Sarah J. Short, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The effects of maternal influenza exposure on the developing fetal brain and the associated risk for behavioral and hormone dysfunction will be examined. The importance of virus-induced changes in maternal immunity and placental physiology will be analyzed with respect to the development of the infant postpartum. The studies proposed for this fellowship are designed to: 1) create a nonhuman primate model of flu infection during pregnancy; 2) identify the physical, behavioral, and neuroendocrine profiles of flu-exposed and control infants; 3) measure hippocampal vulnerability to prenatal insult using structural MR imaging and assessment of the HPA axis in cortisol release and negative feedback. Development of a nonhuman primate model that utilizes a human derived strain of the influenza virus has important implications for understanding how flu exposure during pregnancy may impact the mental and physical health of children. Furthermore, these findings are relevant to neuropsychiatric diseases and cognitive disorders that may be due to disturbed prenatal development, involving high levels of maternal cytokines or steroid hormones that interrupt normal neuronal differentiation and development of the brain [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application for an NIMH Mentored Research Scientist Career Development (K01) award seeks support to develop a program of research focused on characterizing the development of white matter and working memory in children who are typically developing and in children who are at genetic high-risk for schizophrenia from 1 to 8 years of age. An additional aim of this program is to conduct a pilot study with typical children to determine the feasibility of measuring experience-dependent structural plasticity in white matter, following training with a standardized adaptive working memory program. The candidate seeks career development training in three areas to support her long-term career goals: 1) Advance her neuroimaging background with novel instruction in joint analysis of structural (sMRI) and diffusion tensor imaging (DTI) across multiple stages of early brain development, 2) Develop a strong knowledge base for the biostatistical methods used in longitudinal and multivariate analyses important for examining developmental trajectories, structure-function relationships, and subtle brain changes over time, and 3) Gain experience in the design, planning and implementation of neurocognitive interventions in young children. This program of training and research will improve current understanding of early brain development in typical and high-risk children in relation to an early emerging and formative cognitive skill, working memory. Results from the proposed research will be used to identify early biomarkers of risk, which can be used to inform the design of targeted preventive intervention strategies for high-risk children. Schizophrenia is a debilitating disease with early neurodevelopmental origins that impact the structure, function and connectivity of the brain. Impairments in network connectivity are likely responsible for many of the core features of schizophrenia, including poor working memory. By the time clinical symptoms present, in late adolescence or adulthood, the underlying pathologic brain development has already occurred and is most likely irreversible. Neuroimaging studies have consistently shown that patients had reduced gray matter (GM) volumes and increased lateral ventricles, prior to the onset of psychosis. Likewise, DTI studies suggest that white matter (WM) integrity is also reduced early in schizophrenia. Therefore the importance of identifying early indicators or biomarkers of risk is critical for determining who is at-risk and how to design targeted preventive interventions. Relatively little is known about how the brain develops during one of the most dynamic and critical periods of maturation, from birth to 6 years of age. As a consequence, our understanding of structure-function relationships during this developmental period is limited as well. Working memory emerges in infancy and serves as a cognitive building block for the formation of other executive functions. Poor working memory is a core feature of schizophrenia that is typically present in childhood, long before the onset of psychosis. Therefore, improving our understanding of brain development in relation to cognitive functions is critical for advancing our ability to identify individuals at-risk early in development and for promoting healthy long-term outcomes. Until recently, technological and methodological limitations prevented researchers from non- invasively characterizing these early periods of human brain development. Our multidisciplinary research team at the University of North Carolina, Chapel Hill has pioneered recent advances in noninvasive neuroimaging (sMRI and DTI), and has also developed innovative analysis techniques to characterize microstructural features of white matter in children. Our research team at UNC has generated the only longitudinal dataset available, with neuroimaging and cognitive measures, collected from birth through 6 years of age, from large cohorts of children who are typically developing and at genetic high-risk for schizophrenia. This existing data will serve as the basis for the proposed research and career development training. The importance of identifying early indicators or biomarkers of risk is critical for determining who is at-risk and how to design targeted preventive interventions. The proposed research will help identify white matter connections that are important for the development of working memory and will determine whether they are altered in children at risk for schizophrenia. In addition, the feasibility study f working memory training in typical children will provide valuable information about the capacity to measure experience-dependent structural changes in white matter tracts. Strengthening neural networks associated with early foundational cognitive processes may help to ameliorate later impairments in other cognitive, social and developmental capacities that depend on working memory.

Project Summary Chronic stress for children growing up in poverty may lead to lasting effects on social, behavioral, and cognitive development. The difficulties of living in economic hardship has, indeed, been associated with deficits in cognitive and academic performance. The current study examines the link between poverty and executive functions (cognitive processes that facilitate learning, self-monitoring, and decision making) which are known to undergo rapid developmental change during the first years of life. Early neurological development will be examined as a mediator of this association examined from pregnancy to age 3. In addition to distal risk associated with living in poverty, we will investigate critical experiences within the proximal context (i.e., language exposure, caregiver behavior, child sleep hygiene) that may mediate the effect of this risk on child structural and functional brain development. Participants (n= 230) will be seen during the 28th week of pregnancy, and at 5 visits across the first 3 years of their child's life. Neuroimaging will be conducted at 2 weeks, 15 and 24 months (with an accompanying lab visit at 15 months). We will focus on developing white matter tracts that support cognitive processes of emerging executive functions: anterior cingulum (error monitoring); uncinate (joint attention); arcuate fasciculus (language processing) and individual differences in functional brain development, including resting state networks of salience, attention, executive control, and default-mode. At 6 and 24 months of age, an intensive home visit will include observational and objective measures of caregiver behavior, language exposure (via speech recorders) and sleep hygiene (via actigraphy for 7 days). Child cognitive development will be assessed at each assessment and an executive functioning battery will be administered at 36 months of age. This study will be the first to investigate the influence of poverty on emerging executive functioning at age 3 via effects on child neurological development over the first two years of life. In addition, findings will contribute critical information regarding whether specific measures of proximal experience (language exposure, caregiver behavior, child sleep hygiene) may mediate this risk.