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处 刺激(DBS)疗法治疗帕金森氏病(PD)在某些人身上比在另一些人身上效果更好，并 开发降低DBS治疗帕金森病个别运动体征的变异性的方法。提供星展银行 在与最好的应答者一致的水平上进行治疗，关键是要调查(1)DBS的出现- 妨碍提供更有效的刺激参数的引起的副作用，(2)后勤挑战 在个体基础上优化每个帕金森患者运动体征的刺激设置，以及(3)多尺度 个体所在的基底节、丘脑和脑干的神经生理学差异 DBS治疗的变异性。该项目将充分利用帕金森病的非人类灵长类动物模型 (系统性MPTP)植入两种缩小版本的人类DBS导联(丘脑底核，STN) 和苍白球，GP)。该方法涉及高场成像(7T/10.5T，成像)的新组合 CORE)，DBS的计算神经元建模，基于量化的优化算法的开发 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治疗跨越单细胞、整体和全脑水平的电生理学分析。目标1 将研究窄DBS脉冲宽度延长治疗参数空间窗口的能力 缓解帕金森氏症运动体征和引起运动副作用之间的关系。这一目标将进一步加强我们的 了解DBS参数设置与其结果治疗之间的功能关系 基于特定对象、特定路径的效果大小和洗入/洗出时间常数。目标2将 开发了一种新的实时、基于行为的优化算法，用于自动高效地选择数据库 使帕金森患者个体运动体征的表达最小化的参数，包括僵直，运动迟缓， 行动不便，还有步态/姿势。目标3将确定特定于受试者的电生理特征 与前两个目标中发现的对DBS的临时和稳态行为反应相关。这个 同时记录将包括STN和GP中的局部场电位以及 由苍白球分离投射神经元支配的三个核团(即运动丘脑、中央正中-束旁核 丘脑和桥脑脚核复合体)。在实验结束时，全脑 两个代谢标志物(c-fos和egr-1)的转录因子分析将通过组织学进行 为行为优化的DBS调制的神经通路提供单细胞分辨率的技术 心理治疗。总之，这些目标将提供关键的新的洞察力，以了解 帕金森病患者各运动体征的表达以及哪些特定的靶向通路和电生理 功能与为每个人提供最有效和最高效的DBS治疗最相关。

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.