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; 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。麻醉作用的人类研究 全身麻醉是一种引人入胜的人造神经生理现象，已经开发 从经验上讲，多年来，可以实现手术和非手术程序的安全和人道的表现。 具体而言，它是一种药物引起的疾病，包括无意识，健忘症，镇痛和不动， 以及生理稳定性。每天对联合的60,000名患者进行全身麻醉 国家，麻醉药在大脑中如何创建麻醉状态的机制不好 理解。最近在表征麻醉的分子位点方面取得了重大进展 目标。但是，特定分子靶标的行动如何导致行为状态的理解较少。 解决此问题需要采用系统神经科学方法来定义药物在特定方面的作用 分子靶标和神经回路导致全身麻醉的行为状态。在这个程序项目中 我们将开发一个集成系统的题为“综合系统神经科学研究” 神经科学计划由人类，非人类灵长类动物，啮齿动物和建模研究组成 麻醉药：Gabaa特工，丙泊酚和七氟烷； Alpha-2肾上腺素激动剂，右美托咪定； NMDA受体拮抗剂氯胺酮。程序项目还将包括数据分析核心， 这将为助手提供数据分析并进行统计方法研究。具体目标 要了解麻醉药在特定分子靶标和神经回路上的作用如何产生 振荡动力学（EEG节奏，LFP的变化和神经尖峰活动）可能是主要的 麻醉剂会产生改变唤醒状态的常见机制（镇静，幻觉， 无意识）。在我们的第一组人类研究中，我们将使一群正常的人类志愿者队列。 在执行行为任务时，每个志愿者将收到一种麻醉剂的受控剂量。这 麻醉的控制剂量将被系统地增加以诱发意识的丧失 系统地减少以恢复。在归纳，维护和恢复期间，我们将记录 除标准生理变量外，还多达256个EEG活性。我们将描述更改的 每种麻醉剂引起的唤醒状态通过将神经生理学的动力学和 生理变量与行为变化。在我们的第二组人类研究中，我们将研究 特定于神经外科患者的六氟烷和氯胺酮引起的镇静和无意识 植入物质内电极。这些后者的研究为记录和研究提供了独特的机会 在丧失和恢复期间 意识。这些研究还将提供有关神经生理学的基本知识 大脑的唤醒电路将与昏迷，睡眠障碍，疼痛和抑郁症等问题有关。