Pathophysiology Of Dystonia Research Articles

Smell and taste in cervical dystonia

The pathophysiology of cervical dystonia is not completely understood. Current concepts of the pathophysiology propose that it is a network disorder involving the basal ganglia, cerebellum and sensorimotor cortex. These structures are primarily concerned with sensorimotor control but are also involved in non-motor functioning such as the processing of information related to the chemical senses. This overlap lets us hypothesize a link between cervical dystonia and altered sense of smell and taste. To prove this hypothesis and to contribute to the better understanding of cervical dystonia, we assessed olfactory and gustatory functioning in 40 adults with idiopathic cervical dystonia and 40 healthy controls. The Sniffin Sticks were used to assess odor threshold, discrimination and identification. Furthermore, the Taste Strips were applied to assess the combined taste score. Motor and non-motor deficits of cervical dystonia including neuropsychological and psychiatric alterations were assessed as cofactors for regression analyses. We found that cervical dystonia subjects had lower scores than healthy controls for odor threshold (5.8 ± 2.4 versus 8.0 ± 3.2; p = 0.001), odor identification (11.7 ± 2.3 versus 13.1 ± 1.3; p = 0.001) and the combined taste score (9.5 ± 2.2 versus 11.7 ± 2.7; p < 0.001), while no difference was found in odor discrimination (12.0 ± 2.5 versus 12.9 ± 1.8; p = 0.097). Regression analysis suggests that age is the main predictor for olfactory decline in subjects with cervical dystonia. Moreover, performance in the Montreal Cognitive Assessment is a predictor for gustatory decline in cervical dystonia subjects. Findings propose that cervical dystonia is associated with diminished olfactory and gustatory functioning.

Dystonia: Sparse Synapses for D2 Receptors in Striatum of a DYT1 Knock-out Mouse Model.

Dystonia pathophysiology has been partly linked to downregulation and dysfunction of dopamine D2 receptors in striatum. We aimed to investigate the possible morpho-structural correlates of D2 receptor downregulation in the striatum of a DYT1 Tor1a mouse model. Adult control Tor1a+/+ and mutant Tor1a+/− mice were used. The brains were perfused and free-floating sections of basal ganglia were incubated with polyclonal anti-D2 antibody, followed by secondary immune-fluorescent antibody. Confocal microscopy was used to detect immune-fluorescent signals. The same primary antibody was used to evaluate D2 receptor expression by western blot. The D2 receptor immune-fluorescence appeared circumscribed in small disks (~0.3–0.5 µm diameter), likely representing D2 synapse aggregates, densely distributed in the striatum of Tor1a+/+ mice. In the Tor1a+/− mice the D2 aggregates were significantly smaller (µm2 2.4 ± SE 0.16, compared to µm2 6.73 ± SE 3.41 in Tor1a+/+) and sparse, with ~30% less number per microscopic field, value correspondent to the amount of reduced D2 expression in western blotting analysis. In DYT1 mutant mice the sparse and small D2 synapses in the striatum may be insufficient to “gate” the amount of presynaptic dopamine release diffusing in peri-synaptic space, and this consequently may result in a timing and spatially larger nonselective sphere of influence of dopamine action.

Advances in the pathophysiology of adult-onset focal dystonias: recent neurophysiological and neuroimaging evidence.

Focal dystonia is a movement disorder characterized by involuntary muscle contractions that determine abnormal postures. The traditional hypothesis that the pathophysiology of focal dystonia entails a single structural dysfunction (i.e. basal ganglia) has recently come under scrutiny. The proposed network disorder model implies that focal dystonias arise from aberrant communication between various brain areas. Based on findings from animal studies, the role of the cerebellum has attracted increased interest in the last few years. Moreover, it has been increasingly reported that focal dystonias also include nonmotor disturbances, including sensory processing abnormalities, which have begun to attract attention. Current evidence from neurophysiological and neuroimaging investigations suggests that cerebellar involvement in the network and mechanisms underlying sensory abnormalities may have a role in determining the clinical heterogeneity of focal dystonias.

Historical view on the pathogenesis and surgical treatment of cervical dystonia

In the past few decades, approaches to surgical treatment of dystonia passed through paradigmatic shift. Intradural upper cervical anterior rhizotomy was replaced by selective peripheral denervation with lesser spectrum of side-effects. Such techniques as microvascular decompression of accessory nerve or spinal cord stimulation for cervical dystonia were abandoned due to lack of proven efficacy. Introducing globus pallidus interna (GPi) DBS in 1990's to treat all types of dystonia, including cervical dystonia, was a fundamental factor. With the growing body of knowledge on the pathophysiology of dystonia, GPi DBS appears to be the most expedient, effective and safe method with limited indications to peripheral destructive procedures.

