White matter microstructure and cognitive outcomes in relation to neonatal inflammation in 6-year-old children born preterm.

BACKGROUND: Cognitive outcomes in preterm (PT) children have been associated with microstructural properties of white matter. PT children who experienced neonatal inflammatory conditions have poorer cognitive outcomes than those who did not. The goal of this study was to contrast white matter microstructure and cognitive outcomes after preterm birth in relation to the presence or absence of severe inflammatory conditions in the neonatal period. METHODS: PT children (n = 35), born at gestational age 22-32 weeks, were classified as either PT+ (n = 12) based on a neonatal history of inflammatory conditions, including bronchopulmonary dysplasia, necrotizing enterocolitis or culture positive sepsis, or PT- (n = 23) based on the absence of the three inflammatory conditions. Full term (FT) children (n = 43) served as controls. Participants underwent diffusion MRI and cognitive testing (intelligence, reading, and executive function) at age 6 years. The corpus callosum was segmented into 7 regions using deterministic tractography and based on the cortical projection zones of the callosal fibers. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for each segment. General linear models with planned contrasts assessed group differences in FA, MD and cognitive outcomes. Pearson correlations assessed associations of white matter metrics and cognitive outcome measures. RESULTS: FA was significantly lower and MD was significantly higher in PT+ compared to PT- or FT groups in multiple callosal segments, even after adjusting for gestational age. Executive function scores, but not intelligence or reading scores, were less favorable in PT+ than in PT- groups. Among the entire sample, occipital FA was significantly correlated with IQ (r = 0.25, p < 0.05), reading (r = 0.32, p < 0.01), and executive function (r = -0.28, p < 0.05) measures. Anterior frontal FA and superior parietal FA were significantly correlated with executive function (r = -0.25, r = 0.23, respectively, p < 0.05). CONCLUSIONS: We observed differences in the white matter microstructure of the corpus callosum and in the cognitive skills of 6-year-old PT children based on their history of neonatal inflammation. Neonatal inflammation is one medical factor that may contribute to variation in long-term neurobiological and neuropsychological outcomes in PT samples.

White Matter Plasticity in Reading-Related Pathways Differs in Children Born Preterm and at Term: A Longitudinal Analysis.

Children born preterm (PT) are at risk for white matter injuries based on complications of prematurity. They learn to read but on average perform below peers born full term (FT). Studies have yet to establish whether properties of white matter pathways at the onset of learning to read are associated with individual variation later in reading development in PT children. Here, we asked whether fractional anisotropy (FA) at age 6 years is associated with reading outcome at age 8 years in PT children in the same pathways as previously demonstrated in a sample of FT children. PT (n = 34, mean gestational age = 29.5 weeks) and FT children (n = 37) completed diffusion MRI and standardized measures of non-verbal IQ, language, and phonological awareness at age 6 years. Reading skills were assessed at age 8 years. Mean tract-FA was extracted from pathways that predicted reading outcome in children born FT: left arcuate fasciculus (Arc), bilateral superior longitudinal fasciculus (SLF), and left inferior cerebellar peduncle (ICP). We explored associations in additional pathways in the PT children: bilateral inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus. Linear regression models examined whether the prediction of reading outcome at age 8 years based on mean tract-FA at age 6 years was moderated by birth group. Children born PT and FT did not differ significantly in tract-FA at age 6 years or in reading at age 8 years. Sex, socioeconomic status, and non-verbal IQ at age 6 years were associated with reading outcome and were included as covariates in all models. Birth group status significantly moderated associations between reading outcome and mean tract-FA only in the left Arc, right SLF, and left ICP, before and after consideration of pre-literacy skills. Microstructural properties of these cerebral and cerebellar pathways predicted later reading outcome in FT but not in PT children. Children born PT may rely on alternative pathways to achieve fluent reading. These findings have implications for plasticity of neural organization after early white matter injury.

More than myelin: Probing white matter differences in prematurity with quantitative T1 and diffusion MRI.

OBJECTIVE: We combined diffusion MRI (dMRI) with quantitative T1 (qT1) relaxometry in a sample of school-aged children born preterm and full term to determine whether reduced fractional anisotropy (FA) within the corpus callosum of the preterm group could be explained by a reduction in myelin content, as indexed by R1 (1/T1) from qT1 scans. METHODS: 8-year-old children born preterm (n = 29; GA 22-32 weeks) and full term (n = 24) underwent dMRI and qT1 scans. Four subdivisions of the corpus callosum were segmented in individual native space according to cortical projection zones (occipital, temporal, motor and anterior-frontal). Fractional anisotropy (FA) and R1 were quantified along the tract trajectory of each subdivision and compared across two birth groups. RESULTS: Compared to controls, preterm children demonstrated significantly decreased FA in 3 of 4 analyzed corpus callosum subdivisions (temporal, motor, and anterior frontal segments) and decreased R1 in only 2 of 4 corpus callosum subdivisions (temporal and motor segments). FA and RD were significantly associated with R1 within temporal but not anterior frontal subdivisions of the corpus callosum in the term group; RD correlated with R1 in the anterior subdivision in the preterm group only. CONCLUSIONS: Myelin content, as indexed by R1, drives some but not all of the differences in white matter between preterm and term born children. Other factors, such as axonal diameter and directional coherence, likely contributed to FA differences in the anterior frontal segment of the corpus callosum that were not well explained by R1.

Predicting text reading skills at age 8 years in children born preterm and at term.

