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

项目摘要 在麻醉学和围手术期疼痛领域，ESI Mira计划的研究旨在更好地 了解麻醉剂和止痛剂如何阻止记忆的形成，防止条件性恐惧 反应，并在其他无法忍受的经历中缓解疼痛。目前提供的临床麻醉 在实现这些目标方面并不普遍有效，因为在理解 这些药物如何起作用和相互作用的系统水平的神经科学。私家侦探是一名内科麻醉师 生物工程师，他建立了独特的、创新的跨学科框架来解决这一重要问题 有问题。一支由资深合作者组成的团队，拥有心理学、功能核磁共振分析、核磁共振工程、 麻醉剂药理学已经被组合起来，以利用一种非常富有成效的学术 环境。该项目将确定临床上七大机械类麻醉剂- 使用的代理作用和相互作用影响认知功能，包括大脑中发生变化的位置。稳定- 麻醉剂的状态浓度将在高场磁共振环境中传递，同时受试者进行 精确计时的急性疼痛刺激的认知任务；脑电、皮肤电和心脏 将同时获取节奏数据。包括急性疼痛，使用高场功能磁共振， 与以前的人类相比，多模式数据和对行为的广泛描述都代表了更严格的要求 麻醉神经科学工作，并建立在PI最近研究咪达唑仑和氯胺酮的基础上。第一个计划中的 该项目将完成比较异丙酚、右旋美托咪定和芬太尼的机械性临床试验，该试验具有 根据公安部的K23开始。这是一项随机、安慰剂对照、平行手臂神经成像研究。 健康成年志愿者(NCT04062123)。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的代表性实例的个别调查 常用的麻醉药。第三套拟议项目将通过以下方式解决取得进展的一个重要障碍 在两个或更多先前描述的机械类中使用麻醉剂的组合。 这将标志着范式的转变，以更现实地模拟临床上无处不在的多药房 麻醉练习。麻醉药的组合将被限制在那些可以实施的药物上 临床实践中的共同选择将基于对每一项数据的广泛量化分析 单独研究代理，目标是利用关键的协同行为和神经交互 机械上不同的麻醉剂。这一系统级神经科学实质性项目的总体目标 研究是确定对麻醉剂诱导的关键神经信号既必要又充分 抑制记忆形成、恐惧条件作用和疼痛处理。这将为以下工作奠定必要的基础 通过更知情的剂量组合，朝着改善临床实践的长期愿景取得进展 或加强术中措施，以确保所有患者在麻醉下失忆和止痛。

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.