Claudia Buss, PhD - US grants

DESCRIPTION (provided by applicant): Alterations of normal brain structure and white matter integrity are known to underlie many neuropsychiatric, neurodevelopmental, and behavioral disorders. Although these brain disorders can produce alterations in brain morphology, the vulnerability hypothesis suggests it also is possible that the incidence of these disorders may, in part, be a consequence of pre-existing alterations in brain morphology. It is believed that the origins of many of these pre-existing alterations in brain morphology can be traced back to the fetal period of life, when the developing fetus responds to suboptimal conditions during critical periods of cellular proliferation, differentiation and maturation by producing structural and functional changes in cells, tissues and organ systems. The goal of this proposed research is to test specific hypotheses about the effects of in utero biological stress exposure on human brain morphology and white matter integrity at birth and over the first year of postnatal life. Our proposal emphasizes the use of maternal-placental-fetal (MPF) endocrine and inflammatory measures of stress over gestation as the principal marker of exposure to intrauterine insults. The specific aims addressed in our proposal relate to determining the impact of prenatal MPF endocrine (CRH, cortisol) and immune/inflammatory (IL-6, TNF-1) markers of intrauterine stress on brain morphology and white matter integrity at birth and over the first year of postnatal life, and to examine the interrelationships between intrauterine perturbations, brain volume and white matter integrity, and brain function. We propose to conduct a prospective, longitudinal, follow-up study in a population-based cohort of children born to mothers who will participate in an NIH-funded study of biological and behavioral processes in pregnancy. We will have extensive characterization in this child cohort over the course of their intrauterine life and birth with all the prenatal measures required to address the above questions, including serial measures of the maternal-placental- fetal endocrine and immune/inflammatory milieu, clinical measures of obstetric complications, laboratory results of clinical/diagnostic tests, measures of maternal sociodemographic, behavioral, and psychosocial characteristics, measures of the birth phenotype, and banked samples of maternal biologic tissue and extracted maternal and child DNA samples. We will recruit a sample of 120-140 children from this cohort at birth and follow them up until 12 months age. We propose two major study assessments at T1= 2-4 weeks and T2= 12 months age. Our primary study outcomes, brain morphology (size of the hippocampus, amygdala and prefrontal cortex) will be derived from serial MRI scans, and white matter integrity (fractional anisotropy along major white matter tracts: corpus callosum genu and splenium tracts and uncinate fasciculus) will be derived from serial DTI scans. For all predictor variables (CRH, cortisol, IL-6 and TNF-alpha), the area under the curve (AUC) will be estimated using General Additive Models (GAM) via cubic B-splines, which will be used as the predictors for measures of brain morphology and white matter integrity. In order to determine if there are particular time points during pregnancy that represent "sensitive periods" in predicting size of HC, AG and PFC, polynomial distributed lag models will be employed. Infants'mental and motor development will be assessed at concurrent time points (at T1 and T2) with the Bayley Scales of Infant Development. Mediation models will be applied to test whether alterations in the brain associated with MPF parameters account for the association between the same MPF parameters and BSID performance. By providing novel neuroimaging data in human newborns/young infants and linking these outcomes to well-characterized measures of the intrauterine and early postnatal environment, we suggest the study will set the stage for translational research with implications for early identification of risk/vulnerable populations, and will thereby inform the subsequent development of primary and secondary intervention strategies.

DESCRIPTION (provided by applicant): There is a major resurgence of interest in brown adipose tissue (BAT) biology following the relatively recent discoveries that, contrary to prior belief, BAT does in fact persist into adulthood and appears to play an important, beneficial role in reduced obesity/adiposity risk. The nature of BAT as a specialized heat-producing and energy- expending tissue, its presence in substantial amount in newborns, and its role in neonatal thermogenesis has long been established. However, very little is known about the relationship of BAT characteristics in early life in humans and its implications for obesity/adiposity and metabolic function in subsequent periods of life. Thus, as an important first step to addressing this broad issue, the specific aims of the current proposal are (1) to characterize in a sample of healthy human newborns inter-and intra-individual variation in the volume of BAT at birth and reduction in BAT mass over the first year of life, and (2) to study the associations of BAT mass at birth and BAT mass attrition over the first year of life with key biophysical, metabolic and other developmental parameters, including body composition, total energy expenditure and insulin sensitivity. A unique strength of our proposal is the availability f a cohort of newborns and infants who are extensively characterized over the course of their intrauterine and postnatal life. We are currently conducting NIH-funded prospective, longitudinal projects in a representative, population-based cohort from birth (T1) and over the early postnatal growth phase until 12 months age (T2). These births occur in mothers who, in turn, were extensively and longitudinally studied over the entire course of their index pregnancy. The infant assessments include serial measures of growth, body composition, energy expenditure, and insulin sensitivity, and magnetic resonance imaging (MRI) assessments of the brain during natural sleep. The current R21 proposal seeks funds to incorporate the study of an additional, related outcome of high interest and relevance - newborn and infant brown adipose tissue (BAT) volume - using a non-invasive water-fat separated MRI protocol that our group has validated for the use in human infants. Within the 2-year time frame of the current proposal we propose to assess BAT volume in a subpopulation of N=100 infants longitudinally from birth until 12 months age. Our proposal addresses the following knowledge gaps: a) the developmental ontogeny of brown adipose tissue depots from birth until 12 months age; and b) the consequences and implications of BAT depots in infancy for subsequent obesity risk and associated metabolic dysfunction. The significance and impact of this study derives from the importance of achieving a better understanding of the underlying processes that increase risk or vulnerability for obesity (adiposity) and metabolic dysfunction. This study will collect novel data (serial measures of infant brown adipose tissue mass) and produce results that set the stage for the development of subsequent, testable hypotheses and translational research with important implications for early identification of risk/vulnerable populations, in order to inform the subsequent development of primary and secondary intervention strategies.