Hemodynamic responses are abnormal in isolated cervical dystonia.

Neuroimaging studies using functional magnetic resonance imaging (fMRI), which measures brain activity by detecting the changes in blood oxygenation levels, are advancing our understanding of the pathophysiology of dystonia. Neurobiological disturbances in dystonia, however, may affect neurovascular coupling and impact the interpretability of fMRI studies. We evaluated here whether the hemodynamic response patterns during a behaviorally matched motor task are altered in isolated cervical dystonia (CD). Twenty-five CD patients and 25 healthy controls (HCs) underwent fMRI scanning during a paced finger tapping task (nondystonic task in patients). Imaging data were analyzed using a constrained principal component analysis-a statistical method that combines regression analysis and principal component analysis and enables the extraction of task-related functional networks and determination of the spatial and temporal hemodynamic response patterns associated with the task performance. Data from three patients and two controls were removed due to excessive movement. No significant differences in demographics or motor performance were observed. Three task-associated functional brain networks were identified. During task performance, reduced hemodynamic responses were seen in a sensorimotor network and in a network that included key nodes of the default mode, executive control and visual networks. During rest, reductions in hemodynamic responses were seen in the cognitive/visual network. Lower hemodynamic responses within the primary sensorimotor network in patients were correlated with the increased dystonia severity. Pathophysiological disturbances in isolated CD, such as alterations in inhibitory signaling and dopaminergic neurotransmission, may impact neurovascular coupling. Not accounting for hemodynamic response differences in fMRI studies of dystonia could lead to inaccurate results and interpretations.

Ten-Year Reflections on the Neurophysiological Abnormalities of Focal Dystonias in Humans.

The physiological landscape of dystonia has changed considerably over the past 10 years. Initial ideas that dystonic motor symptoms could be explained by a combination of loss of inhibition and increased plasticity, together with subtle deficits in sensory processing, have been questioned, whereas the possible role of the cerebellum has risen in importance. In addition, it has been recognized that symptoms affect more than just the motor and sensory systems and encompass independent cognitive and psychological changes. Finally, it has become clear that, despite similarities in symptoms, there may be pathophysiological differences between idiopathic, inherited, and acquired forms of dystonia. In other words, progress in the pathophysiology of dystonia has followed the usual pattern from an initial phase in which core deficits are readily explained by highly simplified models to a realization that within a highly interconnected network, effects are more nuanced with widespread changes that might either compensate or contribute to the clinical symptoms to different degrees in different individuals. © 2019 International Parkinson and Movement Disorder Society.

A Study of the Midbrain Network for Covert Attentional Orienting in Cervical Dystonia Patients using Dynamic Causal Modelling.

Understanding the neuronal network dynamics underlying the third most common movement disorder, cervical dystonia, can be achieved using dynamic causal modelling. Current literature establishes structures of the midbrain network for covert attentional orienting as dysfunctional in patients with cervical dystonia. One of these structures is the superior colliculus, for which it is hypothesised that deficient GABAergic activity therein causes cervical dystonia. To understand the role that this node plays in cervical dystonia, various connectivity models of the midbrain network were compared under the influence of a loom-recede visual stimulus fMRI paradigm. These models included the thalamus and striatum, crucial nodes in the direct/indirect pathways for motor movement and inhibition. The parametric empirical Bayes approach was used to quantify the difference in connection strengths across the winning models between patients and controls. Our findings demonstrated greater modulation by a looming stimulus event on the strength of connection from the striatum to the superior colliculus in patients. These results offer new means to understanding the pathophysiology of cervical dystonia.

Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia.

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico‐striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico‐striatal synaptic plasticity contributes to abnormal reward‐learning behavior in patients with focal dystonia. Forty patients and 40 controls performed a reward gain and loss avoidance reversal learning task. Participant's behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico‐striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesized receptor specific abnormalities of cortico‐striatal long‐term potentiation (LTP) and long‐term depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post‐reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient's motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient's behavior, suggesting excessive D2 cortico‐striatal synaptic depotentiation could underpin biased reward‐learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioral correlate of D2‐specific abnormalities in cortico‐striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward‐learning behavior in these patients.

Top-down alteration of functional connectivity within the sensorimotor network in focal dystonia.

