Intranasal oxytocin modulates the social salience network in adult men with autism

Background: Autism spectrum disorder is a prevalent neurodevelopmental condition featuring marked social difficulties. Oxytocin supplementation shows promising therapeutic efficacy in alleviating autism-like traits in rodent models, but clinical effects in humans remain inconsistent. The rodent-derived social salience network (SSN) comprises several oxytocin-modulated brain regions implicated in social behavior, but its conservation has not been established in humans. Here we assess, for the first time, functional connectivity (FC) within a homologous human SSN in autistic men to examine its relationship with behavioral traits and modulation by oxytocin. Methods: The human SSN atlas was collated from open-access cortical and subcortical parcellations, and used to retrospectively analyze a resting-state fMRI dataset of adult men with autism from a previously published, randomized, placebo-controlled oxytocin trial. SSN-wide and sub-network ROI-to-ROI FC correlations with social trait expression and salivary oxytocin concentrations were performed at baseline and post-administration. Treatment specific outcomes on FC were calculated using ANCOVA. Results: We observed SSN sub-network FC correlations with social and repetitive behavioral scores and identified strong oxytocin sensitivity of nucleus accumbens-somatosensory and paraventricular nucleus-somatosensory circuits at baseline. Following nasal spray administration, a strengthening of amygdala-somatosensory circuit was detected as the largest oxytocin-induced FC shift. Notably, baseline connectivity within this circuit strongly predicted treatment response, with individuals having lower baseline FC showing greater post-treatment FC. Conclusions: These findings provide first evidence for clinical relevance of the SSN in humans with autism and highlight circuits that may represent promising biomarkers for predicting oxytocin responsiveness.