Cortical-Subcortical Network Dynamics of Anesthesia and Consciousness

项目总结/摘要 全身麻醉（GA）是一种药理学诱导的无反应性和无意识状态， 每年都有数百万人经历。尽管它无处不在，一个清晰和一致的大脑回路的图片， 中介意识和反应能力还没有出现。非侵入性人体研究的结论 (i.e.脑电图和脑成像），建模和动物研究牵连的关键皮层和皮层下的大脑区域 （包括皮质、丘脑和基底神经节（BG））。然而，迄今为止的研究受到以下限制： 在人类中缺乏来自皮质和皮质下区域的具有足够空间，时间， 和光谱分辨率。我们的总体假设是 意识的中间回路模型最初被提出来表征脑损伤后的恢复， 更广泛地理解意识的机制。目前的研究建议 重点是实验性地探测神经外科患者的中间回路， 关于基底神经节疾病的患者群体（例如，帕金森病[PD] vs原发性震颤[ET]）， 同步采集高分辨率BG和皮质神经生理学的能力，以及 通过脑深部电刺激（DBS）以有针对性的方式调节回路，以询问大脑行为 关系。我们追求三个具体目标：目标1：证明基底神经节病变患者 病理对异丙酚的敏感性高于其他患者。具体来说，我们将使用靶控输注 丙泊酚的特征药代动力学-药效学参数在PD和ET患者中获得 BG电路在调节意识中的潜在作用的见解，对我们更普遍的模型产生影响 意识的中介回路。目的2：研究基底节-额顶叶的时间演变 皮层回路动力学与异丙酚麻醉诱导和苏醒的行为相关性。我们 将使用高空间、时间和光谱分辨率的人类受试者记录，以提供直接证据 电路功能，时间演变，因果电路流和大脑行为相关。目标3：评估 靶向中间电路DBS（包括苍白球内外）对异丙酚诱导的 意识和反应的丧失和恢复。这项研究在利用自然资源方面是创新的。 神经系统疾病的变化以及同时进行的侵入性记录和刺激， 机械和因果研究设计。这项研究的重要性在于，它将展示一种复杂的 皮质和皮质下网络的相互作用与麻醉作用部分分离，与大多数 测量麻醉深度的单一、连续缩放度量的常用临床方法。这 该计划将提供重要的人类数据，以阐明中电路模型的普遍性， 调节意识以及验证人类实验模型以进行进一步研究， 麻醉剂对人脑的影响的表征。

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.