Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment.
Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment.
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DOI：
10.1016/j.bpsc.2017.04.006
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Mathalon DH
中科院分区：
文献类型：
--
作者：
Abdallah CG;Averill CL;Salas R;Averill LA;Baldwin PR;Krystal JH;Mathew SJ;Mathalon DH
前额叶全局脑连接与全局信号回归（GBCr）被认为是抑郁症的一个强大的生物标志物，并与氯胺酮的作用机制有关。在这里，我们调查了难治性抑郁症（TRD）在基线和治疗后的前额叶GBCr。然后，我们在健康受试者中进行了一系列药理学挑战，以研究GBCr的谷氨酸神经传递相关性。在研究A中，我们使用功能性磁共振成像（fMRI）比较22例TRD和29例健康对照者的GBCr。然后，我们检查了氯胺酮和咪达唑仑对TRD患者治疗后24小时GBCr的影响。在研究B中，我们在18名健康受试者中获得了重复的fMRI，以确定拉莫三嗪（谷氨酸释放抑制剂），氯胺酮和拉莫三嗪与氯胺酮相互作用的影响。在研究A中，与健康对照组相比，TRD患者的背内侧和背外侧前额叶GBCr显著降低。在TRD患者中，氯胺酮（效应量= 1.0 [0.3 1.8]）给药后24小时，改变簇中的GBCr显著增加，但咪达唑仑（效应量= 0.5 [-0.6 1. 3]）未增加。在研究B中，口服拉莫三嗪降低了给药后2小时的GBCr，而氯胺酮在输注期间增加了内侧前额叶GBCr。拉莫三嗪显著降低氯胺酮诱导的GBCr峰。探索性分析显示，健康受试者中TRD的腹侧前额叶GBCr升高，氯胺酮输注期间腹侧前额叶GBCr显著降低。这项研究首次复制了氯胺酮使抑郁相关的前额叶连接障碍正常化的能力。它还提供了间接证据，表明这些作用可能是由氯胺酮增强谷氨酸神经传递的能力引发的。
Prefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression, and was associated with ketamine’s mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr. In study A, we used functional magnetic resonance imaging (fMRI) to compare GBCr between 22 TRD and 29 healthy control. Then, we examined the effects of ketamine and midazolam on GBCr in TRD patients 24h post-treatment. In study B, we acquired repeated fMRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction. In study A, TRD patients showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared to healthy control. In TRD patients, GBCr in the altered clusters significantly increased 24h following ketamine (effect size = 1.0 [0.3 1.8]), but not midazolam (effect size = 0.5 [−0.6 1.3]). In study B, oral lamotrigine reduced GBCr 2h post-administration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects. This study provides first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission.
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