PURPOSE:To evaluate the extent to which the appearance of HOD in the brain following systemic administration of a deuterated substrate is due to local brain metabolism versus body metabolism. METHODS:[6,6-2H2]glucose, which is transported across the blood-brain barrier (BBB), and [6,6-2H2]fructose (Fruc), which does not cross the BBB, were administered to four mouse cohorts. Cohorts included wild-type mice, glucose transporter deficiency mice, which have decreased brain glucose uptake from the blood, and littermate control mice. A separate wild-type cohort received a 15-μL intramuscular (leg) injection of D2O. Brain-localized DMRS experiments employed the ISIS single-voxel protocol at 11.74 T. RESULTS:Following leg D2O injection, semi-heavy water (HOD) appears within the brain in minutes, reaching steady state shortly thereafter. Body metabolism of [6,6-2H2]fructose produces HOD that also appears in the brain within minutes following subcutaneous administration, with an initial rate (mM/min) substantially greater than following administration of [6,6-2H2]glucose. Deuterated glucose from body metabolism of [6,6-2H2]fructose also appears in the brain. The terminal rates for HOD appearance in the brain are indistinguishable for the four cohorts examined despite there being up to a five-fold difference in brain concentration (mM) of deuterium-labeled glucose. CONCLUSION:Body production of HOD dominates the initial increase of HOD in brain following administration of [6,6-2H2]fructose and likely contributes significantly to the increase of HOD in brain following administration of [6,6-2H2]glucose. Interpretation of HOD concentrations as representative of organ-specific metabolism requires careful consideration of control experiments and assessment of HOD contributions from body metabolism of the administered deuterated substrate.

Neuroimaging has a vital role in assessing the neonatal neuroaxis in many different clinical contexts and in stratifying risk for neurodevelopmental differences. Advances in hardware and computational techniques across modalities have burgeoned in the last several decades, contributing to an improved understanding of brain maturation, development, and plasticity in this unique clinical population.

OBJECTIVE:Early life adversity alters the structure and function of higher-order brain networks that subserve executive function (EF). The extent that prenatal exposure to adversity and neonatal white matter (WM) microstructure and resting-state functional connectivity (rs-fc) underlie problems in emerging EF remains unclear. METHOD:This prospective study includes 164 infants (45% female, 85% term-born) who were recruited prenatally and underwent neonatal diffusion and rs-fc magnetic resonance imaging scans. Social disadvantage and maternal psychosocial stress were assessed in the prenatal period. At age 2 years, children completed the Minnesota Executive Function Scale. Multivariable regression, moderation, and mediation analyses examined associations between prenatal adversity, neonatal WM microstructure and rs-fc, and emerging EF outcome. RESULTS:Prenatal social disadvantage (PSD), but not maternal psychosocial stress, was associated with poorer emerging EF. After multiple comparison correction, higher mean diffusivity (MD) and lower fractional anisotropy (FA) in the corpus callosum, as well as higher MD in the inferior fronto-occipital fasciculus and corticospinal tract and lower FA in the uncinate, related to poorer emerging EF. In moderation analysis, associations between neonatal WM microstructure and emerging EF did not vary as a function of PSD. In mediation analyses, neonatal WM microstructure did not attenuate the association between PSD and emerging EF. The rs-fc findings did not pass multiple comparison correction. CONCLUSION:PSD was related to poorer emerging EF outcomes. Neonatal WM microstructure was also related to emerging EF, with similar associations for children with lower or higher PSD. Prenatal social welfare programs may support neonatal brain development and early neurodevelopmental outcomes. PLAIN LANGUAGE SUMMARY:Prenatal exposure to social disadvantage is related to early alterations in neonatal brain structure and function. This study sought to understand the implications of these relationships for the early emergence of executive function (EF). In a sample of 164 infants, this longitudinal study found that prenatal exposure to social disadvantage and less-developed neonatal brain pathways were key risk factors associated with problems in emerging EF at age 2 years. These associations persisted after accounting for maternal and child general cognitive ability. Findings provide insight into the mechanisms of early EF development and suggest that addressing family socioeconomic hardships early in life may support infant neurodevelopment. DIVERSITY & INCLUSION STATEMENT:We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way.

