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

标题：揭示帕金森病患者动机的神经生理学 植入式自适应脑刺激器 项目摘要 行为症状，如冷漠和冲动，代表了一个普遍的，高度残疾的特点， 帕金森病（PD）和许多其他神经系统疾病，目前对其治疗非常困难。 有限公司该奖项的长期目标是了解动机的神经回路，以便开发 针对神经系统疾病的运动和非运动症状的精确和个性化治疗。整体 目的是建立帕金森病中支持动机的神经结构和信号。我的核心假设是 人类的动机系统包括两个功能不同的额叶皮层-基底神经节（FC）， BG）驱动行为的回路：1）前额叶-基底神经节回路评估奖励并在大脑中运作。 θ（3- 7 Hz）频率范围和2）前运动-基底神经节回路评估动作成本， 由β（13- 30 Hz）频率信号介导，两者都由多巴胺调节。因此， 该项目是，了解FC-BG奖励电路的神经结构和信号对于 开发针对PD行为症状的有效刺激疗法。核心假设是 通过追求两个特定目标进行测试：目标1）识别奖励成本效益的神经生理学特征 在PD中进行评估。长期植入感知脑刺激器的患者将进行奖励 同时进行FC-BG记录的成本效益评估任务，使用和停用多巴胺药物。 此外，患者将在家中触发神经信号的记录，配对的自我报告冷漠， 冲动目的2）评价额叶皮质-基底神经节结构和信号与脑梗死的因果关系。 行为空间-时间靶向脑刺激将在奖励期间传递到FC-BG网络 成本效益评估，以测试这些结构和信号的因果作用，以激励行为。的 这项研究是创新的，因为它使用了a）慢性侵入性大脑记录，在患者的行为过程中， 索引动机的任务，B）在家中的记录，以确定受试者内的再现性，并与 自然主义动机状态和c）因果干预，以证明机械关系。是 重要的是，确定对奖励神经回路的准确理解将使 精确的时空靶向自适应脑刺激治疗冷漠和冲动的未来发展 在PD，一个主要的未满足的需求。因此，利特尔博士组建了一个多学科的指导小组，由教授领导。 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·伯克开发了一种 全面的结构化培训计划，包括1）认知情感神经科学2）皮层脑电图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， 在运动和非运动神经系统的神经生理学和治疗的研究方面的专业知识 症状它还将为将来的R 01应用程序提供基础， 临床冷漠，冲动和神经生理学在一个广泛的队列神经系统患者。

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.