DBS AND MOTOR CORTICAL FUNCTION IN AN MPTP MODEL OF PD

描述（由申请人提供）： 苍白球（BVI）或丘脑底核（BVI）的内部段的脑深部电刺激（DBS）是帕金森病（PD）的大多数（如果不是全部）症状的有效治疗。DBS减轻症状的几个方面提供了诱人的提示，即不同的症状可能由涉及运动和运动前皮质的不同通路和/或生理过程介导。本项目的目标是使用非人灵长类PD模型，以更好地了解DBS产生临床受益的皮质机制，以及确定不同症状是否具有不同的神经解剖学/生理学基质。动物将执行测量运动相关行为参数的任务：运动选择/启动/排序（运动不能）、运动学（运动迟缓）和僵硬。将使用多电极阵列监测四个主要运动皮质[在不同动物中，初级运动（M1）、腹侧前运动（PMv）、背侧前运动（PMd）或近中前运动（SMA）]中多个位置的神经元活动。在通过颈动脉内输注MPTP使动物患帕金森病之前和之后，将评估单细胞活性的静息放电率、任务相关活动和GPI或SPECT中响应DBS的细胞间相互作用（同步放电）的变化。预测是：DBS相关的静息放电的变化将不会与症状的具体变化。SMA的活动和同步性增加将与运动不能减少相关。M1中相同的增加将伴随运动迟缓的减少。刚性的降低将与被动运动的M1反应下降和运动相关活动的方向特异性增加有关。此外，DBS可能会减少异常增加的活动在PMV和PMd这些假设将在三个具体目标进行测试：具体目标我将研究DBS的相互作用和正在执行的运动任务的类型。具体目标2和3将识别与DBS症状减轻的时间过程（SA 2）和参数关系（SA 3、DBS位置、频率和强度）一致变化的皮质活动。这些实验的结果将提高对PD的不同症状的神经元基础和DBS的作用机制的理解。最终，这些研究将推进一个更完整的帕金森病的病理生理模型，纳入帕金森病症状的全部阵列。

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) of either the internal segment of the globus pallidus (GPO or the subthalamic nucleus (STN) is an effective treatment for most if not all symptoms of Parkinson's disease (PD). Several aspects of the reduction of symptoms with DBS provide tantalizing hints that different symptoms may be mediated by distinct pathways and/or physiological processes involving the motor and premotor cortices. The goals of this project are to use a non-human primate model of PD to gain a better understanding of the cortical mechanisms by which DBS produces clinical benefit, as well as to determine if different symptoms have different neuroanatomic/physiologic substrates. Animals will perform tasks that measure symptom-relevant behavioral parameters: movement selection/initiation/sequencing (akinesia), movement kinematics (bradykinesia), and rigidity. Neuronal activity at multiple locations in the four principal motor cortices [in different animals, primary motor (M1), ventral premotor (PMv), dorsal premotor (PMd), or mesial premotor (SMA)] will be monitored using a multielectrode array. Single cell activity will be assessed for changes in resting firing rate, task-related activity, and cell-to-cell interactions (synchronized firing) in response to DBS in GPI or STN before and after animals are rendered parkinsonian by intracarotid infusion of MPTP. The predictions are that: DBS-related changes in resting discharge will not be correlated with specific changes in symptoms. Increased activity and synchrony in SMA will be associated with reduced akinesia. Increases of the same in M1 will accompany reduced bradykinesia. Reductions in rigidity will be linked with a drop in M1 responses to passive movement and increased directional specificity in movement related activity. In addition, DBS may reduce abnormally-increased activity in PMv and PMd These hypotheses will be tested in three specific aims: Specific aim I will study the interacting effects of DBS and the type of motor task being performed. Specific aims 2 and 3 will identify cortical activities that change in concert with the time course (SA 2) and parametric relations (SA 3, DBS location, frequency, and strength) of symptom reduction with DBS. The results of these experiments will improve understanding of both the neuronal basis of different symptoms of PD and the mechanisms of action of DBS. Ultimately, these studies will advance a more complete pathophysiologic model of PD by incorporating the full array of parkinsonian symptoms.