Dystonia最新文献

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.

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 (n = 3) and M. fascicularis (n = 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, p < 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 (n = 2); dystonia severity correlated with striatal dopamine depletion when residual nigral cell loss was less than 50% ([11] r = -0.83, p < 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.

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.

Focal Hand Dystonia (FHD) is a disabling movement disorder characterized by involuntary movements, cramps and spasms. It is associated with pathological neural microcircuits in the cortical somatosensory system. While invasive preclinical modalities allow researchers to probe specific neural microcircuits of cortical layers and columns, conventional functional magnetic resonance imaging (fMRI) cannot resolve such small neural computational units. In this study, we take advantage of recent developments in ultra-high-field MRI hardware and MR-sequences to capture altered digit representations and laminar processing in FHD patients. We aim to characterize the capability and challenges of layer-specific imaging and analysis tools in resolving laminar and columnar structures in clinical research setups. We scanned N = 4 affected and N = 5 unaffected hemispheres at 7T and found consistent results of altered neural microcircuitry in FHD patients: 1) In affected hemispheres of FHD patients, we found a breakdown of ordered finger representation in the primary somatosensory cortex, as suggested from previous low-resolution fMRI. 2) In affected primary motor cortices of FHD patients, we furthermore found increased fMRI activity in superficial cortico-cortical neural input layers (II/III), compared to relatively weaker activity in the cortico-spinal output layers (Vb/VI). Overall, we show that layer-fMRI acquisition and analysis tools have the potential to address clinically-driven neuroscience research questions about altered computational mechanisms at the spatial scales that were previously only accessible in animal models. We believe that this study paves the way for easier translation of preclinical work into clinical research in focal hand dystonia and beyond.

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.

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.

Background: Blepharospasm (BSP) is a focal dystonia. There is a lack of standardization in the length of time necessary to get a measure of BSP severity for rating scales.

Objectives: 1) Determine the difference between evaluating the number of eye closures in patients with blepharospasm in 1 vs. 2 min. 2) Characterize the prevalence, phenomenology and concordance of sensory trick in subjects with only blepharospasm compared to those with blepharospasm associated with other dystonias of the head.

Methods: Thirty-eight, 2-min-long standardized videos of subjects with BSP without any other dystonias were reviewed (group1). Eye closure rate was measured in 0-60 s vs. 60-120 s. Wilcoxon signed-rank test and Spearman correlation coefficient were used to compare the eye closure rate between these two intervals. An additional 68 standardized videos of subjects with blepharospasm associated with dystonia of the head were reviewed (group2). Presence, phenomenology and concordance between what subjects verbally reported as their sensory trick and what they demonstrated was classified for both groups then qualitatively compared.

Results/conclusion: Eye closure rates between 0-60 s and 0-120 s were not statistically different. There is no added benefit of counting the number of eye closures in 2 min, compared to 1 min, in patients with BSP. Sensory trick was reported by 57% of subjects with BSP and 80% of subjects who have blepharospasm and other dystonias of the head. With 100% and 97% concordance, patients' self-reported sensory trick accurately describes the movements that alleviate their dystonic movements.

Dystonia is the third most common movement disorder. It causes debilitating twisting postures that are accompanied by repetitive and sometimes intermittent co- or over-contractions of agonist and antagonist muscles. Historically diagnosed as a basal ganglia disorder, dystonia is increasingly considered a network disorder involving various brain regions including the cerebellum. In certain etiologies of dystonia, aberrant motor activity is generated in the cerebellum and the abnormal signals then propagate through a "dystonia circuit" that includes the thalamus, basal ganglia, and cerebral cortex. Importantly, it has been reported that non-motor defects can accompany the motor symptoms; while their severity is not always correlated, it is hypothesized that common pathways may nevertheless be disrupted. In particular, circadian dysfunction and disordered sleep are common non-motor patient complaints in dystonia. Given recent evidence suggesting that the cerebellum contains a circadian oscillator, displays sleep-stage-specific neuronal activity, and sends robust long-range projections to several subcortical regions involved in circadian rhythm regulation, disordered sleep in dystonia may result from cerebellum-mediated dysfunction of the dystonia circuit. Here, we review the evidence linking dystonia, cerebellar network dysfunction, and cerebellar involvement in sleep. Together, these ideas may form the basis for the development of improved pharmacological and surgical interventions that could take advantage of cerebellar circuitry to restore normal motor function as well as non-motor (sleep) behaviors in dystonia.