PROJECT SUMMARY: Children born prematurely are at elevated risk for psychiatric disorders, including ADHD, autism and anxiety. Indeed, the ‘preterm behavioral phenotype’ is comprised of inattention, anxiety and social- communication impairments. This constellation of comorbid disorders persists across the lifespan, accounting for long-term impairment and diminished quality of life among very preterm (VPT; born ≤32 weeks gestation) children, a population at high risk for altered brain development. Yet, the neurobiological mechanisms underlying the increased prevalence of these symptoms remain undetermined. Further, VPT children face high exposure rates to deleterious psychosocial risk factors which have similarly been linked to adverse psychiatric outcomes and changes in brain development. We posit that decreased connectivity and the resulting diminished developmental trajectories within and across key functional networks (e.g., default mode, frontoparietal control and cingulo-opercular networks) and related white matter tracts (e.g., cingulum, corpus callosum and uncinate) underlie comorbid preterm behavioral phenotype symptoms that persist or worsen at age 9-10. This process begins during infancy and extends to middle childhood, with psychosocial risk playing an important modifying role. Advances in MRI methodology now enable characterization of structural and functional brain networks with unparalleled spatial and temporal resolution. Here, we couple these highly innovative, state-of-the-art MRI techniques with detailed psychiatric assessments to study our unique, sociodemographically-diverse longitudinal cohort of VPT and term-born children (N=302) with high rates of psychosocial adversity now reaching age 9-10. The cohort has been followed since birth, including prospective collection of high-quality neonatal functional and structural connectivity MRI data and longitudinal assessments of preterm behavioral phenotype symptoms and psychosocial and familial factors at ages 2 and 5, with >80% cohort retention to date at both assessment waves. Continued evaluation of this enriched cohort provides an opportunity to determine: 1) trajectories of preterm behavioral phenotype symptoms to define early indicators of later impairment enabling targeted interventions, 2) relationships between neonatal and age 9-10 functional and structural connectivity and these deficits, and 3) the modifying role of psychosocial adversity. Application of cutting-edge MRI acquisition and analysis methods, including machine learning approaches, enables unprecedented characterization of the effects of VPT birth on connectivity in the developing brain. We will extend these methods to delineate relationships between imaging measures and preterm behavioral phenotype symptoms, improving understanding of modifiable effects of early life exposures and psychosocial risk on psychiatric outcomes. These data are critical for developing individual- level neuroimaging, behavioral and psychosocial presymptomatic predictive models for adverse mental health outcomes, measures necessary to inform and evaluate treatments applicable during sensitive developmental periods which mitigate risks of psychopathology associated with prematurity and psychosocial adversity.

RELEVANCE TO PUBLIC HEALTH This study is designed to improve our understanding of the changes in brain structure and function that underlie the elevated rates of inattention, anxiety and autism spectrum symptoms now increasingly recognized in prematurely-born children. Using cutting-edge magnetic resonance imaging methods, we will investigate these relationships in a unique, longitudinally-studied cohort of very preterm and term-born children with high rates of psychosocial adversity now reaching age 9-10 years and previously studied using neuroimaging during infancy and detailed assessments of psychiatric symptoms during early childhood. The overarching goal is development of new approaches for earlier, more accurate identification of children at risk for these disorders, enabling progress toward targeted interventions which improve outcomes by limiting risks for psychopathology associated with prematurity and psychosocial adversity.