Cortical and basal ganglia local field potentials in human movement disorders

描述（由申请人提供）：我们的目标是通过对接受神经外科治疗的人类皮质和基底神经节局部场电位（LFPs）的研究，促进对运动障碍病理生理学和治疗机制的理解。LFP代表突触前终末和突触后神经元同步的阈下和阈上活动。目前的帕金森病（PD）模型认为，关键的电路水平异常是基底神经节神经元活动的过度同步，特别是在β (13- 30 Hz)频率。在本研究的初始阶段（2010-2013），我们利用术中记录显示，在PD中，皮层β节律的相位与γ活动的振幅（50-250 Hz）存在夸张的耦合。这种“相位振幅耦合”（PAC）已经被认为是皮层控制认知和运动功能的重要机制。由于皮质伽马活动反映了局部人口的峰值，我们认为过度的PAC是神经元同步增加的皮质表现。我们认为这将运动皮层限制在一种不灵活的活动模式，导致运动不足。在这里，我们进一步研究两种运动障碍PD和原发性肌张力障碍的网络同步方面，采用有创术中记录和无创头皮脑电图（EEG）方法。首先，在运动序列的哪个部分（保持姿势、运动准备或动作），皮层和基底神经节的振荡活动最受干扰，以及最重要的皮层异常的解剖定位（在4mm分辨率下）是什么？其次，脑深部电刺激（DBS）在运动障碍中是如何破坏皮质同步的，这种破坏的时间过程及其行为后遗症是什么？第三，急性和慢性DBS对皮质功能的影响是否可以无创研究？为了解决这些问题，在术中记录中，我们使用基于触摸屏的二元选择任务，将运动计划与运动执行分开。我们引入高空间分辨率硬脑膜下记录网格（28通道），以询问最大生理异常的皮质“热点”在哪里。为了解决DBS对皮质同步无创的影响，我们将在门诊设置的几个时间点使用头皮脑电图，基于令人惊讶和新颖的发现，即皮层PAC可在头皮脑电图中检测到。皮质生理学是这些研究的主要焦点，因为在先前的资助期，我们发现皮质信号比基底神经节lfp对疾病状态更敏感。这些研究的影响将是：1)提供对PD和肌张力障碍中皮层异常同步的更详细的了解，为这些疾病的网络异常提供新的模型。2)提供治疗性DBS对皮质和基底神经节功能影响的机制理解。3)为开发闭环脑深部刺激奠定基础，利用临床实用的皮层信号自动控制刺激参数。

DESCRIPTION (provided by applicant): Our goal is to advance the understanding of movement disorders pathophysiology, and therapeutic mechanisms, through studies of cortical and basal ganglia local field potentials (LFPs) in humans undergoing neurosurgical treatment. The LFP represents synchronized sub- and supra-threshold activity in presynaptic terminals and postsynaptic neurons. The current model of Parkinson's disease (PD) posits that the critical circuit-level abnormality is excessive synchronization of basal ganglia neuronal activity, especially at beta (13- 30 Hz) frequencies. In the initial period of this grant (2010-2013), we utilized intraoperative recordings to show that in PD, there is exaggerated coupling of the phase of the cortical beta rhythm to the amplitude of gamma activity (50-250 Hz). This "phase amplitude coupling" (PAC) is already known as an important mechanism for the cortical control of cognitive and motor function. Since cortical gamma activity reflects local population spiking, we interpret excessive PAC is a cortical manifestation of increased neuronal synchronization. We propose that this constrains motor cortex to an inflexible pattern of activity, leading to a paucity of movement. Here, we further investigate aspects of network synchronization in two movement disorders, PD and primary dystonia, using both invasive intraoperative recording and noninvasive scalp electroencephalography (EEG) methods. First, in what part of a movement sequence (holding a position, movement preparation, or action) are cortical and basal ganglia oscillatory activity most disrupted, and what is the anatomic localization (at 4 mm resolution) of the most important cortical abnormalities? Second, how does deep brain stimulation (DBS) in movement disorders disrupt cortical synchronization and what is the time course of this disruption and its behavioral sequelae? Third, can effects of acute and chronic DBS on cortical function be studied non- invasively? To address these, in intraoperative recordings we utilize a touch screen based binary choice task that separates movement planning from movement execution. We introduce high spatial resolution subdural recording grids (28 channel), to ask where are the cortical "hot spots" of greatest physiologic abnormality. To address effects of DBS on cortical synchronization noninvasively, we will utilize scalp EEG at several time points in the outpatient setting, based on the surprising and novel finding that cortical PAC is detectable in scalp EEG. Cortical physiology is a primary focus of these studies, since in the prior grant period we found that cortical signals are more sensitive to disease state than basal ganglia LFPs. The impact of these studies will be to: 1) Provide a more detailed understanding of abnormal cortical synchronization in PD and dystonia, informing new models of network abnormalities in these disorders. 2) Provide a mechanistic understanding of the effects of therapeutic DBS on cortical and basal ganglia function. 3) Create a foundation for the development of a closed loop deep brain stimulation, which could utilize a clinically practical cortical signal for automated control of stimulation parameters.