Mechanisms of Parkinsonian Impulsivity in Human Subthalamic Nucleus

描述（由申请人提供）：虽然帕金森病（PD）的典型治疗方法，多巴胺能药物和深部脑刺激（DBS），已被证明可以有效减轻与该疾病相关的运动缺陷，但这些方法也会产生行为副作用，包括强迫性赌博、性欲亢进和复杂的、无目的的刻板行为（“punding”）。虽然已经有很多工作研究了引起震颤、僵硬和其他D的运动效应的神经活动的潜在模式，但对人类冲动副作用的神经机制知之甚少。我们建议在实际PD患者接受DBS电极植入手术时，描述这些冲动控制失败的神经活动模式。由于外科医生依靠术中电生理学来识别丘脑下核（STN）的解剖边界，这种手术提供了一个独特的机会来收集人类单个神经元水平的数据，而STN是PD中DBS的典型靶点。使用多通道Ad-Tech微线阵列，我们将同时记录STN和附近结构中单个活动（峰值和场电位）的多个通道，同时受试者执行与人类冲动相关的认知任务。在气球模拟风险任务（BART）中，参与者必须平衡风险和回报，因为他们决定何时停止给一个计算机控制的气球充气，该气球的点值和破裂风险都随着尺寸的增大而增加。在停止信号反应任务（SSRT）中，当“走”提示出现时，参与者必须尽可能快地做出反应，但当播放“停止”音时，参与者必须撤销这种反应。在神经层面，BART允许我们阐明风险、结果（奖励和厌恶）和预期的相关性，而SSRT，一个在动物模型和人类模型中得到充分研究的冲动性模型，与计算模型有很强的联系，将使我们不仅可以确定单个单元，还可以确定网络层面的活动模式，这些活动模式是冲动控制失败的基础。通过这些实验，以及计算模型，我们将表征PD患者冲动的神经相关因素，这将允许设计DBS方案，减轻冲动副作用。R21机制将用于进一步发展和简化术中多通道记录和认知测试的过程，并验证停止信号任务中单个神经元活动与行为模型之间的假设联系。

DESCRIPTION (provided by applicant): While the typical treatments for Parkinson's disease (PD), dopaminergic drugs and deep brain stimulation (DBS), are proven to be effective in mitigating the motor deficits associated with the disease, these same methods also give rise to behavioral side effects including compulsive gambling, hypersexuality, and complex, purposeless stereotyped behavior ("punding"). And while much work has investigated the underlying patterns of neural activity giving rise to tremor, rigidity, and other motor effects of D, little is known about the neural genesis of impulsive side effects in humans. We propose to characterize the patterns of neural activity underlying these failures of impulse control in an actual PD patient population undergoing surgery for the implantation of DBS electrodes. Such procedures offer a unique opportunity to collect data at the single neuron level in humans, since surgeons rely on intraoperative electrophysiology to identify the anatomical boundaries of the subthalamic nucleus (STN), the typical target of DBS in PD. Using multi-channel Ad-Tech microwire arrays, we will simultaneously record multiple channels of single unit activity (both spikes and field potentials ) in STN and nearby structures while subjects perform cognitive tasks with validated links to impulsivity in human populations. In the balloon analogue risk task (BART) participants must balance risk and reward as they decide when to stop inflating a computerized balloon whose point value and risk of popping both grow with size. In the stop signal reaction task (SSRT), participants must respond as quickly as possible when a "go" cue appears, but countermand this response when a "stop" tone is played. At the neural level, the BART allows us to elucidate correlates of risk, outcome (both rewarding and aversive), and anticipation, while the SSRT, a well-studied model of impulsivity in both animal models and humans with strong links to computational models, will allow us to determine not only single unit but network-level patterns of activity underlying failures in impulse control. Through these experiments, as well as computational modeling, we will characterize neural correlates of impulsivity in PD patients that will allow for the design of DBS protocols that mitigate impulsive side effects. The R21 mechanism will be used to further develop and streamline the process of multichannel recording and cognitive testing in the intraoperative setting and validate the hypothesized link between single neuron activity and models of behavior in the stop signal task.