Neurophysiological Mechanisms of Recovery of Consciousness

意识恢复的神经生理学机制

• 批准号: 10208897
• 负责人: Alexander Proekt
• 金额: $ 35.79万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208897
• 关键词: Affect; Algorithms; Anesthesia procedures; Anesthetics; Arousal; Awareness; Behavior; Brain; Cell Nucleus; Characteristics; Cluster Analysis; Cognition; Conscious; Data; Delirium; Development; Dimensions; Event; Exhibits; Functional disorder; Goals; Halothane; Health Care Costs; Hypothalamic structure; Isoflurane; Ketamine; Lead; Length of Stay; Measures; Mediating; Methodology; Monitor; Morbidity - disease rate; Neurons; Operative Surgical Procedures; Output; Pathway interactions; Patients; Pattern; Pharmacology; Play; Pontine structure; Population; Post-Traumatic Stress Disorders; Process; Propofol; Public Health; Recovery; Research; Risk; Role; Sleep; Speed; Synapses; System; Testing; Thalamic structure; Wakefulness; Work; base; clinical practice; cognitive function; experience; innovation; locus ceruleus structure; neurophysiology; noradrenergic; optogenetics; premature; prevent; targeted treatment; tool

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.

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。一些患者在 外科手术。术中意识与创伤后应激障碍的重大风险有关。其他的 相反，在停用麻醉剂后，请勿恢复认知功能。延迟恢复 与发病率更高，住院时间更长以及医疗保健成本增加有关。而大脑活动 监测器已被用来减轻这些警闭并发症，当前的大脑监测器 活动不足。无法可靠地检测或预防和延迟恢复性麻醉意识 认知会影响大量发生麻醉的患者。 所有现有的大脑活动监测器都认为麻醉的深度是连续的一维 测量与麻醉浓度紧密相关的测量。相比之下，我们表明在恢复期间 异氟烷丘脑皮层系统突然过渡到少数离散的意识 活动模式。离散活动模式之间的过渡即使麻醉浓度是 固定的。虽然许多这样的过渡发生在恢复期间，但所有通向清醒的路径都通过一个小的漏斗 离散活动模式的子集。我们的中心假设是：少数 离散活动模式是从麻醉中恢复的普遍特征，该特征是指向的 此类过渡的干扰延迟或加速恢复。在AIM 1中，我们将直接记录神经元 从不同麻醉药中恢复过程中皮质和丘脑的活性。我们将检测和量化 使用强大的统计方法论开发和验证的分散活动模式之间的过渡 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和 精确的光遗传学扰动，以确定甲状腺素能和去甲肾上腺素能神经元途径在 介导不同离散活动模式之间的过渡。我们通过操纵这些假设 唤醒途径将能够加速或相反阻碍恢复。这个贡献是 意义重大，因为我们建议提供前所未有的监测和影响麻醉的能力 状态。在短期内，这项工作可能导致发展鲁棒的方法来监测大脑活动 在麻醉下。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导致开发有针对性的疗法，以防止意外 麻醉后意识和加速恢复。拟议的研究具有创新性，因为 关注离散活动模式之间突然过渡的机制，我们将确定 以前未知的神经元过程雕刻了麻醉后意识的恢复。