to highlight that both the basal ganglia and the cerebellum are pathologically altered in these animal models for dystonia. Techniques such as optogenetics and chemogenetics now offer the opportunity for targeted modulation of brain regions and most importantly cell populations and circuits. This could not only allow for a better understanding of the dystonic brain, but potentially improve and expand treatment options. In hopes that the insights from these neuromodulation techniques will eventually translate into therapies, we aim to summarize and critically discuss the findings from different in vivo approaches used to dissect the network dysfunctions underlying dystonia.
{"title":"Unraveling dystonia circuitry in rodent models using novel neuromodulation techniques","authors":"L. Rauschenberger, Chi Wang Ip","doi":"10.3389/dyst.2024.11793","DOIUrl":"https://doi.org/10.3389/dyst.2024.11793","url":null,"abstract":"Dystonia is a network disorder presumed to result from abnormalities in multiple brain regions and in multiple cell populations. The specific pathomechanisms affecting the motor circuits in dystonia are, however, still largely unclear. Animal models for dystonia have long been used to advance our understanding on how specific brain regions and cell populations are involved in dystonia symptomatogenesis. Lesioning, pharmacological modulation and electrical stimulation paradigms were able to highlight that both the basal ganglia and the cerebellum are pathologically altered in these animal models for dystonia. Techniques such as optogenetics and chemogenetics now offer the opportunity for targeted modulation of brain regions and most importantly cell populations and circuits. This could not only allow for a better understanding of the dystonic brain, but potentially improve and expand treatment options. In hopes that the insights from these neuromodulation techniques will eventually translate into therapies, we aim to summarize and critically discuss the findings from different in vivo approaches used to dissect the network dysfunctions underlying dystonia.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140449611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dystonia refers to a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions leading to repetitive twisting movements and abnormal postures. Dystonia has a broad clinical spectrum and can affect different body regions, causing significant disability and reduced quality of life. Despite significant progress in understanding the disorder, many challenges in dystonia research remain. This mini-review aims to highlight the major challenges facing basic and translational research in this field, including 1) heterogeneity of the disorder, 2) limited understanding of its pathophysiology, 3) complications of using animal models, 4) lack of a framework linking genes, biochemistry, circuits, and clinical phenomenology, and 5) limited research funding. Identifying and discussing these challenges can help prioritize research efforts and resources, highlight the need for further investigation and funding, and inspire action towards addressing these challenges.
{"title":"Piecing together a complex puzzle: 5 key challenges in basic dystonia research","authors":"M. Scarduzio, David G. Standaert","doi":"10.3389/dyst.2023.11615","DOIUrl":"https://doi.org/10.3389/dyst.2023.11615","url":null,"abstract":"Dystonia refers to a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions leading to repetitive twisting movements and abnormal postures. Dystonia has a broad clinical spectrum and can affect different body regions, causing significant disability and reduced quality of life. Despite significant progress in understanding the disorder, many challenges in dystonia research remain. This mini-review aims to highlight the major challenges facing basic and translational research in this field, including 1) heterogeneity of the disorder, 2) limited understanding of its pathophysiology, 3) complications of using animal models, 4) lack of a framework linking genes, biochemistry, circuits, and clinical phenomenology, and 5) limited research funding. Identifying and discussing these challenges can help prioritize research efforts and resources, highlight the need for further investigation and funding, and inspire action towards addressing these challenges.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138953038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jason S. Gill, Megan X. Nguyen, Mariam Hull, Meike E. van der Heijden, Ken Nguyen, Sruthi P. Thomas, R. Sillitoe
Dystonia is a highly prevalent movement disorder that can manifest at any time across the lifespan. An increasing number of investigations have tied this disorder to dysfunction of a broad “dystonia network” encompassing the cerebellum, thalamus, basal ganglia, and cortex. However, pinpointing how dysfunction of the various anatomic components of the network produces the wide variety of dystonia presentations across etiologies remains a difficult problem. In this review, a discussion of functional network findings in non-mendelian etiologies of dystonia is undertaken. Initially acquired etiologies of dystonia and how lesion location leads to alterations in network function are explored, first through an examination of cerebral palsy, in which early brain injury may lead to dystonic/dyskinetic forms of the movement disorder. The discussion of acquired etiologies then continues with an evaluation of the literature covering dystonia resulting from focal lesions followed by the isolated focal dystonias, both idiopathic and task dependent. Next, how the dystonia network responds to therapeutic interventions, from the “geste antagoniste” or “sensory trick” to botulinum toxin and deep brain stimulation, is covered with an eye towards finding similarities in network responses with effective treatment. Finally, an examination of how focal network disruptions in mouse models has informed our understanding of the circuits involved in dystonia is provided. Together, this article aims to offer a synthesis of the literature examining dystonia from the perspective of brain networks and it provides grounding for the perspective of dystonia as disorder of network function.
