Fetal White Matter Research Articles

Maternal obesity alters fetal neuroinflammation in a murine model of preterm birth

BackgroundPreterm birth from intrauterine infection is a leading cause of neonatal neurologic morbidity. Maternal obesity is also associated with intra-amniotic infection and inflammation. It remains unknown if maternal obesity is a risk factor for fetal brain injury that occurs with premature birth. We hypothesize that maternal obesity intensifies fetal neuroinflammation within the setting of premature delivery. ObjectiveUtilizing a murine model, we aimed to examine the influence of maternal obesity on perinatal neuroinflammatory responses that arise with preterm birth. Study DesignObese dams were generated via a high-fat diet that was maintained through pregnancy. In parallel, non-obese (normal) dams received a control diet. All dams were paired with males on normal diet. Pregnant dams were randomized to receive an intrauterine injection of bacterial endotoxin (LPS) or the vehicle (PBS) on embryo day 15.5 of what it typically a 19-21 day gestation. Fetal brains were harvested 6 hours following injections and the expression of key inflammatory cytokines (Il1b, Il6, and Tnf) as well as panels of metabolic, immune, and inflammatory genes was analyzed. ResultsWith PBS there were no differences in gene expression related to maternal obesity. There were substantial differences in Il6 and immune/inflammatory expression profiles in fetal brains from obese versus normal dams that received LPS. Few differences were observed among the metabolic genes examined under these conditions. Gene expression patterns with maternal obesity associated with pathways related to white matter injury. ConclusionThe expression of neuroinflammatory markers instigated by bacterial endotoxin via intrauterine LPS, was greater in embryo brains obtained from obese dams. Expression profiles suggest that in combination with intrauterine inflammation, maternal obesity may increase the risk of fetal white matter injury. Further investigation is warranted towards understanding the relationship between maternal health and neurologic outcomes associated with prematurity.

Maternal psychological distress during the COVID-19 pandemic and structural changes of the human fetal brain

BackgroundElevated maternal psychological distress during pregnancy is linked to adverse outcomes in offspring. The potential effects of intensified levels of maternal distress during the COVID-19 pandemic on the developing fetal brain are currently unknown.MethodsWe prospectively enrolled 202 pregnant women: 65 without known COVID-19 exposures during the pandemic who underwent 92 fetal MRI scans, and 137 pre-pandemic controls who had 182 MRI scans. Multi-plane, multi-phase single shot fast spin echo T2-weighted images were acquired on a GE 1.5 T MRI Scanner. Volumes of six brain tissue types were calculated. Cortical folding measures, including brain surface area, local gyrification index, and sulcal depth were determined. At each MRI scan, maternal distress was assessed using validated stress, anxiety, and depression scales. Generalized estimating equations were utilized to compare maternal distress measures, brain volume and cortical folding differences between pandemic and pre-pandemic cohorts.ResultsStress and depression scores are significantly higher in the pandemic cohort, compared to the pre-pandemic cohort. Fetal white matter, hippocampal, and cerebellar volumes are decreased in the pandemic cohort. Cortical surface area and local gyrification index are also decreased in all four lobes, while sulcal depth is lower in the frontal, parietal, and occipital lobes in the pandemic cohort, indicating delayed brain gyrification.ConclusionsWe report impaired fetal brain growth and delayed cerebral cortical gyrification in COVID-19 pandemic era pregnancies, in the setting of heightened maternal psychological distress. The potential long-term neurodevelopmental consequences of altered fetal brain development in COVID-era pregnancies merit further study.

Abnormal development of transient fetal zones in mild isolated fetal ventriculomegaly.

Mild isolated fetal ventriculomegaly (iFVM) is the most common abnormality of the fetal central nervous system. It is characterized by enlargement of one or both of the lateral ventricles (defined as ventricular width greater than 10 mm, but less than 12 mm). Despite its high prevalence, the pathophysiology of iFVM during fetal brain development and the neurobiological substrate beyond ventricular enlargement remain unexplored. In this work, we aimed to establish the relationships between the structural development of transient fetal brain zones/compartments and increased cerebrospinal fluid volume. For this purpose, we used in vivo structural T2-weighted magnetic resonance imaging of 89 fetuses (48 controls and 41 cases with iFVM). Our results indicate abnormal development of transient zones/compartments belonging to both hemispheres (i.e. on the side with and also on the contralateral side without a dilated ventricle) in fetuses with iFVM. Specifically, compared to controls, we observed enlargement of proliferative zones and overgrowth of the cortical plate in iFVM with associated reduction of volumes of central structures, subplate, and fetal white matter. These results indicate that enlarged lateral ventricles might be linked to the development of transient fetal zones and that global brain development should be taken into consideration when evaluating iFVM.

