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.

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.
OBJECTIVE: To identify reliably traceable fibers in fetal brains and assess whether reproducibility varies with gestational age (GA) and varies between brain regions.
METHODS: Prospective cohort study.
METHODS: A total of 44 healthy fetuses with GAs between 25 and 37 (31 ± 6).
UNASSIGNED: 3-T, diffusion-weighted echo-planar imaging sequence (2-5 repeated dMRI scans within the same session per subject).
RESULTS: 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.
METHODS: 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.
CONCLUSIONS: The study indicates that the reliability of fetal brain tractography depends on GA and varies among different fibers.
METHODS: 2 TECHNICAL EFFICACY: Stage 2.

UNASSIGNED: Cortical neural progenitor cells possess the capacity to differentiate into both excitatory and inhibitory neurons. However, the precise proportions in which these progenitor cells differentiate remain unclear.
UNASSIGNED: Human fetal prefrontal cortical tissues were collected at various fetal stages and cultured in vitro. Bulk and single-cell RNA sequencing techniques were employed to analyze the resulting neuronal cell types, cell proportions, and the expression levels of cell-type marker genes.
UNASSIGNED: The culture of fetal prefrontal cortex tissues obtained at gestation weeks 11 and 20 predominantly consisted of excitatory and inhibitory neurons, respectively. This abrupt transition in cell proportions was primarily driven by the differential lineage specificity of neural progenitors in the fetal cortical tissues at distinct stages of fetal brain development. Additionally, it was observed that the transcriptional profiles of cultured fetal cortical tissues were strongly influenced by the presence of FGF2.
UNASSIGNED: This study presents a novel strategy to obtain excitatory and inhibitory neuronal cells from the culture of fetal cortical tissues. The findings shed light on the mechanisms underlying neurogenesis and provide an approach that might contribute to future research investigating the pathophysiology of various neural disorders.

Prenatal quantitative evaluation of myelin is important. However, few techniques are suitable for the quantitative evaluation of fetal myelination.
To optimize a modified Look-Locker inversion recovery (MOLLI) T1 mapping sequence for fetal brain development study.
Prospective observational preliminary cohort study.
A total of 71 women with normal fetuses divided into mid-pregnancy (gestational age 24-28 weeks, N = 25) and late pregnancy (gestational age > 28 weeks, N = 46) groups.
A 3 T/MOLLI sequence.
T1 values were measured in pedunculus cerebri, basal ganglia, thalamus, posterior limb of the internal capsule, temporal white matter, occipital white matter, frontal white matter, and parietal white matter by two radiologists (11 and 16 years of experience, respectively).
The Kruskal-Wallis test was used for reginal comparison. For each region of interest (ROI), differences in T1 values between the mid and late pregnancy groups were assessed by the Mann Whitney U test. Pearson correlation coefficients (r) were used to evaluate the correlations between T1 values and gestational age for each ROI. Intraobserver and interobserver agreement was determined by the intraclass correlation coefficient (ICC). A P value <0.05 was considered statistically significant.
Interobserver and intraobserver agreements of T1 were good for all ROIs (all ICCs > 0.700). There were significant differences in T1 values between lobal white matter and deep regions, respectively. Significant T1 values differences were found between middle and late pregnancy groups in pedunculus cerebri, basal ganglion, thalamus, posterior limb of the internal capsule, temporal, and occipital white matter. The T1 values showed significantly negative correlations with gestational weeks in pedunculus cerebri (r = -0.80), basal ganglion (r = -0.60), thalamus (r = -0.68), and posterior limb of the internal capsule (r = -0.77).
The T1 values of fetal brain may be assessed using the MOLLI sequence and may reflect the myelination.
3 TECHNICAL EFFICACY: Stage 2.

