Mechanisms of Pallidal Deep Brain Stimulation

描述(申请人提供)：脑深部刺激苍白球(GP)是一种有效的治疗晚期帕金森病(PD)患者。尽管最近取得了成功，但该疗法的确切部位(S)和治疗的生理机制(S)仍然不确定，部分原因是我们对DBS的神经反应了解有限。我们假设帕金森病的运动症状在全科医生中有不同的治疗靶点。通过确定GP-DBS的机制，我们可以开发新的刺激模式和电极，以选择性地针对与治疗益处有关的细胞组，同时将刺激引起的副作用降至最低。在这项研究中，我们建议为四只MPTP治疗的半帕金森病猕猴建立苍白球外球(GPE)和苍白内球(GPI)DBS的解剖学和生物物理学准确模型。每只动物都已经或将被植入猴子尺寸的临床DBS导线，这样四个电极接触就跨越了GPE和GPI的感觉运动区。这些计算模型将被追溯应用于确定两只猴子在治疗性和非治疗性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的效果。我们的工作假设是，直接刺激后腹侧感觉运动GPI将主要改善僵直和左旋多巴诱导的运动障碍，而靶向刺激背侧GPI和腹侧GPE的感觉运动方面将主要改善运动迟缓。如果这项研究的结果支持这一假说并进行回顾和前瞻性评估，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来指导DBS参数选择的技术，更重要的是，为GP-DBS种植体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.