Stopping behavior and interrupting cognition via subthalamic nucleus

通过丘脑底核停止行为并中断认知

• 批准号: 9927692
• 负责人: Adam Robert Aron
• 金额: $ 47.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927692
• 关键词: Affect; Area; Attention; Attention deficit hyperactivity disorder; Basal Ganglia; Behavior; Behavioral; Brain; Cognition; Cognitive; Conflict (Psychology); Data; Deep Brain Stimulation; Event; Frequencies; Functional Magnetic Resonance Imaging; Goals; Human; Influentials; Interruption; Literature; Maps; Methods; Motor; Motor Cortex; Mus; Output; Parkinson Disease; Pathway interactions; Patients; Recurrence; Research; Research Project Summaries; Role; Short-Term Memory; Signal Transduction; Structure of subthalamic nucleus; System; Testing; Text Messaging; Thalamic structure; Thinking; Transcranial magnetic stimulation; Viral; base; clinically relevant; combinatorial; defined contribution; design; distraction; experimental study; flexibility; forgetting; frontal lobe; insight; neural circuit; novel; novel strategies; optogenetics; recruit; relating to nervous system; response; theories

PROJECT SUMMARY Research in several species shows that rapidly stopping action activates the subthalamic nucleus (STN) of the basal ganglia (BG) – and that the STN may be recruited via a hyperdirect pathway (HDP) from prefrontal cortical stopping nodes. Human research also shows that unexpected events (such as a surprising tones) also recruit the stopping system (including the STN), and interrupt working memory (WM). At the core of this proposal is the idea that WM is maintained via a recurrent cortico-BG loop, and that this can be interrupted via HDP recruitment of the STN. The interruption is induced via stop signals and unexpected events, and could function to `clear cognition'. This is a radical new theory: that a fronto-BG circuit for stopping underlies cognitive interruptions. Validating this theory has broad implications for understanding the BG, for mechanisms of cognitive interruptions, and for potential cognitive under-and-over flexibility in Parkinson's disease (PD) and ADHD. Here we propose to systematically test this theory using parallel human-mouse studies, based on extensive preliminary data and using several novel approaches, including event-related Deep Brain Stimulation (eDBS). Aim 1 (motor stop) will use STN eDBS in humans and optogenetic stimulation in mice to test whether the STN is causally important for stopping action. Aim 2 (cognitive stop) will use eDBS and functional MRI in humans and optogenetics in mice to test whether the STN is causally important for decrementing WM. Aim 3 (HDP) will use combinatorial optogenetics in mice and novel combinations of transcranial magnetic stimulation with concurrent local field recordings in human STN to test whether motor and cognitive Stops are implemented via HDP inputs to STN from frontal cortex. Throughout the proposal we focus on designing complementary experiments across species, so that what is learned in mice can directly inform our understanding of human neural circuit function and behavior.

项目概要 对多个物种的研究表明，快速停止动作会激活丘脑底核（STN） 基底神经节 (BG) – STN 可以通过前额叶的超直接通路 (HDP) 募集 皮质停止节点。人类研究还表明，意外事件（例如令人惊讶的音调）也会 招募停止系统（包括 STN），并中断工作记忆（WM）。这的核心是 提案的想法是 WM 通过循环皮质-BG 环路维持，并且可以通过以下方式中断： HDP 招募 STN。中断是通过停止信号和意外事件引起的，并且可能 具有“清晰认知”的功能。这是一个全新的理论：用于停止的额叶-BG 回路是认知的基础 中断。验证这一理论对于理解 BG、其机制具有广泛的意义。 认知中断，以及帕金森病 (PD) 和认知障碍中潜在的认知灵活性不足和过度 多动症。在这里，我们建议使用平行的人鼠研究来系统地测试这一理论，基于 广泛的初步数据并使用几种新颖的方法，包括与事件相关的深部脑刺激 （电子数据库系统）。目标 1（电机停止）将在人类中使用 STN eDBS 并在小鼠中使用光遗传学刺激来测试是否 STN 对于停止行动具有重要的因果关系。目标 2（认知停止）将使用 eDBS 和功能 MRI 人类和小鼠的光遗传学测试 STN 是否对于减少 WM 具有重要的因果关系。目标 3 （HDP）将在小鼠中使用组合光遗传学和经颅磁刺激的新型组合 在人类 STN 中同时进行局部现场记录，以测试运动和认知停止是否有效 通过从额叶皮层到 STN 的 HDP 输入来实现。在整个提案中，我们专注于设计 跨物种的互补实验，这样在老鼠身上学到的东西就可以直接告诉我们 了解人类神经回路的功能和行为。