Brain atlases are of fundamental importance for analyzing the dynamic neurodevelopment in fetal brain studies. Since the brain size, shape, and anatomical structures change rapidly during the prenatal period, it is essential to construct a spatiotemporal (4D) atlas equipped with tissue probability maps, which can preserve sharper early brain folding patterns for accurately characterizing dynamic changes in fetal brains and provide tissue prior informations for related tasks, e.g., segmentation, registration, and parcellation. In this work, we propose a novel unsupervised age-conditional learning framework to build temporally continuous fetal brain atlases by incorporating tissue segmentation maps, which outperforms previous traditional atlas construction methods in three aspects. First, our framework enables learning age-conditional deformable templates by leveraging the entire collection. Second, we leverage reliable brain tissue segmentation maps in addition to the low-contrast noisy intensity images to enhance the alignment of individual images. Third, a novel loss function is designed to enforce the similarity between the learned tissue probability map on the atlas and each subject tissue segmentation map after registration, thereby providing extra anatomical consistency supervision for atlas building. Our 4D temporally-continuous fetal brain atlases are constructed based on 82 healthy fetuses from 22 to 32 gestational weeks. Compared with the atlases built by the state-of-the-art algorithms, our atlases preserve more structural details and sharper folding patterns. Together with the learned tissue probability maps, our 4D fetal atlases provide a valuable reference for spatial normalization and analysis of fetal brain development.

Faster and motion robust magnetic resonance imaging (MRI) sequences are desirable in fetal brain MRI. T1-weighted images are essential for evaluating fetal brain development. We optimized the radial volumetric interpolated breath-hold examination (VIBE) sequence for qualitative T1-weighted images of the fetal brain with improved image contrast and reduced motion sensitivity.
This was an institutional review board-approved prospective study. Thirty-five pregnant subjects underwent fetal brain scan at 3 Tesla MRI. T1-weighted images were acquired using a 3D radial VIBE sequence with flip angles of 6º, 9º, 12º, and 15º. T1-weighted images of Cartesian VIBE sequence were acquired in three of the subjects. Qualitative assessments including image quality and motion artifact severity were evaluated. The image contrast ratio between gray and white matter were measured. Interobserver reliability and intraobserver repeatability were assessed using intraclass correlation coefficient (ICC).
Interobserver reliability and intraobserver repeatability universally revealed almost perfect agreement (ICC > 0.800). Significant differences in image quality were detected in basal ganglia (P = 0.023), central sulcus (P = 0.028), myelination (P = 0.007) and gray matter (P = 0.023) among radial VIBE with flip angles 6º, 9º, 12º, 15º. Image quality at the 9º flip angle in radial VIBE was generally better than flip angle of 15º. Radial VIBE sequence with 9º flip angle of gray matter was significantly different by gestational age (GA) before and after 28 weeks (P = 0.036). Quantified image contrast was significantly different among different flip angles, consistent with qualitative analysis of image quality.
Three-dimensional radial VIBE with 9º flip angle provides optimal, stable T1-weighted images of the fetal brain. Fetal brain structure and development can be evaluated using high-quality images obtained using this angle. However, different scanners will achieve different TRs and so the FA should be re-optimized each time a new protocol is employed.

Fetal Magnetic Resonance Imaging (MRI) is challenged by the fetal movements and maternal breathing. Although fast MRI sequences allow artifact free acquisition of individual 2D slices, motion commonly occurs in between slices acquisitions. Motion correction for each slice is thus very important for reconstruction of 3D fetal brain MRI, but is highly operator-dependent and time-consuming. Approaches based on convolutional neural networks (CNNs) have achieved encouraging performance on prediction of 3D motion parameters of arbitrarily oriented 2D slices, which, however, does not capitalize on important brain structural information. To address this problem, we propose a new multi-task learning framework to jointly learn the transformation parameters and tissue segmentation map of each slice, for providing brain anatomical information to guide the mapping from 2D slices to 3D volumetric space in a coarse to fine manner. In the coarse stage, the first network learns the features shared for both regression and segmentation tasks. In the refinement stage, to fully utilize the anatomical information, distance maps constructed based on the coarse segmentation are introduced to the second network. Finally, incorporation of the signed distance maps to guide the regression and segmentation together improves the performance in both tasks. Experimental results indicate that the proposed method achieves superior performance in reducing the motion prediction error and obtaining satisfactory tissue segmentation results simultaneously, compared with state-of-the-art methods.

