Frontoparietal Mechanisms of Anesthetic-induced Unconsciousness

描述（由申请人提供）：尽管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导致患者并发症，因为麻醉不足（例如，意识和创伤后应激障碍）以及麻醉过度（例如，延迟出现，谵妄，神经毒性）。许多商业上可用的大脑监测器目前在手术室中使用，但这些设备显示出有限的效用，并且通常基于专有或经验算法。神经生物学的最新进展预示着一个更复杂的大脑监测时代的到来，并改善了患者的安全。现在迫切需要的是确定全身麻醉的可测量的神经生理特征，这些特征是由意识的神经生物学所告知的，并且可以用神经化学机制来解释。我们最近进行了人类和动物研究，确定了大脑中前额到顶叶反馈连接的优先抑制，作为全身麻醉的候选神经生理学关联。然而，目前尚不清楚如何最好地测量麻醉期间的皮质反馈抑制，它对意识状态的变化有多敏感，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。本研究的目的是证明对额顶叶反馈连接的优先抑制是人类全身麻醉的可靠测量，并阐明其在动物模型中的神经化学机制。我们的中心假设是，额顶叶反馈抑制是一种常见的全麻网络水平机制，由前额叶皮层的乙酰胆碱活性调节。提出这项研究的基本原理是了解麻醉引起的额顶叶连通性的变化将通过改善患者监测显著影响临床实践。此外，对乙酰胆碱在网络连接中的作用的机制理解将促进痴呆或谵妄患者的麻醉护理，这两种疾病都被认为与胆碱能有关

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.