To determine the directionality of regional interactions and influences of one region on another within the functionally abnormal sensorimotor network in isolated focal dystonia. A total of 40 patients with spasmodic dysphonia with and without dystonic tremor of voice and 35 healthy controls participated in the study. Independent component analysis (ICA) of resting-state fMRI was used to identify 4 abnormally coupled brain regions within the functional sensorimotor network in all patients compared to controls. Follow-up spectral dynamic causal modeling (DCM) estimated regional effective connectivity between patients and controls and between patients with spasmodic dysphonia with and without dystonic tremor of voice to expand the understanding of symptomatologic variability associated with this disorder. ICA found abnormally reduced functional connectivity of the left inferior parietal cortex, putamen, and bilateral premotor cortex in all patients compared to controls, pointing to a largely overlapping pathophysiology of focal dystonia and dystonic tremor. DCM determined that the disruption of the sensorimotor network was both top-down, involving hyperexcitable parieto-putaminal influence, and interhemispheric, involving right-to-left hyperexcitable premotor coupling in all patients compared to controls. These regional alterations were associated with their abnormal self-inhibitory function when comparing patients with spasmodic dysphonia patients with and without dystonic tremor of voice. Abnormal hyperexcitability of premotor-parietal-putaminal circuitry may be explained by altered information transfer between these regions due to underlying deficient connectivity. Identification of brain regions involved in processing of sensorimotor information in preparation for movement execution suggests that complex network disruption is staged well before the dystonic behavior is produced by the primary motor cortex.

Increased Finger-Tapping Related Cerebellar Activation in Cervical Dystonia, Enhanced by Transcranial Stimulation: An Indicator of Compensation?

Background: Cervical dystonia is a movement disorder causing abnormal postures and movements of the head. While the exact pathophysiology of cervical dystonia has not yet been fully elucidated, a growing body of evidence points to the cerebellum as an important node.Methods: Here, we examined the impact of cerebellar interference by transcranial magnetic stimulation on finger-tapping related brain activation and neurophysiological measures of cortical excitability and inhibition in cervical dystonia and controls. Bilateral continuous theta-burst stimulation was used to modulate cerebellar cortical excitability in 16 patients and matched healthy controls. In a functional magnetic resonance imaging arm, data were acquired during simple finger tapping before and after cerebellar stimulation. In a neurophysiological arm, assessment comprised motor-evoked potentials amplitude and cortical silent period duration. Theta-burst stimulation over the dorsal premotor cortex and sham stimulation (neurophysiological arm only) served as control conditions.Results: At baseline, finger tapping was associated with increased activation in the ipsilateral cerebellum in patients compared to controls. Following cerebellar theta-burst stimulation, this pattern was even more pronounced, along with an additional movement-related activation in the contralateral somatosensory region and angular gyrus. Baseline motor-evoked potential amplitudes were higher and cortical silent period duration shorter in patients compared to controls. After cerebellar theta-burst stimulation, cortical silent period duration increased significantly in dystonia patients.Conclusion: We conclude that in cervical dystonia, finger movements—though clinically non-dystonic—are associated with increased activation of the lateral cerebellum, possibly pointing to general motor disorganization, which remains subclinical in most body regions. Enhancement of this activation together with an increase of silent period duration by cerebellar continuous theta-burst stimulation may indicate predominant disinhibitory effects on Purkinje cells, eventually resulting in an inhibition of cerebello-thalamocortical circuits.

Neuropathology of Dystonia.

BackgroundDystonia is characterized by sustained or intermittent muscle contractions resulting in abnormal, often repetitive, movements, postures, or both. Neuropathologic research has been essential in understanding the etiology and disease progression of other movement disorders, including Parkinson’s disease and cerebellar ataxias. In the field of dystonia, however, research is stymied by the paucity of post-mortem tissue available and the phenotypic heterogeneity found in those with dystonia.MethodsA PubMed search was conducted using the term “neuropathology of dystonia”. The resulting list of references was limited to English-language human neuropathology articles. A total of 20 publications were retrieved and reviewed.ResultsHistorically, based on study of acquired forms of dystonia, lesions of the putamen and globus pallidus have been identified as causing dystonia. After the identification of genetic causes of dystonia and the study of limited tissue available from those cases, as well as findings from cases of isolated focal and segmental dystonia, there is evidence that brainstem cholinergic neurons and specific cell populations within the cerebellum also play a role in the pathophysiology of dystonia.DiscussionBased on limited available brain tissue, there is evidence that the pathophysiology of dystonia may involve a combination of dysfunction within neurons of the brainstem, cerebellum, putamen, and globus pallidus. In order to gain a better understanding of the pathophysiology of dystonia, a prospective, quantitative study in well-phenotyped subjects with different types of genetic and isolated dystonia is required.