Association Between Socioeconomic Status and In Utero Fetal Brain Development

Children raised in settings with lower parental socioeconomic status are at increased risk for neuropsychological disorders. However, to date, the association between socioeconomic status and fetal brain development remains poorly understood. To determine the association between parental socioeconomic status and in vivo fetal brain growth and cerebral cortical development using advanced, 3-dimensional fetal magnetic resonance imaging. This cohort study of fetal brain development enrolled 144 healthy pregnant women from 2 low-risk community obstetrical hospitals from 2012 through 2019 in the District of Columbia. Included women had a prenatal history without complications that included recommended screening laboratory and ultrasound studies. Exclusion criteria were multiple gestation pregnancy, known or suspected congenital infection, dysmorphic features of the fetus, and documented chromosomal abnormalities. T2-weighted fetal brain magnetic resonance images were acquired. Each pregnant woman was scanned at up to 2 points in the fetal period. Data were analyzed from June through November 2020. Parental education level and occupation status were documented. Regional fetal brain tissue volume (for cortical gray matter, white matter, cerebellum, deep gray matter, and brainstem) and cerebral cortical features (ie, lobe volume, local gyrification index, and sulcal depth) in the frontal, parietal, temporal, and occipital lobes were calculated. Fetal brain magnetic resonance imaging studies were performed among 144 pregnant women (median [interquartile range] age, 32.5 [27.0-36.1] years) with gestational age from 24.0 to 39.4 weeks; 75 fetuses (52.1%) were male, and 69 fetuses (47.9%) were female. Higher parental education level was associated with significantly increased volume in the fetal white matter (mothers: β, 2.86; 95% CI, 1.26 to 4.45; P = .001; fathers: β, 2.39; 95% CI, 0.97 to 3.81; P = .001), deep gray matter (mothers: β, 0.16; 95% CI, 0.002 to 0.32; P = .048; fathers: β, 0.16; 95% CI, 0.02 to 0.31; P = .02), and brainstem (mothers: β, 0.06; 95% CI, 0.02 to 0.10; P = .01; fathers: β, 0.04; 95% CI, 0.004 to 0.08; P = .03). Higher maternal occupation status was associated with significantly increased volume in the fetal white matter (β, 2.07; 95% CI, 0.88 to 3.26; P = .001), cerebellum (β, 0.17; 95% CI, 0.04 to 0.29; P = .01), and brainstem (β, 0.03; 95% CI, 0.001 to 0.07; P = .04), and higher paternal occupation status was associated with significantly increased white matter volume (β, 1.98; 95% CI, 0.71 to 3.25; P < .01). However, higher socioeconomic status was associated with significantly decreased fetal cortical gray matter volume (mothers: β, -0.11; 95% CI, -0.18 to -0.03; P = .01; fathers: β, -0.10; 95% CI, -0.18 to -0.03; P = .01). Higher parental socioeconomic status was associated with increased volumes of 3 brain lobes of white matter: frontal lobe (mothers: β, 0.07; 95% CI, 0.02 to 0.13; P = .01; fathers: β, 0.06; 95% CI, 0.01 to 0.11; P = .03), parietal lobe (mothers: β, 0.07; 95% CI, 0.03 to 0.11; P < .001; fathers: β, 0.06; 95% CI, 0.03 to 0.10; P = .001), and temporal lobe (mothers: β, 0.04; 95% CI, 0.02 to 0.07; P < .001; fathers: β, 0.04; 95% CI, 0.02 to 0.07; P < .001), and maternal SES score was associated with significantly decreased volume in the occipital lobe (β, 0.02; 95% CI, 0.002 to 0.04; P = .03). Higher parental socioeconomic status was associated with decreased cortical local gyrification index (for example, for the frontal lobe, mothers: β, -1.1; 95% CI, -1.9 to -0.3; P = .01; fathers: β, -0.8; 95% CI, -1.6 to -0.1; P = .03) and sulcal depth, except for the frontal lobe (for example, for the parietal lobe, mothers: β, -9.5; 95% CI, -13.8 to -5.3; P < .001; fathers: β, -8.7; 95% CI, -13.0 to -4.4; P < .001). This cohort study found an association between parental socioeconomic status and altered in vivo fetal neurodevelopment. While being born and raised in a lower socioeconomic status setting is associated with poorer neuropsychological, educational, and socioeconomic outcomes in children, these findings suggest that altered prenatal programming may be associated with these outcomes and that future targeted prenatal interventions may be needed.

