Early White Matter Development Research Articles

Abnormality of Early White Matter Development in Tuberous Sclerosis Complex and Autism Spectrum Disorder: Longitudinal Analysis of Diffusion Tensor Imaging Measures.

Background: Abnormalities in white matter development may influence development of autism spectrum disorder in tuberous sclerosis complex (TSC). Our goals for this study were as follows: (1) use data from a longitudinal neuroimaging study of tuberous sclerosis complex (TACERN) to develop optimized linear mixed effects models for analyzing longitudinal, repeated diffusion tensor imaging metrics (fractional anisotropy, mean diffusivity) pertaining to select white matter tracts, in relation to positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months, and (2) perform an exploratory analysis using optimized models applied to all white matter tracts from these data. Methods: Eligible participants (3-12 months) underwent brain magnetic resonance imaging (MRI) at repeated time points from ages 3 to 36 months. Positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months was used. Linear mixed effects models were fine-tuned separately for fractional anisotropy values (using fractional anisotropy corpus callosum as test outcome) and mean diffusivity values (using mean diffusivity right posterior limb internal capsule as test outcome). Fixed effects included participant age, within-participant longitudinal age, and autism spectrum disorder diagnosis. Results: Analysis included data from n = 78. After selecting separate optimal models for fractional anisotropy and mean diffusivity values, we applied these models to fractional anisotropy and mean diffusivity of all 27 white matter tracts. Fractional anisotropy corpus callosum was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = 0.0093, P = .0612), and mean diffusivity right inferior cerebellar peduncle was related to positive Autism Diagnostic Observation Schedule-Second Edition classification (coefficient = -0.00002071, P = .0445), though these findings were not statistically significant after multiple comparisons correction. Conclusion: These optimized linear mixed effects models possibly implicate corpus callosum and cerebellar pathology in development of autism spectrum disorder in tuberous sclerosis complex, but future studies are needed to replicate these findings and explore contributors of heterogeneity in these models.

Threat-induced cortisol is positively associated with white matter microarchitecture in infant rhesus monkeys

Cortisol is a stress hormone that mediates key physiological responses to threatening situations and modulates neural systems. However, its impact on brain structure in early-life, particularly white matter (WM) microarchitecture, remains poorly understood. In a longitudinal study of infant macaques, we use diffusion tensor imaging and quantitative relaxometry to characterize the early-life link between threat-induced cortisol and WM microarchitecture. 35 rhesus macaques were imaged with DTI and the MPnRAGE sequence on a 3T-scanner at 3, 7, 13, 25, and 53 weeks old to compute FA and qR1 (higher values~increased WM-microstructure) and MD and RD (higher values~decreased WM-microstructure). At each timepoint, subjects underwent 30 min of the no-eye-contact paradigm (NEC), in which they were exposed to an indirect threat, the profile of a human intruder. Plasma cortisol was measured after each NEC. Linear mixed-effects models assessed within-subject relations between cortisol and each WM metric in 18 WM ROIs, controlling for age-at-scan and sex. On a within-subject level (p<0.05-corrected), cortisol was positively associated with FA in 15/18 ROIs (mean-R2=0.08) and qR1 in 18/18 ROIs (mean-R2=0.12). Cortisol was negatively associated with MD in 11/18 ROIs (mean-R2=0.11) and RD in 14/18 ROIs (mean-R2=0.11). Threat-induced cortisol predicts WM microarchitecture, as measured by multimodal imaging, across the infant macaque brain. Interestingly, cortisol relates most widely to qR1 and RD, metrics thought to be relatively sensitive markers of myelin. These findings warrant further study into cortisol’s role in very early WM development and neuroplasticity, particularly as it may relate to myelination processes.

Neonatal genetic epilepsies display convergent white matter microstructural abnormalities.

White matter undergoes rapid development in the neonatal period. Its structure during and after development is influenced by neuronal activity. Pathological neuronal activity, as in seizures, might alter white matter, which in turn may contribute to network dysfunction. Neonatal epilepsy presents an opportunity to investigate seizures and early white matter development. Our objective was to determine whether neonatal seizures in the absence of brain injury or congenital anomalies are associated with altered white matter microstructure. In this retrospective case-control study of term neonates, cases had confirmed or suspected genetic epilepsy and normal brain magnetic resonance imaging (MRI) and no other conditions independently impacting white matter. Controls were healthy neonates with normal MRI results. White matter microstructure was assessed via quantitative mean diffusivity (MD). In 22 cases, MD was significantly lower in the genu of the corpus callosum, compared to 22 controls, controlling for gestational age and postmenstrual age at MRI. This finding suggests convergent abnormal corpus callosum microstructure in neonatal epilepsies with diverse suspected genetic causes. Further study is needed to determine the specific nature, causes, and functional impact of seizure-associated abnormal white matter in neonates, a potential pathogenic mechanism.

