Mechanisms and effects of pallidal deep brain stimulation on levodopa resistant motor signs in Parkinson's disease

项目概要/摘要 很大比例的帕金森病（PD）患者会出现使人衰弱的左旋多巴耐药， 在疾病过程中，姿势稳定性受损和步态障碍，包括步态冻结。许多 这些人将成为候选人治疗与脑深部电刺激（DBS）由于疾病 与长期使用多巴胺替代疗法相关的进展和不良反应。而 使用标准临床靶点和刺激的丘脑底核（DBS）和苍白球（GP）DBS 参数可以非常有效地治疗PD的主要运动症状，这两种治疗通常 无法控制PD的左旋多巴抵抗运动特征。以前的研究，以及我们正在进行的研究， 提供的证据表明，缓解运动不能和运动迟缓的最有效部位是 GPi的后外侧背侧区，靠近内部和外部（GPe）段之间的边界，背侧 到GPi DBS的典型目标区域。此外，在该区域的DBS可以有效地治疗左旋多巴耐药 汽车标志目前，介导刺激GPi-GPe边界附近的促动力效应的机制 (GPi/e-DBS）的了解很少。本项目的主要目标是更好地了解 通路介导GPi/e-DBS对左旋多巴抵抗运动体征的益处。该项目将利用 DBS电极导线设计的技术进步，允许电流导向和电场方向的调整， 结合患者特异性计算模型，调整刺激以优先激活促动力 轴突通路（目的1和3）。此外，我们将长期无线记录导线的局部场电位 植入GP DBS（Aim 2）患者体内，并使用可穿戴技术监测步态和移动性， 家庭环境中的慢性刺激（目标2）。目标1将检查改变方向的影响， 由GPi/e-DBS诱导的电场是平行的或正交的（最低或最高的净轴突激活 阈值）到假定的纹状体-GPi和GPe到GPi传入通路（ 基底神经节）。目标2将使用Medtronic Percept™ PC DBS系统（具有主动感知功能）研究：（i）苍白球 与步态障碍的重新出现（洗脱）和抑制（洗脱）相关的振荡， GPi/e-DBS，（2）使用3 T fMRI研究GP DBS对运动网络活动的上游和下游影响，以及（iii） 日常生活活动期间步态波动与GP LFP之间的关系（记录超过4周）。 目的3将检查刺激GPe的联合/边缘区对步态和姿势的影响。 在认知负荷增加和不增加的情况下进行控制（双任务）。总之，这些实验将提供关键的 深入了解GPi/e-DBS对基底神经节和皮质-皮质下回路的机制和影响， 步态和姿势控制措施。这可能会导致一种新的方法，使用GP DBS治疗左旋多巴- PD的运动障碍

Project Summary/Abstract A large percentage of people with Parkinson’s disease (PD) will develop debilitating levodopa-resistant impairment in postural stability and gait disturbances, including freezing of gait, over the course of disease. Many of these individuals will be become candidates for treatment with deep brain stimulation (DBS) due to disease progression and adverse effects associated with prolonged use of dopamine replacement therapy. While subthalamic nucleus (STN) and globus pallidus (GP) DBS using standard clinical targets and stimulation parameters can be highly effective for the treatment of the cardinal motor symptoms of PD, both treatments often fail to control levodopa-resistant motor features of PD. Previous studies, and our ongoing research, have provided evidence that the most effective site for alleviating akinesia and bradykinesia was the posterolaterodorsal region of the GPi, near the border between the internal and external (GPe) segments, dorsal to the region typically targeted for GPi DBS. Moreover, DBS in this region can be effective for levodopa-resistant motor signs. Currently, the mechanisms mediating the prokinetic effects of stimulation near the GPi-GPe border (GPi/e-DBS) are poorly understood. The primary goal of this project is to gain a better understanding of the pathways mediating the benefits of GPi/e-DBS on levodopa-resistant motor signs. The project will leverage technical advances in DBS lead design that allow current steering and adjustment of electric field orientation, in conjunction with patient-specific computational models, to tune stimulation to preferentially activate prokinetic axonal pathways (Aims 1 and 3). In addition, we will wirelessly record local field potentials from leads chronically implanted in people with GP DBS (Aim 2), and use wearable technology to monitor gait and mobility during chronic stimulation in the home environment (Aim 2). Aim 1 will examine the effects of altering the orientation of the electric field induced by GPi/e-DBS to be either parallel or orthogonal (lowest or highest net axonal activation thresholds, repectively) to putative striato-GPi and GPe to GPi afferent pathways (prokinetic connections of the basal ganglia). Aim 2 will use the Medtronic Percept™ PC DBS system with active sensing to study: (i) pallidal oscillations associated with the re-emergence (wash-out) and suppression (wash-in) of gait impairment with GPi/e-DBS, (2) the up- and down-stream effects of GP DBS on motor network activity using 3T fMRI, and (iii) the relationship between fluctuations in gait and GP LFPs during activities of daily living (recorded over 4 weeks). Aim 3 will examine the effects of stimulation in the associative/limbic region of the GPe on gait and postural control with and without an increased cognitive load (dual-task). Together, these experiments will provide critical insight into the mechanisms and effects of GPi/e-DBS on basal ganglia and cortical-subcortical circuitry and measures of gait and postural control. This could lead to a new approach to using GP DBS to treat levodopa- resistant motor signs of PD.