Grey or White: What Matters? Fraction of White Matter Tract Fibers Recruited by Deep Brain Stimulation is Causally Related to Tremor Suppression

Background Deep brain stimulation (DBS) targets grey matter structures for most clinical indications, such as the thalamic ventral intermediate nucleus (VIM) to treat essential tremor (ET). Alternatively, white matter tracts like the dentatorubrothalamic tract (DRTT) in ET have been suggested to be the actual effector sites of DBS. A direct link between excitation of myelinated fibers and clinically relevant behavior, however, is missing. Here, we retrospectively analyze clinical measurements in patients assessed for VIM-DBS to test the hypothesis that tremor suppression is directly related to the fraction of DRTT-fibers recruited by DBS. Methods Tremor intensity was accelerometrically quantified at 100 different electrode contacts in 15 patients, while stimulation amplitude was systematically varied. Contact positions were located by stereotactic x-ray imaging. We determined the fraction of fibers recruited within the range of effective DBS-spread by diffusion tensor imaging (DTI) and probabilistic fiber tracking. Results Utilizing regression analysis, we found that the fraction of activated DRTT-fibers was linearly related to tremor suppression (F(1,592) = 451.55, p < 0.001) with a slope of 1.02 (95% confidence interval [0.93, 1.12]), i.e., relative tremor suppression matched identically the fraction of recruited DRTT-fibers. Conclusion Our results show that tremor suppression by DBS is causally related to the recruitment of DRTT-fibers and that clinically relevant behavioral effects of DBS can be already predicted from fiber densities pre-operatively. Our analysis approach would enable retrospective identification of DBS effector sites in neuropsychiatric diseases, as well as personalized prospective planning of DBS, substantially reducing intra- and post-operative clinical testing time. What is already known on this topic Previous studies have demonstrated correlations between clinical outcome in essential tremor suppression by DBS and electrode contact distance to the DRTT. In order to prove that the DRTT is the actual effector site of DBS a direct, a quantitative link between excitation of DRTT fibers and tremor suppression is required. What this study adds Our study shows that the percent tremor suppression identically matches the fraction of DRTT-fibers recruited by DBS up to a constant offset demonstrating a causal link between tremor suppression and DRTT excitation. How this study might affect research, practice or policy Our finding solves a long standing dispute and paves the way for novel network interventions through deep brain stimulation. Our analysis approach further paves the way for novel connectomic DBS-targeting strategies. It would allow for personalized prospective planning of DBS substantially reducing intra- and post-operative clinical testing time. It could also be key for the retrospective identification of novel effector sites among candidate sites in various neuropsychiatric diseases. ### Competing Interest Statement J. Voges occasionally received honoraria from Boston Scientific. There are no other conflicts of interest to declare. L. Buentjen occasionally has given educational talks for Boston Scientific, Medtronic, SJM/ Abott in the past, but none of them during the last 3 years. ### Clinical Trial DRKS00032906 ### Funding Statement This research received no external funding. CMSR received personal funding from the Deutsche Forschungsgemeinschaft (SW 214/2-1). ### 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 conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Medical Faculty of the Otto-von-Guericke-University Magdeburg (Approval no. 25/18). 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 Raw data were generated at the University Hospital Magdeburg. Derived data supporting the findings of this study are available from the corresponding author on request. * AC-PC : anterior commissure - posterior commissure CI : confidence interval CT : computer tomography COG : center of gravity DBS : deep brain stimulation DRTT : dentatorubrothalamic tract DTI : diffusion tensor imaging ET : essential tremor IPG : implantable pulse generator PCP : posterior commissural point SEM : standard error of the mean TRS : tremor rating scale VIM : ventral intermediate nucleus