Oxytocin Reduces Subjective Fear in Naturalistic Social Contexts via Enhancing Top-Down Middle Cingulate Amygdala Regulation and Brain-Wide Fear Representations

Accumulating evidence from animal and human studies suggests a fear-regulating potential of the neuropeptide oxytocin (OT), yet the clinical translation into novel interventions for pathological fear requires a behavioral and neurofunctional characterization under close-to-real-life conditions. Here, we combined a naturalistic fMRI-design that elicited strong and immersive fear experience in social and non-social contexts with a preregistered between-subjects randomized double-blind placebo-controlled intranasal OT trial (24 IU, n = 67 healthy men). OT selectively reduced subjective fear in social contexts but not in non-social contexts. On the neural level OT enhanced left middle cingulate cortex (lMCC) activation and its functional connectivity with the contralateral amygdala, with both neural indices significantly and inversely associated with subjective fear following OT. On the network level, OT enhanced communication between the dorsal attention network (DAN) with the fronto-parietal (FPN) and the default-mode network (DMN), and modulated brain-wide communication patterns. Utilizing an independent activity-connectivity neuromarker for fear in naturalistic contexts (CAFE) confirmed that OT attenuated brain-wide fear expressions. Findings indicate an ecologically valid and socially specific fear-reducing effect of OT, highlighting its promise as a treatment option for disorders characterized by excessive fear in social situations.