Ketamine's Antidepressant Actions: Potential Mechanisms in the Primate Medial Prefrontal Circuits That Represent Aversive Experience.
Ketamine's Antidepressant Actions: Potential Mechanisms in the Primate Medial Prefrontal Circuits That Represent Aversive Experience.
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DOI：
10.1016/j.biopsych.2016.02.014
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发表时间：
2016-05-01
影响因子：
10.6
通讯作者：
Lee D
中科院分区：
文献类型：
--
作者：
Arnsten AF;Murray JD;Seo H;Lee D
人们对N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂氯胺酮(1)快速抗抑郁作用的机制越来越感兴趣。与传统的抗抑郁药物治疗相比，氯胺酮的疗效需要几周时间才能建立起来，而氯胺酮的作用可以在静脉注射后几小时内看到，甚至在鼻腔注射后几分钟内就能看到[2]，并且可以在一次注射后持续几天。在他们对麻醉猴子的功能磁共振成像研究中，Lv等人(3)发现，在功能磁共振成像扫描前18小时肌肉注射氯胺酮降低了与奖励相关的内侧前额叶皮质(MPFC)回路中自发的血氧水平依赖(BOLD)信号波动的相关性，图1A以深蓝色示意地说明了这一点。这一模式特别令人感兴趣，因为在患有严重抑郁障碍的患者中，mPFC回路通常是失调的。特别是，抑郁症患者表现出腹侧mPFC亚膝状体皮质Brodmann区(BA)25(4)的过度激活，而背内侧前扣带回皮质(BA24)对恐惧面孔的激活增加与随后的氯胺酮抗抑郁反应相关[综述在(2)]。因此，发现氯胺酮减少了猴子这些回路中的相关活动，这表明它可能会使抑郁症患者的大脑活动正常化。Lv等人(3)应用图论分析框架来表征氯胺酮诱导的大规模功能网络结构的变化。网络中的节点被定义为分隔的脑区，包括皮质区域和皮质下结构。节点之间的连接由功能连接的强度来定义，功能连接的强度被测量为粗体信号时间序列的相关性，在每个地块内进行空间平均。网络测量显示，氯胺酮导致了小世界架构的拓扑结构的变化，降低了集群和效率。网络中的每个节点以其节点强度为特征，该节点强度是与所有其他节点的功能连通性的平均值。受影响最大的结节表现为结节强度降低；关键脑区
There is increasing interest in the mechanisms underlying the rapid antidepressant actions of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine (1). In contrast to classical antidepressant treatments where efficacy builds over weeks, ketamine’s actions can be seen within hours after intravenous administration, or even within minutes following intranasal administration (2), and can last for several days after a single administration. In their functional magnetic resonance imaging study of anesthetized monkeys, Lv et al.(3) found that intramuscular administration of ketamine 18 hours before the functional magnetic resonance imaging scan reduced the correlations of spontaneous blood oxygen level–dependent (BOLD) signal fluctuations within the medial prefrontal cortex (mPFC) circuits associated with reward, schematically illustrated in Figure 1A in dark blue. This pattern was of particular interest, as mPFC circuits are often dysregulated in patients with major depressive disorder. In particular, depressed patients show overactivation of the ventral mPFC subgenual cortex, Brodmann area (BA) 25 (4), while increased activation of the dorsomedial anterior cingulate cortex (BA24) to fearful faces correlates with subsequent ketamine antidepressant response [reviewed in (2)]. Thus, the finding that ketamine reduced correlated activity in these circuits in monkeys suggests it may normalize brain activity in patients with depression.Lv et al.(3) applied a graph-theoretic analysis framework to characterize ketamine-induced changes in large-scale functional network architecture. Nodes in the network were defined as parcellated brain regions, including cortical areas and subcortical structures. Links between nodes were defined by the strength of functional connectivity, which is measured as the correlation of the BOLD signal time series, spatially averaged within each parcel. Network measures revealed that ketamine induced changes in the topology of the small-world architecture, with reduced clustering and efficiency. Each node in the network was characterized by its nodal strength, which is the mean value of functional connectivity to all other nodes. Most affected nodes showed reductions in nodal strength; key brain regions