{"title":"Function and dysfunction of the dystonia network: an exploration of neural circuits that underlie the acquired and isolated dystonias","authors":"Jason S. Gill, Megan X. Nguyen, Mariam Hull, Meike E. van der Heijden, Ken Nguyen, Sruthi P. Thomas, R. Sillitoe","doi":"10.3389/dyst.2023.11805","DOIUrl":"https://doi.org/10.3389/dyst.2023.11805","url":null,"abstract":"Dystonia is a highly prevalent movement disorder that can manifest at any time across the lifespan. An increasing number of investigations have tied this disorder to dysfunction of a broad “dystonia network” encompassing the cerebellum, thalamus, basal ganglia, and cortex. However, pinpointing how dysfunction of the various anatomic components of the network produces the wide variety of dystonia presentations across etiologies remains a difficult problem. In this review, a discussion of functional network findings in non-mendelian etiologies of dystonia is undertaken. Initially acquired etiologies of dystonia and how lesion location leads to alterations in network function are explored, first through an examination of cerebral palsy, in which early brain injury may lead to dystonic/dyskinetic forms of the movement disorder. The discussion of acquired etiologies then continues with an evaluation of the literature covering dystonia resulting from focal lesions followed by the isolated focal dystonias, both idiopathic and task dependent. Next, how the dystonia network responds to therapeutic interventions, from the “geste antagoniste” or “sensory trick” to botulinum toxin and deep brain stimulation, is covered with an eye towards finding similarities in network responses with effective treatment. Finally, an examination of how focal network disruptions in mouse models has informed our understanding of the circuits involved in dystonia is provided. Together, this article aims to offer a synthesis of the literature examining dystonia from the perspective of brain networks and it provides grounding for the perspective of dystonia as disorder of network function.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139005146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.
{"title":"Cerebellar dysfunction in rodent models with dystonia, tremor, and ataxia","authors":"Meike E. van der Heijden, R. Sillitoe","doi":"10.3389/dyst.2023.11515","DOIUrl":"https://doi.org/10.3389/dyst.2023.11515","url":null,"abstract":"Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138587892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Task-specific tremor (TST) is a specific type of tremor that occurs when performing or attempting to perform a specific task, such as writing or playing a musical instrument. The clinical entity of TST remains heterogeneous. Some TSTs can only be induced by conducting a specific task, while others can be elicited when adopting a particular position simulating a task. The pathophysiology of TST is controversial. Whether TST is an isolated tremor syndrome, a spectrum of dystonic tremor syndrome (DTS), or essential tremor (ET) is not yet clear. Evidence from electrophysiological studies suggests that TST patients have normal reciprocal inhibition responses but abnormal motor cortical excitability, especially relating to the maladaptive long-interval intracortical inhibitory circuitry. The blink recovery study and eyeblink classical conditioning studies demonstrated possible hyperexcitability of the brainstem circuits and cerebellar dysfunction in patients with TST. Functional MRI studies have further shown that patients with TST have reduced functional connectivity in the cerebellum, similar to patients with DTS and ET. Due to variable methodologies and the sparsity of functional MRI studies in TST, it remains uncertain if patients with TST share the connectivity abnormalities between the cortical or subcortical areas that have been demonstrated in patients with DTS. Comprehensive electrophysiological and functional neuroimaging studies may help to elucidate the pathophysiology of TST.
