Mapping Genetic Topography of Cortical Thickness and Surface Area in Neonatal Brains.

Adult twin neuroimaging studies have revealed that cortical thickness (CT) and surface area (SA) are differentially influenced by genetic information, leading to their spatially distinct genetic patterning and topography. However, the postnatal origins of the genetic topography of CT and SA remain unclear, given the dramatic cortical development from neonates to adults. To fill this critical gap, this study unprecedentedly explored how genetic information differentially regulates the spatial topography of CT and SA in the neonatal brain by leveraging brain magnetic resonance (MR) images from 202 twin neonates with minimal influence by the complicated postnatal environmental factors. We capitalized on infant-dedicated computational tools and a data-driven spectral clustering method to parcellate the cerebral cortex into a set of distinct regions purely according to the genetic correlation of cortical vertices in terms of CT and SA, respectively, and accordingly created the first genetically informed cortical parcellation maps of neonatal brains. Both genetic parcellation maps exhibit bilaterally symmetric and hierarchical patterns, but distinct spatial layouts. For CT, regions with closer genetic relationships demonstrate an anterior-posterior (A-P) division, while for SA, regions with greater genetic proximity are typically within the same lobe. Certain genetically informed regions exhibit strong similarities between neonates and adults, with the most striking similarities in the medial surface in terms of SA, despite their overall substantial differences in genetic parcellation maps. These results greatly advance our understanding of the development of genetic influences on the spatial patterning of cortical morphology.SIGNIFICANCE STATEMENT Genetic influences on cortical thickness (CT) and surface area (SA) are complex and could evolve throughout the lifespan. However, studies revealing distinct genetic topography of CT and SA have been limited to adults. Using brain structural magnetic resonance (MR) images of twins, we unprecedentedly discovered the distinct genetically-informed parcellation maps of CT and SA in neonatal brains, respectively. Each genetic parcellation map comprises a distinct spatial layout of cortical regions, where vertices within the same region share high genetic correlation. These genetic parcellation maps of CT and SA of neonates largely differ from those of adults, despite their highly remarkable similarities in the medial cortex of SA. These discoveries provide important insights into the genetic organization of the early cerebral cortex development.

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.

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.

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.

Imaging structural and functional brain development in early childhood.

In humans, the period from term birth to ∼2 years of age is characterized by rapid and dynamic brain development and plays an important role in cognitive development and risk of disorders such as autism and schizophrenia. Recent imaging studies have begun to delineate the growth trajectories of brain structure and function in the first years after birth and their relationship to cognition and risk of neuropsychiatric disorders. This Review discusses the development of grey and white matter and structural and functional networks, as well as genetic and environmental influences on early-childhood brain development. We also discuss initial evidence regarding the usefulness of early imaging biomarkers for predicting cognitive outcomes and risk of neuropsychiatric disorders.

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.

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.

The role of social adversity on emotional dysregulation during infancy and early childhood.

PURPOSE: The purpose of this study was to investigate if social adversity is associated with mother reported emotional dysregulation behaviors and trajectories during infancy and early childhood. DESIGN & METHODS: A secondary data analysis from the Durham Child Health and Development study study included 206 child-mother dyads. Three models were used to explore the relationship between social adversity and mother reported emotional dysregulation during infancy (Infant Behavior Questionnaire-Revised) and early childhood (Child Behavior Checklist - Dysregulation Profile). Linear mixed effects models were adopted to investigate if social adversity was associated with mother reported emotional dysregulation longitudinally. Regression analysis was conducted to explore if social adversity was associated with maternal reported emotional dysregulation trajectory slope scores and maternal reported emotional dysregulation trajectory class. Maternal psychological distress and the child's sex assigned at birth were included as covariates in each analysis. RESULTS: Infants with greater social adversity scores had significantly higher maternal reported fear responses across the first year of life. Social adversity was associated with maternal reported distress to limitations trajectory, dysregulated recovery class, and dysregulated distress to limitations class. During early childhood social adversity was significantly associated with maternal reported emotional dysregulation but not trajectories which showed little variability. CONCLUSION & PRACTICAL IMPLICATIONS: Our results indicate that social adversity is associated with maternal reported emotional dysregulation during infancy and early childhood. Nursing and other professionals can participate in early screening to determine risk and provide intervention.

