Deciphering the Pathophysiological Mechanisms Underpinning Myoclonus Dystonia Using Pluripotent Stem Cell-Derived Cellular Models.

Dystonia is a movement disorder with an estimated prevalence of 1.2% and is characterised by involuntary muscle contractions leading to abnormal postures and pain. Only symptomatic treatments are available with no disease-modifying or curative therapy, in large part due to the limited understanding of the underlying pathophysiology. However, the inherited monogenic forms of dystonia provide an opportunity for the development of disease models to examine these mechanisms. Myoclonus Dystonia, caused by SGCE mutations encoding the ε-sarcoglycan protein, represents one of now >50 monogenic forms. Previous research has implicated the involvement of the basal ganglia-cerebello-thalamo-cortical circuit in dystonia pathogenesis, but further work is needed to understand the specific molecular and cellular mechanisms. Pluripotent stem cell technology enables a patient-derived disease modelling platform harbouring disease-causing mutations. In this review, we discuss the current understanding of the aetiology of Myoclonus Dystonia, recent advances in producing distinct neuronal types from pluripotent stem cells, and their application in modelling Myoclonus Dystonia in vitro. Future research employing pluripotent stem cell-derived cellular models is crucial to elucidate how distinct neuronal types may contribute to dystonia and how disruption to neuronal function can give rise to dystonic disorders.

Psychiatric phenotype in neurodevelopmental myoclonus-dystonia is underpinned by abnormality of cerebellar modulation on the cerebral cortex.

Psychiatric symptoms are common in neurodevelopmental movement disorders, including some types of dystonia. However, research has mainly focused on motor manifestations and underlying circuits. Myoclonus-dystonia is a rare and homogeneous neurodevelopmental condition serving as an illustrative paradigm of childhood-onset dystonias, associated with psychiatric symptoms. Here, we assessed the prevalence of psychiatric disorders and the severity of depressive symptoms in patients with myoclonus-dystonia and healthy volunteers (HV). Using resting-state functional neuroimaging, we compared the effective connectivity within and among non-motor and motor brain networks between patients and HV. We further explored the hierarchical organization of these networks and examined the relationship between their connectivity and the depressive symptoms. Comparing 19 patients to 25 HV, we found a higher prevalence of anxiety disorders and more depressive symptoms in the patient group. Patients exhibited abnormal modulation of the cerebellum on the cerebral cortex in the sensorimotor, dorsal attention, salience, and default mode networks. Moreover, the salience network activity was directed by the cerebellum in patients and was related to depressive symptoms. Altogether, our findings highlight the role of the cerebellar drive on both motor and non-motor cortical areas in this disorder, suggesting cerebellar involvement in the complex phenotype of such neurodevelopmental movement disorders.

Structural and functional brain alterations in laryngeal dystonia: A coordinate-based activation likelihood estimation meta-analysis.

Laryngeal dystonia (LD) is an isolated, task-specific, focal dystonia characterized by intermittent spasms of laryngeal muscles impairing speech production. Although recent studies have demonstrated neural alterations in LD, the consistency of findings across studies is not well-established, limiting their translational applicability. We conducted a systematic literature search to identify studies reporting stereotactic coordinates of peak structural and functional abnormalities in LD patients compared to healthy controls, followed by a coordinate-based activation likelihood estimation meta-analysis. A total of 21 functional and structural neuroimaging studies, including 31 experiments in 521 LD patients and 448 healthy controls, met the study inclusion criteria. The multimodal meta-analysis of these studies identified abnormalities in the bilateral primary motor cortices, the left inferior parietal lobule and striatum, the right insula, and the supplementary motor area in LD patients compared to healthy controls. The meta-analytical findings reinforce the current view of dystonia as a neural network disorder and consolidate evidence for future investigations probing these targets with new therapies.

Beyond Pallidal or Subthalamic Deep Brain Stimulation to Treat Dystonia.

Deep brain stimulation of the subthalamic nucleus and globus pallidus internus is approved by the Food and Drug Administration for treating dystonia. Both targets have shown effectiveness in improving symptoms, but post-operative outcomes can vary significantly among patients. This variability has led researchers to explore alternative neuromodulation targets that might offer more consistent results. Emerging research has highlighted several promising new targets for DBS in dystonia. This review examines pre-clinical and clinical data on novel DBS targets for dystonia and explores non-invasive neuromodulation studies that shed light on the disease's underlying pathological circuitry.

