Background: The Social Motivation Hypothesis proposes that individuals with autism spectrum disorder (ASD) experience social interactions as less rewarding than their neurotypical (TD) peers, which may lead to reduced social initiation. Existing studies of the brain's reward system in individuals with ASD report varied findings for anticipation of and response to social rewards. Given discrepant findings, the anticipation of and response to social rewards should be further evaluated, particularly in the context of intervention outcome. We hypothesized that individual characteristics may help predict neural changes from pre- to post-intervention. Methods: Thirteen adolescents with ASD received the Program for the Education and Enrichment of Relational Skills (PEERS) intervention for 16 weeks; reward-related EEG was collected before and after intervention. Fourteen TD adolescents were tested at two timepoints but did not receive intervention. Event-related potentials were calculated to measure anticipation of (stimulus-preceding negativity; SPN) and response to (reward-related positivity; RewP) social and non-social rewards. Additionally, measures of social responsiveness, social skills, and intervention-engagement were collected. Group differences were analyzed as well as individual differences using prediction models. Result: Parent-reported social responsiveness and social skills improved in adolescents with ASD after participation in PEERS. ASD adolescents displayed marginally decreased anticipation of social rewards at post-intervention compared to pre-intervention. Regression models demonstrated that older adolescents and those with lower parent-reported social motivation prior to participation in PEERS displayed marginally increased social reward anticipation (more robust SPN) from pre- to post-intervention. Participants who displayed more parent-reported social motivation before intervention and were more actively engaged in the PEERS intervention evidenced increased social reward processing (more robust RewP) from pre- to post-intervention. Conclusion: Findings suggest that there may be differences in saliency between wanting/anticipating social rewards vs. liking/responding to social rewards in individuals with ASD. Our findings support the hypothesis that identification of individual differences may predict which adolescents are poised to benefit the most from particular interventions. As such, reported findings set the stage for the advancement of "precision medicine." This investigation is a critical step forward in our ability to understand and predict individual response to interventions in individuals with ASD.

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