An introduction to the HEALthy Brain and Child Development Study (HBCD) study.

The fundamental organization of the human brain is established before birth, with rapid growth continuing over the first postnatal years. Children exposed before or after birth to various biological (e.g., substance exposure) or psychosocial hazards (e.g., maltreatment) are at elevated likelihood of deviating from a typical developmental trajectory, which in turn can be associated with psychological, behavioral, and physical health sequelae. In the HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, brain, physical, biological, cognitive, behavioral, social, and emotional development is being examined starting in pregnancy and planned through age 10 (data are sampled at varying degrees of granularity depending on age, with more dense sampling earlier in life). HBCD aims to determine the short- and long-term impacts of a variety of both harmful and protective factors, including prenatal substance use, on developmental trajectories through early childhood. Organized as a nationwide consortium across 27 sites, the HBCD Study will collect multimodal data that will be made publicly available on a yearly basis, through a data use application and approval process. Here we provide an overview of the HBCD Study design, sampling, protocol development, and data management. Data collected through HBCD will be fundamental to informing future prenatal and early childhood interventions and policies to promote wellbeing and resilience in all children.

International medical graduates in orthopaedic surgery: An opportunity to improve diversity and inclusion?

Background/aims: Racial and ethnic minorities are under-represented in orthopaedic surgery despite efforts to promote diversity and inclusion in the specialty. The purpose of this study was to determine the proportion of international medical graduates (IMGs) in the surgical workforce and future residency pipeline. We further analyze IMG applicant qualifications relative to their US-based counterparts to assess the viability of recruiting IMG candidates as one strategy to advance diversity and inclusion in orthopaedic surgery. Methods: Physician workforce data from the American Medical Association and residency match data from the National Resident Match Program were analyzed for Orthopaedic Surgery. Trends in the proportion of IMG applicants were compared with those from other specialties. Qualifications of applicants were compared including board exam scores, number of abstracts/publications, and additional graduate degrees. Results: In 2020, orthopaedic surgery had the lowest percentage of IMGs relative to otolaryngology (5.8 %, p < 0.001), neurosurgery (12.1 %, p < 0.001), obstetrics & gynecology (14.0 %, p < 0.001), and general surgery (19.1 %, p < 0.001). From 1986 to 2021, IMG Graduates who matched into orthopaedic surgery increased from 1 (0.3 %) to 8 (0.9 %). Compared to other surgical specialties, orthopaedic surgery had among the lowest annual rates of incoming IMG residents. In 2021, most respondents to the orthopaedic surgery residency program directors survey reported never selecting IMG applicants for interview (74 % for non-US IMG applicants and 53 % for US IMG applicants). From 2020 to 2021, non-US IMG applicants (17 %) and US IMG applicants (26 %) had lower match rates than DO Senior (74 %) and MD Senior (80 %) applicants (p < 0.001). In 2020, matched non-US IMGs had similar board scores as matched US MD Senior applicants, but more abstracts/publications. Conclusion: The recruitment of IMGs into orthopaedic surgery residency remains limited and lower than other surgical specialties. IMGs have similar board scores and more abstracts/publications, thus representing a potential pipeline for workforce diversity. More research is needed to understand the special needs of IMGs in the orthopaedic surgery match.

Altered associations between white matter structure and psychopathology in previously institutionalized adolescents.

Previously institutionalized adolescents show increased risk for psychopathology, though placement into high-quality foster care can partially mitigate this risk. White matter (WM) structure is associated with early institutional rearing and psychopathology in youth. Here we investigate associations between WM structure and psychopathology in previously institutionalized youth. Adolescent psychopathology data were collected using the MacArthur Health and Behavior Questionnaire. Participants underwent diffusion MRI, and data were processed using fixel-based analyses. General linear models investigated interactions between institutionalization groups and psychopathology on fixel metrics. Supplementary analyses also examined the main effects of psychopathology and institutionalization group on fixel metrics. Ever-Institutionalized children included 41 randomized to foster care (Mage=16.6), and 40 to care-as-usual (Mage=16.7)). In addition, 33 participants without a history of institutionalization were included as a reference group (Mage=16.9). Ever-Institutionalized adolescents displayed altered general psychopathology-fixel associations within the cerebellar peduncles, inferior longitudinal fasciculi, corticospinal tract, and corpus callosum, and altered externalizing-fixel associations within the cingulum and fornix. Our findings indicate brain-behavior associations reported in the literature may not be generalizable to all populations. Previously institutionalized youth may develop differential brain development, which in turn leads to altered neural correlates of psychopathology that are still apparent in adolescence.

