The peripheral epigenome predicts white matter volume contingent on developmental stage: An ECHO study.

Epigenetic processes, including DNA methylation, are emerging as key areas of interest for their potential roles as biomarkers and contributors to the risk of neurodevelopmental, psychiatric, and other brain-based disorders. Despite this growing focus, there remains a notable gap in our understanding of how DNA methylation correlates with individual variations in brain function and structure. Additionally, the dynamics of these relationships during developmental periods, which are critical windows during which many disorders first appear, are still largely unexplored. The current study extends the field by examining if peripheral DNA methylation of myelination-related genes predicts white matter volume in a healthy pediatric population [N = 250; females = 113; age range 2 months-14 years; Mage = 5.14, SDage = 3.60]. We assessed if DNA methylation of 17 myelin-related genes predict white matter volume and if age moderates these relationships. Results highlight low variability in myelin-related epigenetic variance at birth, which rapidly increases non-linearly with age, and that DNA methylation, measured at both the level of a CpG site or gene, is highly predictive of white matter volume, in early childhood but not late childhood. These novel findings propel the field forward by establishing that DNA methylation of myelin-related genes from a peripheral tissue is a predictive marker of white matter volume in children and is influenced by developmental stage. The research underscores the significance of peripheral epigenetic patterns as a proxy for investigating the effects of environmental factors, behaviors, and disorders associated with white matter.

Associations between neighborhood characteristics and child well-being before and during the COVID-19 pandemic: A repeated cross-sectional study in the Environmental influences on Child Health Outcomes (ECHO) program.

The corona virus disease (COVID-19) pandemic disrupted daily life worldwide, and its impact on child well-being remains a major concern. Neighborhood characteristics affect child well-being, but how these associations were affected by the pandemic is not well understood. We analyzed data from 1039 children enrolled in the Environmental influences on Child Health Outcomes Program whose well-being was assessed using the Patient-Reported Outcomes Measurement Information System Global Health questionnaire and linked these data to American Community Survey (ACS) data to evaluate the impacts of neighborhood characteristics on child well-being before and during the pandemic. We estimated the associations between more than 400 ACS variables and child well-being t-scores stratified by race/ethnicity (non-Hispanic white vs. all other races and ethnicities) and the timing of outcome data assessment (pre-vs. during the pandemic). Network graphs were used to visualize the associations between ACS variables and child well-being t-scores. The number of ACS variables associated with well-being t-scores decreased during the pandemic period. Comparing non-Hispanic white with other racial/ethnic groups during the pandemic, different ACS variables were associated with child well-being. Multiple ACS variables representing census tract-level housing conditions and neighborhood racial composition were associated with lower well-being t-scores among non-Hispanic white children during the pandemic, while higher percentage of Hispanic residents and higher percentage of adults working as essential workers in census tracts were associated with lower well-being t-scores among non-white children during the same study period. Our study provides insights into the associations between neighborhood characteristics and child well-being, and how the COVID-19 pandemic affected this relationship.

FTO variation and early frontostriatal brain development in children.

OBJECTIVE: Common obesity-associated genetic variants at the fat mass and obesity-associated (FTO) locus have been associated with appetitive behaviors and altered structure and function of frontostriatal brain regions. The authors aimed to investigate the influence of FTO variation on frontostriatal appetite circuits in early life. METHODS: Data were drawn from RESONANCE, a longitudinal study of early brain development. Growth trajectories of nucleus accumbens and frontal lobe volumes, as well as total gray matter and white matter volume, by risk allele (AA) carrier status on FTO single-nucleotide polymorphism rs9939609 were examined in 228 children (102 female, 126 male) using magnetic resonance imaging assessments obtained from infancy through middle childhood. The authors fit functional concurrent regression models with brain volume outcomes over age as functional responses, and FTO genotype, sex, BMI z score, and maternal education were included as predictors. RESULTS: Bootstrap pointwise 95% CI for regression coefficient functions in the functional concurrent regression models showed that the AA group versus the group with no risk allele (TT) had greater nucleus accumbens volume (adjusted for total brain volume) in the interval of 750 to 2250 days (2-6 years). CONCLUSIONS: These findings suggest that common genetic risk for obesity is associated with differences in early development of brain reward circuitry and argue for investigating dynamic relationships among genotype, brain, behavior, and weight throughout development.

