Establishing Early Brain Signatures associated with Maternal Immune Activation Exposure

While 1 in 5 children are at risk for psychiatric disorders, only 1 in 20 young children receive mental health care. There remains a gap in knowledge of early causes and precursor symptoms of psychiatric disorders; therefore, many children are not identified as at risk until school age, when a diagnosis can reliably be made. Prenatal maternal immune activation (MIA) from infection, stress, medical conditions, and environmental pathogens has been associated with offspring risk of psychiatric disorders. There remains a gap in our knowledge of the early brain and behavioral antecedents of this risk. Preclinical studies suggest that MIA may lead to biochemical changes in the developing brain that disrupt brain-behavior functional associations. We propose to examine whether prenatal exposure to MIA leads to metabolic and functional modifications in the developing brain and analogous behavioral phenotypes in human offspring. Our prior work demonstrated that MIA (interleukin-6; IL- 6) was associated with functional connectivity of the salience network (SAN), a network integral for emotion regulation, in neonates. Extending this, we will conduct longitudinal magnetic resonance imaging (MRI) scans in fetuses, neonates, and infants to determine if the alterations in the SAN originate in the fetal period and map developmental trajectories of the SAN in early life. In tandem, we plan to collect longitudinal magnetic resonance spectroscopy (MRS), which provides mechanistic information about the metabolic and cellular properties that may correspond to disruptions of SAN functional activity. Our pilot data suggests that MIA is associated with myo-inositol, an indicator of astroglial cell activation, in the newborn brain. Our central hypothesis is that MIA, evidenced by levels of inflammation (primary: IL-6) and infection (primary: Total immunoglobulin G), is associated with brain connectivity and metabolites in the SAN and behavioral reactivity from the fetal to infancy periods. One hundred and seventy-five pregnant women-fetal dyads will participate in this study from 12 weeks gestation to 9 months postnatal life. The pregnant women will have blood draws and psychological assessments at three timepoints and fetal physiologic assessment and MRI at 33-36 weeks. The infants will participate in MRI (2-6 weeks and 4 months postnatally) and observer-based behavioral paradigms at 4- and 9-months of age. Our proposal uses a collaborative science approach, bringing together perinatal-developmental neuroscience (Marisa Spann), psychoneuroimmunology (Staci Bilbo), maternal-fetal medicine (Mirella Mourad), and quantitatively trained biomedical engineers in the areas of developmental functional imaging and data science (Dustin Scheinost) and MRS (Christoph Juchem). This proposal is significant because it will provide mechanistic and system levels information about the rapidly developing brain that map on to an important behavioral system, emotion regulation. This research has the potential to reveal trajectories of behavioral health in early childhood and present approaches to detect early markers of psychiatric risk.