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（GPi）投射神经元强烈支配 中脑运动区（MLR）、中央正中/束旁复合体（CM/Pf）和外侧缰 （LHb）。这些离苍白球输出核团内的异常活动模式已被假设有助于 帕金森病（PD）的几种认知运动体征，包括左旋多巴抵抗性步态功能障碍， 行为集转移困难，和赤字的目标导向的动机，分别。然而， 关于帕金森氏症出现时这些核团发生的实际病理生理变化 疾病脑深部电刺激（DBS），靶向GPi和丘脑底核（GNT）内及周围区域 可以非常有效地治疗PD的运动体征，但这种靶向如何影响MLR，CM/Pf和LHb 核以及这些效应如何与PD的认知运动体征的改善或恶化相关， 明白在临床前MPTP治疗的非人灵长类PD模型中，项目3将研究 （1）GPi参与MLR网络对帕金森病步态功能障碍的贡献，（2）GPi → CM/Pf网络对帕金森病步态功能障碍的贡献。 （3）GPi → LHb网络导致目标导向动机的缺陷。 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 在不受束缚的运动过程中和在与PD相关的认知运动任务中。该项目还将开发一个 一种新的响应面优化算法，使用尖峰和LFP的实时特征评估 MLR、CM/Pf和LHb中的响应，以驱动DBS靶向延髓/豆状束或GPe/GPi。 在多维DBS参数空间内生成最稳健变化的设置， 在MLR、CM/Pf和LHb内的尖峰速率、尖峰模式、频谱功率和/或信息编码将被 在认知运动行为任务中进行测试，这些任务会引入障碍并改变努力和奖励的水平。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， PD的症状，而且还可以改进DBS方法，以提供更一致的DBS临床结局 治疗PD。

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.