Directional Stimulus-Evoked Pallidal Electrophysiology in Primary Dystonia.

Background: Deep brain stimulation for dystonia improves motor symptoms but variable and delayed responses challenge patient selection, targeting, and device programming. Case Report: Here we studied intracranial electrophysiology in a patient with primary dystonia and observed evoked resonant neural activity (ERNA) in the globus pallidus interna. These local stimulus-evoked potentials displayed refractory periods and paired-pulse facilitation at clinically relevant interstimulus intervals. Sensing from directional DBS contacts localized ERNA to an effective stimulation site in the ventral posterolateral portion of the pallidum. Discussion: To the best of our knowledge, this is the first observation of ERNA in the globus pallidus interna in a patient with primary dystonia. Stimulus-evoked activity could eventually guide both directional and adaptive stimulation for dystonia and other complex neuropsychiatric disorders.

Striato-pallidal oscillatory connectivity correlates with symptom severity in dystonia patients.

Dystonia is a hyperkinetic movement disorder that has been associated with an imbalance towards the direct pathway between striatum and internal pallidum, but the neuronal underpinnings of this abnormal basal ganglia pathway activity remain unknown. Here, we report invasive recordings from ten dystonia patients via deep brain stimulation electrodes that allow for parallel recordings of several basal ganglia nuclei, namely the striatum, external and internal pallidum, that all displayed activity in the low frequency band (3-12 Hz). In addition to a correlation with low-frequency activity in the internal pallidum (R = 0.88, P = 0.001), we demonstrate that dystonic symptoms correlate specifically with low-frequency coupling between striatum and internal pallidum (R = 0.75, P = 0.009). This points towards a pathophysiological role of the direct striato-pallidal pathway in dystonia that is conveyed via coupling in the enhanced low-frequency band. Our study provides a mechanistic insight into the pathophysiology of dystonia by revealing a link between symptom severity and frequency-specific coupling of distinct basal ganglia pathways.

Exploring White Matter Microstructure with Symptom Severity and Outcomes Following Deep Brain Stimulation in Tremor Syndromes.

Background: Essential tremor (ET) and dystonic tremor (DT) are movement disorders that cause debilitating symptoms, significantly impacting daily activities and quality of life. A poor understanding of their pathophysiology, as well as the mediators of clinical outcomes following deep brain stimulation (DBS), highlights the need for biomarkers to accurately characterise and optimally treat patients. Objectives: We assessed the white matter microstructure of pathways implicated in the pathophysiology and therapeutic intervention in a retrospective cohort of patients with DT (n = 17) and ET (n = 19). We aimed to identity associations between white matter microstructure, upper limb tremor severity, and tremor improvement following DBS. Methods: A fixel-based analysis pipeline was implemented to investigate white matter microstructural metrics in the whole brain, cerebello-thalamic pathways and tracts connected to stimulation volumes following DBS. Associations with preoperative and postoperative severity were analysed within each disorder group and across combined disorder groups. Results: DBS led to significant improvements in both groups. No group differences in stimulation positions were identified. When white matter microstructural data was aligned according to the maximally affected upper limb, increased fiber density, and combined fiber density & cross-section of fixels in the left cerebellum were associated with greater tremor severity across DT and ET patients. White matter microstructure did not show associations with postoperative changes in cerebello-thalamic pathways, or tracts connected to stimulation volumes. Discussion: Diffusion changes of the cerebellum are associated with the severity of upper limb tremor and appear to overlap in essential or dystonic tremor disorders.

Thalamic ventral-Oralis complex/rostral zona incerta deep brain stimulation for midline tremor.