Exploring background aperiodic electroencephalography (EEG) activity in the Bucharest Early Intervention Project.

Aperiodic activity is a background arrhythmic component of electroencephalogram (EEG) that is present in the power spectrum and characterized by an aperiodic offset and an aperiodic exponent. These components have been proposed as a marker of brain maturation, reflecting alterations in excitatory-inhibitory (E:I) balance and exhibiting developmental changes over time. Currently, there is limited understanding regarding how aperiodic activity changes over the course of an individual's life, particularly from early childhood to adolescence, a period when the brain undergoes significant structural and functional transformation. More importantly, considering that brain development is affected by early experience, there is no evidence on how early adversity might affect these parameters. Here, we examined the developmental trajectories of aperiodic activity from EEG data collected in the Bucharest Early Intervention Project, from early childhood to mid adolescence (from 42 months of age up to 16 years old). We examined the effects of a history of early adversity and the impact of early intervention on background aperiodic EEG activity. Surprisingly, we found little influence of a history of adversity or early intervention on these characteristics of the signal. Rather, we found nonlinear age-related trajectories in both aperiodic offset and aperiodic exponent and sex differences in the trajectory for aperiodic offset (but not exponent). These findings provide information on the maturational patterns and trajectories of brain development from early childhood to mid adolescence and how background aperiodic activity describes one aspect of EEG development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Early Family Experiences and Neural Activity in Rural Pakistani Children: The Differential Role of Gender.

Adversity within low- and middle-income countries (LMICs) poses severe threats to neurocognitive development, which can be partially mitigated by high-quality early family experiences. Specifically, maternal scaffolding and home stimulation can buffer cognitive development in LMIC, possibly by protecting underlying neural functioning. However, the association between family experiences and neural activity remains largely unexplored in LMIC contexts. This study explored the relation of early family experiences to later cognitive skills and absolute gamma power (21-45 Hz), a neural marker linked to higher-order cognitive skills. Drawing data from the PEDS trial, a longitudinal study in rural Pakistan, we examined maternal scaffolding at 24 months and home stimulation quality at 18 months as predictors of verbal IQ, executive functions, and absolute gamma at 48 months for 105 mother-child dyads (52 girls). Maternal scaffolding interacted with gender to predict absolute gamma power, such that higher maternal scaffolding was related to higher gamma more strongly for girls. Maternal scaffolding also interacted with absolute gamma to predict executive functions, such that higher gamma was related to better executive functions only when maternal scaffolding was average to high. Individual differences in early family experiences may partially buffer the neural underpinnings of cognitive skills from adversity in LMIC.

Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids.

Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MeCP2 mutations - a missense mutation (R306C) and a truncating mutation (V247X) - using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutation. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABAA receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.

Exploration of auditory statistical learning, socioeconomic status, and language outcomes in Bangladeshi children: A functional near-infrared spectroscopy study.

Auditory statistical learning, or the ability to detect statistical regularities in continuously presented stimuli, is thought to be one element that underlies language acquisition. Prior studies have uncovered behavioral and neural correlates of statistical learning, yet additional work is needed from low- and middle-income countries to explore whether statistical learning varies across cultures or underlies associations often found between socioeconomic status (SES) and language outcomes. In the present study, we explored the feasibility of using functional near-infrared spectroscopy (fNIRS) to explore auditory statistical learning in Bangladesh, a lower-middle-income country. Participants were 102 2-year-old (M = 25.72 months, SD = 2.07 months) and 125 5-year-old children (M = 62.35 months, SD = 2.46 months) living in a low-income urban neighborhood of Dhaka (average family income of 28,145.13 Bangladeshi Takas or 260.06 U.S. dollars per month). We also collected measures of SES and language outcomes. Brain responses during the statistical learning paradigm could be detected with fNIRS in both two- and 5-year-olds, with 2-year-olds exhibiting a higher response to predictable sequences and 5-year-olds exhibiting higher responses to unpredictable sequences. fNIRS correlates of statistical learning were not related to language outcomes but were associated with SES in the 5-year-old cohort. This study demonstrates the utility of employing fNIRS to study the neural correlates of statistical learning in low- and middle-income countries and the feasibility of expanding the representativeness of the existing literature. These findings also highlight potential areas for inquiry into how SES may relate to individual differences in statistical learning responses. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Caregiving stress and maternal mental health during the COVID-19 pandemic.

