Human fetal brain self-organizes into long-term expanding organoids.

Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding organoids can be grown directly from multiple somatic tissues, yet to date, brain organoids can solely be established from pluripotent stem cells. Here, we show that healthy human fetal brain in vitro self-organizes into organoids (FeBOs), phenocopying aspects of in vivo cellular heterogeneity and complex organization. FeBOs can be expanded over long time periods. FeBO growth requires maintenance of tissue integrity, which ensures production of a tissue-like extracellular matrix (ECM) niche, ultimately endowing FeBO expansion. FeBO lines derived from different areas of the central nervous system (CNS), including dorsal and ventral forebrain, preserve their regional identity and allow to probe aspects of positional identity. Using CRISPR-Cas9, we showcase the generation of syngeneic mutant FeBO lines for the study of brain cancer. Taken together, FeBOs constitute a complementary CNS organoid platform.

Development of the Fetal Brain Corticocortical Structural Network during the Second-to-Third Trimester Based on Diffusion MRI.

During the second-to-third trimester, the neuronal pathways of the fetal brain experience rapid development, resulting in the complex architecture of the interwired network at birth. While diffusion MRI-based tractography has been employed to study the prenatal development of structural connectivity network (SCN) in preterm neonatal and postmortem fetal brains, the in utero development of SCN in the normal fetal brain remains largely unknown. In this study, we utilized in utero dMRI data from human fetuses of both sexes between 26 and 38 gestational weeks to investigate the developmental trajectories of the fetal brain SCN, focusing on intrahemispheric connections. Our analysis revealed significant increases in global efficiency, mean local efficiency, and clustering coefficient, along with significant decrease in shortest path length, while small-worldness persisted during the studied period, revealing balanced network integration and segregation. Widespread short-ranged connectivity strengthened significantly. The nodal strength developed in a posterior-to-anterior and medial-to-lateral order, reflecting a spatiotemporal gradient in cortical network connectivity development. Moreover, we observed distinct lateralization patterns in the fetal brain SCN. Globally, there was a leftward lateralization in network efficiency, clustering coefficient, and small-worldness. The regional lateralization patterns in most language, motor, and visual-related areas were consistent with prior knowledge, except for Wernicke's area, indicating lateralized brain wiring is an innate property of the human brain starting from the fetal period. Our findings provided a comprehensive view of the development of the fetal brain SCN and its lateralization, as a normative template that may be used to characterize atypical development.

A joint brain extraction and image quality assessment framework for fetal brain MRI slices.

Brain extraction and image quality assessment are two fundamental steps in fetal brain magnetic resonance imaging (MRI) 3D reconstruction and quantification. However, the randomness of fetal position and orientation, the variability of fetal brain morphology, maternal organs around the fetus, and the scarcity of data samples, all add excessive noise and impose a great challenge to automated brain extraction and quality assessment of fetal MRI slices. Conventionally, brain extraction and quality assessment are typically performed independently. However, both of them focus on the brain image representation, so they can be jointly optimized to ensure the network learns more effective features and avoid overfitting. To this end, we propose a novel two-stage dual-task deep learning framework with a brain localization stage and a dual-task stage for joint brain extraction and quality assessment of fetal MRI slices. Specifically, the dual-task module compactly contains a feature extraction module, a quality assessment head and a segmentation head with feature fusion for simultaneous brain extraction and quality assessment. Besides, a transformer architecture is introduced into the feature extraction module and the segmentation head. We utilize a multi-step training strategy to guarantee a stable and successful training of all modules. Finally, we validate our method by a 5-fold cross-validation and ablation study on a dataset with fetal brain MRI slices in different qualities, and perform a cross-dataset validation in addition. Experiments show that the proposed framework achieves very promising performance.

Anatomically constrained tractography of the fetal brain.

