Dystonia最新文献

Introduction: Pain is a common symptom of cervical dystonia (CD). The mainstay of treatment of CD is botulinum toxin, which is known to have benefits in relieving pain. We aimed to characterize the locations of pain in patients with CD, and to assess what factors may predict pain reduction following botulinum toxin injection.

Methods: We conducted a single-center observational study of CD patients who reported pain and who received botulinum toxin treatment. On the day of their toxin injection (in the untreated state), they filled out a survey evaluating primary and secondary sites of pain as indicated on a diagram, as well as Pain Numeric Rating Scale assessing average pain over the past 24 h. Two weeks later, they filled out a follow-up survey (in the treated state) to evaluate whether location and pain intensity changed.

Results: 55 people with CD participated in the study, and 40 of them completed both surveys. Most patients reported pain localization over the posterior musculature, especially in the areas overlying superior trapezius and levator scapulae. 21 of 40 (52.5%) patients reported improvement of pain intensity by ≥ 30% in the primary site of pain. The mean improvement in pain intensity was 30.4% (SD = 32.4%), with a mean improvement on Numeric Rating Scale of 2.13 (SD = 2.02). 68% of patients received injections into or close to their primary site of pain. Using univariate linear regression, there was no clear effect of age, sex, muscles injected, or TWSTRS motor subscale on the degree of pain improvement. The locations of pain remained relatively stable in the post-treatment state.

Conclusion: We confirmed that botulinum toxin is effective for treatment of pain related to CD. We also gained insight into the typical locations of pain in CD by generating a heat map, showing pain most often in the regions of upper trapezius, levator scapulae, and splenius cervicus and capitis. Although there was not a significant correlation between the site of botulinum toxin injection and pain improvement, larger studies are needed to better determine optimal treatment strategies.

DYT1 dystonia is an inherited early-onset generalized dystonia characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice or global KI mice show motor deficits and abnormal Purkinje cell firing. However, Purkinje cell-specific heterozygous ΔGAG conditional KI mice (Pcp2-KI) show improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, and reduced functional connectivity of the striatum with the anterior medulla. Whether Pcp2-KI mice show similar abnormal Purkinje cell firing as the global KI mice, suggesting a cell-autonomous effect causes the abnormal Purkinje cell firing in the global KI mice, is unknown. We used acute cerebellar slice recording in Pcp2-KI mice to address this issue. The Pcp2-KI mice exhibited no changes in spontaneous firing and intrinsic excitability compared to the control mice. While membrane properties were largely unchanged, the resting membrane potential was slightly hyperpolarized, which was associated with decreased baseline excitability. Our results suggest that the abnormal Purkinje cell firing in the global KI mice was not cell-autonomous and was caused by physiological changes elsewhere in the brain circuits. Our results also contribute to the ongoing research of how basal ganglia and cerebellum interact to influence motor control in normal states and movement disorders.

Background and objectives: Dystonia is the third most common movement disorder. Motor and non-motor manifestations of dystonia may impact Health Related Quality of Life (HRQoL), with lower HRQoL scores compared to the healthy population. People with generalized dystonia report worse HRQoL scores (vs. people with focal distributions). Social determinants of health (SDOH) may play a role in HRQoL outcomes in dystonia, but scant data exists. We aimed to examine differences in HRQoL scores in people with focal vs. non-focal (e.g., segmental, multifocal, generalized) dystonia and the association with SDOH.

Methods: 129 participants with isolated dystonia, who were recruited through Mass General Brigham movement disorders clinic and enrolled in the Dystonia Partners Research Bank, completed a follow-up survey on SDOH and HRQoL: Quality of Life in Neurological Disorders Version 2.0 Short Form (Neuro- QoL-SF) and the EuroGroup 5-level (Euro-QoL). Linear regression analyses were performed.