Structural Changes of the Human Fetal Brain During the COVID-19 Pandemic

Background: Elevated maternal psychological distress during pregnancy is linked to adverse short- and long-term outcomes in the offspring. The potential deleterious effects of intensified levels of maternal distress during the COVID-19 pandemic on the developing fetal brain are currently unknown.Methods: We prospectively enrolled 202 pregnant women: 65 with negative COVID-19 diagnoses during the pandemic who underwent 92 fetal MRI scans, and 137 pre-pandemic controls who had 182 MRI scans. Multi-plane, multi-phase single shot fast spin echo T2-weighted images were acquired on a GE 1.5T MRI Scanner. High-resolution 3D models of the fetal brains were reconstructed, and volumes of six brain tissue types were calculated: cortical gray matter (CGM), white matter (WM), cerebellum, deep gray matter (DGM), brainstem, and hippocampus. Cortical folding measures, including brain surface area, local gyrification index (LGI), and sulcal depth were determined. At each MRI scan, maternal distress was assessed using validated stress, anxiety and depression scales. Generalized estimating equations (GEEs) were utilized to compare maternal distress measures, brain volume and cortical folding differences between pandemic and pre-pandemic cohorts.Findings: Stress and depression scores were significantly higher in the pandemic cohort (14.2 vs. 10.4 for stress; 5.9 vs. 4.2 for depression; pConclusion: We relate heightened maternal psychological distress with impaired fetal brain growth and delayed cerebral cortical gyrification in COVID-19 pandemic era pregnancies. The potential long-term neurodevelopmental consequences of altered fetal brain development in COVID-era pregnancies complicated by elevated maternal distress merit further study.Funding: This study was funded by National Institutes of Health (NHLBI R01 HL116585-01), Intellectual and Developmental Disabilities Research Center (IDDRC), and A. James & Alice B. Clark Foundation.Declaration of Interest: None to declare. Ethical Approval: These studies received ethical approval from Children's National Hospital Institutional Review Board (Protocol: 1373 and 14257).

Developmental Remodelling of the Motor Cortex in Hemiparetic Children With Perinatal Stroke

BackgroundPerinatal stroke often leads to lifelong motor impairment. Two common subtypes differ in timing, location, and mechanism of injury: periventricular venous infarcts (PVI) are fetal white matter lesions while most arterial ischemic strokes (AIS) are cortical injuries acquired near term birth. Both alter motor system development and primary motor cortex (M1) plasticity, often with retained ipsilateral corticospinal fibers from the non-lesioned motor cortex (M1′). MethodsTask-based functional magnetic resonance imaging was used to define patterns of motor cortex activity during paretic and unaffected hand movement. Peak coordinates of M1, M1′, and the supplementary motor area in the lesioned and intact hemispheres were compared to age-matched controls. Correlations between displacements and clinical motor function were explored. ResultsForty-nine participants included 14 PVI (12.59 ± 3.7 years), 13 AIS (14.91 ± 3.9 years), and 22 controls (13.91 ± 3.4 years). AIS displayed the greatest M1 displacement from controls in the lesioned hemisphere while PVI locations approximated controls. Peak M1′ activations were displaced from the canonical hand knob in both PVI and AIS. Extent of M1 and M1′ displacement were correlated (r = 0.50, P = 0.025) but were not associated with motor function. Supplementary motor area activity elicited by paretic tapping was displaced in AIS compared to controls (P = 0.003). ConclusionMotor network components may be displaced in both hemispheres after perinatal stroke, particularly in AIS and those with ipsilateral control of the affected limb. Modest correlations with clinical function may support that more complex models of developmental plasticity are needed to inform targets for individualized neuromodulatory therapies in children with perinatal stroke.

In vivo characterization of emerging white matter microstructure in the fetal brain in the third trimester.