Diffusion-weighted Magnetic Resonance Imaging (dMRI) is increasingly used to study the fetal brain in utero. An important computation enabled by dMRI is streamline tractography, which has unique applications such as tract-specific analysis of the brain white matter and structural connectivity assessment. However, due to the low fetal dMRI data quality and the challenging nature of tractography, existing methods tend to produce highly inaccurate results. They generate many false streamlines while failing to reconstruct the streamlines that constitute the major white matter tracts. In this paper, we advocate for anatomically constrained tractography based on an accurate segmentation of the fetal brain tissue directly in the dMRI space. We develop a deep learning method to compute the segmentation automatically. Experiments on independent test data show that this method can accurately segment the fetal brain tissue and drastically improve the tractography results. It enables the reconstruction of highly curved tracts such as optic radiations. Importantly, our method infers the tissue segmentation and streamline propagation direction from a diffusion tensor fit to the dMRI data, making it applicable to routine fetal dMRI scans. The proposed method can facilitate the study of fetal brain white matter tracts with dMRI.

Altered thalamocortical tract trajectory growth with undisrupted thalamic parcellation pattern in human lissencephaly brain at mid-gestational stage.

Proper topographically organized neural connections between the thalamus and the cerebral cortex are mandatory for thalamus function. Thalamocortical (TC) fiber growth begins during the embryonic period and completes by the third trimester of gestation, so that human neonates at birth have a thalamus with a near-facsimile of adult functional parcellation. Whether congenital neocortical anomaly (e.g., lissencephaly) affects TC connection in humans is unknown. Here, via diffusion MRI fiber-tractography analysis of long-term formalin-fixed postmortem fetal brain diagnosed as lissencephaly in comparison with an age-matched normal one, we found similar topological patterns of thalamic subregions and of internal capsule parcellated by TC fibers. However, lissencephaly fetal brain showed white matter structural changes, including fewer/less organized TC fibers and optic radiations, and much less cortical plate invasion by TC fibers - particularly around the shallow central sulcus. Diffusion MRI fiber tractography of normal fetal brains at 15, 23, and 26 gestational weeks (GW) revealed dynamic volumetric change of each parcellated thalamic subregion, suggesting coupled developmental progress of the thalamus with the corresponding cortex. Moreover, from GW23 and GW26 normal fetal brains, TC endings in the cortical plate could be delineated to reflect cumulative progressive TC invasion of cortical plate. By contrast, lissencephaly brain showed a dramatic decrease in TC invasion of the cortical plate. Our study thus shows the feasibility of diffusion MRI fiber tractography in postmortem long-term formalin-fixed fetal brains to disclose the developmental progress of TC tracts coordinating with thalamic and neocortical growth both in normal and lissencephaly fetal brains at mid-gestational stage.

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment.

BACKGROUND: The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. METHODS AND RESULTS: We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls. CONCLUSION: These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.

Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders.

Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.

Pathological shifts in tryptophan metabolism in human term placenta exposed to LPS or poly I:C†.

Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (lipopolysaccharides/LPS) and viral (polyinosinic:polycytidylic acid/poly I:C) placental infection on TRP metabolism using an ex vivo model. Human placenta explants were exposed to LPS or poly I:C, and the release of TRP metabolites was analyzed together with the expression of related genes and proteins and the functional activity of key enzymes in TRP metabolism. The rate-limiting enzyme in the serotonin pathway, tryptophan hydroxylase, showed reduced expression and functional activity in explants exposed to LPS or poly I:C. Conversely, the rate-limiting enzyme in the kynurenine pathway, indoleamine dioxygenase, exhibited increased activity, gene, and protein expression, suggesting that placental infection mainly promotes TRP metabolism via the kynurenine (KYN) pathway. Furthermore, we observed that treatment with LPS or poly I:C increased activity in the kynurenine monooxygenase branch of the KYN pathway. We conclude that placental infection impairs TRP homeostasis, resulting in decreased production of serotonin and an imbalance in the ratio between quinolinic acid and kynurenic acid. This disrupted homeostasis may eventually expose the fetus to suboptimal/toxic levels of neuroactive molecules and impair fetal brain development.

In vivo T2 measurements of the fetal brain using single-shot fast spin echo sequences.

