Alignment of cortical development trajectories with emergent dimensional psychopathology and related risk factors among adolescents in the ABCD Study

PROJECT SUMMARY Efforts to discover biological signatures for mental illness focus increasingly on adolescence, a period of rapid brain development that immediately precedes the peak age of onset for many disorders. Maturation of the cerebral cortex during this time has long been thought to mediate emergence of early symptoms. The ongoing Adolescent Brain Cognitive Development (ABCD) Study provides an unprecedented opportunity to align emergence of psychopathology with specific changes in cortical maturation within a diverse population of nearly 12,000 youth. Enrolled at age 9-10, participants are being studied with 6 standardized MRI assessments over a 10 year period, along with developmental history, genotype, and annual measures of dimensional symptoms and of their home, school, and social environment. This application seeks to renew an R01 grant that is focused on eliciting cortical developmental signatures of emergent psychopathology in ABCD and triangulating these signatures with causal genomic and environmental risk factors. The award period coincides with the second half of the ABCD Study (ages 14-20), and we will use publicly available data from annual releases to test our hypotheses. Supported by findings from the first award period, our central scientific premise is that (1) variance in late cortical thinning, as it proceeds along anterior and lateral brain territory, will predict emergent psychopathology in late adolescence; and (2) progressive associations between thinning and emergent symptoms will reflect a gradient of temporally distal (prenatal) to proximal (postnatal) risk factors. Aim 1 will ultimately use all 6 biennial measures of cortical thickness and annual measures of dimensional psychopathology from ages 9 to 20, enabling precise temporal and spatial alignment of cortical maturation and symptom emergence. Aim 2 will consider this alignment within the frame of available postmortem transcriptomic data, to assess the contributions of polygenic risk scores and temporospatial gene co- expression programs from pre- and postnatal periods. Aim 3 will focus on pre- and postnatal environmental risk factors, and will determine whether prenatal adversity and disruptions related to the Covid-19 pandemic shape relationships between cortical thinning and emergent psychopathology. These analyses will be supported by new methods that we developed during the last award period, including a rigorous quality control pipeline for reducing measurement errors in structural MRI studies of children, and a novel method of parsing polygenic risk based on pre- versus postnatal gene expression. By the conclusion of the proposed studies we will establish specific cortical signatures that bridge causal factors with emergent psychopathology in adolescence, and that can be leveraged for early recognition and intervention studies.