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

项目摘要/摘要 很大比例的帕金森氏病(PD)患者会出现对左旋多巴的抵抗力 在病程中姿势稳定性受损和步态紊乱，包括步态僵硬。许多 其中一些人将因疾病而接受脑深部刺激(DBS)治疗 与长期使用多巴胺替代疗法相关的进展和不良反应。而当 使用标准临床靶点和刺激的丘脑底核(STN)和苍白球(GP)DBS 参数可以非常有效地治疗帕金森病的主要运动症状，这两种治疗方法通常 未能控制帕金森病的左旋多巴抗性马达特征。之前的研究和我们正在进行的研究已经 提供了证据表明，缓解运动障碍和运动迟缓最有效的部位是 GPI背侧后区，靠近内、外节段交界处，背侧 到通常以GPI DBS为目标的地区。此外，该地区的DBS可以有效地治疗左旋多巴耐药 机动标志。目前，在GPI-GPE边界附近，介导刺激促进运动效应的机制 (GPI/e-DBS)被理解得很少。这个项目的主要目标是更好地了解 介导GPI/e-DBS对左旋多巴抵抗运动标志的益处的途径。该项目将利用 DBS引线设计中的技术进步，允许电流方向和电场方向的调整 结合患者特定的计算模型，调整刺激以优先激活促动力 轴突通路(目标1和3)。此外，我们还将长期无线记录导线的局部场势 植入患有GP DBS的人体内(AIM 2)，并使用可穿戴技术监测 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 GPI/e-DBS诱导的电场为平行或垂直的(最低或最高净轴突激活 阈值分别)到可能的纹状体-GPI和GPE到GPI的传入通路(促运动性连接 基底节)。Aim 2将使用具有主动传感功能的美敦力Percept™PC DBS系统来研究：(I)苍白球 与步态损害的重新出现(洗出)和抑制(洗入)相关的振荡 GPI/e-DBS，(2)用3T fMRI研究GP DBS对运动网络活动的上行和下行影响，以及(Iii) 日常生活活动中步态波动与GP LFP之间的关系(记录4周以上)。 目标3将研究刺激GPE的联合/边缘区域对步态和姿势的影响 在认知负荷增加的情况下和不增加认知负荷的情况下进行控制(双重任务)。总而言之，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-皮质下环路的机制和影响 步态和姿势控制的措施。这可能导致一种使用GP DBS治疗左旋多巴的新方法。 帕金森病的阻力运动征象。

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.