Dystonia最新文献

{"title":"The role of protein kinase R in dystonia","authors":"Benjamin Dodd, Stephanie L. Moon","doi":"10.3389/dyst.2023.11718","DOIUrl":"https://doi.org/10.3389/dyst.2023.11718","url":null,"abstract":"Dystonia is a progressive neurological motor disease with few treatment options and no cure. This review synthesizes the results of recent studies that implicate protein kinase R in mediating the molecular mechanisms of dystonia pathogenesis. Mutations in the PKR gene EIF2AK2 and the PKR activator protein PACT are associated with early-onset generalized dystonia. Protein kinase R (PKR) is important for neuronal function. Genetic depletion or inhibition of PKR is associated with increased long-term potentiation and memory, while also causing neuronal hyper-excitability and seizures in mouse models. PKR also senses double stranded RNA within cells and activates the integrated stress response (ISR). The ISR is a conserved signaling pathway that hinges on controlled translational suppression to remodel gene expression during stress. When PKR is activated through binding double stranded RNA or the PKR activator protein PACT, PKR dimerizes, autophosphorylates, and phosphorylates the translation initiation factor eIF2. Translation suppression by p-eIF2 causes stress granule formation and the upregulation of stress-induced genes. The ISR is thought to drive cellular resilience during acute stress. However, chronic ISR activation is associated with neurological diseases, traumatic brain injury, and aging. Neurodevelopmental and neurodegenerative diseases are associated with mutations in other integrated stress response genes, suggesting a critical role for ISR regulation in neuronal health. A growing body of work suggests the ISR is also dysfunctional in dystonia. Future research investigating the molecular mechanisms of the ISR in dystonia will likely reveal therapeutic targets and treatment strategies for this currently incurable disease.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136061112","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}

{"title":"Editorial: Models, mechanisms, and maturation in developmental dystonia","authors":"Jason S. Gill, Meike E. van der Heijden, A. Shaikh, R. Sillitoe","doi":"10.3389/dyst.2023.11922","DOIUrl":"https://doi.org/10.3389/dyst.2023.11922","url":null,"abstract":"","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139341067","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}

{"title":"Disrupted sleep in dystonia depends on cerebellar function but not motor symptoms in mice","authors":"Luis E. Salazar Leon, Roy V. Sillitoe","doi":"10.3389/dyst.2023.11487","DOIUrl":"https://doi.org/10.3389/dyst.2023.11487","url":null,"abstract":"Although dystonia is the third most common movement disorder, patients often also experience debilitating nonmotor defects including impaired sleep. The cerebellum is a central component of a “dystonia network” that plays various roles in sleep regulation. Importantly, the primary driver of sleep impairments in dystonia remains poorly understood. The cerebellum, along with other nodes in the motor circuit, could disrupt sleep. However, it is unclear how the cerebellum might alter sleep and mobility. To disentangle the impact of cerebellar dysfunction on motion and sleep, we generated two mouse genetic models of dystonia that have overlapping cerebellar circuit miswiring but show differing motor phenotype severity: Ptf1a Cre ; Vglut2 fx/fx and Pdx1 Cre ; Vglut2 fx/fx mice. In both models, excitatory climbing fiber to Purkinje cell neurotransmission is blocked, but only the Ptf1a Cre ; Vglut2 fx/fx mice have severe twisting. Using in vivo ECoG and EMG recordings we found that both mutants spend greater time awake and in NREM sleep at the expense of REM sleep. The increase in awake time is driven by longer awake bouts rather than an increase in bout number. We also found a longer latency to reach REM in both mutants, which is similar to what is reported in human dystonia. We uncovered independent but parallel roles for cerebellar circuit dysfunction and motor defects in promoting sleep quality versus posture impairments in dystonia.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135420542","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}

{"title":"Transcranial magnetic stimulation: the road to clinical therapy for dystonia","authors":"Patrick J. Mulcahey, Angel V. Peterchev, Nicole Calakos, Noreen Bukhari-Parlakturk","doi":"10.3389/dyst.2023.11660","DOIUrl":"https://doi.org/10.3389/dyst.2023.11660","url":null,"abstract":"Despite many research studies, transcranial magnetic stimulation (TMS) is not yet an FDA-approved clinical therapy for dystonia patients. This review describes the four major challenges that have historically hindered the clinical translation of TMS. The four challenges described are limited types of clinical trial designs, limited evidence on objective behavioral measures, variability in the TMS clinical response, and the extensive TMS parameters to optimize for clinical therapy. Progress has been made to diversify the types of clinical trial design available to clinical researchers, identify evidence-based objective behavioral measures, and reduce the variability in TMS clinical response. Future studies should identify objective behavioral measures for other dystonia subtypes and expand the optimal TMS stimulation parameters for clinical therapy. Our review highlights the key progress made to overcome these barriers and gaps that remain for TMS to develop into a long-lasting clinical therapy for dystonia patients.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136391349","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}

