Amanda E. Guyer - US grants

DESCRIPTION (provided by applicant): The developmental timing of the increase in the rate and the emergence of sex differences in depression points to adolescence as a critical period for understanding the causal mechanisms underlying the development of depressive disorders in females. Adolescent neural development is likely to play a key role in the etiology of depression, but little is known about the interface between the development of neural circuitry and depression across adolescence. In response to PA-09-108 Women's Mental Health and Sex/Gender Differences Research, we will determine if developmental changes in the neural circuitry engaged by emotionally evocative stimuli are related to adolescent depression in girls. Mapping developmental trajectories of depression symptoms onto relevant neural systems will further our understanding of the maturational changes in brain function that contribute to age-related vulnerability. Investigators: Drs. Keenan, Guyer and Forbes are the PIs;they began collaborating on the neuroscience of depression two years ago. Dr. Kevin Grimm, a statistician specializing in longitudinal modeling, and Dr. Alison Hipwell an expert in female mental health, are Co- Investigators. Consultants are Drs. Gang Chen, Ronald Dahl, Constance Hammen, and Daniel Pine. Innovation: Brain-behavior perturbations in information processing are a major focus of clinical neuroscience research. Developmental shifts in neural circuits during adolescence are critical to understanding the emergence of psychopathology during this period. No study to date, however, has been designed to test the hypothesis that development of the functional connections between affective and cognitive circuits during the adolescent period is related to depression-onset, or to characterize the patterns of neural development that in fact confer risk for depression onset. Approach: This proposal builds on a recently completed NIMH-funded study of precursors to depression in girls, in which depression symptoms and negative life events were documented from ages 9-14. Half of the sample was selected on measures indicative of high risk for developing depressive disorders. For this PA, we propose to study this sample from ages 15-19 years and to conduct annual assessments of depression and environmental stressors and annual assessments of emotional memory and reward processing using neuroimaging. Developmental patterns in functional connectivity between amygdala-ventral-lateral prefrontal cortex (vlPFC) circuitry and striatum-medial prefrontal cortex (mPFC) circuitry during memory for emotional faces and reward processing, respectively, will be captured across four time points, as will environmental stress exposure. Environment: This proposal involves a multi-institutional investigation at the Universities of Chicago, Pittsburgh, and California-Davis. Assessments of depression, stress exposure, and brain function will be conducted in the University of Pittsburgh's Department of Psychiatry and the Neuroimaging of Emotional Disorders Lab at Western Psychiatric Institute and Clinic, which is internationally recognized for research on brain functioning and child psychopathology. PUBLIC HEALTH RELEVANCE: We propose to determine if developmental changes in how the brain responds to emotional stimuli during adolescence can inform us regarding which girls are at risk for developing depressive disorders. Adolescence appears to be a time of vulnerability in terms of developing circuits in the brain that help regulate emotional responses. By conducting a longitudinal study from ages 15-19 we will be able to examine individual differences in brain functioning from mid to late adolescence and test whether different pathways to developing mature brain circuits explains individual differences in risk for depression.

Project Summary Interpersonal functioning is vital across a range of mental health outcomes, with particular significance for adolescent girls. Adolescence is a critical period for promoting or hindering development of adaptive interpersonal functioning due to dramatic changes in social behaviors and significant maturation of brain regions that facilitate social-emotional processing. Despite this importance, very few prospective, longitudinal studies have used repeated functional neuroimaging data to chart the trajectory of connectivity of social-emotional brain regions across adolescence. The proposed project is rigorously designed to use the Research Domain Criteria (RDoC) framework for Social Processes to address a gap in the field about how functional connectivity of social- emotional brain regions during introspection changes within the same girls across several years of adolescence. First, we will characterize trajectories of connectivity between the mPFC, precuneus/posterior cingulate cortex, and bilateral middle temporal gyrus across ages 16-18. We will then determine if change in functional connectivity from age 16 to 18 promotes or hinders girls' effective interpersonal functioning at age 18. Finally, we will test whether girls' emotion expression and emotion socialization experiences across ages 9-13 moderate the association between trajectories of brain connectivity and interpersonal functioning. We capitalize on an unprecedented existing dataset of neuroimaging, psychosocial functioning, and social-emotional behavior collected on 185 girls from the ages of 9-18 years who are part of the Pittsburgh Girls Study of Emotion. The project will investigate multiple units of analysis (e.g., circuits, paradigms, behavior, self-reports) of the RDoC Affiliation and Perception/Understanding of Self and Others constructs, and situates these units of analysis in the context of neurodevelopment and environmental experiences. Several aspects of the proposed study will allow us to generate highly impactful data. First, the sample size would be one of the largest to date for examining trajectories of task-based functional connectivity (e.g., latent growth, moderation). Second, potential findings can inform the development of more precise treatments and interventions designed to target affective processes, socialization and interpersonal functioning of adolescent girls at risk for psychopathology. Third, assessments of emotional socialization, emotion expression and self-reported interpersonal functioning are completed within each subject, providing an opportunity to test more refined models of how functional connectivity underlying psychological processes may become disrupted and lead to poor interpersonal functioning. Fourth, leveraging existing prospectively collected data provides an unprecedented, and economical, test of individual factors that may moderate brain-behavior associations. This will be one of the most comprehensive and rigorous tests of the associations among early adolescent emotion socialization and emotion expression, trajectories of brain connectivity linked to introspection across adolescence, and interpersonal functioning in young adulthood.