Project 1: Human Studies of Anesthetic Action

项目 1：麻醉作用的人体研究

• 批准号: 10093071
• 负责人: EMERY N BROWN
• 金额: $ 38.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093071
• 关键词: Absence of pain sensation; Address; Adrenergic Agonists; Amnesia; Anesthesia procedures; Anesthetics; Anterior; Area; Arousal; Behavioral; Brain; Cerebral cortex; Coma; Conscious; Coupled; Data Analyses; Dexmedetomidine; Dose; Electrodes; Electroencephalogram; Epilepsy; GABA Agents; General Anesthesia; Hallucinations; Human; Human Volunteers; Implant; Implanted Electrodes; Ketamine; Knowledge; Lead; Macrophage-1 Antigen; Maintenance; Measures; Mental Depression; Modeling; Molecular; Molecular Target; Motor; N-Methylaspartate; NMDA receptor antagonist; Neurons; Neurosciences; Operative Surgical Procedures; Pain; Parietal; Participant; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Propofol; Recovery; Research; Rodent; Rodent Model; Scalp structure; Sedation procedure; Sensory; Sleep Disorders; Source; Statistical Methods; Stimulus; Structure; Study models; System; Testing; Thalamic structure; Unconscious State; United States; alpha 2 agonist; behavior test; cingulate cortex; cohort; density; drug action; experimental study; fascinate; man; mathematical model; molecular site; neural circuit; neurophysiology; nonhuman primate; programs; relating to nervous system; sedative; sensor; sevoflurane; somatosensory; source localization; spatiotemporal; volunteer

PROJECT 1. HUMAN STUDIES OF ANESTHETIC ACTION General anesthesia is a fascinating man-made, neurophysiological phenomenon that has been developed empirically over many years to enable safe and humane performance of surgical and non-surgical procedures. Specifically it is a drug-induced condition consisting of unconsciousness, amnesia, analgesia and immobility, along with physiological stability. General anesthesia is administered daily to 60,000 patients in the United States, the mechanisms for how anesthetics act in the brain to create the states of anesthesia are not well understood. Significant progress has been made recently in characterizing the molecular sites that anesthetics target. However, how actions at specific molecular targets lead to the behavioral states is less well understood. Addressing this issue requires a systems neuroscience approach to define how actions of the drugs at specific molecular targets and neural circuits lead to a behavioral state of general anesthesia. In this program project entitled, Integrated Systems Neuroscience Studies of Anesthesia, we will develop an integrated systems neuroscience program consisting of human, non-human primate, rodent and modeling studies of four anesthetics: the GABAA agents, propofol and sevoflurane; the alpha-2 adrenergic agonist, dexmedetomidine; and the NMDA receptor antagonist, ketamine. The program project will also include a DATA ANALYSIS CORE, which will provide assistant with data analysis and conduct research on statistical methods. The Specific Aims are to understand how the actions of the anesthetics at specific molecular targets and neural circuits produce the oscillatory dynamics (EEG rhythms, changes in LFPs and neural spiking activity) that are likely a primary common mechanism through which anesthetics create altered states of arousal (sedation, hallucination, unconsciousness). In our first set of human studies we will empanel a cohort of normal human volunteers. Each volunteer will receive a controlled-dosing of one of the anesthetics while executing a behavioral task. The controlled-dosing of the anesthetic will be systematically increased to induce loss of consciousness then systematically decreased to allow recovery. During induction, maintenance and recovery, we will record in addition to standard physiological variables, up to 256-leads of EEG activity. We will characterize the altered states of arousal induced by each anesthetics by relating the dynamics of the neurophysiological and physiological variables to the changes in behavioral. In our second set of human studies we will study specifically sevoflurane and ketamine induced sedation and unconsciousness in neurosurgical patients with implanted intracortical electrodes. These latter studies provide the unique opportunity to record and study multiple single neuron spiking activity and local field potentials in the human brain during loss and recovery of consciousness. These studies will also provide fundamental new knowledge about the neurophysiology of the brain's arousal circuits that will be relevant to problems such as coma, sleep disorders, pain and depression.

项目1.麻醉作用的人体研究 全身麻醉是一个迷人的人造，神经生理学现象，已开发 多年来的经验，以实现安全和人道的手术和非手术程序的性能。 具体来说，它是一种药物引起的疾病，包括意识丧失、健忘、镇痛和不动， 沿着生理稳定性。在美国，每天有60，000名患者接受全身麻醉 关于麻醉剂在大脑中如何作用以产生麻醉状态的机制， 明白近年来，在麻醉剂作用的分子位点的表征方面取得了重大进展， 目标然而，在特定的分子靶点上的作用如何导致行为状态还不太清楚。 解决这个问题需要一个系统神经科学的方法来定义药物的作用，在特定的 分子靶点和神经回路导致全身麻醉的行为状态。在这个项目中， 名为“麻醉的集成系统神经科学研究”，我们将开发一个集成系统， 神经科学计划，包括人类，非人类灵长类动物，啮齿动物和建模研究的四个 麻醉剂：GABAA药物，丙泊酚和七氟烷; α-2肾上腺素能激动剂，右美托咪定; 和NMDA受体拮抗剂氯胺酮该计划项目还将包括一个数据分析核心， 协助进行数据分析和统计方法研究。具体目标 是为了了解麻醉剂在特定分子靶点和神经回路中的作用， 振荡动力学（EEG节律，LFP和神经尖峰活动的变化）可能是主要的 麻醉剂通过其产生改变的唤醒状态（镇静，幻觉， 无意识）。在我们的第一组人体研究中，我们将挑选一组正常人类志愿者。 每名志愿者在执行行为任务时将接受一种麻醉剂的控制剂量。的 麻醉剂的控制剂量将系统地增加以诱导意识丧失，然后 系统性地降低以允许恢复。在入职、维持和恢复期间，我们将在 除了标准的生理变量，高达256个导联的脑电图活动。我们将描述 通过将神经生理学的动力学和 生理变量与行为变化之间的关系。在我们的第二组人体研究中， 尤其是七氟烷和氯胺酮在神经外科患者中诱导的镇静和意识丧失， 植入皮质内电极。这些后期研究提供了独特的机会，记录和研究 脑电活动丧失和恢复过程中的多个单神经元放电活动和局部场电位 意识这些研究还将提供有关神经生理学的基本新知识。 大脑的唤醒回路，这将与昏迷，睡眠障碍，疼痛和抑郁等问题有关。