{"title":"Spinal dystonia and other spinal movement disorders","authors":"Shlok Sarin, Temitope Lawal, H. Abboud","doi":"10.3389/dyst.2023.11303","DOIUrl":"https://doi.org/10.3389/dyst.2023.11303","url":null,"abstract":"While traditionally considered a disorder of the basal ganglia, brainstem, and cerebellum, multiple reports have shown that spinal cord pathologies may lead to dystonia. In this article, we first discuss various spinal movement disorders and the differences between tonic spasms, spinal dystonia, spinal myoclonus, spinal tremors, and paroxysmal dyskinesia. We review potential pathogenesis of spinal dystonia. We then focus on reports of dystonia secondary to spinal cord demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorders. We conclude by discussing the potential treatment options for spinal dystonia.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48419445","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}

{"title":"Gait and balance in cervical dystonia and dystonic head tremor","authors":"A. Wagle Shukla, Angela Gurrala, V. Vedam-Mai","doi":"10.3389/dyst.2023.11231","DOIUrl":"https://doi.org/10.3389/dyst.2023.11231","url":null,"abstract":"Background: Previous studies have found gait and balance abnormalities in patients with cervical dystonia. However, the characteristics of gait and balance in cervical dystonia with head tremors have not been ascertained. A midline constant head tremor when walking would likely render gait and balance more difficult. The pathophysiology of dystonia has also been increasingly linked with cerebellar function abnormality, commonly implicated in gait and balance disorders.Methods: We examined the gait and balance characteristics of cervical dystonia presenting with head tremors. We used the timed up-and-go (TUG) walk test, 10 m walk test, Berg Balance Scale (BBS), and Gait and Freezing questionnaire. We then assessed the gait on an instrumented walkway system to capture spatiotemporal measures such as speed, cadence, step time, step length, stride width, swing%, stance%, single support%, double support%, and gait variability index (GVI). We also assessed whether the gait in dystonic tremor (DT) differed from essential tremor (ET) and orthostatic tremor (OT), as these tremor disorders share the cerebello-thalamo-cortical pathway as the common pathological pathway.Results: 50 participants comprising DT (20 patients), ET (15 patients), and OT (15 patients) were enrolled. While the gait abnormalities were subclinical, 11/20 DT patients (55%) walked at a slower speed on the TUG, 11/20 (55%) had reduced scores on the BBS, 9/20 (45%) had increased step time, 4/20 (20%) had reduced step length, 4/20 (20%) had wider stride width, 9/20 (45%) spent greater time during double support and 8/20 (40%) patients had an abnormal GVI. Comparisons of DT with healthy control data revealed a slower gait velocity (p = 0.001) and a reduced step length (p = 0.001). Compared to DT, the ET group revealed a reduced cadence (p = 0.04) and the OT group revealed an increased TUG time (p = 0.03), reduced BBS scores (p = 0.02), reduced step length (p = 0.02), reduced cadence (p = 0.03), reduced GVI (p = 0.01), and increased double support phase (p = 0.045).Conclusion: DT is accompanied by multiple abnormalities affecting gait and balance, albeit subclinical and less pronounced than ET and OT, possibly related to more effective compensatory mechanisms. Nevertheless, these abnormalities indicate that rehabilitative measures warrant consideration when managing in clinical settings.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44311404","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}

{"title":"Bradykinesia and dystonia","authors":"G. Paparella, A. Guerra, S. Galosi, A. Cannavacciuolo, Luca Angelini, Traian Popa, A. Berardelli, M. Bologna","doi":"10.3389/dyst.2023.11448","DOIUrl":"https://doi.org/10.3389/dyst.2023.11448","url":null,"abstract":"Background: Bradykinesia has been reported in patients with dystonia. Despite this, the pathophysiological mechanisms of bradykinesia in dystonia remain largely unknown.Methods: We here performed a comprehensive literature search and reviewed clinical and experimental studies on bradykinesia in patients with dystonia.Results: Many studies have documented the presence of bradykinesia in patients with idiopathic and inherited isolated dystonia, regardless of the presence of parkinsonism. In addition, bradykinesia has been observed as a side effect in dystonic patients who have undergone deep brain stimulation, in those with functional dystonia as well as in those with combined dystonia, e.g., dystonia-parkinsonism. These clinical and experimental findings support the hypothesis that dysfunction in a brain network involving the basal ganglia, primary sensorimotor cortex, and cerebellum may play a key role in the pathophysiology of both bradykinesia and dystonia.Conclusion: Bradykinesia is frequently observed in dystonia. We may gain insights into the pathophysiological underpinnings of two distinct movement disorders by investigating this issue. Furthermore, a deeper understanding of bradykinesia in dystonia may have terminological implications in this field.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48434823","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}

