Uncovering the neurophysiology of motivation in ParkinsonÃÂs disease with implanted adaptive brain stimulation

通过植入适应性脑刺激揭示帕金森病动机的神经生理学

• 批准号: 10371051
• 负责人: Simon Little
• 金额: $ 20.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371051
• 关键词: Address; Alzheimer' s Disease; Award; Basal Ganglia; Behavior; Behavior Disorders; Behavior Therapy; Behavioral; Behavioral Symptoms; Biometry; Brain; Characteristics; Chronic; Clinical; Cognitive; Costs and Benefits; Craniocerebral Trauma; Decision Making; Deep Brain Stimulation; Development; Diagnostic; Disease; Dopamine; Educational Curriculum; Electrocorticogram; Electrodes; Epilepsy; Evaluation; Foundations; Frequencies; Frontotemporal Dementia; Future; Ganglia; Goals; Home; Human; Huntington Disease; Implant; Impulsivity; Intelligence; Intervention; Investigation; Knowledge; Laboratories; Lead; Link; Machine Learning; Mediating; Mental Depression; Mentors; Motivation; Motor; Neurologic; Neurologic Symptoms; Parkinson Disease; Patient Self-Report; Patients; Pharmaceutical Preparations; Prefrontal Cortex; Quality of life; Reproducibility; Research; Rewards; Role; Schizophrenia; Self Assessment; Signal Transduction; Specific qualifier value; Stroke; Structure; Symptoms; System; Techniques; Testing; Training; Work; addiction; affective neuroscience; cohort; cost; effective therapy; experimental study; frontal lobe; indexing; innovation; motivated behavior; multidisciplinary; nervous system disorder; neural circuit; neurophysiology; neurotransmission; non-motor symptom; novel; personalized medicine; relating to nervous system; reward circuitry; spatiotemporal; statistics; symptomatology; targeted treatment; trial design

TITLE: UNCOVERING THE NEUROPHYSIOLOGY OF MOTIVATION IN PARKINSON’S DISEASE WITH IMPLANTED ADAPTIVE BRAIN STIMULATION PROJECT SUMMARY Behavioral symptoms such as apathy and impulsivity represent a prevalent, highly-disabling feature of Parkinson’s disease (PD) and many other neurological conditions, for which treatments are currently very limited. The long-term goal of this award is to understand the neurocircuitry of motivation in order to develop precise and personalized therapies for motor and non-motor symptoms in neurological disorders. The overall objective is to establish the neural structures and signals that underpin motivation in PD. My central hypothesis is that the human motivation system comprises two functionally distinct frontal cortex - basal ganglia (FC- BG) circuits that drive behavior: 1) the prefrontal - basal ganglia circuit evaluates rewards and operates in the theta (3-7Hz) frequency range and 2) the premotor - basal ganglia circuit evaluates action costs, and is mediated by beta (13-30Hz) frequency signals, with both modulated by dopamine. Therefore, the rationale of the project is that understanding the neural structures and signals of the FC-BG reward circuit is critical for the development of effective stimulation therapies for behavioral symptoms in PD. The central hypothesis will be tested by pursuing two Specific Aims: Aim 1) Identify the neurophysiological signatures of reward cost-benefit evaluation in PD. Patients with chronically implanted, sensing-enabled brain stimulators will perform reward cost-benefit evaluation tasks with simultaneous FC-BG recordings, on and off dopamine medication. Additionally, patients will trigger recordings of neural signals at home, with paired self-reports of apathy and impulsivity. Aim 2) Evaluate the causal relationship of frontal cortex-basal ganglia structures & signals to behavior. Spatio-temporally targeted brain stimulation will be delivered to the FC-BG network during reward cost-benefit evaluation to test the causal role of these structures and signals to motivated behavior. The research is innovative because it uses a) chronic invasive brain recordings, in patients, during behavioral tasks that index motivation, b) recordings at home to determine within-subject reproducibility and link to naturalistic motivational states and c) causal interventions to demonstrate mechanistic relationships. It is significant because determining an accurate understanding of the neurocircuitry of reward will enable the future development of precise, spatio-temporally targeted adaptive brain stimulation for apathy and impulsivity in PD, a major unmet need. As such, Dr. Little has assembled a multidisciplinary mentoring group led by Prof. Philip Starr and supported by advisors Profs. Edward Chang, Wendy Mendes and Joshua Berke to develop a comprehensive structured training plan involving 1) cognitive-affective neuroscience 2) electrocorticography 3) machine learning and 4) trial design and statistics. This award will propel Dr. Little towards independence and expertise in the investigation of the neurophysiology, and treatment, of motor and non-motor neurological symptoms. It will also provide the foundation for a future R01 application investigating the relationship between clinical apathy, impulsivity and neurophysiology in a wide cohort of neurological patients.

标题：揭示帕金森病动机的神经生理学 植入式适应性脑刺激 项目总结 冷漠和冲动等行为症状代表着一种普遍的、高度残疾的特征 帕金森病(PD)和许多其他神经疾病，目前对这些疾病的治疗非常 有限的。该奖项的长期目标是了解动机的神经回路，以便开发 针对神经系统疾病中的运动性和非运动性症状的精确和个性化治疗。整体而言 目的是建立支持帕金森病动机的神经结构和信号。我的中心假设 人类的动机系统由两个功能截然不同的额叶皮质--基底节(FC-Fc)组成。 Bg)驱动行为的电路：1)前额-基底节电路评估奖励并在 Theta(3-7赫兹)频率范围和2)运动前-基底节电路评估动作成本，并 由β(13-30赫兹)频率信号介导，两者均由多巴胺调制。因此，其基本原理是 该项目是，了解FC-BG奖励电路的神经结构和信号对于 治疗帕金森病行为症状的有效刺激疗法的发展。中心假设将是 通过追求两个特定目标进行测试：目标1)确定奖励成本-收益的神经生理学特征 帕金森病的评估。长期植入感官脑刺激器的患者将执行奖励 使用同时进行FC-BG记录、开启和关闭多巴胺药物的成本效益评估任务。 此外，患者将在家中触发神经信号的记录，并配对报告冷漠和 冲动。目的2)评估额叶皮质-基底节结构的因果关系及信号转导 行为。在奖励期间，时空定向脑刺激将被传递到FC-BG网络 成本效益评估，以测试这些结构和信号对动机行为的因果作用。这个 这项研究具有创新性，因为它使用了慢性侵入性脑记录，在患者的行为过程中 索引动机的任务，b)在家录制以确定受试者内部的可重复性并链接到 自然主义动机状态和c)展示机械关系的因果干预。它是 重要的是，确定对奖赏神经回路的准确理解将使 针对冷漠和冲动的精确、时空定向适应性脑刺激的未来发展 在PD中，一个主要的未得到满足的需求。因此，利特尔博士组建了一个由利特尔教授领导的多学科指导小组。 菲利普·斯塔尔和顾问教授的支持。爱德华·张、温迪·门德斯和约书亚·伯克将开发一种 全面系统的训练计划，包括1)认知-情感神经科学2)皮质脑电图术3) 机器学习和4)试验设计和统计。这一奖项将推动利特尔博士走向独立和 在运动神经学和非运动神经学的神经生理学和治疗方面的专业知识 症状。它还将为未来的R01应用程序提供基础，该应用程序将研究 广泛的神经科患者的临床冷漠、冲动和神经生理学。