Neurophysiological Mechanisms of Recovery of Consciousness

项目摘要 这项研究的长期目标是阐明允许大脑恢复的神经机制。 麻醉后的意识和认知。一些患者在治疗过程中过早恢复意识 做手术。术中意识与创伤后应激障碍的显著风险有关。其他 相反，在麻醉药停药后很长一段时间内，认知功能不会恢复。延迟恢复 与更高的发病率、更长的住院时间和更高的医疗成本有关。当大脑活动时 几十年来，监护仪一直被用来减轻麻醉期并发症，目前的大脑监护仪 活动不足。麻醉意识不能可靠地检测或预防并延迟恢复 认知障碍影响了接受麻醉的患者中的很大一部分。 所有现有的脑活动监测器都假设麻醉深度是一个连续的一维 测量与麻醉浓度密切相关。相反，我们表明在恢复过程中 异氟醚丘脑皮质系统在少数离散患者之间突然转变后的意识 活动模式。即使在麻醉剂浓度达到 已修复。虽然在恢复过程中会发生许多这样的转变，但所有通向觉醒的路径都是通过一个小的 离散活动模式的子集。我们的中心假设是：少数人之间的转变 离散的活动模式是麻醉后恢复和定向活动的普遍特征 这种过渡的干扰延缓或加速了复苏。在目标1中，我们将直接记录神经元 不同麻醉剂苏醒期间大脑皮质和丘脑的活动。我们将检测并量化 使用稳健的统计方法开发和验证离散活动模式之间的转换 最近在我们的实验室。在目标2和目标3中，我们将使用神经元活动的直接记录和 精确的光遗传学微扰以确定增食欲素能和去甲肾上腺素能神经元通路在 协调不同离散活动模式之间的过渡。我们假设通过操纵这些 觉醒途径将能够加速或反过来阻碍恢复。这一贡献是 意义重大，因为我们提议提供一种前所未有的能力来监测和影响麻醉 州政府。在短期内，这项工作可能会导致开发强有力的监测大脑活动的手段 在麻醉状态下。从长远来看，识别负责相互转换的神经元机制 离散的活动模式可能会导致针对预防意外的靶向疗法的开发 麻醉后意识和加速恢复。这项拟议的研究具有创新性，因为 关注离散活动模式之间突然转变的潜在机制，我们将确定 以前不为人知的神经元过程，在麻醉后恢复意识。

Project Summary The long-term goal of this research is to elucidate neuronal mechanisms that allow the brain to recover consciousness and cognition after anesthesia. Some patients recover consciousness prematurely during surgery. Intraoperative awareness is associated with a significant risk of post-traumatic stress disorder. Others conversely, do not recover cognitive function long after anesthetics have been discontinued. Delayed recovery is associated with higher morbidity, longer hospital stays, and increased healthcare costs. While brain activity monitors have been used for decades to mitigate these peri-anesthetic complications, current monitors of brain activity are inadequate. Anesthetic awareness cannot be reliably detected or prevented and delayed recovery of cognition affects a large fraction of patients who undergo anesthesia. All existing brain activity monitors assume that depth of anesthesia is a continuous one-dimensional measure closely tied to the anesthetic concentration. In contrast, we show that during recovery of consciousness after isoflurane thalamocortical system abruptly transitions among a small number of discrete activity patterns. Transitions among discrete activity patterns persist even when anesthetic concentration is fixed. While many such transitions occur during recovery, all paths towards wakefulness funnel through a small subset of discrete activity patterns. Our central hypothesis is that: Transitions among a small number of discrete activity patterns is a universal feature of recovery from anesthesia and that directed disturbances of such transitions delay or accelerate recovery. In Aim 1 we will directly record neuronal activity in the cortex and thalamus during recovery from different anesthetics. We will detect and quantify transitions among discrete activity patterns using robust statistical methodology developed and validated recently in our lab. In Aims 2 and 3 we will use a combination of direct recordings of neuronal activity and precise optogenetic perturbations to determine the role of orexinergic and noradrenergic neuronal pathways in mediating transitions between different discrete activity patterns. We hypothesize that by manipulating these arousal pathways will be able to either accelerate or conversely impede recovery. This contribution is significant because we propose to provide an unprecedented ability to monitor and influence the anesthetic state. In the short term, this work may lead to the development of robust means of monitoring brain activity under anesthesia. In the long run, identification of neuronal mechanisms responsible for transitions among discrete activity patterns may lead to the development of targeted therapies for preventing unintended awareness and accelerating recovery after anesthesia. The proposed research is innovative because by focusing on mechanisms underlying abrupt transitions between discrete activity patterns we will identify previously unknown neuronal processes that sculpt the recovery of consciousness after anesthesia.