Long-term effects of oxytocin on fronto-amygdala connectivity in autism: A randomized placebo-controlled trial

Autism spectrum disorders (ASD) are characterized by impairments in social interaction and repetitive and restricted behaviors. To date, no pharmacological treatment exists targeting the core symptoms of ASD, yet the pharmacological use of the neuropeptide oxytocin (OT) has gained interest from the research community to explore its potential for elevating social deficits in ASD. We aimed to examine neural and behavioral effects of single- and multiple-dose OT treatment and the possibility of retention effects one month post-treatment using a double-blind, randomized, placebo-controlled, between-subject clinical trial including thirty-eight adult men with ASD. A key question was to determine whether similar neural effects are observed after single- versus multiple-dose treatment; whether the neural effects are paralleled by behavioral improvements on core ASD symptoms and specifically, whether the observed effects can outlast the period of actual administration. Doses of 24 IU oxytocin (Syntocinon®, Sigma-tau) or placebo nasal spray (saline natrium-chloride solution) were administered daily for four weeks. Resting-state fMRI neuroimaging was adopted to evaluate ‘intrinsic’ OT-induced changes in functional connectivity of amygdala-prefrontal circuits at rest (medial prefrontal cortex and orbitofrontal cortex). Behavioral effects of OT treatment were primarily assessed on two core ASD symptoms via self-report questionnaires: restricted and repetitive behavior and social responsiveness, and secondarily, on self-reports of state attachment, trait attachment, and quality of life. Data showed that four-week OT-treatment (24 IU/day) reduced functional connectivity of the amygdala with prefrontal regions in the orbitofrontal cortex until one month post-treatment. Neural changes in amygdala-prefrontal coupling were shown to be paralleled by behavioral improvements in repetitive behavior, attachment avoidance and social motivation. These findings provide further insights into the biological mechanism by which oxytocin exerts its prosocial effects and the observation that the neural and behavioral effects outlasted the period of actual administration further supports the therapeutic potential of oxytocin interventions for ASD.status: accepte