OXYTOCIN MODULATES SOCIAL SALIENCE NETWORK CONNECTIVITY IN AUTISM

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental condition featuring marked social difficulties. Preclinical rodent studies implicate the neuropeptide oxytocin as a key modulator of social behavior; yet its clinical efficacy in ASD remains inconsistent, highlighting a major translational gap. The social salience network (SSN), a rodent-derived framework supporting socio-sensory integration, has been strongly linked to oxytocinergic function (Patwardhan & Choe, 2025, ProgNeurobiol). Indeed, mice lacking the ASD risk gene Cntnap2, exhibit reduced sociability and weakened intra-SSN functional connectivity (FC), both rescued by oxytocin administration (Choe et al., 2022, Neuron); however, its conservation in humans remains unestablished. To address this, we re-examined a resting-state FC dataset (Alaerts et al., 2019, BiolPsych CNNI) of adult males with ASD receiving intranasal oxytocin (n=8; 24 IU) or placebo (n=12). We hypothesise that 1) autistic individuals exhibit aberrant SSN FC, and 2) intranasal oxytocin stimulates SSN nodes to rescue SSN connectivity.
Baseline salivary oxytocin positively correlated with SSN-wide FC (r=0.522, p=0.032). Moreover, a negative correlation was observed in ventromedial prefrontal cortex (vmPFC)-amygdala coupling and social responsiveness scores (r=-0.461). Oxytocin administration did not alter global SSN FC but significantly increased intra-SSN FC (most notably vmPFC-paraventricular nucleus (PVN), and nucleus accumbens (NAc)-somatosensory cortex, p<0.01). Subsequent data-driven independent component analysis (K=20) identified one network (IC13) negatively associated with social trait expression (r=-0.591), and overlapping with SSN regions (PVN, NAc and somatosensory cortex). Together, these findings provide convergent evidence for SSN conservation, relation to social trait expression, and its modulation by oxytocin in ASD.