Marisa N. Spann, Ph.D. - US grants

PROJECT SUMMARY Self-regulatory deficits are common across a variety of childhood psychiatric disorders in which children have difficulty regulating their thoughts, emotions, and behaviors. By leveraging previously collected prenatal and neonatal data and acquiring new data from mother-infant dyads, this study will identify circuit-based markers of regulatory deficits that are passed inter-generationally, and persist from infancy to childhood. We will enroll 15- 45 year-old pregnant women/mothers, approximately 75% Latina, who are receiving health care from our ur- ban medical center, a sample that is underrepresented in U.S. biomedical research and facing significant psy- chosocial adversity. Age-appropriate measures of regulatory control processes will be acquired from their off- spring at 4- and 14-months and during preschool and school age, including resting-state fMRI data from neo- nates and both resting and task-based fMRI data from school-aged children who were previously scanned as neonates. Behavioral measures of regulatory capacity and resting and task-based fMRI will also be acquired from the mothers, allowing us to associate maternal-neonatal indices of self-regulatory control. Thus, this study will uncover trajectories of control processes and circuits from infancy to school age and the intergenerational transmission of regulatory deficits from mothers to offspring. Findings will set the stage for future research aimed at engaging these circuits as targets for strategies to prevent the risk for future maladaptive behaviors and at identifying prenatal mechanisms underlying the intergenerational transmission of regulatory deficits, such as epigenetic and stress-mediated biological alterations. This study supports the NIMH strategic objective to chart mental illness trajectories to determine when, where, and how to intervene by elucidating the develop- ment of regulatory control across the first decade of life. This study also supports both the NIH BRAIN and pre- cision medicine initiatives by evaluating the functional organization of control circuits across family generations and longitudinally, as well as using a novel imaging method to predict behavioral outcomes.

An estimated 1 in 5 children are diagnosed with a neurodevelopmental disorder. Neurodevelopmental disorders increase the likelihood of poor academic performance and social challenges. Although there has been some research on early risk for later neurodevelopmental disorders, there are few studies in the first years of life. Maternal immune activation (MIA) to infectious and inflammatory agents raises the risk of neurodevelopmental disorders, such as intellectual disabilities and autism. The overarching purpose of the Career Development Award (K23) is for the candidate, Marisa Spann, a clinical child neuropsychologist, to gain training and mentored research experience on prenatal immunological antecedents of infant brain and behavioral development. With mentorship from Drs. Catherine Monk, Alan Brown, and R. Todd Constable, the application includes training activities for the candidate to achieve the following career goals: 1) develop knowledge of developmental and maternal-fetal immunology; (2) develop skills in perinatal biobehavioral study design and methods; and (3) develop skills in functional neuroimaging and longitudinal statistical modeling. The training and mentored research will occur at Columbia University Medical Center (CUMC)?a top research institution with multi-disciplinary research programs. The research plan will capitalize on a cross-disciplinary model that combines the strengths of a population-based Finnish birth cohort from an extant dataset, and new data collection with a clinical sample of pregnant women recruited from CUMC. The primary goal of the study is to detect associations between prenatal MIA and early brain (head circumference, brain morphometry and connectivity) and behavioral development. In the population-based birth cohort, the candidate will investigate the associations between prenatal maternal influenza infection (influenza immunoglobulin G) and an inflammatory (C-reactive protein) marker, and growth velocity of head circumference from birth to one year. The new data collection will include the recruitment of a new hospital-based sample of pregnant women. In the newly established clinical cohort from CUMC, the candidate will detect associations of maternal influenza and inflammatory markers with neonatal brain morphometry and functional connectivity indices and behavioral reactivity in 3rd trimester fetuses and 4 month old infants. With the well-integrated training and research plans, the K23 award will ensure that the candidate develops the skills necessary to achieve independence in a novel interdisciplinary career area as a perinatal?developmental neuroscience researcher. The candidate will be uniquely positioned to discover distinct and common neurobiological and behavioral trajectories of neurobehavioral health prior to age one, in the service of determining risks for neurodevelopmental disorders, and its early identification.

Despite evidence that 1 in 5 children are at risk for psychiatric disorders, only 1 in 20 young children receive mental health care. Thus, a high number of children who would benefit from mental health care remain untreated. My long-term goal is to improve brain-based targets for early detection and behavioral interventions of childhood psychiatric disorders. The area of perinatal-developmental neuroscience (PDN) is of high public health significance as a substantial proportion of pregnant women will experience health, environmental, or psychological stressors, which have early and long-lasting effects on offspring. Increasing the number of research programs that can support training in PDN is paramount. The K24 will allow me to: 1) expand my expertise in advanced analytic methods to support trainee research, and 2) establish an internationally recognized research and training program focused on fetal-infant brain and behavioral origins of mental health. My K24 training program, the Columbia Engagement, Stability, and Success in PDN will provide an individualized approach to research training: assessing the research skills and career goals of mentees early on and developing personalized training modules; didactics; experiential, hands-on training; and research productivity that follow their individualized plan. The program also includes a monthly seminar series alternating between science and career-networking topics. Our prior studies suggest there may be common biological pathways by which early exposures exert their influence on offspring conferring psychiatric risk ? with recent attention to the immune system and/or hypothalamic-pituitary-adrenal axis, and brain regions involved in behavioral regulation. Using the expanded analytic skills obtained through this K24, my mentees and I will conduct studies to examine whether four key prenatal exposures: maternal depression, body mass index, infection, and blood glucose are associated with connectivity and morphology of brain regions (e.g., dorsal anterior cingulate) involved in behavioral regulation. In a subset of the cohort, we will also consider the potential mediating effects of inflammation and glucocorticosteriods. I have a unique opportunity to pool data from cohorts of pregnant women-fetal dyads involved in research studies (2004 to present; n~500) at Columbia University Irving Medical Center ? a large center with a diverse patient population ? and perform new data collection harnessing health information technology (e.g., electronic medical records). The data set will serve as a platform for my mentees to produce pilot projects and manuscripts, and practical experience conducting a project in an area of PDN that matches his/her career goals within the scope of this funding mechanism. My strong commitment to and ongoing research in patient-oriented research focused on identifying early antecedents of psychiatric risk, individualized mentorship plans, direct involvement of mentees in the conduct of research, and tailored career development program at Columbia University Irving Medical Center are strengths of this application. The K24 mentees will be uniquely positioned to discover neurobiological and behavioral pathways associated with risk.