One side effect – two networks? Lateral and postero-medial stimulation spreads induce dysarthria in subthalamic deep brain stimulation for Parkinson’s Disease

Objective This study aims to shed light on structural networks associated with stimulation-induced dysarthria (SID) and to derive a data-driven model to predict SID in patients with Parkinson’s Disease (PD) and deep brain stimulation (DBS) of the subthalamic nucleus (STN). Methods Randomized, double-blinded monopolar reviews determining SID thresholds were conducted in 25 patients with PD and STN-DBS. A fiber-based mapping approach, based on the calculation of fiber-wise Odds Ratios for SID, was employed to identify the distributional pattern of SID in the STN’s vicinity. The ability of the data-driven model to classify stimulation volumes as “causing SID” or “not causing SID” was validated by calculating receiver operating characteristics (ROC) in an independent out-of-sample cohort comprising 14 patients with PD and STN-DBS. Results Local fiber-based stimulation maps showed an involvement of fibers running lateral and postero-medial to the STN in the pathogenesis of SID, independent of the investigated hemisphere. ROC-analysis in the independent out-of-sample cohort resulted in a good fit of the data-driven model for both hemispheres (AUCleft = 0.88, AUCright = 0.88). Interpretation This study reveals an involvement of both, cerebello-thalamic fibers, as well as the pyramidal tract, in the pathogenesis of SID in STN-DBS. The results may impact future postoperative programming strategies to avoid SID in patients with PD and STN-DBS. ### Competing Interest Statement HJ reports personal fees from Boston Scientific unrelated to this work. JPS has nothing to report. JH has nothing to report. TT has nothing to report. JNS has received research funding for an investigator-initiated trial (IIT; Reference number: ERP-2021-12740) and received speakers honoraria from Medtronic GmbH. IRS has nothing to report. JQ has nothing to report. JCB has nothing to report. DM has nothing to report. GRF serves as an editorial board member of Cortex, Neurological Research and Practice, NeuroImage: Clinical, Zeitschrift fur Neuropsychologie, DGNeurologie, and Info Neurologie & Psychiatrie; receives royalties from the publication of the books Funktionelle MRT in Psychiatrie und Neurologie, Neurologische Differentialdiagnose, and SOP Neurologie; receives royalties from the publication of the neuropsychological tests KAS and Koepps; received honoraria for speaking engagements from Bayer, Desitin, DGN, Ergo DKV, Forum fur medizinische Fortbildung FomF GmbH, GSK, Medica Academy Messe Dusseldorf, Medicbrain Healthcare, Novartis, Pfizer, and Sportaerztebund NRW. VVV received speakers honoraria and advisory honoraria from Boston Scientific and Medtronic. TAD received speakers honoraria from Medtronic and Boston Scientific unrelated to this work. MTB received speakers honoraria from Medtronic, Boston Scientific, Abbott (formerly St. Jude), FomF, GE Medical, UCB, Bial, Apothekerverband Koln e.V., BDN, Esteve as well as research funding from the Felgenhauer-Stiftung, Forschungspool Klinische Studien (University of Cologne), Horizon 2020 (Gondola), Medtronic (ODIS, OPEL, BeAble), Boston Scientific and advisory honoraria for the IQWIG, Medtronic, Esteve and Abbvie. ### Funding Statement JPS and TAD were funded by the Cologne Clinician Scientist Program (CCSP)/ Faculty of Medicine/ University of Cologne. Funded by the German Research Foundation (DFG, FI 773/15-1). JH was supported by the Koeln Fortune Program/ Faculty of Medicine, University of Cologne. JCB and GRF were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): Project-ID 431549029 - SFB 1451. Additionally, JCB was funded by the Else Kroener-Fresenius-Stiftung (grant number 2022 EKES.23) and receives funding from the German Research Foundation (CRC-1451). DM and TT were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): Project-ID 281511265 - SFB1252. ### 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: Approval of the study procedures was obtained from the ethics board of the university of Cologne 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * ANTs : advanced normalization tools AUC : Area-under-the curve CAPSIT-PD : Core assessment program for surgical interventional therapies in Parkinson’s disease DBS : Deep Brain Stimulation FDG-PET : fluorodeoxyglucose (FDG)-positron emission tomography (PET) J : Youden’s-index PD : Parkinson’s Disease ROC : Receiver operating characteristics PPMI : Parkinson’s Progression Markers Initiative SD : standard deviation SID : stimulation-induced dysarthria STN : Subthalamic Nucleus TPR : True positive rate TNR : True negative rate UK : United Kingdom UPDRS : Unified Parkinson’s Disease Rating Scale VAS : Visual Analogue Scale