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

丘脑协调复位深部脑刺激治疗上肢特发性震颤：原理研究证明

• 批准号: 10575895
• 负责人: Jerrold L Vitek
• 金额: $ 104.22万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575895
• 关键词: Acute; Address; Advanced Development; Affect; Animal Model; Appearance; Area; Ataxia; Brain; Cell Nucleus; Chronic; Clinical; Clinical Research; Data; Deep Brain Stimulation; Development; Disease Progression; Dose; Dysarthria; Energy consumption; Essential Tremor; Evaluation; Frequencies; Future; Goals; Hour; Incidence; Lead; Location; Maps; Mental disorders; Microelectrodes; Motor; Neurons; Operative Surgical Procedures; Outcome; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Phase; Physiological; Probability; Quality of life; Randomized; Reporting; Risk; Safety; Schedule; Self Assessment; Severities; Structure; Thalamic structure; Therapeutic Effect; Time; Treatment Efficacy; Tremor; United States; Upper Extremity; clinical effect; effective therapy; habituation; implantation; improved; nervous system disorder; novel; novel strategies; pre-clinical; side effect

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.

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 发生的基础。丘脑腹侧中间核（VIM）的传统高频等时深部脑刺激（T-DBS）一直是治疗 ET 的有效方法，然而，至少 30% 的患者会出现构音障碍和共济失调等刺激相关副作用。电流扩散到非预期的大脑区域被认为是大多数观察到的与刺激相关的副作用的基础。此外，据报道，30-50% 的患者出现了习惯化，即尽管进行了最佳编程，但仍失去效果。 DBS 习惯化的原因尚不清楚，但可能反映了 CTC 网络的重新同步。协调重置 (CR) 刺激是一种新颖的 DBS 方法，旨在抵消神经元网络中的异常同步，从而解决这些问题。通过使用较低的电流幅度和 DBS 导线多个接触点的交替刺激，CR-DBS 已被证明可以在帕金森病患者中产生与 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持续益处。使用较低的刺激电流，VIM 中的 CR-DBS 有可能最大限度地减少电流扩散到邻近结构/通路的副作用，并保持治疗效果。由于没有 ET 慢性动物模型，因此在临床前评估 VIM CR-DBS 对 ET 的影响是不可行的，并且从未评估过其对 ET 患者的效果。本研究的目的是评估 VIM CR-DBS 作为 ET 患者治疗的可行性、安全性和有效性，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。为了实现这一目标，我们将 (1) 确定 VIM 中震颤相关振荡活动的峰值频率和空间位置，并使用这些数据来指导 CR 周期频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 的残留效应。这项研究的结果将为 CR-DBS 作为一种新的 ET 治疗方法的安全性和有效性提供概念证明。了解残留效应将有助于确定未来 CR 研究中 CR-DBS 的给药方案（连续或间歇给药）。如果成功，这项研究的结果将显着推进用于治疗 ET 的 CR-DBS 的开发，最大限度地减少副作用并可能减少习惯，最终改善接受 VIM DBS 的 ET 患者的临床结果和更好的生活质量。