Big data, developing brains: The neurobiological origins of fearful temperament

About This Grant

PROJECT SUMMARY/ABSTRACT Fearful temperament marks risk for developing mental health challenges, including anxiety, later in life. Emerging neuroscience data suggests that the subset of fearful children who exhibit perturbations in amygdala circuitry may be most likely to develop anxiety. However, limited data directly implicates amygdala circuitry in infancy, when fearfulness first emerges. At present, there are three major barriers to progress: (1) the reproducibility and specificity of existing infant brain-behavior associations remains unknown; (2) studies have not yet accounted for the dynamic functional changes in the infant brain; and (3) the extent to which these effects have prenatal origins in maternal stress or psychopathology remains unknown. This application responds to these critical gaps by leveraging data from a global infant MRI database (ENIGMA-ORIGINs; N=1,479 total; N=341 with longitudinal MRI data) and the ongoing HEALthy Brain and Child Development (HBCD) study (N=5,025 total). Both ENIGMA- ORIGINs and HBCD include infant MRI, parent-reports of infant temperament, and measures of maternal perceived stress. HBCD additionally includes observed assessments of fearfulness and rich maternal psychopathology data obtained during pregnancy. The primary objectives of this application are to (1) identify amygdala connectivity associated with fearful temperament across the first two years of life; (2) characterize longitudinal changes in amygdala connectivity associated with fearful temperament; and (3) characterize the impact of prenatal stress and infant amygdala connectivity on fearful temperament. Across all aims, we evaluate how maternal anxiety impacts these associations. Our approach evaluates brain-behavior associations across time (to isolate developmentally sensitive patterns), evaluates out-of-sample reproducibility, and utilizes sophisticated statistical techniques (mediation) to examine pathways to fearfulness. Sensitivity analyses will determine whether observed patterns generalize to other negative affect states or persist across different methods of measuring fearful temperament (i.e., observational assessments vs. parent-report). By pinpointing neurobiological profiles of infant fearfulness that converge across phenotyping methods, our approach builds on research showing that cross-informant information may possess enhanced predictive power for long-term psychopathology risk. This project will be the largest infant MRI study to evaluate associations between prenatal stress, resting state functional connectivity, and infant temperament. By leveraging ‘big data’ this work is uniquely suited to model sex-specific patterns and isolate the effects of demographics, which will enhance neurodevelopmental models of early-life risk. This rigorous work will advance our understanding of the neural mechanisms that underlie fearful temperament in infancy and prenatal risk transmission and will provide new insight into early brain development. The insights gained from pinpointing neurobiological profiles of infant fearfulness could aid in identification of developmentally sensitive neural markers of risk and inform how to pair at-risk infants with treatments.