OBJECTIVE:To examine the mediating and moderating associations between prenatal exposure to adversity and neonatal white matter (WM) development on language outcomes at age 2 years. STUDY DESIGN:This longitudinal study includes 160 infants (gestational ages 41 - 39 weeks, n = 83; 38 - 37 weeks, n = 62; 36 - 34 weeks, n = 15) with neonatal diffusion MRI and language assessments at age 2 years using the Bayley Scales of Infant and Toddler Development-III. Prenatal social disadvantage (PSD) and maternal psychosocial stress were assessed throughout the prenatal period. Multivariable and stepwise linear regression, mediation, and moderation analyses were used to investigate associations between prenatal adversities and neonatal WM on language outcomes. Maternal cognition and stimulation provided in the home were included as covariates. RESULTS:PSD and maternal psychosocial stress were associated with poorer language outcomes (P < .001). When PSD and maternal Psychosocial Stress were modeled simultaneously, only PSD was associated with language outcomes (P < .001). Independent of PSD (P < .001), lower neonatal fractional anisotropy (FA) in the corpus callosum (CC) was associated with poorer language outcomes (P = .02). CC FA did not mediate the association between PSD and language outcomes (indirect effect 95% CIs: -0.96 - 0.15), and there was no interaction between PSD and CC FA on language outcomes (P > .05). CONCLUSIONS:PSD and neonatal CC FA were independently related to language outcomes, with no significant mediating or moderating pathways at this stage of development. These findings suggest the need for investigation of prenatal provision of poverty-reducing services and maternal psychosocial intervention services to promote offspring WM and language development.

How brain structure relates to function is a critical and open question in neuroscience. Here, we characterize regional variation in structure-function coupling, capturing the degree to which a cortical region's structural connections relate to patterns of coordinated neural activity in healthy, term-born neonates (n = 239). Regional structure-function coupling is heterogeneously patterned across the cortex, with higher coupling in the auditory, lateral prefrontal, and inferior parietal cortices. Average structure-function coupling is negatively associated with age during the first month of life, with age-associated decreases seen in primary sensory systems, specifically in auditory and somatomotor regions. Age-associated "decoupling" of structure and function reflects increasingly segregated patterns of functional connectivity and increasingly integrated patterns of white matter connectivity with age. Notably, higher structure-function coupling after accounting for age in the dorsal attention, cingulo-opercular, and visual systems at birth is associated with faster visuospatial attention to faces at one year of age. These results yield valuable insight into the development of structural and functional connectivity across the cortex, including how interregional variation in structure-function coupling during the first month of life might shape later attention.

Environmental influences on brain structure and function during early development have been well-characterized. In pre-registered analyses, we test the theory that socioeconomic status (SES) is associated with differences in trajectories of intrinsic brain network development from birth to three years (n = 261). Prenatal SES is associated with developmental increases in cortical network segregation, with neonates and toddlers from lower-SES backgrounds showing a steeper increase in cortical network segregation with age, consistent with accelerated network development. Associations between SES and cortical network segregation occur at the local scale and conform to a sensorimotor-association hierarchy of cortical organization. SES-associated differences in cortical network segregation are associated with language abilities at two years, such that lower segregation is associated with improved language abilities. These results yield key insight into the timing and directionality of associations between the early environment and trajectories of cortical development.

