Establishing the neural mechanisms responsible for the altered global states of consciousness during anesthesia and dissociating these from other drug-related effects remains a challenge in consciousness research. We investigated differences in brain activity between connectedness and disconnectedness by administering various anesthetics at concentrations designed to render 50% of the subjects unresponsive. One hundred and sixty healthy male subjects were randomized to receive either propofol (1.7 μg/ml; n = 40), dexmedetomidine (1.5 ng/ml; n = 40), sevoflurane (0.9% end-tidal; n = 40), S-ketamine (0.75 μg/ml; n = 20), or saline placebo (n = 20) for 60 min using target-controlled infusions or vaporizer with end-tidal monitoring. Disconnectedness was defined as unresponsiveness to verbal commands probed at 2.5-min intervals and unawareness of external events in a postanesthesia interview. High-resolution positron emission tomography (PET) was used to quantify regional cerebral metabolic rates of glucose (CMR_glu) utilization. Contrasting scans where the subjects were classified as connected and responsive versus disconnected and unresponsive revealed that for all anesthetics, except S-ketamine, the level of thalamic activity differed between these states. A conjunction analysis across the propofol, dexmedetomidine and sevoflurane groups confirmed the thalamus as the primary structure where reduced metabolic activity was related to disconnectedness. Widespread cortical metabolic suppression was observed when these subjects, classified as either connected or disconnected, were compared with the placebo group, suggesting that these findings may represent necessary but alone insufficient mechanisms for the change in the state of consciousness.

SIGNIFICANCE STATEMENT Experimental anesthesia is commonly used in the search for measures of brain function which could distinguish between global states of consciousness. However, most previous studies have not been designed to separate effects related to consciousness from other effects related to drug exposure. We employed a novel study design to disentangle these effects by exposing subjects to predefined EC₅₀ doses of four commonly used anesthetics or saline placebo. We demonstrate that state-related effects are remarkably limited compared with the widespread cortical effects related to drug exposure. In particular, decreased thalamic activity was associated with disconnectedness with all used anesthetics except for S-ketamine.

建立导致麻醉过程中整体意识状态改变的神经机制，并将其与其他药物相关效应分开，仍然是意识研究中的一个挑战。我们通过使用各种麻醉剂来研究连通性和断开性之间大脑活动的差异，麻醉剂的浓度旨在使 50% 的受试者失去反应。160 名健康男性受试者随机接受异丙酚（1.7 μg/ml；n = 40）、右美托咪定（1.5 ng/ml；n = 40）、七氟醚（0.9% 呼气末；n = 40）、S -氯胺酮（0.75 μg/ml；n = 20），或生理盐水安慰剂（n= 20) 使用目标控制输注或带有潮气末监测的蒸发器持续 60 分钟。脱节被定义为对每隔 2.5 分钟探测一次的口头命令无反应，并且在麻醉后访谈中对外部事件不知情。高分辨率正电子发射断层扫描 (PET) 用于量化葡萄糖的区域脑代谢率 (CMR _glu）利用。对比扫描将受试者分类为连接且有反应与断开连接且无反应，结果显示，对于除 S-氯胺酮外的所有麻醉剂，这些状态之间的丘脑活动水平有所不同。异丙酚、右美托咪定和七氟烷组的联合分析证实，丘脑是主要结构，其中代谢活动的减少与断开有关。当这些被分类为有联系或无联系的受试者与安慰剂组进行比较时，观察到广泛的皮质代谢抑制，这表明这些发现可能代表了意识状态改变的必要但单独的​​机制还不够。

意义声明 实验麻醉通常用于寻找可以区分整体意识状态的大脑功能测量方法。然而，大多数先前的研究并未旨在将与意识相关的影响与与药物暴露相关的其他影响分开。我们采用了一种新颖的研究设计，通过将受试者暴露于预定义 EC ₅₀剂量的四种常用麻醉剂或盐水安慰剂来消除这些影响。我们证明，与药物暴露相关的广泛的皮质效应相比，与状态相关的效应非常有限。特别是，丘脑活动减少与除 S-氯胺酮外的所有使用的麻醉剂的断开有关。