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，但对于全身麻醉的目标器官：大脑，仍然没有标准的监测器。缺乏可靠的神经生理学监测可能导致患者并发症，因为麻醉不足（例如，意识和创伤后应激障碍）以及过度麻醉（例如，延迟苏醒、谵妄、神经毒性）。目前在手术室中使用了许多市售的脑监测器，但这些设备的实用性有限，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和改善患者安全的可能性。目前迫切需要的是识别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告知，并且可以由神经化学机制解释。我们最近进行了人类和动物的研究，确定优先抑制额顶叶反馈连接在大脑中作为一个候选的神经生理学相关的全身麻醉。然而，目前还不清楚如何最好地测量麻醉期间的皮层反馈抑制，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器，以提高患者的安全性。拟议研究的目的是证明额顶叶反馈连接的优先抑制是人类全身麻醉的可靠措施，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，额顶叶反馈抑制是全身麻醉的一种常见的网络水平机制，受前额叶皮层中乙酰胆碱活性的调节。拟议研究的基本原理是，了解麻醉诱导的额顶叶连接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性理解将促进痴呆或谵妄风险患者的麻醉护理，这两种风险都被认为涉及胆碱能神经元。 神经传递最后，这项关于反馈连接的基础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人状态有关。 公共卫生相关性：该项目与公共卫生有关，因为它试图了解全身麻醉剂如何影响大脑以及如何最好地测量。获得麻醉和大脑的更详细的知识将有助于通过更好地监测手术室和开发更安全的麻醉药物来改善患者护理。

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. PUBLIC HEALTH RELEVANCE: This project is relevant to public health because it seeks to understand how general anesthetics affect the brain and how this can best be measured. Gaining a more detailed knowledge of anesthesia and the brain will help improve patient care through better monitoring in the operating room and the development of safer anesthetic drugs.