Mechanisms of Parkinsonian Impulsivity in Human Subthalamic Nucleus

人丘脑底核帕金森病冲动的机制

• 批准号: 8702698
• 负责人: John Pearson
• 金额: $ 23.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702698
• 关键词: Adverse effects; Animal Model; Animals; Basal Ganglia; Behavior; Behavioral; Brain; Brain Part; Characteristics; Cognitive; Complex; Computer Simulation; Cues; Data; Deep Brain Stimulation; Disease; Dopaminergic Agents; Electrodes; Electrophysiology (science); Equilibrium; Event; Exploratory/Developmental Grant; Failure; Functional disorder; Gambling; Human; Impulse Control Disorders; Impulsive Behavior; Impulsivity; Knowledge; Lead; Learning; Link; Location; Measures; Methods; Modeling; Motivation; Motor; Nature; Neurons; Operative Surgical Procedures; Outcome; Parkinson Disease; Parkinsonian Disorders; Participant; Pathological Gambling; Patients; Pattern; Pharmacological Treatment; Play; Population; Probability; Procedures; Process; Protocols documentation; Reaction; Reaction Time; Research; Rewards; Risk; Signal Transduction; Stereotyped Behavior; Stimulus; Structure; Structure of subthalamic nucleus; Study models; Surgeon; Symptoms; Testing; Translating; Tremor; Work; analog; awake; common treatment; computerized; design; experience; implantation; motor deficit; neural patterning; neuromechanism; nonhuman primate; patient population; premature; public health relevance; relating to nervous system; research study; response; sensor; theories; virtual reality

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.

描述（由申请人提供）：虽然帕金森病（PD）的典型治疗方法，多巴胺能药物和脑深部电刺激（DBS）已被证明可有效缓解与疾病相关的运动缺陷，但这些相同的方法也会引起行为副作用，包括强迫性赌博、性欲亢进和复杂的刻板行为（“punding”）。虽然许多工作已经研究了引起震颤的神经活动的潜在模式，僵硬，以及D的其他运动效应，但对人类冲动副作用的神经起源知之甚少。我们建议在接受DBS电极植入手术的实际PD患者人群中描述这些脉冲控制失败的神经活动模式。这样的程序提供了一个独特的机会，在人类单个神经元水平上收集数据，因为外科医生依靠术中电生理学来识别丘脑底核（DBS）的解剖边界，DBS在PD中的典型目标。使用多通道Ad-Tech微线阵列，我们将同时记录多个通道的单个单元活动（尖峰和场电位）在大脑和附近的结构，而受试者执行认知任务与验证链接到人类群体的冲动。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充气一个计算机化的气球，其点值和爆裂的风险都随着大小而增加。在停止信号反应任务（SSRT）中，当“开始”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，参与者必须取消这种反应。在神经层面上，BART让我们能够阐明风险、结果（包括奖励和厌恶）和预期的相关性，而SSRT是一个在动物模型和人类中得到充分研究的冲动模型，与计算模型有着密切的联系，它将使我们不仅能够确定单个单元，而且能够确定冲动控制失败背后的网络水平活动模式。通过这些实验，以及计算建模，我们将表征PD患者冲动性的神经相关性，这将允许设计DBS协议，减轻冲动的副作用。R21机制将用于进一步开发和简化术中多通道记录和认知测试的过程，并验证单神经元活动与停止信号任务中行为模型之间的假设联系。