The third trimester of pregnancy is a period of rapid development of fiber bundles in the fetal white matter. Using a recently developed motion‐tracked slice‐to‐volume registration (MT‐SVR) method, we aimed to quantify tract‐specific developmental changes in apparent diffusion coefficient (ADC), fractional anisotropy (FA), and volume in third trimester healthy fetuses. To this end, we reconstructed diffusion tensor images from motion corrected fetal diffusion magnetic resonance imaging data. With an approved protocol, fetal MRI exams were performed on healthy pregnant women at 3 Tesla and included multiple (2–8) diffusion scans of the fetal head (1–2 b = 0 s/mm2 images and 12 diffusion‐sensitized images at b = 500 s/mm2). Diffusion data from 32 fetuses (13 females) with median gestational age (GA) of 33 weeks 4 days were processed with MT‐SVR and deterministic tractography seeded by regions of interest corresponding to 12 major fiber tracts. Multivariable regression analysis was used to evaluate the association of GA with volume, FA, and ADC for each tract. For all tracts, the volume and FA increased, and the ADC decreased with GA. Associations reached statistical significance for: FA and ADC of the forceps major; volume and ADC for the forceps minor; FA, ADC, and volume for the cingulum; ADC, FA, and volume for the uncinate fasciculi; ADC of the inferior fronto‐occipital fasciculi, ADC of the inferior longitudinal fasciculi; and FA and ADC for the corticospinal tracts. These quantitative results demonstrate the complex pattern and rates of tract‐specific, GA‐related microstructural changes of the developing white matter in human fetal brain.

Sublaminar organization of the human subplate: developmental changes in the distribution of neurons, glia, growing axons and extracellular matrix.

The objective of this paper was to collect normative data essential for analyzing the subplate (SP) role in pathogenesis of developmental disorders, characterized by abnormal circuitry, such as hypoxic-ischemic lesions, autism and schizophrenia. The main cytological features of the SP, such as low cell density, early differentiation of neurons and glia, plexiform arrangement of axons and dendrites, presence of synapses and a large amount of extracellular matrix (ECM) distinguish this compartment from the cell-dense cortical plate (CP; towards pia) and large fiber bundles of external axonal strata of fetal white matter (towards ventricle). For SP delineation from these adjacent layers based on combined cytological criteria, we analyzed the sublaminar distribution of different microstructural elements and the associated maturational gradients throughout development, using immunocytochemical and histological techniques on postmortem brain material (Zagreb Neuroembryological Collection). The analysis revealed that the SP compartment of the lateral neocortex shows changes in laminar organization throughout fetal development: the monolayer in the early fetal period (presubplate) undergoes dramatic bilaminar transformation between 13 and 15 postconceptional weeks (PCW), followed by subtle sublamination in three 'floors' (deep, intermediate, superficial) of midgestation (15-21 PCW). During the stationary phase (22-28 PCW), SP persists as a trilaminar compartment, gradually losing its sublaminar organization towards the end of gestation and remains as a single layer of SP remnant in the newborn brain. Based on these sublaminar transformations, we have documented developmental changes in the distribution, maturational gradients and expression of molecular markers in SP synapses, transitional forms of astroglia, neurons and ECM, which occur concomitantly with the ingrowth of thalamo-cortical, basal forebrain and cortico-cortical axons in a deep to superficial fashion. The deep SP is the zone of ingrowing axons - 'entrance (ingrowth) zone'. The process of axonal ingrowth begins with thalamo-cortical fibers and basal forebrain afferents, indicating an oblique geometry. During the later fetal period, deep SP receives long cortico-cortical axons exhibiting a tangential geometry. Intermediate SP ('proper') is the navigation and 'nexus' sublamina consisting of a plexiform arrangement of cellular elements providing guidance and substrate for axonal growth, and also containing transient connectivity of dendrites and axons in a tangential plane without radial boundaries immersed in an ECM-rich continuum. Superficial SP is the axonal accumulation ('waiting compartment') and target selection zone, indicating a dense distribution of synaptic markers, accumulation of thalamo-cortical axons (around 20 PCW), overlapping with dendrites from layer VI neurons. In the late preterm brain period, superficial SP contains a chondroitin sulfate non-immunoreactive band. The developmental dynamics for the distribution of neuronal, glial and ECM markers comply with sequential ingrowth of afferents in three levels of SP: ECM and synaptic markers shift from deep to superficial SP, with transient forms of glia following this arrangement, and calretinin neurons are concentrated in the SP during the formation phase. These results indicate developmental and morphogenetic roles in the SP cellular (transient glia, neurons and synapses) and ECM framework, enabling the spatial accommodation, navigation and establishment of numerous connections of cortical pathways in the expanded human brain. The original findings of early developmental dynamics of transitional subtypes of astroglia, calretinin neurons, ECM and synaptic markers presented in the SP are interesting in the light of recent concepts concerning its functional and morphogenetic role and an increasing interest in SP as a prospective substrate of abnormalities in cortical circuitry, leading to a cognitive deficit in different neurodevelopmental disorders.

