White matter microstructure and functional connectivity in the brains of infants with Turner syndrome.

Turner syndrome, caused by complete or partial loss of an X-chromosome, is often accompanied by specific cognitive challenges. Magnetic resonance imaging studies of adults and children with Turner syndrome suggest these deficits reflect differences in anatomical and functional connectivity. However, no imaging studies have explored connectivity in infants with Turner syndrome. Consequently, it is unclear when in development connectivity differences emerge. To address this gap, we compared functional connectivity and white matter microstructure of 1-year-old infants with Turner syndrome to typically developing 1-year-old boys and girls. We examined functional connectivity between the right precentral gyrus and five regions that show reduced volume in 1-year old infants with Turner syndrome compared to controls and found no differences. However, exploratory analyses suggested infants with Turner syndrome have altered connectivity between right supramarginal gyrus and left insula and right putamen. To assess anatomical connectivity, we examined diffusivity indices along the superior longitudinal fasciculus and found no differences. However, an exploratory analysis of 46 additional white matter tracts revealed significant group differences in nine tracts. Results suggest that the first year of life is a window in which interventions might prevent connectivity differences observed at later ages, and by extension, some of the cognitive challenges associated with Turner syndrome.

Early cognitive development and psychopathology in children at familial high risk for schizophrenia.

Schizophrenia is a neurodevelopmental disorder associated with deficits in cognitive development and childhood psychopathology. Previous studies have focused on older children and the few studies of early childhood have yielded inconsistent findings. We studied cognitive development and psychopathology in children at familial high risk (FHR) of schizophrenia and matched controls from 1 to 6 years and hypothesized that FHR children would show consistent deficits across cognitive and behavioral measures in early childhood. STUDY DESIGN: Cognitive development in children at high familial risk for schizophrenia or schizoaffective disorder (n = 33) and matched healthy controls (n = 66) was assessed at 1 and 2 years with the Mullen Scales of Early Learning, and at 4 and 6 years with the Stanford Binet Intelligence Scales, BRIEF-P/BRIEF and CANTAB. Psychopathology was assessed at 4 and 6 years with the BASC-2. General linear models were used to examine differences on outcome scores, and chi-square analyses were used to explore differences in the proportion of "at risk" or "below average" score profiles. STUDY RESULTS: FHR children scored significantly lower than controls on Mullen Composite at age 2, and demonstrated broad deficits in IQ, executive function and working memory and 4 and 6 years. FHR children were also rated as significantly worse on most items of the BASC-2 at ages 4 and 6. CONCLUSIONS: Children at FHR for schizophrenia demonstrate abnormal cognitive development and psychopathology at younger ages than previously detected, suggesting that early detection and intervention needs to be targeted to very early childhood.

Sex differences in brain-behavior relationships in the first two years of life.

Background: Evidence for sex differences in cognition in childhood is established, but less is known about the underlying neural mechanisms for these differences. Recent findings suggest the existence of brain-behavior relationship heterogeneities during infancy; however, it remains unclear whether sex underlies these heterogeneities during this critical period when sex-related behavioral differences arise. Methods: A sample of 316 infants was included with resting-state functional magnetic resonance imaging scans at neonate (3 weeks), 1, and 2 years of age. We used multiple linear regression to test interactions between sex and resting-state functional connectivity on behavioral scores of working memory, inhibitory self-control, intelligence, and anxiety collected at 4 years of age. Results: We found six age-specific, intra-hemispheric connections showing significant and robust sex differences in functional connectivity-behavior relationships. All connections are either with the prefrontal cortex or the temporal pole, which has direct anatomical pathways to the prefrontal cortex. Sex differences in functional connectivity only emerge when associated with behavior, and not in functional connectivity alone. Furthermore, at neonate and 2 years of age, these age-specific connections displayed greater connectivity in males and lower connectivity in females in association with better behavioral scores. Conclusions: Taken together, we critically capture robust and conserved brain mechanisms that are distinct to sex and are defined by their relationship to behavioral outcomes. Our results establish brain-behavior mechanisms as an important feature in the search for sex differences during development.

Associations between early trajectories of amygdala development and later school-age anxiety in two longitudinal samples.

Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6-12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In the IBIS sample, children with higher anxiety showed accelerated amygdala growth from 6 to 24 months. ASD diagnosis and ASD familial likelihood were not significant predictors. In the EBDS sample, amygdala growth from birth to 24 months was associated with anxiety. More anxious children had smaller amygdala volume and slower rates of amygdala growth. We explore reasons for the contrasting results between high-familial likelihood for ASD and TD samples, grounding results in the broader literature of variable associations between early amygdala volume and later anxiety. Results have the potential to identify mechanisms linking early amygdala growth to later anxiety in certain groups.

Structural and functional connectome relationships in early childhood.

There is strong evidence that the functional connectome is highly related to the white matter connectome in older children and adults, though little is known about structure-function relationships in early childhood. We investigated the development of cortical structure-function coupling in children longitudinally scanned at 1, 2, 4, and 6 years of age (N = 360) and in a comparison sample of adults (N = 89). We also applied a novel graph convolutional neural network-based deep learning model with a new loss function to better capture inter-subject heterogeneity and predict an individual's functional connectivity from the corresponding structural connectivity. We found regional patterns of structure-function coupling in early childhood that were consistent with adult patterns. In addition, our deep learning model improved the prediction of individual functional connectivity from its structural counterpart compared to existing models.

Longitudinal developmental trajectories of functional connectivity reveal regional distribution of distinct age effects in infancy.

Prior work has shown that different functional brain networks exhibit different maturation rates, but little is known about whether and how different brain areas may differ in the exact shape of longitudinal functional connectivity growth trajectories during infancy. We used resting-state functional magnetic resonance imaging (fMRI) during natural sleep to characterize developmental trajectories of different regions using a longitudinal cohort of infants at 3 weeks (neonate), 1 year, and 2 years of age (n = 90; all with usable data at three time points). A novel whole brain heatmap analysis was performed with four mixed-effect models to determine the best fit of age-related changes for each functional connection: (i) growth effects: positive-linear-age, (ii) emergent effects: positive-log-age, (iii) pruning effects: negative-quadratic-age, and (iv) transient effects: positive-quadratic-age. Our results revealed that emergent (logarithmic) effects dominated developmental trajectory patterns, but significant pruning and transient effects were also observed, particularly in connections centered on inferior frontal and anterior cingulate areas that support social learning and conflict monitoring. Overall, unique global distribution patterns were observed for each growth model indicating that developmental trajectories for different connections are heterogeneous. All models showed significant effects concentrated in association areas, highlighting the dominance of higher-order social/cognitive development during the first 2 years of life.

Sex differences in resting state functional connectivity across the first two years of life.

Sex differences in behavior have been reported from infancy through adulthood, but little is known about sex effects on functional circuitry in early infancy. Moreover, the relationship between early sex effects on the functional architecture of the brain and later behavioral performance remains to be elucidated. In this study, we used resting-state fMRI and a novel heatmap analysis to examine sex differences in functional connectivity with cross-sectional and longitudinal mixed models in a large cohort of infants (n = 319 neonates, 1-, and 2-year-olds). An adult dataset (n = 92) was also included for comparison. We investigated the relationship between sex differences in functional circuitry and later measures of language (collected in 1- and 2-year-olds) as well as indices of anxiety, executive function, and intelligence (collected in 4-year-olds). Brain areas showing the most significant sex differences were age-specific across infancy, with two temporal regions demonstrating consistent differences. Measures of functional connectivity showing sex differences in infancy were significantly associated with subsequent behavioral scores of language, executive function, and intelligence. Our findings provide insights into the effects of sex on dynamic neurodevelopmental trajectories during infancy and lay an important foundation for understanding the mechanisms underlying sex differences in health and disease.

Genetic and environmental factors influencing neonatal resting-state functional connectivity.

Functional magnetic resonance imaging has been used to identify complex brain networks by examining the correlation of blood-oxygen-level-dependent signals between brain regions during the resting state. Many of the brain networks identified in adults are detectable at birth, but genetic and environmental influences governing connectivity within and between these networks in early infancy have yet to be explored. We investigated genetic influences on neonatal resting-state connectivity phenotypes by generating intraclass correlations and performing mixed effects modeling to estimate narrow-sense heritability on measures of within network and between-network connectivity in a large cohort of neonate twins. We also used backwards elimination regression and mixed linear modeling to identify specific demographic and medical history variables influencing within and between network connectivity in a large cohort of typically developing twins and singletons. Of the 36 connectivity phenotypes examined, only 6 showed narrow-sense heritability estimates greater than 0.10, with none being statistically significant. Demographic and obstetric history variables contributed to between- and within-network connectivity. Our results suggest that in early infancy, genetic factors minimally influence brain connectivity. However, specific demographic and medical history variables, such as gestational age at birth and maternal psychiatric history, may influence resting-state connectivity measures.

