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

项目总结/摘要 数百万的病人被麻醉师置于可逆的无意识状态以挽救生命 每年的手术。麻醉护理的基本目标是可靠地熄灭意识， 在手术期间和手术后迅速恢复患者的基线认知状态。这两种 然而，这些目标今天是可以可靠地实现的。有些病人在手术过程中会恢复知觉。集 目前基于EEG的术中监测不能可靠地检测到意识， 创伤后压力和焦虑症相比之下，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障碍。术后谵妄 影响着数百万患者，每年花费340亿美元， 下降这种认知功能的持续性损伤可能持续数月。目前还不清楚 为什么有些病人会出现围麻醉期并发症，而其他病人接受 看起来相同的麻醉剂具有无事件的围手术期过程。为了解决这个问题，我们建议 研究基于个体的麻醉药理学，而不是以前的基于人群的方法。 我们最近开发了实验和计算方法来量化基于个人的 测量小鼠的麻醉反应。使用这些方法，我们发现传统的 基于人群的药理学概念（如药物效力）不足以描述个体 应答我们确定了两个独立的衡量标准，它们确实反映了个体反应的范围： 灵敏度和状态转换电阻（Rst）。敏感度描述了一个人清醒或 Rst描述了清醒和清醒之间的转换频率， 麻醉状态我们证明，药理学可以差异调节敏感性和Rst。我们 还表明，化学激活的唤醒途径-蓝斑-降低Rst 而药物敏感性没有变化。因为Rst在基于人群的药理学研究中完全模糊， 研究中，我们假设Rst是隐藏变量，这可能有助于解释为什么一些患者 经历麻醉期并发症，而其他人没有。 我们建议通过蓝斑降低Rst的机制进行调查。使用 药理学和遗传学的方法，我们将确定神经递质系统所使用的基因座 蓝斑调节Rst.另外，我们将确定蓝斑对神经生理的影响， 状态变化，包括行为Rst的相关性，使用我们实验室开发的高密度EEG系统。 最后，我们将确定通过蓝斑的神经通路的行为，以调节RST。的 提出的调查路线将澄清蓝斑的活动如何影响个体化 麻醉反应，并将是向提供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.