in the early development of the cognitive assessment protocols, Vince Magnotta, PhD, and Andrew Metzger for their extensive work on the development of the automated pipeline for 12-month-old infant scans, Corinne Hamlin, MAT, in recruitment, scheduling, and administration of this study, Holly Dirks, RN (Brown University) for her tremendous amount of guidance and training in the infant MRI sleep protocol, MRI research technologists Autumn Craig and Marla Kleingartner for their assistance during

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... ur infant scans, Jane Brumbaugh, M.D., Diane Eastman, ARNP in the high-risk followup pediatric clinic, and clinical research coordinators Karen Johnson, BSN, and Gretchen Cress, BSN, MPH in the Department of Pediatrics for their significant role and assistance in recruitment of infant participants, members of the PPG Research Group (Project Number 5P01HL046925-17 "PRETERM TRANSFUSIONS: BRAIN STRUCTURE AND FUNCTION OUTCOMES") for supporting my graduate work and providing critical evaluations and suggestions for direction over the past four years, , and Russell Valentin for his assistance in the coding of cognitive tasks. Finally, I would like to thank my mentor, Peg Nopoulos, for her foremost and invaluable role in my graduate training and scientific development over the past four years, and iii even more importantly, for always being the positive and encouraging source for me as I progressed through the sometimes difficult stages of graduate school. iv ABSTRACT Due to a steady increase in preterm birth rates over the past 20 years, prematurity has emerged as an important public health concern. Among the morbidities observed in this preterm population is a predominance of cognitive and behavioral deficits, suggesting the study of brain development, in particular, as an area of importance. The current study investigates neurodevelopmental outcomes in the first years of life of both brain structure, with the use of structural magnetic resonance imaging (MRI), and function, with the use of three novel cognitive tasks: (1) Visual Working Memory (VWM) task 1 , a variant of changedetection paradigms commonly used in adults to assess VWM capacity; (2) Infant Orienting With Attention (IOWA) task, a "spatial-cueing" task that assesses visual orienting and attention; and (3) Encoding speed task (EST), a continuous familiarization paradigm assessing speed of information processing. Healthy 12-month-old full-term and preterm infants were recruited through University of Iowa's High-Risk Follow-up program and Neonatal Admissions Registry. [Demographics of participants: mean corrected age: 12.84 months, gestational age (GA) range: 23.00-41.14 weeks. ]. An MRI imaging acquisition protocol was developed in order to scan infants during their naptime without sedation. A novel automated atlas-based segmentation approach to tissue classification developed at the University of Iowa was implemented in order to generate structural brain volumes of gray matter (GM), white matter (WM), cerebrospinal fluid, (CSF) and blood for each of the following regions of interest (ROI): total intracranial, cerebrum, cerebellum, striatum (consisting of caudate and putamen), globus pallidus, thalamus, and hippocampus, and all four cerebral lobes (frontal, occipital, parietal, temporal). Performance measures for each of the cognitive tasks were based on recorded infant eye movements (latency & direction), and included: "Change preference scores", shift rate, and total looking v time (VWM task); visual spatial orienting measures (mean reaction time, mean error rate [MER]), and attention proficiency scores (cue facilitation, cue interference, and cue sensitivity) (IOWA task); Number of trials to reach "criterion," novelty score, shift rate, and average "look" duration (EST). Linear regression analyses demonstrated gestational age (GA) as a significant predictor of performance in all three cognitive tasks: (1) On the more challenging multi-item VWM task, "older GA" preterm infants had significantly shorter total looking times than "early preterm" infants; (2) from the IOWA task, both MER and two attentional proficiency measures (cue facilitation and cue sensitivity) were associated with GA, again with superior performance from the "older GA" infants; and (3) two measures of processing speed on the EST were associated with GA, with older GA infants having better performance. Neuroimaging data demonstrated that increased GA predicted increased cerebral GM volumes (in particular, occipital and temporal lobe GM), in addition to increased striatal and thalamic volumes. Brain structure-function analyses showed associations of decreased occipital GM volume with increased total looking time (VWM task), while temporal GM and thalamic volumes were directly correlated with the two measures of attention: cue facilitation and cue sensitivity scores (IOWA task). Decreased volumes in multiple subcortical and cortical areas were correlated with worse performance on the EST, including temporal GM, occipital GM, striatum, and thalamus. Therefore, results of this study support the use of these cognitive tasks as sensitive enough to detect specific functional differences in performance based on GA early in development, and that performance may be directly related to underlying brain structures. 12month-old infants born at earlier GAs demonstrate selective functional deficits, as opposed to the global cognitive delay currently assessable by Bayley-III in clinics 2 . Therefore, these tasks may be potential early markers of risk in preterm and/or other high-risk infant populations. Continued investigations using more direct evaluations of the underlying brain structural vi correlates of memory, attention, and processing speed, through the use of multi-modality structural and functional brain imaging currently available, will provide a deeper understanding of early brain-behavior relationships during this critical period of dynamic maturation in the infant. vii PUBLIC ABSTRACT Due to a steady increase in the number of babies born prematurely over the past 20 years, prematurity (a birth occurring before 37 weeks gestation) has emerged as an important public health concern. Even with improved survival of these infants, they remain at risk for many unfavorable health outcomes. Most of those risks include cognitive and behavioral deficits that show up later in life, highlighting the importance of studying the development of the brain, in particular. The current study investigates brain development outcomes in the first years of life using: (1) structural magnetic resonance imaging (MRI) to study brain structure, and (2) three novel cognitive assessments of visual working memory, attention, and speed of processing information. Healthy 12-month-old infants were recruited through University of Iowa's Neonatal Admissions Registry. An MRI imaging acquisition protocol was developed in order to scan infants during their naptime without sedation. Additionally, a new automatic approach to classifying areas of the brain was developed at the University of Iowa Department of Radiology for 12-month-old brain images. These novel cognitive assessments are based on infant eye movements (including how long it takes for an infant to react to certain stimuli and the direction of their looking). Results from this study support the use of these cognitive tasks to detect specific functional changes in performance based on gestational age. Therefore, these tasks may be potential early markers of risk in preterm populations, but continued investigations are necessary to fully elucidate early brain outcomes during this critical period of development. viii