Results: Participants with isolated dystonia were predominantly female (72.1%), non-Hispanic white (79.8%), and highly educated (79.8%; ≥ bachelor's degree). 71.3% of the participants had focal dystonia and 28.7% of the participants had non-focal dystonia. Participants with focal dystonia (vs. non-focal dystonia) reported older age at diagnosis (49.2 ± 11.7 vs. 40.6 ± 19.2, p = 0.004). Participants with focal dystonia (vs. non-focal dystonia) reported higher (i.e., better) overall health scores (80.4 ± 13.9 vs. 72.8 ± 13.5, p = 0.005), higher ability to participate in social activities (51.3 ± 7.7 vs. 47.2 ± 6.0, p = 0.003), lower fatigue (44.7 ± 8.4 vs. 49.8 ± 7.2, p = 0.001), and lower sleep disturbance (48.0 ± 8.2 vs. 53.0 ± 7.9, p = 0.002). Independent predictors of higher overall health ratings included focal distribution of dystonia (b = 7.5; p = 0.01), a higher level of education (b = 9.2; p = 0.04) and not having a mental health diagnosis (b = 7.5; p = 0.01).

Conclusion: Participants with focal dystonia were diagnosed later and had higher (i.e., better) HRQoL measures vs. participants with non-focal dystonia. Predictors of better HRQoL were having focal dystonia and higher level of education, whereas the presence of a mental health diagnosis was associated with lower HRQoL (i.e., worse) scores. SDOH such as employment status, medical literacy, and ability to afford basic needs may influence HRQoL ratings for participants with isolated dystonia. Our findings may not be generalizable to the general population of patients with isolated dystonia. We highlight areas for further research and development.

Dystonia causes involuntary, patterned movements and posturing, often leading to disability, pain, and reduced quality-of-life. Despite standard treatments such as botulinum toxin (BoNT) injections, oral medications, and deep brain stimulation therapy, many patients continue to experience persistent symptoms. There is growing evidence supporting the use of rehabilitation-based therapies in the management of certain forms of dystonia. This review summarizes the current body of evidence, which primarily focuses on cervical dystonia (CD) and task-specific dystonia (TSD). The greatest therapeutic potential appears to lie in using these interventions as adjuncts to BoNT therapy. In CD, physical therapy has shown effectiveness when aimed at reducing overactivity in the affected neck muscles through techniques such as stretching, massage, and biofeedback. Concurrently, strengthening the opposing muscle groups helps promote improved posture, reduce pain, and enhance range of motion. In TSD, many studies applied splinting of unaffected body parts (sensory-motor retuning) to encourage adaptive retraining of affected body parts (principles of constraint-induced movement therapy), or alternatively restricting movements of affected body parts to promote sensory reorganization. Although there is high risk of bias, neuroplasticity-based strategies like motor and sensorimotor training appear to be promising for TSD. Use of kinesiotaping, vibrotactile stimulation, TENS, and orthotics can help modify movement patterns, while biofeedback can reinforce and sustain motor control improvements. Emerging evidence for functional dystonia supports the role of multimodal approach, combining PT with cognitive behavioral therapy or mind-body strategies. The focus is movement retraining to shift attention away from abnormal movements and restore confidence in normal movement to improve outcomes. Regardless of dystonia type, individualized therapy plans are essential. Home-based exercises play a critical role in maintaining the gains achieved during supervised sessions, supporting ongoing progress, and preventing regression.

Dystonias are a group of neurodegenerative disorders that result in altered physiology associated with motor movements. Both the basal ganglia and the cerebellum, brain regions involved in motor learning, sensory perception integration, and reward, have been implicated in the pathology of dystonia, but the cellular and subcellular mechanisms remain diverse and for some forms of dystonia, elusive. The goal of the current review is to summarize recent evidence of cerebellar involvement in different subtypes of dystonia with a focus on Purkinje cell (PC) and cerebellar nuclei (CN) dysfunction, to find commonalities in the pathology that could lay the groundwork for the future development of therapeutics for patients with dystonia. Here we will briefly discuss the physical and functional connections between the basal ganglia and the cerebellum and how these connections could contribute to dystonic symptoms. We proceed to use human and animal model data to discuss the contributions of cerebellar cell types to specific dystonias and movement disorders where dystonia is a secondary symptom. Ultimately, we suggest PC and CN irregularity could be a locus for dystonia through impaired calcium dynamics.