Human Fetal Brain Connectome: Structural Network Development from Middle Fetal Stage to Birth.

Complicated molecular and cellular processes take place in a spatiotemporally heterogeneous and precisely regulated pattern in the human fetal brain, yielding not only dramatic morphological and microstructural changes, but also macroscale connectomic transitions. As the underlying substrate of the fetal brain structural network, both dynamic neuronal migration pathways and rapid developing fetal white matter (WM) fibers could fundamentally reshape early fetal brain connectome. Quantifying structural connectome development can not only shed light on the brain reconfiguration in this critical yet rarely studied developmental period, but also reveal alterations of the connectome under neuropathological conditions. However, transition of the structural connectome from the mid-fetal stage to birth is not yet known. The contribution of different types of neural fibers to the structural network in the mid-fetal brain is not known, either. In this study, diffusion tensor magnetic resonance imaging (DT-MRI or DTI) of 10 fetal brain specimens at the age of 20 postmenstrual weeks (PMW), 12 in vivo brains at 35 PMW, and 12 in vivo brains at term (40 PMW) were acquired. The structural connectome of each brain was established with evenly parcellated cortical regions as network nodes and traced fiber pathways based on DTI tractography as network edges. Two groups of fibers were categorized based on the fiber terminal locations in the cerebral wall in the 20 PMW fetal brains. We found that fetal brain networks become stronger and more efficient during 20–40 PMW. Furthermore, network strength and global efficiency increase more rapidly during 20–35 PMW than during 35–40 PMW. Visualization of the whole brain fiber distribution by the lengths suggested that the network reconfiguration in this developmental period could be associated with a significant increase of major long association WM fibers. In addition, non-WM neural fibers could be a major contributor to the structural network configuration at 20 PMW and small-world network organization could exist as early as 20 PMW. These findings offer a preliminary record of the fetal brain structural connectome maturation from the middle fetal stage to birth and reveal the critical role of non-WM neural fibers in structural network configuration in the middle fetal stage.

Complex Trajectories of Brain Development in the Healthy Human Fetus.

This study characterizes global and hemispheric brain growth in healthy human fetuses during the second half of pregnancy using three-dimensional MRI techniques. We studied 166 healthy fetuses that underwent MRI between 18 and 39 completed weeks gestation. We created three-dimensional high-resolution reconstructions of the brain and calculated volumes for left and right cortical gray matter (CGM), fetal white matter (FWM), deep subcortical structures (DSS), and the cerebellum. We calculated the rate of growth for each tissue class according to gestational age and described patterns of hemispheric growth. Each brain region demonstrated major increases in volume during the second half of gestation, the most pronounced being the cerebellum (34-fold), followed by FWM (22-fold), CGM (21-fold), and DSS (10-fold). The left cerebellar hemisphere, CGM, and DSS had larger volumes early in gestation, but these equalized by term. It has been increasingly recognized that brain asymmetry evolves throughout the human life span. Advanced quantitative MRI provides noninvasive measurements of early structural asymmetry between the left and right fetal brain that may inform functional and behavioral laterality differences seen in children and young adulthood.

MicroRNA Expression Patterns in Human Astrocytes in Relation to Anatomical Location and Age

Anatomic distribution and age are variables linked to functions of astrocytes under physiologic and pathologic conditions. We measured the relative expression of a panel of microRNAs (miRNAs) in astrocytes captured by laser micro-dissection from normal human adult white and grey matter, human fetal white matter and germinal matrix samples. Although expression of most miRNAs was comparable between adult and fetal samples, regional differences were observed. In the adult cerebral cortex, expression of miRNAs in morphologically distinct inter-laminar astrocytes underlying the glial limitans differed from those in deeper cortical layers, suggesting functional specialization possibly related to structural stability and defense from potentially harmful factors in the cerebrospinal fluid. Differences between adult white and grey matter miRNA expression included higher expression of pro-inflammatory miRNAs in the former, potentially contributing to differences in inflammation between grey and white matter plaques in multiple sclerosis. Lower expression of miRNAs in fetal versus adult white matter astrocytes likely reflects the immaturity of these migrating cells. Highly expressed miRNAs in the fetal germinal matrix are probably relevant in development and also recapitulate some responses to injury. Future studies can address regional alterations of miRNA expression in pathological conditions.

