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）：虽然帕金森氏病（PD）的典型治疗方法，多巴胺能药物和深脑刺激（DBS）被证明可以有效缓解与疾病相关的运动缺陷，但这些相同的方法还会引起行为副作用，包括强迫性赌博，强迫性赌博，疾病，复杂性，目的性，无用的表情（pucky）''''''尽管许多工作已经调查了神经活动的潜在模式，从而引起了震颤，僵化和D的其他运动作用，但对人类脉冲副作用的神经起源知之甚少。我们建议表征这些脉冲控制失败的神经活动模式在实际的PD患者人群中接受手术的DBS电极的植入。此类程序为人类的单个神经元水平收集数据提供了独特的机会，因为外科医生依靠术中电生理学来识别丘脑下核（STN）的解剖学边界，这是PD中DBS的典型靶标。使用多渠道AD-TECH微线阵列，我们将同时记录STN和附近结构中的多个单位活动（尖峰和现场电位）的多个通道，而受试者执行了认知任务，并具有验证的人类人群冲动性链接的认知任务。在气球模拟风险任务（BART）中，参与者必须平衡风险和回报，因为他们何时停止膨胀计算机气球，其点值和弹出风险都随大小而增长。在停止信号反应任务（SSRT）中，出现“ GO”提示时，参与者必须尽快做出响应，但是当播放“停止”音调时，参与者对此反应。在神经层面上，巴特使我们能够阐明风险，结果（有益和厌恶性）和预期的相关性，而SSRT是动物模型和与计算模型有密切联系的冲动模型的SSRT，它不仅可以使我们不仅可以确定单个单位模式，而且还可以确定单个单位模式的失败模式，而不是在Impelse Sneverse Conterulse控制中进行失败。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，这些神经相关性将允许设计DBS方案，从而减轻冲动性副作用。 R21机制将用于进一步开发和简化术中设置中的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。