{"title":"A mini-review of the pathophysiology of task-specific tremor: insights from electrophysiological and neuroimaging findings","authors":"Yih-Chih Jacinta Kuo, Kai-Hsiang Stanley Chen","doi":"10.3389/dyst.2023.11347","DOIUrl":"https://doi.org/10.3389/dyst.2023.11347","url":null,"abstract":"Task-specific tremor (TST) is a specific type of tremor that occurs when performing or attempting to perform a specific task, such as writing or playing a musical instrument. The clinical entity of TST remains heterogeneous. Some TSTs can only be induced by conducting a specific task, while others can be elicited when adopting a particular position simulating a task. The pathophysiology of TST is controversial. Whether TST is an isolated tremor syndrome, a spectrum of dystonic tremor syndrome (DTS), or essential tremor (ET) is not yet clear. Evidence from electrophysiological studies suggests that TST patients have normal reciprocal inhibition responses but abnormal motor cortical excitability, especially relating to the maladaptive long-interval intracortical inhibitory circuitry. The blink recovery study and eyeblink classical conditioning studies demonstrated possible hyperexcitability of the brainstem circuits and cerebellar dysfunction in patients with TST. Functional MRI studies have further shown that patients with TST have reduced functional connectivity in the cerebellum, similar to patients with DTS and ET. Due to variable methodologies and the sparsity of functional MRI studies in TST, it remains uncertain if patients with TST share the connectivity abnormalities between the cortical or subcortical areas that have been demonstrated in patients with DTS. Comprehensive electrophysiological and functional neuroimaging studies may help to elucidate the pathophysiology of TST.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135476615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advances in sequencing technologies have identified novel genes associated with inherited forms of dystonia, providing valuable insights into its genetic basis and revealing diverse genetic pathways and mechanisms involved in its pathophysiology. Since identifying genetic variation in the transcription factor coding THAP1 gene linked to isolated dystonia, numerous investigations have employed transcriptomic studies in DYT-THAP1 models to uncover pathogenic molecular mechanisms underlying dystonia. This review examines key findings from transcriptomic studies conducted on in vivo and in vitro DYT-THAP1 models, which demonstrate that the THAP1-regulated transcriptome is diverse and cell-specific, yet it is bound and co-regulated by a common set of proteins. Prominent among its functions, THAP1 and its co-regulatory network target molecular pathways critical for generating myelinating oligodendrocytes that ensheath axons and generate white matter in the central nervous system. Several lines of investigation have demonstrated the importance of myelination and oligodendrogenesis in motor function during development and in adults, emphasizing the non-cell autonomous contributions of glial cells to neural circuits involved in motor function. Further research on the role of myelin abnormalities in motor deficits in DYT6 models will enhance our understanding of axon-glia interactions in dystonia pathophysiology and provide potential therapeutic interventions targeting these pathways.
{"title":"Transcriptional regulatory network for neuron-glia interactions and its implication for DYT6 dystonia","authors":"Dhananjay Yellajoshyula","doi":"10.3389/dyst.2023.11796","DOIUrl":"https://doi.org/10.3389/dyst.2023.11796","url":null,"abstract":"Advances in sequencing technologies have identified novel genes associated with inherited forms of dystonia, providing valuable insights into its genetic basis and revealing diverse genetic pathways and mechanisms involved in its pathophysiology. Since identifying genetic variation in the transcription factor coding THAP1 gene linked to isolated dystonia, numerous investigations have employed transcriptomic studies in DYT-THAP1 models to uncover pathogenic molecular mechanisms underlying dystonia. This review examines key findings from transcriptomic studies conducted on in vivo and in vitro DYT-THAP1 models, which demonstrate that the THAP1-regulated transcriptome is diverse and cell-specific, yet it is bound and co-regulated by a common set of proteins. Prominent among its functions, THAP1 and its co-regulatory network target molecular pathways critical for generating myelinating oligodendrocytes that ensheath axons and generate white matter in the central nervous system. Several lines of investigation have demonstrated the importance of myelination and oligodendrogenesis in motor function during development and in adults, emphasizing the non-cell autonomous contributions of glial cells to neural circuits involved in motor function. Further research on the role of myelin abnormalities in motor deficits in DYT6 models will enhance our understanding of axon-glia interactions in dystonia pathophysiology and provide potential therapeutic interventions targeting these pathways.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136102305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathryn J. Peall, Brian D. Berman, Norbert Bruggemann, Giovanni Defazio, Hortensia Gimeno, H. A. Jinnah, Joel S. Perlmutter, Sarah E. Pirio Richardson, Emmanuel Roze, Anette Schrag, Michele Tinazzi, Marie Vidailhet, Aparna Wagle Shukla, Yulia Worbe, Jan K. Teller, Davide Martino
The Dystonia Medical Research Foundation organized an expert virtual workshop in March 2023 to review the evidence on non-motor symptoms across the spectrum of dystonia, discuss existing assessment methods, need for their harmonisation and roadmap to achieve this, and evaluate potential treatment approaches. Albeit the most investigated non-motor domains, experts highlighted the need to identify the most accurate screening procedure for depression and anxiety, clarify their mechanistic origin and quantify their response to already available therapies. Future exploration of sleep disruption in dystonia should include determining the accuracy and feasibility of wearable devices, understanding the contribution of psychotropic medication to its occurrence, and defining the interaction between maladaptive plasticity and abnormal sleep patterns. Despite recent advances in the assessment of pain in dystonia, more research is needed to elucidate the relative importance of different mechanisms called into play to explain this impactful sensory feature and the most appropriate treatments. Amongst the different non-motor features investigated in dystonia, cognitive dysfunction and fatigue require an in-depth observation to evaluate their functional impact, their clinical profile and assessment methods and, in the case of cognition, whether impairment represents a prodrome of dementia. Finally, experts identified the development and field validation of a self-rated screening tool encompassing the full spectrum of non-motor symptoms as the most urgent step towards incorporating the management of these features into routine clinical practice.
