Neurophysiological Basis of General Anesthesia

全身麻醉的神经生理学基础

基本信息

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
项目类别：
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

项目摘要

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）：一个多世纪以前的全身麻醉药的出现通过允许为手术患者提供人道护理来彻底改变医学的实践。然而，尽管常规临床使用，但对神经生理基础尚无详细的理解麻醉药的作用。麻醉药对分布在许多大脑区域中的各种分子靶标的作用。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 - 在高度相互联系的脑电路中定义麻醉药的作用。我在诱导全身麻醉期间分析了来自人类受试者和非人类灵长类动物的皮质摄影记录。对这些动力学的稳定性分析表明，在清醒的大脑中，皮质活性精确地调整为阻尼和增长振荡之间的关键状态。动力临界性使大脑对外部刺激有反应。我表明，在与机械上不同的麻醉剂的麻醉诱导过程中，动力临界性丧失。因此，动态临界性是一般麻醉剂破坏皮质活性的新型系统级特性。我建议调查电路级别的动态临界性不同皮质区域之间相互作用的可塑性以及在Natura睡眠和全身麻醉期间如何破坏它。皮质记录并不能解决丘脑和网状激活系统等更深层次的大脑结构的贡献。因此，我开发了一种动物制备，用于从麻醉出现期间从皮质，丘脑和脑干中同时进行多站点记录。使用这种技术，我证明，在稳态麻醉浓度下，大脑在几种不同的活性状态之间表现出波动，并且这些波动的动力学因麻醉浓度而变化。我假设这些波动的动力学介导了大脑恢复意识出现所需的功能复杂性的过程，并提议通过记录和操纵从麻醉中出现的大脑唤醒电路中特定神经元种群的特定神经元的活动来研究这些波动的神经生理基础。具体目的是：特定目标1：在自然睡眠和全身麻醉期间人类受试者中神经元活性的动力学临界性的表征（1 - 5年）。特定目的2：表征导致麻醉后意识出现的神经元机制（1 - 5年）。申请人Alexander Proekt博士是一名麻醉师，专门照顾接受神经外科手术的患者。他概述了一项为期5年的研究计划，该计划基于他的神经生理学和生物物理学的背景。在国际知名的神经科学家唐纳德·普法夫（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的结合来研究全身麻醉的神经生理基础。 Proekt博士将由由国际认可的专家组成的咨询委员会指导，这些专家具有不同的专业知识和互补领域。这项研究将在包括洛克菲勒大学，威尔·康奈尔医学院和纪念斯隆·凯特林（Memorial Sloan Kettering）在内的三机构企业集团的学术丰富的协作环境中进行。这是申请人载体开发的理想环境。在K08提供的支持下，拟议的研究计划可能会导致对麻醉剂作用神经生理学基础的转变见解，并将帮助将申请人确立为独立资助的研究者和临床医生。