BACKGROUND: Children born preterm are at risk for developing reading difficulties and for decrements in other cognitive skills compared to children born at term. AIMS: To assess how domains of function, often negatively impacted by preterm birth, predict reading development in children born preterm and at term. STUDY DESIGN: Longitudinal descriptive cohort study. SUBJECTS: Preterm (n = 48; gestational age 22-32 weeks, 30 males) and term (n = 41, 18 males) participants were assessed at age 6 years on a battery of verbal and non-verbal cognitive skills and reassessed at age 8 using the Gray Oral Reading Tests-5. Linear regressions assessed the contributions of phonological awareness, language, executive function, and non-verbal IQ at age 6 to reading outcome at age 8. RESULTS: Children born preterm had lower scores than children born at term on all measures (Cohen's d from 0.46 to 1.08, all p < .05). Phonological awareness and language abilities predicted reading in both groups (accounting for 19.9% and 25.0% of variance, respectively, p < .001). Birth group did not moderate the association. By contrast, the association between executive function and non-verbal intelligence and reading outcome was moderated by birth group (interaction accounted for 3.9-6.7% of variance, respectively, p < .05). Positive predictions to reading from executive function and non-verbal IQ were found only in children born preterm. CONCLUSIONS: Non-verbal cognitive skills improved the prediction of reading outcome only in the preterm group, suggesting that reading decrements represent a component of global deficits. These findings have implications for evaluation of children born preterm at school entry and treatment of reading difficulties.

Microstructural properties of white matter pathways in relation to subsequent reading abilities in children: a longitudinal analysis.

Microstructural properties of white matter pathways are associated with concurrent reading abilities in children. In this longitudinal study, we asked whether properties of white matter pathways at the onset of learning to read would be associated with reading abilities at older ages. Children (N = 37) with a wide range of reading abilities completed standardized measures of language and phonological awareness and diffusion MRI at age 6 years. Mean tract-fractional anisotropy (FA) was extracted from reading-related pathways. At age 8, the same children were re-assessed using a standardized reading measure. Using linear regressions, we examined the contribution of tract-FA at age 6 to reading outcome at age 8, beyond known demographic and pre-literacy predictors of reading. Tract-FA of the left arcuate, left and right superior longitudinal fasciculus (SLF), and left inferior cerebellar peduncle (ICP) made unique contributions to reading outcome after consideration of sex and family history of reading delays. Tract-FA of the left and right SLF and left ICP made unique contributions to reading outcome after the addition of pre-literacy skills. Thus, cerebellar and bilateral cortical pathways represented a network associated with subsequent reading abilities. Early white matter properties may be associated with other neuropsychological functions that predict reading or may influence reading development, independent of reading-related abilities. Tract FA at early stages of learning to read may serve as a biomarker of later reading abilities.

White matter properties associated with pre-reading skills in 6-year-old children born preterm and at term.

AIM: To assess associations between white matter properties and pre-reading skills (phonological awareness and receptive and expressive language) in children born preterm and at term at the onset of reading acquisition. METHOD: Six-year-old children born preterm (n=36; gestational age 22-32wks) and at term (n=43) underwent diffusion magnetic resonance imaging and behavioural assessments. Tracts were selected a priori based on findings from a study of 6-year-old children born at term: the left-hemisphere arcuate fasciculus and superior longitudinal fasciculus, and right-hemisphere uncinate fasciculus. Using linear regression, we assessed associations between fractional anisotropy of tracts and phonological awareness and receptive and expressive language scores. We investigated whether associations were moderated by prematurity. RESULTS: Fractional anisotropy of the left-hemisphere arcuate fasciculus contributed unique variance to phonological awareness across birth groups. The association between fractional anisotropy of the right-hemisphere uncinate fasciculus and receptive and expressive language was significantly moderated by prematurity. INTERPRETATION: A left-hemisphere tract was associated with phonological awareness in both birth groups. A right-hemisphere tract was associated with language only in the term group, suggesting that expressive and receptive language is mediated by different white matter pathways in 6-year-old children born preterm. These findings provide novel insights into similarities and differences of the neurobiology of pre-reading skills between children born preterm and at term at reading onset. WHAT THIS PAPER ADDS: White matter properties and pre-reading abilities were associated in children born preterm at the onset of reading. The neurobiology of phonological awareness was similar in children born preterm versus children born at term at 6 years. The neurobiology of language was different in children born preterm versus children born at term at 6 years.

White matter microstructure of 6-year old children born preterm and full term.

AIM: We previously observed a complex pattern of differences in white matter (WM) microstructure between preterm-born (PT) and full-term-born (FT) children and adolescents age 9-17 years. The aim of this study was to determine if the same differences exist as early as age 6 years. METHOD: We obtained diffusion MRI (dMRI) scans in children born PT at age 6 years (n = 20; 11 males) and FT (n = 38; 14 males), using two scanning protocols: 30 diffusion directions (b = 1000 s/mm2) and 96 diffusion directions (b = 2500 s/mm2). We used deterministic tractography and analyzed fractional anisotropy (FA) along bilateral cerebral WM pathways that demonstrated differences in the older sample. RESULTS: Compared to the FT group, the PT group showed (1) significantly decreased FA in the uncinate fasciculi and forceps major and (2) significantly increased FA in the right anterior thalamic radiation, inferior fronto-occipital fasciculi, and inferior longitudinal fasciculi. This pattern of group differences resembles findings in the previous study of older PT and FT participants. Group differences were similar across dMRI acquisition protocols. INTERPRETATION: The underlying neurobiology driving the pattern of PT-FT differences in FA is present as early as age 6 years. Generalization across dMRI acquisition protocols demonstrates the robustness of group differences in FA. Future studies will use quantitative neuroimaging techniques to understand the tissue properties that give rise to this consistent pattern of WM differences after PT birth.