Mechanisms and pathways mediating the motor effects of pallidal deep brain stimulation

项目总结/摘要 在苍白球（GP）或丘脑底核（BTH）区域中的深部脑刺激（DBS）已经被证实是有效的。 经证明，可提供具有临床意义的运动功能改善，并改善患者的生活质量 帕金森氏病（PD）患者中。虽然在大多数神经外科手术中， 中心，有一个在选择GP作为目标的兴趣死灰复燃。这种兴趣是基于 有证据表明，总体临床效果与DBS相当，但GP DBS可能更少 神经心理学副作用，并为药物的编程和调整提供更大的灵活性。 然而，患者对GP DBS的反应存在相当大的差异，左旋多巴剂量通常保持不变。 高，并且，与STN DBS一样，它对左旋多巴抵抗运动特征（例如姿势不稳定、步态）是否无效 步态紊乱和冻结。我们认为，GP DBS疗效的显著改善可以 通过增加对调节运动的机制、位置和途径的理解而获得 DBS对人类苍白球的影响。本项目的前提是，传统GP的运动效果 DBS受到抑制左旋多巴诱导的运动障碍（运动不能） 并减少运动迟缓（促运动）。我们将测试的假设，机制和地点调解 这些“相反的效应”在GP的功能上和形貌上分离的区域中。这一假设将 通过进行GP刺激位置对左旋多巴和左旋多巴的影响的系统研究来测试， PD的反应性（僵硬和运动迟缓）和左旋多巴抵抗性（平衡、步态、冻结）运动特征 (Aim 2），以及苍白球内运动相关振荡活动的地形图（GPi和GPe）， 通过记录长期植入电极的人的局部场电位进行验证（目标3）。State-of-the-art 高场MRI（7 T）和患者特异性纤维束成像激活模型将用于将刺激集中到 感兴趣的区域（腹侧GPi，背侧GPi，腹侧GPe），并估计 刺激（目标1）。这些实验的结果将提供有关刺激的关键信息 位置和轴突通路介导GP DBS运动体征的改善或恶化， 运动障碍的神经生理学生物标志物，以及这些生物标志物如何通过 药物和DBS。这些知识可以转化为下一代DBS设备， 电流引导和闭环控制，以提供最佳的治疗效果。

Project Summary/Abstract Deep brain stimulation (DBS) in the region of the globus pallidus (GP) or subthalamic nucleus (STN) has been demonstrated to provide clinically meaningful improvements in motor function and improve patient quality of life in people with Parkinson’s disease (PD). While the STN is the typical target of choice at most neurosurgical centers, there has been a resurgence of interest in selecting the GP as a target. This interest is based on evidence that the overall clinical effects are comparable to those of STN DBS, but GP DBS may have fewer neuropsychological side-effects and affords greater flexibility for programming and adjustment of medications. Yet, there is considerable variability in response to GP DBS across patients, levodopa dose typically remains high, and, like STN DBS, is it ineffective for levodopa-resistant motor features such as postural instability, gait disturbances and freezing of gait. We argue that significant improvements in the efficacy of GP DBS can be gained through an increased understanding of the mechanisms, locations and pathways mediating the motor effects of DBS in the human pallidum. The premise of this project is that the motor effects of conventional GP DBS are compromised by a balance between the need to suppress levodopa-induced dyskinesias (akinetic) and reduce bradykinesia (prokinetic). We will test the hypothesis that the mechanisms and locations mediating these “opposite effects” are in functionally and topographically separate regions of the GP. This hypothesis will be tested by conducting a systematic study of the effects of GP stimulation location on both levodopa- responsive (rigidity and bradykinesia) and levodopa-resistant (balance, gait, freezing) motor features of PD (Aim 2), and the topography of movement-related oscillatory activity within the pallidum (GPi and GPe) and STN by recording local field potentials in people with chronically implanted electrodes (Aim 3). State-of-the-art high-field MRI (7T) and patient-specific tractography-activation models will be used to focus stimulation to the region of interest (ventral GPi, dorsal GPi, ventral GPe) and estimate the pallidofugal pathways activated by stimulation (Aim 1). The results of these experiments will provide critical information about the stimulation location and axonal pathways mediating improvement or deterioration of motor signs with GP DBS, the neurophysiological biomarkers of disordered movement, and how these biomarkers are changed by medication and DBS. This knowledge can be translated to the next generation of DBS devices that provide current steering and closed-loop control to provide optimal therapeutic outcomes.