White matter microstructure is differently associated with executive functioning in youth born with congenital heart disease and youth born preterm.

INTRODUCTION: Executive function deficits and adverse psychological outcomes are common in youth with congenital heart disease (CHD) or born preterm. Association white matter bundles play a critical role in higher order cognitive and emotional functions and alterations to their microstructural organization may result in adverse neuropsychological functioning. This study aimed to examine the relationship of myelination and axon density and orientation alterations within association bundles with executive functioning, psychosocial well-being, and resilience in youth with CHD or born preterm. METHODS: Youth aged 16 to 26 years born with complex CHD or preterm at ≤33 weeks of gestational age and healthy controls completed a brain MRI and self-report assessments of executive functioning, psychosocial well-being, and resilience. Multicomponent driven equilibrium single-pulse observation of T1 and T2 and neurite orientation dispersion and density imaging were used to calculate average myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index values for eight bilateral association bundles. The relationships of bundle-average metrics with neuropsychological outcomes were explored with linear regression and mediation analyses. RESULTS: In the CHD group, lower MWF in several bundles was associated with poorer working memory and behavioral self-monitoring and mediated self-monitoring deficits relative to controls. In the preterm group, lower NDI in several bundles was associated with poorer emotional control and lower MWF in the left superior longitudinal fasciculus III mediated planning/organizing deficits relative to controls. No significant relationships were observed for psychosocial well-being or resilience. CONCLUSION: The findings of this study suggest that microstructural alterations to association bundles, including lower myelination and axon density, have different relationships with executive functioning in youth with CHD and youth born preterm. Future studies should aim to characterize other neurobiological, social, and environmental influences that may interact with white matter microstructure and neuropsychological functioning in these at-risk individuals.

A comparison of altered white matter microstructure in youth born with congenital heart disease or born preterm.

Introduction: Alterations to white matter microstructure as detected by diffusion tensor imaging have been documented in both individuals born with congenital heart disease (CHD) and individuals born preterm. However, it remains unclear if these disturbances are the consequence of similar underlying microstructural disruptions. This study used multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) and neurite orientation dispersion and density imaging (NODDI) to characterize and compare alterations to three specific microstructural elements of white matter - myelination, axon density, and axon orientation - in youth born with CHD or born preterm. Methods: Participants aged 16 to 26 years with operated CHD or born ≤33 weeks gestational age and a group of healthy peers of the same age underwent a brain MRI including mcDESPOT and high angular resolution diffusion imaging acquisitions. Using tractometry, average values of myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index (ODI) were first calculated and compared between groups for 30 white matter bundles. Afterwards, bundle profiling was performed to further characterize the topology of the detected microstructural alterations. Results: The CHD and preterm groups both presented with widespread bundles and bundle segments with lower MWF, accompanied by some occurrences of lower NDI, relative to controls. While there were no differences in ODI between the CHD and control groups, the preterm group presented with both higher and lower ODI compared to the control group and lower ODI compared to the CHD group. Discussion: While youth born with CHD or born preterm both presented with apparent deficits in white matter myelination and axon density, youth born preterm presented with a unique profile of altered axonal organization. Future longitudinal studies should aim to better understand the emergence of these common and distinct microstructural alterations, which could orient the development of novel therapeutic approaches.

At-home dried blood spot (DBS) collection to increase population heterogeneity representation in pediatric research: An ECHO study.

Self-collection of dried blood samples (DBS) in the participant's home provides an alternative to university/hospital visits for research and has the potential to improve the representation of population heterogeneity in research. This study aimed to assess the feasibility of guardian and/or self-DBS collection in healthy youth in the lab and home. Guardians/youth [N = 140; females = 63; M age = 8.73, SD age = 3.56] who enrolled in a longitudinal study of typical development were asked during a lab visit to provide a DBS. Upon providing a sample, the participants were asked if they would be willing to self-collect in the home and return the sample via the post office. Of those asked to provide a sample in the lab, 82% consented and 18% declined, with a significant difference in age but no significant difference in sex, ethnicity, race, or family income. Of those who provided a sample in the lab, 75% were willing to self-collect DBS in the home, with no significant difference in demographic variables between them. We report a quality assessment and DNA extraction results from a subset of samples. The results demonstrate a high feasibility of DBS collection from healthy youth for research purposes both in the laboratory and in the home across different demographic variables. Developmental researchers should consider including this approach in their studies to increase population heterogeneity representation.

