Neurophysiological Mechanisms of Recovery of Consciousness

项目摘要 这项研究的长期目标是阐明使大脑恢复的神经元机制 麻醉后的意识和认知。有些病人在手术过程中过早恢复意识。 手术术中意识与创伤后应激障碍的重大风险相关。别人 相反，在麻醉剂停用后很长时间内，认知功能不会恢复。延迟恢复 与较高的发病率、较长的住院时间和增加的医疗费用相关。当大脑活动 几十年来，监护仪一直被用来减轻这些围麻醉期并发症， 活动不够。无法可靠地检测或预防麻醉意识，延迟恢复 认知能力的下降影响了大部分接受麻醉的患者。 所有现有的脑活动监测器都假设麻醉深度是连续的一维 与麻醉剂浓度密切相关的指标。相反，我们表明，在恢复期间， 异氟烷后的意识丘脑皮质系统突然在少数离散中转变 活动模式。即使在麻醉剂浓度为 固定.虽然许多这样的转变发生在恢复过程中，但所有通往清醒的途径都是通过一个小通道， 离散活动模式子集。我们的中心假设是：少数人之间的过渡 离散的活动模式是麻醉恢复的普遍特征， 这种转变的干扰延迟或加速恢复。在目标1中，我们将直接记录神经元 在不同麻醉剂的恢复过程中皮质和丘脑的活动。我们将检测并量化 使用已制定和验证的强有力的统计方法在离散活动模式之间进行过渡 最近在我们的实验室。在目标2和3中，我们将使用神经元活动的直接记录的组合， 精确的光遗传学扰动，以确定食欲素能和去甲肾上腺素能神经元通路在 调节不同离散活动模式之间的转换。我们假设通过操纵这些 唤醒通路将能够加速或相反地阻碍恢复。这种贡献 重要的是，我们建议提供前所未有的能力来监测和影响麻醉剂， 状态从短期来看，这项工作可能会导致监测大脑活动的强大手段的发展 在麻醉状态下从长远来看，识别负责过渡的神经元机制， 离散的活动模式可能会导致靶向治疗的发展，以防止意外的 意识和加速麻醉后的恢复。这项研究具有创新性，因为 我们将重点关注离散活动模式之间突然转变的潜在机制， 以前未知的神经元过程，塑造麻醉后意识的恢复。

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.