BACKGROUND: Midline Tremor is defined as an isolated or combined tremor that affects the neck, trunk, jaw, tongue, and/or voice and could be part of Essential Tremor (ET), or dystonic tremor. The clinical efficacy of deep brain stimulation for Midline Tremor has been rarely reported. The Ventral Intermediate Nucleus and Globus Pallidus Internus are the preferred targets, but with variable outcomes. Thalamic Ventral-Oralis (VO) complex and Zona Incerta (ZI) are emerging targets for tremor control in various etiologies. OBJECTIVE: To report on neuroradiological, neurophysiological targeting and long-term efficacy of thalamic Ventral-Oralis complex and Zona Incerta deep brain stimulation in Midline Tremor. METHODS: Three patients (two males and one female) with Midline Tremor in dystonic syndromes were recruited for this open-label study. Clinical, surgical, neurophysiological intraoperative testing and long-term follow-up data are reported. RESULTS: Intraoperative testing and reconstruction of volume of tissue activated confirmed the position of the electrodes in the area stimulated between the thalamic Ventral-Oralis complex and Zona Incerta in all patients. All three patients showed optimal control of both tremor and dystonic features at short-term (6 months) and long-term follow-up (up to 6 years). No adverse events occurred. CONCLUSION: In the syndromes of Midline Tremor of various origins, the best target for DBS might be difficult to identify. Our results showed that thalamic Ventral-Oralis complex/Zona Incerta may be a viable and safe option even in specific forms of tremor with axial distribution.

Connecting the dots - A systematic review on coherence analysis in dystonia.

BACKGROUND: Increased 4-12 Hz oscillatory activity in the cortico-basal ganglia-thalamo-cortical (CBGTC) loop is reported in dystonia. Coherence analysis is a measure of linear coupling between two signals, revealing oscillatory activity drives that are common across motor units. By performing coherence analysis, activity of the CBGTC-loop can be measured with modalities like local field potentials (LFPs), electromyography (EMG), and electro-encephalography (EEG). The aim of this study is to perform a systematic review on the use of coherence analysis for clinical assessment and treatment of dystonia. METHODS: A systematic review was performed on a search in Embase and PubMed on June 28th, 2023. All studies incorporating coherence analysis and an adult dystonia cohort were included. Three authors evaluated the eligibility of the articles. Quality was assessed using the QUADAS-2 checklist. RESULTS: A total of 41 articles were included, with data of 395 adult dystonia patients. In the selected records, six different types of coherence were investigated: corticocortical, corticopallidal, corticomuscular, pallidopallidal, pallidomuscular, and intermuscular coherence. Various types of 4-12 coherence were found to be increased in all dystonia subtypes. CONCLUSION: There is increased 4-12 Hz coherence found between the cortex, basal ganglia, and affected muscles in all dystonia subtypes. However, the relationship between 4-12 Hz coherence and the dystonic clinical state has not been established. DBS treatment leads to a reduction of 4-12 Hz coherence. In combination with the results of this review, the 4-12 Hz frequency band can be used as a promising phenomenon for the development of a biomarker.

Neural correlates of anxiety in adult-onset isolated dystonia.

Psychiatric disturbances are commonly associated with adult-onset isolated dystonia (AOID); however, the mechanisms underlying psychiatric abnormalities in AOID remain unknown. We aimed to investigate the structural and functional brain changes in AOID patients with anxiety, and identify imaging biomarkers for diagnosing anxiety. Structural and functional magnetic resonance was performed on 69 AOID patients and 35 healthy controls (HCs). The Hamilton Anxiety Scale (HAMA) was used to assess anxiety symptoms in AOID patients and assign patients to AOID with and without anxiety groups. Group differences in grey matter volume, amplitude of low-frequency fluctuations (ALFF), fractional ALFF, and regional homogeneity (ReHo) were evaluated. Area under the receiver operating characteristic curve (ROC AUC) was used as a metric to identify imaging biomarkers for diagnosing anxiety. AOID patients with anxiety exhibited an increased ALFF and ReHo in the left angular gyrus (ANG.L) compared with those without and HCs (voxel P<0.001 and cluster P<0.05, corrected using GRF). A significant positive correlation was observed between ALFF (r = 0.627, P<0.001) and ReHo (r = 0.515, P<0.001) in the ANG.L and HAMA scores in AOID patients. ALFF and ReHo in the ANG.L exhibited an ROC AUC of 0.904 and 0.851, respectively, in distinguishing AOID patients with anxiety from those without and an ROC AUC of 0.887 and 0.853, respectively, in distinguishing AOID patients with anxiety from HCs. These findings provide new insights into the pathophysiology of psychiatric disturbances and highlight potential candidate biomarkers for identifying anxiety in AOID patients.

