Abstract
Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.
Highlights
Based on the increasing evidence of glutamate-modulating agents having strong and rapid antidepressant properties [1,2], the NMDA receptor antagonist ketamine has been firmly established as a research tool for the investigation of the neurobiology of the glutamatergic system in major depressive disorder (MDD) and novel molecular targets associated with rapid onset of antidepressant drug action [3,4,5,6,7]
Default mode network At the whole brain level, we observed a focal decrease in functional connectivity between the left and right posterior cingulate cortex (PCC) seed region and the bilateral dorsal medial prefrontal cortex (DMPFC), the pregenual anterior cingulate (PACC) and the medioprefrontal cortex (MPFC) following ketamine administration (n = 17, paired t-test: puncorr,0.001, extent threshold of k.15, resulting in a cluster-level pcorr,0.05; Fig. 3)
The difference in mean Fisher z-transformed correlation values extracted from the corresponding seed (PCC) and projection region in the bilateral DMPFC and MPFC/pregenual anterior cingulate cortex (PACC) was significant for the ketamine condition (n = 17, paired t-test: p,0.001), with no change after placebo administration (Fig. 3 and 5)
Summary
Based on the increasing evidence of glutamate-modulating agents having strong and rapid antidepressant properties [1,2], the NMDA receptor antagonist ketamine has been firmly established as a research tool for the investigation of the neurobiology of the glutamatergic system in major depressive disorder (MDD) and novel molecular targets associated with rapid onset of antidepressant drug action [3,4,5,6,7]. Since glutamate is the most abundant and major excitatory neurotransmitter in the human brain, pathophysiological changes in glutamatergic signaling associated with chronic stress exposure and disease progression emerge as a powerful explanatory framework to integrate the observed findings into a comprehensive disease model and provide novel molecular targets for therapeutic interventions [1] This notion is further supported by several findings at different levels of neuronal organization, demonstrating beneficial effects of ketamine on glutamatergic signaling [24,25,26,27,28], AMPA-to-NMDA-receptor throughput [11,29], intracellular signaling [8,10], and neurotrophic factors [30,31]. Those findings indicate that ketamine may have a stimulating effect on overall glutamateglutamine-cycling, which is supposed to be reduced in MDD [12,17,32]
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