Exploring Functional Connectivity in Anxiety: The Role of the Hippocampus, Insula, and Amygdala During a Ketamine Infusion

Background Ketamine, an NMDA receptor antagonist, is used in treating psychiatric disorders. While ketamine may induce anxiety-like symptoms acutely, its potential of long-term anxiety alleviation has been discussed (1). Key brain regions implicated in ketamine’s effects include the hippocampus, insula, amygdala, and anterior cingulate cortex (ACC) (2,3), each crucial for emotional processing and fear regulation (4). The hippocampus exerts different functions along its longitudinal axis, with the anterior hippocampus being involved in emotional processing and fear regulation, the posterior hippocampus in memory-retrieval. These functional differences are reflected in different connectivity patterns, with the anterior hippocampus linked to anterior regions, whereas the posterior hippocampus is connecting to posterior areas (5,6). Moreover, our group has recently shown the anterior hippocampus’s role in anxiety-related experiences during a ketamine infusion (7). Aims & Objectives This study aimed to investigate ketamine’s impact on functional connectivity in the aforementioned areas and whether connectivity correlates with the experienced anxiety during infusion. Method Thirty-one healthy volunteers (17 females, 23.2 ± 2.9 years) received in a single-blind, crossover manner either 0.5 mg/kg ketamine or a saline solution four hours before an MRI scan. An anxiety-score was extracted of the 5-Dimensional Altered State of Consciousness questionnaire, completed immediately post-infusion. Functional connectivity was estimated for the anterior hippocampus with the anterior insula (AI), the amygdala with the ACC and the posterior hippocampus with the posterior cingulate cortex (PCC). Differences in functional connectivity between the ketamine and placebo condition were assessed using repeated measures ANOVA. Partial correlations between anxiety scores and functional connectivity were calculated, adjusted for gender. Results A positive correlation between the anxiety-score and the functional connectivity of the anterior hippocampus and the AI (r = 0.449, p = 0.013) as well as of the amygdala and the ACC (r = 0.393, p = 0.032) was observed in the ketamine condition. No such relation emerged between the posterior hippocampus and PCC nor between any region in the placebo condition. Similarly, no significant changes in functional connectivity between the ketamine and the placebo condition were observed. Discussion & Conclusions These correlations suggest the involvement of the anterior hippocampus, AI, amygdala and ACC in the experience of anxiety during a ketamine infusion. These regions are believed to be crucial for fear memory retrieval (8) and reconsolidation (9). Fear memory retrieval is required to destabilize fear memory (10), facilitating fear extinction, which is hypothesized to be enhanced by ketamine (11). Therefore, higher functional connectivity could be associated with enhanced fear processing during the infusion, supporting ketamine’s role in modulating fear processing. While the results are limited as they don’t remain significant after correction for multiple comparison, our results provide initial evidence between anxiety-related experiences and functional connectivity in the anterior hippocampus and AI. Increasing the sample size might enhance the robustness of these findings. Moreover, the MRI scans were conducted four hours post-infusion and might have missed acute changes in functional connectivity. In conclusion, our results support ketamine’s potential for modulating fear memory and anxiety, further studies are required to explore ketamine’s impact on fear extinction.