Incobotulinum Toxin-A in Professional Musicians with Focal Task-Specific Dystonia: A Double Blind, Placebo Controlled, Cross-Over Study.

Background: Musician's focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials of botulinum toxin in upper limb task-specific dystonia, and prior studies have yielded variable results, leading to skepticism regarding the utility of this approach in elite performers. Methods: We conducted a double-blind, placebo-controlled, randomized, cross-over study of incobotulinum toxin-A in 21 professional musicians with focal upper extremity task-specific dystonia affecting performance on their instrument, using a novel paradigm of initial injections followed by booster injections at two- and four-week intervals. The primary outcome measure was the change in blinded dystonia rating of the active arm by two expert raters using a Clinical Global Impression numeric scale at week 8 compared to enrollment. Findings: 19 men and 2 women with musicians' dystonia were enrolled over a six-year period. Nineteen patients completed the study. Analysis of the primary outcome measure in comparison to baseline revealed a change in dystonia severity of P = 0.04 and an improvement in overall musical performance of P = 0.027. No clinically significant weakness was observed, and neutralizing antibodies to toxin were not found. Interpretation: Despite its small sample size, our study demonstrated a statistically significant benefit of incobotulinum toxin-A injections as a treatment for musicians' task-specific dystonia. Tailoring the use of toxin with booster injections allowed refinement of dosing strategy and outcomes, with benefits that were meaningful to patients clearly visible on videotaped evaluations. In addition to its application to musicians' dystonia, this approach may have relevance to optimize application of botulinum toxin in other forms of focal dystonia such as blepharospasm, cervical dystonia, writer's cramp, and spasmodic dysphonia.

How Do I Examine Laryngeal Dystonia?

Laryngeal dystonia is a potentially disabling task specific dystonia primarily affecting speech. The evaluation and diagnosis of laryngeal dystonia remain challenging, and often require a multi-disciplinary approach, involving collaboration among speech language pathologists, neurologists and laryngologists (1-5). It is crucial to correctly differentiate between the types of laryngeal dystonia due to the distinct therapeutic approaches and responses to botulinum toxin therapy or speech therapy. For educational purposes, we have divided laryngeal dystonia into two main types: adductor and abductor dystonia. In this article, we describe a series of examination techniques that can assist movement disorders neurologists diagnosing this condition, and appropriately differentiating the most common forms of laryngeal dystonia.

Boundaries of task-specificity: bimanual finger dexterity is reduced in musician's dystonia.

Task-specific dystonia leads to loss of sensorimotor control for a particular motor skill. Although focal in nature, it is hugely disabling and can terminate professional careers in musicians. Biomarkers for underlying mechanism and severity are much needed. In this study, we designed a keyboard device that measured the forces generated at all fingertips during individual finger presses. By reliably quantifying overflow to other fingers in the instructed (enslaving) and contralateral hand (mirroring) we explored whether this task could differentiate between musicians with and without dystonia. 20 right-handed professional musicians (11 with dystonia) generated isometric flexion forces with the instructed finger to match 25%, 50% or 75% of maximal voluntary contraction for that finger. Enslaving was estimated as a linear slope of the forces applied across all instructed/uninstructed finger combinations. Musicians with dystonia had a small but robust loss of finger dexterity. There was increased enslaving and mirroring, primarily during use of the symptomatic hand (enslaving p = 0.003; mirroring p = 0.016), and to a lesser extent with the asymptomatic hand (enslaving p = 0.052; mirroring p = 0.062). Increased enslaving and mirroring were seen across all combinations of finger pairs. In addition, enslaving was exaggerated across symptomatic fingers when more than one finger was clinically affected. Task-specific dystonia therefore appears to express along a gradient, most severe in the affected skill with subtle and general motor control dysfunction in the background. Recognition of this provides a more nuanced understanding of the sensorimotor control deficits at play and can inform therapeutic options for this highly disabling disorder.