PROJECT SUMMARY The human fetal brain is complex, highly plastic, and extremely vulnerable. Mild variation in utero can drastically impair life-long learning and neurological health. Despite growing appreciation for the relevance of this period to numerous developmental, psychiatric and neurological disorders, macroscale functional organization of the fetal brain remains a `black box' for neuroscience research. While there are phenomenal technologies for examining fetal brain anatomy, only very recently have we possessed non-invasive means of studying coordinated function in the living human fetal brain. This project is focused on understanding the emergence of whole brain functional circuitry beginning in fetal life, and identifying relationships between prenatal brain connectivity and preschoolers' attainment of key developmental milestones. Given that the womb is the first environment for the fetus, and is thus the place where biology and environment first interact, we will also examine the effects of prenatal stress exposure on human fetal brain functional connectivity. Sixty women will be recruited in weeks 25-32 of pregnancy and entered into a longitudinal functional magnetic resonance imaging (MRI) protocol. Brain resting-state functional connectivity (RSFC) MRI data will be obtained 3x longitudinally prior to and following birth, spanning ages 25 weeks gestational age to 12 weeks postnatal age. Discoveries about network emergence in this first step will provide a basis for subsequent evaluation of the relationship between brain maturation in utero and attainment of developmental milestones in childhood. To this end, self-regulatory behavior will then be measured in an existing sample of 110 preschoolers that underwent fetal brain RSFC imaging 4 years ago. In these participants, associations between maternal prenatal stress, fetal brain functional connectivity, and child neurobehavioral development will be examined. The primary aims of this project are to (i) break new ground in our understanding of the emergence of whole brain functional circuitry beginning in fetal life, (ii) identify variations in prenatal brain connectivity that may predispose 4-year-old children to delayed attainment of key developmental milestones that prognosticate life long health, and (iii) examine the influence of prenatal stress on emergent fetal brain functional connectivity. With its innovative focus on precursors, vulnerability, and consequences of fetal RSFC, this project is ideally suited to the NIMH BRAINS award aiming to support a productive early stage investigator in the implementation of high-impact, novel research. Initiation and achievement of these research aims will be the first step in a career focused on identifying neurobiological pathways through which early developmental risk may be conferred and also ultimately prevented.

PUBLIC HEALTH RELEVANCE: Many neuropsychiatric disorders likely originate during prenatal development. This work will lay critical foundations for establishing the normal functional developmental trajectories of the human fetal brain. This project will also evaluate causes and consequences of altered brain functional connectivity in utero to gain better mechanistic understanding of candidate disease pathways, rendering new opportunities for early detection, prevention, and treatment of disease.