Early Childhood Development of Node Centrality in the White Matter Connectome and Its Relationship to IQ at Age 6 Years.

BACKGROUND: The white matter (WM) connectome is important for cognitive development and intelligence and is altered in neuropsychiatric illnesses. Little is known about how the WM connectome develops or its relationship to IQ in early childhood. METHODS: The development of node centrality in the WM connectome was studied in a longitudinal cohort of 226 (123 female) children from the University of North Carolina Early Brain Development Study. Structural and diffusion-weighted images were acquired after birth and at 1, 2, 4, and 6 years, and IQ was assessed at 6 years. Eigenvector centrality, betweenness centrality, and the global graph metrics of global efficiency, small worldness, and modularity were determined at each age. RESULTS: The greatest developmental change in eigenvector centrality and betweenness centrality occurred during the first year of life, with relative stability between ages 1 and 6 years. Most of the high-centrality hubs at age 6 were also high-centrality hubs at 1 year, and many were already high-centrality hubs at birth. There were generally small but significant changes in global efficiency and modularity from birth to 6 years, while small worldness increased between 2 and 4 years. Individual node centrality was not significantly correlated with IQ at 6 years. CONCLUSIONS: Node centrality in the WM connectome is established very early in childhood and is relatively stable from age 1 to 6 years. Many high-centrality hubs are established before birth, and most are present by age 1.

Influence of gonadal steroids on cortical surface area in infancy.

Sex differences in the human brain emerge as early as mid-gestation and have been linked to sex hormones, particularly testosterone. Here, we analyzed the influence of markers of early sex hormone exposure (polygenic risk score (PRS) for testosterone, salivary testosterone, number of CAG repeats, digit ratios, and PRS for estradiol) on the growth pattern of cortical surface area in a longitudinal cohort of 722 infants. We found PRS for testosterone and right-hand digit ratio to be significantly associated with surface area, but only in females. PRS for testosterone at the most stringent P value threshold was positively associated with surface area development over time. Higher right-hand digit ratio, which is indicative of low prenatal testosterone levels, was negatively related to surface area in females. The current work suggests that variation in testosterone levels during both the prenatal and postnatal period may contribute to cortical surface area development in female infants.

Genetic Influences on Longitudinal Trajectories of Cortical Thickness and Surface Area during the First 2 Years of Life.

Genetic influences on cortical thickness (CT) and surface area (SA) are known to vary across the life span. Little is known about the extent to which genetic factors influence CT and SA in infancy and toddlerhood. We performed the first longitudinal assessment of genetic influences on variation in CT and SA in 501 twins who were aged 0-2 years. We observed substantial additive genetic influences on both average CT (0.48 in neonates, 0.37 in 1-year-olds, and 0.44 in 2-year-olds) and total SA (0.59 in neonates, 0.74 in 1-year-olds, and 0.73 in 2-year-olds). In addition, we found strong heritability of the change in average CT (0.49) from neonates to 1-year-olds, but not from 1- to 2-year-olds. Moreover, we found strong genetic correlations for average CT (rG = 0.92) between 1- and 2-year-olds and strong genetic correlations for total SA across all timepoints (rG = 0.96 between neonates and 1-year-olds, rG = 1 between 1- and 2-year-olds). In addition, we found CT and SA are strongly genetic correlated at birth, but weaken over time. Overall, results suggest a dynamic genetic relationship between CT and SA during first 2 years of life and provide novel insights into how genetic influences shape the cortical structure during early brain development.

Turner syndrome: language profile of young girls at 12 and 24 months of age.

