Network-Level Mechanisms of Ketamine and Nitrous Oxide in the Primate Brain

 描述（由申请人提供）：麻醉和镇痛的神经机制是基本的科学问题，对手术患者具有深刻的临床意义。大多数全身麻醉药增强GABA传递，从而抑制神经元功能，可预见地诱导意识丧失。然而，氯胺酮和一氧化二氮是具有麻醉和镇痛特性的独特药物，这是值得注意的例外：GABA受体不是主要的分子靶点，两种药物都增加了脑电图的高频活动。然而，尽管在分子和神经生理学水平上存在这些差异，但我们实验室的最新数据表明，这些药物在脑网络水平上可能与GABA能麻醉剂具有机制相似性。我们的长期目标是发现可以在围手术期监测的麻醉和镇痛的基本神经科学原理。本申请的目的是确定使用功能性磁共振成像（fMRI），脑电图（EEG），皮层多电极阵列记录，和图形理论分析，氯胺酮和一氧化二氮在镇痛和麻醉剂量的网络水平的机制。我们的中心假设是氯胺酮和一氧化二氮改变了网络模块化（即，皮质“模块”的整合水平）和网络效率。我们特别假设，这些药物的低剂量增加网络效率和破坏疼痛处理，导致瘫痪，而高剂量降低网络效率和破坏皮层代表性，导致麻醉。拟议研究的基本原理不仅仅是确定这些特定药物的工作原理。对这些独特药物的网络效应的更好理解可能会导致对全身麻醉和镇痛机制的更根本的理解。我们计划通过实现以下具体目标来测试我们的中心假设：1。在接受氯胺酮或一氧化二氮的健康志愿者中，使用组合的fMRI/EEG研究确定脑网络的剂量依赖性变化。我们已经成功地开发了一个范例，结合功能磁共振成像/脑电图在人类接受麻醉药物，初步数据支持我们的中心假设。在拟议的研究中，我们将评估在亚麻醉和麻醉剂量下氯胺酮或一氧化二氮的脑反应，重点是网络措施，如模块化，效率和枢纽结构。2.在接受氯胺酮或一氧化二氮的非人灵长类动物中，使用皮层阵列记录评估感觉运动表征的剂量依赖性变化。我们已经获得了初步的证据，表明初级皮层代表可以在氯胺酮麻醉期间持续存在，而通常在清醒期间发现的跨通道感觉代表被取消（例如，消除M1中的次级感觉表征）。这项创新的研究设计是第一个测量暴露于麻醉药物后大脑网络中的认知表征，而不是目前测量功能连接等替代品的技术。

 DESCRIPTION (provided by applicant): The neural mechanisms of anesthesia and analgesia are fundamental scientific questions, with profound clinical relevance for surgical patients. Most general anesthetics potentiate GABA transmission and thus depress neuronal function, predictably inducing unconsciousness. However, ketamine and nitrous oxide are unique drugs with both anesthetic and analgesic properties that are noteworthy exceptions: GABA receptors are not the primary molecular target and both drugs increase high-frequency activity of the electroencephalogram. However, despite these differences at the molecular and neurophysiological level, recent data from our laboratory suggest that these drugs may have mechanistic similarities to GABAergic anesthetics at the level of brain networks. Our long-term goal is to discover fundamental neuroscientific principles of anesthesia and analgesia that can be monitored in the perioperative period. The objective for this application is to identify-using functional magnetic resonance imaging (fMRI), electroencephalography (EEG), cortical multielectrode array recordings, and graph-theoretical analysis-the network-level mechanisms of ketamine and nitrous oxide at analgesic and anesthetic doses. Our central hypothesis is that ketamine and nitrous oxide alter network modularity (i.e., the level of integration of cortical "modules") and network efficiency. We specifically hypothesize that lower doses of these drugs increase network efficiency and disrupt pain processing-resulting in analgesia-and that higher doses decrease network efficiency and disrupt cortical representation-resulting in anesthesia. The rationale for the proposed studies extends beyond determining how these particular drugs work. An improved understanding of the network effects of these unique agents could lead to a more fundamental understanding of general anesthetic and analgesic mechanisms. We plan to test our central hypothesis by accomplishing the following specific aims: 1. Identify dose-dependent changes in brain networks using combined fMRI/EEG studies in healthy volunteers receiving ketamine or nitrous oxide. We have successfully developed a paradigm of combined fMRI/EEG in humans receiving anesthetic drugs, with preliminary data supporting our central hypothesis. In the proposed studies we will assess brain responses to ketamine or nitrous oxide at subanesthetic and anesthetic doses, with a focus on network measures such as modularity, efficiency, and hub structure. 2. Assess dose-dependent changes in sensorimotor representations using cortical array recordings in nonhuman primates receiving ketamine or nitrous oxide. We have obtained preliminary evidence that primary cortical representations can persist during ketamine anesthesia, while the cross-modal sensory representation normally found during waking is abolished (e.g., elimination of secondary sensory representation in M1). This innovative study design is the first to measure cognitive representation in brain networks after exposure to anesthetic drugs, as opposed to current techniques of measuring surrogates such as functional connectivity.