Differential Deep Brain Stimulation Sites and Networks for Cervical vs. Generalized Dystonia

Dystonia is a debilitating disease with few conservative treatment options but many types of isolated dystonia can be effectively treated using deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations between optimal stimulation sites and potential network effects in the two types of dystonia have not been carried out. Here, we retrospectively investigate clinical results following DBS for cervical and generalized dystonia in a multi-center cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce a novel approach to map optimal stimulation sites to anatomical space. Second, we analyse stimulation in context of a detailed pathway model of the subcortex to investigate the modulation of which tracts accounts for optimal clinical improvements. Third, we investigate stimulation in context of a broad-lense whole-brain functional connectome to illustrate potential multisynaptic network effects. Finally, we construct a joint model using local, tract- and network-based effects to explain variance in clinical outcomes in cervical and generalized dystonia. Our results show marked differences in optimal stimulation sites that map to the somatotopic structure of the internal pallidum. We further highlight that modulation of the pallidofugal main axis of the basal ganglia may be optimal for treatment of cervical dystonia, while pallidothalamic bundles account for effects in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in form of connectivity to cerebellum and somatomotor cortex. Our results suggest a multi-level model that could account for effectivity of treatment in cervical and generalized dystonia and could potentially help guide DBS programming and surgery, in the future. ### Competing Interest Statement A.H. reports lecture fee for Medtronic and Boston Scientific outside the submitted work. A.-K.H. reports lecture fees by Medtronic, travel grants by Boston Scientific and Abbott and personal fees from Aleva, all outside the submitted work. J.K. is a consultant to Medtronic and Boston Scientific. A.A.K. reports personal fees from Medtronic, personal fees from Boston Scientific, personal fees from Abbott and Stadapharm, all outside the submitted work. All other authors have nothing to disclose. ### Funding Statement A.H. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619 and 424778381 - TRR 295) as well as Deutsches Zentrum fuer Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND). A.H. is participant in the BIH-Charite Clinician Scientist Program funded by the Charite - Universitaetsmedizin Berlin and the Berlin Institute of Health. ### 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: The study was carried out in accordance with the Declaration of Helsinki and approved by the institutional review board of the University Hospital of Wuerzburg (registration no. 150/15). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 The DBS MRI datasets generated during and analyzed during the current study are not publicly available due to data privacy regulations of patient data but are available from the corresponding author on reasonable request. All code used to analyze the dataset is available within Lead-DBS /-Connectome software (https://github.com/leaddbs/leaddbs).