BACKGROUND: Turner syndrome (TS) is a genetic disorder associated with complete or partial absence of an X chromosome affecting approximately 1/2000 live female births. Available evidence suggests that, in the school-age years, girls with TS often require speech and language services; however, little is known about the language development of infants and toddlers. METHOD: This study (N = 31) explored the language profiles of 12- and 24-month-old girls with TS, as well as the percentage of girls who might be "at risk" for language delays. We also followed a subset of 12-month-old girls with TS to 24 months of age to determine the stability of the 12-month findings. RESULTS: Although all mean scores were within the average range at both time points, results revealed a higher prevalence of 24-month-old girls with TS "at risk" for receptive language difficulties. In addition, expressive language skills significantly exceeded receptive language skills at both time points. We found 12-month-old girls to be "at risk" for social and symbolic difficulties based on clinical assessment; only symbolic difficulties were significant based on caregiver report. At 24 months, clinical assessment indicated greater use of speech sounds and words than normative expectations. Caregivers reported greater use of speech sounds, and also, greater use of gestures. Although some changes occurred over a 1-year time span (12 to 24 months), all mean test scores remained within the average range and the changes in the percentage of girls manifesting "at risk" status on either the PLS-4 or CSBS-DP were non-significant. CONCLUSIONS: Although within normal limits, receptive language skills were found to be significantly lower than expressive language skills at both ages. Social and symbolic communication skills also were in the average range, with both showing significant improvement from 12 to 24 months based on clinical assessment. Caregiver report found that use of gestures and production of speech sounds not only improved from 12 to 24 months, but also exceeded normative expectations. Findings suggest the presence of relatively intact speech and language abilities during the first 2 years of life, with perhaps some emergent concerns for receptive language development. Ongoing developmental surveillance will be important.

Developmental heatmaps of brain functional connectivity from newborns to 6-year-olds.

Different functional networks exhibit distinct longitudinal trajectories throughout development, but the timeline of the dynamics of functional connectivity across the whole brain remains to be elucidated. Here we used resting-state fMRI to investigate the development of voxel-level changes in functional connectivity across the first six years of life. Globally, we found that developmental changes in functional connectivity are nonlinear with more changes during the first postnatal year than the second, followed by most significant changes from ages 2-4 and from ages 4-6. However, the overall global difference observed between the first and second year appears to have been driven by girls. Limbic and subcortical areas consistently demonstrated the most substantial changes, whereas primary sensory areas were the most stable. These patterns were consistent in full-term and preterm subgroups. Validation on randomly divided subsamples as well as in an independent cross-sectional sample revealed global patterns consistent with the main results. Overall, the derived developmental heatmaps reveal novel dynamics underlying functional circuit development during the first 6 years of life.

Hippocampal functional connectivity development during the first two years indexes 4-year working memory performance.

The hippocampus is a key limbic region involved in higher-order cognitive processes including learning and memory. Although both typical and atypical functional connectivity patterns of the hippocampus have been well-studied in adults, the developmental trajectory of hippocampal connectivity during infancy and how it relates to later working memory performance remains to be elucidated. Here we used resting state fMRI (rsfMRI) during natural sleep to examine the longitudinal development of hippocampal functional connectivity using a large cohort (N = 202) of infants at 3 weeks (neonate), 1 year, and 2 years of age. Next, we used multivariate modeling to investigate the relationship between both cross-sectional and longitudinal growth in hippocampal connectivity and 4-year working memory outcome. Results showed robust local functional connectivity of the hippocampus in neonates with nearby limbic and subcortical regions, with dramatic maturation and increasing connectivity with key default mode network (DMN) regions resulting in adult-like topology of the hippocampal functional connectivity by the end of the first year. This pattern was stabilized and further consolidated by 2 years of age. Importantly, cross-sectional and longitudinal measures of hippocampal connectivity in the first year predicted subsequent behavioral measures of working memory at 4 years of age. Taken together, our findings provide insight into the development of hippocampal functional circuits underlying working memory during this early critical period.

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.

Subdural Hemorrhage in Asymptomatic Neonates: Neurodevelopmental Outcomes and MRI Findings at 2 Years.

