Discussion
MDD, mental disorders, anxiety
REGRESSION, DRUG ACTION, DISORDERS
In this placebo-controlled cross-over study in healthy male participants, we showed that a single S-ketamine administration resulted in an atypical pattern of the AMSR one day after infusion, mainly driven by the decreased modulation of the startle reflex by pleasant pictures compared to baseline. While an attenuated startle reflex amplitude was seen during the presentation of pleasant pictures relative to neutral pictures at baseline, this pattern was abolished 24 h after ketamine infusion. The decrease in pleasant modulation showed a positive correlation with the end-of-infusion plasma levels of ketamine's metabolite norketamine, supporting that this effect was induced by the ketamine administration. Based on the recent literature highlighting the role of the PnC and CMA in the AMSR in humansIn the current study, the pleasant modulation was attenuated one day after ketamine administration, while there was a positive correlation with the plasma levels of norketamine. Another antidepressant agent that abolishes the pleasant modulation is agomelatine, a melatonergic receptor agonist and 5HT2C receptor antagonistIn line with our hypothesis, we found that rsFC in the modulatory pathways of the startle, namely between left PnC and left CMA, decreased 24 h after ketamine administration. This effect was also evident bilaterally, though not statistically significant. Moreover, the association between ketamine-induced decrease in rsFC and plasma norketamine levels showed a rough negative trend. The PnC receives information from cochlear root neurons and serves as a hub that connects primary and modulatory startle reflex pathwaysAlthough we could show a decrease in the rsFC within the modulatory pathway after ketamine application, there was no ketamine effect on unpleasant modulation in the AMSR task. As we discussed above, it is plausible that ketamine might show no effect on the motivational processing of unpleasant stimuli, which might be explained by its pharmacodynamic properties. However, our results bear an interesting parallel to other studies in the literature that reported changes in neuronal processing of emotional stimuli after ketamine without a ketamine effect on task performanceSeveral limitations need to be mentioned. Firstly, startle responses were induced by speakers instead of headphones, and the amplitude of the stimulus ranged between 85 to 95 dB(A). Based on the high rate of missing startle responses, it is possible that we might not have reliably induced startle responses. However, the probability of a startle response did not differ between picture categories and sessions (see STable Of note, this study relies on the standard confounding regression of physiological noise in the fMRI data. However, brainstem nuclei are more prone to be affected by motion and physiological noise (respiration and pulse-oxygen/heart rate). Recording these brainstem-specific physiological signals would help in future studies to delineate a more reliable view of the presented results. Lastly, despite the study being double-blind, many participants were able to distinguish between the ketamine and placebo infusions due to the evident subjective effects produced by ketamine. This situation highlights the challenge of maintaining complete blinding when studying substances with distinct psychoactive properties.In conclusion, a single S-ketamine infusion decreased the rsFC within the modulatory pathway of the AMSR and pleasant modulation of the AMSR without an effect on unpleasant modulation. These results indicate an effect of ketamine on motivational and affective processing in healthy participants. This may help to understand the mechanism of drug action not only in MDD but also in many other mental disorders, such as addiction and anxiety disorders, which show an atypical AMSR pattern