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

灵长类动物大脑中氯胺酮和一氧化二氮的网络级机制

• 批准号: 9110270
• 负责人: RICHARD E HARRIS
• 金额: $ 35.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110270
• 关键词: Absence of pain sensation; Analgesics; Anesthesia and Analgesia; Anesthesia procedures; Anesthetics; Attention; Behavioral; Brain; Clinical; Cognitive; Data; Depressed mood; Dose; Electroencephalogram; Electroencephalography; Exposure to; Frequencies; Functional Magnetic Resonance Imaging; GABA Receptor; General Anesthesia; General anesthetic drugs; Goals; Graph; Health; Human; Ketamine; Laboratories; Lead; Measures; Medicine; Modern Medicine; Molecular; Molecular Target; Monitor; Neurons; Nitrous Oxide; North America; Operative Surgical Procedures; Pain; Pain management; Pathway Analysis; Patients; Perioperative; Pharmaceutical Preparations; Primates; Process; Property; Psychiatry; Research Design; Scientific Advances and Accomplishments; Sensory; Structure; Techniques; Testing; Therapeutic; Unconscious State; Work; clinically relevant; gamma-Aminobutyric Acid; healthy volunteer; improved; innovation; multi-electrode arrays; neuromechanism; neurophysiology; nonhuman primate; novel; response; transmission process

 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.

 描述（由适用提供）：麻醉和镇痛的神经机制是基本的科学问题，对手术患者具有深远的临床意义。大多数通用麻醉剂潜在的GABA传播，从而降低神经元功能，可以预见地引起无意识。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受体不是主要分子靶标，并且两种药物都会增加电脑电图的高频活性。然而，尽管在分子和神经生理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能麻醉药具有机械相似性。我们的长期目标是发现可以在围手术期间监测的麻醉和镇痛的基本神经科学原理。该应用的目的是识别使用功能性磁共振成像（fMRI），脑电图（EEG），皮质多电极阵列记录以及图理论分析 - 氯胺酮和硝酸氧化物的网络级别机制在止痛药和麻醉剂量时。我们的中心假设是，氯胺酮和一氧化二氮改变了网络模块性（即皮层“模块”的整合水平）和网络有效性。我们特别假设这些药物的较低剂量提高了网络效率并破坏镇痛中的疼痛处理 - 较高的剂量会降低网络效率并破坏麻醉的皮层表示。拟议研究的基本原理范围超出了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改进理解可能会导致对一般麻醉和镇痛机制的更基本的理解。我们计划通过完成以下特定目的来检验中心假设：1。使用fMRI/EEG研究在接受氯胺酮或一氧化二氮的健康志愿者中，确定脑网络中的剂量依赖性变化。我们已经成功地开发了接受麻醉药物的人类中fMRI/EEG组合的范式，并提供了支持我们中心假设的初步数据。在拟议的研究中，我们将以亚警觉和麻醉剂量评估大脑对氯胺酮或一氧化二氮的反应，重点关注网络测量值，例如模块化，效率和枢纽结构。 2。使用非人类原发性氯胺酮或一氧化二氮的皮质阵列记录评估感觉运动表示的剂量依赖性变化。我们已经获得了初步证据，表明氯胺酮麻醉期间的主要皮质表示可以持续存在，而在醒来期间通常发现的跨模式感觉表示（例如，消除M1中的次级感觉表示）。这种创新的研究设计是暴露于麻醉药物后的脑网络认知表达的第一个测量，而不是当前测量替代物（例如功能连接性）的技术。