Dystonia最新文献

{"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":" ","pages":""},"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":"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":" ","pages":""},"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":"Correlated activity in globus pallidus and thalamus during voluntary reaching movement in three children with primary dystonia","authors":"M. Kasiri, Sina Javadzadeh, Jaya Nataraj, Seyyed Alireza Seyyed Mousavi, T. Sanger","doi":"10.3389/dyst.2023.11117","DOIUrl":"https://doi.org/10.3389/dyst.2023.11117","url":null,"abstract":"Classical models of the physiology of dystonia suggest that involuntary muscle contractions are caused by inappropriately low activity in Globus Pallidus internus (GPi) that fails to adequately inhibit thalamic inputs to cortex. We test this prediction in three children with primary dystonia undergoing depth electrode recording in basal ganglia and thalamus during selection of targets for deep brain stimulation (DBS) implantation. We compare muscle activity to the power in the spectrogram of the local field potential, as well as to counts of identified spikes in GPi, subthalamic nucleus (STN), and the Ventral oralis (VoaVop) and Ventral Anterior (VA) subnuclei of the thalamus, while subjects are at rest or attempting to make active voluntary arm or leg reaching movements. In all three subjects, both spectrogram power and spike activity in GPi, STN, VoaVop, and VA are significantly positively correlated with movement. In particular, GPi and STN both increase activity during attempted movement. These results contradict the classical rate model of the physiology of dystonia, and support more recent models that propose abnormalities in the detailed pattern of activity rather than the overall lumped activity of pallidum and thalamus.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47899247","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":"DYT-TOR1A genotype alters extracellular vesicle composition in murine cell model and shows potential for biomarker discovery","authors":"Connor S. King, Z. Caffall, E. Soderblom, N. Calakos","doi":"10.3389/dyst.2023.11053","DOIUrl":"https://doi.org/10.3389/dyst.2023.11053","url":null,"abstract":"Introduction: Biomarkers that can be used to identify patient subgroups with shared pathophysiology and/or that can be used as pharmacodynamic readouts of disease state are valuable assets for successful clinical trial design. In translational research for brain diseases, extracellular vesicles (EVs) have become a high-priority target for biomarker discovery because of their ubiquity in peripheral biofluids and potential to indicate brain state. Materials and methods: Here, we applied unbiased quantitative proteomics of EVs isolated from DYT-TOR1A knockin mouse embryonic fibroblasts and littermate controls to discover candidates for protein biomarkers. We further examined the response of genotype perturbations to drug treatment conditions to determine their pharmacodynamic properties. Results: We found that many DYT-TOR1A MEF EV differences were significantly corrected by ritonavir, a drug recently shown to correct DYT-TOR1A phenotypes in cell and mouse disease models. We also used tool compounds to explore the effect of the integrated stress response (ISR), which regulates protein synthesis and is implicated in dystonia pathogenesis. Integrated stress response inhibition in WT cells partially phenocopied the effects of DYT-TOR1A on EV proteome composition, and ISR potentiation in DYT-TOR1A caused changes that paralleled ritonavir treatment. Conclusion: These results collectively show that DYT-TOR1A genotype alters EV protein composition, and these changes can be dynamically modulated by a candidate therapeutic drug and ISR activity state. These mouse model findings provide proof-of-concept that EVs may be a useful source of biomarkers in human populations and further suggest specific homologs to evaluate in cross-species validation.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43789194","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":"Treatment of writer’s cramp based on current pathophysiological concepts","authors":"K. Zeuner, A. Baumann, K. Witt","doi":"10.3389/dyst.2023.11067","DOIUrl":"https://doi.org/10.3389/dyst.2023.11067","url":null,"abstract":"Task specific dystonia belongs to the group of focal dystonias. They are debilitating movement disorders that present with co-contraction of antagonist muscles during a specific task. The most common one is writer’s cramp. Botulinum toxin is the symptomatic standard treatment. Its response rate is 50% after 1 year, and the overall efficacy limited due to unwanted weakness in not injected muscles. The pathophysiology of writer’s cramp remains unclear, but genetic and additional environmental causes have been proposed. A possible underlying mechanism may be maladaptive reorganization in the sensorimotor cortex. Based on this background alternative treatment strategies were developed such as several different sensory and motor training programs that have been applied to reverse these brain abnormalities. In some studies, sensory and motor