PROJECT SUMMARY The social reorientation of the adolescent period is accompanied by extensive neurodevelopmental changes. To understand the neurodevelopmental networks underlying responses to social environments and how social connectedness influences neurodevelopment, manipulation of social connectedness among youth is required, which is impossible in a large-scale setting. In 2020, the COVID pandemic happened, in the midst of longitudinal follow-up of participants in the Adolescent Brain Cognition Development (ABCD) study, inducing dramatic changes to social connectedness in adolescents in the study. Because the levels of stay-at-home restriction were imposed agnostically to participants' pre-pandemic status, this becomes a naturally occurred experiment on social connectedness among adolescents. Together with the comprehensive pre-pandemic assessments, longitudinal follow-up with surveys and geolocation data collected during the pandemic period, and the resumption of multimodal imaging scans and regular assessments restarting during, and continuing after 2021, we can use longitudinal ABCD data to critically examine the relationships between social connectedness and neurodevelopment among youth. In particular, we propose to use ABCD data to investigate 1) the neurobiological and social factors (pre-pandemic) that render an individual more sensitive to the disruption of social connectedness (peri-pandemic), contributing to emotional turmoil during and beyond the pandemic period; 2) the modulating factors that buffer/exacerbate the emotion responses during a prolonged period of social disruption (peri-pandemic); and 3) the extent of deviation in neurodevelopment after the pandemic (post-pandemic) in relation to the varying levels of social disruptions in ABCD participants during the pandemic. We will pursue these aims by utilizing a novel combination of methods from high-dimensional data analysis and population inference, innovatively tailoring the analytic strategies to avoid potential biases and spurious associations. The proposed research is of high public health interest because the identified neurobiological mechanisms underlying the emotional responses toward the disruption of social connectedness will provide novel insights for therapeutics and public health interventions in adolescents, due to the population-informed ABCD sample. By sharing our developed tools and derived social variables for this research program, we will impact the field immediately. These novel analytic tools enable us and others to more deeply investigate with ABCD data, neurodevelopmental processes specifically related to social connectedness. Results can inform peri- and post-pandemic clinical practice to regain and improve mental health in youth.