Background:Early life adversity is associated with microstructural alterations in white matter regions that subserve language. However, the mediating and moderating pathways between adversities experienced in utero and key neonatal white matter tracts including the corpus callosum (CC), superior longitudinal fasciculus (SLF), arcuate fasciculus (AF), inferior fronto- occipital fasciculus (IFOF), and uncinate on early language outcomes remains unknown. Methods:This longitudinal study includes 160 neonates, oversampled for prenatal exposure to adversity, who underwent diffusion MRI (dMRI) in the first weeks of life. dMRI parameters were obtained using probabilistic tractography in FSL. Maternal Social Disadvantage and Psychosocial Stress was assessed throughout pregnancy. At age 2 years, the Bayley Scales of Infant and Toddler Development-III evaluated language outcomes. Linear regression, mediation, and moderation assessed associations between prenatal adversities and neonatal white matter on language outcomes. Results:Prenatal exposure to Social Disadvantage (p<.001) and Maternal Psychosocial Stress (p<.001) were correlated with poorer language outcomes. When Social Disadvantage and maternal Psychosocial Stress were modeled simultaneously in relation to language outcomes, only Social Disadvantage was significant (p<.001). Independent of Social Disadvantage (p<.001), lower neonatal CC fractional anisotropy (FA) was related to poorer global (p=.02) and receptive (p=.02) language outcomes. CC FA did not mediate the association between Social Disadvantage and language outcomes (indirect effect 95% CIs -0.96-0.15), and there was no interaction between Social Disadvantage and CC FA on language outcomes (p>.05). Bilateral SLF/AF, IFOF, and uncinate were not significant (p>.05). Conclusions:Prenatal exposure to Social Disadvantage and neonatal CC FA were independently related to language problems by age 2, with no evidence of mediating or moderating associations with language outcomes. These findings elucidate the early neural underpinnings of language development and suggest that the prenatal period may be an important time to provide poverty- reducing support to expectant mothers to promote offspring neurodevelopmental outcomes.

Prenatal exposure to heightened maternal inflammation has been associated with adverse neurodevelopmental outcomes, including atypical brain maturation and psychiatric illness. In mothers experiencing socioeconomic disadvantage, immune activation can be a product of the chronic stress inherent to such environmental hardship. While growing preclinical and clinical evidence has shown links between altered neonatal brain development and increased inflammatory states in utero, the potential mechanism by which socioeconomic disadvantage differentially impacts neural-immune crosstalk remains unclear. In the current study, we investigated associations between socioeconomic disadvantage, gestational inflammation, and neonatal white matter microstructure in 320 mother-infant dyads over-sampled for poverty. We analyzed maternal serum levels of four cytokines (IL-6, IL-8, IL-10, TNF-α) over the course of pregnancy in relation to offspring white matter microstructure and socioeconomic disadvantage. Higher average maternal IL-6 was associated with very low socioeconomic status (SES; INR < 200% poverty line) and lower neonatal corticospinal fractional anisotropy (FA) and lower uncinate axial diffusivity (AD). No other cytokine was associated with SES. Higher average maternal IL-10 was associated with lower FA and higher radial diffusivity (RD) in corpus callosum and corticospinal tracts, higher optic radiation RD, lower uncinate AD, and lower FA in inferior fronto-occipital fasciculus and anterior limb of internal capsule tracts. SES moderated the relationship between average maternal TNF-α levels during gestation and neonatal white matter diffusivity. When these interactions were decomposed, the patterns indicated that this association was significant and positive among very low SES neonates, whereby TNF-α was inversely and significantly associated with inferior cingulum AD. By contrast, among the more advantaged neonates (lower-to-higher SES [INR ≥ 200% poverty line]), TNF-α was positively and significantly associated with superior cingulum AD. Taken together, these findings suggest that the relationship between prenatal cytokine exposure and white matter microstructure differs as a function of SES. These patterns are consistent with a scenario where gestational inflammation’s effects on white matter development diverge depending on the availability of foundational resources in utero.

The brain develops rapidly from the final trimester of gestation through childhood, with cortical surface area expanding greatly in the first decade of life. However, it is unclear exactly where and how cortical surface area changes after birth, or how prematurity affects these developmental trajectories. Fifty-two very preterm (gestational age at birth = 26 +/- 1.6 weeks) and 41 full-term (gestational age at birth = 39 +/- 1.2 weeks) infants were scanned using structural magnetic resonance imaging at term-equivalent age and again at 9/10 years of age. Individual cortical surface reconstructions were extracted for each scan. Infant and 9/10 cortical surfaces were aligned using anatomically constrained Multimodal Surface Matching (aMSM), a technique that allows calculation of local expansion gradients across the cortical surface for each individual subject. At the neonatal time point, very preterm infants had significantly smaller surface area than their full-term peers (P < 0.001), but at the age 9/10-year time point, very preterm and full-term children had comparable surface area (P > 0.05). Across all subjects, cortical expansion by age 9/10 years was most pronounced in frontal, temporal, and supramarginal/inferior parietal junction areas, which are key association cortices (P-Spin < 0.001). Very preterm children showed greater cortical surface area expansion between term-equivalent age and age 9/10 compared to their full-term peers in the medial and lateral frontal areas, precuneus, and middle temporal/banks of the superior sulcus junction (P < 0.05). Furthermore, within the very preterm group, expansion was highly variable within the orbitofrontal cortex and posterior regions of the brain. By mapping these patterns across the cortex, we identify differences in association cortices that are known to be important for executive functioning, emotion processing, and social cognition. Additional longitudinal work will be needed to understand if increased expansion in very preterm children is adaptive, or if differences persist into adulthood.