It has now been extensively documented that parental mental health has deteriorated since the beginning of the COVID-19 pandemic. Although pandemic-related stress has been widespread, parents faced the unique challenge of navigating remote schooling. Parental oversight of children's education, loss of access to school supportive resources, and the challenges of remote learning may have been most problematic for parents of children with or at elevated risk for mental health difficulties. In the current study, we examined interactive effects of parent-reported pandemic-related caregiving stress and child internalizing and externalizing problems on parental depressive symptoms in a community-based cohort (N = 115) in the Northeast of the United States. Results indicated that parents experiencing higher levels of pandemic-related caregiving stress whose children exhibited elevated externalizing behaviors reported heightened levels of depressive symptoms. Greater child internalizing problems were associated with higher parental depressive symptoms independent of caregiving stress. These findings point to conditions that might heighten risk for parent mental health challenges in the context of ongoing remote or hybrid learning and pandemic-associated restrictions. Further, the findings point to conditions and characteristics that may be screened to identify and intervene with vulnerable families to mitigate mental health problems.

Resting state EEG in young children with Tuberous Sclerosis Complex.

Background: Tuberous Sclerosis Complex (TSC) manifests behaviorally with features of autism, epilepsy, and intellectual disability. Resting state electroencephalography (EEG) offers a window into neural oscillatory activity and may serve as an intermediate biomarker between gene expression and behavioral manifestations. Such a biomarker could be useful in clinical trials as an endpoint or predictor of treatment response. However, seizures and antiepileptic medications also affect resting neural oscillatory activity and could undermine the utility of resting state EEG features as biomarkers in neurodevelopmental disorders such as TSC. Methods: This paper compares resting state EEG features in a cross-sectional cohort of young children with TSC (n=49, ages 12-37 months) to 49 age- and sex-matched typically developing controls. Within children with TSC, associations were examined between resting state EEG features, seizure severity composite score, and use of GABA agonists. Results: Compared to matched typically developing controls, children with TSC showed significantly greater alpha and beta power in permutation cluster analyses iterated across a broad frequency range (2-50Hz). Children with TSC also showed significantly greater aperiodic offset after power spectra were parameterized using SpecParam into aperiodic and periodic components. Within children with TSC, greater seizure severity was significantly related to increased periodic peak beta power. Use of GABA agonists was also independently and significantly associated with increased periodic peak beta power; the interaction between seizure severity and GABA agonist use had no significant effect on peak beta power. Conclusions: The elevated peak beta power observed in children with TSC compared to matched typically developing controls may be driven by both seizures and GABA agonist use. It is recommended to collect seizure and mediation data alongside EEG data for clinical trials. These results highlight the challenge of using resting state EEG features as biomarkers in trials with neurodevelopmental disabilities when epilepsy and anti-epileptic medication are common.

Developmental trajectories of EEG aperiodic and periodic components in children 2-44 months of age.

The development of neural circuits has long-lasting effects on brain function, yet our understanding of early circuit development in humans remains limited. Here, periodic EEG power features and aperiodic components were examined from longitudinal EEGs collected from 592 healthy 2-44 month-old infants, revealing age-dependent nonlinear changes suggestive of distinct milestones in early brain maturation. Developmental changes in periodic peaks include (1) the presence and then absence of a 9-10 Hz alpha peak between 2-6 months, (2) nonlinear changes in high beta peaks (20-30 Hz) between 4-18 months, and (3) the emergence of a low beta peak (12-20 Hz) in some infants after six months of age. We hypothesized that the emergence of the low beta peak may reflect maturation of thalamocortical network development. Infant anesthesia studies observe that GABA-modulating anesthetics do not induce thalamocortical mediated frontal alpha coherence until 10-12 months of age. Using a small cohort of infants (n = 23) with EEG before and during GABA-modulating anesthesia, we provide preliminary evidence that infants with a low beta peak have higher anesthesia-induced alpha coherence compared to those without a low beta peak.

