Impact of prenatal opioid exposure on neurobehavioral development

About This Grant

PROJECT SUMMARY/ABSTRACT This K01 proposal aims to elucidate mechanisms underlying effects of prenatal opioid exposure (PODE) on infant brain and behavioral development. PODE is related to behavioral and cognitive deficits that emerge during infancy and persist through adolescence, but the neural mechanisms contributing to these divergent trajectories are virtually unknown. The proposed research addresses this gap by identifying PODE effects on longitudinal brain growth and characterizing associations between brain structure-function coupling, environmental factors, and behavioral outcomes. This K01 application presents a program of research and training that will support the PI’s transition to an independent investigator with a focus on examining early origins of neurodevelopmental heterogeneity using a multidisciplinary approach. In addition to building on the PI’s prior training and experience, this training plan capitalizes on an exceptional mentorship team and translational research environment to foster the candidate’s expertise in: 1) cross-modal neuroimaging analysis for brain structure-function integration, 2) big data analysis using advanced statistical methods for longitudinal and multivariate modeling, 3) environmental impacts on brain development in the context of marginalized populations, and 4) interpretable machine learning approaches for generating predictive models of outcome. This project will capitalize on the largest cohorts of infants with PODE to date and investigate PODE effects on development of brain structure-function coupling across the first year (Specific Aim 1), dissect the moderating impact of environmental factors on brain growth (Specific Aim 2), and build interpretable machine learning models to predict 12-month cognitive and language outcomes (Specific Aim 3). The central hypothesis is that longitudinal development of higher-order cognitive networks (i.e., circuits that are enriched with opioid receptors) is impaired by PODE and shaped by environmental factors, such that the interaction between brain and environment is predictive of behavioral outcomes. This work will elucidate biological mechanisms underlying the impact of PODE on neurodevelopmental heterogeneity and improve early intervention strategies and personalized treatments. The proposed research will take place at Cedars-Sinai Medical Center under the mentorship of Drs. Wei Gao (cross-modal neuroimaging), John Gilmore (structural network analysis in pediatric populations), Rina Eiden (prenatal substance exposure and environmental adversity/resilience), Jason Moore (machine learning methodologies), Wesley Thompson (nonlinear trajectories), Vinicius Calsavara (multivariate statistical analysis), and Kimberly Gregory (marginalized populations). Together, the research and training experiences and the expertise developed through this K01 award will support the PI’s career development as an independent investigator and leading expert in the developmental etiology of prenatal substance exposure and neurodevelopmental disorders. Findings will support a future R01 extending this work to population-level datasets in youth with prenatal substance exposure to investigate mechanisms underlying neurobehavioral heterogeneity across the entire developmental period.