PURPOSE: We propose a quantitative framework for motion-corrected T2 fetal brain measurements in vivo and validate the single-shot fast spin echo (SS-FSE) sequence to perform these measurements. METHODS: Stacks of two-dimensional SS-FSE slices are acquired with different echo times (TE) and motion-corrected with slice-to-volume reconstruction (SVR). The quantitative T2 maps are obtained by a fit to a dictionary of simulated signals. The sequence is selected using simulated experiments on a numerical phantom and validated on a physical phantom scanned on a 1.5T system. In vivo quantitative T2 maps are obtained for five fetuses with gestational ages (GA) 21-35 weeks on the same 1.5T system. RESULTS: The simulated experiments suggested that a TE of 400 ms combined with the clinically utilized TEs of 80 and 180 ms were most suitable for T2 measurements in the fetal brain. The validation on the physical phantom confirmed that the SS-FSE T2 measurements match the gold standard multi-echo spin echo measurements. We measured average T2s of around 200 and 280 ms in the fetal brain grey and white matter, respectively. This was slightly higher than fetal T2* and the neonatal T2 obtained from previous studies. CONCLUSION: The motion-corrected SS-FSE acquisitions with varying TEs offer a promising practical framework for quantitative T2 measurements of the moving fetus.

High-resolution anatomical imaging of the fetal brain with a reduced field of view using outer volume suppression.

PURPOSE: To achieve high-resolution fetal brain anatomical imaging without introducing image artifacts by reducing the FOV, and to demonstrate improved image quality compared to conventional full-FOV fetal brain imaging. METHODS: Reduced FOV was achieved by applying outer volume suppression (OVS) pulses immediately prior to standard single-shot fast spin echo (SSFSE) imaging. In the OVS preparation, a saturation RF pulse followed by a gradient spoiler was repeated three times with optimized flip-angle weightings and a variable spoiler scheme to enhance signal suppression. Simulations and phantom and in-vivo experiments were performed to evaluate OVS performance. In-vivo high-resolution SSFSE images acquired using the proposed approach were compared with conventional and high-resolution SSFSE images with a full FOV, using image quality scores assessed by neuroradiologists and calculated image metrics. RESULTS: Excellent signal suppression in the saturation bands was confirmed in phantom and in-vivo experiments. High-resolution SSFSE images with a reduced FOV acquired using OVS demonstrated the improved depiction of brain structures without significant motion and blurring artifacts. The proposed method showed the highest image quality scores in the criteria of sharpness, contrast, and artifact and was selected as the best method based on overall image quality. The calculated image sharpness and tissue contrast ratio were also the highest with the proposed method. CONCLUSION: High-resolution fetal brain anatomical images acquired using a reduced FOV with OVS demonstrated improved image quality both qualitatively and quantitatively, suggesting the potential for enhanced diagnostic accuracy in detecting fetal brain abnormalities in utero.

Fully automated planning for anatomical fetal brain MRI on 0.55T.

PURPOSE: Widening the availability of fetal MRI with fully automatic real-time planning of radiological brain planes on 0.55T MRI. METHODS: Deep learning-based detection of key brain landmarks on a whole-uterus echo planar imaging scan enables the subsequent fully automatic planning of the radiological single-shot Turbo Spin Echo acquisitions. The landmark detection pipeline was trained on over 120 datasets from varying field strength, echo times, and resolutions and quantitatively evaluated. The entire automatic planning solution was tested prospectively in nine fetal subjects between 20 and 37 weeks. A comprehensive evaluation of all steps, the distance between manual and automatic landmarks, the planning quality, and the resulting image quality was conducted. RESULTS: Prospective automatic planning was performed in real-time without latency in all subjects. The landmark detection accuracy was 4.2 ± $$ \pm $$ 2.6 mm for the fetal eyes and 6.5 ± $$ \pm $$ 3.2 for the cerebellum, planning quality was 2.4/3 (compared to 2.6/3 for manual planning) and diagnostic image quality was 2.2 compared to 2.1 for manual planning. CONCLUSIONS: Real-time automatic planning of all three key fetal brain planes was successfully achieved and will pave the way toward simplifying the acquisition of fetal MRI thereby widening the availability of this modality in nonspecialist centers.

Reproducibility of Diffusion MRI-Based Tractography in the Fetal Brain.