Genome-Wide Association Analysis of Neonatal White Matter Microstructure.

A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles. HFPRM revealed a latent measure of white matter microstructure that explained approximately 50% of variation in our tractography-based measures and accounted for a large proportion of heritable variation in each individual bundle. An intronic SNP in PSMF1 on chromosome 20 exceeded the conventional GWAS threshold of 5 x 10-8 (p = 4.61 x 10-8). Additional loci nearing genome-wide significance were located near genes with known roles in axon growth and guidance, fasciculation, and myelination.

Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder

BackgroundAutism spectrum disorder (ASD) is prevalent in tuberous sclerosis complex (TSC), occurring in approximately 50% of patients, and is hypothesized to be caused by disruption of neural circuits early in life. Tubers, or benign hamartomas distributed stochastically throughout the brain, are the most conspicuous of TSC neuropathology, but have not been consistently associated with ASD. Widespread neuropathology of the white matter, including deficits in myelination, neuronal migration, and axon formation, exist and may underlie ASD in TSC. We sought to identify the neural circuits associated with ASD in TSC by identifying white matter microstructural deficits in a prospectively recruited, longitudinally studied cohort of TSC infants.MethodsTSC infants were recruited within their first year of life and longitudinally imaged at time of recruitment, 12 months of age, and at 24 months of age. Autism was diagnosed at 24 months of age with the ADOS-2. There were 108 subjects (62 TSC-ASD, 55% male; 46 TSC+ASD, 52% male) with at least one MRI and a 24-month ADOS, for a total of 187 MRI scans analyzed (109 TSC-ASD; 78 TSC+ASD). Diffusion tensor imaging properties of multiple white matter fiber bundles were sampled using a region of interest approach. Linear mixed effects modeling was performed to test the hypothesis that infants who develop ASD exhibit poor white matter microstructural integrity over the first 2 years of life compared to those who do not develop ASD.ResultsSubjects with TSC and ASD exhibited reduced fractional anisotropy in 9 of 17 white matter regions, sampled from the arcuate fasciculus, cingulum, corpus callosum, anterior limbs of the internal capsule, and the sagittal stratum, over the first 2 years of life compared to TSC subjects without ASD. Mean diffusivity trajectories did not differ between groups.ConclusionsUnderconnectivity across multiple white matter fiber bundles develops over the first 2 years of life in subjects with TSC and ASD. Future studies examining brain-behavior relationships are needed to determine how variation in the brain structure is associated with ASD symptoms.

The Effects of Placental Transfusion on 12‐Month Brain Myelin Content in Term Infants: A Randomized Controlled Trial

IntroductionImmediate cord clamping (ICC) continues to be the standard practice in the United States. This results in leaving about 30% of the fetal‐placental iron‐rich blood behind in the placenta and puts an infant at risk for lower iron stores. Evidence (animal and human) suggests iron is critical to early brain white matter development as it plays a significant role in myelin formation. The purpose of this study was to determine, at 12 months of age, if infants who received a full placental transfusion at birth differ in myelin content and developmental outcomes compared to infants who received no placental transfusion. The hypothesis was that healthy, term infants who received a full placental transfusion via delayed cord clamping (DCC) will have greater brain myelin content and better neurodevelopmental outcomes compared to infants who received no placental transfusion (ICC) at 12 months of age.MethodsSeventy‐three term pregnant women with singleton fetuses were enrolled in a prospective randomized controlled trial and randomized to either ICC (&lt; 20 s) or DCC (≥ 5 min). At 4 and 12 months, the infants’ hemoglobin and ferritin levels were measured, and the infants underwent a non‐sedated MRI and neurodevelopmental testing.ResultsMaternal and infant demographics were not different between groups. Mean (SD) cord clamping time was 318 (158) seconds in the DCC group versus 10 (5) seconds in the ICC group (P &lt; .0001). At 4 months, infants who received DCC had higher ferritin levels (91 [57] vs 61 [30] ng/mL, P &lt; .04). At 12 months, infants randomized to DCC had significantly greater brain myelin content in the following brain regions: left and right (R) internal capsule, R parietal, R occipital, R frontal, and R orbital areas. The DCC group had a slightly higher social‐emotional performance than the ICC group using the BITSEA Competence score (17 [3] vs 15 [3], P = .08). No differences were seen in ferritin or hemoglobin levels between groups at 12 months.DiscussionAt 12 months, placental transfusion at birth appears to increase brain myelin content in regions involving motor and visual/spatial pathways and sensory processing. Neurodevelopmental testing suggests a trend of better social‐emotional outcomes associated with DCC. In conclusion, the endowment of iron‐rich blood obtained through DCC may offer a longitudinal advantage for early white matter development in the brain.

