Autism spectrum disorders (ASD) are marked by significant impairments in social functioning and social cognition;although these symptoms are core features of ASD-and perhaps the most debilitating-there has been little headway in the development of pharmacological treatments for the social domain and it is widely acknowledged that such treatments are sorely needed. Oxytocin (OXT) plays a critical role in social behavior and social cognition and, thus, may be a promising candidate to target the social deficits in ASD. However, most of what we know about OXT comes from research with animals, and little is known about the precise role of OXT in humans, much less in ASD. This study will use a challenge methodology in conjunction with functional magnetic resonance imaging (fMRI) to investigate the acute effects of intranasal OXT on Empathic Accuracy-a novel, ecologically valid measure of complex social cognition-in adults with ASD. The specific aims of this research are to: 1) test the efficacy of OXT in ASD with respect to improving complex social cognition and 2) elucidate the neurobiological mechanism involved in this process. Specifically, 35 adults with ASD will randomly receive a single dose of synthetic OXT, administered via nasal spray, or a matching placebo on two separate occasions. Participants will then perform the Empathic Accuracy task, in which they watch a series of videos of targets discussing an emotional event, and make attributions about the internal emotional state of each target. An index of Empathic Accuracy is calculated by comparing participants'ratings about the target's emotional state to ratings made by the targets themselves about their own emotional state during the narrative. The Empathic Accuracy task will be performed in conjunction with fMRI to elucidate the neural correlates of OXT on Empathic Accuracy in study participants. Regions of interest include regions implicated in social cognition and Empathic Accuracy, and previously found to be disrupted in individuals with ASD, in particular, the medial prefrontal cortex, superior temporal sulcus, as well as the premotor cortex and inferior parietal lobule. While many drugs are not amenable to a single-dose challenge, data suggests that a single dose of OXT produces significant cognitive and neurobiological effects. If positive, this research will point to a novel, potentially groundbreaking therapeutic candidate to target social dysfunction in ASD, and as such is consistent with objectives of the Interagency Autism Coordinating Committee (IACC) autism research matrix and addresses a major unmet need in the field. Moreover, the focus on adults with ASD will be an important contribution to the field of autism because to date there is a paucity of effective interventions for adults with ASD. Although the benefits of early intervention cannot be denied, social functioning difficulties-even subtle ones-can persist into adulthood and present a significant barrier to adaptive functioning and productivity. PUBLIC HEALTH RELEVANCE: The prevalence of autism ranges from one in 250 to one in 1000 in the U.S., and the cost of the disability is estimated to be in the range of $30 billion a year, underscoring the enormous public health impact of this illness. Social impairment is a central, unifying feature of autism and autism spectrum disorders (ASD), and perhaps also the most debilitating, but there has been little headway in the development of pharmacological treatments for the social domain. The purpose of this research is to determine whether OXT-a peptide hormone that plays a role in affiliative behavior in animals-facilitates complex social cognition in adults with ASD, and to elucidate the neurobiological mechanism involved in this process to clarify the viability of this potentially ground breaking treatment.