Premyelinated central axons express neurotoxic NMDA receptors: relevance to early developing white-matter injury.

Ischemic-type injury to developing white matter is associated with the significant clinical condition cerebral palsy and with the cognitive deficits associated with premature birth. Premyelinated axons are the major cellular component of fetal white matter and loss of axon function underlies the disability, but the cellular mechanisms producing ischemic injury to premyelinated axons have not previously been described. Injury was found to require longer periods of modelled ischemia than at latter developmental points. Ischemia produced initial hyperexcitability in axons followed by loss of function after Na(+) and Ca(2+) influx. N-methyl-D-aspartate- (NMDA) type glutamate receptor (GluR) agonists potentiated axon injury while antagonists were protective. The NMDA GluR obligatory Nr1 subunit colocalized with markers of small premyelinated axons and expression was found at focal regions of axon injury. Ischemic injury of glial cells present in early developing white matter was NMDA GluR independent. Axons in human postconception week 18 to 23 white matter had a uniform prediameter expansion phenotype and postembedded immuno-gold labelling showed Nr1 subunit expression on the membrane of these axons, demonstrating a shared key neuropathologic feature with the rodent model. Premyelinated central axons therefore express high levels of functional NMDA GluRs that confer sensitivity to ischemic injury.

Effects of Intra-Amniotic Lipopolysaccharide and Maternal Betamethasone on Brain Inflammation in Fetal Sheep

RationaleChorioamnionitis and antenatal glucocorticoids are common exposures for preterm infants and can affect the fetal brain, contributing to cognitive and motor deficits in preterm infants. The effects of antenatal glucocorticoids on the brain in the setting of chorioamnionitis are unknown. We hypothesized that antenatal glucocorticoids would modulate inflammation in the brain and prevent hippocampal and white matter injury after intra-amniotic lipopolysaccharide (LPS) exposure.MethodsTime-mated ewes received saline (control), an intra-amniotic injection of 10 mg LPS at 106d GA or 113d GA, maternal intra-muscular betamethasone (0.5 mg/kg maternal weight) alone at 113d GA, betamethasone at 106d GA before LPS or betamethasone at 113d GA after LPS. Animals were delivered at 120d GA (term=150d). Brain structure volumes were measured on T2-weighted MRI images. The subcortical white matter (SCWM), periventricular white matter (PVWM) and hippocampus were analyzed for microglia, astrocytes, apoptosis, proliferation, myelin and pre-synaptic vesicles.ResultsLPS and/or betamethasone exposure at different time-points during gestation did not alter brain structure volumes on MRI. Betamethasone alone did not alter any of the measurements. Intra-amniotic LPS at 106d or 113d GA induced inflammation as indicated by increased microglial and astrocyte recruitment which was paralleled by increased apoptosis and hypomyelination in the SCWM and decreased synaptophysin density in the hippocampus. Betamethasone before the LPS exposure at 113d GA prevented microglial activation and the decrease in synaptophysin. Betamethasone after LPS exposure increased microglial infiltration and apoptosis.ConclusionIntra-uterine LPS exposure for 7d or 14d before delivery induced inflammation and injury in the fetal white matter and hippocampus. Antenatal glucocorticoids aggravated the inflammatory changes in the brain caused by pre-existing intra-amniotic inflammation. Antenatal glucocorticoids prior to LPS reduced the effects of intra-uterine inflammation on the brain. The timing of glucocorticoid administration in the setting of chorioamnionitis can alter outcomes for the fetal brain.