SPN Position Statement: The Role of Pediatric Nurses in the Promotion and Protection of Human Milk and Breastfeeding

SPN Position Statement: The Role of Pediatric Nurses in the Promotion and Protection of Human Milk and Breastfeeding

Longitudinal Study of White Matter Development and Outcomes in Children Born Very Preterm

Identifying trajectories of early white matter development is important for understanding atypical brain development and impaired functional outcomes in children born very preterm (<32 weeks gestational age [GA]). In this study, 161 diffusion images were acquired in children born very preterm (median GA: 29 weeks) shortly following birth (75), term-equivalent (39), 2 years (18), and 4 years of age (29). Diffusion tensors were computed to obtain measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), which were aligned and averaged. A paediatric atlas was applied to obtain diffusion metrics within 12 white matter tracts. Developmental trajectories across time points demonstrated age-related changes which plateaued between term-equivalent and 2 years of age in the majority of posterior tracts and between 2 and 4 years of age in anterior tracts. Between preterm and term-equivalent scans, FA rates of change were slower in anterior than posterior tracts. Partial least squares analyses revealed associations between slower MD and RD rates of change within the external and internal capsule with lower intelligence quotients and language scores at 4 years of age. These results uniquely demonstrate early white matter development and its linkage to cognitive functions.

Nutritional influences on early white matter development: Response to Anderson and Burggren

Does breastfeeding alter early brain development? In a recent retrospective study, our group examined the cross-sectional relationship between early infant feeding practice and white matter maturation and cognitive development. In groups matched for child and mother age, gestation duration, birth weight, gender distribution, and socio-economic status; we observed that children who were breastfed exclusively for at least 3months showed, on average, increased white matter myelin development compared to children who either were exclusively formula-fed, or received a mixture of breast milk and formula. In secondary analysis on sub-sets of these children, again matched for important confounding variables, we found improved cognitive test scores of receptive language in the exclusively breast-fed children compared to formula or formula+breast-fed children; and that prolonged breastfeeding was associated with increased motor, language, and visual functioning in exclusively breast-fed children. In response to this work, Anderson and Burggren have questioned our methodology and, by association, our findings. Further, they use their critique as a platform for advancing an alternative interpretation of our findings: that observed results were not associated with prolonged breast-feeding, but rather delayed the introduction of cow's milk. In this response, we address and clarify some of the misconceptions presented by Anderson and Burggren.

Breastfeeding and early white matter development: A cross-sectional study

Does breastfeeding alter early brain development? The prevailing consensus from large epidemiological studies posits that early exclusive breastfeeding is associated with improved measures of IQ and cognitive functioning in later childhood and adolescence. Prior morphometric brain imaging studies support these findings, revealing increased white matter and sub-cortical gray matter volume, and parietal lobe cortical thickness, associated with IQ, in adolescents who were breastfed as infants compared to those who were exclusively formula-fed. Yet it remains unknown when these structural differences first manifest and when developmental differences that predict later performance improvements can be detected. In this study, we used quiet magnetic resonance imaging (MRI) scans to compare measures of white matter microstructure (mcDESPOT measures of myelin water fraction) in 133 healthy children from 10months through 4years of age, who were either exclusively breastfed a minimum of 3months; exclusively formula-fed; or received a mixture of breast milk and formula. We also examined the relationship between breastfeeding duration and white matter microstructure. Breastfed children exhibited increased white matter development in later maturing frontal and association brain regions. Positive relationships between white matter microstructure and breastfeeding duration are also exhibited in several brain regions, that are anatomically consistent with observed improvements in cognitive and behavioral performance measures. While the mechanisms underlying these structural differences remains unclear, our findings provide new insight into the earliest developmental advantages associated with breastfeeding, and support the hypothesis that breast milk constituents promote healthy neural growth and white matter development.