FSEM: Functional Structural Equation Models for Twin Functional Data

The aim of this article is to develop a novel class of functional structural equation models (FSEMs) for dissecting functional genetic and environmental effects on twin functional data, while characterizing the varying association between functional data and covariates of interest. We propose a three-stage estimation procedure to estimate varying coefficient functions for various covariates (e.g., gender) as well as three covariance operators for the genetic and environmental effects. We develop an inference procedure based on weighted likelihood ratio statistics to test the genetic/environmental effect at either a fixed location or a compact region. We also systematically carry out the theoretical analysis of the estimated varying functions, the weighted likelihood ratio statistics, and the estimated covariance operators. We conduct extensive Monte Carlo simulations to examine the finite-sample performance of the estimation and inference procedures. We apply the proposed FSEM to quantify the degree of genetic and environmental effects on twin white matter tracts obtained from the UNC early brain development study. Supplementary materials for this article are available online

White matter development in infants at risk for schizophrenia

Background: Schizophrenia is considered a neurodevelopmental disorder with a pathophysiology that likely begins long before the onset of clinical symptoms. White matter abnormalities have been observed in schizophrenia and we hypothesized that the first 2 years of life is a period in which white matter abnormalities associated with schizophrenia risk may emerge. Methods: 38 infants at high risk for schizophrenia and 202 healthy controls underwent diffusion tensor MRIs after birth and at 1 and 2 years of age. Quantitative tractography was used to determine diffusion properties (fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD)) of 18 white matter tracts and a general linear model was used to analyze group differences at each age. Results: Adjusting gestational age at birth, postnatal age at MRI, gender, MRI scanner type, and maternal education, neonates at high risk had significantly lower FA (p = 0.02) and AD (p = 0.03) in the superior segment of the left cingulate, and higher RD in the hippocampal segment of the left cingulate (p = 0.04). High risk one year olds had significantly lower FA (p < 0.01) and AD (p = 0.02) in the hippocampal segment of the left cingulate. High risk two year olds had significantly lower FA in the left prefrontal cortico-thalamic tract (p = 0.04) and higher RD in the right uncinate fasciculus (p = 0.04). None of the tract differences remained significant after correction for multiple comparisons. Conclusions: There is evidence of abnormal white matter development in young children at risk for schizophrenia, especially in the hippocampal segment of left cingulum. These results support the neurodevelopmental theory of schizophrenia and indicate that impaired white matter may be present in early childhood

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

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

Quantitative tract-based white matter heritability in 1- and 2-year-old twins

White matter (WM) microstructure, as determined by diffusion tensor imaging (DTI), is increasingly recognized as an important determinant of cognitive function and is also altered in neuropsychiatric disorders. Little is known about genetic and environmental influences on WM microstructure, especially in early childhood, an important period for cognitive development and risk for psychiatric disorders. We studied the heritability of DTI parameters, fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) along 34 tracts, including 10 bilateral fiber pathways and the respective subdivision, using quantitative tractography in a longitudinal sample of healthy children at 1 year (N = 215) and 2 years (N = 165) of age. We found that heritabilities for whole brain AD, RD, and FA were 0.48, 0.69, and 0.72 at age 1, and 0.59, 0.77, and 0.76 at age 2 and that mean heritabilities of tract-averaged AD, RD, and FA for individual bundles were moderate (over 0.4). However, the heritability of DTI change between 1 and 2 years of age was not significant for most tracts. We also demonstrated that point-wise heritability tended to be significant in the central portions of the tracts and was generally spatially consistent at ages 1 and 2 years. These results, especially when compared to heritability patterns in neonates, indicate that the heritability of WM microstructure is dynamic in early childhood and likely reflect heterogeneous maturation of WM tracts and differential genetic and environmental influences on maturation patterns

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

Individual differences in neonatal white matter are associated with executive function at 3 years of age

