At the head and heart of oxytocin: An RCT investigating stress-regulatory neural and cardiac effects of chronic administration in children with autism

Intranasal administration of oxytocin is increasingly explored as a new approach to facilitate social development and reduce disability associated with a diagnosis of autism spectrum disorder (ASD). In light of the growing number of trials, it is crucial to gain deeper insights into the neuroplastic changes that are induced from multiple-dose, chronic use of oxytocin, over a course of weeks. To date however, the neuromodulatory impact of oxytocin in the pediatric brains remains unknown. Here, we present a double-blind, randomized, placebo-controlled pharmaco-neuroimaging trial examining the neural effects of a four-week intranasal oxytocin administration regime (12 IU, twice daily) in pre-pubertal school-aged children with ASD (8-12 years, 45 boys, 12 girls). Resting-state fMRI scanning and simultaneous, in-scanner heart rate measurements were assessed before, immediately after and four weeks after the nasal spray administration period. Four weeks of chronic oxytocin administration in children with ASD induced significant reductions in intrinsic functional connectivity between amygdala and orbitofrontal cortex, particularly at the four-week follow-up session, thereby replicating prior observations of neuromodulatory changes in the adult brain. Notably, the observed reductions in amygdala-orbitofrontal connectivity were associated with improved autonomic stress-regulation, indexed by increased high-frequency heart rate variability. Further, oxytocin-related neural and cardiac autonomic effects were significantly modulated by epigenetic modifications of the oxytocin receptor gene, indicating that oxytocin-induced stress-regulatory effects were more pronounced in children with reduced epigenetic methylation, and thus higher oxytocin receptor expression. Finally, whole-brain exploratory functional connectivity analyses also revealed an overall oxytocin-induced enhancing effect on amygdala coupling to regions of the salience network (insula, anterior cingulate cortex), likely reflective of oxytocin-induced (social) salience effects. Together, these observations provide initial insights into the stress-regulatory neural and cardiac effects induced by chronic oxytocin administration in children with ASD, and point toward important epigenetic modulators that may explain inter-individual variations in oxytocin-induced responses.