Intergenerational transmission of the effects of maternal exposure to childhood maltreatment in the USA: a retrospective cohort study.

BACKGROUND: Childhood maltreatment is associated with adverse health outcomes and this risk can be transmitted to the next generation. We aimed to investigate the association between exposure to maternal childhood maltreatment and common childhood physical and mental health problems, neurodevelopmental disorders, and related comorbidity patterns in offspring. METHODS: We conducted a retrospective cohort study using data from the Environmental influences on Child Health Outcomes (ECHO) Program, which was launched to investigate the influence of early life exposures on child health and development in 69 cohorts across the USA. Eligible mother-child dyads were those with available data on maternal childhood maltreatment exposure and at least one child health outcome measure (autism spectrum disorder, attention-deficit hyperactivity disorder [ADHD], internalising problems, obesity, allergy, and asthma diagnoses). Maternal history of childhood maltreatment was obtained retrospectively from the Adverse Childhood Experiences or Life Stressor Checklist questionnaires. We derived the prevalence of the specified child health outcome measures in offspring across childhood and adolescence by harmonising caregiver reports and other relevant sources (such as medical records) across cohorts. Child internalising symptoms were assessed using the Child Behavior Checklist. Associations between maternal childhood maltreatment and childhood health outcomes were measured using a series of mixed-effects logistic regression models. Covariates included child sex (male or female), race, and ethnicity; maternal and paternal age; maternal education; combined annual household income; maternal diagnosis of depression, asthma, ADHD, allergy, or autism spectrum disorder; and maternal obesity. Two latent class analyses were conducted: to characterise patterns of comorbidity of child health outcomes; and to characterise patterns of co-occurrence of childhood maltreatment subtypes. We then investigated the association between latent class membership and maternal childhood maltreatment and child health outcomes, respectively. FINDINGS: Our sample included 4337 mother-child dyads from 21 longitudinal cohorts (with data collection initiated between 1999 and 2016). Of 3954 mothers in the study, 1742 (44%) had experienced exposure to abuse or neglect during their childhood. After adjustment for confounding, mothers who experienced childhood maltreatment were more likely to have children with internalising problems in the clinical range (odds ratio [OR] 2·70 [95% CI 1·95-3·72], p<0·0001), autism spectrum disorder (1·70 [1·13-2·55], p=0·01), ADHD (2·09 [1·63-2·67], p<0·0001), and asthma (1·54 [1·34-1·77], p<0·0001). In female offspring, maternal childhood maltreatment was associated with a higher prevalence of obesity (1·69 [1·17-2·44], p=0·005). Children of mothers exposed to childhood maltreatment were more likely to exhibit a diagnostic pattern characterised by higher risk for multimorbidity. Exposure to multiple forms of maltreatment across all subtypes of maternal childhood maltreatment was associated with the highest risk increases for most offspring health outcomes, suggesting a dose-response relationship. INTERPRETATION: Our findings suggest that maternal childhood maltreatment experiences can be a risk factor for disease susceptibility in offspring across a variety of outcomes and emphasise the need for policies focusing on breaking the intergenerational transmission of adversity. FUNDING: Environmental influences on Child Health Outcomes Program, Office of the Director, National Institutes of Health.

In vivo T1 mapping of neonatal brain tissue at 64 mT.

