Prenatal exposure to maternal disadvantage-related inflammatory biomarkers: associations with neonatal white matter microstructure.

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.

Subcutaneous deuterated substrate administration in mice: An alternative to tail vein infusion.

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.

Prenatal environment is associated with the pace of cortical network development over the first three years of life.

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.

Neurodevelopmental patterns of early postnatal white matter maturation represent distinct underlying microstructure and histology.

Cerebral white matter undergoes a rapid and complex maturation during the early postnatal period. Prior magnetic resonance imaging (MRI) studies of early postnatal development have often been limited by small sample size, single-modality imaging, and univariate analytics. Here, we applied nonnegative matrix factorization, an unsupervised multivariate pattern analysis technique, to T2w/T1w signal ratio maps from the Developing Human Connectome Project (n = 342 newborns) revealing patterns of coordinated white matter maturation. These patterns showed divergent age-related maturational trajectories, which were replicated in another independent cohort (n = 239). Furthermore, we showed that T2w/T1w signal variations in these maturational patterns are explained by differential contributions of white matter microstructural indices derived from 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 concise and effective representation of early postnatal white matter reorganization.

Rat Brain Global Ischemia-Induced Diffusion Changes Revisited: Biophysical Modeling of the Water and NAA MR "Diffusion Signal".

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, bmax  = 19 ms/µm2 ) 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 (DL and DT , respectively). In this model, DL represents the "free" diffusivity of NAA, whereas DT reflects highly restricted diffusion. Using oscillating gradients, the frequency dependence of DT [DT (ω)] gave estimates of the cylinder (axon/dendrite) radius. RESULTS: A 10% decrease in DL,NAA followed global ischemia, dropping from 0.391 ± 0.012 µm2 /ms to 0.350 ± 0.009 µm2 /ms. Modeling DT,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 DL,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 DT (ω) were consistent with literature values.

Synthesizing pseudo-T2w images to recapture missing data in neonatal neuroimaging with applications in rs-fMRI.

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.

Brain White Matter Development Over the First 13 Years in Very Preterm and Typically Developing Children Based on the T 1-w/T 2-w Ratio.

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 T 1- and T 2-weighted MRI (T 1-w/T 2-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. T 1-w/T 2-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 T 1-w/T 2-w data from at least one timepoint. T 1-w/T 2-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 T 1-w/T 2-w values in childhood and adolescence. Increased T 1-w/T 2-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 T 1-w/T 2-w values from term equivalent to 7 years were associated with poorer attention and executive function, and higher T 1-w/T 2-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 T 1-w/T 2-w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Increased T 1-w/T 2-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.

Microstructural Periventricular White Matter Injury in Post-Hemorrhagic Ventricular Dilatation.

BACKGROUND AND OBJECTIVES: The neurological 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 extra-fiber pathologies. Objectives included characterizing DBSI measures in periventricular tracts, associating measures with ventricular size, and examining MRI findings in the context of post-mortem 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 (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 non-restricted 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 extra-fiber 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 and/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 extra-fiber 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 neuropathological effects of PHH on neonatal brain development.

Structural and functional connectivity in premature neonates.

Advances in neuroimaging have increasingly enabled researchers to investigate whether alterations in brain development commonly identified in preterm infants underlie their high risk of long-term neurodevelopmental impairment, including sensory, motor, cognitive, and psychiatric deficits. This review begins by examining the growing body of literature utilizing advanced magnetic resonance imaging (MRI) techniques to probe structural (via diffusion MRI) and functional (via resting state-functional MRI) connectivity development in the preterm brain during the neonatal period, both in the presence and absence of brain injury. It then details the recent work linking neonatal brain connectivity measures to neurodevelopmental and psychiatric outcomes in prematurely-born cohorts. Finally, building upon the recent substantive growth in the utilization of these neuroimaging modalities, it concludes by highlighting areas in which continued optimization of age-specific acquisition and analysis techniques for these data remains necessary, efforts fundamental to advancing the field toward establishing individual-level predictive capabilities in this high-risk population.

Diffusion Magnetic Resonance Imaging of Infants.

Diffusion magnetic resonance imaging (MRI) offers a wealth of information regarding the neonatal brain. Diffusion anisotropy values reflect changes in the microstructure that accompany early maturation of white and gray matter. In term neonates with neonatal encephalopathy, diffusion imaging provides a useful means of assessing brain injury during the first week of life. In preterm neonates, measures of white matter anisotropy provide information on the nature and extent of white matter disruption. Subsequently, diffusion MRI plays an important role in illuminating fundamental elements of brain development and fulfilling the clinical need to develop prognostic indicators for term and preterm infants.

Probing in vivo cortical myeloarchitecture in humans via line-scan diffusion acquisitions at 7 T with 250-500 micron radial resolution.

