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

特发性震颤（ET）是一种常见的神经系统疾病，影响着美国超过1000万人。小脑-丘脑-皮质（CTC）网络的病理同步性被认为是ET发展的基础。传统的丘脑腹侧中间核（VIM）高频等时深部脑刺激（T-DBS）是治疗ET的有效方法，然而，至少30%的患者出现与刺激相关的副作用，如构音障碍和失调。电流扩散到意想不到的大脑区域被认为是大多数观察到的与刺激有关的副作用的基础。此外，据报道，30-50%的患者出现了习惯化，定义为尽管进行了最佳规划，但仍失去了效果。对DBS习以为常的原因尚不清楚，但它可能反映了CTC网络的再同步。协调复位（CR）刺激是一种新的DBS方法，可以解决这些问题，以抵消神经元网络中的异常同步。通过在DBS导联的多个接触点上使用较低的电流振幅和交替刺激，CR-DBS在帕金森病患者中显示出与T-DBS相当的急性治疗效果，并且在停止刺激后持续数天或数周的益处。使用较低的刺激电流，在VIM中进行CR-DBS有可能将电流扩散到邻近结构/通路的副作用降到最低，并保持治疗效果。由于没有ET的慢性动物模型，临床前评估VIM CR-DBS对ET的影响是不可行的，其在ET患者中的作用也从未被评估过。本研究的目的是评估VIM CR- dbs治疗ET患者的可行性、安全性和有效性，并根据震颤相关VIM活动的生理特征确定CR周期率和刺激接触次数。为了实现这一目标，我们将(1)识别VIM中震颤相关振荡活动的峰值频率和空间位置，并利用这些数据指导CR周期率和刺激接触的选择，(2)比较VIM CR- dbs与临床优化的T-DBS的效果，以及(3)表征VIM CR- dbs的传递效应。这项研究的结果将为CR- dbs作为一种治疗ET的新方法的安全性和有效性提供概念证明。了解遗留效应将有助于在未来的CR研究中确定CR- dbs的给药计划（连续或间歇给药）。如果这项研究的结果成功，将显著推进CR-DBS治疗ET的发展，最大限度地减少副作用，并可能减少习惯化，最终导致接受VIM DBS的ET患者改善临床结果和更好的生活质量。

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.