Deep Brain Stimulation in the Parkinsonian Monkey

描述(申请人提供)：脑深部刺激使帕金森病的治疗发生了革命性变化，并重新探索了一系列神经系统疾病的手术治疗方法，包括震颤、肌张力障碍、强迫症、抑郁症、抽动症、成瘾、疼痛和癫痫。尽管星展银行被广泛使用，但其作用机制仍不清楚。关于DBS的有益作用是否直接与抑制、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有关的争论仍在继续。有三个主要问题限制了对先前试图解决DBS作用机制的研究的解释：1)在无法评估行为状态的情况下，研究DBS对神经元活动的影响(例如，脑片或麻醉动物)；2)监测DBS在刺激部位的影响，而不研究DBS对刺激部位投射到的大脑区域的影响；以及3)仅在由于与电刺激伪影相关的问题而停止刺激后，才研究DBS的影响。许多这些研究的结果是相互矛盾的，很可能是次要的，因为这些实验是在不同的条件下进行的。此外，这些研究大多没有评估刺激对运动中神经元活动的影响，在运动状态下，DBS的大部分治疗效果是直接的，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中检查治疗性DBS在STN和GPI中的效果，同时从基底节丘脑皮质网络的多个结点进行记录。神经元的活动将在四种情况下进行评估：休息时和运动时，有无刺激。这项研究将对GPI和STN DBS治疗帕金森病运动体征的网络活动的变化提供重要的洞察。公共卫生相关性：这项研究的目标是了解大脑中的电刺激如何改善与帕金森病(PD)相关的运动症状。帕金森病的动物模型将被用来研究治疗性脑深部刺激对不同大脑结构的电活动的影响，这些结构被认为是帕金森病患者功能异常的。刺激的区域将是丘脑底核(STN)和苍白球内段(GPI)，这两个结构现在用于治疗特发性帕金森病患者。这项研究是独一无二的，因为它将同时研究许多不同大脑结构在运动过程中的神经元活动；以前的大多数工作只研究了休息时的一个神经元。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是如何共同工作来产生运动的，在帕金森病期间出了什么问题，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，以帮助开发更好的方法来刺激当前的靶向大脑区域，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治疗帕金森病和其他神经疾病的疗效。

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.