Christopher J. Trentacosta, Ph.D. - US grants

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award (K01) application is intended to provide training in areas that will lead to a program of longitudinal research on externalizing psychopathology and inform preventive interventions for at-risk children and families. The training and research proposed in this application will build upon the candidate's background in emotion theory and research on the development of psychopathology in at-risk populations. In line with National Institute of Mental Health's current Strategic Plan, the candidate proposes training to fulfill the following goals: (1) to learn approaches in molecular and behavior genetics that can increase understanding of how genotype and environment operate together in the development of externalizing psychopathology;(2) to increase the candidate's understanding of sensitive periods in the development of emotion regulation and risk for externalizing psychopathology;and (3) to learn advanced techniques to measure and analyze emotion expression and emotion regulation, especially in situations that induce anger and frustration. Training activities will include intensive training in genetics, guided discussion of directed readings on two sensitive developmental periods (toddlerhood and adolescence), coursework and tutorials on coding of emotion and advanced analytic approaches for dyadic data, and attendance at scientific workshops and conferences. These activities will be applied in studies of the relations among parental risk, parent-toddler hostility and rigidity, and toddler emotion regulation and conduct problem outcomes. In Study 1, maternal emotion dysregulation will be examined among 100 low- income, adolescent mothers in relation to hostile and rigid parent-toddler interactions, and hostility and rigidity in interactions will be examined as predictors of early-starting conduct problems. In Study 2, the candidate will apply the genetics training to an investigation of similar processes in an ongoing longitudinal study of birth parents, adoptive children, and their adoptive families (the Early Growth and Development Study). PUBLIC HEALTH RELEVANCE (See instructions): The knowledge gained from this KOI award will inform translational research to alter pathways to early- starting conduct problems. The interplay of genetic and socioemotional factors is likely to be a key process in initiating these problematic pathways. Research-based preventive intervention techniques that consider these processes may be especially beneficial to at-risk individuals, their families, and society.

PROJECT SUMMARY The association between early inflammation and altered child neurobehavioral development is indisputable, but understanding of neurological phenomena underlying this association is almost entirely lacking. Studies in animals suggest that, even before birth, inflammation acts on developing neural connections to alter the course of development. However, these critical associations remain to be tested in the human brain. Here, we will examine prenatal inflammation, fetal neural programming effects, and child neurodevelopment in a unified framework. We will leverage an existing longitudinal cohort to evaluate whether inflammation in the prenatal period exerts influence over the developing fetal neural connectome, and subsequently increases risk for childhood disorders. We will pair advances in fetal resting-state functional connectivity (RSFC) MRI with innovations in tooth-biomarker assays to address prenatal neural-immune interactions, and using advanced modeling techniques will rigorously investigate protective and resilience factors in early life that mitigate maladaptive childhood outcomes. To achieve these objectives, we will attain deciduous tooth samples from children enrolled in a longitudinal neurodevelopmental protocol that included fetal brain RSFC MRI. A new wave of data collection, partially harmonized with the NIH?s Adolescent Brain Cognitive Development (ABCD) study protocol, will be conducted at age 9 and will include MRI on the same scanner used prenatally. In these participants, associations between fetal systemic inflammation, fetal brain functional connectivity, and child neurobehavioral development will be examined. Our technique involves high temporal resolution sampling of five inflammatory markers, C reactive protein, Interleukin (IL) 1, 6, 10, TNF-a, across post conception week 15 through postnatal week 12, enabling isolation of sensitive periods and interactive effects. The primary aims of this project are to (i) identify fetal brain connectome abnormalities associated with heightened prenatal inflammation, (ii) characterize long-term brain and behavioral consequences of heightened prenatal inflammation, and (iii) isolate protective factors in the postnatal environment that predict advantageous long- term outcomes. We will thus be able to meaningfully evaluate whether and how prenatal inflammatory events affect functional neurocircuitry of the developing fetal brain, and the long-term neurobehavioral consequences of those associations. Such work would constitute a substantial advance in our understanding of not only the long-term effects of prenatal inflammation, but also the origins of child neurological disorders.

PROJECT SUMMARY Maternal toxicant exposure and nutritional status during pregnancy contribute to the emergence of attention deficit hyperactivity disorder (ADHD) and serious externalizing behavioral problems. A prevailing belief is that toxicants and fetal micronutrient deficiencies disrupt fetal brain development, with subsequent long-term implications for offspring health and development. However, evidence that prenatal toxicant exposure and micronutrient imbalances influence fetal neural systems in humans is lacking, as is evidence that changes in the fetal brain precede nutrient- and toxicant-related developmental concerns of childhood. Filling these gaps in knowledge is critical, given the high prevalence of prenatal toxicant exposure worldwide and evidence that events during gestation influence long-range health and well-being. The central objective of this proposal is to examine development of human neural networks in utero, and to link variation in prenatal brain development to prenatal toxicant and nutrient levels (measured in the fetus) and to child outcomes. This will be done in a way that is sensitive both to chemical mixture effects and to time-variant exposure across the course of gestation, which are both likely to have specific neurodevelopmental consequences. We will pair advances in fetal resting-state functional connectivity (RSFC) MRI with innovations in tooth-biomarker assays to rigorously investigate associations between prenatal chemical/micronutrient exposures and human fetal neural connectome development, and will determine how exposome and connectome development in utero relate to child neurobehavioral development. Data collection in a Detroit-based pregnancy cohort was initiated more than 7 years ago, beginning with fetal brain RSFC MRI. Children have been followed over time, with assessments at birth, 7 months, age 3 and age 5, and have begun to naturally shed their deciduous teeth. The primary aims of this project are to (i) identify fetal brain connectome abnormalities associated with prenatal toxicant exposure and micronutrient imbalance, and identify key windows of gestational vulnerability; (ii) evaluate prenatal exposures and fetal neural connectivity as longitudinal predictors of executive function, externalizing problems and school readiness at age 5; and (iii) isolate protective factors in the postnatal environment that promote resilient outcomes in children with prenatal micronutrient deficiency and toxicant exposure. We will thus be able to meaningfully evaluate whether and how prenatal nutrient availability and toxic exposure events affect functional neurocircuitry of the developing fetal brain, and the longer-term neurobehavioral consequences of those associations. Such work would constitute a substantial advance in our understanding of both the longitudinal effects of micronutrient and toxicant exposures in the prenatal period and the origins of child neurobehavioral disorders.