Brain Networks in Dystonia

Completed

• Conditions: Spasmodic Dysphonia; Singer's Dystonia; Musician's Focal Hand Dystonia; Writer's Cramp

• Registration Number: NCT03042962
• Lead Sponsor: Kristina Simonyan

Brief Summary

Task-specific focal dystonias are characterized by selective activation of dystonic movements during performance of highly learned motor tasks, such as writing or playing a musical instrument. To date, there is only limited knowledge about the distinct neural abnormalities that lead to the development of task-specificity in focal dystonias, which affect similar muscle groups but result in different clinical manifestations, such as writer's cramp vs. pianist's dystonia or spasmodic dysphonia vs. singer's dystonia. Our goal is to dissect the pathophysiological mechanisms underlying the phenomenon of task specificity in isolated focal dystonias using multi-level brain network analysis in conjunction with neuropathological examination of postmortem brain tissue from patients with dystonia. Rather than viewing these disorders as interesting curiosities, understanding the biology of task-specific activation of motor programs is central to understanding dystonia.

Detailed Description

Task-specific primary focal dystonias (tsPFDs) are characterized by selective activation of dystonic movements during performance of highly learned motor tasks, such as writing, playing a musical instrument, speaking, or singing. Despite the recent advances in describing the clinical features of dystonia, there is a fundamental gap in understanding the neural abnormalities underlying the development of tsPFDs, which affect the same muscles but result in different clinical manifestations as in writer's cramp vs. pianist's dystonia or spasmodic dysphonia vs. singer's dystonia. Continued existence of this gap is an important problem because it renders us unable to differentiate between primary and secondary brain changes contributing to the tsPFD pathophysiology and to develop novel treatment options targeting disorder-specific brain alterations. The objective of this application is to identify the brain mechanisms underlying the phenomenon of task specificity in two representative groups of patients with writer's cramp vs. musician's hand dystonia and spasmodic dysphonia vs. singer's laryngeal dystonia using a novel approach of combined clinico-behavioral examination, brain network analysis and quantitative neuropathology of postmortem brain tissue. Our central hypothesis is that each tsPFD is characterized by distinct brain abnormalities, which selectively affect the focal segments of brain networks responsible for the performance of the respective motor task. The rationale for the proposed research is that identification of tsPFD-specific brain changes and associated neuropathology will clarify the neural mechanisms (primary vs. secondary) contributing to the clinical manifestation of these disorders and thus explain the phenomenon of tsPFDs. The obtained results are expected to provide strong scientific bases for the next series of studies directed towards identification and validation of novel pharmacological and/or surgical therapies for these patients. The researchers will pursue the following two specific aims: (1) determine distinct features of brain functional network abnormalities underlying task-specificity in different tsPFDs, and (2) establish structural correlates of functional neuroimaging abnormalities in tsPFDs. The proposed research is significant because it is expected to establish scientific evidence that tsPFD is a network disorder with abnormalities following distinct patterns in different tsPFDs and certain abnormalities showing structure-function correlations are associated with underlying neuropathology. By converging the results from multimodal cross-disciplinary studies to a coherent and pathophysiologically meaningful picture, the researchers will be well positioned to identify primary vs. secondary changes in tsPFDs and establish a scientific framework for the development of diagnostic biomarkers and novel treatment options for these disorders.

Study Timeline

• Study Start: 2015-08-01
• Study First Submitted: 2017-01-31
• Study First Submitted QC: 2017-02-01
• Study First Posted: 2017-02-03
• Primary Completion: 2022-05-31
• Study Completion: 2022-05-31
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-18
• Last Update Posted: 2025-03-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 141

Inclusion Criteria

• Patients will have clinically documented focal dystonia (including spasmodic dysphonia, singer's dystonia, writer's cramp, musician's focal hand dystonia)
• Healthy controls will be healthy volunteers with a negative history of neurological, laryngeal or psychiatric problems
• Age from 21 to 80 years.
• Native English speakers.
• Right-handedness (based on Edinburgh Handedness Inventory).

Exclusion Criteria

• Subjects who are incapable of giving an informed consent.
• Pregnant or breastfeeding women until a time when they are no longer pregnant or breastfeeding. All women of childbearing potential will have a urine pregnancy test performed, which must be negative for participation in the imaging studies.
• Subjects with past or present medical history of (a) neurological problems, such as stroke, movement disorders (other than dystonia in the patient groups), brain tumors, traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases, alcoholism, drug depend-ence; (b) psychiatric problems, such as schizophrenia, major and/or bipolar depression, obsessive-compulsive disorder; (c) laryngeal problems, such as vocal fold paralysis, paresis, vocal fold nodules and polyps, carcinoma, chronic laryngitis.
• Patients who are not symptomatic due to treatment with botulinum toxin injections into the laryngeal muscles. The duration of positive effects of botulinum toxin vary from patient to patient but lasts on average for 3-4 months. All patients will be evaluated to ensure that they are fully symptomatic prior to entering the study.
• Patients with other forms of dystonia.
• Patients with hereditary forms of dystonia (e.g., DYT1, DYT6, GNAL). If ARSG gene is identified in musician's dystonia patients, it will be used as a nuisance covariate in imaging analysis.
• Patients who have dystonia symptoms at rest in order to avoid the potential confound of dystonic spasms occurring during the scanning.
• To avoid the possibility of confounding effects of drugs acting upon the central nervous system, all study participants will be questioned about any prescribed or over-the-counter medications as part of their initial intake screening. Those patients who receive medication(s) affecting the central nervous system will be excluded from the study.
• The patients will be asked whether they have undergone any head, neck, or hand surgeries, which resulted in changes in regional anatomy or innervation. Because brain, hand and laryngeal surgery may potentially lead to the brain structure and function re-organization, all patients with history of brain, hand and/or laryngeal surgery will be excluded from the study.
• Subjects who have tattoos, ferromagnetic objects in their bodies (e.g., implanted stimulators, surgical clips, prosthesis, artificial heart valve, etc.) that cannot be removed for the purpose of study participation.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Incidence of brain structural and functional changes	5 years	Identify imaging alterations responsible for task specificity in dystonia. Identify changes in brain activity and gray and white matter in patients with task-specific dystonia

Trial Locations

Locations (1)

Massachusetts Eye and Ear Infirmary; 🇺🇸 Boston, Massachusetts, United States