Intergenerational Transmission of Deficits in Self-Regulatory Control
Self-regulatory deficits are common across a variety of childhood psychiatric disorders in which children have difficulty regulating their thoughts, emotions, and behaviors. By leveraging previously collected prenatal and neonatal data and acquiring new data from mother-infant dyads, this study will identify circuit-based markers of regulatory deficits that are passed inter-generationally, and persist from infancy to childhood. We will enroll 15- 45 year-old pregnant women/mothers, approximately 75% Latina, who are receiving health care from our urban medical center, a sample that is underrepresented in U.S. biomedical research and facing significant psychosocial adversity. Age-appropriate measures of regulatory control processes will be acquired from their off- spring at 4- and 14-months and during preschool and school age, including resting-state fMRI data from neo-nates and both resting and task-based fMRI data from school-aged children who were previously scanned as neonates. Behavioral measures of regulatory capacity and resting and task-based fMRI will also be acquired from the mothers, allowing us to associate maternal-neonatal indices of self-regulatory control. Thus, this study will uncover trajectories of control processes and circuits from infancy to school age and the intergenerational transmission of regulatory deficits from mothers to offspring. Findings will set the stage for future research aimed at engaging these circuits as targets for strategies to prevent the risk for future maladaptive behaviors and at identifying prenatal mechanisms underlying the intergenerational transmission of regulatory deficits, such as epigenetic and stress-mediated biological alterations.
This study supports the NIMH strategic objective to chart mental illness trajectories to determine when, where, and how to intervene by elucidating the development of regulatory control across the first decade of life. This study also supports both the NIH BRAIN and precision medicine initiatives by evaluating the functional organization of control circuits across family generations and longitudinally, as well as using a novel imaging method to predict behavioral outcomes.
Maternal Immune Activation and Fetal-Infant Neurobehavioral Development
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.