DBS AND MOTOR CORTICAL FUNCTION IN AN MPTP MODEL OF PD

描述(由申请人提供)： 脑深部刺激(DBS)苍白球内段(GPO)或丘脑底核(STN)是治疗帕金森病(PD)大多数症状(如果不是全部)的有效方法。DBS减轻症状的几个方面提供了诱人的线索，表明不同的症状可能是由涉及运动和运动前皮质的不同通路和/或生理过程调节的。该项目的目标是使用非人类灵长类帕金森病模型，以更好地了解DBS产生临床益处的皮质机制，并确定不同的症状是否有不同的神经解剖/生理基础。动物将执行测量与症状相关的行为参数的任务：运动选择/启动/排序(运动迟缓)、运动运动学(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)或近侧前运动(SMA)]中多个位置的神经元活动。单细胞活性将被评估静息放电率、任务相关活动和细胞与细胞之间的相互作用(同步放电率)在GPI或STN中对DBS的反应的变化，在通过颈动脉内注射MPTP造成帕金森病动物之前和之后。预测是：与DBS相关的静息放电变化不会与症状的具体变化相关。SMA中活动性和同步性的增加将与运动障碍的减少相关。M1的增加将伴随着运动迟缓的减少。僵硬的减少将与被动运动的M1反应的下降和与运动相关的活动的方向性增加有关。此外，DBS可能会减少PMV和PMD中异常增加的活动。这些假说将在三个特定目标下进行验证：特定目标我将研究DBS与正在执行的运动任务的类型之间的交互作用。具体目标2和3将确定与DBS缓解症状的时间进程(SA2)和参数关系(SA3、DBS位置、频率和强度)一致的皮质活动。这些实验结果将加深对帕金森病不同症状的神经元基础和DBS的作用机制的理解。最终，这些研究将通过纳入帕金森症状的全部序列来推进更完整的帕金森病病理生理学模型。

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.