BACKGROUND: Tractography based on diffusion MRI (dMRI) is a useful tool to study white matter of the developing brain. However, its application in fetal brains is limited due to motion artifacts and low resolution of in utero dMRI, leading to reduced reliability, which was scarcely investigated in previous studies. PURPOSE: To identify reliably traceable fibers in fetal brains and assess whether reproducibility varies with gestational age (GA) and varies between brain regions. STUDY TYPE: Prospective cohort study. SUBJECTS: A total of 44 healthy fetuses with GAs between 25 and 37 (31 ± 6). FIELD STRENGTH/SEQUENCE: 3-T, diffusion-weighted echo-planar imaging sequence (2-5 repeated dMRI scans within the same session per subject). ASSESSMENT: We fitted dMRI with constrained spherical deconvolution model and conducted tractography on eight fibers. We extracted volume, fractional anisotropy, and fiber count for each fiber and assessed the reproducibility of these metrics between repeated scans within each subject. Data were divided into two age-based subgroups (≤30 weeks, N = 28, and >30 weeks, N = 16) for further tests. STATISTICAL TESTS: The reproducibility were compared between fibers by analysis of variance and two-sample t tests. Multiple comparisons were corrected by the false discovery rate (5% was accepted). RESULTS: The reproducibility of the anterior thalamic radiation, inferior longitudinal fasciculus (ILF), genu of the corpus callosum (GCC), and body of the corpus callosum (BCC) significantly decreased with advancing GA (correlation coefficient = 0.525-0.823), as confirmed by group comparisons between fetuses in early GA (≤30 weeks) and late GA (>30 weeks) groups. Corticospinal tract, inferior fronto-occipital fasciculus, and GCC showed high reproducibility for fiber count (weighted dice average = 0.846 vs. 0.814), while BCC and ILF exhibited the lowest reproducibility in both age groups. DATA CONCLUSION: The study indicates that the reliability of fetal brain tractography depends on GA and varies among different fibers. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Quantifying Brain Myelin Water Fraction in a Guinea Pig Model of Spontaneous Intrauterine Growth Restriction.

BACKGROUND: Intrauterine growth restriction (IUGR) is an obstetrical condition where a fetus has not achieved its genetic potential. A consequence of IUGR is a decrease in brain myelin content. Myelin water imaging (MWI) has been used to assess fetal myelin water fraction (MWF) and might potentially assess myelination changes associated with IUGR. PURPOSE: To quantify and compare the MWF of non-IUGR and IUGR fetal guinea pigs (GPs) in late gestation. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Dunkin-Hartley GP model of spontaneous IUGR (mean ± SD: 60 ± 1.2 days gestation; 19 IUGR, 52 control). FIELD STRENGTH/SEQUENCE: Eight spoiled gradient-recalled (SPGR) gradient echo volumes (flip angles [α]: 2°-16°), and two sets of eight balanced steady-state free precession (bSSFP) gradient echo volumes (α: 8° - 64°), at 0° and 180° phase increments, at 3.0 T. ASSESSMENT: MWF maps were generated for each fetal GP brain using multicomponent driven equilibrium single pulse observation of T1 /T2 (mcDESPOT). MWF was quantified in the fetal corpus callosum (CC), fornix (FOR), parasagittal white matter (PSW), and whole fetal brain. STATISTICAL TESTS: Linear regression was performed between five fetal IUGR markers (body volume, body-to-pregnancy volume ratio, brain-to-liver volume ratio, brain-to-placenta volume ratio, and brain-to-body volume ratio) and MWF (coefficient of determination, R2 ). A t-test with a linear mixed model compared the MWF of non-IUGR and IUGR fetal GPs (significance was determined at α < 0.05). RESULTS: The MWF of the control fetuses are (mean ± SD): 0.23 ± 0.02 (CC), 0.31 ± 0.02 (FOR), 0.28 ± 0.02 (PSW), and 0.20 ± 0.01 (whole brain). The MWF of the IUGR fetuses are (mean ± SD): 0.19 ± 0.02 (CC), 0.27 ± 0.01 (FOR), 0.24 ± 0.03 (PSW), and 0.16 ± 0.01 (whole brain). Significant differences in MWF were found between the non-IUGR and IUGR fetuses in every comparison. DATA CONCLUSION: The mean MWF of IUGR fetal GPs is significantly lower than non-IUGR fetal GPs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

