Novel fMRI Strategy to Assess Consciousness in Brain-Injured Patients

多项研究表明，一些在严重脑损伤后仍然行为迟钝的患者可以根据指令调节他们的大脑活动。然而，在其他患者中，缺乏对命令遵循范式的反应不能作为意识缺失的证据。因此，迫切需要一种神经成像工具，能够在不依赖任务的情况下诊断行为无反应受试者的隐性意识。之前关于意识的神经相关的神经影像学研究大多采用状态间范式（例如，清醒与睡眠）或基于报告的对比，将支持意识的大脑活动差异与支持行为或任务反应的大脑活动差异相结合。为了解决这些限制，我的赞助人（朱利奥·托诺尼博士）开发了一种状态内，无报告范式，使用连续唤醒来对比睡眠期间的意识状态和无意识状态，这是一种生理上的无反应状态。利用高密度脑电图（EEG），他的研究小组已经证明，睡眠中做梦意识的发生与后皮层“热区”（包括枕叶、顶叶和颞叶皮层）的delta活动（睡眠慢波）减少有关。为了进行临床应用，现在必须使用脑电图-功能磁共振成像（fmri）联合证实和扩展这些发现。为此，在一项重要的新进展中，托诺尼博士及其合作者最近表明，通过fMRI中明显的高频（~0.17 Hz）血氧水平依赖（BOLD）振荡，可以忠实地跟踪睡眠期间的脑电图慢波活动。这一发现为研究睡眠期间的NCCs提供了前所未有的机会，具有高空间分辨率，避免了脑电图源建模的潜在缺陷，并且可以不受限制地访问皮层下结构。利用这些新发现，在本项目中，我建议将睡眠慢波的新型fMRI特征与连续唤醒范式相结合，以定位睡眠期间的ncc。具体来说，我将在40名健康受试者的睡眠中获取约1080次醒来时的fMRI-EEG数据，并研究做梦意识存在与不存在的神经相关性（目的1）。我推测，与无梦睡眠相比，高频BOLD振荡——追踪睡眠慢波——在做梦期间会显示出特定后皮层区域的区域减少。在目标2中，我将使用基于高频BOLD功率和常规BOLD振幅的单变量和多变量建模方法来识别特定梦境内容（例如，面孔的存在）和复杂性的ncc。如果实验成功，那么在确定在行为无反应状态下维持意识及其内容的大脑区域方面，将迈出重要的一步。这些结果可以为改善DOC患者的临床护理开辟新的途径，并为麻醉受试者术中意识的评估提供信息。

Multiple studies have shown that some patients who remain behaviorally unresponsive after severe brain damage can modulate their brain activity in response to command. A lack of response to the command- following paradigm in other patients, however, cannot be taken as evidence that consciousness is absent. There is thus an urgent need for neuroimaging tools that are able to diagnose covert consciousness in behaviorally unresponsive subjects without relying on a task. Previous neuroimaging studies of the neural correlates of consciousness (NCCs) have mostly utilized between-state paradigms (e.g., wakefulness vs. sleep) or report-based contrasts, which conflate differences in brain activity supporting consciousness with differences in brain activity supporting behavior or task response. To address these limitations, my sponsor (Dr. Giulio Tononi) has developed a within-state, no-report paradigm that uses serial awakenings to contrast states of consciousness versus unconsciousness during sleep, a physiological unresponsive state. Using high density electroencephalography (EEG), his group has shown that the occurrence of dreaming consciousness during sleep is associated with a reduction of delta activity (sleep slow waves) in a posterior cortical ‘hot zone’ encompassing occipital, parietal and temporal cortices. To proceed towards clinical applications, it is now essential to confirm and extend these findings using combined EEG-fMRI (functional magnetic resonance imaging). To this effect, in an important new development, Dr. Tononi and collaborators have recently shown that it is possible to faithfully track EEG slow wave activity during sleep by means of a high-frequency (~0.17 Hz) blood-oxygenation level dependent (BOLD) oscillation evident in fMRI. This finding provides an unprecedented opportunity to investigate the NCCs during sleep with high spatial resolution, avoiding potential pitfalls of EEG source modeling, and with unrestricted access to subcortical structures. Taking advantage of these new findings, in this project, I propose to combine the novel fMRI signature of sleep slow waves with a serial awakenings paradigm to locate the NCCs during sleep. Specifically, I will acquire fMRI-EEG data during ~1,080 awakenings from sleep across 40 healthy subjects and investigate the neural correlates of the presence versus absence of dreaming consciousness (Aim 1). I hypothesize that high-frequency BOLD oscillation—which tracks sleep slow-waves—will show regional decreases in specific posterior cortical areas during dreaming compared to dreamless sleep. In Aim 2, I will use univariate and multivariate modeling approaches based on high-frequency BOLD power and conventional BOLD amplitude to identify the NCCs of specific dream contents (e.g., presence of faces) and complexity. If successful, the proposed experiments will constitute an important step forward in identifying brain regions that sustain consciousness and its contents during behaviorally unresponsive states. These results can open new avenues to improve clinical care in patients with a DOC and inform the assessment of intraoperative awareness in anesthetized subjects.