Identifying the neural mechanisms of goal-directed decision-making in Parkinson's disease using closed-loop deep brain stimulation

使用闭环深部脑刺激识别帕金森病目标导向决策的神经机制

• 批准号: 10608842
• 负责人: Colin Hoy
• 金额: $ 7.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608842
• 关键词: Address; Applications Grants; Automobile Driving; Basal Ganglia; Behavior; Behavior Disorders; Behavioral Research; Biological Markers; Brain; Brain imaging; Choice Behavior; Choices and Control; Chronic; Clinical; Cognitive deficits; Communication; Computer Models; Conflict (Psychology); Decision Making; Deep Brain Stimulation; Development; Devices; Diagnosis; Dopaminergic Agents; Economic Burden; Electrocorticogram; Electrophysiology (science); Ethics; Evaluation; Evolution; Feedback; Fellowship; Frequencies; Functional disorder; Future; Globus Pallidus; Goals; Home; Human; Impulsivity; Individual; K-Series Research Career Programs; Knowledge; Learning; Link; Measures; Mental disorders; Mentors; Modeling; Motivation; Motor; Motor Cortex; Neurobiology; Neurosciences; Parkinson Disease; Pathology; Patients; Persons; Pharmaceutical Preparations; Population; Prefrontal Cortex; Prevention; Psychological reinforcement; Quality of life; Reporting; Research; Research Personnel; Rewards; Role; Signal Transduction; Site; Structure; Structure of subthalamic nucleus; Symptoms; System; Testing; Training; Work; career; cohort; design; effective therapy; experimental study; frontal lobe; imaging study; implantable device; indexing; innovation; motor symptom; nervous system disorder; neural; neural circuit; neural network; neuroethics; neuromechanism; neurophysiology; neuropsychiatric disorder; neuropsychiatry; neuroregulation; neurotechnology; neurotransmission; non-motor symptom; novel; novel therapeutics; prevent; reward processing; secondary analysis; targeted treatment; therapy development

TITLE: IDENTIFYING THE NEURAL MECHANISMS OF GOAL-DIRECTED DECISION-MAKING IN PARKINSON’S DISEASE USING CLOSED-LOOP DEEP BRAIN STIMULATION PROJECT SUMMARY People with Parkinson’s disease commonly suffer from non-motor symptoms, including motivation deficits, that impact quality of life more than classical motor symptoms and are exacerbated by current treatments like dopaminergic drugs and deep brain stimulation. The long-term goal of this research is to understand the neural basis of motivated decision-making to develop new therapies that can re-tune reward networks and address this therapy gap. The overall objective of this proposal is to identify the neural signals that implement top-down, goal-directed control of choices and their causal role in decision-making. My central hypothesis is that theta frequency activity in the basal ganglia is required for implementing top-down control over decisions, and that inhibiting the basal ganglia with closed-loop neurostimulation based on theta activity will reduce goal-directed decision-making. Therefore, the rationale of the project is that identifying the neural signals underlying goal- directed decision-making and causally manipulating them in a reward learning paradigm will reveal biomarkers that can be used to re-tune these circuits and treat behavioral disorders. The central hypothesis will be tested by pursuing two Specific Aims: Aim 1) Identify spatially and spectrally specific neural network signals for goal- directed decision-making. We will record chronic frontal cortical and basal ganglia activity using electrocorticography and sensing-enabled deep brain stimulation devices implanted in patients with Parkinson’s disease while they perform a reward learning task. We will quantify choice strategies using reinforcement learning models and relate goal-directed decision-making to neural signals, both ON and OFF dopaminergic medications. Aim 2) Test the causal role of theta in goal-directed decision-making using closed- loop brain stimulation. We will trigger inhibitory deep brain stimulation in the basal ganglia when theta power is high to disrupt goal-directed decisions, thereby establishing the causal role of theta in top-down control of decision-making. The research is innovative because it will be the first to use chronic, multi-site, invasive electrophysiology and closed-loop brain stimulation to establish causal relationships between specific neural signals and goal-directed decision-making in humans. It is significant because it will lead to biomarkers to guide diagnosis and treatment of motivation deficits in patients with Parkinson’s disease and other neuropsychiatric conditions. Dr. Hoy has assembled an interdisciplinary team of mentors led by Dr. Simon Little and supported by Drs. Philip Starr, Wouter Kool, and Winston Chiong. Together, they have designed a comprehensive training plan involving (1) closed-loop deep brain stimulation and subcortical neurophysiology, (2) reinforcement learning computational modeling, (3) neuroethics, and (4) professional development. This fellowship will facilitate Dr. Hoy’s evolution into a leader in reward neuroscience and invasive human neurotechnology. It will also prepare him to develop a K award grant application as a means to transition into an independent academic researcher.

标题：确定目标指导决策的神经机制 帕金森氏病使用闭环深脑刺激 项目摘要 患有帕金森氏病的人通常患有非运动症状，包括动机缺陷，这些症状 与经典运动症状相比，影响生活质量的质量更大，并且被当前的治疗方法加剧了 多巴胺能药物和深脑刺激。这项研究的长期目标是了解神经 励志决策的基础，以开发可以重新调整奖励网络并解决的新疗法 这个疗法差距。该提案的总体目的是确定实施自上而下的神经信号， 目标指导的选择及其因果关系在决策中的作用。我的中心假设是Theta 基础神经节中的频率活动需要对决策实施自上而下的控制，并且 用基于theta活性抑制基本的神经节的基本神经节将减少目标定向 决策。因此，该项目的理由是确定目标的神经信号 - 指导决策并随便在奖励学习范式中随意操纵它们，将揭示生物标志物 可以用来重新调整这些电路并治疗行为障碍。中央假设将进行测试 通过追求两个具体目标：目标1）经常识别目标的频繁和频谱特定的神经网络信号以实现目标 - 指导决策。我们将使用使用 植入患者的电视图和具有灵敏度的深脑刺激装置 帕金森氏病在执行奖励学习任务时。我们将使用 强化学习模型以及针对神经信号的相关目标指导的决策 多巴胺能药物。目标2）测试theta在目标定向决策中的因果作用， 循环大脑刺激。当Theta Power是 高高破坏目标指导的决策，从而确立theta在自上而下控制中的因果作用 决策。这项研究具有创新性，因为它将是第一个使用慢性，多站点的侵入性 电生理学和闭环大脑刺激以在特定神经之间建立因果关系 人类的信号和目标指导的决策。这很重要，因为它会导致生物标志物 指导诊断和治疗帕金森氏病和其他患者的动机缺陷 神经精神疾病。霍伊博士召集了由西蒙博士领导的跨学科导师团队 很少，得到了博士的支持。 Philip Starr，Wouter Kool和Winston Chiong。他们一起设计了 涉及（1）闭环深脑刺激和皮质下神经生理学的综合培训计划， （2）强化学习计算建模，（3）神经伦理学和（4）专业发展。这 奖学金将帮助霍伊博士的发展成为奖励神经科学和侵入性人的领导者 神经技术。这也将使他准备开发K颁奖授予申请，以作为过渡到 独立的学术研究员。