Background and Objectives:Children born very preterm (VPT) have high rates of motor disability, but mechanisms for early identification remain limited, especially for children who fall behind in early childhood. This study examines the relationship between functional connectivity (FC) measured at term-equivalent age and motor outcomes at 2 and 5 years. Methods:In this longitudinal observational cohort study, VPT children (gestational age 30 weeks and younger) with and without high-grade brain injury underwent FC MRI at term-equivalent age. Motor development was assessed using the Bayley Scales of Infant Development, Third Edition, at corrected age 2 years and Movement Assessment Battery for Children, Second Edition, at age 5 years. Logistic and negative binomial/Poisson regression models examined relationships between FC measures and 5-year task scores, with and without 2-year scores as covariates. Infants were categorized as "injured" or "uninjured" based on structural MRI findings at term-equivalent age. Results:In the injured group (n = 34), each 1 SD decrease in neonatal left-right motor cortex FC was related to approximately 4× increased odds of being unable to complete a fine motor task at age 5 (log odds = -1.34, p < 0.05). In the uninjured group (n = 41), stronger basal ganglia-motor cortex FC was related to poorer fine motor scores (Est = -0.40, p < 0.05) and stronger cerebellum-motor cortex FC was related to poorer balance and fine motor scores (Est = -0.05 to -0.23, p < 0.05), with balance persisting with adjustment for 2-year scores. Discussion:In VPT children with brain injury, interhemispheric motor cortex FC was related to motor deficits at 5-year assessment, similar to previous findings at 2 years. In uninjured children, FC-measured disruption of the motor system during the neonatal period was associated with motor planning/coordination difficulties that were not apparent on 2-year assessment but emerged at 5 years, suggesting that the neural basis of these deficits was established very early in life. Subsequently, 2-year follow-up may not be sufficient to detect milder motor deficits in VPT children, and they should be monitored for motor difficulties throughout the preschool years. For all VPT children, FC at term-equivalent age has the potential to improve our ability to predict disability before it presents behaviorally.

PURPOSE:Tail-vein catheterization and subsequent in-magnet infusion is a common route of administration of deuterium (2 H)-labeled substrates in small-animal deuterium (D) MR studies. With mice, because of the tail vein's small diameter, this procedure is challenging. It requires considerable personnel training and practice, is prone to failure, and may preclude serial studies. Motivated by the need for an alternative, the time courses for common small-molecule deuterated substrates and downstream metabolites in brain following subcutaneous infusion were determined in mice and are presented herein. METHODS:Three 2 H-labeled substrates-[6,6-2 H2 ]glucose, [2 H3 ]acetate, and [3,4,4,4-2 H4 ]beta-hydroxybutyrate-and 2 H2 O were administered to mice in-magnet via subcutaneous catheter. Brain time courses of the substrates and downstream metabolites (and semi-heavy water) were determined via single-voxel DMRS. RESULTS:Subcutaneous catheter placement and substrate administration was readily accomplished with limited personnel training. Substrates reached pseudo-steady state in brain within ∼30-40 min of bolus infusion. Time constants characterizing the appearance in brain of deuterated substrates or semi-heavy water following 2 H2 O administration were similar (∼15 min). CONCLUSION:Administration of deuterated substrates via subcutaneous catheter for in vivo DMRS experiments with mice is robust, requires limited personnel training, and enables substantial dosing. It is suitable for metabolic studies where pseudo-steady state substrate administration/accumulation is sufficient. It is particularly advantageous for serial longitudinal studies over an extended period because it avoids inevitable damage to the tail vein following multiple catheterizations.

