Neuronal Activity in MC and SMA during STN and GPi DBS in the Parkinsonian Monkey

描述（由申请人提供）：运动皮质（MC）和辅助运动区（SMA）是皮质下-皮质和皮质-皮质网络的组成部分，与运动控制密切相关，介导帕金森病（PD）运动体征的发展，以及脑深部电刺激（DBS）期间运动功能的改善。然而，这些皮质运动区在PD运动体征和病理生理学发展中的作用仍然不明确。类似地，丘脑底核（DBS）和苍白球内段（GPi）中DBS对MC和SMA中神经元活动的影响在很大程度上是未知的。到目前为止，只有少数研究帕金森病动物检查了MC和SMA的神经元活动变化，更少的是在DBS期间在大脑皮层或GPi进行了这些研究。本提案将表征MPTP猴PD模型中的这些变化以及静息和被动和主动运动期间DBS（DBS和GPi）期间MC和SMA中发生的神经元活动变化。我们将确定特定的神经元活动变化是否与DBS期间检测到的运动症状改善相关。此外，我们将使用长期植入的微阵列来评估在慢性单侧刺激过程中大脑两侧皮质活动的变化，将其与动物同侧和对侧运动体征的同步变化相关联。本研究将为PD的病理生理学提供新的见解，更好地了解DBS期间运动症状改善的皮质机制，并研究单侧刺激期间同侧运动体征改善的皮质机制。本研究的结果将使我们能够更好地确定哪些皮质活动的神经元模式对应于运动体征的发展和改善，并为设计旨在修改皮质活动的程控算法提供具体依据，以优化接受DBS治疗的PD患者的临床结局，并形成闭环程控方法开发的基础。 公共卫生相关性：在美国和世界各地，数百万人被诊断患有帕金森病，这是一种以运动功能异常为特征的渐进性衰弱性疾病。幸运的是，许多对药物不再有充分反应的晚期疾病患者已经成功地接受了FDA批准的植入式设备的治疗，该设备在大脑深处提供电刺激，这种疗法被称为脑深部电刺激（DBS）。虽然DBS在许多情况下可以显着减轻症状，但它的工作方式仍有很多未知之处，特别是在不同的条件下。我们的目标是更好地了解DBS如何在大脑的特定区域内和之间工作，以改善运动功能，并应用这些知识来优化受运动障碍（如帕金森病）影响的患者的DBS治疗。在这项研究中，我们将使用具有帕金森样症状的非人类灵长类动物来检查慢性刺激对大脑两个特定区域的影响，这些区域已知可以改善受影响的非人类灵长类动物和患者的症状。这些区域的刺激会导致大脑皮层区域内和之间的活动变化，这些区域参与规划和执行身体运动。在不同的刺激条件和位置下，皮层活动的变化与特定运动的速率和质量的变化相关的纵向研究将为开发或改进新的DBS疗法提供基础。

DESCRIPTION (provided by applicant): The motor cortex (MC) and supplementary motor area (SMA) are components of a subcortical-cortical and cortical-cortical network intimately involved in motor control, in mediation of the development of motor signs in Parkinson's disease (PD), and the improvement in motor function during deep brain stimulation (DBS). Yet, the role of these cortical motor areas in the development of motor signs and pathophysiology of PD remains ill-defined. Similarly, the effects of DBS in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) on neuronal activity in the MC and SMA are largely unknown. To date, there are only a few studies in parkinsonian animals that have examined neuronal activity changes in the MC and SMA and fewer still that have performed these studies during DBS in the STN or GPi. The current proposal will characterize these changes in the MPTP monkey model of PD and those neuronal activity changes that occur in the MC and SMA during DBS (STN and GPi) both at rest and during passive and active movement. We will determine if specific neuronal activity changes correlate with improvements in motor symptoms detected during DBS. In addition, we will use chronically implanted microarrays to assess the changes in cortical activity on each side of the brain during chronic unilateral stimulation correlating them to coincident changes in motor signs on both the ipsilateral and contralateral sides of the animal. This study will provide new insights into the pathophysiology of PD, provide a greater understanding of the cortical mechanisms underlying the improvement in motor symptoms during DBS and investigate the cortical mechanisms that underlie improvement in ipsilateral motor signs during unilateral stimulation. Results from this study will allow us to beter determine which neuronal patterns of cortical activity correspond to the development of, and improvement in, motor signs and provide specific rationale for designing programming algorithms directed at modifying cortical activity to optimize clinical outcomes in PD patients treated with DBS and form the basis upon which closed loop programming methods could be developed. PUBLIC HEALTH RELEVANCE: Millions of people in the U.S. and worldwide have been diagnosed with Parkinson's disease, a progressively debilitating disorder characterized by abnormal movement function. Fortunately, many patients with advanced disease who no longer respond adequately to medications have been successfully treated with an FDA- approved implantable device that provides electrical stimulation deep within the brain, a therapy known as deep brain stimulation (DBS). While DBS may significantly reduce symptoms in many cases, there is still much that is unknown about the way it works, especially under different conditions. Our goal is to obtain a better understanding of how DBS works in and between specific regions of the brain to improve movement function and to apply this knowledge to optimize DBS therapy for patients affected by movement disorders, such as Parkinson's disease. In this study, we will use non-human primates with Parkinson-like symptoms to examine the effects of chronic stimulation in two specific areas of the brain that are known to improve symptoms in both affected non-human primates and patients. Stimulation in these areas causes activity changes in and between cortical regions of the brain involved in planning and executing physical movement. A longitudinal study of the changes in cortical activity in relation to changes in the rate and quality of specific movements under different stimulation conditions and locations will provide a basis upon which new DBS therapies may be developed or improved.