The role of sensory information in the pathophysiology of focal dystonias.

Over the past few decades, abnormalities in sensory functions, such as tactile, proprioceptive and nociceptive processing, have been increasingly recognized in patients with focal dystonias. In this Review, we ask whether sensory system abnormalities are specific to particular types of dystonia, whether a causal link exists between sensory alterations and dystonic motor activity and how mechanisms underlying the sensory abnormalities fit in with the proposed 'network model' of dystonia. We suggest that alterations in the various sensory modalities participate at three different levels in the pathophysiological cascade that leads to dystonia: a background level that predisposes individuals to dystonia, a disease-related level that is evident only when dystonia becomes manifest and a causative level that triggers dystonia. We conclude that it is crucial to study sensory as well as motor pathophysiology to fully understand focal dystonias.

Abnormal cerebellar connectivity and plasticity in isolated cervical dystonia.

There is increasing evidence that supports the role of the cerebellum in the pathophysiology of dystonia. We used transcranial magnetic stimulation to test the hypothesis that patients with cervical dystonia may have a disrupted cerebellar cortical connectivity at rest, and that cerebellar plasticity is altered too. We enrolled 12 patients with isolated cervical dystonia and 13 controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right cerebellum and the left primary motor area. Changes in the amplitude of motor evoked potentials were analysed. Continuous and intermittent Theta Burst Stimulation over the cerebellum was also applied. The effects of these repetitive protocols on cortical excitability, on intra-cortical circuits and on cerebellar cortical inhibition were analysed. In healthy subjects, but not in dystonic patients, a conditioning stimulus over the cerebellum was able to inhibit the amplitude of the motor evoked potentials from primary motor cortex. In healthy subjects continuous and intermittent cerebellar Theta Burst Stimulation were able to decrease and increase respectively motor cortex excitability. Continuous Theta Burst Stimulation was able to abolish the cerebellar cortical inhibition observed in basal condition. These effects were not observed in patients with cervical dystonia. Cerebellar cortical connectivity and cerebellar plasticity is altered at rest in patients with cervical dystonia.

The role of pallidum in the neural integrator model of cervical dystonia

Dystonia is the third most common movement disorder affecting three million people worldwide. Cervical dystonia is the most common form of dystonia. Despite common prevalence the pathophysiology of cervical dystonia is unclear. Traditional view is that basal ganglia is involved in pathophysiology of cervical dystonia, while contemporary theories suggested the role of cerebellum and proprioception in the pathophysiology of cervical dystonia. It was recently proposed that the cervical dystonia is due to malfunctioning of the head neural integrator – the neuron network that normally converts head velocity to position. Most importantly the neural integrator model was inclusive of traditional proposal emphasizing the role of basal ganglia while also accommodating the contemporary view suggesting the involvement of cerebellum and proprioception. It was hypothesized that the head neural integrator malfunction is the result of impairment in cerebellar, basal ganglia, or proprioceptive feedback that converge onto the integrator. The concept of converging input from the basal ganglia, cerebellum, and proprioception to the network participating in head neural integrator explains that abnormality originating anywhere in the network can lead to the identical motor deficits – drifts followed by rapid corrective movements – a signature of neural integrator dysfunction. We tested this hypothesis in an experiment examining simultaneously recorded globus pallidal single-unit activity, synchronized neural activity (local field potential), and electromyography (EMG) measured from the neck muscles during the standard-of-care deep brain stimulation surgery in 12 cervical dystonia patients (24 hemispheres). Physiological data were collected spontaneously or during voluntary shoulder shrug activating the contralateral trapezius muscle. The activity of pallidal neurons during shoulder shrug exponentially decayed with time constants that were comparable to one measured from the pretectal neural integrator and the trapezius electromyography. These results show that evidence of abnormal neural integration is also seen in globus pallidum, and that latter is connected with the neural integrator. Pretectal single neuron responses consistently preceded the muscle activity; while the globus pallidum internus response always lagged behind the muscle activity. Globus pallidum externa had equal proportion of lag and lead neurons. These results suggest globus pallidum receive feedback from the muscles or the efference copy from the integrator or the other source of the feedback. There was bi-hemispheric asymmetry in the pallidal single-unit activity and local field potentials. The asymmetry correlated with degree of lateral head turning in cervical dystonia patients. These results suggest that bihemispheric asymmetry in the feedback leads to asymmetric dysfunction in the neural integrator causing head turning.

