Efforts to decipher biological signatures for mental illness now 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.
However, while specific cortical changes have been implicated in a small number of specific syndromes, for the
most part, patterns in cortical development that underlie the differentiation of psychopathology remain
uncertain. The ongoing Adolescent Brain Cognitive Development (ABCD) study provides an unprecedented
opportunity to align emergence of specific patterns of psychopathology with specific changes in cortical
maturation. Over the next 5 years, ABCD will obtain annual, standardized measures dimensional
psychopathology, and biennial MRI scans, of 11,875 youths across 21 US-based sites, covering age 9 to 16.
The proposed studies will leverage this longitudinal design to discover regionally- and temporally-specific
features of cortical development that associate with emergence of dimensional psychopathology, and then to
relate these patterns to specific profiles of underlying genomic and environmental risk. Analysis of baseline
data from age 9-10, included in this application, indicates that psychopathology is in early stages of
differentiation, although already strongly related to polygenic risk for child-onset disorders, and to well-
established pre- and post-natal environmental insults. Aim 1 of the proposed studies will juxtapose clinical and
imaging data from baseline through three follow-up time points, focusing primarily on whether departures from
neurotypical age-related cortical thinning trajectories (assessed via intercept, slope, and quadratic indices)
associate with emergence of specific dimensions of illness. The precise temporal alignment of clinical and
cortical thinning trajectories will take an initial step towards inferring causal relationships, which will be further
substantiated through triangulation with genomic (Aim 2) and environmental (Aim 3) risk profiles. Polygenic
scoring methods developed by the Psychiatric Genomics Consortium will be used to determine whether
cortical maturation trajectories developed in Aim 1 mediate relationships between genomic risk and emergent
dimensional psychopathology. Then, using data from hundreds of environmental measures that canvass
participants’ daily activities, nutrition, life stressors, socioeconomic status, family dynamics, neighborhood
safety, and numerous other factors, we will use novel machine learning methods to develop profiles of
exposomic risk factors that predict emergent dimensional psychopathology, and determine whether cortical
maturation patterns mediate the relationship between environmental risk profiles and clinical course. By the
conclusion of the proposed studies we hope to establish specific cortical signatures that bridge causal factors
with emergent psychopathology in adolescence, and that can be leveraged to develop new preventative
interventions.
