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.