ABSTRACT Loneliness, or the feeling of distress that accompanies perceived social disconnection, confers significant risk for negative physical and mental health outcomes, such as chronic disease, depression, and self-harm. Adolescence is a period of increasing loneliness and thus a critical time to identify risk and protective factors. Adolescents with autism spectrum disorder (ASD) demonstrate higher rates of loneliness than the typical population, making them especially vulnerable to these negative outcomes. While developmental research has identified peer relations as risk and protective factors in typically developing (TD) populations, gaps remain in our understanding of how peer relations relate to the development of loneliness in ASD. Thus, understanding the mechanisms that confer risk and protection in the development of loneliness in adolescence, and whether they differ in high-risk populations, is critical to effectively intervening and ameliorating loneliness before the onset of significant deleterious consequences. Research in adults points to several cognitive and neural factors associated with loneliness and social connection: social-cognitive systems, social reward systems, and dissimilarity from others. These brain mechanisms are also atypical in ASD and posited to relate to atypical social interaction. The current proposal will test a novel biopsychosocial model of the development of loneliness in which these posited neural mechanisms serve as predictors in the development of loneliness via their effects on social experiences. In our model, peer relations may confer both risk and protective factors between social experience and the development of loneliness. We will test this model using a prospective- longitudinal design to follow 75 ASD and 120 TD adolescents mean-matched in age and IQ, and followed every four months for twenty months. Importantly, this project will be the first to integrate across these neural, cognitive/affective, and behavioral levels of analysis to investigate risk and protective mechanisms in the developmental emergence of loneliness in adolescents with TD and ASD, and to examine whether these mechanisms differ between groups. The current proposal is innovative in its use of ecologically valid, naturalistic, and social-interactive fMRI approaches that the PI Dr. Redcay has developed. Further, the proposal builds on existing work from co-Is Drs. Shackman and Lemay and Consultant Dr. Silk to use ecological momentary assessment (EMA) to obtain real-world, in-the-moment assessments of social experiences and their effects on mood and loneliness. These contributions will be significant to the scientific field and relevant to the strategic mission of NIMH because they will provide novel, critical missing information on the developmental trajectory of loneliness in ASD and will identify mechanisms of risk for and protection against loneliness outcomes. Knowledge gained from this project has direct implications for...