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Abstract:
Background: Antidepressants are thought to alter affective processing prior to and underlie the antidepressant effects [1]. Previous studies have shown that ketamine influences the affective processing of both patients with major depression disorder [2], [3] and healthy individuals [4]. Affect-modulated startle reflex (AMSR) paradigm allows for examining the valence-specific aspects of affective reactivity. The startle reflex is a motor response to an unexpected and intense stimulus, characterized by rapid muscle contractions intending to protect the body against an attack or enable the escape response. Even though the startle reflex is stereotypical, the magnitude of the reflex is variable and reflects the state of the organism and varies as a function of the affective state [5]. The brainstem (i.e., nucleus reticularis pontis caudalis PcN) and the centromedial amygdala (CeA) play a key role in integrating valence information into differential startle magnitude, and recent advances in neuroimaging enabled to highlight in AMSR also in humans [6]. Previously it has been shown that the intake of serotonin re-uptake blockers reinstates the typical affect-modulated startle reflex in MDD patients [7] and reduces the unpleasant stimuli induced affect-modulation in healthy participants [8]. However, the effect of ketamine on AMSR remained to be elucidated. The current work explores the impact of a single dose of S-Ketamine administration on the affective modulation of the startle reflex using multimodal measurements (EMG, fMRI).
Methods: In a randomized, double-blind, placebo-controlled, cross-over study (SFB779/A06), thirty-five healthy male subjects (mean age ± standard deviation (SD)=25.08 ± 4.18 years) were scanned with 7T high-field functional MRI, both before and one day after ketamine or placebo infusions. Additionally, subjects completed the AMSR task at baseline and one day after an infusion. The blood samples from the non-infusing arm vein were collected at 8, 13, and 48 minutes after the start of the infusion, and the Ketamine and Ketamine Metabolites (norketamine, HNK) plasma levels were obtained.
Results: We found no significant difference in unpleasant modulation between the baseline session and one day after ketamine or placebo infusion; however, there was a decrease in positive attenuation one day after ketamine infusion compared to the baseline session, which was significantly correlated with end-of-infusion plasma levels of ketamine and its metabolites norketamine. Further, there was a significant decrease in rsFC between PnC to CeA after ketamine compared to the placebo session.
Conclusion: In summary, a single dose of s-ketamine administration leads to pleasant modulation of AMSR and decreases the rsFC within the modulatory pathway of AMSR, which may help to understand drug action mechanisms in psychiatric disorders with atypical AMSR patterns. To brighten the path of understanding the effect of ketamine on affective reactivity, future studies are advised to have a larger sample size, including both genders and patients with atypical AMSR patterns.