Purpose To assess changes in intracellular diffusion as a mechanism for the reduction in water ADC that accompanies brain injury. Using NAA as a marker of neuronal cytoplasmic diffusion, NAA diffusion was measured before and after global ischemia (immediately postmortem) in the female Sprague–Dawley rat. Methods Diffusion‐weighted PRESS spectra, with diffusion encoding in a single direction, were acquired from large voxels of rat brain gray matter in vivo and postischemia employing either pairs of pulsed half‐sine–shaped gradients (in vivo and postischemia, b max = 19 ms/μm 2 ) or sinusoidal oscillating gradients (in vivo only) with frequencies of 99.2–250 Hz. A 2D randomly oriented cylinder (neurite) model gave estimates of longitudinal and transverse diffusivities ( D L and D T , respectively). In this model, D L represents the “free” diffusivity of NAA, whereas D T reflects highly restricted diffusion. Using oscillating gradients, the frequency dependence of D T [ D T (ω)] gave estimates of the cylinder (axon/dendrite) radius. Results A 10% decrease in D L,NAA followed global ischemia, dropping from 0.391 ± 0.012 μm 2 /ms to 0.350 ± 0.009 μm 2 /ms. Modeling D T,NAA (ω) provided an estimate of the neurite radius of 1.0 ± 0.6 μm. Conclusion Whereas the increase in apparent intraneuronal viscosity suggested by changes in D L,NAA may contribute to the overall reduction in water ADC associated with brain injury, it is not sufficient to be the sole explanation. Estimates of neurite radius based on D T (ω) were consistent with literature values.

NMR in BiomedicineVolume 36, Issue 1 e4841 EDITORIAL Metabolic activity diffusion imaging (MADI): A new paradigm Jeffrey J. Neil, Jeffrey J. Neil Washington University School of Medicine, St. Louis, Missouri, USASearch for more papers by this authorJoseph J. H. Ackerman, Corresponding Author Joseph J. H. Ackerman [email protected] Washington University School of Medicine, St. Louis, Missouri, USA Correspondence Joseph J. H. Ackerman, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110, USA. Email: [email protected]Search for more papers by this author Jeffrey J. Neil, Jeffrey J. Neil Washington University School of Medicine, St. Louis, Missouri, USASearch for more papers by this authorJoseph J. H. Ackerman, Corresponding Author Joseph J. H. Ackerman [email protected] Washington University School of Medicine, St. Louis, Missouri, USA Correspondence Joseph J. H. Ackerman, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110, USA. Email: [email protected]Search for more papers by this author First published: 02 November 2022 https://doi.org/10.1002/nbm.4841Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume36, Issue1January 2023e4841 RelatedInformation

T1- and T2-weighted (T1w and T2w) images are essential for tissue classification and anatomical localization in Magnetic Resonance Imaging (MRI) analyses. However, these anatomical data can be challenging to acquire in non-sedated neonatal cohorts, which are prone to high amplitude movement and display lower tissue contrast than adults. As a result, one of these modalities may be missing or of such poor quality that they cannot be used for accurate image processing, resulting in subject loss. While recent literature attempts to overcome these issues in adult populations using synthetic imaging approaches, evaluation of the efficacy of these methods in pediatric populations and the impact of these techniques in conventional MR analyses has not been performed. In this work, we present two novel methods to generate pseudo-T2w images: the first is based in deep learning and expands upon previous models to 3D imaging without the requirement of paired data, the second is based in nonlinear multi-atlas registration providing a computationally lightweight alternative. We demonstrate the anatomical accuracy of pseudo-T2w images and their efficacy in existing MR processing pipelines in two independent neonatal cohorts. Critically, we show that implementing these pseudo-T2w methods in resting-state functional MRI analyses produces virtually identical functional connectivity results when compared to those resulting from T2w images, confirming their utility in infant MRI studies for salvaging otherwise lost subject data.

