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.

Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine

“…During infusion, on the neurometabolic level, no glutamatergic changes were observed, as expected for the investigated region. The lack of immediate glutamatergic modulation is consistent with a recent study that did not find significant changes in Glu, Gln, or Gln/Glu ratio in the pgACC during S-ketamine infusion [38]. This may be due to a very transient increase in Glu that was not captured by our measurement.…”

“…Healthy participants were therefore chosen to allow for investigations without confounding effects of an antidepressant treatment. Furthermore, since both immediate [37,38] and delayed [28,29] brain changes in healthy participants have been already reported in the literature, we expected to observe the hypothesized relationship also in healthy participants. Indeed, a previous study performed in healthy participants showed the association between the effects 1 h and 24 h after infusion [28].…”

“…In contrast to rsFC changes, another study of our group investigated metabolic changes in the pgACC 1 h after infusion and did not observe any significant changes in glutamatergic measures [33]. While the study from Li et al [33] acquired rather sub-acute spectral measures, a recent study investigating changes directly during infusion in healthy volunteers provided further evidence for an absence of immediate changes in Glu or Gln levels in the pgACC [38]. On the level of subjective effects, the psychotomimetic side effects during S-ketamine infusion have also been linked to changes in pgACC rsFC 24 h after administration [31].…”

Neurometabolite changes in response to antidepressant medication: A systematic review of 1H-MRS findings

“…Notably, the change from baseline in Glx over the entire infusion period was not significantly different between treatment groups. Gärtner et al (2022) reported a trend increase in Glu, but no changes in Gln or Gln/Glu 25 min after esketamine infusion compared to a baseline session (∼0.4 mg/kg) in 17 participants.…”

“… Racemic ketamine 0.5 mg/kg n.s. 24 h post- infusion 7 T PRESS pgACC 20 × 20 × 20 Glu, Gln In-house linear combination program = Glu from baseline to post-administration = Gln between baseline and post-administration Gärtner et al (2022) HC N = 16 open-label pre-post design without placebo i.v. Es-ketamine 0.12 mg/kg + 0.25 mg/kg/h n.s.…”