Personalized Anesthesia: The Role of the Locus Coeruleus in Individual Anesthetic Responses

项目概要/摘要 麻醉师将数百万患者置于可逆的昏迷状态以挽救生命 每年都会进行手术。麻醉护理的基本目标是可靠地消除患者的意识 手术持续时间和手术后，使患者迅速恢复到基线认知状态。这些都不是 然而，今天的目标可以可靠地实现。一些患者在手术过程中恢复意识。剧集数 目前基于脑电图的术中监测无法可靠地检测到意识状态，并可能导致 创伤后应激障碍和焦虑症。相比之下，其他患者需要很长时间才能恢复正常 认知。这可能表现为术后谵妄和认知紊乱。术后谵妄 影响数百万患者，每年花费 340 亿美元，并且可能是持续认知的先兆 下降。这种认知功能的持续损害可能会持续数月。目前尚不清楚 为什么有些患者会出现围麻醉期并发症，而其他患者则接受 看似相同的麻醉剂在围手术期过程中却很顺利。为了解决这个问题，我们建议 研究基于个体的麻醉药理学，而不是以前基于人群的方法。 我们最近开发了实验和计算方法来量化基于个人的 小鼠麻醉反应的测量。使用这些方法，我们发现传统的 基于人群的药理学概念（例如药物效力）不足以描述个体 回应。我们确定了两个独立的衡量标准，可以捕捉个人反应的范围： 对状态转换的敏感性和抵抗力（Rst）。敏感性描述了一个人清醒或清醒的频率 以麻醉剂量麻醉，而 Rst 描述清醒和清醒之间发生转变的频率 麻醉状态。我们证明药理学可以差异性地调节敏感性和 Rst。我们 还证明了唤醒途径（蓝斑）的化学遗传学激活会降低 Rst 不改变药物敏感性。因为 Rst 在基于人群的药理学中完全被掩盖了 研究中，我们假设 Rst 是隐藏变量，可能有助于解释为什么某些患者 经历围麻醉期并发症，而其他人则不会。 我们建议研究蓝斑减少 Rst 的机制。使用 药理学和遗传学方法，我们将确定该基因座使用的神经递质系统 蓝藻调节第一。另外，我们将确定蓝斑对神经生理学的影响 使用我们实验室开发的高密度脑电图系统来检测状态变化，包括行为第一的相关性。 最后，我们将确定蓝斑调节 Rst 的神经元通路。的 拟议的调查路线将阐明蓝斑的活动如何影响个体化 麻醉反应，这将是实现个性化麻醉的重要一步。

PROJECT SUMMARY/ABSTRACT Millions of patients are placed into a reversible state of unconsciousness by anesthesiologists for life saving surgeries every year. The basic goals of anesthetic care are to reliably extinguish consciousness for the duration of surgery and afterwards to swiftly return the patient to their baseline cognitive state. Neither of these goals can be reliably achieved today, however. Some patients regain consciousness during surgery. Episodes of consciousness are not reliably detected by current intraoperative EEG-based monitoring and can result in post-traumatic stress and anxiety disorders. In contrast, other patients take a long time to resume normal cognition. This can manifest as postoperative delirium and cognitive derangements. Postoperative delirium affects millions of patients, costs 34 billion dollars annually, and can be a harbinger of ongoing cognitive decline. Such persistent impairments in cognitive function can last for many months. It is presently unclear why some patients experience peri-anesthetic complications while other patients that receive seemingly identical anesthetics have an uneventful perioperative course. To address this, we propose to study individual-based anesthetic pharmacology rather than the previous population-based approach. We have recently developed experimental and computational methods to quantify individual-based measures of anesthetic responses in mice. Using these methods, we discovered that conventional population-based pharmacological concepts such as drug potency are not sufficient to describe individual responses. We identified two independent measures that do capture the range of individual responses: sensitivity and resistance to state transitions (Rst). Sensitivity describes how often an individual is awake or anesthetized at an anesthetic dose, while Rst describes how frequently transitions happen between awake and anesthetized states. We demonstrated that pharmacology can differentially modulate sensitivity and Rst. We also demonstrated that chemogenetic activation of an arousal pathway – the locus coeruleus – decreases Rst without a change in drug sensitivity. Because Rst is completely obscured in population-based pharmacological studies, we hypothesize that Rst is the hidden variable that may help explain why some patients experience peri-anesthetic complications while others do not. We propose to investigate the mechanisms through which the locus coeruleus decreases Rst. Using pharmacologic and genetic approaches, we will identify the neurotransmitter systems used by the locus coeruleus to modulate Rst. Separately, we will identify the effects of the locus coeruleus on neurophysiologic state change, including correlates of behavioral Rst, using a high-density EEG system developed by our lab. Finally, we will identify the neuronal pathways through which locus coeruleus acts to modulate Rst. The proposed lines of investigation will clarify how activity of the locus coeruleus influences individualized anesthetic responses, and will be an important step towards delivering personalized anesthesia.