During the early postnatal period, cerebral white matter undergoes rapid maturation through a complex series of interrelated cellular and histogenetic processes. Accurately quantifying these processes is important for improving understanding of early brain development, developmental abnormalities related to prematurity, and neurodevelopmental diseases. Past efforts have used magnetic resonance imaging (MRI) to track these developmental processes in vivo . However, most previous studies have relied on single imaging modality data and have often been limited by small samples and analytics that do not evaluate complex multivariate imaging patterns. Here, we applied an advanced unsupervised multivariate pattern analysis technique, non-negative matrix factorization (NMF), to T 2 w/T 1 w signal ratio maps from a large cohort of newborns (Developing Human Connectome Project [dHCP], n=342), revealing patterns of synchronous white matter maturation. These patterns showed divergent age-related maturational trajectories and differential susceptibility to premature birth, which were replicated in an independent large sample of newborns (Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders [eLABE], n=239). Furthermore, we showed that T 2 w/T 1 w signal variations in white matter maturational patterns are explained by differential contributions of white matter microstructure indices (i.e., free water content and neurite density index) derived from neurite orientation dispersion and density imaging (NODDI) modeling of diffusion-weighted MRI. Finally, we demonstrated how white matter maturation patterns relate to distinct histological features by comparing our findings with postmortem late fetal/early postnatal brain tissue staining. Together, these results delineate a novel MRI representation of white matter microstructural and histological reorganization during the early postnatal development.

Background and Objectives The neurologic deficits of neonatal post-hemorrhagic hydrocephalus (PHH) have been linked to periventricular white matter injury. To improve understanding of PHH-related injury, diffusion basis spectrum imaging (DBSI) was applied in neonates, modeling axonal and myelin integrity, fiber density, and extrafiber pathologies. Objectives included characterizing DBSI measures in periventricular tracts, associating measures with ventricular size, and examining MRI findings in the context of postmortem white matter histology from similar cases. Methods A prospective cohort of infants born very preterm underwent term equivalent MRI, including infants with PHH, high-grade intraventricular hemorrhage without hydrocephalus (IVH), and controls (very preterm [VPT]). DBSI metrics extracted from the corpus callosum, corticospinal tracts, and optic radiations included fiber axial diffusivity, fiber radial diffusivity, fiber fractional anisotropy, fiber fraction (fiber density), restricted fractions (cellular infiltration), and nonrestricted fractions (vasogenic edema). Measures were compared across groups and correlated with ventricular size. Corpus callosum postmortem immunohistochemistry in infants with and without PHH assessed intra- and extrafiber pathologies. Results Ninety-five infants born very preterm were assessed (68 VPT, 15 IVH, 12 PHH). Infants with PHH had the most severe white matter abnormalities and there were no consistent differences in measures between IVH and VPT groups. Key tract-specific white matter injury patterns in PHH included reduced fiber fraction in the setting of axonal or myelin injury, increased cellular infiltration, vasogenic edema, and inflammation. Specifically, measures of axonal injury were highest in the corpus callosum; both axonal and myelin injury were observed in the corticospinal tracts; and axonal and myelin integrity were preserved in the setting of increased extrafiber cellular infiltration and edema in the optic radiations. Increasing ventricular size correlated with worse DBSI metrics across groups. On histology, infants with PHH had high cellularity, variable cytoplasmic vacuolation, and low synaptophysin marker intensity. Discussion PHH was associated with diffuse white matter injury, including tract-specific patterns of axonal and myelin injury, fiber loss, cellular infiltration, and inflammation. Larger ventricular size was associated with greater disruption. Postmortem immunohistochemistry confirmed MRI findings. These results demonstrate DBSI provides an innovative approach extending beyond conventional diffusion MRI for investigating neuropathologic effects of PHH on neonatal brain development.

