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：确定目标导向决策的神经机制 应用闭合环深部脑刺激治疗帕金森病 项目总结 帕金森氏症患者通常患有非运动症状，包括动力不足， 对生活质量的影响超过经典的运动症状，目前的治疗方法如 多巴胺能药物和脑深部刺激。这项研究的长期目标是了解神经 激励决策的基础，以开发新的疗法，重新调整奖励网络并解决 这个治疗缺口。这项建议的总体目标是识别实现自上而下的神经信号， 目标导向的选择控制及其在决策中的因果作用。我的中心假设是theta 基底节的频率活动是实现自上而下的决策控制所必需的，而且 用基于theta活动的闭环神经刺激抑制基底节将减少目标导向 决策。因此，该项目的基本原理是识别潜在目标的神经信号- 定向决策和在奖励学习范式中对它们进行因果操作将揭示生物标志物 可以用来重新调整这些回路和治疗行为障碍。核心假说将得到检验 通过追求两个具体目标：目标1)为目标识别空间和光谱上特定的神经网络信号 指导决策。我们将记录慢性额叶皮质和基底节的活动 脑电地形图和感觉型脑深部刺激装置植入患者的临床研究 当他们执行奖励学习任务时，帕金森氏症患者。我们将使用以下工具来量化选择策略 强化学习模型和将目标导向决策与神经信号相关联，包括开关 多巴胺能药物。目的2)在目标导向的决策中，使用封闭的 循环脑刺激。当theta功率被激活时，我们将在基底节触发抑制性脑深部刺激 高，以扰乱目标导向的决定，从而建立在自上而下控制 决策。这项研究具有创新性，因为它将是第一个使用慢性、多部位、有创的 电生理学和闭环脑刺激以建立特定神经之间的因果关系 人类的信号和目标导向决策。这一点意义重大，因为它将导致生物标志物 指导帕金森病等患者动机缺陷的诊断和治疗 神经精神疾病。霍伊博士组建了一个由西蒙博士领导的跨学科导师团队 由菲利普·斯塔尔博士、温特·库尔和温斯顿·琼博士支持。他们一起设计了一种 全面的训练计划，包括(1)闭环式脑深部刺激和皮质下神经生理学， (2)强化学习计算模型，(3)神经伦理学，(4)专业发展。这 奖学金将促进霍伊博士成为奖励神经科学和侵入性人类领域的领先者 神经科技。它还将为他开发K奖励拨款申请做好准备，作为过渡到 独立的学术研究人员。