LPS and TNF alpha modulate AMPA/NMDA receptor subunit expression and induce PGE2 and glutamate release in preterm fetal ovine mixed glial cultures

BackgroundWhite matter injury (WMI) is the major antecedent of cerebral palsy in premature infants, and is often associated with maternal infection and the fetal inflammatory response. The current study explores the therapeutic potential of glutamate receptor blockade or cyclooxygenase-2 (COX-2) inhibition for inflammatory WMI.MethodsUsing fetal ovine derived mixed glia cultures exposed to tumour necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl D-aspartate (NMDA) glutamate receptors and their contribution to inflammation mediated pre-oligodendrocyte (OL) death was evaluated. The functional significance of TNF-α and COX-2 signalling in glutamate release in association with TNF-α and LPS exposure was also assessed.ResultsAMPA and NMDA receptors were expressed in primary mixed glial cultures on developing OLs, the main cell-type present in fetal white matter at a period of high risk for WMI. We show that glutamate receptor expression and configuration are regulated by TNF-α and LPS exposure, but AMPA and NMDA blockade, either alone or in combination, did not reduce pre-OL death. Furthermore, we demonstrate that glutamate and prostaglandin E2 (PGE2) release following TNF-α or LPS are mediated by a TNF-α-COX-2 dependent mechanism.ConclusionsOverall, these findings suggest that glial-localised glutamate receptors likely play a limited role in OL demise associated with chronic inflammation, but supports the COX-2 pathway as a potential therapeutic target for infection/inflammatory-mediated WMI.

OC16.02: Fetal white matter abnormalities in cytomegalovirus infection

<scp>OC</scp>16.02: Fetal white matter abnormalities in cytomegalovirus infection

Relationship between gestational age and apparent diffusion coefficient values in different regions of fetal brain from middle to late trimester

To analyze the relationship between gestational age and apparent diffusion coefficient (ADC) values in different regions of fetal brain from middle to late trimester. DW images performed in 70 singleton non-sedated fetuses with questionably abnormal results on sonography and normal fetal MR imaging results were retrospectively reviewed. The median gestational age was 32.4 weeks (range, 24-38).With the formula of ADC = ln (S600/S0)/(B0-B600), the mean ADC values were obtained for fetal parietal white matter (WM), frontal WM, temporal WM, occipital WM, pons, cerebellum, basal ganglia and thalamus. The relationship of mean ADC values in different regions with gestational age was analyzed with linear regression. The mean ADC values were 1.77 ± 0.32 mm(2)/s (SD) in fetal parietal white matter (WM), 1.71 ± 0.32 mm(2)/s in occipital WM, 1.31 ± 0.18 mm(2)/s in thalamus, 1.34 ± 0.15 mm(2)/s in basal ganglia. And the mean ADC values in cerebellum, pons, frontal WM and temporal WM were 1.17 ± 0.16, 1.41 ± 0.18, 1.87 ± 0.18 and 1.74 ± 0.19 mm(2)/s respectively. A significant negative correlation between ADC values and gestational age was found for parietal WM, occipital WM, pons, cerebellum, basal ganglia and thalamus (P < 0.05). Frontal WM ADC (P > 0.05) and temporal WM ADC (P = 0.05) did not significantly change with gestational age whereas only a downward trend was present. The correlation coefficient (r) and coefficient of regression (b) were 0.420 and -0.045 in parietal WM; 0.470 and -0.052 in occipital WM; 0.370 and -0.027 in cerebellum; 0.027 and -0.020 in pons; 0.320 and -0.027 in thalamus; 0.300 and -0.021 in basal ganglia. The mean ADC values peaked in frontal WM and lowest in pons. The mean ADC values in white matter were higher than those in deep gray nuclei, cerebellum and pons.With the development of fetal brain,ADC values declined the fastest in cerebellum and occipital WM, followed by basal ganglia and thalamus. Regional differences in non-sedated fetal brain ADC values and their evolutions with gestational age are likely to reflect variations in brain maturation.

Gaining insight of fetal brain development with diffusion MRI and histology

Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic levels. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns.

Radial Coherence of Diffusion Tractography in the Cerebral White Matter of the Human Fetus: Neuroanatomic Insights

High angular resolution diffusion imaging (HARDI) demonstrates transient radial coherence of telencephalic white matter in the human fetus. Our objective was to define the neuroanatomic basis of this radial coherence through correlative HARDI- and postmortem tissue analyses. Applying immunomarkers to radial glial fibers (RGFs), axons, and blood vessels in 18 cases (19 gestational weeks to 3 postnatal years), we compared their developmental profiles to HARDI tractography in brains of comparable ages (n = 11). At midgestation, radial coherence corresponded with the presence of RGFs. At 30-31 weeks, the transition from HARDI-defined radial coherence to corticocortical coherence began simultaneously with the transformation of RGFs to astrocytes. By term, both radial coherence and RGFs had disappeared. White matter axons were radial, tangential, and oblique over the second half of gestation, whereas penetrating blood vessels were consistently radial. Thus, radial coherence in the fetal white matter likely reflects a composite of RGFs, penetrating blood vessels, and radial axons of which its transient expression most closely matches that of RGFs. This study provides baseline information for interpreting radial coherence in tractography studies of the preterm brain in the assessment of the encephalopathy of prematurity.

