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.

项目概要 这项研究的长期目标是阐明让大脑恢复的神经机制 麻醉后的意识和认知。部分患者在治疗过程中过早恢复意识 外科手术。术中意识与创伤后应激障碍的显着风险相关。其他的 相反，在停止麻醉后很长时间内认知功能也不会恢复。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有关。当大脑活动时 几十年来，监视器一直用于减轻这些围麻醉期并发症，目前的脑监视器 活动不够充分。无法可靠地检测或预防麻醉意识并延迟恢复 认知能力的下降影响着大部分接受麻醉的患者。 所有现有的大脑活动监视器都假设麻醉深度是连续的一维 测量与麻醉浓度密切相关。相比之下，我们表明在恢复期间 异氟烷后，丘脑皮质系统的意识突然在少数离散的 活动模式。即使麻醉剂浓度不同，离散活动模式之间的转变仍然存在。 固定的。虽然许多这样的转变发生在恢复期间，但所有通往觉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：少数人之间的转变 离散的活动模式是麻醉恢复的普遍特征，并指导 这种转变的干扰会延迟或加速恢复。在目标 1 中，我们将直接记录神经元 从不同麻醉剂恢复期间皮质和丘脑的活动。我们将检测并量化 使用开发和验证的稳健统计方法在离散活动模式之间进行转换 最近在我们的实验室。在目标 2 和 3 中，我们将结合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食欲素能和去甲肾上腺素能神经元通路的作用 调解不同离散活动模式之间的转换。我们假设通过操纵这些 唤醒途径将能够加速或相反地阻碍恢复。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。从短期来看，这项工作可能会导致开发出强大的大脑活动监测方法 在麻醉下。从长远来看，识别负责之间转换的神经元机制 离散的活动模式可能会导致靶向疗法的开发，以预防意外的发生 意识并加速麻醉后的恢复。拟议的研究具有创新性，因为 重点关注离散活动模式之间突然转变的机制，我们将确定 以前未知的神经元过程塑造了麻醉后意识的恢复。