Kristina A. Uban - US grants

DESCRIPTION (provided by applicant): Prenatal alcohol exposure (PAE) alters the structure and function of specific brain regions, and these alterations correspond with cognitive, behavioral and neurophysiological deficits; however very little is known about how structural and functional connectivity among regions may be altered. Enhanced understanding of how developmental trajectories are altered in individuals with a Fetal Alcohol Spectrum Disorder (FASD) is essential for the timing and design of specialized interventions, and for identifying sensitive periods during which maximal benefits may be achieved. Ultimately, early interventions can help improve healthy development of brain networks, and produce a more beneficial developmental trajectory. Structural (diffusion tensor imaging) and functional (resting state functional MRI) brain connectivity will be assessed using multimodal neuroimaging techniques in FASD youth and age-matched control participants. Moreover, despite accumulating evidence from animal models, nothing is yet known about how these trajectories of brain development and connectivity differ between FASD boys and girls. It also remains to be investigated if the effects of PAE on altering hormone systems is involved with brain abnormalities in FASD boys and girls. Thus, the present proposal aims to use a multimodal imaging approach to assess sex differences in the effects of PAE on brain connectivity. The proposed research project will assess hormone function in PAE boys and girls, and hormones will be integrated with measures of structural and functional brain connectivity. Integrated brain and hormone measures will be correlated with measures of cognitive performance (WISC-IV). The proposed findings have implications for cognitive, behavioral and mental health problems that occur at a high prevalence among individuals with an FASD. Results will help identify sexually dimorphic effects of PAE on underlying neural networks in order to inform future intervention and treatment strategies targeted to a specific sex and specific impairments in neural networks. Enhanced interventions applied during key developmental time periods may help relieve the burden on health care systems by preventing/reducing a range of health problems later in life.

Individuals affected by prenatal alcohol exposure (PAE) can present with a complex profile of cognitive, behavioral, physical, and mental health problems, referred to as fetal alcohol spectrum disorder (FASD). Of particular relevance, up to 90% of individuals with FASD may experience mental health problems over the life course. Animal models of PAE demonstrate that alterations in neuroendocrine function serve as a fundamental neurobiological mechanism for increased mental health problems; thus, improving or normalizing endocrine function may provide a novel approach for improving outcomes. The primary aim of the K01 proposal is to accelerate the candidate's learning opportunities to addresses this translational gap in knowledge through examination of individual differences in endocrine activity in humans with PAE, and their implications for susceptibility for mental health problems. Towards this end, the candidate's unique and independent aims capitalize on 2 independent NIH-funded research programs: 1) 550 adolescents (33% PAE; 33% non-PAE with drinking moms; 33% non-PAE with non-drinking moms; 50% girls; aged 9-12 years) from the Adolescent Brain Cognitive Development (ABCD) study in the United States, and 2) 160 adolescents (50% PAE across all trimesters; 50% non-PAE; 50% girls; aged 9-12 years) as part of the Prenatal Alcohol SIDS and Stillbirth (PASS) birth cohort in South Africa. The K01 proposes to: A) utilize funded neuroimaging and prenatal substance exposure data in ABCD/PASS; B) utilize funded ABCD data on hormones, puberty and mental health; and C) collect new PASS data on hormones, puberty and mental health. Methods for assessing brain, mental health, and puberty will be harmonized between ABCD and PASS cohorts, yet there will be distinctly different experimental designs, each with their unique strengths and limitations. These contrasting cohort designs and populations provide a rare opportunity for acceleration of learning opportunities as well as advancement of our ability to identify the most important components of variance for understanding individual differences in endocrine function in adolescents with PAE. Groups will be matched on age, sex, race and SES within their respective cohorts. Initial findings from the ABCD cohort will inform tests in the independent PASS sample, providing strength for interpreting generalizability of findings across diverse social, racial and cultural environments. The candidate's training will take advantage of the rich expertise of the diverse mentoring team to integrate central/peripheral measures of endocrine function, by bridging the fields of neuroimaging, neuroendocrinology, salivary biosciences and biostatistics to better understand individual differences in endocrine function. The training plan capitalizes on the central location of CHLA, and includes didactic courses and one-on-one mentoring at USC (latent state trait modeling course), UCI (salivary bioscience course), and UCLA (MPlus). The training plan will foster new neuroimaging expertise through learning how to integrate two imaging modalities, as well as building expertise in salivary biosciences, biostatistics and mental health.