PURPOSE: Ultralow-field (ULF) point-of-care MRI systems allow image acquisition without interrupting medical provision, with neonatal clinical care being an important potential application. The ability to measure neonatal brain tissue T1 is a key enabling technology for subsequent structural image contrast optimization, as well as being a potential biomarker for brain development. Here we describe an optimized strategy for neonatal T1 mapping at ULF. METHODS: Examinations were performed on a 64-mT portable MRI system. A phantom validation experiment was performed, and a total of 33 in vivo exams were acquired from 28 neonates with postmenstrual age ranging from 31+4 to 49+0  weeks. Multiple inversion-recovery turbo spin-echo sequences were acquired with differing inversion and repetition times. An analysis pipeline incorporating inter-sequence motion correction generated proton density and T1 maps. Regions of interest were placed in the cerebral deep gray matter, frontal white matter, and cerebellum. Weighted linear regression was used to predict T1 as a function of postmenstrual age. RESULTS: Reduction of T1 with postmenstrual age is observed in all measured brain tissue; the change in T1 per week and 95% confidence intervals is given by dT1  = -21 ms/week [-25, -16] (cerebellum), dT1  = -14 ms/week [-18, -10] (deep gray matter), and dT1  = -35 ms/week [-45, -25] (white matter). CONCLUSION: Neonatal T1 values at ULF are shorter than those previously described at standard clinical field strengths, but longer than those of adults at ULF. T1 reduces with postmenstrual age and is therefore a candidate biomarker for perinatal brain development.

Neuroimaging and verbal memory assessment in healthy aging adults using a portable low-field MRI scanner and a web-based platform: results from a proof-of-concept population-based cross-section study.

Consumer wearables and health monitors, internet-based health and cognitive assessments, and at-home biosample (e.g., saliva and capillary blood) collection kits are increasingly used by public health researchers for large population-based studies without requiring intensive in-person visits. Alongside reduced participant time burden, remote and virtual data collection allows the participation of individuals who live long distances from hospital or university research centers, or who lack access to transportation. Unfortunately, studies that include magnetic resonance neuroimaging are challenging to perform remotely given the infrastructure requirements of MRI scanners, and, as a result, they often omit socially, economically, and educationally disadvantaged individuals. Lower field strength systems (< 100 mT) offer the potential to perform neuroimaging at a participant's home, enabling more accessible and equitable research. Here we report the first use of a low-field MRI "scan van" with an online assessment of paired-associate learning (PAL) to examine associations between brain morphometry and verbal memory performance. In a sample of 67 individuals, 18-93 years of age, imaged at or near their home, we show expected white and gray matter volume trends with age and find significant (p < 0.05 FWE) associations between PAL performance and hippocampus, amygdala, caudate, and thalamic volumes. High-quality data were acquired in 93% of individuals, and at-home scanning was preferred by all individuals with prior MRI at a hospital or research setting. Results demonstrate the feasibility of remote neuroimaging and cognitive data collection, with important implications for engaging traditionally under-represented communities in neuroimaging research.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52). Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. Results: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume. Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.

Systematic Review: White Matter Microstructural Organization in Adolescents With Depression.

Objective: A growing body of literature has focused on the neural mechanisms of depression. Our goal was to conduct a systematic review on the white matter microstructural differences in adolescents with depressive disorders vs adolescents without depressive disorders. Method: We searched PubMed and PsycINFO for publications on August 3, 2022 (original search conducted in July 2021). The review was registered on PROSPERO (registration number: CRD42021268200), and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Eligible studies were original research papers comparing diffusion tensor/spectrum imaging findings in adolescents with vs without depression (originally ages 12-19 years, later expanded to 11-21 years). Studies were excluded if they focused on depression exclusively in the context of another condition, used only dimensional depressive symptom assessment(s), or used the same dataset as another included publication. Results: The search yielded 575 unique records, of which 14 full-text papers were included (824 adolescents with depression and 686 without depression). The following white matter regions showed significant differences in fractional anisotropy in at least 3 studies: uncinate fasciculus, cingulum, anterior corona radiata, inferior fronto-occipital fasciculus, and corpus callosum (genu and body). Most studies reported decreased, rather than increased, fractional anisotropy in adolescents with depression. Limitations include the possibility for selective reporting bias and risk of imprecision, given the small sample sizes in some studies. Conclusion: Our systematic review suggests aberrant white matter microstructure in limbic-cortical-striatal-thalamic circuits, and the corpus callosum, in adolescents with depression. Future research should focus on developmental trajectories in depression, identifying sources of heterogeneity and integrating findings across imaging modalities.