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.

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.

White Matter Development from Birth to 6 Years of Age: A Longitudinal Study.

Human white matter development in the first years of life is rapid, setting the foundation for later development. Microstructural properties of white matter are linked to many behavioral and psychiatric outcomes; however, little is known about when in development individual differences in white matter microstructure are established. The aim of the current study is to characterize longitudinal development of white matter microstructure from birth through 6 years to determine when in development individual differences are established. Two hundred and twenty-four children underwent diffusion-weighted imaging after birth and at 1, 2, 4, and 6 years. Diffusion tensor imaging data were computed for 20 white matter tracts (9 left-right corresponding tracts and 2 commissural tracts), with tract-based measures of fractional anisotropy and axial and radial diffusivity. Microstructural maturation between birth and 1 year are much greater than subsequent changes. Further, by 1 year, individual differences in tract average values are consistently predictive of the respective 6-year values, explaining, on average, 40% of the variance in 6-year microstructure. Results provide further evidence of the importance of the first year of life with regard to white matter development, with potential implications for informing early intervention efforts that target specific sensitive periods.

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.

Exposure to prenatal maternal distress and infant white matter neurodevelopment.

The prenatal period represents a critical time for brain growth and development. These rapid neurological advances render the fetus susceptible to various influences with life-long implications for mental health. Maternal distress signals are a dominant early life influence, contributing to birth outcomes and risk for offspring psychopathology. This prospective longitudinal study evaluated the association between prenatal maternal distress and infant white matter microstructure. Participants included a racially and socioeconomically diverse sample of 85 mother-infant dyads. Prenatal distress was assessed at 17 and 29 weeks' gestational age (GA). Infant structural data were collected via diffusion tensor imaging at 42-45 weeks' postconceptional age. Findings demonstrated that higher prenatal maternal distress at 29 weeks' GA was associated with increased fractional anisotropy (b = .283, t(64) = 2.319, p = .024) and with increased axial diffusivity (b = .254, t(64) = 2.067, p = .043) within the right anterior cingulate white matter tract. No other significant associations were found with prenatal distress exposure and tract fractional anisotropy or axial diffusivity at 29 weeks' GA, nor earlier in gestation.

Maternal trait anxiety symptoms, frontolimbic resting-state functional connectivity, and cognitive development in infancy.

Exposure to maternal anxiety symptoms during infancy has been associated with difficulties in development and greater risk for developing anxiety later in life. Although previous studies have examined associations between prenatal maternal distress, infant brain development, and developmental outcomes, it is still largely unclear if there are associations between postnatal anxiety, infant brain development, and cognitive development in infancy. In this study, we used resting-state functional magnetic resonance imaging to examine the association between maternal anxiety symptoms and resting-state functional connectivity in the first year of life. We also examine the association between frontolimbic functional connectivity and infant cognitive development. The sample consisted of 21 infants (mean age = 24.15 months, SD = 4.17) that were scanned during their natural sleep using. We test the associations between maternal trait anxiety symptoms and amygdala-anterior cingulate cortex (ACC) functional connectivity, a neural circuit implicated in early life stress exposure. We also test the associations between amygdala-ACC connectivity and cognitive development. We found a significant negative association between maternal trait anxiety symptoms and left amygdala-right ACC functional connectivity (p < .05, false discovery rate corrected). We found a significant negative association between left amygdala-right ACC functional connectivity and infant cognitive development (p < .05). These findings have potential implications for understanding the role of postpartum maternal anxiety symptoms in functional brain and cognitive development in infancy.

Individual identification and individual variability analysis based on cortical folding features in developing infant singletons and twins.

