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.
Neuropsychiatric and neurodevelopmental disorders are a major health problem because they confer severe disability upon affected individuals, their families and the human capital of a society; they have a relatively high prevalence; and their underlying causes are not well understood. Alterations in specific brain regions and white matter tracts are associated with increased risk or susceptibility for these conditions. Some studies have suggested that the origins of many of such pre-existing alterations in the brain can be traced back to the fetal period of life. 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. By using biological (maternal-placental-fetal endocrine and immune) measures of stress that are known to reflect a variety of possible intrauterine perturbations, we suggest our approach wil be more efective in capturing fetal exposure to a broader set of factors than other studies that have focused primarily on size at birth or maternal infection or nutrition in pregnancy. By concurrently assessing mental and motor development, we will be able to study the interrelationships between intrauterine perturbations, alterations in brain structure, and variation in brain function. The significance and impact of this study derives from the importance of achieving at a beter understanding of the underlying processes that increased risk or vulnerability for many neuropsychiatric and neurodevelopmental disorders that confer a major burden of disease in society, and from expanding the current view of a predominantly genetic basis for this vulnerability to one that incorporates an innovative and novel application of the fetal programming paradigm to a set of biological measures that may act as 'sensors' of the quality of the intrauterine environment as well as 'transducers' of its effects on the developing fetal brain. We suggest this study may have implications for early identification of risk/vulnerable populations and may inform the development of subsequent primary and secondary intervention strategies.
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