Nim Tottenham - US grants

DESCRIPTION (provided by applicant): The primary aim of this proposal is to investigate the normative development of the neurobiology that results in mental illness associated with emotional difficulties including high reactivity and poor regulation. Such illnesses include, but are not limited to, anxiety, depression, schizophrenia, bipolar disorder, sociopathy, and personality disorders. A failure to effectively recruit a neural circuitry that includes the amygdala and ventromedial prefrontal cortex has been implicated in these mental illnesses in adults. The present research strategy, which uses structural and functional magnetic resonance imaging (MRI) and behavioral measures, will employ a prospective and longitudinal design that identifies biomarkers associated with these difficulties and map their development as children age into adolescence. The second aim is to examine the influence of early adverse caregiving environments on the development of this neurobiology. For long, it has been recognized that environmental stress is associated with a disproportionately high of risk emotional psychopathology. A large animal literature combined with an emerging human neuroimaging literature shows that environmental stress can impair mental health functioning via disruption of the amygdala and the regulatory processes that depend on proper connectivity between amygdala and ventromedial prefrontal cortex. When stress exposure occurs prior to developmental maturity, the effects can be more potent and its impact longer lasting than stress that occurs in adulthood. Therefore, the findings of this project will have a high impact on the field of mental health by identifying biomarkers associated with emotional difficulties prior to their behavioral onset. In this way, we will be better at predicting and preventing the development of mental illnesses that often emerge during the adolescent period. PUBLIC HEALTH RELEVANCE: This project will examine the development of a specific neurobiology that is associated with emotional difficulties such as high reactivity and poor regulation. In addition to mapping out the typical development of this biology, this project will examine the role that adverse early caregiving has on its development. This research is important because identification of biomarkers during development before they emerge into problem behaviors in adulthood will help in the prevention of mental illnesses associated with emotional difficulties.

Project Summary Children with severe Early Caregiving Adversities (ECAs) are the most vulnerable to psychopathology as a result of prolonged neglect, abuse, and care disruptions that impact neurodevelopment. It is currently estimated that addressing ECAs would lead to a 29.8% reduction in worldwide psychiatric illness. Existing research, including findings from the original grant of this renewal, has demonstrated that there is a very strong link between ECA exposures and increased risk for psychopathology and altered neurodevelopment at the population level; and yet, given the heterogeneity in ECA populations, there is a critical gap in knowledge regarding how ECAs increase any specific risks to an individual child. The proposed research addresses this significant mental health problem by combining sophisitcated data-analysis methods that use experiential and phenotypic heterogeneity together with longitudinal neuroimaging and behavioral assessments in school-age children. This approach will increase precision when linking ECAs and child outcomes associated with the Research Domain Criteria constructs of Negative Valence and Cognitive Control Systems (NVS/CCS). The overarching goal of the present work is to create an explanatory model for the heterogeneous impact of ECAs on neurodevelopmental trajectories of NVS/CCS. This project's premise is that children exposed to ECAs have highly heterogeneous developmental histories as well as heterogeneous outcomes; therefore, prediction of ECA outcomes requires cutting-edge, sophisticated data analytic methods. We hypothesize that data-driven approaches will 1) more precisely define NVS/CCS outcomes for school-aged children with ECAs, and 2) provide a more robust explanatory model for links between ECAs and NVS/CCS trajectories. Aim 1A subtypes children with a history of ECAs based on 2.5-year developmental trajectories of NVS/CCS. 300 6-8 year old children (250 sampled from previous institutional and foster care; 50 community comparisons) will provide neuroimaging, behavioral, and self/caregiver reports every 15 months for 2.5 years. Biclustering methods will be applied to the baseline and follow-up data to identify homogeneous NVS/CCS final outcome clusters of children. Aim 1B develops an explanatory model to predict developmental trajectory subtypes for children with ECAs, from early life profiles and brain/behavior phenotypes at the time of enrollment. Machine learning methods applied to early life profiles, baseline NVS/CCS profiles, and sex, will predict developmental trajectory subtypes. Aim 2 identifies adverse and protective life events during the 2.5-year assessment period that are predictive of 2.5-year follow-up outcomes for children with ECAs. The inclusion of child-sex and current life- events will identify potential divergence in pathways across middle childhood. This prospective design of children exposed to various ECAs is designed to develop predictive models for ECA trajectory subtypes and outcomes, which can inform our understanding of risk and protective factors in accord with the goals of precision medicine.  

PROJECT SUMMARY/ ABSTRACT Parents serve as co-regulators for their young children, helping them regulate behaviors, emotions, and physiology and supporting the development of healthy brain circuitry. Neglecting parents often fail to serve as co-regulators, which has implications for young children?s self-regulatory capabilities and brain development. As children become older, these difficulties with self-regulation may become more pronounced. Adolescence represents a period of particular vulnerability for the emergence of mental health problems because of increasing demands for regulation of emotions and behaviors, coupled with on-going development of neural circuits that support emotional and behavioral regulation. In this competing renewal, we propose to follow children into adolescence who initially participated in a randomized clinical trial design of Attachment and Biobehavioral Catch-up (ABC) as infants, allowing us to experimentally assess plasticity and modification of brain circuits and self-regulation as the result of an early intervention. The ABC intervention was designed to help parents learn to interact in responsive and sensitive ways, with the expectation that children would show enhanced ability to regulate behavior, emotions, and physiology. We assessed the efficacy of the ABC intervention among parents involved with Child Protective Services (CPS). Parents were randomized to ABC or to a control intervention. Children were followed at T1 (ages 1-4) and T2 (ages 8-10). At T1, more of the children in the ABC group developed secure and organized attachments than children in the DEF group, and children in ABC showed more normative production of cortisol, less expression of negative emotions, and stronger inhibitory control than children in DEF. ABC parents were more sensitive and showed more optimal neural activity than DEF parents. At T2, ABC children showed greater prefrontal cortex activation in response to photographs of fearful faces than DEF children, suggesting better regulation to threat at the level of brain activation. Also at T2, children in the ABC group reported more secure relationships with parents, and showed more normative cortisol production and more optimal autonomic nervous system functioning than DEF children. In adolescence, the ABC intervention is expected to result in enhanced brain circuitry and more optimal functioning relative to the control intervention. In the proposed study, we will assess behavioral and neurobiological development among 13-, 14- and 15-year-old adolescents whose parents were referred by CPS to a randomized clinical trial in infancy (n=120), and among low-risk adolescents followed since middle childhood (n=80). At each annual assessment, the primary constructs, inhibitory control, emotion regulation, physiological regulation, and attachment/affiliation, will be assessed at the level of brain activation and circuitry, and at the behavioral level.