Exploring in vivo lesion myelination dynamics: Longitudinal Myelin Water Imaging in early Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) lesions are pathologically heterogeneous and the temporal behavior in terms of growth and myelination status of individual lesions is highly variable, especially in the early phase of the disease. Thus, monitoring the development of individual lesion myelination by using quantitative magnetic resonance myelin water imaging (MWI) could be valuable to capture the variability of disease pathology and get an individual insight into the subclinical disease activity. OBJECTIVE: The goal of this work was (1) to observe the variation and longitudinal change of in vivo lesion myelination by means of MWI and its parameter Myelin Water Fraction (MWF), and, (2) to identify individual lesion myelination patterns in early MS. METHODS: In this study n = 12 patients obtained conventional MRI and quantitative MWI derived from multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) within four weeks after presenting a clinically isolated syndrome and remained within the study if clinically definitive MS was diagnosed within the 12 months study period. Four MRI sessions were acquired at baseline, 3, 6, and 12 months. The short-term and long-term variability of MWF maps was evaluated by scan-rescan measures and the coefficient of variation was determined in four healthy controls. Tracking of individual lesions was performed using the Automatic Follow-up of Individual Lesions (AFIL) algorithm. Lesion volume and MWF were evaluated for every individual lesion in all patients. Median lesion MWF change was used to define lesion categories as decreasing, varying, increasing and invariant for MWF variation. RESULTS: In total n = 386 T2 lesions were detected with a subset of n = 225 permanent lesions present at all four time-points. Among those, a heterogeneous lesion MWF reduction was found, with the majority of lesions bearing only mild MWF reduction, approximately a third with an intermediate MWF decrease and highest MWF reduction in acute-inflammatory active lesions. A moderate negative correlation was determined between individual lesion volumes and median MWF consistent across all time-points. Permanent lesions featured variable temporal dynamics with the majority of varying MWF (58 %), however decreasing (16 %), increasing (15 %) and invariant (11 %) subgroups could be identified resembling demyelinating activity and post-demyelinating inactivity known from histopathology studies. Inflammatory-active enhancing lesions showed a distinct pattern of MWF reduction followed by partial recovery after 3 months. This was similar in new enhancing lesions and those with a non-enhancing precursor lesion. CONCLUSION: This work provides in vivo evidence for an individual evolution of early demyelinated MS lesions measured by means of MWF imaging. Our results support the hypothesis, that MS lesions undergo multiple demyelination and remyelination episodes in the early acute phase. The in vivo MRI surrogate of myelin turnover bears capacity as a novel biomarker to select and potentially monitor personalized MS treatment.

Simultaneous high-resolution T2 -weighted imaging and quantitative T2 mapping at low magnetic field strengths using a multiple TE and multi-orientation acquisition approach.

PURPOSE: Low magnetic field systems provide an important opportunity to expand MRI to new and diverse clinical and research study populations. However, a fundamental limitation of low field strength systems is the reduced SNR compared to 1.5 or 3T, necessitating compromises in spatial resolution and imaging time. Most often, images are acquired with anisotropic voxels with low through-plane resolution, which provide acceptable image quality with reasonable scan times, but can impair visualization of subtle pathology. METHODS: Here, we describe a super-resolution approach to reconstruct high-resolution isotropic T2 -weighted images from a series of low-resolution anisotropic images acquired in orthogonal orientations. Furthermore, acquiring each image with an incremented TE allows calculations of quantitative T2 images without time penalty. RESULTS: Our approach is demonstrated via phantom and in vivo human brain imaging, with simultaneous 1.5 × 1.5 × 1.5 mm3 T2 -weighted and quantitative T2 maps acquired using a clinically feasible approach that combines three acquisition that require approximately 4-min each to collect. Calculated T2 values agree with reference multiple TE measures with intraclass correlation values of 0.96 and 0.85 in phantom and in vivo measures, respectively, in line with previously reported brain T2 values at 150 mT, 1.5T, and 3T. CONCLUSION: Our multi-orientation and multi-TE approach is a time-efficient method for high-resolution T2 -weighted images for anatomical visualization with simultaneous quantitative T2 imaging for increased sensitivity to tissue microstructure and chemical composition.

Altered myelination in youth born with congenital heart disease.

