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

标题：识别目标导向决策的神经机制 闭合式脑深部电刺激治疗帕金森病 项目摘要 帕金森病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，并且由于目前的治疗而加剧， 多巴胺能药物和脑深部电刺激。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，可以重新调整奖励网络和解决 这种治疗差距。这个提议的总体目标是识别实现自上而下， 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θ 基底神经节中的频率活动是实现对决策的自上而下控制所必需的，并且 用基于theta活动的闭环神经刺激抑制基底神经节将减少目标导向的 决策的因此，该项目的基本原理是，识别目标背后的神经信号- 在奖励学习范式中，定向决策和因果操纵它们将揭示生物标志物 可以用来重新调整这些电路和治疗行为障碍。中心假设将被检验 通过追求两个特定的目标：目标1）识别空间和频谱特定的神经网络信号， 指导决策。我们将记录慢性额叶皮层和基底神经节活动， 植入患者的皮质电描记术和感知脑深部电刺激装置 帕金森氏症，而他们执行奖励学习任务。我们将量化选择策略， 强化学习模型，并将目标导向的决策与神经信号（ON和OFF）相关联 多巴胺能药物目标2）测试theta在目标导向决策中的因果作用，使用封闭式 循环脑刺激当θ波功率达到 高干扰目标导向的决策，从而建立theta在自上而下的控制中的因果作用。 决策的这项研究是创新的，因为它将是第一个使用慢性，多部位，侵入性 电生理学和闭环脑刺激来建立特定神经元之间的因果关系， 信号和目标导向的决策。这很重要，因为它将产生生物标志物， 指导帕金森病等患者的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Philip Starr博士、Wouter Kool博士和Winston Chiong博士支持。他们一起设计了一个 全面的训练计划，包括（1）闭环脑深部电刺激和皮层下神经生理学， (2)强化学习计算建模，（3）神经伦理学，（4）专业发展。这 奖学金将促进霍伊博士发展成为奖励神经科学和侵入性人类 神经科技它还将准备他开发一个K奖赠款申请作为过渡到 独立的学术研究者。

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.