DYT1 dystonia is an early onset, generalized form of isolated dystonia characterized by sustained involuntary muscle co-contraction, leading to abnormal movements and postures. It is the most common hereditary form of primary dystonia, caused by a trinucleotide GAG deletion in the DYT1 gene, which encodes the TorsinA protein. Recent studies conceptualized dystonia as a functional network disorder involving basal ganglia, thalamus, cortex and cerebellum. However, how TorsinA dysfunction in specific cell types affects network connectivity and dystonia-related pathophysiology remains unclear. In this study, we aimed to elucidate the impact of the GAG TorsinA mutation present globally and when restricted to the cortical and hippocampal neurons. To accomplish this, we generated two distinct Dyt1 mouse models, one with Dyt1 dGAG knock-in throughout the body (dGAG) and another with a cerebral cortex-specific Dyt1 dGAG knock-in using Emx1 promoter (EMX). In both models, we performed in vivo neuroimaging at ultra-high field (11.1T). We employed functional magnetic resonance imaging (fMRI) to assess resting-state and sensory-evoked brain connectivity and activation, along with diffusion MRI (dMRI) to evaluate microstructural changes. We hypothesized that dGAG mice would exhibit widespread network disruptions compared to the cortex-specific EMX mice, due to broader TorsinA dysfunction across the basal ganglia and cerebellum. We also hypothesized that EMX mice would exhibit altered functional connectivity and activation patterns, supporting the idea that TorsinA dysfunction in the sensorimotor cortex alone can induce network abnormalities. In dGAG animals, we observed significantly lower functional connectivity between key sensorimotor nodes, such as the globus pallidus, somatosensory cortex, thalamus, and cerebellum. EMX mice, while showing less extensive network disruptions, exhibited increased functional connectivity between cerebellum and seeds in the striatum and brainstem. These functional connectivity alterations between nodes in the basal ganglia and the cerebellum in both dGAG, EMX models underscore the involvement of cerebellum in dystonia. No significant structural changes were observed in either model. Overall, these results strengthen the concept of dystonia as a network disorder where multiple nodes across the brain network contribute to pathophysiology, supporting the idea that therapeutic strategies in dystonia may benefit from consideration of network properties across multiple brain regions.

Myoclonus is a hyperkinetic movement disorder characterized by sudden, brief, involuntary jerks of single or multiple muscles. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Myoclonus-dystonia (M-D) or DYT11 dystonia is an early-onset genetic disorder characterized by subcortical myoclonus and less pronounced dystonia. DYT11 dystonia is the primary genetic M-D caused by loss of function mutations in SGCE, which codes for ε-sarcoglycan. Sgce knockout (KO) mice model DYT11 dystonia and exhibit myoclonus, motor deficits, and psychiatric-like behaviors. Neuroimaging studies show abnormal cerebellar activity in DYT11 dystonia patients. Acute small hairpin RNA (shRNA) knockdown of Sgce mRNA in the adult cerebellum leads to motor deficits, myoclonic-like jerky movements, and altered Purkinje cell firing. Whether Sgce KO mice show similar abnormal Purkinje cell firing as the acute shRNA knockdown mice is unknown. We used acute cerebellar slice recording in Sgce KO mice to address this issue. The Purkinje cells from Sgce KO mice showed spontaneous and intrinsic excitability changes compared to the wild-type (WT) mice. Intrinsic membrane properties were not altered. The female Sgce KO mice had more profound alterations in Purkinje cell firing than males, which may correspond to the early onset of the symptoms in female human patients and more pronounced myoclonus in female KO mice. Our results suggest that the abnormal Purkinje cell firing in the Sgce KO mice contributes to the manifestation of the myoclonus and other motor symptoms in DYT11 dystonia patients.