Mechanisms of Pallidal Deep Brain Stimulation

描述（由申请人提供）：苍白球深部脑刺激（DBS）是治疗晚期帕金森病（PD）的有效方法。尽管最近取得了一些成功，但由于我们对DBS的神经反应的了解有限，在白质中的确切位置和治疗的生理机制仍然不确定。我们假设帕金森运动症状在GP中具有不同的治疗靶点。通过确定GP-DBS的机制，我们可以开发新的刺激模式和电极，以选择性地靶向与治疗益处相关的细胞群，同时最大限度地减少刺激引起的副作用。在这项研究中，我们建议为4只mptp治疗的半帕金森恒河猴建立解剖学和生物物理精确的外苍白球（GPe）和内苍白球（GPi） DBS模型。每只动物已经或将被植入一个猴子大小的临床DBS引线，这样四个电极接触就跨越了GPe和GPi的感觉运动区域。计算模型将被回顾性地应用于确定两只猴子在治疗和非治疗DBS期间的神经反应。然后，在另外两只猴子身上开发的模型将用于前瞻性地评估特定解剖区域的靶向刺激效果。我们的工作假设是，直接刺激腹侧后感觉运动GPi将主要改善僵硬和左旋多巴诱导的运动障碍，而有针对性地刺激背侧GPi和腹侧GPe的感觉运动方面将主要改善运动迟缓。如果本研究的结果在回顾性和前瞻性评价上都支持这一假设，它将为该领域提供两个重要的贡献：1)证实使用详细的计算模型指导DBS参数选择的技术，更重要的是2)为GP-DBS植入物的临床规划提供解剖学和电学指导。

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) of the globus pallidus (GP) is an effective treatment for patients with advanced Parkinson's disease (PD). Despite recent successes, the precise site(s) within the pallidum and physiological mechanism(s) of the therapy remain uncertain due in part to our limited understanding of the neural response to DBS. We hypothesize that parkinsonian motor symptoms have therapeutically distinct targets within the GP. By identifying the mechanisms of GP-DBS, we can then develop new stimulation patterns and electrodes to selectively target the cell groups implicated in the therapeutic benefit while minimizing stimulation induced side-effects. In this study, we propose to develop anatomically and biophysically accurate models of DBS in the globus pallidus externus (GPe) and globus pallidus internus (GPi) for four MPTP-treated, hemi-parkinsonian rhesus macaques. Each animal has been or will be implanted with a monkey-scaled version of a clinical DBS lead such that the four electrode contacts span the sensorimotor regions of both GPe and GPi. The computational models will be applied retrospectively to determine the neural response during therapeutic and non-therapeutic DBS in two monkeys. Models developed in two additional monkeys will then be used to prospectively evaluate the effects of targeted stimulation of specific anatomical territories. Our working hypothesis is that direct stimulation of the posteroventral sensorimotor GPi will primarily improve rigidity and levodopa-induced dyskinesias, whereas targeted stimulation of the sensorimotor aspects of dorsal GPi and ventral GPe will primarily improve bradykinesia. If the results of this study support this hypothesis with both retrospective and prospective evaluation, it will provide two important contributions to the field: 1) substantiate the technique of using detailed computational models to guide DBS parameter selection, and more importantly 2) provide anatomical and electrical guidelines for the clinical programming of GP-DBS implants.