Grey or white: what matters? Fraction of white matter tract fibers recruited by deep brain stimulation is causally related to tremor suppression.

BackgroundDeep 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. MethodsTremor 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. ResultsUtilizing 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. ConclusionOur 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 topicPrevious 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 addsOur 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 policyOur 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.