The development of executive function (EF) in early childhood contributes to social and academic aspects of school readiness and facilitates emerging self-regulatory competence. Numerous efforts are underway to identify aspects of early brain development that contribute to emerging EF. Existing research supports the importance of multiple white matter tracts for EF in older children and adults. However, this research has not been extended to young children. In this study, we consider neonatal white matter microstructure in relation to children’s performance on a battery of EF tasks three years later. We obtained diffusion tensor imaging data from a sample of neonates (N = 27) shortly after birth. At 3 years of age, children completed a computerized battery of EF tasks. The primary data analyses involved regression models estimated for each white matter tract. Multiple demographic and measure-related covariates were included in each model. A follow-up analysis of tracts determined to be associated with EF examined individual data points along those fibers. Among the white matter tracts analyzed, the cingulum was significantly associated with EF at 3 years of age. Specifically, lower axial diffusivity values along the cingulum were associated with increased performance on the EF battery. Results are discussed as providing initial evidence that individual differences in neonatal brain structure may facilitate the acquisition of EF abilities in early childhood. These findings are consistent with previous research that supports the value of the cingulum for higher-order cognitive abilities. Cautions and implications of these results are considered

Neonatal hippocampal volume moderates the effects of early postnatal enrichment on cognitive development

Environmental enrichment, particularly during the early life phases of enhanced neuroplasticity, can stimulate cognitive development. However, individuals exhibit considerable variation in their response to environmental enrichment. Recent evidence suggests that certain neurophenotypes such as hippocampal size may index inter-individual differences in sensitivity to environmental conditions. We conducted a prospective, longitudinal investigation in a cohort of 75 mother-child dyads to investigate whether neonatal hippocampal volume moderates the effects of the postnatal environment on cognitive development. Newborn hippocampal volume was quantified shortly after birth (26.2 ± 12.5 days) by structural MRI. Measures of infant environmental enrichment (assessed by the IT-HOME) and cognitive state (assessed by the Bayley-III) were obtained at 6 months of age (6.09 ± 1.43 months). The interaction between neonatal hippocampal volume and enrichment predicted infant cognitive development (b = 0.01, 95 % CI [0.00, 0.02], t = 2.08, p =.04), suggesting that exposure to a stimulating environment had a larger beneficial effect on cognitive outcomes among infants with a larger hippocampus as neonates. Our findings suggest that the effects of the postnatal environment on infant cognitive development are conditioned, in part, upon characteristics of the newborn brain, and that newborn hippocampal volume is a candidate neurophenotype in this context

Maternal Influenza Infection During Pregnancy Impacts Postnatal Brain Development in the Rhesus Monkey

Background: Maternal infection with influenza and other pathogens during pregnancy has been associated with increased risk for schizophrenia and neurodevelopmental disorders. In rodent studies, maternal inflammatory responses to influenza affect fetal brain development. However, to verify the relevance of these findings to humans, research is needed in a primate species with more advanced prenatal corticogenesis. Methods: Twelve pregnant rhesus monkeys were infected with influenza, A/Sydney/5/97 (H3N2), 1 month before term (early third trimester) and compared with 7 control pregnancies. Nasal swabs and blood samples confirmed viral shedding and immune activation. Structural magnetic resonance imaging was conducted at 1 year; behavioral development and cortisol reactivity were also assessed. Results: Maternal infections were mild and self-limiting. At birth, maternally derived influenza-specific immunoglobulin G was present in the neonate, but there was no evidence of direct viral exposure. Birth weight and gestation length were not affected, nor were infant neuromotor, behavioral, and endocrine responses. However, magnetic resonance imaging analyses revealed significant reductions in cortical gray matter in flu-exposed animals. Regional analyses indicated the largest gray matter reductions occurred bilaterally in cingulate and parietal areas; white matter was also reduced significantly in the parietal lobe. Conclusions: Influenza infection during pregnancy affects neural development in the monkey, reducing gray matter throughout most of the cortex and decreasing white matter in parietal cortex. These brain alterations are likely to be permanent, given that they were still present at the monkey-equivalent of older childhood and thus might increase the likelihood of later behavioral pathology

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 ± 2.8 weeks [S.D.]), mid (20.4 ± 1.5 weeks [S.D.]) and late (30.3 ± 1.3 weeks [S.D.]) gestation. Offspring brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ± 1.7 weeks [S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ± 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