T2*-Relaxometry MRI to Assess Third Trimester Placental and Fetal Brain Oxygenation and Placental Characteristics in Healthy Fetuses and Fetuses With Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) has been linked to impaired placental and fetal brain development. Assessing the placenta and fetal brain in parallel may help further our understanding of the relationship between development of these organs. HYPOTHESIS: 1) Placental and fetal brain oxygenation are correlated, 2) oxygenation in these organs is reduced in CHD compared to healthy controls, and 3) placental structure is altered in CHD. STUDY TYPE: Retrospective case-control. POPULATION: Fifty-one human fetuses with CHD (32 male; median [IQR] gestational age [GA] = 32.0 [30.9-32.9] weeks) and 30 from uncomplicated pregnancies with normal birth outcomes (18 male; median [IQR] GA = 34.5 [31.9-36.7] weeks). FIELD STRENGTH/SEQUENCE: 1.5 T single-shot multi-echo-gradient-echo echo-planar imaging. ASSESSMENT: Masking was performed using an automated nnUnet model. Mean brain and placental T2* and quantitative measures of placental texture, volume, and morphology were calculated. STATISTICAL TESTS: Spearman's correlation coefficient for determining the association between brain and placental T2*, and between brain and placental characteristics with GA. P-values for comparing brain T2*, placenta T2*, and placental characteristics between groups derived from ANOVA. Significance level P < 0.05. RESULTS: There was a significant positive association between placental and fetal brain T2* (⍴ = 0.46). Placental and fetal brain T2* showed a significant negative correlation with GA (placental T2* ⍴ = -0.65; fetal brain T2* ⍴ = -0.32). Both placental and fetal brain T2* values were significantly reduced in CHD, after adjusting for GA (placental T2*: control = 97 [±24] msec, CHD = 83 [±23] msec; brain T2*: control = 218 [±26] msec, CHD = 202 [±25] msec). Placental texture and morphology were also significantly altered in CHD (Texture: control = 0.84 [0.83-0.87], CHD = 0.80 [0.78-0.84]; Morphology: control = 9.9 [±2.2], CHD = 10.8 [±2.0]). For all fetuses, there was a significant positive association between placental T2* and placental texture (⍴ = 0.46). CONCLUSION: Placental and fetal brain T2* values are associated in healthy fetuses and those with CHD. Placental and fetal brain oxygenation are reduced in CHD. Placental appearance is significantly altered in CHD and shows associations with placental oxygenation, suggesting altered placental development and function may be related. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Evidence of brain injury in fetuses of mothers with preterm labor with intact membranes and preterm premature rupture of membranes.

