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Randomized Controlled Trial
. 2023 Aug 16;13(1):13323.
doi: 10.1038/s41598-023-40099-4.

The effect of ketamine on affective modulation of the startle reflex and its resting-state brain correlates

Zümrüt Duygu Sen #  1   2   3   4 , Tara Chand #  1   2   5   6 , Lena Vera Danyeli  1   2   3 , Vinod Jangir Kumar  7 , Lejla Colic  1   2   4 , Meng Li  1   2   4 , Merve Yemisken  2 , Nooshin Javaheripour  1   2 , Alexander Refisch  1 , Nils Opel  1   4 , Tamar Macharadze  8   9   10 , Moritz Kretzschmar  8 , Esra Ozkan  11 , Matthias Deliano  12   13 , Martin Walter  14   15   16   17   18   19   20
Affiliations
Randomized Controlled Trial

The effect of ketamine on affective modulation of the startle reflex and its resting-state brain correlates

Zümrüt Duygu Sen et al. Sci Rep. .

Erratum in

Abstract

Ketamine is a rapid-acting antidepressant that also influences neural reactivity to affective stimuli. However, the effect of ketamine on behavioral affective reactivity is yet to be elucidated. The affect-modulated startle reflex paradigm (AMSR) allows examining the valence-specific aspects of behavioral affective reactivity. We hypothesized that ketamine alters the modulation of the startle reflex during processing of unpleasant and pleasant stimuli and weakens the resting-state functional connectivity (rsFC) within the modulatory pathway, namely between the centromedial nucleus of the amygdala and nucleus reticularis pontis caudalis. In a randomized, double-blind, placebo-controlled, cross-over study, thirty-two healthy male participants underwent ultra-high field resting-state functional magnetic resonance imaging at 7 T before and 24 h after placebo and S-ketamine infusions. Participants completed the AMSR task at baseline and one day after each infusion. In contrast to our hypothesis, ketamine infusion did not impact startle potentiation during processing of unpleasant stimuli but resulted in diminished startle attenuation during processing of pleasant stimuli. This diminishment significantly correlated with end-of-infusion plasma levels of ketamine and norketamine. Furthermore, ketamine induced a decrease in rsFC within the modulatory startle reflex pathway. The results of this first study on the effect of ketamine on the AMSR suggest that ketamine might attenuate the motivational significance of pleasant stimuli in healthy participants one day after infusion.

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Conflict of interest statement

MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. All other authors report no biomedical financial interests or other potential conflicts of interest.

Figures

Figure 1
Figure 1
T-standardized startle reflex amplitudes for each picture category and session. Pleasant pictures elicited a significantly less startle reflex amplitude relative to unpleasant pictures in the baseline (T = 6.00, padj < 0.001) and post-placebo sessions (T = 3.09, padj = 0.02) but not in post-ketamine session (T = 2.21, padj = 0.21). Compared to neutral pictures, pleasant pictures elicited a less startle reflex amplitude only in the baseline session (T = 3.81, padj = 0.002). Error bars represent ± 1 standard error of the mean.; *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 2
Figure 2
The association between the ketamine-induced change in pleasant modulation (pleasant-neutral) and end-of-infusion plasma levels of ketamine (A) and its metabolite norketamine (B). The shaded area around the line represents the 95% confidence interval.
Figure 3
Figure 3
The effect of treatment on rsFC in modulatory of startle pathways. RsFC in left CMA and PnC pre- and post-ketamine infusion (A) and pre- and post-placebo infusion (B). RsFC in right CMA and PnC pre- and post-ketamine infusion (C) and pre- and post-placebo infusion (D).
See this image and copyright information in PMC

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