Structural brain network fingerprints of focal dystonia.

Background:Focal dystonias are severe and disabling movement disorders of a still unclear origin. The structural brain networks associated with focal dystonia have not been well characterized. Here, we investigated structural brain network fingerprints in patients with blepharospasm (BSP) compared with those with hemifacial spasm (HFS), and healthy controls (HC). The patients were also examined following treatment with botulinum neurotoxin (BoNT).Methods:This study included matched groups of 13 BSP patients, 13 HFS patients, and 13 HC. We measured patients using structural-magnetic resonance imaging (MRI) at baseline and after one month BoNT treatment, at time points of maximal and minimal clinical symptom representation, and HC at baseline. Group regional cross-correlation matrices calculated based on grey matter volume were included in graph-based network analysis. We used these to quantify global network measures of segregation and integration, and also looked at local connectivity properties of different brain regions.Results:The networks in patients with BSP were more segregated than in patients with HFS and HC (p < 0.001). BSP patients had increased connectivity in frontal and temporal cortices, including sensorimotor cortex, and reduced connectivity in the cerebellum, relative to both HFS patients and HC (p < 0.05). Compared with HC, HFS patients showed increased connectivity in temporal and parietal cortices and a decreased connectivity in the frontal cortex (p < 0.05). In BSP patients, the connectivity of the frontal cortex diminished after BoNT treatment (p < 0.05). In contrast, HFS patients showed increased connectivity in the temporal cortex and reduced connectivity in cerebellum after BoNT treatment (p < 0.05).Conclusions:Our results show that BSP patients display alterations in both segregation and integration in the brain at the network level. The regional differences identified in the sensorimotor cortex and cerebellum of these patients may play a role in the pathophysiology of focal dystonia. Moreover, symptomatic reduction of hyperkinesia by BoNT treatment was associated with different brain network fingerprints in both BSP and HFS patients.

Distinct roles of brain activity and somatotopic representation in pathophysiology of focal dystonia

Two main neural mechanisms including loss of cortical inhibition and maladaptive plasticity have been thought to be involved in the pathophysiology of focal task-specific dystonia. Such loss of inhibition and maladaptive plasticity likely correspond to cortical overactivity and disorganized somatotopy, respectively. However, the most plausible mechanism of focal task-specific dystonia remains unclear. To address this question, we assessed brain activity and somatotopic representations of motor-related brain areas using functional MRI and behavioral measurement in healthy instrumentalists and patients with embouchure dystonia as an example of focal task-specific dystonia. Dystonic symptoms were measured as variability of fundamental frequency during long tone playing. We found no significant differences in brain activity between the embouchure dystonia and healthy wind instrumentalists in the motor-related areas. Assessment of somatotopy, however, revealed significant differences in the somatotopic representations of the mouth area for the right somatosensory cortex between the two groups. Multiple-regression analysis revealed brain activity in the primary motor and somatosensory cortices, cerebellum, and putamen was significantly associated with variability of fundamental frequency signals representing dystonic symptoms. Conversely, somatotopic representations in motor-related brain areas were not associated with variability of fundamental frequency signals in embouchure dystonia. The present findings suggest that abnormal motor-related network activity and aberrant somatotopy correlate with different aspects of mechanisms underlying focal task-specific dystonia.

Motor Cortical Plasticity Relates to Symptom Severity and Clinical Benefit From Deep Brain Stimulation in Cervical Dystonia

To investigate the relationship between motor cortical plasticity, intracortical inhibition, and clinical response to pallidal deep brain stimulation (DBS) in patients with cervical dystonia (CD). Response to paired associative stimulation (PAS) and short interval intracortical inhibition (SICI) were assessed in patients with CD before and after three months of DBS and correlated with severity of dystonic symptoms as assessed by Toronto-Western-Spasmodic Torticollis Rating Scale (TWSTRS) severity score. Relations of electrophysiological parameters with clinical improvement were explored with correlation analysis. Patients with higher levels of plasticity before surgery showed higher symptom severity (R = 0.83, p = 0.008) but had also the larger clinical benefit following DBS (R = 0.88, p = 0.003). This correlation was independent from preoperative (preOP) TWSTRS motor score as revealed by partial correlation analysis. Intracortical inhibition was not altered in CD and not related to clinical outcome after DBS. Our findings indicate that a high degree of preOP plasticity is associated with higher symptom severity, underlining the role of abnormal plasticity in the pathophysiology of dystonia. At the same time individual degree of plasticity may drive reestablishment of normal motor programs, leading to better clinical outcome with DBS. The latter suggests that individual PAS-response may indicate the susceptibility for neuromodulatory processes as an important factor for clinical DBS effects. It might therefore serve as a neurophysiological marker to predict outcome and guide patient selection.