PURPOSE: The goal of this study was to measure diffusion signals within the cerebral cortex using the line-scan technique to achieve extremely high resolution in the radial direction (ie, perpendicular to the cortical surface) and to demonstrate the utility of these measurements for investigating laminar architecture in the living human brain. METHODS: Line-scan diffusion data with 250-500 micron radial resolution were acquired at 7 T on 8 healthy volunteers, with each line prescribed perpendicularly to primary somatosensory cortex (S1) and primary motor cortex (M1). Apparent diffusion coefficients, fractional anisotropy values, and radiality indices were measured as a function of cortical depth. RESULTS: In the deep layers of S1, we found evidence for high anisotropy and predominantly tangential diffusion, with low anisotropy observed in superficial S1. In M1, moderate anisotropy and predominantly radial diffusion was seen at almost all cortical depths. These patterns were consistent across subjects and were conspicuous without averaging data across different locations on the cortical sheet. CONCLUSION: Our results are in accord with the myeloarchitecture of S1 and M1, known from prior histology studies: in S1, dense bands of tangential myelinated fibers run through the deep layers but not the superficial ones, and in M1, radial myelinated fibers are prominent at most cortical depths. This work therefore provides support for the idea that high-resolution diffusion signals, measured with the line-scan technique and receiving a boost in SNR at 7 T, may serve as a sensitive probe of in vivo laminar architecture.

Tracking regional brain growth up to age 13 in children born term and very preterm.

Serial regional brain growth from the newborn period to adolescence has not been described. Here, we measured regional brain growth in 216 very preterm (VP) and 45 full-term (FT) children. Brain MRI was performed at term-equivalent age, 7 and 13 years in 82 regions. Brain volumes increased between term-equivalent and 7 years, with faster growth in the FT than VP group. Perinatal brain abnormality was associated with less increase in brain volume between term-equivalent and 7 years in the VP group. Between 7 and 13 years, volumes were relatively stable, with some subcortical and cortical regions increasing while others reduced. Notably, VP infants continued to lag, with overall brain size generally less than that of FT peers at 13 years. Parieto-frontal growth, mainly between 7 and 13 years in FT children, was associated with higher intelligence at 13 years. This study improves understanding of typical and atypical regional brain growth.

MR diffusion changes in the perimeter of the lateral ventricles demonstrate periventricular injury in post-hemorrhagic hydrocephalus of prematurity.

OBJECTIVES: Injury to the preterm lateral ventricular perimeter (LVP), which contains the neural stem cells responsible for brain development, may contribute to the neurological sequelae of intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus of prematurity (PHH). This study utilizes diffusion MRI (dMRI) to characterize the microstructural effects of IVH/PHH on the LVP and segmented frontal-occipital horn perimeters (FOHP). STUDY DESIGN: Prospective study of 56 full-term infants, 72 very preterm infants without brain injury (VPT), 17 VPT infants with high-grade IVH without hydrocephalus (HG-IVH), and 13 VPT infants with PHH who underwent dMRI at term equivalent. LVP and FOHP dMRI measures and ventricular size-dMRI correlations were assessed. RESULTS: In the LVP, PHH had consistently lower FA and higher MD and RD than FT and VPT (p<.050). However, while PHH FA was lower, and PHH RD was higher than their respective HG-IVH measures (p<.050), the MD and AD values did not differ. In the FOHP, PHH infants had lower FA and higher RD than FT and VPT (p<.010), and a lower FA than the HG-IVH group (p<.001). While the magnitude of AD in both the LVP and FOHP were consistently less in the PHH group on pairwise comparisons to the other groups, the differences were not significant (p>.050). Ventricular size correlated negatively with FA, and positively with MD and RD (p<.001) in both the LVP and FOHP. In the PHH group, FA was lower in the FOHP than in the LVP, which was contrary to the observed findings in the healthy infants (p<.001). Nevertheless, there were no regional differences in AD, MD, and RD in the PHH group. CONCLUSION: HG-IVH and PHH results in aberrant LVP/FOHP microstructure, with prominent abnormalities among the PHH group, most notably in the FOHP. Larger ventricular size was associated with greater magnitude of abnormality. LVP/FOHP dMRI measures may provide valuable biomarkers for future studies directed at improving the management and neurological outcomes of IVH/PHH.

Perioperatively Inhaled Hydrogen Gas Diminishes Neurologic Injury Following Experimental Circulatory Arrest in Swine.

