Elysia P. Davis, Ph.D. - US grants

The primary aim of this proposal is to determine the effects of prenatal treatment with glucocorticoids (GCs) on the HPA axis, affect regulation, cognition and the brain in children born preterm and term. Animal models have demonstrated that prenatal exposure to elevated levels of GCs has persisting consequences for health and development. The lasting influences of GC exposure on development of the human child are not known. Every year hundreds of thousands of women at risk of premature labor are treated with GCs to facilitate lung development in the fetus. As many as 20% of children who were exposed to prenatal GC treatment subsequently were born at term. This group is important for two reasons. First, they are at risk for the consequences of GC exposure without receiving the medical benefits evident for preterm infants. Second, inclusion of this critical group allows the impact of GC treatment to be evaluated independently from the known and deleterious long-term effects on the brain and behavior of premature delivery. Despite the importance to health and development of exposure to GCs, existing research has not separated their effects from the impact of preterm delivery. Participants will include a racially diverse sample of 300 six to eight year old children (100 controls, 100 GC treatment, 100 multiple treatments). The specific aims are to: (i) Assess the influence of prenatal treatment with GCs on hypothalamic pituitary adrenocortical axis (HPA) function and affect regulation. Salivary cortisol levels will be measured at baseline and in response to challenge to assess the integrity of the HPA axis. Parent report measures of fear/anxiety will be employed as a measure of affect regulation, (ii) Evaluate the impact of prenatal treatment with GCs on cognition. Cognition will be assessed using both standardized intelligence measures and neuropsychological tasks that evaluate memory and executive functions, (iii) Determine the effect prenatal treatment with GCs on brain structure, specifically on the volume of the hippocampus, amygdala, and prefrontal cortex (PFC). Magnetic Resonance Imaging (MRI) will be employed, in a subset of 80 children (40 GC exposed), for the in vivo characterization of brain structure. This project will provide the first opportunity to examine the independent influence of fetal exposure to GC's in a group of children born at term.

[unreadable] DESCRIPTION (provided by applicant): The aim of this proposal is to determine the effects of intrauterine exposure to maternal stress and maternal glucocorticoids (GCs) on temperament and hypothalamic-pituitary-adrenocortical (HPA) axis regulation in two-year-old children. Although it is established that prenatal exposure to maternal stress and elevated GCs has life-long implications for health and development in animal models, the lasting impact on the human child is not known. A small, but growing literature is beginning to demonstrate that prenatal exposure to maternal stress and stress hormones has persisting influences on postnatal development. One of the primary consequences of prenatal maternal stress is an increase in behavioral inhibition or emotionality in response to challenge in the offspring. These studies, however, are often limited by their reliance on retrospective report of stress during pregnancy or parent report of child behavior and thus, may reflect differences in the ways that anxious mothers perceive their children. This project will provide the opportunity to examine prospectively and using laboratory observational measures the influence of prenatal exposure to maternal psychosocial and endocrine indicators of stress in 100 two-year-old children from pregnancies followed with serial measures from early gestation (week 14) through term and then postpartum until the age of two years. The specific aims are to: (i) Evaluate the impact of prenatal maternal psychosocial stress and maternal GCs on the development of behaviorally inhibited temperament. Behaviorally inhibited temperament will be assessed with a standardized laboratory observational measure in which children's behavioral and affective responses to a series of novel challenges is observed, (ii) Assess the influence of prenatal maternal psychosocial stress and maternal GCs on HPA axis regulation. Salivary cortisol levels will be measured at baseline and in response to a standardized laboratory challenge to evaluate the integrity of the HPA axis. Behavioral inhibition and increased stress reactivity early in childhood are likely consequences of exposure to prenatal maternal stress and are predictive of the development of anxiety disorders. A number of retrospective studies have indicated that many of the diseases of adult life have part of their origin in the prenatal period. Prospective studies, such as this one, are needed to better understand processes that might underlie this association. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The goal of this proposal is to determine whether postnatal maternal care can moderate the effects of prenatal exposure to maternal stress on infant/toddler development. Accumulating data indicate that prenatal exposure to maternal psychosocial stress and stress hormones has lasting consequences for development. In the animal literature, there is evidence that postnatal maternal care can moderate the impact of these prenatal exposures. While there is a large body of human work documenting the critical role that maternal care plays in shaping a variety of developmental outcomes, little is known about whether postnatal care moderates prenatal stress exposures. The proposed project will address this question using a prospective design and objective laboratory observational measures. We have prospective data collected on mother infant/toddler pairs collected serially from 14 weeks of gestation through two years of age. Maternal psychosocial and endocrine indicators of maternal stress were collected five times during the prenatal period. Infant development was assessed four times from 3 to 24- months. The purpose of this application is to obtain funds to score existing digital video recordings of maternal child interactions to determine whether the quality of maternal care (level and stability) moderates the influence of prenatal stress on the development of (i) fearful temperament, (ii) stress regulation, and (iii) cognitive development during the first two postnatal years. Observations of mother-infant/toddler interactions were collected at 3, 6, 12 and 24-months using a standardized protocol to assess the quality of maternal care including evaluation of maternal sensitivity and responsiveness that was developed for the NICHD Early Child Care Research Network. Thus we have the unique opportunity to determine whether both the quality of maternal care and the continuity over the first two postnatal years moderate the developmental consequences of prenatal stress in human infants as it appears to in animal models.