Brain injury and dysmaturation is common in fetuses and neonates with congenital heart disease (CHD) and is hypothesized to result in persistent myelination deficits. This study aimed to quantify and compare myelin content in vivo between youth born with CHD and healthy controls. Youth aged 16 to 24 years born with CHD and healthy age- and sex-matched controls underwent brain magnetic resonance imaging including multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). Average myelin water fraction (MWF) values for 33 white matter tracts, as well as a summary measure of average white matter MWF, the White Matter Myelination Index, were calculated and compared between groups. Tract-average MWF was lower throughout the corpus callosum and in many bilateral association tracts and left hemispheric projection tracts in youth with CHD (N = 44) as compared to controls (N = 45). The White Matter Myelination Index was also lower in the CHD group. As such, this study provides specific evidence of widespread myelination deficits in youth with CHD, likely representing a long-lasting consequence of early-life brain dysmaturation in this population. This deficient myelination may underlie the frequent neurodevelopmental impairments experienced by CHD survivors and could eventually serve as a biomarker of neuropsychological function.

Development of a mobile low-field MRI scanner.

Magnetic resonance imaging (MRI) allows important visualization of the brain and central nervous system anatomy and organization. However, unlike electroencephalography (EEG) or functional near infrared spectroscopy, which can be brought to a patient or study participant, MRI remains a hospital or center-based modality. Low magnetic field strength MRI systems, however, offer the potential to extend beyond these traditional hospital and imaging center boundaries. Here we describe the development of a modified cargo van that incorporates a removable low-field permanent magnet MRI system and demonstrate its proof-of-concept. Using phantom scans and in vivo T2-weighted neuroimaging data, we show no significant differences with respect to geometric distortion, signal-to-noise ratio, or tissue segmentation outcomes in data acquired in the mobile system compared to a similar static system in a laboratory setting. These encouraging results show, for the first time, MRI that can be performed at a participant's home, community center, school, etc. Breaking traditional barriers of access, this mobile approach may enable imaging of patients and participants who have mobility challenges, live long distances from imaging centers, or are otherwise unable to travel to an imaging center or hospital.

A Nutrient Formulation Affects Developmental Myelination in Term Infants: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Observational studies suggest differences between breast-fed and formula-fed infants in developmental myelination, a key brain process for learning. The study aims to investigate the efficacy of a blend of docosahexaenoic acid (DHA), arachidonic acid (ARA), iron, vitamin B12, folic acid, and sphingomyelin (SM) from a uniquely processed whey protein concentrate enriched in alpha-lactalbumin and phospholipids compared with a control formulation on myelination, cognitive, and behavioral development in the first 6 months of life. METHODS: These are 6-month results from an ongoing two-center, randomized controlled trial with a 12-month intervention period (completed for all participants). In this study, full term, neurotypical infants of both sexes (N = 81) were randomized into investigational (N = 42) or control groups (N = 39). In addition, non-randomized breast-fed children (N = 108) serve as a natural reference group. Main outcomes are myelination (MRI), cognitive (Bayley Scales of Infant and Toddler Development, 3rd edition [Bayley-III]), social-emotional development (Ages and Stages Questionnaires: Social-Emotional, 2nd edition [ASQ:SE-2]), sleep (Brief Infant Sleep Questionnaire [BISQ]), and safety (growth and adverse events [AEs]). RESULTS: The full analyses set comprises N = 66 infants. Significant differences in myelin structure, volume, and rate of myelination were observed in favor of the investigational myelin blend at 3 and 6 months of life. Effects were demonstrated for whole brain myelin and for cerebellar, parietal, occipital, and temporal regions, known to be functionally involved in sensory, motor, and language skills. No statistically significant differences were found for early behavior and cognition scores. CONCLUSIONS: This is the first study demonstrating the efficacy of a myelin nutrient blend in well-nourished, term infants on developmental myelination, which may be foundational for later cognitive and learning outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03111927.

Influences of Chronic Physical and Mental Health Conditions on Child and Adolescent Positive Health.

