Cortical-Subcortical Network Dynamics of Anesthesia and Consciousness

项目摘要/摘要 全身麻醉(GA)是一种药物诱导的无反应和意识丧失状态， 每年都有数以百万计的人经历。尽管它无处不在，但对大脑回路的清晰和一致的图景 调解意识和反应能力尚未出现。来自非侵入性人体研究的断言 (即脑电和脑成像)、建模和动物研究牵涉到关键的皮质和皮质下大脑区域 (包括大脑皮层、丘脑和基底节)。然而，迄今为止的研究受到以下因素的限制 缺乏来自皮质和皮质下区域的直接记录，具有足够的空间，时间， 以及药物诱导麻醉期间的光谱分辨率。我们的总体假设是 最初提出的用来描述脑损伤后恢复的意识的中脑回路模型可以 被推广到更广泛地理解意识的机制。目前的研究提案 重点是对神经外科患者的系膜环路进行实验探测，利用 关于基底节疾病的患者群体(例如，帕金森病[PD]与特发性震颤[ET])， 同步获得高分辨率BG和皮质神经生理学的能力，以及有机会 使用脑深部刺激(DBS)以有针对性的方式调制电路以询问大脑行为 两性关系。我们追求三个具体目标：目标1：证明基础基底节患者 病理上对异丙酚比其他患者更敏感。具体地说，我们将使用靶控输液 异丙酚用于PD和ET患者的药代动力学-药效学参数研究 对BG回路在调节意识中的潜在作用的洞察，与我们更普遍的模型有关 意识的中间回路中介。目的2：研究基底节-额顶叶的时间演变 异丙酚麻醉诱导和苏醒行为相关的皮质回路动力学。我们 将使用人类受试者的高空间、时间和光谱分辨率记录来提供直接证据 电路功能、时间演化、因果电路流和大脑行为相关。目标3：评估 靶向环路DBS(包括苍白球内、外区)对异丙酚诱导的影响 意识和反应能力的丧失和恢复。这项研究在使用自然资源方面具有创新性。 阿尔茨海默病患者神经系统疾病和并发侵入性记录和刺激的变异 机械性和因果性研究设计。这项拟议的研究意义重大，因为它将展示一个复杂的 皮层和皮质下网络的相互作用与麻醉的部分分离效应，与大多数 临床上常用的测量麻醉深度的单一、连续标度的方法。这 该计划将提供重要的人体数据，以阐明介观电路模型的普适性 调节意识以及验证人类实验模型以供进一步研究和 描述麻醉剂对人脑的影响。

PROJECT SUMMARY/ABSTRACT General anesthesia (GA) is a pharmacologically-induced state of unresponsiveness and unconsciousness which millions of people experience every year. Despite its ubiquity, a clear and consistent picture of the brain circuits mediating consciousness and responsiveness has not emerged. Assertions from non-invasive human studies (i.e. EEG and brain imaging), modeling and animal studies implicate key cortical and subcortical brain areas (including cortex, thalamus, and basal ganglia (BG)) during anesthesia. However, studies to date are limited by the lack of direct recordings in humans from both cortical and subcortical regions with sufficient spatial, temporal, and spectral resolution during pharmacologically-induced anesthesia. Our overall hypothesis is that the mesocircuit model of consciousness, which was original proposed to characterize recovery after brain injury, can be generalized to understand mechanisms of consciousness more broadly. The current research proposal focuses on experimentally probing the mesocircuit in neurosurgical patients, taking advantage of differences in patient populations with respect to basal ganglia disease (e.g., Parkinson disease [PD] vs essential tremor [ET]), the ability to synchronously acquire high resolution BG and cortical neurophysiology, and the opportunity to modulate the circuit in a targeted fashion with deep brain stimulation (DBS) to interrogate brain-behavior relationships. We pursue three specific aims: Aim 1: To demonstrate that patients with underlying basal ganglia pathology are more sensitive to propofol than other patients. Specifically, we will use target-controlled infusion of propofol to characterize pharmacokinetic-pharmacodynamic parameters in patients with PD and ET to gain insights into the potential role of BG circuitry in regulating consciousness, bearing on our more generalized model of mesocircuit mediation of consciousness. Aim 2: To correlate temporal evolution of basal ganglia-frontoparietal cortical circuit dynamics with behavioral correlates of induction and emergence from propofol anesthesia. We will use high spatial, temporal, and spectral resolution recordings in human subjects to provide direct evidence of circuit function, temporal evolution, causal circuit flow, and brain-behavior correlates. Aim 3: To evaluate the effects of targeted mesocircuit DBS (including both globus pallidus internus and externus) on propofol induced loss and recovery of consciousness and responsiveness. The research is innovative in its use of natural variations in neurological disease and concurrent invasive recording and stimulation in humans with a mechanistic and causal study design. The proposed research is significant because it will demonstrate a complex interplay of cortical and subcortical networks with partially separable effects of anesthesia, contrary to the most common clinical approach of measuring a single, continuously scaled metric for depth of anesthesia. This program will provide important human data to shed light on the generalizability of the mesocircuit model of regulating consciousness as well as validate a human experimental model for further investigation and characterization of anesthetic effects on the human brain.