This study used a swine model of mildly hypothermic prolonged circulatory arrest and found that the addition of 2.4% inhaled hydrogen gas to inspiratory gases during and after the ischemic insult significantly decreased neurologic and renal injury compared with controls. With proper precautions, inhalational hydrogen may be administered safely through conventional ventilators and may represent a complementary therapy that can be easily incorporated into current workflows. In the future, inhaled hydrogen may diminish the sequelae of ischemia that occurs in congenital heart surgery, cardiac arrest, extracorporeal life-support events, acute myocardial infarction, stroke, and organ transplantation.

Neonatal brain injury and aberrant connectivity.

Brain injury sustained during the neonatal period may disrupt development of critical structural and functional connectivity networks leading to subsequent neurodevelopmental impairment in affected children. These networks can be characterized using structural (via diffusion MRI) and functional (via resting state-functional MRI) neuroimaging techniques. Advances in neuroimaging have led to expanded application of these approaches to study term- and prematurely-born infants, providing improved understanding of cerebral development and the deleterious effects of early brain injury. Across both modalities, neuroimaging data are conducive to analyses ranging from characterization of individual white matter tracts and/or resting state networks through advanced 'connectome-style' approaches capable of identifying highly connected network hubs and investigating metrics of network topology such as modularity and small-worldness. We begin this review by summarizing the literature detailing structural and functional connectivity findings in healthy term and preterm infants without brain injury during the postnatal period, including discussion of early connectome development. We then detail common forms of brain injury in term- and prematurely-born infants. In this context, we next review the emerging body of literature detailing studies employing diffusion MRI, resting state-functional MRI and other complementary neuroimaging modalities to characterize structural and functional connectivity development in infants with brain injury. We conclude by reviewing technical challenges associated with neonatal neuroimaging, highlighting those most relevant to studying infants with brain injury and emphasizing the need for further targeted study in this high-risk population.

Recent advances in the use of MRI to assess early human cortical development.

Over the past decade, a number of advanced magnetic resonance-based methods have been brought to bear on questions related to early development of the human cerebral cortex. Herein, we describe studies employing analysis of cortical surface folding (cortical cartography), cortical microstructure (diffusion anisotropy), and cortically-based functional networks (resting state-functional connectivity MRI). The fundamentals of each MR method are described, followed by a discussion of application of the method to developing cortex and potential clinical uses. We use premature birth as an exemplar of how these modalities can be used to investigate the effects of medical and environmental variables on early cortical development.

Differential Rates of Perinatal Maturation of Human Primary and Nonprimary Auditory Cortex.

Primary and nonprimary cerebral cortex mature along different timescales; however, the differences between the rates of maturation of primary and nonprimary cortex are unclear. Cortical maturation can be measured through changes in tissue microstructure detectable by diffusion magnetic resonance imaging (MRI). In this study, diffusion tensor imaging (DTI) was used to characterize the maturation of Heschl's gyrus (HG), which contains both primary auditory cortex (pAC) and nonprimary auditory cortex (nAC), in 90 preterm infants between 26 and 42 weeks postmenstrual age (PMA). The preterm infants were in different acoustical environments during their hospitalization: 46 in open ward beds and 44 in single rooms. A control group consisted of 15 term-born infants. Diffusion parameters revealed that (1) changes in cortical microstructure that accompany cortical maturation had largely already occurred in pAC by 28 weeks PMA, and (2) rapid changes were taking place in nAC between 26 and 42 weeks PMA. At term equivalent PMA, diffusion parameters for auditory cortex were different between preterm infants and term control infants, reflecting either delayed maturation or injury. No effect of room type was observed. For the preterm group, disturbed maturation of nonprimary (but not primary) auditory cortex was associated with poorer language performance at age two years.

Brain growth in the NICU: critical periods of tissue-specific expansion.

ObjectiveTo examine, using serial magnetic resonance imaging (MRI), total and tissue-specific brain growth in very-preterm (VPT) infants during the period that coincides with the early and late stages of the third trimester.MethodsStructural MRI scans were collected from two prospective cohorts of VPT infants (≤30 weeks of gestation). A total of 51 MRI scans from 18 VPT subjects were available for volumetric analysis. Brain tissue was classified into cerebrospinal fluid, cortical gray matter, myelinated and unmyelinated white matter, deep nuclear gray matter, and cerebellum. Nine infants had sufficient serial scans to allow comparison of tissue growth during the periods corresponding to the early and late stages of the third trimester.ResultsTissue-specific differences in ex utero brain growth trajectories were observed in the period corresponding to the third trimester. Most notably, there was a marked increase in cortical gray matter expansion from 34 to 40 weeks of postmenstrual age, emphasizing this critical period of brain development.ConclusionUtilizing serial MRI to document early brain development in VPT infants, this study documents regional differences in brain growth trajectories ex utero during the period corresponding to the first and second half of the third trimester, providing novel insight into the maturational vulnerability of the rapidly expanding cortical gray matter in the NICU.