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

优化中脑和丘脑核的苍白球调节以治疗帕金森病的认知运动体征

• 批准号: 10282964
• 负责人: Matthew Douglas Johnson
• 金额: $ 33.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10282964
• 关键词: Affect; Algorithms; Attention; Attenuated; Behavior; Behavioral; Brain; Cell Nucleus; Chronic; Clinical; Cognitive; Complement; Complex; Consumption; Data; Data Analyses; Deep Brain Stimulation; Electrophysiology (science); Environment; Event; Freezing; Frequencies; Functional disorder; Gait; Globus Pallidus; Goals; Habenula; Human; Impairment; Lateral; Lead; Length; Lentiform nucleus structure; Levodopa; MPTP treatment; Maintenance; Maps; Medial; Methodology; Midbrain structure; Modeling; Moods; Motivation; Motor; Movement; Neurons; Outcome; Output; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathway interactions; Pattern; Physiological; Primates; Quality of life; Resistance; Rewards; Role; Sensory; Signal Transduction; Specificity; Stimulus; Structure; Structure of subthalamic nucleus; Surface; Testing; Thalamic Nuclei; Thalamic structure; Time; Wireless Technology; base; cost; disability; dopamine replacement therapy; experimental study; improved; motor control; motor symptom; neural circuit; nonhuman primate; noradrenergic; novel; parkinsonian non-human primate; pre-clinical; relating to nervous system; response; stem

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.

抽象的： 神经解剖学研究表明，内素（GPI）投影神经元强烈支配 中脑运动区域（MLR），centromedian /副副膜复合物（CM / PF）和外侧Habenula （LHB）。这些颗粒高铁输出核中的异常活性模式已被认为有助于 帕金森氏病（PD）的几种认知运动迹象，包括抗左旋多巴的功能障碍， 行为集转移难度，并分别定义为目标的动机。但是，鲜为人知 关于随着帕金森氏症的出现，这些核中发生的实际病理生理变化 疾病。深脑刺激（DBS）靶向GPI和丘脑下核（STN）内外区域的靶向区域 可以非常有效地治疗PD的运动符号，但是这种靶向如何影响MLR，CM/PF和LHB 细胞核以及这些效果与PD认知运动符号的改善或担心如何相关 理解齿。在PD临床前MPTP处理的非人类私人模型中，项目3将调查 （1）GPI↔MLR网络对帕金森步态功能障碍的贡献，（2）GPI→CM/PF网络对 行为设置转移的困难，以及（3）GPI→LHB网络在目标方向动机中定义。 该项目将利用我们从慢性微型驾驶中执行无线尖峰和LFP录音的能力 在不束缚的运动和与PD相关的认知运动任务期间。该项目还将开发 新的响应表面优化算法，该算法使用峰值和LFP的实时特征评估 MLR，CM/PF和LHB中的响应驱动DBS靶向STN/LENTICULAL筋膜或GPE/GPI。 多维DBS参数空间内的设置，生成最健壮的变化 在MLR，CM/PF和LHB中编码的尖峰速率，尖峰图案，光谱功率和/或信息将为/或 在认知运动行为任务中进行了测试，这些任务引入了障碍和不同水平的努力和回报。这 研究不仅要更好地了解认知运动的神经回路至关重要 PD的症状，也可以完善DBS方法，以提供与DBS的更一致的临床结果 PD的疗法。