Nx4 attenuated stress-induced activity of the anterior cingulate cortex—A post-hoc analysis of a randomized placebo-controlled crossover trial

OBJECTIVE: Stress-related symptoms are associated with significant health and economic burden. Several studies suggest Nx4 for the pharmacological management of the stress response and investigated the underlying neural processes. Here we hypothesized that Nx4 can directly affect the stress response in a predefined stress network, including the anterior cingulate cortex (ACC), which is linked to various stress-related symptoms in patients. METHODS: In a randomized, placebo-controlled, double-blind, crossover trial, 39 healthy males took a single dose of placebo or Nx4. Psychosocial stress was induced by the ScanSTRESS paradigm inside an MRI scanner, and stress network activation was analyzed in brain regions defined a priori. RESULTS: Using the placebo data only, we could validate the activation of a distinct neural stress pattern by the ScanSTRESS paradigm. For Nx4, we provide evidence of an attenuating effect on this stress response. A statistically significant reduction in differential stress-induced activation in the right supracallosal ACC was observed for the rotation stress task of the ScanSTRESS paradigm. The results add to previously published results of Nx4 effects on emotion regulation. CONCLUSIONS: Our results strengthen the hypothesis that Nx4 modulates the stress response by reducing the activation in parts of the neural stress network, particularly in the ACC

Association among childhood adversity and susceptibility to interference during varying salience: two studies in healthy males

Childhood adversity, a prevalent experience, is related to a higher risk for externalizing and internalizing psychopathology. Alterations in the development of cognitive processes, for example in the attention-interference domain may link childhood adversity and psychopathology. Interfering stimuli can vary in their salience, i.e. ability to capture attentional focus, and valence. However, it is not known if interference by salience or valence is associated with self-reported adversity. In two independent study samples of healthy men (Study 1: n = 44; mean age [standard deviation (SD)] = 25.9 [3.4] years; Study 2: n = 37; 43.5 [9.7] years) we used the attention modulation task (AMT) that probed interference by two attention-modulating conditions, salience and valence separately across repeated target stimuli. The AMT measures the effects of visual distractors (pictures) on the performance of auditory discrimination tasks (target stimuli). We hypothesized that participants reporting higher levels of childhood adversity, measured with the childhood trauma questionnaire, would show sustained interference in trials with lower salience. Due to conflicting reports on the valence-modulation, we tested the valence condition in an exploratory manner. Linear mixed models revealed an interaction between reported childhood adversity and the salience condition across tone presentations in both study samples (Sample 1: p = .03; Sample 2: p = .04), while there were no effects for the valence condition across both studies. Our study suggests that higher self-reported childhood adversity is related to faster processing of target cues during high salience, but slower during low salience conditions. These results hint to the mechanisms linking childhood adversity and psychopathological symptoms in the attentional domain

fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial

Social stress contributes to major societal health burdens, such as anxiety disorders and nervousness. Nx4 has been found to modulate stress responses. We investigated whether dampening of such responses is associated with neuronal correlates in brain regions involved in stress and anxiety. In a randomized, placebo-controlled, double-blind, cross-over trial, 39 healthy males took a single dose (three tablets) of either placebo or Nx4, 40 to 60 minutes before an fMRI scan session. We here report on drug effects on amygdala responses during a face-matching task, which was performed during a complex test battery further including resting-state brain connectivity and a social stress experiment. The first of the Primary Outcomes, defined in a hierarchical order, concerned reduced amygdala effects after intake of verum compared to placebo. We found a statistically significant reduction in differential activations in the left amygdala for the contrast negative faces versus forms during verum versus placebo condition. Our results indicate that effects of Nx4 can be monitored in the brain. Previously noted effects on stress responses may thus be modulated by affective brain regions including the amygdala