Neurophysiological Basis of General Anesthesia

全身麻醉的神经生理学基础

• 批准号: 8723258
• 负责人: Alexander Proekt
• 金额: $ 18.4万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723258
• 关键词: Address; Advisory Committees; Affect; Anesthesia procedures; Anesthetics; Animal Model; Animals; Area; Arousal; Awareness; Behavior; Behavioral; Behavioral Paradigm; Biological Models; Biophysics; Brain; Brain Stem; Brain region; Caring; Clinical; Collection; Communication; Conscious; Delirium; Development; Electrocorticogram; Electroencephalography; Environment; Exhibits; Experimental Models; Funding; General Anesthesia; General anesthetic drugs; High Prevalence; Human; Impaired cognition; Infusion procedures; Ketamine; Lead; Leadership; Measures; Mediating; Medicine; Mentors; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Target; Neurons; Neurosciences; Neurosurgical Procedures; Operative Surgical Procedures; Patient Care; Patients; Pattern; Play; Population; Postoperative Period; Preparation; Process; Property; Propofol; Rattus; Recovery; Research; Research Personnel; Role; Scientist; Site; Sleep; Stimulus; Structure; System; Techniques; Testing; Thalamic structure; Unconscious State; Universities; Wakefulness; awake; base; cingulate cortex; human subject; in vivo; insight; interest; medical schools; neurophysiology; nonhuman primate; novel; public health relevance; research study

DESCRIPTION (provided by applicant): Advent of general anesthetics over a century ago revolutionized the practice of medicine by allowing humane care for surgical patients. Yet despite routine clinical use, there is no detailed understanding of the neurophysiological basis of action of anesthetics. Anesthetics act on a variety of molecular targets distributed among many brain regions. Understanding how these molecular-level actions lead to reversible loss of consciousness requires a systems neuroscience analysis - defining the actions of anesthetics within the context of highly interconnected brain circuits. I analyzed electrocorticography recordings from human subjects and non-human primates during induction of general anesthesia. Stability analysis of these dynamics revealed that in the awake brain, cortical activity is tuned precisely to the critical regime between damping and growing oscillations. Dynamical criticality renders the brain responsive to external stimuli. I show that dynamical criticality is lost during induction of anesthesia with mechanistically distinct anesthetic agents. Thus, dynamical criticality is a novel systems-level property of cortical activity disrupted by general anesthetics. I propose to investigate how circuit level dynamical criticality arises out of plasticity of the interactions among different cortical areas and how it is disrupted during natura sleep and general anesthesia. Cortical recordings do not address the contribution of deeper brain structures such as thalamus and the reticular activating system. Thus, I developed an animal preparation for simultaneous multi-site recordings from the cortex, thalamus, and brain stem during emergence from anesthesia. Using this technique, I demonstrate that under steady state anesthetic concentration the brain exhibits fluctuations among several distinct activity states and that the dynamics of these fluctuations change depending on the concentration of anesthetic. I hypothesize that the dynamics of these fluctuations mediate the processes through which the brain recovers the complexity of function required for emergence of consciousness and propose to investigate the neurophysiological basis of these fluctuations by recording and manipulating activity of specific neuronal populations within the brain arousal circuitry during emergence from anesthesia. The specific Aims are: Specific Aim 1: Characterization of dynamical criticality of neuronal activity in human subjects during natural sleep and general anesthesia (years 1-5). Specific Aim 2: Characterization of neuronal mechanisms that lead to the emergence of consciousness after anesthesia (years 1-5). The applicant, Dr. Alexander Proekt, is an anesthesiologist specializing in caring for patients undergoing neurosurgical procedures. He has outlined a 5 year research plan that builds upon his background in neurophysiology and biophysics. Under the leadership of Dr. Donald Pfaff, an internationally renowned neuroscientist, he seeks to utilize a combination of cutting edge experimental techniques and novel theoretical approaches to study the neurophysiological basis of general anesthesia. Dr. Proekt will be mentored by an Advisory Committee comprised of internationally recognized experts with diverse and complementary areas of expertise. The research will be conducted in an academically rich collaborative environment of Tri-Institutional conglomerate that includes the Rockefeller University, Weill Cornell Medical College, and Memorial Sloan Kettering. This is an ideal environment for the applicant's carrier development. With support provided by K08, the proposed research plan will likely lead to transformative insights into the neurophysiological basis of action of anesthetics and will help establish the applicant as an independently funded investigator and clinician- scientist.

描述（由申请人提供）：世纪前全身麻醉剂的出现通过允许对手术患者进行人道护理而彻底改变了医学实践。然而，尽管常规的临床使用，没有详细了解的神经生理学基础， 麻醉剂的作用。麻醉剂作用于分布在许多大脑区域中的各种分子靶点。了解这些分子水平的作用如何导致可逆的意识丧失需要系统神经科学分析-在高度互连的大脑回路的背景下定义麻醉剂的作用。 我分析了在全身麻醉诱导过程中人类受试者和非人类灵长类动物的皮层脑电图记录。对这些动力学的稳定性分析表明，在清醒的大脑中，皮层活动被精确地调整到阻尼和增长振荡之间的临界状态。动态临界性使大脑对外部刺激做出反应。我表明，动力学的关键是失去了在麻醉诱导与机械不同的麻醉剂。 因此，动力学临界性是一种新的系统水平的皮质活动被全身麻醉剂中断的属性。我建议调查电路级动态临界性如何产生的 不同皮层区域之间相互作用的可塑性以及在自然睡眠和全身麻醉期间它是如何被破坏的。皮质记录并不涉及大脑深层结构的贡献，如丘脑和网状激活系统。因此，我开发了一种动物准备，用于在麻醉苏醒期间从皮层、丘脑和脑干同时进行多部位记录。使用这种技术，我表明，在稳态麻醉剂浓度下，大脑表现出几个不同的活动状态之间的波动，这些波动的动态变化取决于麻醉剂的浓度。我假设，这些波动的动态介导的过程中，大脑恢复所需的意识出现的功能的复杂性，并建议调查这些波动的神经生理学基础，通过记录和操纵活动的特定神经元群体内的大脑唤醒电路在出现从麻醉。具体目标是：具体目标1：自然睡眠和全身麻醉期间人类受试者神经元活动动态临界性的表征（1-5年）。 具体目标2：表征导致麻醉后意识出现的神经元机制（1-5年）。申请人亚历山大普罗埃克特博士是一名麻醉师，专门负责护理接受神经外科手术的患者。他概述了一个5年的研究计划，建立在他的神经生理学和生物物理学的背景。在国际知名神经科学家Donald Pfaff博士的领导下，他试图利用尖端实验技术和新颖的理论方法来研究全身麻醉的神经生理学基础。Proekt博士将接受一个咨询委员会的指导，该委员会由具有不同和互补专业知识领域的国际公认专家组成。该研究将在三机构集团的学术丰富的合作环境中进行，其中包括洛克菲勒大学，威尔康奈尔医学院和纪念斯隆凯特琳。这是申请人载体开发的理想环境。在K 08提供的支持下，拟议的研究计划可能会导致对麻醉剂作用的神经生理学基础的变革性见解，并将帮助申请人成为独立资助的研究者和临床医生-科学家。