Prediction of chronological age from resting-state EEG power in the first three years of life.

The infant brain undergoes rapid and significant developmental changes in the first three years of life. Understanding these changes through the prediction of chronological age using neuroimaging data can provide insights into typical and atypical brain development. We utilized longitudinal resting-state EEG data from 457 typically developing infants, comprising 938 recordings, to develop age prediction models. The multilayer perceptron model demonstrated the highest accuracy with an R2 of 0.82 and a mean absolute error of 92.4 days. Aperiodic offset and periodic theta, alpha, and beta power were identified as key predictors of age via Shapley values. Application of the model to EEG data from infants later diagnosed with autism spectrum disorder or Down syndrome revealed significant underestimations of chronological age. This study establishes the feasibility of using EEG to assess brain maturation in early childhood and supports its potential as a clinical tool for early identification of alterations in brain development.

Neural network classification of beams carrying orbital angular momentum after propagating through controlled experimentally generated optical turbulence.

We generate an alphabet of spatially multiplexed Laguerre-Gaussian beams carrying orbital angular momentum, which are demultiplexed at reception by a convolutional neural network (CNN). In this investigation, a methodology for optimizing alphabet design for best classification rates is proposed, and three 256-symbol alphabets are designed for performance evaluation in optical turbulence. The beams were propagated in three environments: through underwater optical turbulence generated by Rayleigh-Bénard (RB) convection (C n2≅10-11 m -2/3), through a simulated propagation path derived from the Nikishov spectrum (C n2≅10-13 m -2/3), and through optical turbulence from a thermal point source located in a water tank (C n2≅10-10 m -2/3). We report a classification accuracy of 93.1% for the RB environment, 99.99% in simulation, and 48.5% in the point source environment. The project demonstrates that the CNN can classify the complex alphabet symbols in a practical turbulent flow that exhibits strong optical turbulence, provided sufficient training data is available and testing data is representative of the specific environment. We find the most important factor in a high classification accuracy is a diversification in the intensity profiles of the alphabet symbols.

Long-term measurement and characterization of boundary layer optical turbulence.

The United States Naval Academy long-term scintillation measurement campaign was a multi-year effort to characterize optical turbulence in the near-maritime atmospheric boundary layer (ABL). At its core, the field experiment consists of in situ measurements of bulk atmospheric and oceanographic parameters, as well as path-averaged measurements of the refractive index structure parameter, C n2, collected using a large-aperture scintillometer. The field experiment ran from January 1st, 2020, through September 26th, 2023, representing the most comprehensive collection of optical turbulence measurements in the near-maritime ABL to date. Long-term measurements enable researchers to evaluate existing theory and develop new models applicable to this environment. The present study characterizes some of the physical relationships that affect optical turbulence. This characterization focuses on the relationship between local optical turbulence and select atmospheric and oceanographic parameters. The impact of temperature gradients on the extent of optical turbulence was analyzed, along with its interactions with relative humidity and wind speed. The diurnal and seasonal variations in measured C n2 were examined, with comparisons drawn against other environments. Further information and the full dataset are publicly available through the optical turbulence benchmark repository [Jellen et al., GitHub, 2023].

Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging.

Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.

Neurodevelopment of children exposed to prolonged anesthesia in infancy: GABA study interim analysis of resting-state brain networks at 2, 4, and 10-months old.

BACKGROUND: Previous studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. METHODS: EEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. RESULTS: Models showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05-0.34). An effect of age was apparent in many of these measures. CONCLUSIONS: We could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.

Electroencephalographic Correlates of Clinical Severity in the Natural history study of RTT and Related Disorders.

OBJECTIVE: This study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders and to assess the potential for these features to act as objective measures of cortical function for Rett syndrome (RTT). METHODS: EEG amplitude and power features were derived from the resting EEG of 60 females with RTT (median age = 10.7 years) and 26 neurotypical females (median age = 10.6 years). Analyses focus on group differences and within the RTT group, associations between the EEG parameters and clinical severity. For a subset of participants (n = 20), follow-up data were available for assessing the reproducibility of the results and the stability in the parameters over 1 year. RESULTS: Compared to neurotypical participants, participants with RTT had greater amplitude variability and greater low-frequency activity as reflected by greater delta power, more negative 1/f slope, and lower theta/delta, alpha/delta, beta/delta, alpha/theta, and beta/theta ratios. Greater delta power, more negative 1/f slope, and lower power ratios were associated with greater severity. Analyses of year 1 data replicated the associations between 1/f slope and power ratios and clinical severity and demonstrated good within-subject consistency in these measures. INTERPRETATION: Overall, group comparisons reflected a greater predominance of lower versus higher frequency activity in participants with RTT, which is consistent with prior clinical interpretations of resting EEG in this population. The observed associations between the EEG power measures and clinical assessments and the repeatability of these measures underscore the potential for EEG to provide an objective measure of cortical function and clinical severity for RTT. ANN NEUROL 2024;96:175-186.

Mapping the Cellular Biogeography of Human Bone Marrow Niches Using Single-Cell Transcriptomics and Proteomic Imaging.

The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their spatial organization remain largely uncharacterized as they have been technically challenging to study in humans. Here, we used fresh femoral head samples and performed single-cell RNA sequencing (scRNA-Seq) to profile 29,325 enriched non-hematopoietic bone marrow cells and discover nine transcriptionally distinct subtypes. We next employed CO-detection by inDEXing (CODEX) multiplexed imaging of 18 individuals, including both healthy and acute myeloid leukemia (AML) samples, to spatially profile over one million single cells with a novel 53-antibody panel. We discovered a relatively hyperoxygenated arterio-endosteal niche for early myelopoiesis, and an adipocytic, but not endosteal or perivascular, niche for early hematopoietic stem and progenitor cells. We used our atlas to predict cell type labels in new bone marrow images and used these predictions to uncover mesenchymal stromal cell (MSC) expansion and leukemic blast/MSC-enriched spatial neighborhoods in AML patient samples. Our work represents the first comprehensive, spatially-resolved multiomic atlas of human bone marrow and will serve as a reference for future investigation of cellular interactions that drive hematopoiesis.

Perinatal inflammation, fetal growth restriction, and long-term neurodevelopmental impairment in Bangladesh.

BACKGROUND: There are limited data on the impact of perinatal inflammation on child neurodevelopment in low-middle income countries and among growth-restricted infants. METHODS: Population-based, prospective birth cohort study of 288 infants from July 2016-March 2017 in Sylhet, Bangladesh. Umbilical cord blood was analyzed for interleukin(IL)-1α, IL-1ß, IL-6, IL-8, and C-reactive protein(CRP). Child neurodevelopment was assessed at 24 months with Bayley-III Scales of Infant Development. We determined associations between cord blood inflammation and neurodevelopmental outcomes, controlling for potential confounders. RESULTS: 248/288 (86%) live born infants were followed until 24 months, among whom 8.9% were preterm and 45.0% small-for-gestational-age(SGA) at birth. Among all infants, elevated concentrations (>75%) of CRP and IL-6 at birth were associated with increased odds of fine motor delay at 24 months; elevated CRP was also associated with lower receptive communication z-scores. Among SGA infants, elevated IL-1α was associated with cognitive delay, IL-8 with language delay, CRP with lower receptive communication z-scores, and IL-1ß with lower expressive communication and motor z-scores. CONCLUSIONS: In rural Bangladesh, perinatal inflammation was associated with impaired neurodevelopment at 24 months. The associations were strongest among SGA infants and noted across several biomarkers and domains, supporting the neurobiological role of inflammation in adverse fetal development, particularly in the setting of fetal growth restriction. IMPACT: Cord blood inflammation was associated with fine motor and language delays at 24 months of age in a community-based cohort in rural Bangladesh. 23.4 million infants are born small-for-gestational-age (SGA) globally each year. Among SGA infants, the associations between cord blood inflammation and adverse outcomes were strong and consistent across several biomarkers and neurodevelopmental domains (cognitive, motor, language), supporting the neurobiological impact of inflammation prominent in growth-restricted infants. Prenatal interventions to prevent intrauterine growth restriction are needed in low- and middle-income countries and may also result in long-term benefits on child development.