Behavioral Optimization of Deep Brain Stimulation Therapy for Parkinson's disease

摘要： 明尼苏达大学（UMN）Udall中心项目3的总体目标是调查为什么大脑深部 帕金森病（PD）的DBS治疗在某些个体中比在其他个体中效果更好， 开发降低DBS治疗PD个体运动体征的变异性的方法。输送DBS 在与最佳应答者一致的水平上进行治疗，关键是要研究（1）DBS的出现- 阻碍更有效刺激参数输送的诱导副作用，（2）后勤挑战 在个体基础上优化每个帕金森运动体征的刺激设置，以及（3）多尺度 神经生理学差异横跨基底神经节，丘脑和脑干，构成个体的基础 DBS治疗的可变性。该项目将利用PD的非人灵长类动物模型 （全身MPTP）植入两个缩小版本的人类DBS电极导线（丘脑底核， 和苍白球，GP）。该方法涉及高场成像（7 T/10.5T，成像）的新组合。 核心），DBS的计算神经元建模，基于定量 行为评估、多参数回归分析技术（生物统计学核心）和多尺度 DBS治疗的电生理学分析跨越单细胞、整体和全脑水平。要求1 将研究窄DBS脉冲宽度扩展治疗参数空间窗口的能力 缓解帕金森运动症状和引起运动副作用之间的联系。这一目标将进一步加强我们的 了解DBS参数设置与其最终治疗效果之间的功能关系 效应量和洗入/洗出时间常数，基于受试者特异性、途径特异性。目标2将 开发一种新的实时，基于行为的优化算法，用于自动有效地选择DBS 最小化个体帕金森病运动体征的表达的参数，包括僵硬，运动迟缓， 运动不能和步态/姿势。目标3将确定与患者最密切相关的受试者特异性电生理特征， 与前两个目标中发现的DBS的时间和稳态行为反应相关。的 同步记录将包括在EEG和GP中的局部场电位以及在EEG中的单位尖峰记录。 三个核团由离苍白球投射神经元支配（即运动丘脑、中央-束旁核 丘脑复合体和脚桥核）。在实验结束时，全脑 将通过组织学方法对两种代谢标志物（c-fos和fos-1）进行转录因子分析。 为行为优化DBS调制的神经通路提供单细胞分辨率的技术 疗法总之，这些目标将提供关键的新见解的病理生理基础， 每种帕金森病运动体征的表达，以及哪些特定的靶向通路和电生理 这些功能与为每个人提供最有效和最高效的DBS治疗水平最相关。

Abstract: The overall goal of project 3 of the University of Minnesota (UMN) Udall Center is to investigate why deep brain stimulation (DBS) therapy for Parkinson's disease (PD) works better in some individuals than in others and to develop methods to decrease the variability of DBS therapy for individual motor signs of PD. To deliver DBS therapy at a level consistent with the best responders, it is critical to investigate the (1) emergence of DBS- induced side effects that impede the delivery of more effective stimulation parameters, (2) logistical challenges in optimizing stimulation settings for each parkinsonian motor sign on an individual basis, and (3) multi-scale neurophysiological differences across the basal ganglia, thalamus, and brainstem that underlie the individual variability to DBS therapy. This project will leverage the well-characterized non-human primate model of PD (systemic MPTP) implanted with two scaled-down versions of the human DBS lead (subthalamic nucleus, STN and globus pallidus, GP). The approach involves a novel combination of high-field imaging (7T/10.5T, Imaging Core), computational neuron modeling of DBS, development of optimization algorithms based on quantitative behavioral assessments, multi-parameter regression analysis techniques (Biostatistics Core), and multi-scale electrophysiological analysis of DBS therapy that spans single-cell, ensemble, and whole-brain levels. Aim 1 will investigate the ability for narrow DBS pulse widths to extend the therapeutic parameter space window between alleviating parkinsonian motor signs and evoking motor side-effects. This aim will further enhance our understanding of the functional relationships between DBS parameter settings and their resultant therapeutic effect sizes and wash-in/wash-out time constants on a subject-specific, pathway-specific basis. Aim 2 will develop a novel real-time, behavior-based optimization algorithm for automatic and efficient selection of DBS parameters that minimize the expression of individual parkinsonian motor signs including rigidity, bradykinesia, akinesia, and gait/posture. Aim 3 will identify the subject-specific electrophysiological features that most closely correlate with the temporal and steady-state behavioral responses to DBS found in the first two aims. The simultaneous recordings will include local field potentials in the STN and GP as well as unit-spike recordings in three nuclei innervated by pallidofugal projection neurons (i.e. motor thalamus, centromedian-parafascicular complex of thalamus, and pedunculopontine nucleus). At the conclusion of the experiments, whole-brain transcription factor analysis for two metabolic markers (c-fos and egr-1) will be conducted through histological techniques to provide single-cell resolution for the neural pathways modulated by behaviorally-optimized DBS therapy. Together, these aims will provide critical new insight into the pathophysiological basis for the expression of each parkinsonian motor sign and which specific targeted pathways and electrophysiological features are most relevant to delivering the most effective and efficient level DBS therapy for each individual.