Optimizing pallidofugal modulation of midbrain and thalamic nuclei for treating cognitive-motor signs of Parkinson's disease

摘要： 神经解剖学研究表明，苍白球内侧核(GPI)投射神经元强烈地支配 中脑运动区(MLR)、中央正中/束旁复合体(CM/PF)和外侧缰核 (LHB)。这些苍白球分离输出核团内的异常活动模式被假设为有助于 帕金森氏病(PD)的几个认知运动体征，包括左旋多巴抵抗步态障碍， 行为定势转换困难和目标导向动机缺陷。然而，人们对此知之甚少 帕金森氏症出现时，这些核团实际发生的病理生理变化 疾病。脑深部刺激(DBS)靶向GPI和丘脑底核(STN)内及其周围区域 可以非常有效地治疗帕金森病的运动体征，但这种靶向如何影响MLR、CM/Pf和LHb 这些影响与帕金森病认知运动体征的改善或恶化之间的关系尚不清楚 明白了。在临床前MPTP治疗的帕金森病非人类灵长类动物模型中，项目3将研究 (1)GpI↔MLR网络在帕金森病步态障碍中的作用；(2)Gpi→CM/PF网络在帕金森病步态障碍中的作用 行为定势转换困难，以及(3)GPI→LHb网络目标导向动机缺失。 该项目将利用我们的能力从慢性微驱动器执行无线尖峰和LFP记录 在自由运动和与帕金森病相关的认知运动任务中。该项目还将开发一种 一种使用SPEKE和LFP实时特征评估的响应面优化算法 MLR、CM/Pf和LHb的反应促使DBS靶向STN/豆状核束或GPE/GPI。 在多维DBS参数空间中产生最稳健变化的设置 尖峰速率、尖峰模式、频谱功率和/或MLR、CM/PF和LHb内的信息编码将是 在认知运动行为任务中进行测试，这些任务会引入障碍，并会带来不同程度的努力和奖励。这 这项研究不仅对更好地理解认知运动背后的神经回路至关重要 帕金森病的症状，但也改进DBS方法，以提供更一致的临床结果 帕金森病的治疗。

Abstract: Neuroanatomical studies have shown globus pallidus internus (GPi) projection neurons strongly innervate the mesencephalic locomotor region (MLR), centromedian / parafascicular complex (CM/Pf), and lateral habenula (LHb). Abnormal activity patterns within these pallidofugal output nuclei has been hypothesized to contribute to several cognitive-motor signs of Parkinson's disease (PD), including levodopa-resistant gait dysfunction, behavioral set shifting difficulties, and deficits in goal-oriented motivation, respectively. However, little is known about the actual pathophysiological changes that occur in these nuclei with the emergence of Parkinson's disease. Deep brain stimulation (DBS) targeting regions in and around the GPi and subthalamic nucleus (STN) can be highly effective for treating motor signs of PD, but how such targeting affects MLR, CM/Pf, and LHb nuclei and how those effects relate to improvement or worsening of cognitive-motor signs of PD is not well understood. In the preclinical MPTP-treated non-human primate model of PD, Project 3 will investigate the contribution of (1) the GPi ↔ MLR network to parkinsonian gait dysfunction, (2) the GPi → CM/Pf network to difficulties with behavioral set shifting, and (3) the GPi → LHb network to deficits in goal-oriented motivation. This project will leverage our capacity to perform wireless spike and LFP recordings from chronic microdrives during untethered movement and during cognitive-motor tasks relevant to PD. The project will also develop a novel response surface optimization algorithm that uses real-time feature assessments of spike and LFP responses in the MLR, CM/Pf, and LHb to drive DBS targeting of the STN/lenticular fasciculus or GPe/GPi. The settings within the multi-dimensional DBS parameter space that generate the most robust changes in spike rate, spike pattern, spectral power, and/or information encoding within the MLR, CM/Pf, and LHb will be tested in cognitive-motor behavioral tasks that introduce obstacles and vary levels of effort and reward. This study will be critically important for not only better understanding the neural circuitry underlying cognitive-motor symptoms of PD but also to refine DBS methodologies to provide more consistent clinical outcomes with DBS therapies for PD.