Striking deficits in social interaction are hallmark features of autism spectrum disorders (ASD). Oxytocin plays an important role in social behavior in animals and humans and has recently emerged as a promising candidate for targeting social impairment in ASD. However, little is known about the neural mechanisms by which oxytocin influences social behavior in humans in general and ASD in particular. This project aims to investigate the impact of oxytocin treatment on the neural systems underlying social impairments in children with ASD. We are participating in an NIH ACE network grant to conduct a definitive randomized, double-blind, placebo-controlled clinical trial of sustained intranasal oxytocin treatment on reciprocal social behaviors in children with ASD. This presents a unique opportunity to take advantage of existing infrastructure that will enable us to provide important information on the neural mechanisms underlying oxytocin treatment response in autism. The specific aims of this project are to examine: 1) how oxytocin impacts the neural circuitry underlying fundamental aspects of social information processing-namely, the 'mirror neuron' system and social reward, and 2) the extent to which activity in these circuits predicts or correlates with treatment response. The central hypothesis is that treatment with oxytocin will enhance activity in these 'social brain' systems and that increases in key brain areas (e.g., pars opercularis of the inferior frontal gyrus, ventral striatum, amygdala, and medial prefrontal cortex will correlate with clinical improvement in social behavior. We will use previously validated fMRI paradigms to examine differences in brain activity before and after treatment with oxytocin and placebo in children with ASD participating in the network trial. The rationale for the proposed research is that a better understanding of the neural systems impacted by oxytocin will pave the road for developing new pharmacological strategies for targeting these networks, whether they are social brain or compensatory circuits. The approach is innovative in its use of fMRI tasks that tap circuitry known to be dysfunctional in autism, correlate with severity of social symptoms, and have a direct link to a hypothesized mechanism of oxytocin. The proposed project is significant because it will yield important information on the therapeutic mechanism of oxytocin in children with ASD, and offer a scientific basis on which to ultimately develop individualized approaches to treatment. Increasing knowledge about the neural architecture impacted by oxytocin in an ASD sample is expected to help stimulate the development of novel strategies for increasing activation in affected networks. This study is also expected to help identify neural predictors and correlates of treatment response, which will likely support the development of biomarkers, and thus, personalization of treatments-a target widely acknowledged as critically important for the field.