Discussion
depressive, DLPFC, depressive symptoms
To our knowledge, this is the first study to investigate not only acute and delayed effects of a single dose of ketamine on CBF, but also consequences of modulated glutamate release via lamotrigine pretreatment. Our findings demonstrate region- and time- specific effects of ketamine administration per se as well as of lamotrigine pretreatment. Compared to placebo, acute ketamine administration was associated with a higher perfusion in IFG and DLPFC, but not in ACC, amygdala, hippocampus, and thalamus. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine’s effect on perfusion. Perfusion increases both in IFG and DLPFC occurred in the right, but not in the left hemisphere. At the delayed time point, there was no longer an effect of ketamine administration per se on IFG perfusion, while pretreatment with lamotrigine was associated with lower perfusion. Ketamine-induced CBF changes in the investigated regions were associated with mood, but not with dissociative and psychotomimetic phenomena nor with plasma concentration of ketamine.Our findings regarding increased perfusion during ketamine administration are partly consistent with results of prior studies. However, while previous reports included widespread increases in CBF in prefrontal and cingulate cortices as well as in subcortical regions such as thalamus [Results indicated large effects of acute ketamine administration on IFG perfusion. IFG and adjacent anterior insula (AI) are part of the salience network and have been proposed as a hub that ensures dynamic switching between external and internal control modalities [Ketamine administration also led to CBF increases in the DLPFC, a part of the cognitive control network and crucially involved in executive functions and emotion regulation [Administration of ketamine results in a surge of glutamate [Results of our previous study in depressive patients also demonstrated an increase in thalamus perfusion 24 h after ketamine administration, that was associated with greater improvement of depressive symptoms [There are several limitations to this study. Previous reports described strongest effects of ketamine soon after beginning of the infusion [To conclude, we here provide first evidence of region- and time- specific effects of modulated glutamate release on perfusion. The increase of perfusion in IFG and DLPFC during acute ketamine administration was abolished by inhibition of glutamate release via pretreatment with lamotrigine, which furthermore led to decreased IFG perfusion 24 h later. These findings underscore the idea that regionally selective patterns of CBF changes reflect proximate effects of modulated glutamate release on neuronal activity. Furthermore, region- specific sustained effects indicate both a swift restoration of disturbed homeostasis in DLPFC as well changes occurring beyond the immediate effects on glutamate signaling in IFG.