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: 9293345
• 负责人: RICHARD E HARRIS
• 金额: $ 36.18万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293345
• 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; Human; Ketamine; Laboratories; Lead; Measures; Medicine; Modality; Modern Medicine; Molecular; Molecular Target; Monitor; Neurons; Nitrous Oxide; North America; Operative Surgical Procedures; Pain; Pain management; Pathway Analysis; Patients; Perioperative; Pharmaceutical Preparations; Primates; 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; public health relevance; 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（由申请人提供）：麻醉和镇痛的神经机制是基本科学问题，对手术患者具有深远的临床意义。大多数全身麻醉剂会增强 GABA 传递，从而抑制神经元功能，可预见地导致意识丧失。具有麻醉和镇痛特性的独特药物是值得注意的例外：GABA 受体不是主要分子靶标，并且这两种药物都会增加脑电图的高频活动。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，这些药物在大脑网络水平上可能与 GABA 麻醉剂具有相似性，我们的长期目标是发现麻醉和镇痛的基本神经科学原理。该应用的目的是使用功能性磁共振成像 (fMRI)、脑电图 (EEG)、皮质多电极阵列记录来识别。图论分析-氯胺酮和一氧化二氮在镇痛和麻醉剂量下的网络水平机制我们的中心假设是氯胺酮和一氧化二氮改变网络模块性（即皮质“模块”的整合水平）和网络效率。我们特别认为，较低剂量的这些药物会提高网络效率并扰乱疼痛处理，从而产生镇痛作用，而较高剂量会降低网络效率并扰乱皮质表征，从而产生镇痛作用。所提出的研究的基本原理不仅限于确定这些特殊药物的作用原理，还可以加深对全身麻醉和镇痛机制的了解。通过实现以下具体目标： 1. 在接受氯胺酮或一氧化二氮的健康志愿者中，使用联合功能磁共振成像/脑电图研究来确定大脑网络的剂量依赖性变化。支持我们中心假设的初步数据。在拟议的研究中，我们将评估亚麻醉和麻醉剂量下的大脑对氯胺酮或一氧化二氮的反应，重点是模块化、效率和中枢结构等网络测量。 评估剂量依赖性变化。在接受氯胺酮或一氧化二氮的非人类灵长类动物中使用皮质阵列记录的感觉运动表征中，我们获得了初步证据，表明在氯胺酮麻醉期间初级皮质表征可以持续存在，而跨模式感觉表征通常存在。清醒时发现的认知表征被废除（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的技术，这与目前测量功能连接等替代物的技术不同。