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

项目摘要/摘要 数以百万计的病人为挽救生命而被麻醉医生置于可逆的昏迷状态 每年都要做手术。麻醉护理的基本目标是为患者可靠地消除意识。 手术持续时间，然后迅速使患者恢复到其基线认知状态。两个人都不是 然而，这些目标今天可以可靠地实现。一些患者在手术过程中恢复了意识。 目前基于脑电的术中监测不能可靠地检测到意识事件，并且可以 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 正常的认知。这可能表现为术后精神错乱和认知障碍。术后 精神错乱影响数以百万计的患者，每年花费340亿美元，本身就是认知障碍的先兆。 术后用药。这种认知功能的持续下降可能会持续数月。它目前是 不清楚为什么一些患者会出现麻醉期并发症，而另一些患者则会接受 看似相同的麻醉剂有一个平淡无奇的围手术期。为解决这一问题，我们建议 研究以个体为基础的麻醉剂药理学，而不是以前基于群体的措施。 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。这些方法的使用表明，传统的 基于群体的药理学概念，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，它们确实涵盖了个体回答的范围： 状态转换的灵敏度和阻力(RST)。敏感度描述了一个人醒着或 在麻醉剂剂量下麻醉，而RST描述了这两者之间发生转换的频率 各州。我们证明了敏感性和RST可以通过不同的药物调节。我们也 证明了兴奋通路-蓝斑-的化学激活降低了RST，而不是 药物敏感性的变化。因为RST在基于群体的药理学研究中是完全模糊的， 我们假设RST是一个“隐藏变量”，这可能有助于解释为什么有些患者 麻醉期间的并发症，而其他人则没有。 我们建议研究蓝斑降低RST的机制。vbl.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 蓝斑调节RST。另外，我们将确定蓝斑对神经生理学的影响。 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脑电系统。 最后，我们将转向确定蓝斑参与调制的神经通路。 RST。拟议的研究路线将阐明蓝斑的活动如何影响个体化 麻醉反应，并将是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 swiftly return the patient to their baseline cognitive state. Neither one 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 itself be a harbinger of cognitive dcline after surgery. Such persistent decrements 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 previously used population-based measures. We have recently developed experimental and computational methods to quantify individual-based measures of anesthetic responses in mice. The use of these methods revealed 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 those two states. We demonstrated that sensitivity and Rst can be differentially pharmacologically modulated. We also demonstrated that chemogenetic activation of an arousal pathway – 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 turn towards identifying 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.