Neurophysiological Biomarkers of Movement Facilitation in Parkinson’s Disease

项目总结 改善帕金森氏症神经调节疗法(如脑深部刺激)的有前景的策略 疾病(PD)是开发针对特定神经信号的刺激范例。大多数以前的工作都有 目的识别和减少病理信号。一种尚未探索的替代方法是识别和增强 促进运动的神经信号。已知可以改善帕金森病患者运动的几种情况是 存在视觉运动目标、有节奏的听觉刺激和动机激励。这样做的目的是 建议是利用这些情景来确定促进运动的生物标记物，这些生物标记物可能起到 未来神经调节疗法的靶点。这种方法有可能提供新的治疗方法。 目前的治疗方法难以治愈的症状，如步态僵硬。以前的工作是检查神经 帕金森病患者运动促进机制的研究结果并不一致。这可能是由于未能 解释了众所周知的PD患者行为益处的异质性，并假设 不同的提示现象通过单一的神经机制发挥运动优势。这项研究建议 这里测试了三种不同类型的线索(视觉目标、有节奏的听觉刺激和 奖励激励)通过不同的神经解剖回路和电生理促进行动 机制，通过利用已知的可变性的行为线索对患者的好处。目标1是 在患者体内展示三种运动促进形式之间的行为分离，并与 提示的可变性有利于可分离神经解剖回路的完整性，通过静息状态和 扩散张量磁共振成像(MRI)。目标2是描述电生理相关的特征 使用脑电(EEG)和术中不同线索类型的行为益处 苍白球植入脑深部刺激器时的电生理记录 内脏。这项工作将增强我之前在任务fMRI、经颅磁刺激(TMS)和 通过多种方式扩展训练的电生理学(高密度脑电、静息状态功能磁共振成像、DTI)；建立 我在高级多元统计方面的分析技能；以及在帕金森病运动生理学方面的专业知识。我的 导师团队由帕金森病神经生理学和神经调节疗法以及非侵入性治疗方面的专家组成 运动神经生理学的个体差异研究。多元统计和统计课程 高级脑电和神经成像应用方面的研讨会将进一步促进我的发展。位于的环境 加州大学洛杉矶分校拥有丰富的跨学科神经成像社区，最先进的图像获取设施包括 Ahmanson-Lovelace Brian测绘中心和Staglin认知神经科学中心 临床运动障碍科。职业发展计划为独立人士开辟了一条道路 医生-科学家，使用多种方式表征异质性的神经生理学生物标记物 帕金森氏病的疾病特征，以改进治疗开发和交付。

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.