training were combined and adjunct with fitness exercises. They were conducted either as an outpatient setting or were established home based. Clinical outcome was measured with different clinical scales such as the writer’s cramp rating scale, the arm dystonia rating scale or the Burke, Fahn Marsden Scale. For objective assessment, kinematic handwriting parameters were analyzed. Functional or structural changes of the sensorimotor cortex were estimated using functional magnetic tomography, magnetencephalography and voxel-based morphometry. The results of these training programs were promising; however, one drawback is that the number of patients studied were small and the programs were not controlled since it is difficult to establish a control training to conduct a randomized controlled study.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43389272","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":"Treatment of tardive dystonia: A review","authors":"Paola Testini, S. Factor","doi":"10.3389/dyst.2023.10957","DOIUrl":"https://doi.org/10.3389/dyst.2023.10957","url":null,"abstract":"Tardive dystonia (TD), the second most common but most disabling form of tardive syndrome, was initially described in 1982. It is caused by exposure to dopamine receptor blocking agents including antipsychotics and antiemetics. It most commonly presents as cranial or cervical dystonia. Characteristics suggestive of a TD diagnosis include a young age of onset, male predominance, and the higher prevalence of phasic cervical dystonia and retrocollis. Treatment of TD is limited. In this paper we review the literature on treatment options for TD as well as discussing a strategic approach. Options include use of clozapine which appears to have anti-dystonia properties. Other medications reported on with limited evidence include VMAT2 inhibitors, anticholinergics, clonazepam, and baclofen. Botulinum toxin has been shown to provide relief in TD in a manner similar to primary dystonia. The largest literature is on the use of deep brain stimulation (DBS) of the globus pallidus pars interna which includes blinded studies. We finish with providing an algorithm based on current knowledge.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46044119","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":"Aparna Wagle Shukla, Robert Chen, Wei Hu","doi":"10.3389/dyst.2023.11362","DOIUrl":"10.3389/dyst.2023.11362","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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, <i>p</i> = 0.001; SAI ISI 30 ms, <i>p</i> = 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.</p><p><strong>Conclusion: </strong>Pain control in CD from BoNT therapy relates to modulation of sensorimotor integration at the cortical level.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11981640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47575901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient dystonia correlates with parkinsonism after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in nonhuman primates.","authors":"S A Norris, L Tian, E L Williams, J S Perlmutter","doi":"10.3389/dyst.2023.11019","DOIUrl":"10.3389/dyst.2023.11019","url":null,"abstract":"<p><p>Unilateral internal carotid artery 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion in non-human primates produces transient contralateral hemi-dystonia followed by stable contralateral hemi-parkinsonism; the relationship between dystonia and parkinsonism remains unclear. We hypothesized that transient dystonia severity following MPTP correlates with parkinsonism severity. In male Macaca nemestrina (<i>n</i> = 3) and M. fascicularis (<i>n</i> = 17) we administered unilateral intra-carotid MPTP, then correlated validated blinded ratings of transient peak dystonia and delayed parkinsonism. We also correlated dystonia severity with post-mortem measures of residual striatal dopamine and nigral neuron counts obtained a mean 53 ± 15 days following MPTP, after resolution of dystonia but during stable parkinsonism. Median latency to dystonia onset was 1 day, and peak severity 2.5 days after MPTP; total dystonia duration was 13.5 days. Parkinsonism peaked a median of 19.5 days after MPTP, remaining nearly constant thereafter. Peak dystonia severity highly correlated with parkinsonism severity (r[18] = 0.82, <i>p</i> < 0.001). Residual cell counts in lesioned nigra correlated linearly with peak dystonia scores (r[18] = -0.68, p=<0.001). Dystonia was not observed in monkeys without striatal dopamine depletion (<i>n</i> = 2); dystonia severity correlated with striatal dopamine depletion when residual nigral cell loss was less than 50% ([11] r = -0.83, <i>p</i> < 0.001) but spanned a broad range with near complete striatal dopamine depletion, when nigral cell loss was greater than 50%. Our data indicate that residual striatal dopamine may not reflect dystonia severity. We speculate on mechanisms of transient dystonia followed by parkinsonism that may be studied using this particular NHP MPTP model to better understand relationships of transient dystonia to nigrostriatal injury and parkinsonism.