Abstract
Ketamine exerts its rapid antidepressant effects via modulation of the glutamatergic system. While numerous imaging studies have investigated the effects of ketamine on a functional macroscopic brain level, it remains unclear how altered glutamate metabolism and changes in brain function are linked. To shed light on this topic we here conducted a multimodal imaging study in healthy volunteers (N = 23) using resting state fMRI and proton (1H) magnetic resonance spectroscopy (MRS) to investigate linkage between metabolic and functional brain changes induced by ketamine. Subjects were investigated before and during an intravenous ketamine infusion. The MRS voxel was placed in the pregenual anterior cingulate cortex (pgACC), as this region has been repeatedly shown to be involved in ketamine’s effects. Our results showed functional connectivity changes from the pgACC to the right frontal pole and anterior mid cingulate cortex (aMCC). Absolute glutamate and glutamine concentrations in the pgACC did not differ significantly from baseline. However, we found that stronger pgACC activation during ketamine was linked to lower glutamine concentration in this region. Furthermore, reduced functional connectivity between pgACC and aMCC was related to increased pgACC activation and reduced glutamine. Our results thereby demonstrate how multimodal investigations in a single brain region could help to advance our understanding of the association between metabolic and functional changes.
Highlights
Over the last 2 decades, ketamine has become an important research tool to investigate rapid antidepressant mechanisms of action [1]
In this multimodal imaging study, we investigated acute effects of ketamine on spontaneous brain activation, functional connectivity, and metabolism in the glutamatergic system
We focused our analysis on the pregenual anterior cingulate cortex because ketamine-induced brain changes have been repeatedly reported in this region, and the specific receptor profile of this region suggests that the antidepressant mechanism of ketamine might be linked to metabolic changes in this region
Summary
Over the last 2 decades, ketamine has become an important research tool to investigate rapid antidepressant mechanisms of action [1]. The molecular and systemic changes ketamine induces in the central nervous system are notoriously complex and it is a matter of ongoing research to pin down which of these changes bring forward the antidepressant effects. A considerable amount of imaging studies investigated the effects of ketamine on functional brain activations and networks in humans [5]. The results of this research have not yet converged, and no clear antidepressant mechanism of action has been identified, some interesting themes and involved brain regions, such as the anterior cingulate cortex [6], have emerged. Evidence remains sparse how ketamineinduced molecular changes in the glutamatergic system are linked to macroscopic functional activation and network changes in the human brain
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