Mounting evidence supports the rapid antidepressant efficacy of the N-methyl-D-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven in part by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful antidepressant treatment. This study aimed to examine whether task-based sgACC activity was higher in patients with MDD compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol at baseline and following a 40 min infusion of ketamine (0.5 mg/kg). Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its antidepressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.

中文翻译：

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氯胺酮可正常化抑郁症中的舌下扣带回皮层活动过度。

越来越多的证据支持N-甲基-D-天冬氨酸受体拮抗剂氯胺酮对重度抑郁症（MDD）的快速抗抑郁功效；然而，其神经作用机制仍知之甚少。休息期间亚属前扣带回皮层（sgACC）过度活跃一直与MDD的病理生理有关，可能部分由过度海马向sgACC发出的谷氨酸能传递所致。sgACC活性的降低与成功的抗抑郁药治疗有关。这项研究旨在检查与对照组相比，MDD患者基于任务的sgACC活性是否更高，并确定单剂量氯胺酮是否改变了该活性。在研究1中，MDD（N = 28）和健康对照（N = 20）的患者使用已建立的激励处理任务完成了基于任务的功能磁共振成像。在研究2中，第二批MDD患者（N = 14）在基线和输注氯胺酮40分钟（0.5 mg / kg）后完成了相同的扫描方案。sgACC的基于任务的激活通过种子驱动的分析进行了评估，评估了治疗前后治疗组的差异和变化。与对照组相比，MDD患者显示出更高的sgACC激活对正向和负向金钱刺激的作用，分别与快感缺乏症和焦虑症相关。此外，MDD患者在海马和sgACC之间具有更高的静息状态功能连接性，与sgACC过度激活相关，具有积极的诱因，但没有消极的诱因。最后，氯胺酮将sgACC过度激活降低为正向诱因，而不是负向激励。这些发现表明，氯胺酮通过迅速减弱异常的sgACC对阳性诱因的过度反应而发挥其抗抑郁功效的神经机制。