Faculty Bibliography

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The longitudinal collection of biological samples from over 7000 birthing parents and their children within the HBCD study enables research on pre- and postnatal exposures (e.g., substance use, toxicants, nutrition), and biological processes (e.g., genetics, epigenetic signatures, proteins, metabolites) on neurobehavioral developmental outcomes. The following biosamples are collected from the birthing parent: 1) blood (i.e., whole blood, serum, plasma, buffy coat, and dried blood spots) during pregnancy, 2) nail clippings during pregnancy and one month postpartum, 3) urine during pregnancy, and 4) saliva during pregnancy and at in-person postnatal assessments. The following samples are collected from the child at in-person study assessments: 1) saliva, 2) stool, and 3) urine. Additionally, placenta tissue, cord blood, and cord tissue are collected by a subset of HBCD sites. Here, we describe the rationale for the collection of these biospecimens, their current and potential future uses, the collection protocol, and collection success rates during piloting. This information will assist research teams in the planning of future studies utilizing this collection of biological samples.

Fetal inflammation, typically measured indirectly through prenatal maternal cytokine markers, has been shown to impact early childhood executive functions (EFs), which are central to later cognitive and life outcomes. Here, we assessed the impact of prenatal inflammation on EF developmental trajectories using direct placenta histopathology measures in 131 mothers who predominantly self-identified as Black (90.8% Black; 0.8% Asian American, 1.5% biracial, 0.8% Latinx, 3.1% White, 3.1% Missing). We found that placental measures of inflammation were associated with limited gain in EF development from 3 to 5 years old. In follow up analyses, we addressed whether screening questionnaires in infancy might aid in classification of infants as higher risk for subsequent EF problems. We found that parent responses to the Ages & Stages Questionnaire and the Infant/Toddler Sensory Profile at 12 months predict the development of EF abilities in children exposed to chronic inflammation. These findings open promising opportunities for early screening of children at risk for poor executive functioning in children exposed to prenatal inflammation.

Understanding the sequence and timing of brain functional network development at the beginning of human life is critically important from both normative and clinical perspectives. Yet, we presently lack rigorous examination of the longitudinal emergence of human brain functional networks over the birth transition. Leveraging a large, longitudinal perinatal functional magnetic resonance imaging (fMRI) data set, this study models developmental trajectories of brain functional networks spanning 25 to 55 weeks of post-conceptual gestational age (GA). The final sample includes 126 fetal scans (GA = 31.36 ± 3.83 weeks) and 58 infant scans (GA = 48.17 ± 3.73 weeks) from 140 unique subjects. In this study, we document the developmental changes of resting-state functional connectivity (RSFC) over the birth transition, evident at both network and graph levels. We observe that growth patterns are regionally specific, with some areas showing minimal RSFC changes, while others exhibit a dramatic increase at birth. Examples with birth-triggered dramatic change include RSFC within the subcortical network, within the superior frontal network, within the occipital-cerebellum joint network, as well as the cross-hemisphere RSFC between the bilateral sensorimotor networks and between the bilateral temporal network. Our graph analysis further emphasized the subcortical network as the only region of the brain exhibiting a significant increase in local efficiency around birth, while a concomitant gradual increase was found in global efficiency in sensorimotor and parietal-frontal regions throughout the fetal to neonatal period. This work unveils fundamental aspects of early brain development and lays the foundation for future work on the influence of environmental factors on this process.

BACKGROUND/UNASSIGNED:Preterm birth (birth at <37 completed weeks gestation) is a significant public heatlh concern worldwide. Important health, and developmental consequences of preterm birth include altered temperament development, with greater dysregulation and distress proneness. AIMS/UNASSIGNED:The present study leveraged advanced quantitative techniques, namely machine learning approaches, to discern the contribution of narrowly defined and broadband temperament dimensions to birth status classification (full-term vs. preterm). Along with contributing to the literature addressing temperament of infants born preterm, the present study serves as a methodological demonstration of these innovative statistical techniques. STUDY DESIGN/UNASSIGNED:= 402) born at term, with data combined across investigations to perform classification analyses. SUBJECTS/UNASSIGNED:Participants included infants born preterm and term-born comparison children, either matched on chronological age or age adjusted for prematurity. OUTCOME MEASURES/UNASSIGNED:Infant Behavior Questionnaire-Revised Very Short Form (IBQ-R VSF) was completed by mothers, with factor and item-level data considered herein. RESULTS AND CONCLUSIONS/UNASSIGNED:Accuracy estimates were generally similar regardless of the comparison groups. Results indicated a slightly higher accuracy and efficiency for IBQR-VSF item-based models vs. factor-level models. Divergent patterns of feature importance (i.e., the extent to which a factor/item contributed to classification) were observed for the two comparison groups (chronological age vs. adjusted age) using factor-level scores; however, itemized models indicated that the two most critical items were associated with effortful control and negative emotionality regardless of comparison group.

