Functional Brain Networks in Focal Dystonia and their Associations with Dystonic Behavior

Multiple neuroimaging studies suggest that dystonia is a network-level brain disorder, but the key networks to target for brain therapy in dystonia remain poorly understood. This study identified impaired functional networks (FNs) in writer’s cramp (WC) dystonia while participants performed hand motor tasks in the scanner. Task-fMRI images were acquired from twelve WC and twelve healthy volunteers (HV) while they performed writing, tapping, and flexion-extension motor tasks. Group independent component analysis was used to derive FNs, and functional network connectivity (FNC) between the FNs was computed to evaluate their associations with dystonic behavior. Our approach revealed three novel findings: First, we found that the basal ganglia, orbitofrontal, and superior parietal FNs were aberrant during the on-block of the task and, interestingly, also during the off-block period reminiscent of the loss of network inhibitory response during writing in WC. Second, we found multiple impaired FNC patterns in WC primarily in these three FNs these results were further validated through non-parametric testing via Monte Carlo simulations. Third, using FNC deficits and FNC-writing legibility correlations, we characterized these FNC patterns as primary or secondary associations with the motor program for writing. Findings from our data-driven whole-brain analysis approach reveal new FNs disrupted in dystonia and they may serve as key targets for the treatment of this disorder. Impact Statement Dystonia is a rare and disabling brain disorder affecting motor function. In this study, novel functional network differences in dystonia were identified. Associations between functional network connectivity and dystonic behavior were found. Through a data-driven approach, this study reveals new targets for dystonia treatment. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants to NBP from Duke Clinical and Translational Science Association from National Center for Advancing Translational Science (NCATS, 1KL2TR002554), Duke Clinical Translational Science Institute, Dystonia Medical Research Foundation (Clinical Fellowship Training Program from), and Doris Duke Charitable Foundation (Fund to Retain Clinician Scientist). NBP was also supported by a career development award from the Dystonia Coalition (NS065701, TR001456, NS116025) which is part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported by the Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the National Institute of Neurological Diseases and Stroke (NINDS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Duke IRB I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data available upon request from the authors * (WC) : Writer’s cramp (HV) : Healthy volunteers (FN) : Functional network (FNC) : Functional network connectivity