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

项目摘要 这个ESI MIRA研究计划，在麻醉学和围手术期疼痛领域，旨在更好地 了解麻醉剂和止痛剂如何阻断记忆的形成，防止条件性恐惧 反应，并减轻疼痛，否则难以忍受的经验。临床麻醉的现状 在实现这些目标方面并不普遍有效，因为在理解 这些药物如何作用和相互作用的系统级神经科学。PI是一名麻醉医师， 生物工程师谁建立了一个独特的和创新的跨学科框架，以解决这一重要的 问题.一个由资深合作者组成的团队，拥有心理学、功能性磁共振成像分析、磁共振成像工程方面的专业知识， 和麻醉药理学已经被组装起来，以利用一个非常富有成效的学术 环境该项目将确定如何麻醉剂从七个主要的机械类的临床- 使用的药剂作用并相互作用以影响认知功能，包括大脑中发生变化的位置。稳住- 将在高场MRI环境中输送规定浓度的麻醉剂，同时受试者执行 精确定时急性疼痛刺激的认知任务;脑电图、皮肤电和心脏电 将同时采集节律数据。包括急性疼痛，使用高场功能磁共振成像， 多模态数据和广泛的行为表征都代表了与先前人类相比增加的严格性。 麻醉神经科学的工作，并建立在PI的最近研究咪达唑仑和氯胺酮。述第一计划 该项目将完成比较丙泊酚、右美托咪定和芬太尼的机制临床试验， 开始于PI的K23这是一项随机、安慰剂对照、单盲、平行臂神经影像学研究 健康成人志愿者（NCT 04062123）。第二组项目将检查利多卡因和七氟烷， 完成对每个主要机械类别的代表性实例的单独调查， 常用的麻醉剂。第三组拟议项目将通过以下方式解决阻碍进展的一个重要障碍： 使用两种或多种先前表征的机械类别的麻醉剂的组合。 这将标志着范式的转变，以更现实地模拟临床上普遍存在的多种药物 麻醉实践麻醉剂的组合将被限制在那些可行的实施 在临床实践和选择中，将基于对每种药物获得的数据进行广泛的定量分析， 代理人单独研究，目的是利用关键的协同行为和神经相互作用， 不同的麻醉剂。这个系统级神经科学实质性计划的总体目标 研究的目的是确定关键的神经信号，这是必要的和充分的麻醉诱导 抑制记忆形成、恐惧条件反射和疼痛处理。这将奠定必要的基础， 通过更知情的给药组合，朝着改善临床实践的长期愿景取得进展 或加强术中措施，以确保麻醉下所有患者的遗忘和镇痛。

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.