DESCRIPTION (provided by applicant): Exposure to severe trauma in childhood such as physical or sexual abuse represents one of the most pervasive and pernicious stressors in society. Its sequelae, which may endure over the entire lifespan, include depression, PTSD, endocrine and immune function dysregulation, obesity, substance abuse, and also increased likelihood of subsequent exposure to trauma in adulthood. Moreover, emerging evidence suggests the long shadow cast by childhood trauma may not be restricted to only the lifespan of this vulnerable population of abused women, but also may be transmitted to another yet even more vulnerable population - their children - who then go on to exhibit an increased prevalence of neurodevelopmental and psychiatric disorders. Thus, a vicious cycle of perpetuation and possible amplification may become established. The prevailing view is that the intergenerational transmission from mother to child of the effects of maternal exposure to childhood trauma likely occurs after her child's birth via the effects of maternal dysfunctional states and behaviors (e.g. low maternal sensitivity, depression). We postulate that the process of intergenerational transmission may start earlier during the highly sensitive period of fetal development. In the current proposal we focus on the newborn child's brain stress circuit morphology and connectivity as the outcome of primary interest and on CT-related alterations in the maternal-placental-fetal (MPF) endocrine and immune stress biology as the proximate pathway of transmission. We propose to conduct a prospective, longitudinal study from early gestation till the neonatal period in a population-based cohort of approximately 200 mother-child dyads. We will collect serial measures of stress biology in early, mid and late pregnancy to characterize the endocrine (CRH, cortisol) and immune (CRP, IL-6) milieu at each trimester as well as their trajectories across gestation. We will acquire newborn brain scans to quantify the volumes of fronto-limbic regions (hippocampus, amygdala, prefrontal cortex) and their structural and functional connectivity as the primary outcomes of interest. Causal pathway models will be used to assess whether the effects of maternal CT exposure on her newborn's brain and mediated by MPF stress biology. Among CT+ women we will delineate the relative importance of psychiatric/psychological, behavioral and biophysical states and conditions in modulating the effects of CT exposure. This project addresses scientific and public health issues of critical importance. Our results will reveal new information about the health status of vulnerable populations and shed light on the mechanisms of intergenerational cycles of vulnerability. Our findings may suggest new avenues for early identification of at-risk individuals, as well as for th subsequent development and testing of prevention and intervention strategies to limit the intergenerational perpetuation of poor health and disadvantage. Study results will be disseminated through scientific publications and presentations at scientific conferences as well as at advanced training events for medical and social work personnel.

ABSTRACT There is rapidly growing evidence that the health and development of the child and adult can be traced to early environmental influences. However, the vast majority of the evidence is correlational: fundamental questions remain about which specific early exposures confer risk, when in development exposure may have significant and lasting influence, and the mechanisms of effects. This application to the Environmental Influences on Child Health Outcomes (ECHO) RFA (OD-16-004) synthesizes two recently initiated and highly compatible pediatric cohort studies in which environmental exposures are being tracked in 500 pregnant mothers from the 1st trimester; we are already collecting extensive prenatal biological samples and placental samples as well as detailed psychological, socio-demographic, and life history data. We especially target the prenatal period to examine if and how prenatal exposures may ?program? adaptive biological responses in the fetus and child, with carry-forward effects on brain and somatic health; furthermore, we focus particularly on inflammation as a mediator of environmental exposures because it is a compelling biological mechanism by which a wide range of exposures may shape child neurodevelopment and obesity. These data, which cover cellular mechanisms and social demography, will help translate how the range of environmental influences from pregnancy shape child health outcomes. The 500 children will be extensively studied at newborn, 6 months, 1 year, 2 years, 3 years, and 4 years of age using clinically derived and state-of-the-art behavioral, physical and biological assessments of neurodevelopment and obesity. In the UG3 phase we will harmonize protocol development across sites; complete collection of prenatal and a substantial majority of placental samples and perinatal outcomes across cohorts; commence collection of neonatal brain imaging and physical development outcomes. We will also develop models for the biological and social and demographic exposure data in preparation for analyses of child health outcomes in the UH3 phase. For the UH3 phase, we will characterize inflammation from multiple sources throughout pregnancy, in the placenta, and in early infant development to identify its psychosocial, developmental, and environmental exposure origins and sources. In addition, we will test alternative mechanisms by which prenatal exposures and indicators of inflammation predict perinatal outcomes, child obesity, and child neurodevelopment. We will also complete the complex task of biobanking extensive blood, urine, saliva and place samples on approximately 1,000 individuals and contributing the broader ECHO consortium research agenda. The proposed study will add significant new information to our understanding of which environmental influences may have causal influence on child health outcomes, and the timing and mechanisms of these effects. This information will provide a much-needed empirical foundation to know how and when in development to intervene to promote child health outcomes.