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10501383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10653943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered brain state during episodic dystonia in tottering mice decouples primary motor cortex from limb kinematics.","authors":"Madelyn M Gray,&nbsp;Anant Naik,&nbsp;Timothy J Ebner,&nbsp;Russell E Carter","doi":"10.3389/dyst.2023.10974","DOIUrl":"10.3389/dyst.2023.10974","url":null,"abstract":"Episodic Ataxia Type 2 (EA2) is a rare neurological disorder caused by a mutation in the CACNA1A gene, encoding the P/Q-type voltage-gated Ca2+ channel important for neurotransmitter release. Patients with this channelopathy exhibit both cerebellar and cerebral pathologies, suggesting the condition affects both regions. The tottering (tg/tg) mouse is the most commonly used EA2 model due to an orthologous mutation in the cacna1a gene. The tg/tg mouse has three prominent behavioral phenotypes: a dramatic episodic dystonia; absence seizures with generalized spike and wave discharges (GSWDs); and mild ataxia. We previously observed a novel brain state, transient low-frequency oscillations (LFOs) in the cerebellum and cerebral cortex under anesthesia. In this study, we examine the relationships among the dystonic attack, GSWDs, and LFOs in the cerebral cortex. Previous studies characterized LFOs in the motor cortex of anesthetized tg/tg mice using flavoprotein autofluorescence imaging testing the hypothesis that LFOs provide a mechanism for the paroxysmal dystonia. We sought to obtain a more direct understanding of motor cortex (M1) activity during the dystonic episodes. Using two-photon Ca2+ imaging to investigate neuronal activity in M1 before, during, and after the dystonic attack, we show that there is not a significant change in the activity of M1 neurons from baseline through the attack. We also conducted simultaneous, multi-electrode recordings to further understand how M1 cellular activity and local field potentials change throughout the progression of the dystonic attack. Neither putative pyramidal nor inhibitory interneuron firing rate changed during the dystonic attack. However, we did observe a near complete loss of GSWDs during the dystonic attack in M1. Finally, using spike triggered averaging to align simultaneously recorded limb kinematics to the peak Ca2+ response, and vice versa, revealed a reduction in the spike triggered average during the dystonic episodes. Both the loss of GSWDs and the reduction in the coupling suggest that, during the dystonic attack, M1 is effectively decoupled from other structures. Overall, these results indicate that the attack is not initiated or controlled in M1, but elsewhere in the motor circuitry. The findings also highlight that LFOs, GSWDs, and dystonic attacks represent three brain states in tg/tg mice.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10554815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41177608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anatomical categorization of isolated non-focal dystonia: novel and existing patterns using a data-driven approach.","authors":"J R Younce, R H Cascella, B D Berman, H A Jinnah, S Bellows, J Feuerstein, A Wagle Shukla, A Mahajan, F C F Chang, K R Duque, S Reich, S Pirio Richardson, A Deik, N Stover, J M Luna, S A Norris","doi":"10.3389/dyst.2023.11305","DOIUrl":"10.3389/dyst.2023.11305","url":null,"abstract":"<p><p>According to expert consensus, dystonia can be classified as focal, segmental, multifocal, and generalized, based on the affected body distribution. To provide an empirical and data-driven approach to categorizing these distributions, we used a data-driven clustering approach to compare frequency and co-occurrence rates of non-focal dystonia in pre-defined body regions using the Dystonia Coalition (DC) dataset. We analyzed 1,618 participants with isolated non-focal dystonia from the DC database. The analytic approach included construction of frequency tables, variable-wise analysis using hierarchical clustering and independent component analysis (ICA), and case-wise consensus hierarchical clustering to describe associations and clusters for dystonia affecting any combination of eighteen pre-defined body regions. Variable-wise hierarchical clustering demonstrated closest relationships between bilateral upper legs (distance = 0.40), upper and lower face (distance = 0.45), bilateral hands (distance = 0.53), and bilateral feet (distance = 0.53). ICA demonstrated clear grouping for the a) bilateral hands, b) neck, and c) upper and lower face. Case-wise consensus hierarchical clustering at k = 9 identified 3 major clusters. Major clusters consisted primarily of a) cervical dystonia with nearby regions, b) bilateral hand dystonia, and c) cranial dystonia. Our data-driven approach in a large dataset of isolated non-focal dystonia reinforces common segmental patterns in cranial and cervical regions. We observed unexpectedly strong associations between bilateral upper or lower limbs, which suggests that symmetric multifocal patterns may represent a previously underrecognized dystonia subtype.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49426200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}