{"title":"Non-motor symptoms in dystonia: from diagnosis to treatment","authors":"Kathryn J. Peall, Brian D. Berman, Norbert Bruggemann, Giovanni Defazio, Hortensia Gimeno, H. A. Jinnah, Joel S. Perlmutter, Sarah E. Pirio Richardson, Emmanuel Roze, Anette Schrag, Michele Tinazzi, Marie Vidailhet, Aparna Wagle Shukla, Yulia Worbe, Jan K. Teller, Davide Martino","doi":"10.3389/dyst.2023.11860","DOIUrl":"https://doi.org/10.3389/dyst.2023.11860","url":null,"abstract":"The Dystonia Medical Research Foundation organized an expert virtual workshop in March 2023 to review the evidence on non-motor symptoms across the spectrum of dystonia, discuss existing assessment methods, need for their harmonisation and roadmap to achieve this, and evaluate potential treatment approaches. Albeit the most investigated non-motor domains, experts highlighted the need to identify the most accurate screening procedure for depression and anxiety, clarify their mechanistic origin and quantify their response to already available therapies. Future exploration of sleep disruption in dystonia should include determining the accuracy and feasibility of wearable devices, understanding the contribution of psychotropic medication to its occurrence, and defining the interaction between maladaptive plasticity and abnormal sleep patterns. Despite recent advances in the assessment of pain in dystonia, more research is needed to elucidate the relative importance of different mechanisms called into play to explain this impactful sensory feature and the most appropriate treatments. Amongst the different non-motor features investigated in dystonia, cognitive dysfunction and fatigue require an in-depth observation to evaluate their functional impact, their clinical profile and assessment methods and, in the case of cognition, whether impairment represents a prodrome of dementia. Finally, experts identified the development and field validation of a self-rated screening tool encompassing the full spectrum of non-motor symptoms as the most urgent step towards incorporating the management of these features into routine clinical practice.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135266082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Much remains to be learned about the mechanism of benefit of deep brain stimulation in movement disorders in general and dystonia specifically. A full accounting of the pathophysiology of dystonia additionally remains unclear. Given its ability to evaluate whole-brain network changes, functional neuroimaging is an important tool to advance understanding of the effects of deep brain stimulation, which in turn could offer insight into the pathophysiology of dystonia and suggest novel deep brain stimulation targets for the disorder. This review surveys the published literature of functional neuroimaging studies evaluating deep brain stimulation effects in dystonia, including PET, SPECT, and functional MRI studies. To date, study cohorts have been relatively small, though several general patterns emerge when studies are viewed collectively, including reduced functional activation patterns with stimulation turned on during motor tasks, particularly in frontal cortical regions. During rest with stimulation on, several studies showed areas of relatively decreased perfusion only in those participants who experienced clinical benefit from deep brain stimulation. Future research may benefit from larger cohorts with more homogeneous forms of dystonia, potentially enabled by multi-center initiatives. Additional benefits may result from more detailed longitudinal assessments and greater use of functional MRI, with study designs that take into account the technical limitations of this modality in the context of movement disorders and deep brain stimulation.
{"title":"Functional imaging of deep brain stimulation in dystonia: a review","authors":"Ian O. Bledsoe, Melanie A. Morrison","doi":"10.3389/dyst.2023.11440","DOIUrl":"https://doi.org/10.3389/dyst.2023.11440","url":null,"abstract":"Much remains to be learned about the mechanism of benefit of deep brain stimulation in movement disorders in general and dystonia specifically. A full accounting of the pathophysiology of dystonia additionally remains unclear. Given its ability to evaluate whole-brain network changes, functional neuroimaging is an important tool to advance understanding of the effects of deep brain stimulation, which in turn could offer insight into the pathophysiology of dystonia and suggest novel deep brain stimulation targets for the disorder. This review surveys the published literature of functional neuroimaging studies evaluating deep brain stimulation effects in dystonia, including PET, SPECT, and functional MRI studies. To date, study cohorts have been relatively small, though several general patterns emerge when studies are viewed collectively, including reduced functional activation patterns with stimulation turned on during motor tasks, particularly in frontal cortical regions. During rest with stimulation on, several studies showed areas of relatively decreased perfusion only in those participants who experienced clinical benefit from deep brain stimulation. Future research may benefit from larger cohorts with more homogeneous forms of dystonia, potentially enabled by multi-center initiatives. Additional benefits may result from more detailed longitudinal assessments and greater use of functional MRI, with study designs that take into account the technical limitations of this modality in the context of movement disorders and deep brain stimulation.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135345562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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