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。 手术持续时间和之后迅速使患者恢复到他们的基线认知状态。这两个都不是 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了意识。剧集 目前基于脑电的术中监测不能可靠地检测到意识障碍，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 认知力。这可能表现为术后精神错乱和认知障碍。术后精神错乱 影响数百万患者，每年花费340亿美元，并可能是持续认知的先兆 拒绝。这种认知功能的持续性损害可能会持续好几个月。目前尚不清楚 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药理学，而不是以前的以群体为基础的方法。 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 在麻醉剂剂量下被麻醉，而RST描述在清醒和 麻醉状态。我们证明了药理学可以不同地调节敏感性和RST。我们 也证明了兴奋通路--蓝斑--的化学激活降低了RST 而对药物的敏感性没有改变。因为RST在基于群体的药理学中是完全模糊的 研究中，我们假设RST是隐藏的变量，这可能有助于解释为什么一些患者 体验麻醉期并发症，而其他患者则不会。 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，我们将确定蓝斑调节RST的神经通路。这个 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，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 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.