Studying the early dynamic development of cortical folding with remarkable individual variability is critical for understanding normal early brain development and related neurodevelopmental disorders. This study focuses on the fingerprinting capability and the individual variability of cortical folding during early brain development. Specifically, we aim to explore (a) whether the developing neonatal cortical folding is unique enough to be considered as a "fingerprint" that can reliably identify an individual within a cohort of infants; (b) which cortical regions manifest more individual variability and thus contribute more for infant identification; (c) whether the infant twins can be distinguished by cortical folding. Hence, for the first time, we conduct infant individual identification and individual variability analysis involving twins based on the developing cortical folding features (mean curvature, average convexity, and sulcal depth) in 472 neonates with 1,141 longitudinal MRI scans. Experimental results show that the infant individual identification achieves 100% accuracy when using the neonatal cortical folding features to predict the identities of 1- and 2-year-olds. Besides, we observe high identification capability in the high-order association cortices (i.e., prefrontal, lateral temporal, and inferior parietal regions) and two unimodal cortices (i.e., precentral gyrus and lateral occipital cortex), which largely overlap with the regions encoding remarkable individual variability in cortical folding during the first 2 years. For twins study, we show that even for monozygotic twins with identical genes and similar developmental environments, their cortical folding features are unique enough for accurate individual identification; and in some high-order association cortices, the differences between monozygotic twin pairs are significantly lower than those between dizygotic twins. This study thus provides important insights into individual identification and individual variability based on cortical folding during infancy.

Environmental Influences on Infant Cortical Thickness and Surface Area.

Cortical thickness (CT) and surface area (SA) vary widely between individuals and are associated with intellectual ability and risk for various psychiatric and neurodevelopmental conditions. Factors influencing this variability remain poorly understood, but the radial unit hypothesis, as well as the more recent supragranular cortex expansion hypothesis, suggests that prenatal and perinatal influences may be particularly important. In this report, we examine the impact of 17 major demographic and obstetric history variables on interindividual variation in CT and SA in a unique sample of 805 neonates who received MRI scans of the brain around 2 weeks of age. Birth weight, postnatal age at MRI, gestational age at birth, and sex emerged as important predictors of SA. Postnatal age at MRI, paternal education, and maternal ethnicity emerged as important predictors of CT. These findings suggest that individual variation in infant CT and SA is explained by different sets of environmental factors with neonatal SA more strongly influenced by sex and obstetric history and CT more strongly influenced by socioeconomic and ethnic disparities. Findings raise the possibility that interventions aimed at reducing disparities and improving obstetric outcomes may alter prenatal/perinatal cortical development.

Common and heritable components of white matter microstructure predict cognitive function at 1 and 2 y.

Previous studies indicate that the microstructure of individual white matter (WM) tracts is related to cognitive function. More recent studies indicate that the microstructure of individual tracts is highly correlated and that a property common across WM is related to overall cognitive function in adults. However, little is known about whether these common WM properties exist in early childhood development or how they are related to cognitive development. In this study, we used diffusion tensor imaging (DTI) to investigate common underlying factors in 12 fiber tracts, their relationship with cognitive function, and their heritability in a longitudinal sample of healthy children at birth (n = 535), 1 y (n = 322), and 2 y (n = 244) of age. Our data show that, in neonates, there is a highly significant correlation between major WM tracts that decreases from birth to 2 y of age. Over the same period, the factor structure increases in complexity, from one factor at birth to three factors at age 2 y, which explain 50% of variance. The identified common factors of DTI metrics in each age group are significantly correlated with general cognitive scores and predict cognitive ability in later childhood. These factors are moderately heritable. These findings illustrate the anatomical differentiation of WM fiber from birth to 2 y of age that correlate with cognitive development. Our results also suggest that the common factor approach is an informative way to study WM development and its relationship with cognition and is a useful approach for future imaging genetic studies.

A review on neuroimaging studies of genetic and environmental influences on early brain development.

The past decades witnessed a surge of interest in neuroimaging study of normal and abnormal early brain development. Structural and functional studies of normal early brain development revealed massive structural maturation as well as sequential, coordinated, and hierarchical emergence of functional networks during the infancy period, providing a great foundation for the investigation of abnormal early brain development mechanisms. Indeed, studies of altered brain development associated with either genetic or environmental risks emerged and thrived. In this paper, we will review selected studies of genetic and environmental risks that have been relatively more extensively investigated-familial risks, candidate risk genes, and genome-wide association studies (GWAS) on the genetic side; maternal mood disorders and prenatal drug exposures on the environmental side. Emerging studies on environment-gene interactions will also be reviewed. Our goal was not to perform an exhaustive review of all studies in the field but to leverage some representative ones to summarize the current state, point out potential limitations, and elicit discussions on important future directions.

Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life.

Maternal inflammation during pregnancy can alter the trajectory of fetal brain development and increase risk for offspring psychiatric disorders. However, the majority of relevant research to date has been conducted in animal models. Here, in humans, we focus on the structural connectivity of frontolimbic circuitry as it is both critical for socioemotional and cognitive development, and commonly altered in a range of psychiatric disorders associated with intrauterine inflammation. Specifically, we test the hypothesis that elevated maternal concentration of the proinflammatory cytokine interleukin-6 (IL-6) during pregnancy will be associated with variation in microstructural properties of this circuitry in the neonatal period and across the first year of life. Pregnant mothers were recruited in early pregnancy and maternal blood samples were obtained for assessment of maternal IL-6 concentrations in early (12.6 ±â€¯2.8 weeks [S.D.]), mid (20.4 ±â€¯1.5 weeks [S.D.]) and late (30.3 ±â€¯1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ±â€¯1.7 weeks [S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ±â€¯3.1 weeks [S.D.]). Diffusion Tensor Imaging (DTI) was used to characterize fractional anisotropy (FA) along the left and right uncinate fasciculus (UF), representing the main frontolimbic fiber tract. In N = 30 of the infants with serial MRI data at birth and 12-mo age, cognitive and socioemotional developmental status was characterized using the Bayley Scales of Infant Development. All analyses tested for potentially confounding influences of household income, prepregnancy Body-Mass-Index, obstetric risk, smoking during pregnancy, and infant sex, and outcomes at 12-mo age were additionally adjusted for the quality of the postnatal caregiving environment. Maternal IL-6 concentration (averaged across pregnancy) was prospectively and inversely associated with FA (suggestive of reduced integrity under high inflammatory conditions) in the newborn offspring (bi-lateral, p < 0.01) in the central portion of the UF proximal to the amygdala. Furthermore, maternal IL-6 concentration was positively associated with rate of FA increase across the first year of life (bi-lateral, p < 0.05), resulting in a null association between maternal IL-6 and UF FA at 12-mo age. Maternal IL-6 was also inversely associated with offspring cognition at 12-mo age, and this association was mediated by FA growth across the first year of postnatal life. Findings from the current study support the premise that susceptibility for cognitive impairment and potentially psychiatric disorders may be affected in utero, and that maternal inflammation may constitute an intrauterine condition of particular importance in this context.

Exploring folding patterns of infant cerebral cortex based on multi-view curvature features: Methods and applications.

The highly convoluted cortical folding of the human brain is intriguingly complex and variable across individuals. Exploring the underlying representative patterns of cortical folding is of great importance for many neuroimaging studies. At term birth, all major cortical folds are established and are minimally affected by the complicated postnatal environments; hence, neonates are the ideal candidates for exploring early postnatal cortical folding patterns, which yet remain largely unexplored. In this paper, we propose a novel method for exploring the representative regional folding patterns of infant brains. Specifically, first, multi-view curvature features are constructed to comprehensively characterize the complex characteristics of cortical folding. Second, for each view of curvature features, a similarity matrix is computed to measure the similarity of cortical folding in a specific region between any pair of subjects. Next, a similarity network fusion method is adopted to nonlinearly and adaptively fuse all the similarity matrices into a single one for retaining both shared and complementary similarity information of the multiple characteristics of cortical folding. Finally, based on the fused similarity matrix and a hierarchical affinity propagation clustering approach, all subjects are automatically grouped into several clusters to obtain the representative folding patterns. To show the applications, we have applied the proposed method to a large-scale dataset with 595 normal neonates and discovered representative folding patterns in several cortical regions, i.e., the superior temporal gyrus (STG), inferior frontal gyrus (IFG), precuneus, and cingulate cortex. Meanwhile, we have revealed sex difference in STG, IFG, and cingulate cortex, as well as hemispheric asymmetries in STG and cingulate cortex in terms of cortical folding patterns. Moreover, we have also validated the proposed method on a public adult dataset, i.e., the Human Connectome Project (HCP), and revealed that certain major cortical folding patterns of adults are largely established at term birth.