BACKGROUND: Brain injury and poor neurodevelopment have been consistently reported in infants and adults born before term. These changes occur, at least in part, prenatally and are associated with intra-amniotic inflammation. The pattern of brain changes has been partially documented by magnetic resonance imaging but not by neurosonography along with amniotic fluid brain injury biomarkers. OBJECTIVE: This study aimed to evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm premature rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a risk mediator. STUDY DESIGN: In this prospective cohort study, fetal brain remodeling and injury were evaluated using neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm premature rupture of membranes between 24.0 and 34.0 weeks of gestation, with (n=41) and without (n=54) intra-amniotic inflammation. The controls for neurosonography were outpatient pregnant patients without preterm labor or preterm premature rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm premature rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin 6 concentrations of >13.4 ng/mL in preterm labor and >1.43 ng/mL in preterm premature rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. Neuron-specific enolase, protein S100B, and glial fibrillary acidic protein were selected as amniotic fluid brain injury biomarkers. Data were adjusted for cephalic biometrics, fetal growth percentile, fetal sex, noncephalic presentation, and preterm premature rupture of membranes at admission. RESULTS: Fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes showed signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in the intra-amniotic inflammation, non-intra-amniotic inflammation, and control groups, the transcerebellar diameter measurements were 32.7 mm (interquartile range, 29.8-37.6), 35.3 mm (interquartile range, 31.2-39.6), and 35.0 mm (interquartile range, 31.3-38.3), respectively (P=.019), and the vermian height measurements were 16.9 mm (interquartile range, 15.5-19.6), 17.2 mm (interquartile range, 16.0-18.9), and 17.1 mm (interquartile range, 15.7-19.0), respectively (P=.041). Second, they presented a lower corpus callosum area (0.72 mm2 [interquartile range, 0.59-0.81], 0.71 mm2 [interquartile range, 0.63-0.82], and 0.78 mm2 [interquartile range, 0.71-0.91], respectively; P=.006). Third, they showed delayed cortical maturation (the Sylvian fissure depth-to-biparietal diameter ratios were 0.14 [interquartile range, 0.12-0.16], 0.14 [interquartile range, 0.13-0.16], and 0.16 [interquartile range, 0.15-0.17], respectively [P<.001], and the right parieto-occipital sulci depth ratios were 0.09 [interquartile range, 0.07-0.12], 0.11 [interquartile range, 0.09-0.14], and 0.11 [interquartile range, 0.09-0.14], respectively [P=.012]). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes had higher concentrations of neuron-specific enolase (11,804.6 pg/mL [interquartile range, 6213.4-21,098.8], 8397.7 pg/mL [interquartile range, 3682.1-17,398.3], and 2393.7 pg/mL [interquartile range, 1717.1-3209.3], respectively; P<.001), protein S100B (2030.6 pg/mL [interquartile range, 993.0-4883.5], 1070.3 pg/mL [interquartile range, 365.1-1463.2], and 74.8 pg/mL [interquartile range, 44.7-93.7], respectively; P<.001), and glial fibrillary acidic protein (1.01 ng/mL [interquartile range, 0.54-3.88], 0.965 ng/mL [interquartile range, 0.59-2.07], and 0.24 mg/mL [interquartile range, 0.20-0.28], respectively; P=.002). CONCLUSION: Fetuses with preterm labor with intact membranes or preterm premature rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in fetuses with intra-amniotic inflammation.

Nurturing development: how a mother's nutrition shapes offspring's brain through the gut.

Pregnancy is a transformative period marked by profound physical and emotional changes, with far-reaching consequences for both mother and child. Emerging research has illustrated the pivotal role of a mother's diet during pregnancy in influencing the prenatal gut microbiome and subsequently shaping the neurodevelopment of her offspring. The intricate interplay between maternal gut health, nutrition, and neurodevelopmental outcomes has emerged as a captivating field of investigation within developmental science. Acting as a dynamic bridge between mother and fetus, the maternal gut microbiome, directly and indirectly, impacts the offspring's neurodevelopment through diverse pathways. This comprehensive review delves into a spectrum of studies, clarifying putative mechanisms through which maternal nutrition, by modulating the gut microbiota, orchestrates the early stages of brain development. Drawing insights from animal models and human cohorts, this work underscores the profound implications of maternal gut health for neurodevelopmental trajectories and offers a glimpse into the formulation of targeted interventions able to optimize the health of both mother and offspring. The prospect of tailored dietary recommendations for expectant mothers emerges as a promising and accessible intervention to foster the growth of beneficial gut bacteria, potentially leading to enhanced cognitive outcomes and reduced risks of neurodevelopmental disorders.

Fetal brain development in pregnancies complicated by gestational diabetes mellitus.

