Thalamic Coordinated Reset Deep Brain Stimulation for Upper Extremity Essential Tremor: Proof of Principle Study

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Essential tremor (ET) is a common neurologic disorder affecting over 10 million people in the United States. Pathologic synchrony in the cerebello-thalamo-cortical (CTC) network has been considered to underlie the development of ET. Traditional high frequency isochronal deep brain stimulation (T-DBS) in the ventral intermediate nucleus (VIM) of the thalamus has been an effective treatment for ET, however, stimulation related side effects such as dysarthria and ataxia occur in at least 30% of patients. Current spread into unintended brain areas has been considered to underlie most observed side effects related to stimulation. Moreover, habituation, defined as loss of effect despite optimal programming, has been reported in 30-50% of patients. The cause of habituation to DBS is still unclear, however, it may reflect resynchronization in the CTC network. Coordinated reset (CR) stimulation is a novel DBS approach developed to counteract abnormal synchronization in the neuronal network which can address these issues. By using lower current amplitudes and alternating stimulation across multiple contacts of the DBS lead, CR-DBS has been shown in Parkinson's disease patients to produce acute therapeutic effects comparable to T-DBS as well as carryover benefits that persist for days or weeks after cessation of stimulation. Using lower stimulation current, CR-DBS in the VIM has the potential to minimize side effects from current spread to adjacent structures/pathways and maintain therapeutic efficacy. As a chronic animal model of ET is not available, evaluating the effect of VIM CR-DBS on ET preclinically is not feasible and its effect in patients with ET has never been assessed. The goal of this study is to evaluate the feasibility, safety and efficacy of VIM CR-DBS as a treatment for ET patients, with CR cycle rate and stimulation contacts determined based on the physiological features of tremor related VIM activity. To achieve this goal, we will (1) identify the peak frequency and spatial location of tremor related oscillatory activities in VIM and use these data to guide the selection of CR cycle rate and stimulation contacts, (2) compare the effects of VIM CR-DBS to clinically optimized T-DBS, and (3) characterize the carryover effect of VIM CR-DBS. The findings from this study will provide proof of concept as to the safety and efficacy of CR-DBS as a novel treatment for ET. An understanding of the carryover effect will help determine the dosing schedule of CR-DBS (delivered continuously or intermittently) in future CR studies. If successful the results of this study will significantly advance the development of CR-DBS for the treatment of ET, minimize side effects and potentially reduce habituation, ultimately leading to improved clinical outcomes and a better quality of life for ET patients undergoing VIM DBS.