Neurophysiological Biomarkers of Movement Facilitation in Parkinson’s Disease

项目摘要 改善帕金森病神经调节疗法（例如脑深部电刺激）的一种有前景的策略 疾病（PD）是发展针对特定神经信号的刺激范式。以前的大多数工作 旨在识别和减少病理信号。一种未探索的替代方法是确定和增强 促进运动的神经信号。已知改善PD患者运动的几种情况是 视觉运动目标的存在，有节奏的听觉刺激和动机激励。这个目标 一项建议是利用这些情景来确定运动促进的生物标志物， 未来神经调节疗法的目标。这种方法有可能为癌症提供新的治疗方法。 目前治疗难以治愈的症状，如步态僵硬。以前的工作检查神经 PD的运动促进机制产生了不一致的结果。这可能是由于未能 解释了PD患者行为获益的众所周知的异质性，以及以下假设： 不同的提示现象通过单一的神经机制发挥运动益处。建议的研究 这里测试的总体假设，3种不同类型的线索（视觉目标，节奏听觉刺激和 奖励激励）通过不同的神经解剖学回路和电生理学回路促进运动 机制，通过利用患者之间行为提示益处的已知可变性。目标1： 证明了患者体内3种运动促进形式之间的行为分离， 通过静息状态测量的提示对可分离神经解剖回路完整性的益处的变异性， 扩散张量磁共振成像（MRI）。目的2是表征电生理相关因素 使用脑电图（EEG）和术中不同提示类型的行为益处 在苍白球中植入脑深部刺激器期间获得的电生理记录 内肌这项工作将增强我在任务功能磁共振成像，经颅磁刺激（TMS）和 通过多种方式（高密度EEG，静息状态fMRI，DTI）扩展训练的电生理学;建立 我在高级多元统计学方面的分析技能;并提高我在PD运动生理学方面的专业知识。我 导师团队由PD神经生理学和神经调节疗法专家组成， 运动神经生理学个体间差异的研究。多元统计学课程， 高级脑电图和神经成像应用的研讨会将促进我的发展。的环境 加州大学洛杉矶分校拥有丰富的跨学科神经成像社区，最先进的图像采集设施，包括 Ahmanson-Lovelace布莱恩绘图中心和Staglin认知神经科学中心以及著名的 临床运动障碍科职业发展计划为成为一名独立的 医生-科学家，使用多种模式来表征异质性神经生理学生物标志物 帕金森病的疾病特征，以改善治疗开发和交付。

PROJECT SUMMARY A promising strategy to improve neuromodulation therapies (e.g. deep brain stimulation) in Parkinson’s Disease (PD) is to develop stimulation paradigms that target specific neural signals. Most previous work has aimed to identify and reduce pathologic signals. An unexplored alternative approach is to identify and enhance neural signals that promote movement. Several scenarios known to improve movement in PD patients are the presence of visual movement targets, rhythmic auditory stimuli, and motivational incentives. The goal of this proposal is to capitalize on these scenarios to identify biomarkers of movement facilitation that may serve as targets for future neuromodulation therapies. This approach has potential to provide novel therapies for symptoms refractory to current treatments, such as freezing of gait. Previous work examining neural mechanisms of movement facilitation in PD have yielded inconsistent results. This may be due to a failure to account for well-known heterogeneity in behavioral benefits across PD patients and the assumption that different cueing phenomena exert motor benefits through a single neural mechanism. The studies proposed here test the overarching hypothesis that 3 different types of cues (visual targets, rhythmic auditory stimuli and reward incentives) facilitate movement through distinct neuroanatomic circuits and electrophysiological mechanisms, by leveraging known variability in behavioral cueing benefits across patients. Aim 1 is to demonstrate behavioral dissociations between the 3 forms of movement facilitation within patients and relate variability in cueing benefits to integrity of dissociable neuroanatomic circuits as measured by resting state and diffusion tensor magnetic resonance imaging (MRI). Aim 2 is to characterize the electrophysiological correlates of behavioral benefits for the different cue types using electroencephalography (EEG) and intraoperative electrophysiological recordings obtained during implantation of deep brain stimulator in the globus pallidus internus. This work will augment my prior skills in task fMRI, transcranial magnetic stimulation (TMS) and electrophysiology by extending training in multiple modalities (high density EEG, resting state fMRI, DTI); build my analytic skills in advanced multivariate statistics; and advance my expertise in PD motor physiology. My mentorship team comprises experts in PD neurophysiology and neuromodulation therapies, and non-invasive studies of inter-individual differences in motor neurophysiology. Coursework in multivariate statistics and seminars in advanced EEG and neuroimaging applications will further my development. The environment at UCLA has a rich interdisciplinary neuroimaging community, state-of-the-art image acquisition facilities including Ahmanson-Lovelace Brian Mapping Center and Staglin Center for Cognitive Neuroscience and a renowned clinical Movement Disorders Division. The career development plan forges a path to become an independent physician-scientist, using multiple modalities to characterize neurophysiologic biomarkers of heterogeneous disease features in Parkinson’s disease to improve therapy development and delivery.