Daily ethanol exposure during late ovine pregnancy: physiological effects in the mother and fetus in the apparent absence of overt fetal cerebral dysmorphology

High levels of ethanol (EtOH) consumption during pregnancy adversely affect fetal development; however, the effects of lower levels of exposure are less clear. Our objectives were to assess the effects of daily EtOH exposure (3.8 USA standard drinks) on fetal-maternal physiological variables and the fetal brain, particularly white matter. Pregnant ewes received daily intravenous infusions of EtOH (0.75 g/kg maternal body wt over 1 h, 8 fetuses) or saline (8 fetuses) from 95 to 133 days of gestational age (DGA; term ∼145 DGA). Maternal and fetal arterial blood was sampled at 131-133 DGA. At necropsy (134 DGA) fetal brains were collected for analysis. Maternal and fetal plasma EtOH concentrations reached similar maximal concentration (∼0.11 g/dl) and declined at the same rate. EtOH infusions produced mild reductions in fetal arterial oxygenation but there were no changes in maternal oxygenation, maternal and fetal Pa(CO(2)), or in fetal mean arterial pressure or heart rate. Following EtOH infusions, plasma lactate levels were elevated in ewes and fetuses, but arterial pH fell only in ewes. Fetal body and brain weights were similar between groups. In three of eight EtOH-exposed fetuses there were small subarachnoid hemorrhages in the cerebrum and cerebellum associated with focal cortical neuronal death and gliosis. Overall, there was no evidence of cystic lesions, inflammation, increased apoptosis, or white matter injury. We conclude that daily EtOH exposure during the third trimester-equivalent of ovine pregnancy has modest physiological effects on the fetus and no gross effects on fetal white matter development.

Populations of subplate and interstitial neurons in fetal and adult human telencephalon

In the adult human telencephalon, subcortical (gyral) white matter contains a special population of interstitial neurons considered to be surviving descendants of fetal subplate neurons [Kostovic & Rakic (1980) Cytology and the time of origin of interstitial neurons in the white matter in infant and adult human and monkey telencephalon. J Neurocytol9, 219]. We designate this population of cells as superficial (gyral) interstitial neurons and describe their morphology and distribution in the postnatal and adult human cerebrum. Human fetal subplate neurons cannot be regarded as interstitial, because the subplate zone is an essential part of the fetal cortex, the major site of synaptogenesis and the 'waiting' compartment for growing cortical afferents, and contains both projection neurons and interneurons with distinct input-output connectivity. However, although the subplate zone is a transient fetal structure, many subplate neurons survive postnatally as superficial (gyral) interstitial neurons. The fetal white matter is represented by the intermediate zone and well-defined deep periventricular tracts of growing axons, such as the corpus callosum, anterior commissure, internal and external capsule, and the fountainhead of the corona radiata. These tracts gradually occupy the territory of transient fetal subventricular and ventricular zones.The human fetal white matter also contains distinct populations of deep fetal interstitial neurons, which, by virtue of their location, morphology, molecular phenotypes and advanced level of dendritic maturation, remain distinct from subplate neurons and neurons in adjacent structures (e.g. basal ganglia, basal forebrain). We describe the morphological, histochemical (nicotinamide-adenine dinucleotide phosphate-diaphorase) and immunocytochemical (neuron-specific nuclear protein, microtubule-associated protein-2, calbindin, calretinin, neuropeptide Y) features of both deep fetal interstitial neurons and deep (periventricular) interstitial neurons in the postnatal and adult deep cerebral white matter (i.e. corpus callosum, anterior commissure, internal and external capsule and the corona radiata/centrum semiovale). Although these deep interstitial neurons are poorly developed or absent in the brains of rodents, they represent a prominent feature of the significantly enlarged white matter of human and non-human primate brains.