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，苍白球内部 (GPi) 投射神经元强烈支配 中脑运动区 (MLR)、中心正中/束旁复合体 (CM/Pf) 和外侧缰核 (LHb)。这些苍白球输出核内的异常活动模式已被利用来促进 帕金森病 (PD) 的几种认知运动症状，包括左旋多巴耐药的步态功能障碍， 行为设定转移困难和目标导向动机缺陷然而，人们知之甚少。 关于帕金森病出现时这些细胞核中发生的实际病理生理变化 深部脑刺激 (DBS) 针对 GPi 和丘脑底核 (STN) 内部及其周围的区域。 对于治疗 PD 运动症状非常有效，但这种靶向如何影响 MLR、CM/Pf 和 LHb 细胞核以及这些效应与 PD 认知运动体征的改善或恶化之间的关系尚不清楚 在临床前 MPTP 治疗的非人类灵长类动物模型中，项目 3 将研究 (1) GPi ↔ MLR 网络对帕金森步态功能障碍的贡献，(2) GPi → CM/Pf 网络对帕金森步态功能障碍的贡献 行为设定转变的困难，以及（3）GPi → LHb 网络在目标导向动机方面的缺陷。 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 在不受束缚的运动和与 PD 相关的认知运动任务期间，该项目还将开发一个 新颖的响应面优化算法，使用尖峰和 LFP 的实时特征评估 MLR、CM/Pf 和 LHb 中的反应驱动 DBS 靶向 STN/晶状体束或 GPe/GPi。 多维 DBS 参数空间内的设置可产生最稳健的变化 MLR、CM/Pf 和 LHb 内的尖峰速率、尖峰模式、光谱功率和/或信息编码将是 认知运动行为任务会带来障碍并改变努力和奖励水平。 研究不仅对于更好地理解认知运动背后的神经回路至关重要 还可以改进 DBS 方法，以提供与 DBS 更一致的临床结果 PD 的治疗方法。