OBJECTIVES: Gestational diabetes mellitus (GDM) carries an increased risk of neurocognitive impairment in offsprings. However, the contribution of maternal hyperglycemia in affecting fetal brain development is not fully elucidated yet. The aim of this study was to evaluate fetal brain and sulci development in pregnancies complicated by GDM. METHODS: Prospective observational study including 100 singleton pregnancies complicated by GDM and 100 matched controls. All fetuses underwent neurosonography at 29-34 weeks of gestation, including the assessment of the length of the corpus callosum (CC), cerebellar vermis (CV), Sylvian (SF), parieto-occipital (POF) and calcarine fissures (CF). Sub-group analysis according to the specific treatment regimen adopted (n 67 diet vs. 33 insulin therapy) was also performed. RESULTS: Fetuses from mothers with GDM under insulin therapy had a smaller CC (35.54 mm) compared to both controls (40 mm; p<0.001) and women with GDM under diet (39.26 mm; p=0.022) while there was no difference in the HC between the groups. Likewise, when corrected for HC, CV depth was smaller in fetuses with GDM both under insulin therapy (7.03 mm) and diet (7.05 mm,) compared to controls (7.36 mm; p=0.013). Finally, when assessing the sulci development of the brain SF (p≤0.0001), POF (p≤0.0001) and CF (p≤0.0001) were significantly smaller in fetuses with maternal GDM. Post-hoc analysis showed that fetuses of GDM mothers requiring insulin therapy had significantly lower values of SF (p=0.032), POF (p=0.016) and CF (p=0.001). CONCLUSIONS: Pregnancies complicated by GDM showed a peculiar pattern of fetal brain growth and cortical development and these changes, which are more evident in those requiring insulin supplementation.

Fetal Cerebral Ventriculomegaly: A Narrative Review and Practical Recommendations for Pediatric Neurologists.

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists.

Sensorless volumetric reconstruction of fetal brain freehand ultrasound scans with deep implicit representation.

Three-dimensional (3D) ultrasound imaging has contributed to our understanding of fetal developmental processes by providing rich contextual information of the inherently 3D anatomies. However, its use is limited in clinical settings, due to the high purchasing costs and limited diagnostic practicality. Freehand 2D ultrasound imaging, in contrast, is routinely used in standard obstetric exams, but inherently lacks a 3D representation of the anatomies, which limits its potential for more advanced assessment. Such full representations are challenging to recover even with external tracking devices due to internal fetal movement which is independent from the operator-led trajectory of the probe. Capitalizing on the flexibility offered by freehand 2D ultrasound acquisition, we propose ImplicitVol to reconstruct 3D volumes from non-sensor-tracked 2D ultrasound sweeps. Conventionally, reconstructions are performed on a discrete voxel grid. We, however, employ a deep neural network to represent, for the first time, the reconstructed volume as an implicit function. Specifically, ImplicitVol takes a set of 2D images as input, predicts their locations in 3D space, jointly refines the inferred locations, and learns a full volumetric reconstruction. When testing natively-acquired and volume-sampled 2D ultrasound video sequences collected from different manufacturers, the 3D volumes reconstructed by ImplicitVol show significantly better visual and semantic quality than the existing interpolation-based reconstruction approaches. The inherent continuity of implicit representation also enables ImplicitVol to reconstruct the volume to arbitrarily high resolutions. As formulated, ImplicitVol has the potential to integrate seamlessly into the clinical workflow, while providing richer information for diagnosis and evaluation of the developing brain.

Agreement between Fetal Brain Ultrasonography and Magnetic Resonance Imaging in the Measurements of the Corpus Callosum and Transverse Cerebellar Diameter.

As the use of magnetic resonance imaging of the fetal brain has evolved, the need to understand its efficiency in the biometry of the fetal brain has broadened. This study aimed to assess the level of agreement and correlation between the two cardinal imaging methods of fetal neuroimaging, ultrasonography (US) and magnetic resonance imaging (MRI), by measuring the corpus callosum (CC) and transverse cerebellar diameter (TCD) in terms of length and percentile. Measurements of CC and TCD length and percentile were documented over a 7-year span in a tertiary referral medical center. All US and MRI examinations were performed in the customary planes and subcategorized by valid reference charts. Exclusion and inclusion criteria were set before the collection and processing of the data. A total of 156 fetuses out of 483 were included in the study. A positive, strong correlation and agreement were found (r = 0.78; ICC = 0.76) between US and MRI in TCD measurements. For CC length measurement, a moderate correlation and moderate agreement (r = 0.51; ICC = 0.49) between US and MRI was observed. TCD and CC percentiles had lower levels of correlation and agreement compared with the length variables. Our study indicates good agreement between MRI and US in the assessment of TCD measurement as a part of antenatal neuroimaging. Furthermore, while the two techniques are not always compatible, they are complementary methods.