Evaluating a Motor Progression Connectivity Model Across Parkinson’s Disease Stages

Background Stimulation of a specific site in the dorsolateral subthalamic nucleus (STN) was recently associated with slower motor progression in Parkinson’s Disease (PD), based on the deep brain stimulation (DBS) in early-stage PD pilot trial. Objective To test whether stimulation of this site is associated with improvements of long-term motor outcomes in advanced-stage PD. Methods Active contacts of the early DBS cohort (N=14) were analyzed. Sweet spot and connectivity models derived from this cohort were then used to estimate long-term motor outcomes in an independent DBS cohort of advanced-stage PD patients (N=29). Results In early-stage PD, proximity of stimulation to the dorsolateral STN associated with slower motor progression. In advanced-stage PD, stimulation proximity to the same site associated with better long-term motor outcomes (R=0.60, P<0.001). Conclusions Results suggest stimulation of a specific site in the dorsolateral STN associates with both slower motor progression and long-term motor improvements in PD. ### Competing Interest Statement Funding Sources and Conflict of Interest The DBS in early-stage PD pilot trial was supported by Vanderbilt CTSA grants UL1TR000445 and UL1 TR002243 from the National Center for Advancing Translational Sciences (NCATS), NCATS/NIH award UL1TR000011, NIH R01EB006136, and Medtronic, Inc. The authors were free to independently design and conduct the study. Medtronic representatives did not take part in the collection, management, analysis, or interpretation of the data or in preparation, review, or approval of the manuscript. This work was also supported by a generous gift from Phyllis G. Heard, and her children, Elizabeth Heard, and Tony Heard. MH receives funding from the National Institutes on Aging K01AG066971 and The Consolidated Anti-Aging Foundation. MH is a shareholder of Arena Therapeutics, a company focused on advancing research of DBS for the treatment of patients recently diagnosed with PD. DI receives funding from the National Institute of Neurological Disorders and Stroke (1K23NS131592) and from Teva Branded Pharmaceutical Products, R&D. DC is a shareholder of Arena Therapeutics, a company focused on advancing research of DBS for the treatment of patients recently diagnosed with PD. AH was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381 TRR 295), Deutsches Zentrum fur Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND), the National Institutes of Health (R01 13478451, 1R01NS127892-01, 2R01 MH113929 & UM1NS132358) as well as the New Venture Fund (FFOR Seed Grant). AH reports lecture fees for Boston Scientific and is a consultant for FxNeuromodulation and Abbott. There are no additional disclosures to report for NR, KP, EA, SS, FTP, PH, TLD. Financial Disclosures for the previous 12 months: MH receives funding from the National Institutes on Aging K01AG066971 and The Consolidated Anti-Aging Foundation. MH is a shareholder of Arena Therapeutics, a company focused on advancing research of DBS for the treatment of patients recently diagnosed with PD. DI receives funding from the National Institute of Neurological Disorders and Stroke (1K23NS131592) and from Teva Branded Pharmaceutical Products, R&D. DC is a shareholder of Arena Therapeutics, a company focused on advancing research of DBS for the treatment of patients recently diagnosed with PD. AH was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381 TRR 295), Deutsches Zentrum fur Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND), the National Institutes of Health (R01 13478451, 1R01NS127892-01, 2R01 MH113929 & UM1NS132358) as well as the New Venture Fund (FFOR Seed Grant). AH reports lecture fees for Boston Scientific and is a consultant for FxNeuromodulation and Abbott. There are no additional disclosures to report for NR, KP, EA, SS, FTP, PH, TLD. ### Funding Statement The DBS in early-stage PD pilot trial was supported by Vanderbilt CTSA grants UL1TR000445 and UL1 TR002243 from the National Center for Advancing Translational Sciences (NCATS), NCATS/NIH award UL1TR000011, NIH R01EB006136, and Medtronic, Inc. The authors were free to independently design and conduct the study. Medtronic representatives did not take part in the collection, management, analysis, or interpretation of the data or in preparation, review, or approval of the manuscript. This work was also supported by a generous gift from Phyllis G. Heard, and her children, Elizabeth Heard, and Tony Heard. ### 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 Human Protections Research Program of Vanderbilt University gave ethical approval for this work. 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 xI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The de-identified data from the standard of care DBS cohort will be made available upon reasonable request. The de-identified data and related study documents from the DBS in early-stage PD trial are not being publicly shared at this time as they are currently being used for the development of a proprietary, multicenter, phase III, pivotal clinical trial (IDE G050016).