DESCRIPTION (provided by applicant): Synthetic glucocorticoids (GCs) are widely administered to pregnant women at risk for preterm delivery to enhance fetal lung maturation and have established benefits for respiratory functioning and survival among preterm infants (Crowley, 1995). Ironically, this common prenatal treatment given to promote survival among preterm infants may increase the risk of preterm birth and developmental impairments, particularly among vulnerable fetuses. This is plausible because: (i) GC treatment stimulates placental CRH production resulting in a 1.5 fold increase in CRH concentrations that persists for at least one week (Korebrits et al., 1998; Marinoni et al., 1998), (ii) elevated placental CRH during this gestational period is associated with preterm birth and may be in the causal pathway (Sandman et al., 1994; Wadhwa et al., 1998; Sandman et al., 1999; Smith et al., 2002; Sandman et al., 2003; Wadhwa et al., 2004; Sandman et al., 2006; Smith et al., 2009) and (iii) prenatal exposure to elevated CRH is associated with developmental impairments (Sandman et al., 1999; Davis et al., 2005; Class et al., 2008; Ellman et al., 2008, Preliminary Studies). The goal of the present application is to characterize the placental CRH response to GC therapy and to identify fetuses who are most susceptible to negative consequences resulting from GC treatment. This application will determine if the magnitude of the placental CRH response to GC treatment is associated with birth outcome and infant development. The placental response to synthetic GC treatment will be determined with the serial collection of maternal plasma samples in 150 African American and Caucasian women with singleton pregnancies who present with signs of preterm labor. Samples will be collected before and during the week following glucocorticoid treatment. Infant development will be evaluated with standardized laboratory measures at 6 and 12 months. This project will determine if the magnitude of the placental CRH response to glucocorticoid treatment will be associated with risk for: (i) accelerated time to delivery among women in preterm labor, (ii) increased infant physiological stress reactivity, (iii) infant fearful temperament and (iv) infant mental and neuromotor delays.

Exposure to early life adversity is a risk factor for cognitive dysfunction and psychopathology. The revised Project 3 is informed by discoveries of Project 1 that, in rodents, early-life fragmented patterns of maternal care provokes emotional and cognitive vulnerabilities in adolescence. The Project will test specific hypotheses about how prenatal and early postnatal maternal signals interact to influence the risk for cognitive and emotional vulnerabilities. The long term consequences of exposure to fragmented /unpredictable maternal signals during the fetal and infant periods will be tested with a prospective longitudinal investigation of two cohorts followed from early in gestation and assessed during infancy/toddlerhood (new cohort; N=200) and childhood/adolescence (existing cohort; N=150). Maternal behavior will be observed in real time in the context of interactions with her child and subjected to both linear and nonlinear analyses for the characterization of fragmentation and unpredictability. Child and adolescent behaviors will be evaluated using standardized laboratory measures of indicative of prodromal risk for mental illness. Project 3 will interact closely with Project 2 to create trajectories of emotional and cognitive vulnerabilities. With Project 4 behavioral and imaging tasks will be integrated to construct a matrix of behavioral and brain-network profiles. We will determine: 1) Whether early life exposure to fragmented and unpredictable maternal signals is associated with cognitive and emotional vulnerabilities; 2) The joint role of the prenatal and early postnatal environments for determining later mental health (with Project 2); 3) Whether sex differences in responses to fragmented/unpredictable maternal care contribute to sex specific vulnerabilities to psychiatric disorders; and 4) Consequences of early life exposure to fragmented/unpredictable maternal care (both pre and postnatal) for the structure and network-function of specific brain regions (with Project 4). This project comprises a unique opportunity to investigate the early origins of mental illness. The joint consideration of both fetal and infant periods will lead to a different and broader understanding of the role that early experiences play in determining cognitive and emotional vulnerabilities in contrast to the evaluation of either of these periods in isolation. Further, the coordination between Project 3 and the other projects in this Center will provide new insight into the mechanisms by which early experiences exert lasting effects on cognitive and emotional vulnerabilities.

