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. Trial registration: NCT02602275; ClinicalTrials.gov