Acute effects of ketamine on the pregenual anterior cingulate: linking spontaneous activation, functional connectivity, and glutamate metabolism

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.

Keywords: Glutamate; Ketamine; MR Spectroscopy; Resting state fMRI.

Fig. 1

MRS analyses. A Representative spectroscopy voxel placement in the pregenual anterior cingulate cortex (sagittal view). B Representative one-dimensional projections of the 2D JPRESS data: The measured data (blue), the fitted spectrum (red) and the baseline (orange) are shown for the first (left rows; (i)] and second timepoint (right rows, (iv)]. In addition, the individual signal contribution envelope of Glutamate (ii) and (v) and Glutamine (iii) and (vi) is shown at the first and second time point. C Representative two-dimensional JPRESS data: The acquired spectrum (i), the fitted spectrum (ii) and the fit error (residuum, iii) are shown including the signal contributions of glutamate (iv) and glutamine (v). The common and distinct frequency pattern is shown to help disentangle the signal from Glu and Gln

Fig. 2

Spontaneous brain activation during ketamine. Increased activation is shown in red color, decreased activation is shown in blue color. A Activation changes with standard settings for cluster-based inference. B Activation changes with exploratory settings for cluster-based inference

Fig. 3

Altered resting state functional connectivity during ketamine of the pgACC seed region. Increased activation is shown in red color, decreased activation is shown in blue color. A Activation changes with standard settings for cluster-based inference. B Activation changes with exploratory settings for cluster-based inference

Fig. 4

Relationship between changes in pgACC activation and metabolite levels. A changes in Gln levels and B changes in Gln/Glu levels

Fig. 5

Relationship between changes in pgACC functional connectivity, activation, and metabolite levels. A Relationship between pgACC activation and pgACC-aMCC rsFC. B Relationship between Gln changes and pgACC-aMCC rsFC