Project Summary/Abstract Exposure to maternal depressive symptoms is one of the most well established risk factors for the development of later child psychopathology. Accumulating evidence from naturalistic observational studies documents that fetal exposure to maternal depressive symptoms is associated with risk for later child mental health problems. Maternal depression is one of the most common prenatal complications with approximately 40% of women experiencing elevated levels of depressive symptoms. The majority of past research has been correlational, so potential causal conclusions have been limited. This project will break new ground by testing the hypothesis that manipulating maternal depressive symptoms will benefit infant outcomes. In this project, maternal depressive symptoms will be reduced using brief interpersonal therapy (IPT), a well-established and efficacious treatment, and testing whether this reduction leads to an improvement in the development of infant mechanisms associated with risk for later psychopathology. Consistent with NIMH's priority of Research Domain Criteria (RDoC)-based processes, we will assess infants with multiple measures that assess the constructs of potential threat (?anxiety?) from the Negative Valence System and cognitive (effortful) control from the Cognitive System. We propose to assess 300 pregnant women who report elevated levels of depressive symptoms and their infants. Prior to the intervention, maternal measures will be collected. Then half of the women will be randomized to receive IPT and the other half will receive enhanced usual care. After completion of the intervention, maternal measures will be collected longitudinally through 14 months postpartum. Infants will be evaluated at birth and at 7- and 14-months corrected age. Infants will be assessed across four units of analysis (brain structure and function, physiology, behavior, and maternal-report).

Project 3, integrated with the Center, investigates the processes and mechanisms by which a novel type of early adversity influences the development of psychopathology. Early adversity is one of the strongest and most widely reproduced determinants of subsequent mental illness. Novel findings from the current Center award period identify fragmented and unpredictable early life experiences (FRAG), especially unpredictable maternal signals, as altering trajectories of brain circuit maturation and influencing subsequent mental health. In addition to several emotional and cognitive consequences, we recently discovered anhedonia, a transdiagnostic risk factor for psychopathology, as resulting from exposure to FRAG. Project 3 will capitalize on a carefully characterized longitudinal cohort followed from early fetal life through adolescence, coupled with cutting-edge longitudinal neuroimaging techniques and computational network analyses and recently validated novel assessment tools to uncover the mechanisms by which unpredictable prenatal and postnatal maternal and environmental signals influence neurodevelopmental trajectories and underlying circuit development that contribute to mental health through young adulthood. Sex-specific susceptibilities to the effects of early-life FRAG on trajectories of neural circuit maturation and emotional and cognitive functions will be addressed in all 3 Aims. With Projects 1, 2, 4 and the BCDM and Imaging Cores, we will determine the consequences of early-life FRAG on neural circuits and behavioral trajectories that predict psychopathology with an emphasis on anhedonia during adolescence and young adulthood.

