Project 1: Human Studies of Anesthetic Action

项目1.麻醉作用的人体研究 全麻是一种令人着迷的人造神经生理现象，已经发展起来。 多年来的经验证明，能够安全和人性化地执行手术和非手术程序。 具体地说，它是一种由药物引起的状态，包括意识丧失、健忘、止痛和静止， 以及生理稳定性。在美国，每天有6万名患者接受全身麻醉 麻醉剂如何在大脑中产生麻醉状态的机制还不是很好。 明白了。最近在表征麻醉药的分子位置方面取得了重大进展 目标。然而，对特定分子靶标的作用如何导致行为状态还不太清楚。 解决这一问题需要系统神经科学方法来定义药物在特定情况下的作用 分子靶点和神经回路导致全身麻醉的行为状态。在该计划项目中 题为《麻醉的集成系统神经科学研究》，我们将开发一个集成系统 神经科学项目包括人类、非人灵长类、啮齿动物和四个模型研究 麻醉药：GABAA类药物异丙酚和七氟醚，α-2肾上腺素能激动剂右旋美托咪定； 以及NMDA受体拮抗剂氯胺酮。该计划项目还将包括数据分析核心， 它将为数据分析提供辅助，并对统计方法进行研究。具体目标 是为了了解麻醉剂对特定分子靶点和神经回路的作用是如何产生的 振荡动力学(脑电节律、LFP的变化和神经放电活动)可能是主要的 麻醉剂产生不同的唤醒状态(镇静、幻觉、 无意识)。在我们的第一组人体研究中，我们将安排一组正常的人类志愿者。 每个志愿者在执行一项行为任务时，将获得一种受控剂量的麻醉剂。这个 然后系统地增加麻醉剂的控制剂量以导致意识丧失 系统地减少，以允许恢复。在入职、维护和恢复期间，我们将记录 除了标准的生理变量，高达256导联的脑电活动。我们将描述改变后的 每种麻醉药诱导的唤醒状态通过联系神经生理和 生理变量对行为的影响。在我们的第二套人体研究中，我们将研究 七氟醚和氯胺酮对神经外科手术患者的镇静和意识障碍 植入皮质内电极。这些后一种研究提供了记录和研究的独特机会 人脑内多个单神经元放电活动和局部场电位在脑内的消失和恢复 意识。这些研究还将提供关于老年痴呆症的神经生理学的基本新知识。 大脑的唤醒回路将与昏迷、睡眠障碍、疼痛和抑郁等问题相关。

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.