Clinical research into consciousness has long focused on cortical macroscopic networks and their disruption in pathological or pharmacological consciousness perturbation. Despite demonstrating diagnostic utility in disorders of consciousness (DoC) and monitoring anesthetic depth, these cortico-centric approaches have been unable to characterize which neurochemical systems may underpin consciousness alterations. Instead, preclinical experiments have long implicated the dopaminergic ventral tegmental area (VTA) in the brainstem. Despite dopaminergic agonist efficacy in DoC patients equally pointing to dopamine, the VTA has not been studied in human perturbed consciousness. To bridge this translational gap between preclinical subcortical and clinical cortico-centric perspectives, we assessed functional connectivity changes of a histologically characterized VTA using functional MRI recordings of pharmacologically (propofol sedation) and pathologically perturbed consciousness (DoC patients). Both cohorts demonstrated VTA disconnection from the precuneus and posterior cingulate (PCu/PCC), a main default mode network node widely implicated in consciousness. Strikingly, the stronger VTA–PCu/PCC connectivity was, the more the PCu/PCC functional connectome resembled its awake configuration, suggesting a possible neuromodulatory relationship. VTA-PCu/PCC connectivity increased toward healthy control levels only in DoC patients who behaviorally improved at follow-up assessment. To test whether VTA–PCu/PCC connectivity can be affected by a dopaminergic agonist, we demonstrated in a separate set of traumatic brain injury patients without DoC that methylphenidate significantly increased this connectivity. Together, our results characterize an in vivo dopaminergic connectivity deficit common to reversible and chronic consciousness perturbation. This noninvasive assessment of the dopaminergic system bridges preclinical and clinical work, associating dopaminergic VTA function with macroscopic network alterations, thereby elucidating a critical aspect of brainstem–cortical interplay for consciousness.

意识的临床研究长期以来一直集中在皮质宏观网络及其对病理或药理学意识扰动的破坏。尽管证明了在意识障碍 (DoC) 和监测麻醉深度方面的诊断效用，但这些以皮质为中心的方法无法确定哪些神经化学系统可能支持意识改变。相反，临床前实验长期以来一直涉及脑干中的多巴胺能腹侧被盖区 (VTA)。尽管多巴胺能激动剂在 DoC 患者中的功效同样指向多巴胺，但尚未在人类扰动意识中研究 VTA。为了弥合临床前皮质下和临床皮质中心观点之间的转化差距，我们使用药理学（丙泊酚镇静）和病理性意识障碍（DoC 患者）的功能性 MRI 记录评估了组织学特征 VTA 的功能连接性变化。两个队列都显示 VTA 与楔前叶和后扣带回 (PCu/PCC) 断开连接，这是一个广泛涉及意识的主要默认模式网络节点。引人注目的是，VTA-PCu/PCC 连接性越强，PCu/PCC 功能连接组越类似于其清醒配置，这表明可能存在神经调节关系。只有在随访评估中行为改善的 DoC 患者中，VTA-PCu/PCC 连接性才向健康控制水平增加。为了测试 VTA-PCu/PCC 连接是否会受到多巴胺能激动剂的影响，我们在一组单独的没有 DoC 的创伤性脑损伤患者中证明，哌醋甲酯显着增加了这种连接性。总之，我们的结果表征了可逆和慢性意识扰动常见的体内多巴胺能连接缺陷。这种对多巴胺能系统的无创评估将临床前和临床工作联系起来，将多巴胺能 VTA 功能与宏观网络改变联系起来，从而阐明脑干-皮质相互作用对意识的一个关键方面。