Frontoparietal Mechanisms of Anesthetic-induced Unconsciousness

说明(申请人提供)：虽然麻醉学领域在促进患者安全方面发挥了领导作用，但对于全身麻醉的靶器官：大脑，仍然没有标准的监测。缺乏可靠的神经生理监测可能会导致患者并发症，原因是麻醉不足(例如，意识不足和创伤后应激障碍)以及过度麻醉(例如，苏醒延迟、精神错乱、神经毒性)。目前，许多商业上可用的大脑监测器正在手术室中使用，但此类设备显示出的实用性有限，而且往往基于专有或经验算法。神经生物学的最新进展预示着大脑监测和改善患者安全的更复杂时代的可能性。迫切需要的是确定全身麻醉的可测量的神经生理学特征，这些特征由意识的神经生物学提供信息，并可以通过神经化学机制来解释。我们最近进行了人类和动物研究，发现大脑中额叶到顶叶反馈连接的优先抑制是全身麻醉的候选神经生理学相关性。然而，目前还不清楚麻醉过程中皮层反馈抑制的最佳测量方法，它对意识状态变化的敏感性，以及潜在的机制是什么。我们的长期目标是开发一种用于全身麻醉的神经生理监测仪，以提高患者的安全性。这项研究的目的是证明优先抑制额顶反馈连接是人类全身麻醉的可靠措施，并在动物模型中阐明其神经化学机制。我们的中心假设是，额顶反馈抑制是全身麻醉的一种常见的网络水平机制，该机制受额叶皮质中乙酰胆碱活动的调节。这项拟议研究的基本原理是，通过改善患者监测，了解麻醉剂引起的额顶连通性变化将显著影响临床实践。此外，从机制上理解乙酰胆碱在网络连接中的作用将促进对有痴呆或精神错乱风险的患者的麻醉护理，这两种疾病都被认为涉及胆碱能 神经传递。最后，这项关于反馈连通性的基础性工作将有助于推进对无意识病理状态的理解，因为选择性反馈抑制最近被证明与植物状态有关。

DESCRIPTION (provided by applicant): Although the field of anesthesiology has played a leadership role in promoting patient safety, there is still no standard monitor for the target orga of general anesthesia: the brain. The lack of reliable neurophysiologic monitoring can result in patient complications because of insufficient anesthesia (e.g., awareness and post- traumatic stress disorder) as well as excessive anesthesia (e.g., delayed emergence, delirium, neurotoxicity). A number of commercially-available brain monitors are currently used in the operating room, but such devices have shown limited utility and are often based on proprietary or empirical algorithms. Recent advances in neurobiology herald the possibility of a more sophisticated era of brain monitoring and improved patient safety. What is urgently needed is the identification of measurable neurophysiologic features of general anesthesia that are informed by the neurobiology of consciousness and that can be explained by neurochemical mechanisms. We have recently performed both human and animal studies that identify preferential inhibition of frontal-to-parietal feedback connectivity in the brain as a candidate neurophysiologic correlate of general anesthesia. However, it is still unclear how cortical feedback inhibition during anesthesia is best measured, how sensitive it is to changing states of consciousness, and what the underlying mechanisms are. Our long-term goal is to develop a neurophysiologic monitor for general anesthesia that improves patient safety. The objective of the proposed studies is to demonstrate that preferential inhibition of frontoparietal feedback connectivity is a reliable measure of general anesthesia in humans as well as to elucidate its neurochemical mechanisms in an animal model. Our central hypothesis is that frontoparietal feedback inhibition is a common network-level mechanism of general anesthesia that is regulated by acetylcholine activity in the prefrontal cortex. The rationale for the proposed research is that understanding anesthetic- induced changes in frontoparietal connectivity will significantly impact clinical practice by improved patient monitoring. Furthermore, a mechanistic understanding of the role of acetylcholine in network connectivity will advance the anesthetic care of patients at risk for dementia or delirium, both of which are thought to involve cholinergic neurotransmission. Finally, this fundamental work on feedback connectivity will help advance the understanding of pathologic states of unconsciousness, because selective feedback inhibition has recently been shown to be associated with vegetative states.