Project Summary Postpartum depression (PPD) is the most common form of psychiatric illness occurring after childbirth, affecting nearly 18% of women globally and contributing to suffering and impaired functioning in both mothers and their children. To elucidate factors that contribute to PPD risk, the current project seeks to test the role of inflammatory markers across pregnancy in the prediction of postpartum depressive symptoms. Specifically, reflecting recent theoretical work on the complex and shifting role of the immune system during pregnancy, the current project will utilize a prospective longitudinal design of 165 pregnant women to examine dynamic trajectories of inflammatory markers across pregnancy in the prediction of PPD symptoms and diagnosis at one- and two- months postpartum. Through repeated assessments across the prenatal and postpartum periods, by considering potentially curvilinear trajectories of inflammatory markers instead of single assessments, and by examining a range of immunological markers simultaneously, we will overcome past roadblocks to progress and more closely mirror the alternating immunological priorities of pregnancy. Leveraging stored plasma samples collected prior to the COVID-19 pandemic as part of a parent R01 study of depressive symptoms during pregnancy (MH109662), this work will characterize trajectories of key depression-relevant inflammatory markers across each trimester of pregnancy in women with and without elevated prenatal depressive symptoms (Aim 1) and examine whether inflammatory trajectories prospectively predict depressive symptoms and PPD diagnosis at one- and two-months postpartum (Aim 2). As well, it will probe the predictive specificity of depression-relevant inflammatory markers (versus shifts in Th1 and Th2 cytokines or inflammatory markers implicated in other psychiatric disorders) and will explore whether inflammatory profiles in pregnancy differentially relate to certain PPD symptoms (Aim 3). Through this methodologically rigorous approach, we will be poised to conduct strong tests of directional associations between prenatal inflammation and postpartum depressive symptoms and to identify inflammatory parameters that may serve as risk biomarkers. In doing so, insights from this project will be critical for advancing future hypotheses to elucidate the precise neurobiological cascades that account for links between inflammation and postpartum depressive symptoms, with the ultimate goal to identify novel factors to target in the prevention or treatment of postpartum depression.

PROJECT SUMMARY/ABSTRACT It is critical to understand risk and protective factors for health to optimize developmental outcomes and inform prevention of poor health behaviors across the lifespan. Research using longitudinal designs, multiple levels of analysis, and experimental clinical trials are needed. Cardiovascular disease (CVD) is the leading cause of death worldwide. The origins of adult CVD begin prenatally: High prenatal maternal depressive symptoms robustly predict offspring CVD risk. However, knowledge on risk and protective factors for CVD for offspring of mothers with high depressive symptoms has been correlational. There is a lack of experimental work using a randomized controlled trial (RCT) design to understand potential mechanisms that contribute to children's CVD risk following exposure to high maternal prenatal depressive symptoms across multiple levels (e.g., maternal and child behaviors, physiology) over time. Although efficacious interventions to diminish depressive symptoms among pregnant women exist, research has not investigated whether reducing prenatal maternal depressive symptoms can reduce offspring cardiovascular risk. The current study proposes to leverage a RCT of an effective psychosocial intervention for prenatal maternal depression to test whether reducing prenatal maternal depressive symptoms improves offspring cardiovascular health at ages 3-4 years. We hypothesize that the prenatal intervention operates by reducing both prenatal and postnatal depressive symptoms to improve child outcomes. This study will identify intervention targets for offspring of mothers with high prenatal depressive symptoms to reduce cardiovascular risk. These goals will be accomplished by building on a RCT (R01MH109662) of an established psychosocial intervention that effectively reduces maternal prenatal depressive symptoms. We propose to leverage this unique opportunity to follow up mothers and children who participated in this RCT to test whether this intervention improves offspring cardiovascular health. This project increases rigor of the existing correlational research by using an experimental RCT design. The following 3 aims will be addressed. Aim 1: To test whether reducing prenatal maternal depressive symptoms improves the quality of food the mother feeds her child, maternal feeding behaviors, and modeling of eating behaviors at 3 years. Aim 2: To test whether reducing prenatal maternal depressive symptoms improves child diet, eating behaviors, sleep, and physical activity at 3 years. Aim 3: To test whether reducing prenatal maternal depressive symptoms reduces child CVD risk at 3 and 4 years, including BMI, waist circumference, body fat, blood pressure, and arterial stiffness. This project will provide the strongest evidence to date for a mechanistic model of prenatal maternal depressive symptoms' influence on child cardiovascular health. Importantly, the project will also provide evidence for whether effective psychosocial interventions to reduce prenatal maternal depressive symptoms should be used to reduce the burden of CVD in the next generation.