Neuroimaging to identify the neural correlates of anesthetic and analgesic action in humans

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Project Summary This ESI MIRA program of research, within the field of anesthesiology and perioperative pain, is aimed at better understanding how anesthetic and analgesic agents block memory formation, prevent conditioned fear responses, and relieve pain during otherwise unbearable experiences. Current provision of clinical anesthesia is not universally effective in achieving these goals because of a critical knowledge gap in understanding the systems-level neuroscience of how these drugs act and interact. The PI is a physician-anesthesiologist and bioengineer who has established a unique and innovative interdisciplinary framework to address this important problem. A team of senior collaborators, with expertise in psychology, functional MRI analysis, MRI engineering, and anesthetic pharmacology has been assembled to take advantage of an extremely productive academic environment. The project will determine how anesthetics from the seven major mechanistic classes of clinically- used agents act and interact to affect cognitive functions, including where in the brain changes occur. Steady- state concentrations of anesthetics will be delivered in a high-field MRI environment, while subjects perform cognitive tasks with precisely timed acute pain stimulation; electroencephalography, electrodermal, and cardiac rhythm data will simultaneously be acquired. The inclusion of acute pain, use of high-field functional MRI, multimodal data and broad characterization of behavior all represent increased rigor compared to prior human anesthetic neuroscience work, and builds on the PI’s recent studying midazolam and ketamine. The first planned project will complete the mechanistic clinical trial comparing propofol, dexmedetomidine, and fentanyl, which has begun under the PI’s K23. This is a randomized placebo-controlled single-blind parallel arm neuroimaging study in healthy adult volunteers (NCT04062123). The second set of projects will examine lidocaine and sevoflurane, to complete the individual investigation of representative examples from each major mechanistic class of commonly-used anesthetics. The third set of proposed projects will address an important barrier to progress by employing combinations of anesthetics across two or more of the previously characterized mechanistic classes. This will mark a shift in the paradigm to more realistically model the polypharmacy that is ubiquitous in clinical anesthesia practice. Combinations of anesthetics will be constrained to those that would be feasible to implement together in clinical practice and selection will be based on a broad quantitative analysis of data obtained for each agent studied individually, with the goal of leveraging key synergistic behavioral and neural interactions across mechanistically-different anesthetics. The overall goal of this substantive program of systems-level neuroscience research is to identify the key neural signatures that are both necessary and sufficient for anesthetic-induced inhibition of memory formation, fear conditioning, and pain processing. This will lay the foundation needed to progress towards the long-term vision of improving clinical practice, through more informed dosing combinations or enhanced intraoperative measures, to ensure amnesia and analgesia for all patients under anesthesia.