Background Seizures are underrecognized in preterm infants, and little is known about their impact on brain growth. We aimed to define the association between early seizures and subsequent brain growth. Methods Infants <30 weeks gestation underwent 72 h of prospective amplitude-integrated electroencephalography (aEEG) monitoring, term-equivalent age (TEA) magnetic resonance imaging (MRI), and 2-year neurodevelopmental testing. Seizures were defined as trains of sharp waves >10 s, evolving in frequency/amplitude/morphology, and identified using automated algorithms with manual review. Using T2-weighted images, cortical surface area (CSA) and gyrification index (GI) were calculated and volumes were segmented into five tissue classes: cerebrospinal fluid, gray matter, white matter (WM), deep nuclear gray matter, and cerebellum. Correlations between total seizure burden and tissue-specific volumes were evaluated, controlling for clinical variables of interest. Results Ninety-nine infants underwent aEEG/MRI assessments (mean GA = 26.3 weeks, birthweight = 899 g). Seizure incidence was 55% with a median of two events; median length = 66 s and mean burden = 285 s. Greater seizure burden was associated with smaller CSA and volumes across all tissue types, most prominently in WM (R-2 = -0.603, p < 0.01), even after controlling for confounders. There was no association with GI. Conclusions Seizures in preterm infants are common and associated with smaller TEA brain volumes. This relationship was strongest for WM and independent of clinical factors. Impact Seizures in preterm infants are common. Little is known about the association between early seizures and later brain growth. Greater seizure burden is linked with smaller volumes of all brain tissue types, most prominently the WM. This relationship is true even controlling for other factors. Additional study is needed to identify the optimal EEG monitoring and seizure treatment strategy for improved brain growth and neurodevelopmental outcomes.

Background and Objectives To investigate brain regional white matter development in full-term (FT) and very preterm (VP) children at term equivalent and 7 and 13 years of age based on the ratio of T1- and T2-weighted MRI (T1-w/T2-w), including (1) whether longitudinal changes differ between birth groups or sexes, (2) associations with perinatal risk factors in VP children, and (3) relationships with neurodevelopmental outcomes at 13 years. Methods Prospective longitudinal cohort study of VP (born <30 weeks' gestation or <1,250 g) and FT infants born between 2001 and 2004 and followed up at term equivalent and 7 and 13 years of age, including MRI studies and neurodevelopmental assessments. T1-w/T2-w images were parcellated into 48 white matter regions of interest. Results Of 224 VP participants and 76 FT participants, 197 VP and 55 FT participants had useable T1-w/T2-w data from at least one timepoint. T1-w/T2-w values increased between term equivalent and 13 years of age, with little evidence that longitudinal changes varied between birth groups or sexes. VP birth, neonatal brain abnormalities, being small for gestational age, and postnatal infection were associated with reduced regional T1-w/T2-w values in childhood and adolescence. Increased T1-w/T2-w values across the white matter at 13 years were associated with better motor and working memory function for all children. Within the FT group only, larger increases in T1-w/T2-w values from term equivalent to 7 years were associated with poorer attention and executive function, and higher T1-w/T2-w values at 7 years were associated with poorer mathematics performance. Discussion VP birth and multiple known perinatal risk factors are associated with long-term reductions in the T1-w/T2-w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Increased T1-w/T2-w ratio at 13 years appeared to be associated with better motor and working memory function and there appeared to be developmental differences between VP and FT children in the associations for attention, executive functioning, and mathematics performance.

The human brain undergoes rapid changes from mid-gestation to postnatal 2 years of age. These rapid structural and functional changes underlie initial cognitive and behavioral development. Decades of histological studies have identified strong spatial and functional maturation gradients in human brain. Recent improvements in magnetic resonance imaging (MRI) techniques, especially diffusion MRI (dMRI), functional MRI (fMRI) and perfusion MRI (pMRI) have provided unprecedented opportunities to noninvasively quantify and map these early developmental changes at whole brain and regional levels. Here, we review recent advances in early brain development during the second half of gestation and the first two postnatal years using modern MR techniques. Specifically, we review MRI studies delineating spatiotemporally heterogeneous macro- and micro-structural changes in cerebral cortical regions and white mater tracts, as well as functional maturation across brain regions. In addition, we briefly discuss connectomics, metabolic and physiological changes during this developmental period. These imaging studies converge into typically developing brain structural and functional maturational curves that are distinctive across brain regions, setting the stage for understanding aberrant brain development in neurological or neuropsychiatric disorders.