{"title":"Pain control due to botulinum toxin therapy in cervical dystonia relates to the sensorimotor integration process","authors":"A. Wagle Shukla, Robert Chen, Wei Hu","doi":"10.3389/dyst.2023.11362","DOIUrl":"https://doi.org/10.3389/dyst.2023.11362","url":null,"abstract":"Background: Botulinum toxin (BoNT) injections have been found to improve pain symptoms of isolated cervical dystonia (CD). In addition to muscle relaxation at the peripheral level, few studies suggest that BoNT has effects on the central brain circuitries. The effects of BoNT on central circuitries that may be pain-related have not been examined. We probed these central effects with transcranial magnetic stimulation (TMS) techniques in a CD cohort presenting with significant pain.Methods: TMS-based measures of sensorimotor integration that are mediated through central processes, such as the short and long latency afferent inhibition (SAI and LAI) and measures for motor cortical excitability including short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were recorded. These measures were recorded at specific interstimulus intervals (ISI) using paired-pulse paradigms before and after the peak effects of BoNT injections. Normative TMS data from age-matched healthy controls were collected for comparisons. Clinical pain symptoms were recorded with Toronto Western spasmodic rating scale (TWSTRS)-pain and a visual analog scale (VAS).Results: Eleven CD subjects (mean age ±SD, 53.1 ± 6.3 years) and 10 age-matched healthy controls were enrolled. SAI was found to be increased in CD patients at baseline, however at the time of peak BoNT effects, it revealed a significant change with normalization to healthy control data (SAI ISI 20 ms, p = 0.001; SAI ISI 30 ms, p = 0.03). The change in SAI correlated with improvements in pain levels assessed with TWSTRS-pain and VAS and the total dose of BoNT injected (corrected for multiple correlations). LAI, SICI, and ICF measures were similar to the healthy controls and remained unchanged with BoNT therapy.Conclusion: Pain control in CD from BoNT therapy relates to modulation of sensorimotor integration at the cortical level.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47575901","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}

{"title":"Deconstructing motor and non-motor aspects of dystonia with neuroimaging","authors":"A. Mahajan","doi":"10.3389/dyst.2023.11526","DOIUrl":"https://doi.org/10.3389/dyst.2023.11526","url":null,"abstract":"Dystonia, the third most common movement disorder, is clinically characterized by involuntary muscle contractions leading to abnormal, patterned movements and postures that are often activated or worsened by initiation of movement. In addition to motor features, the presence and contribution of non-motor features including sensory and psychiatric features is increasingly recognized. However, the underlying pathophysiology behind dystonia and its fascinating motor and non-motor presentations remains inadequately understood. Advances in neuroimaging may hold the key. This review outlines brain imaging studies, with an intentional focus on our work, conducted using different structural and functional neuroimaging modalities, focused on dystonia and its motor and non-motor clinical presentations. It highlights the different parts of the human brain that may be implicated with these aspects of this network disorder. Finally, current limitations and promising future directions to deconstruct this knot and take a leap forward are mentioned.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44341662","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}

{"title":"Case Report: Bilateral globus pallidum internus DBS for treating tremor and dystonia in spinocerebellar ataxia 17: a thirteen-year follow-up","authors":"A. Wagle Shukla, Shilpa Chitnis, I. Malaty, Pamela Zeilman","doi":"10.3389/dyst.2023.11363","DOIUrl":"https://doi.org/10.3389/dyst.2023.11363","url":null,"abstract":"Background: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant trinucleotide disorder. There are no effective therapies for addressing the clinical symptoms of SCA17. Case report: We describe a 46-year-old male who presented with symptoms of generalized dystonia and focal arm tremors manifesting during adolescence. He underwent bilateral globus pallidus (GPi) DBS surgery that led to notable improvements in dystonia and tremor symptoms, impacting his quality of life. At the time of surgery, he did not show cerebellar ataxia features; however, these began to manifest 2 years after DBS surgery. He subsequently underwent genetic testing that confirmed the SCA17 diagnosis. Currently, at 13 years of follow-up, although the ataxia has continued to worsen, DBS therapy has led to persistent improvements in dystonia, tremor, and many aspects of quality of life. Discussion: The current case indicates that DBS is a promising symptomatic therapy for dystonia and tremor in SCA17.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49192290","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}