Neurophysiological Basis of General Anesthesia

描述(由申请人提供)：一个多世纪前，全身麻醉药的问世使医疗实践发生了革命性的变化，允许对外科病人进行人道护理。然而，除了常规的临床应用外，目前还没有详细的神经生理学基础的了解。 麻醉剂的作用。麻醉剂作用于分布在大脑多个区域的各种分子靶点。要了解这些分子水平的作用是如何导致可逆性意识丧失的，需要进行系统的神经科学分析--在高度相互联系的大脑回路的背景下定义麻醉剂的作用。在全身麻醉诱导期间，我分析了人类受试者和非人类灵长类动物的皮层脑电记录。对这些动力学的稳定性分析表明，在清醒的大脑中，皮质活动精确地调节到衰减和增长振荡之间的关键区域。动态临界性使大脑对外部刺激做出反应。我指出，在机械分离麻醉剂的麻醉诱导过程中，动力临界性会丢失。 因此，动力学临界性是全身麻醉药干扰皮层活动的一种新的系统水平特性。我建议研究电路级动态临界性是如何产生的 不同皮质区域间相互作用的可塑性及其在自然睡眠和全身麻醉期间如何被破坏。大脑皮层的记录没有涉及更深层的大脑结构，如丘脑和网状激活系统的作用。因此，我开发了一种动物准备，用于在麻醉苏醒期间从皮质、丘脑和脑干同时进行多点记录。使用这项技术，我证明了在稳定的麻醉剂浓度下，大脑在几种不同的活动状态之间表现出波动，并且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力学调节了大脑恢复意识觉醒所需的复杂功能的过程，并建议通过记录和操纵麻醉苏醒期间大脑觉醒回路中特定神经元群体的活动来研究这些波动的神经生理学基础。具体目标是：具体目标1：描述自然睡眠和全身麻醉(1-5岁)期间受试者神经元活动的动态临界性特征。具体目标2：描述导致麻醉后意识恢复的神经机制(1-5岁)。申请者亚历山大·普罗伊特博士是一名麻醉师，专门护理正在接受神经外科手术的患者。他概述了一个五年研究计划，该计划建立在他的神经生理学和生物物理学背景的基础上。在国际著名神经学家Donald Pfaff博士的领导下，他寻求利用尖端实验技术和新颖的理论方法相结合的方式来研究全身麻醉的神经生理学基础。Proekt博士将由一个咨询委员会提供指导，该委员会由具有不同和互补专业领域的国际公认的专家组成。这项研究将在一个学术丰富的三机构集团合作环境中进行，其中包括洛克菲勒大学、威尔·康奈尔医学院和纪念斯隆·凯特林。这是申请者发展运营商的理想环境。在K08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，并将有助于确立申请者作为独立资助的研究员和临床医生兼科学家的地位。

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.