At the head and heart of oxytocin’s stress-regulatory neural and cardiac effects: a chronic administration RCT 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, oxytocin’s chronic neuromodulatory impact in the pediatric brain 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’s 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’s (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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial EudraCT 2018-000769-35 ### Funding Statement This research was supported by an internal C1 and Small Research Equipment fund of the KU Leuven (ELG-D2857-C14/17/102; KA/20/080), a Doctor Gustave Delport fund of the King Baudouin Foundation, the Branco Weiss fellowship of the Society in Science - ETH Zurich, an Excellence of Science EOS grant (G0E8718N) granted to KA or BB. JP is supported by the Marguerite-Marie Delacroix foundation and a postdoctoral fellowship of the Flanders Fund for Scientific Research (FWO; 1257621N). SVDD is supported by a FWO postdoctoral fellowship (12C9723N). MM is supported by a KUL postdoctoral mandate. ME is supported by an FWO aspirant fundamental fellowship (11N1222N). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee Research UZ / KU Leuven at KU Leuven gave ethical approval for this work (S61358) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors