Placental genomic risk scores and early neurodevelopmental outcomes.

Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.

The Subgrouping Structure of Newborns with Heterogenous Brain-Behavior Relationships.

The presence of heterogeneity/subgroups in infants and older populations against single-domain brain or behavioral measures has been previously characterized. However, few attempts have been made to explore heterogeneity at the brain-behavior relationship level. Such a hypothesis posits that different subgroups of infants may possess qualitatively different brain-behavior relationships that could ultimately contribute to divergent developmental outcomes even with relatively similar brain phenotypes. In this study, we aimed to explore such relationship-level heterogeneity and delineate the subgrouping structure of newborns with differential brain-behavior associations based on a typically developing sample of 81 infants with 3-week resting-state functional magnetic resonance imaging scans and 4-year intelligence quotient (IQ) measures. Our results not only confirmed the existence of relationship-level heterogeneity in newborns but also revealed divergent developmental outcomes associated with two subgroups showing similar brain functional connectivity but contrasting brain-behavior relationships. Importantly, further analyses unveiled an intriguing pattern that the subgroup with higher 4-year IQ outcomes possessed brain-behavior relationships that were congruent to their functional connectivity pattern in neonates while the subgroup with lower 4-year IQ not, providing potential explanations for the observed IQ differences. The characterization of heterogeneity at the brain-behavior relationship level may not only improve our understanding of the patterned intersubject variability during infancy but could also pave the way for future development of heterogeneity-inspired, personalized, subgroup-specific models for better prediction.

Cortical Structure and Cognition in Infants and Toddlers.

Cortical structure has been consistently related to cognitive abilities in children and adults, yet we know little about how the cortex develops to support emergent cognition in infancy and toddlerhood when cortical thickness (CT) and surface area (SA) are maturing rapidly. In this report, we assessed how regional and global measures of CT and SA in a sample (N = 487) of healthy neonates, 1-year-olds, and 2-year-olds related to motor, language, visual reception, and general cognitive ability. We report novel findings that thicker cortices at ages 1 and 2 and larger SA at birth, age 1, and age 2 confer a cognitive advantage in infancy and toddlerhood. While several expected brain-cognition relationships were observed, overlapping cortical regions were also implicated across cognitive domains, suggesting that infancy marks a period of plasticity and refinement in cortical structure to support burgeoning motor, language, and cognitive abilities. CT may be a particularly important morphological indicator of ability, but its impact on cognition is relatively weak when compared with gestational age and maternal education. Findings suggest that prenatal and early postnatal cortical developments are important for cognition in infants and toddlers but should be considered in relation to other child and demographic factors.

Home-based intervention for non-Hispanic black families finds no significant difference in infant size or growth: results from the Mothers & Others randomized controlled trial.

BACKGROUND: Non-Hispanic black (NHB) infants are twice as likely as non-Hispanic white infants to experience rapid weight gain in the first 6 months, yet few trials have targeted this population. The current study tests the efficacy of "Mothers & Others," a home-based intervention for NHB women and their study partners versus an attention-control, on infant size and growth between birth and 15 months. METHODS: Mothers & Others was a two-group randomized controlled trial conducted between November 2013 and December 2017 with enrollment at 28-weeks pregnancy and follow-up at 3-, 6-, 9-, 12-, and 15-months postpartum. Eligible women self-identified as NHB, English-speaking, and 18-39 years. The obesity prevention group (OPG) received anticipatory guidance (AG) on responsive feeding and care practices and identified a study partner, who was encouraged to attend home visits. The injury prevention group (IPG) received AG on child safety and IPG partners only completed study assessments. The primary delivery channel for both groups was six home visits by a peer educator (PE). The planned primary outcome was mean weight-for-length z-score. Given significant differences between groups in length-for-age z-scores, infant weight-for-age z-score (WAZ) was used in the current study. A linear mixed model, using an Intent-To-Treat (ITT) data set, tested differences in WAZ trajectories between the two treatment groups. A non-ITT mixed model tested for differences by dose received. RESULTS: Approximately 1575 women were screened for eligibility and 430 were enrolled. Women were 25.7 ± 5.3 years, mostly single (72.3%), and receiving Medicaid (74.4%). OPG infants demonstrated lower WAZ than IPG infants at all time points, but differences were not statistically significant (WAZdiff = - 0.07, 95% CI - 0.40 to 0.25, p = 0.659). In non-ITT models, infants in the upper end of the WAZ distribution at birth demonstrated incremental reductions in WAZ for each home visit completed, but the overall test of the interaction was not significant (F2,170 = 1.41, p = 0.25). CONCLUSIONS: Despite rich preliminary data and a strong conceptual model, Mothers & Others did not produce significant differences in infant growth. Results suggest a positive impact of peer support in both groups. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01938118 , 09/10/2013.

White matter connectomes at birth accurately predict cognitive abilities at age 2.

Cognitive ability is an important predictor of mental health outcomes that is influenced by neurodevelopment. Evidence suggests that the foundational wiring of the human brain is in place by birth, and that the white matter (WM) connectome supports developing brain function. It is unknown, however, how the WM connectome at birth supports emergent cognition. In this study, a deep learning model was trained using cross-validation to classify full-term infants (n = 75) as scoring above or below the median at age 2 using WM connectomes generated from diffusion weighted magnetic resonance images at birth. Results from this model were used to predict individual cognitive scores. We additionally identified WM connections important for classification. The model was also evaluated in a separate set of preterm infants (n = 37) scanned at term-age equivalent. Findings revealed that WM connectomes at birth predicted 2-year cognitive score group with high accuracy in both full-term (89.5%) and preterm (83.8%) infants. Scores predicted by the model were strongly correlated with actual scores (r = 0.98 for full-term and r = 0.96 for preterm). Connections within the frontal lobe, and between the frontal lobe and other brain areas were found to be important for classification. This work suggests that WM connectomes at birth can accurately predict a child's 2-year cognitive group and individual score in full-term and preterm infants. The WM connectome at birth appears to be a useful neuroimaging biomarker of subsequent cognitive development that deserves further study.

White matter microstructural development and cognitive ability in the first 2 years of life.

White matter (WM) integrity has been related to cognitive ability in adults and children, but it remains largely unknown how WM maturation in early life supports emergent cognition. The associations between tract-based measures of fractional anisotropy (FA) and axial and radial diffusivity (AD, RD) shortly after birth, at age 1, and at age 2 and cognitive measures at 1 and 2 years were investigated in 447 healthy infants. We found that generally higher FA and lower AD and RD across many WM tracts in the first year of life were associated with better performance on measures of general cognitive ability, motor, language, and visual reception skills at ages 1 and 2, suggesting an important role for the overall organization, myelination, and microstructural properties of fiber pathways in emergent cognition. RD in particular was consistently related to ability, and protracted development of RD from ages 1 to 2 years in several tracts was associated with higher cognitive scores and better language performance, suggesting prolonged plasticity may confer cognitive benefits during the second year of life. However, we also found that cognition at age 2 was weakly associated with WM properties across infancy in comparison to child and demographic factors including gestational age and maternal education. Our findings suggest that early postnatal WM integrity across the brain is important for infant cognition, though its role in cognitive development should be considered alongside child and demographic factors.

Prenatal exposure to organophosphate esters and cognitive development in young children in the Pregnancy, Infection, and Nutrition Study.

Organophosphate esters (OPEs) are a class of chemicals commonly used as flame retardants and plasticizers. OPEs are applied to a wide variety of consumer products and have a propensity to leach from these products. Consequently, OPEs are ubiquitous contaminants in many human environments and human exposure is pervasive. Accumulating evidence suggests that OPEs are capable of interfering with childhood cognitive development through both neurologic- and endocrine-mediated mechanisms. However, observational evidence of cognitive effects is limited. We used data collected in the third phase of the Pregnancy, Infection, and Nutrition Study to investigate cognitive effects of prenatal exposure to OPEs. In a spot prenatal maternal urine sample, we measured the following OPE metabolites: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). We assessed children's language and multi-faceted and overall cognitive development between two and three years of age using the MacArthur-Bates Communicative Development Inventories (MB-CDI) and the Mullen Scales of Early Learning (MSEL). We used linear regression to estimate the change in children's scores on these developmental assessments per interquartile range (IQR) increase in log-transformed, specific-gravity-corrected prenatal OPE metabolite concentrations, adjusted for maternal age, education, income, race/ethnicity, BMI, and child's sex. A total of 149 children had both OPE metabolite measurements and MB-CDI scores, and 227 children had both OPE metabolite measurements and MSEL scores. We observed that higher concentrations of ip-PPP (ng/ml) were associated with lower scores on the MSEL Cognitive Composite Score (ß = -2.61; 95% CI: -5.69, 0.46), and separately on two of the four MSEL Scales that comprise the Cognitive Composite, specifically the Fine Motor Scale (ß = -3.08; 95% CI: -5.26, -0.91) and the Expressive Language Scale (ß = -1.21; 95% CI: -2.91, 0.49). We similarly observed that prenatal ip-PPP concentrations were inversely associated with age-standardized scores on the MB-CDI Vocabulary assessment (ß = -1.19; 95% CI: -2.53, 0.16). Other OPE metabolites were not strongly associated with performance on either assessment. Our results suggest that isopropylated triarylphosphate isomers, the presumed parent compounds of ip-PPP, may adversely impact cognitive development, including fine motor skills and early language abilities. Our study contributes to the growing body of observational evidence that suggests prenatal exposure to OPEs may adversely affect cognitive development.

The Predictive Value of Developmental Assessments at 1 and 2 for Intelligence Quotients at 6.

Intelligence is an important individual difference factor related to mental health, academic achievement, and life success, yet there is a lack of research into its early cognitive predictors. This study investigated the predictive value of infant developmental assessment scores for school-age intelligence in a large, heterogeneous sample of single- and twin-born subjects (N = 521). We found that Early Learning Composite (ELC) scores from the Mullen Scales of Early Learning have similar predictive power to that of other infant tests. ELC scores at age 2 were predictive of Stanford-Binet abbreviated intelligence (ABIQ) scores at age 6 (r = 0.46) even after controlling for sex, gestation number, and parental education. ELC scores at age 1 were less predictive of 6-year ABIQ scores (r = 0.17). When the sample was split to test robustness of findings, we found that results from the full sample replicated in a subset of children born at ≥32 weeks gestation without birth complications (n = 405), though infant cognitive scores did not predict IQ in a subset born very prematurely or with birth complications (n = 116). Scores at age 2 in twins and singletons showed similar predictive ability for scores at age 6, though twins had particularly high correlations between ELC at age 1 and ABIQ at age 6.

Early Life Characteristics and Neurodevelopmental Phenotypes in the Mount Sinai Children's Environmental Health Center.

Neurodevelopmental outcomes including behavior, executive functioning, and IQ exhibit complex correlational structures, although they are often treated as independent in etiologic studies. We performed a principal components analysis of the behavioral assessment system for children, the behavior rating inventory of executive functioning, and the Wechsler scales of intelligence in a prospective birth cohort, and estimated associations with early life characteristics. We identified seven factors: (1) impulsivity and externalizing, (2) executive functioning, (3) internalizing, (4) perceptual reasoning, (5) adaptability, (6) processing speed, and (7) verbal intelligence. Prenatal fish consumption, maternal education, preterm birth, and the home environment were important predictors of various neurodevelopmental factors. Although maternal smoking was associated with more adverse externalizing, executive functioning, and adaptive composite scores in our sample, of the orthogonally-rotated factors, smoking was only associated with the impulsivity and externalizing factor ([Formula: see text] - 0.82, 95% CI - 1.42, - 0.23). These differences may be due to correlations among outcomes that were accounted for by using a phenotypic approach. Dimension reduction may improve upon traditional approaches by accounting for correlations among neurodevelopmental traits.

Emergence of a hierarchical brain during infancy reflected by stepwise functional connectivity.

The hierarchical nature of the brain's functional organization has long been recognized, but when and how this architecture emerges during development remains largely unknown. Here the development of the brain's hierarchical organization was characterized using a modified stepwise functional connectivity approach based on resting-state fMRI in a fully longitudinal sample of infants (N = 28, with scans after birth, and at 1 and 2 years) and adults. Results obtained by placing seeds in early sensory cortices revealed novel hierarchical patterns of adult brain organization ultimately converging in limbic, paralimbic, basal ganglia, and frontoparietal brain regions. These findings are remarkably consistent with predictive coding accounts of neural processing that place these regions at the top of predictive coding hierarchies. Infants gradually developed toward this architecture in a region- and step-dependent manner, and displayed many of the same regions as adults in top hierarchical positions, starting from 1 year of age. The findings further revealed patterns of inter-sensory connectivity likely reflecting the emergence and development of multisensory processing strategies during infancy, the strengths of which were correlated with early cognitive development scores. Hum Brain Mapp 38:2666-2682, 2017. © 2017 Wiley Periodicals, Inc.

Prenatal exposure to organophosphorus pesticides and childhood neurodevelopmental phenotypes.

Prenatal exposure to organophosphorus pesticides (OPs) has been associated with different neurodevelopmental outcomes across different cohorts. A phenotypic approach may address some of these differences by incorporating information across scales and accounting for the complex correlational structure of neurodevelopmental outcomes. Additionally, Bayesian hierarchical modeling can account for confounding by collinear co-exposures. We use this framework to examine associations between prenatal exposure to OPs and behavior, executive functioning, and IQ assessed at age 6-9 years in a cohort of 404 mother/infant pairs recruited during pregnancy. We derived phenotypes of neurodevelopment with a factor analysis, and estimated associations between OP metabolites and these phenotypes in Bayesian hierarchical models for exposure mixtures. We report seven factors: 1) Impulsivity and Externalizing, 2) Executive Functioning, 3) Internalizing, 4) Perceptual Reasoning, 5) Adaptability, 6) Processing Speed, and 7) Verbal Intelligence. These, along with the Working Memory Index, were standardized and scaled so that positive values reflected positive attributes and negative values represented adverse outcomes. Standardized dimethylphosphate metabolites were negatively associated with Internalizing factor scores (ß^ - 0.13, 95% CI - 0.26, 0.00) but positively associated with Executive Functioning factor scores (ß^ 0.18, 95% CI 0.04, 0.31). Standardized diethylphosphate metabolites were negatively associated with the Working Memory Index (ß^ - 0.17, 95% CI - 0.33, - 0.03). Associations with factor scores were generally stronger and more precise than associations with individual instrument-specific items. Factor analysis of outcomes may provide some advantages in etiological studies of childhood neurodevelopment by incorporating information across scales to reduce dimensionality and improve precision.

Vagal Regulation in Breastfeeding Infants and Their Mothers.

Consistent with the gustatory-vagal hypothesis, vagal stimulation during breastfeeding may contribute to infants' physiological regulatory development independent of caregiving effects. This study examined whether breastfeeding predicted 6-month-old infants' (N = 151) and their mothers' vagal regulation during the face-to-face still-face (FFSF). Although breastfed and nonbreastfed infants showed expected vagal withdrawal during the Still-Face episode, only breastfed infants showed continued withdrawal during the reunion episode, suggesting greater physiological mobilization to repair the interaction. Breastfeeding mothers showed higher vagal tone than nonbreastfeeding mothers at baseline, suggesting greater capacity for regulation, and throughout the FFSF, suggesting calmer states. Breastfeeding effects were independent of maternal sensitivity. Findings suggest that infants' and mothers' physiological regulation may be shaped by breastfeeding independently of associated social factors.

Development of thalamocortical connectivity during infancy and its cognitive correlations.

Although commonly viewed as a sensory information relay center, the thalamus has been increasingly recognized as an essential node in various higher-order cognitive circuits, and the underlying thalamocortical interaction mechanism has attracted increasing scientific interest. However, the development of thalamocortical connections and how such development relates to cognitive processes during the earliest stages of life remain largely unknown. Leveraging a large human pediatric sample (N = 143) with longitudinal resting-state fMRI scans and cognitive data collected during the first 2 years of life, we aimed to characterize the age-dependent development of thalamocortical connectivity patterns by examining the functional relationship between the thalamus and nine cortical functional networks and determine the correlation between thalamocortical connectivity and cognitive performance at ages 1 and 2 years. Our results revealed that the thalamus-sensorimotor and thalamus-salience connectivity networks were already present in neonates, whereas the thalamus-medial visual and thalamus-default mode network connectivity emerged later, at 1 year of age. More importantly, brain-behavior analyses based on the Mullen Early Learning Composite Score and visual-spatial working memory performance measured at 1 and 2 years of age highlighted significant correlations with the thalamus-salience network connectivity. These results provide new insights into the understudied early functional brain development process and shed light on the behavioral importance of the emerging thalamocortical connectivity during infancy.

Lactational exposure to polychlorinated biphenyls, dichlorodiphenyltrichloroethane, and dichlorodiphenyldichloroethylene and infant growth: an analysis of the Pregnancy, Infection, and Nutrition Babies Study.

Polychlorinated biphenyls (PCB), 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (p,p'-DDT) and 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), the most stable metabolite of p,p'-DDT, are persistent organic pollutants and environmental endocrine disruptors. Infant exposure to these chemicals through breast feeding may influence children's growth, but this potential adverse effect could be complicated by the coexisting benefits of breast feeding. This study examined the associations between lactational exposure to these chemicals and infant growth in the first 12 months by using data from the Pregnancy, Infection and Nutrition Babies Study in central North Carolina, United States, 2004-06. The study population was restricted to the infants who were breast fed for 6 months or longer. PCBs, p,p'-DDT and p,p'-DDE were measured in breast milk at 3 months postpartum. Lactational exposure up to 12 months of age was estimated as the product of chemical concentrations and the duration of breast feeding. The infant's weight and length were recorded from the medical record for each routine paediatric well-child visit in the first 12 months. Women-child pairs who breast fed for 6 months or longer and returned the growth card (n = 210) were included in the study. Linear mixed effects models were used to assess the associations between chemical concentrations in breast milk and longitudinal infant weight and length measurements in the first 6 months. Multivariable linear regression models were used to assess the relationships between lactational exposure to chemicals until 12 months of age and the z-scores of infant weight, length and weight-for-length at 12 months. Overall, no association was observed. Breast feeding for 6 months or longer, with lactational exposure to PCBs, p,p'-DDT and p,p'-DDE at the low background level concentrations studied here, resulted in no measurable influence on infant growth in the first 12 months.

Neonatal brain connectivity outliers identify over forty percent of IQ outliers at 4 years of age.

BACKGROUND: Defining reliable brain markers for the prediction of abnormal behavioral outcomes remains an urgent but extremely challenging task in neuroscience research. This is particularly important for infant studies given the most dramatic brain and behavioral growth during infancy. METHODS: In this study, we proposed a novel prediction scheme through abstracting individual newborn's whole-brain functional connectivity pattern to three outlier measures (Triple O) and tested the hypothesis that neonates identified as "brain outliers" based on Triple O were more likely to develop as IQ outliers at 4 years of age. Without need for training with behavioral data, Triple O represents a novel proof-of-concept approach to predict later IQ outcomes based on neonatal brain data. RESULTS: Triple O correctly identified 42.1% true IQ outliers among a mixed cohort of 175 newborns with different term, twin, and maternal disorder statuses. Triple O also reached a high level of specificity (96.2%) and overall accuracy (90.3%). Further incorporating a demographic information indicator, the enhanced Triple O+ could further differentiate between high and low 4YR IQ outliers. Validation tests against seven independent reference samples revealed highly consistent results and a minimum sample size of ~50 for robust performance. CONCLUSIONS: Considering that postnatal brain growth and various environmental factors likely also contribute to 4YR IQ, the fact that Triple O, based purely on neonatal functional connectivity data, could identify >40% of 4YR IQ outliers is striking. Together with the very high level of specificity, each outlier predicted by Triple O represents a meaningful risk but future efforts are needed to explore ways to identify the rest of outliers. Overall, with no need for training, a high level of robustness, and a minimal requirement on sample size, the proposed Triple O approach demonstrates great potential to predict later outlying IQ performances using neonatal functional connectivity data.

Early Development of Infants with Turner Syndrome.

OBJECTIVE: To examine the early cognitive, temperament, and adaptive functioning of infants and toddlers with Turner syndrome (TS). METHODS: Cognitive abilities were measured using the Mullen Scales of Early Learning at 1 year of age for 31 girls with TS and compared with neurotypical female (N = 53) and male (N = 54) control groups. Temperament (Carey Toddler Temperament Scales) and adaptive functioning (Vineland Adaptive Behavior Scales-Second Edition) were measured at 1 year of age and compared with normative data. An exploratory analysis of cognitive/developmental trajectories was also conducted comparing age 12-month to 24-month time points for 22 TS subjects. RESULTS: Infants with TS performed largely within the average range for adaptive behavior, temperament, and early cognitive development with some increased risk for delays in language and significant increased risk for delays in motor skills (p < 0.001). Although exploratory, there was some suggestion of slower rates of progression in fine-motor and visual reception skills from 12 to 24 months of age. CONCLUSIONS: Infants and toddlers with TS exhibit a relatively positive neurodevelopmental profile overall, with some indication of an increasing gap in function in fine-motor and visual perceptual abilities as compared to neurotypical peers. It is unclear whether these apparent differences represent normal variability in this very young population or, perhaps, are early precursors of later phenotypic characteristics of TS in the school-age and young adult years.

Differential recall of consent information and parental decisions about enrolling children in research studies.

In the present simulation research, the authors examined the relations between the type of information that low-income parents (N = 116) recalled from informed-consent materials and their hypothetical decision to enroll a child in a clinical study. The authors gave parents or guardians of Head Start children information about a medical protocol involving high risk and significant potential benefit to child participants. Differential recall of the various categories of information (procedures, benefits, risks and costs, rights, and other) showed that relative to all consent information conveyed to them, participants recalled most about procedures and least about their child's rights as a study participant. Relative to their own recall, they also recounted most about procedures, slightly more about benefits than risks, and least about research rights. The pattern of recall differed among those who agreed to enroll and those who declined. The ratio of recalled risks to benefits predicted enrollment decisions.

Development of Amygdala Functional Connectivity During Infancy and Its Relationship With 4-Year Behavioral Outcomes.

BACKGROUND: The amygdala represents a core node in the human brain's emotional signal processing circuitry. Given its critical role, both the typical and atypical functional connectivity patterns of the amygdala have been extensively studied in adults. However, the development of amygdala functional connectivity during infancy is less well studied; thus, our understanding of the normal growth trajectory of key emotion-related brain circuits during a critical period is limited. METHODS: In this study, we used resting-state functional magnetic resonance imaging (N = 233 subjects with 334 datasets) to delineate the spatiotemporal dynamics of amygdala functional connectivity development during the first 2 years of life. Their relationships with 4-year emotional (i.e., anxiety and inhibitory self-control parent report measures) and cognitive (i.e., IQ) behavioral outcomes were also assessed using multivariate modeling. RESULTS: Our results revealed nonlinear growth of amygdala functional connectivity during the first 2 years of life, featuring dramatic synchronization during the first year followed by moderate growth or fine tuning during the second year. Importantly, functional connectivity growth during the second year had significant behavioral implications exemplified by multiple significant predictions of 4-year emotional and cognitive developmental outcomes. CONCLUSIONS: The delineation of the spatiotemporal dynamics of amygdala functional connectivity development during infancy and their associations with 4-year behavioral outcomes may provide new references on the early emergence of both typical and atypical emotion processing capabilities.

Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study.

Organophosphate esters (OPEs) are commonly used as plasticizers and flame retardants in consumer products, and exposure is relatively ubiquitous in most populations studied. This may be of concern as some OPEs may be neurotoxic, endocrine-disrupting, and interfere with behavioral development; however, observational evidence is limited. We used data from the Pregnancy, Infection, and Nutrition Study, a prospective birth cohort study, to investigate associations between maternal OPE metabolite concentrations during pregnancy and behavioral development in offspring. Women provided a urine sample during pregnancy that was analyzed for concentrations of OPE metabolites, including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). Offspring's behavioral development was assessed by the Behavioral Assessment System for Children (2nd Edition) (BASC-2) at approximately 36 months. Linear regression was used to estimate associations between tertiles in specific gravity-corrected OPE metabolite concentrations and children's scores on the BASC-2, adjusted for maternal age, maternal BMI, maternal race, maternal education, familial income, maternal depression, quality of the home environment, and sex. Higher BDCIPP concentrations were associated with higher scores on the Behavioral Symptoms Index (1st vs. 3rd tertile: ß = 3.03; 95% CI = 0.40, 5.67) and Externalizing Problems (1st vs. 3rd tertile: ß = 2.49; 95% CI: -0.12, 5.10) composites. Among BASC-2 scales, BDCIPP was most strongly associated with Withdrawal, Attention Problems, Depression, Hyperactivity, and Aggression. DPHP concentrations were also associated with higher scores on the Externalizing Problems and Behavioral Symptoms Index composites, but not as strongly as BDCIPP. Conversely, higher concentrations of ip-PPP were associated with fewer adverse behavioral symptoms, including an inverse association with the Internalizing Problems composite (1st vs. 3rd tertile: ß = -3.74; 95% CI = -6.75, -0.74) and constituent scales. BCIPHIPP was not strongly associated with any measured behavioral outcomes. Our results suggest that greater maternal exposure to tris(1,3-dichloro-2-propyl phosphate) (TDCIPP, parent compound of BDCIPP) and, to a lesser degree, triphenyl phosphate (TPHP, parent compound of DPHP) during pregnancy is associated with adverse behavioral development in children. Our study contributes to the growing body of evidence pertaining to adverse developmental effects of prenatal OPE exposure and highlights the need for further research to characterize risks associated with this ubiquitous family of chemicals.

Gut microbiome and brain functional connectivity in infants-a preliminary study focusing on the amygdala.

Recently, there has been a surge of interest in the possibility that microbial communities inhabiting the human gut could affect cognitive development and increase risk for mental illness via the "microbiome-gut-brain axis." Infancy likely represents a critical period for the establishment of these relationships, as it is the most dynamic stage of postnatal brain development and a key period in the maturation of the microbiome. Indeed, recent reports indicate that characteristics of the infant gut microbiome are associated with both temperament and cognitive performance. The neural circuits underlying these relationships have not yet been delineated. To address this gap, resting-state fMRI scans were acquired from 39 1-year-old human infants who had provided fecal samples for identification and relative quantification of bacterial taxa. Measures of alpha diversity were generated and tested for associations with measures of functional connectivity. Primary analyses focused on the amygdala as manipulation of the gut microbiota in animal models alters the structure and neurochemistry of this brain region. Secondary analyses explored functional connectivity of nine canonical resting-state functional networks. Alpha diversity was significantly associated with functional connectivity between the amygdala and thalamus and between the anterior cingulate cortex and anterior insula. These regions play an important role in processing/responding to threat. Alpha diversity was also associated with functional connectivity between the supplementary motor area (SMA, representing the sensorimotor network) and the inferior parietal lobule (IPL). Importantly, SMA-IPL connectivity also related to cognitive outcomes at 2 years of age, suggesting a potential pathway linking gut microbiome diversity and cognitive outcomes during infancy. These results provide exciting new insights into the gut-brain axis during early human development and should stimulate further studies into whether microbiome-associated changes in brain circuitry influence later risk for psychopathology.