Characteristics of Globus Pallidus Internus Local Field Potentials in Hyperkinetic Disease.

Background: Dystonia and Huntington's disease (HD) are both hyperkinetic movement disorders but exhibit distinct clinical characteristics. Aberrant output from the globus pallidus internus (GPi) is involved in the pathophysiology of both HD and dystonia, and deep brain stimulation (DBS) of the GPi shows good clinical efficacy in both disorders. The electrode externalized period provides an opportunity to record local field potentials (LFPs) from the GPi to examine if activity patterns differ between hyperkinetic disorders and are associated with specific clinical characteristics.Methods: LFPs were recorded from 7 chorea-dominant HD and nine cervical dystonia patients. Differences in oscillatory activities were compared by power spectrum and Lempel-Ziv complexity (LZC). The discrepancy band power ratio was used to control for the influence of absolute power differences between groups. We further identified discrepant frequency bands and frequency band ratios for each subject and examined the correlations with clinical scores.Results: Dystonia patients exhibited greater low frequency power (6–14 Hz) while HD patients demonstrated greater high-beta and low-gamma power (26–43 Hz) (p < 0.0298, corrected). United Huntington Disease Rating Scale chorea sub-score was positively correlated with 26–43 Hz frequency band power and negatively correlated with the 6–14 Hz/26–43 Hz band power ratio.Conclusion: Dystonia and HD are characterized by distinct oscillatory activity patterns, which may relate to distinct clinical characteristics. Specifically, chorea may be related to elevated high-beta and low-gamma band power, while dystonia may be related to elevated low frequency band power. These LFPs may be useful biomarkers for adaptive DBS to treat hyperkinetic diseases.

Resting-state basal ganglia network codes a motor musical skill and its disruption From dystonia.

Background: Musician's dystonia critically impacts professional musicians' careers as they may lose musical skills, which have been acquired through long and intensive training. Yet the pathophysiology of musician's dystonia and its link to the neural mechanisms supporting musical skills is poorly understood. We tested if resting‐state functional connectivity might reflect an aspect of musical skill linked to the pathophysiology of musician's dystonia. We also tested a second hypothesis that the region with altered resting‐state functional connectivity might be correlated with a quantitative measure of musical skills. Methods: We studied 21 patients with musician's dystonia affecting their hands and 34 healthy musicians, using resting‐state functional magnetic resonance imaging and behavioral assessment. We tested between‐group differences of resting‐state functional connectivity throughout the whole brain using independent component analysis. Results: We found abnormal basal ganglia resting‐state functional connectivity in the putamina of patients with musician's dystonia compared with those of healthy musicians (P = 0.035 corrected for multiple comparisons). We also found that the temporal precision of keystrokes was correlated with basal ganglia functional connectivity in the putamina of healthy pianists (r = 0.72, P = 0.0005), but not in pianists with musician's dystonia (r = −0.11, P = 0.64). Conclusions: We show that abnormalities of the putamen exist even at rest in musician's dystonia, whereas putaminal abnormality has previously been reported during a task. Moreover, basal ganglia resting‐state functional connectivity in the putamen represented training levels in healthy musicians, and its disruption was associated with musician's dystonia. This novel finding hints at the pathophysiological mechanisms by which musician's dystonia follows extensive musical training. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism.

X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10-15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (-29% voxel intensity) but was most pronounced in the associative subdivision (-41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (-19% and -12%, P<0.001). Cortical thickness was reduced in the frontal (-4.3%) and temporal cortex (-6.1%). In addition, we found grey matter pathology in the associative part of the cerebellum and increased voxel intensities in the anterior sensorimotor part of the cerebellum and the dorsal ponto-mesencephalic brainstem. Taken together, our analysis of subcortical and cortical grey matter in the dystonic phase of X-linked dystonia-parkinsonism showed that (i) the striosome-enriched rostral striatum was most severely affected; and (ii) cortical thickness was only reduced in those regions that predominantly have anatomical connections to striosomes. Moreover, the cerebellum may be implicated in both disease-related and compensatory changes, highlighting the significance of the cerebellum in the pathophysiology of dystonia.