OBJECTIVE: Pediatric positive health refers to children's assessments of their well-being. The purpose of this study was to contrast positive health for children aged 8 to 17 years with and without chronic physical and mental health conditions. METHODS: Data were drawn from the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) research program. Participants included 1764 children ages 8 to 17 years from 13 ECHO cohorts. We measured positive health using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health and Life Satisfaction patient-reported outcome (PRO) measures. We used multiple regression to examine cross-sectional associations between the PROs and parent-reported health conditions and sociodemographic variables. We defined a meaningful difference in average scores as a PROMIS T-score difference of >3. RESULTS: The sample included 45% 13 to 17-year-olds, 50% females, 8% Latinx, and 23% Black/African-American. Fifty-four percent had a chronic health condition. Of the 16 chronic conditions included in the study, only chronic pain (ß = -3.5; 95% CI: -5.2 to -1.9) and depression (ß = -6.6; 95% CI: -8.5 to -4.6) were associated with scoring >3 points lower on global health. Only depression was associated with >3 points lower on life satisfaction (ß = -6.2; 95% CI: -8.1 to -4.3). Among those with depression, 95% also had another chronic condition. CONCLUSIONS: Many children with chronic conditions have similar levels of positive health as counterparts without chronic conditions. The study results suggest that negative associations between chronic conditions and positive health may be primarily attributable to presence or co-occurrence of depression.

Remote and at-home data collection: Considerations for the NIH HEALthy Brain and Cognitive Development (HBCD) study.

The NIH HEALthy Brain and Cognitive Development (HBCD) study aims to characterize the impact of in utero exposure to substances, and related environmental exposures on child neurodevelopment and health outcomes. A key focus of HBCD is opioid exposure, which has disproportionately affected rural areas. While most opioid use and neonatal abstinence syndrome has been reported outside of large cities, rural communities are often under-represented in large-scale clinical research studies that involve neuroimaging, in-person assessments, or bio-specimen collections. Thus, there exists a likely mismatch between the communities that are the focus of HBCD and those that can participate. Even geographically proximal participants, however, are likely to bias towards higher socioeconomic status given the anticipated study burden and visit frequency. Wearables, 'nearables', and other consumer biosensors, however, are increasingly capable of collecting continuous physiologic and environmental exposure data, facilitating remote assessment. We review the potential of these technologies for remote in situ data collection, and the ability to engage rural, affected communities. While not necessarily a replacement, these technologies offer a compelling complement to traditional 'gold standard' lab-based methods, with significant potential to expand the study's reach and importance.

The Effects of Delayed Cord Clamping on 12-Month Brain Myelin Content and Neurodevelopment: A Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine if delayed cord clamping (DCC) affected brain myelin water volume fraction (VFm) and neurodevelopment in term infants. STUDY DESIGN: This was a single-blinded randomized controlled trial of healthy pregnant women with term singleton fetuses randomized at birth to either immediate cord clamping (ICC) (≤ 20 seconds) or DCC (≥ 5 minutes). Follow-up at 12 months of age consisted of blood work for serum iron indices and lead levels, a nonsedated magnetic resonance imaging (MRI), followed within the week by neurodevelopmental testing. RESULTS: At birth, 73 women were randomized into one of two groups: ICC (the usual practice) or DCC (the intervention). At 12 months, among 58 active participants, 41 (80%) had usable MRIs. There were no differences between the two groups on maternal or infant demographic variables. At 12 months, infants who had DCC had increased white matter brain growth in regions localized within the right and left internal capsules, the right parietal, occipital, and prefrontal cortex. Gender exerted no difference on any variables. Developmental testing (Mullen Scales of Early Learning, nonverbal, and verbal composite scores) was not significantly different between the two groups. CONCLUSION: At 12 months of age, infants who received DCC had greater myelin content in important brain regions involved in motor function, visual/spatial, and sensory processing. A placental transfusion at birth appeared to increase myelin content in the early developing brain. KEY POINTS: · DCC resulted in higher hematocrits in newborn period.. · DCC appears to increase myelin at 12 months.. · Gender did not influence study outcomes..

Connecting inside out: Development of the social brain in infants and toddlers with a focus on myelination as a marker of brain maturation.

Early childhood is a sensitive period for learning and social skill development. The maturation of cerebral regions underlying social processing lays the foundation for later social-emotional competence. This study explored myelin changes in social brain regions and their association with changes in parent-rated social-emotional development in a cohort of 129 children (64 females, 0-36 months, 77 White). Results reveal a steep increase in myelination throughout the social brain in the first 3 years of life that is significantly associated with social-emotional development scores. These findings add knowledge to the emerging picture of social brain development by describing neural underpinnings of human social behavior. They can contribute to identifying age-/stage-appropriate early life factors in this developmental domain.