IMPORTANCE/UNASSIGNED:Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. OBJECTIVE/UNASSIGNED:To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. EXPOSURE/UNASSIGNED:SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES/UNASSIGNED:PASC and 89 prolonged symptoms across 9 symptom domains. RESULTS/UNASSIGNED:A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

BACKGROUND:The COVID-19 pandemic dramatically altered the psychosocial environment of pregnant women and new mothers. In addition, prenatal infection is a known risk factor for altered fetal development. Here we examine joint effects of maternal psychosocial stress and COVID-19 infection during pregnancy on infant attention at 6 months postpartum. METHOD/METHODS:One-hundred and sixty-seven pregnant mothers and infants (40% non-White; n = 71 females) were recruited in New York City (n = 50 COVID+, n = 117 COVID-). Infants' attentional processing was assessed at 6 months, and socioemotional function and neurodevelopmental risk were evaluated at 12 months. RESULTS:Maternal psychosocial stress and COVID-19 infection during pregnancy jointly predicted infant attention at 6 months. In mothers reporting positive COVID-19 infection, higher prenatal psychosocial stress was associated with lower infant attention at 6 months. Exploratory analyses indicated that infant attention in turn predicted socioemotional function and neurodevelopmental risk at 12 months. CONCLUSIONS:These data suggest that maternal psychosocial stress and COVID-19 infection during pregnancy may have joint effects on infant attention at 6 months. This work adds to a growing literature on the effects of the COVID-19 pandemic on infant development, and may point to maternal psychosocial stress as an important target for intervention. IMPACT/CONCLUSIONS:This study found that elevated maternal psychosocial stress and COVID-19 infection during pregnancy jointly predicted lower infant attention scores at 6 months, which is a known marker of risk for neurodevelopmental disorder. In turn, infant attention predicted socioemotional function and risk for neurodevelopmental disorder at 12 months. These data suggest that maternal psychosocial stress may modulate the effects of gestational infection on neurodevelopment and highlight malleable targets for intervention.

PURPOSE OF REVIEW/UNASSIGNED:The incorporation of digital technologies and their use in youth's everyday lives has been increasing rapidly over the past several decades with possible impacts on youth development and mental health. This narrative review aimed to consider how the use of digital technologies may be influencing brain development underlying adaptive and maladaptive screen-related behaviors. RECENT FINDINGS/UNASSIGNED:To explore and provide direction for further scientific inquiry, an international group of experts considered what is known, important gaps in knowledge, and how a research agenda might be pursued regarding relationships between screen media activity and neurodevelopment from infancy through childhood and adolescence. While an understanding of brain-behavior relationships involving screen media activity has been emerging, significant gaps exist that have important implications for the health of developing youth. SUMMARY/UNASSIGNED:Specific considerations regarding brain-behavior relationships involving screen media activity exist for infancy, toddlerhood, and early childhood; middle childhood; and adolescence. Transdiagnostic frameworks may provide a foundation for guiding future research efforts. Translating knowledge gained into better interventions and policy to promote healthy development is important in a rapidly changing digital technology environment.

IMPORTANCE/OBJECTIVE:The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS/METHODS:We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER/BACKGROUND:Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

BACKGROUND:Maternal stress has negative consequences on infant behavioral development, and COVID-19 presented uniquely stressful situations to mothers of infants born during the pandemic. We hypothesized that mothers with higher levels of perceived stress during the pandemic would report higher levels of infant regulatory problems including crying and interrupted sleep patterns. METHODS:As part 6 sites of a longitudinal study, mothers of infants born during the pandemic completed the Perceived Stress Scale, the Brief Infant Sleep Questionnaire, and an Infant Crying survey at 6 (n = 433) and 12 (n = 344) months of infant age. RESULTS:Maternal perceived stress, which remained consistent at 6 and 12 months of infant age, was significantly positively correlated with time taken to settle infants. Although maternal perceived stress was not correlated with uninterrupted sleep length, time taken to put the infant to sleep was correlated. Perceived stress was also correlated with the amount of infant crying and fussiness reported at 6 months. CONCLUSIONS:Mothers who reported higher levels of perceived stress during the pandemic reported higher levels of regulatory problems, specifically at 6 months. Examining how varying levels of maternal stress and infant behaviors relate to overall infant developmental status over time is an important next step. IMPACT/CONCLUSIONS:Women giving birth during the COVID-19 pandemic who reported higher levels of stress on the Perceived Stress Scale also reported higher levels of infant fussiness and crying at 6 months old, and more disruptive sleep patterns in their infants at 6 months and 12 months old. Sleeping problems and excessive crying in infancy are two regulatory problems that are known risk factors for emotional and behavioral issues in later childhood. This paper is one of the first studies highlighting the associations between maternal stress and infant behaviors during the COVID-19 pandemic.

Brain iron is vital for core neurodevelopmental processes including myelination and neurotransmitter synthesis and, accordingly, iron accumulates in the brain with age. However, little is known about the association between brain iron and neural functioning and how they evolve with age in early infancy. This study investigated brain iron in 48 healthy infants (22 females) aged 64.00 ± 33.28 days by estimating R2 * relaxometry from multi-echo functional MRI (fMRI). Linked independent component analysis was performed to examine the association between iron deposition and spontaneous neural activity, as measured by the amplitude of low frequency fluctuations (ALFF) by interrogating shared component loadings across modalities. Further, findings were validated in an independent dataset (n = 45, 24 females, 77.93 ± 26.18 days). The analysis revealed developmental coupling between the global R2 * and ALFF within the default mode network (DMN). Furthermore, we observed that this coupling effect significantly increased with age (r = 0.78, p = 9.2e-11). Our results highlight the importance of iron-neural coupling during early development and suggest that the neural maturation of the DMN may correspond to growth in distributed brain iron.