Negative emotionality shapes the modulatory effects of ketamine and lamotrigine in subregions of the anterior cingulate cortex.

Ketamine reduces spontaneous brain activity in three subregions of the anterior cingulate cortex (ACC) during administration in healthy people. Lamotrigine, which inhibits glutamate release, attenuates this effect only in the ventral ACC subregions, suggesting glutamate involvement there. ACC activity returns to baseline 24 hours later, though group differences persist between the lamotrigine and ketamine groups. Trait negative emotionality is closely linked to activity changes in the subgenual ACC after ketamine. These findings clarify how ketamine affects different ACC subregions and may relate to its antidepressant mechanisms.

Study at a glance

Abstract

Neuroimaging studies have identified the anterior cingulate cortex (ACC) as one of the major targets of ketamine in the human brain, which may be related to ketamine's antidepressant (AD) mechanisms of action. However, due to different methodological approaches, different investigated populations, and varying measurement timepoints, results are not consistent, and the functional significance of the observed brain changes remains a matter of open debate. Inhibition of glutamate release during acute ketamine administration by lamotrigine provides the opportunity to gain additional insight into the functional significance of ketamine-induced brain changes. Furthermore, the assessment of trait negative emotionality holds promise to link findings in healthy participants to potential AD mechanisms of ketamine. In this double-blind, placebo-controlled, randomized, single dose, parallel-group study, we collected resting-state fMRI data before, during, and 24 h after ketamine administration in a sample of 75 healthy male and female participants who were randomly allocated to one of three treatment conditions (ketamine, ketamine with lamotrigine pre- treatment, placebo). Spontaneous brain activity was extracted from two ventral and one dorsal subregions of the ACC. Our results showed activity decreases during the administration of ketamine in all three ACC subregions. However, only in the ventral subregions of the ACC this effect was attenuated by lamotrigine. 24 h after administration, ACC activity returned to baseline levels, but group differences were observed between the lamotrigine and the ketamine group. Trait negative emotionality was closely linked to activity changes in the subgenual ACC after ketamine administration. These results contribute to an understanding of the functional significance of ketamine effects in different subregions of the ACC by combining an approach to modulate glutamate release with the assessment of multiple timepoints and associations with trait negative emotionality in healthy participants.