Background Subdural hemorrhage (SDH) is thought to have a benign course in asymptomatic neonates. However, effects on neurodevelopmental outcomes have not been established. Purpose To evaluate neurodevelopmental outcomes, gray matter volumes, and MRI findings in asymptomatic neonates with SDH compared with control neonates. Materials and Methods This retrospective analysis was conducted between 2003 and 2016 and was based on data from the University of North Carolina Early Brain Development Study. Neurodevelopmental outcomes were evaluated at 2 years of age by using the Mullen Scales of Early Learning (MSEL). All infants were imaged with 3.0-T MRI machines and were evaluated for SDH at baseline (neonates) and at ages 1 and 2 years. Volumetric MRI for brain segmentation was performed at ages 1 and 2 years. A secondary analysis was performed in neonates matched 1:1 with control neonates. Differences in categorical variables were measured by using the Fisher exact test, and the t test was used for continuous variables. Results A total of 311 neonates (mean gestational age ± standard deviation, 39.3 weeks ± 1.5), including 57 with SDH (mean gestational age, 39.5 weeks ± 1.2), were evaluated. The subgroup included 55 neonates with SDH (mean gestational age, 39.6 weeks ± 1.2) and 55 matched control neonates (mean gestational age, 39.7 weeks ± 1.2). Fifty-five of 57 neonates with SDH (97%; 95% CI: 92, 100) were delivered vaginally compared with 157 of 254 control neonates (62%, 95% CI: 56, 68; P < .001). Otherwise, there were no differences in perinatal, maternal, or obstetric parameters. There were no differences in composite MSEL scores (115 ± 15 and 109 ± 16 at 2 years, respectively; P = .05) or gray matter volumes between the neonatal SDH group and control neonates (730 cm3 ± 85 and 742 cm3 ± 76 at 2 years, respectively; P = .70). There was no evidence of rebleeding at follow-up MRI. Conclusion Neurodevelopmental scores and gray matter volumes at age 2 years did not differ between asymptomatic neonates with subdural hemorrhage and control neonates. © RSNA, 2020 Online supplemental material is available for this article.

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.

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.

Individual Variation of Human Cortical Structure Is Established in the First Year of Life.

BACKGROUND: Individual differences in cortical gray matter (GM) structure are associated with cognitive function and psychiatric disorders with developmental origins. Identifying when individual differences in cortical structure are established in childhood is critical for understanding the timing of abnormal cortical development associated with neuropsychiatric disorders. METHODS: We studied the development of cortical GM and white matter volume, cortical thickness, and surface area using structural magnetic resonance imaging in two unique cohorts of singleton (121 male and 131 female) and twin (99 male and 83 female) children imaged longitudinally from birth to 6 years. RESULTS: Cortical GM volume increases rapidly in the first year of life, with more gradual growth thereafter. Between ages 1 and 6 years, total surface area expands 29%, while average cortical thickness decreases about 3.5%. In both cohorts, a large portion of individual variation in cortical GM volume (81%-87%) and total surface area (73%-83%) at age 6 years is present by age 1 year. Regional heterogeneity of cortical thickness observed at age 6 is largely in place at age 1. CONCLUSIONS: These findings indicate that individual differences in cortical GM structure are largely established by the end of the first year of life, following a period of rapid postnatal GM growth. This suggests that alterations in GM structure associated with psychiatric disorders with developmental origins may largely arise in the first year of life and that interventions to normalize or mitigate abnormal GM development may need to be targeted to very early childhood.

Extra-axial Cerebrospinal Fluid Relationships to Infant Brain Structure, Cognitive Development, and Risk for Schizophrenia.

BACKGROUND: Increased volume of extra-axial cerebrospinal fluid (EA-CSF) is associated with autism spectrum disorder diagnosis in young children. However, little is known about EA-CSF development in typically developing (TD) children or in children at risk for schizophrenia (SCZHR). METHODS: 3T magnetic resonance imaging scans were obtained in TD children (n = 105) and in SCZHR children (n = 38) at 1 and 2 years of age. EA-CSF volume and several measures of brain structure were generated, including global tissue volumes, cortical thickness, and surface area. Cognitive and motor abilities at 1 and 2 years of age were assessed using the Mullen Scales of Early Learning. RESULTS: In the TD children, EA-CSF volume was positively associated with total brain volume, gray and white matter volumes, and total surface area at 1 and 2 years of age. In contrast, EA-CSF volume was negatively associated with average cortical thickness. Lower motor ability was associated with increased EA-CSF volume at 1 year of age. EA-CSF was not significantly increased in SCZHR children compared with TD children. CONCLUSIONS: EA-CSF volume is positively associated with overall brain size and cortical surface area but negatively associated with cortical thickness. Increased EA-CSF is associated with delayed motor development at 1 year of age, similar to studies of children at risk for autism, suggesting that increased EA-CSF may be an early biomarker of abnormal brain development in infancy. Infants in the SCZHR group did not exhibit significantly increased EA-CSF, suggesting that increased EA-CSF could be specific to neurodevelopmental disorders with an earlier onset, such as autism.