Deep Brain Stimulation in the Parkinsonian Monkey

描述（由申请人提供）：脑深部刺激已经彻底改变了PD的治疗，并重新探索了手术治疗多种神经系统疾病的方法，包括震颤、肌张力障碍、强迫症、抑郁症、妥瑞氏综合征、成瘾、疼痛和癫痫。尽管DBS被广泛使用，但其作用机制尚不清楚。关于DBS的有益作用是否与抑制、兴奋、模式改变或其他一些尚未确定的对神经元活动的影响直接相关的争论仍在继续。三个主要问题限制了先前试图解决DBS作用机制的研究的解释：1)检查DBS对无法评估行为状态的神经元活动的影响（例如脑切片或麻醉动物），2)在刺激部位监测DBS的效果，而不检查对受刺激部位所影响的大脑区域的影响，以及3)仅在刺激因电刺激伪影相关的问题而停止后检查DBS的效果。其中许多研究的结果都是相互矛盾的，这可能是实验进行时各种各样的条件造成的。此外，这些研究大多没有评估运动过程中刺激对神经元活动的影响，而DBS的大部分治疗效果都是在运动过程中产生的，也没有在网络水平上解决神经元活动的变化。为了解决这些局限性，我们建议在执行到达任务的猴子的STN和GPi中检查治疗性DBS的效果，同时从基底节区丘脑皮质网络的多个节点记录。神经元活动将在四种情况下进行评估；在休息和运动时，有或没有刺激。这项研究将为GPi和STN DBS治疗帕金森运动症状的网络活动变化提供重要的见解。公共卫生相关性：本研究的目的是了解脑电刺激如何改善与帕金森病（PD）相关的运动症状。PD的动物模型将用于研究治疗性脑深部刺激对PD中被认为功能异常的不同脑结构的电活动的影响。刺激的区域将是丘脑下核（STN）和苍白球（GPi）的内部段，这两个结构目前用于治疗特发性PD患者。这项研究的独特之处在于，它将同时研究来自许多不同大脑结构的运动过程中的神经元活动；大多数先前的工作只在休息时一次研究一个神经元。通过在运动过程中同时记录许多不同的大脑结构，我们将开始了解这些结构如何协同工作以产生运动，PD期间出现了什么问题，以及电刺激如何改变大脑活动以改善症状。这项研究的结果将提供理论基础，帮助开发更好的方法来刺激当前的目标大脑区域，确定可能比当前更有效的新靶点，并开发新技术，使我们能够优化DBS治疗PD和其他神经系统疾病的治疗效果。

DESCRIPTION (provided by applicant): Deep brain stimulation has revolutionized the treatment of PD and renewed the exploration of surgical therapy for a wide range of neurological disorders including tremor, dystonia, obsessive compulsive disorder, depression, Tourette syndrome, addiction, pain and epilepsy. Despite the widespread use of DBS, its mechanism of action remains unclear. Debate continues over whether the beneficial effects of DBS are directly related to inhibition, excitation, changes in pattern, or some other as yet undetermined effect on neuronal activity. Three major issues limit the interpretation of previous studies that have sought to address the mechanism of action of DBS: 1) examining the effects of DBS on neuronal activity where behavioral state cannot be assessed (e.g. brain slices or anesthetized animals), 2) monitoring the effects of DBS at the site of stimulation without examining the effect on brain regions to which the stimulated site projects, and 3) examining the effects of DBS only after stimulation has been discontinued due to the problems associated with electrical stimulation artifacts. The results from many of these studies have been contradictory, likely secondary to the variety of conditions under which the experiments have been conducted. In addition most of these studies do not assess the effect of stimulation on neuronal activity during movement, the state during which most of the therapeutic effect of DBS is directed nor do they address the changes in neuronal activity at a network level. To address these limitations we propose to examine the effect of therapeutic DBS in the STN and GPi in monkeys performing a reaching task, while simultaneously recording from multiple nodal points in the basal ganglia thalamocortical network. Neuronal activity will be assessed under four conditions; at rest and during movement with and without stimulation. This study will provide significant insight into the changes in network activities that underlie the therapeutic effect of GPi and STN DBS on parkinsonian motor signs. PUBLIC HEALTH RELEVANCE: The goal of this study is to understand how electrical stimulation in the brain improves the motor symptoms associated with Parkinson's disease (PD). An animal model of PD will be used to study the effect of therapeutic deep brain stimulation on the electrical activity of different brain structures that are thought to function abnormally in PD. The areas stimulated will be the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi), two structures now used to treat idiopathic PD in patients. This study is unique because it will investigate neuronal activity during movement from many different brain structures at the same time; most previous work has only studied one neuron at a time during rest. By recording from many different brain structures simultaneously during movement we will begin to understand how these structures work together to produce movement, what goes wrong during PD, and how electrical stimulation changes brain activity to improve symptoms. The results of this study will provide the rationale to help develop better ways to stimulate currently targeted brain regions, identify new targets that may be more effective than current ones, and develop new technology that will allow us to optimize the therapeutic effect of DBS for the treatment of PD and other neurological disorders.