Several published studies have shown alterations of brain development in third-trimester fetuses with congenital heart disease (CHD). However, little is known about the timing and pattern of altered brain development in fetuses with CHD.
To investigate the changes in the volume of intracranial structures in fetuses with CHD by three-dimensional (3D) volumetric magnetic resonance imaging (MRI) in the earlier stages of pregnancy (median gestational age [GA], 26 weeks).
Retrospective.
Forty women carrying a fetus with CHD (including 20 fetuses with GA <26 weeks) and 120 pregnant women carrying a healthy fetus (including 50 fetuses with GA <26 weeks).
Two-dimensional single-shot turbo spin echo sequence at 1.5 -T.
Three-dimensional volumetric parameters from slice-to-volume registered images, including cortical gray matter volume (GMV), subcortical brain tissue volume (SBV), intracranial cavity volume (ICV), lateral ventricles volume (VV), cerebellum, brainstem, and extra-cerebrospinal fluid (e-CSF) were quantified by manual segmentation from one primary and two secondary observers.
Volumes were presented graphically with quadratic curve fitting. Scatterplots were produced mapping volumes against GA in normal and CHD fetuses. For GA <26 weeks, Z scores were calculated and Student\'s t-tests were conducted to compare volumes between the normal and CHD fetuses.
In fetuses with CHD GMV, SBV, cerebellum, and brainstem were significantly reduced (all P < 0.05) in early stages of pregnancy (GA <26 weeks), with differences becoming progressively greater with increasing GA. Compared with normal fetuses, e-CSF, e-CSF to ICV ratio, and VV were higher in fetuses with CHD (all P < 0.05). However, ICV volume and the GMV to SBV ratio were not significantly reduced in the CHD group (P = 0.94 and P = 0.13, respectively) during the middle gestation (GA <26 weeks).
There appear to be alterations of brain development trajectory in CHD fetuses that can be detected by 3D volumetric MRI in the earlier stages of pregnancy.
4 TECHNICAL EFFICACY: Stage 3.

Ingestion of nanoparticles may cause various damages to human body. However, how such ingestion by pregnant mother influences fetal development is not known because, presumably, ingested nanoparticles have to cross multiple biological barriers (such as intestinal and placental) to reach fetus. To answer this crucial question, here we investigated how a relatively biocompatible zirconia nanoparticles (ZrO2 NPs, 16 nm) were translocated to fetal brains in three exposure models of pregnant mice: Model 1, oral exposure of nanoparticles before maternal blood-placental barrier (BPB) was fully developed; Model 2, exposures after BPB was developed, but before fetal blood-brain-barrier (BBB) was fully developed; Model 3, exposures after both maternal BPB and fetal BBB were fully developed. Our experimental results showed that translocation of ZrO2 NPs into fetal brains was 55 % higher in Model 2 and 96 % higher in Model 1 compared with that in Model 3 after nanoparticles (50 mg/kg) were orally exposed to pregnant mice. Therefore, nanoparticles are able to cross multiple biological barriers and nanotoxicity to fetus is highly dependent on stages of pregnancy and fetal development or the maturity of multiple biological barriers. Oral exposures to nanoparticles during pregnancy are dangerous to fetal brain development, especially in early pregnancy.

To construct international ultrasound-based standards for fetal cerebellar growth and Sylvian fissure maturation.
Healthy, well nourished pregnant women, enrolled at < 14 weeks\' gestation in the Fetal Growth Longitudinal Study (FGLS) of INTERGROWTH-21st , an international multicenter, population-based project, underwent serial three-dimensional (3D) fetal ultrasound scans every 5 ± 1 weeks until delivery in study sites located in Brazil, India, Italy, Kenya and the UK. In the present analysis, only those fetuses that underwent developmental assessment at 2 years of age were included. We measured the transcerebellar diameter and assessed Sylvian fissure maturation using two-dimensional ultrasound images extracted from available 3D fetal head volumes. The appropriateness of pooling data from the five sites was assessed using variance component analysis and standardized site differences. For each Sylvian fissure maturation score (left or right side), mean gestational age and 95% CI were calculated. Transcerebellar diameter was modeled using fractional polynomial regression, and goodness of fit was assessed.
Of those children in the original FGLS cohort who had developmental assessment at 2 years of age, 1130 also had an available 3D ultrasound fetal head volume. The sociodemographic characteristics and pregnancy/perinatal outcomes of the study sample confirmed the health and low-risk status of the population studied. In addition, the fetuses had low morbidity and adequate growth and development at 2 years of age. In total, 3016 and 2359 individual volumes were available for transcerebellar-diameter and Sylvian-fissure analysis, respectively. Variance component analysis and standardized site differences showed that the five study populations were sufficiently similar on the basis of predefined criteria for the data to be pooled to produce international standards. A second-degree fractional polynomial provided the best fit for modeling transcerebellar diameter; we then estimated gestational-age-specific 3rd , 50th and 97th smoothed centiles. Goodness-of-fit analysis comparing empirical centiles with smoothed centile curves showed good agreement. The Sylvian fissure increased in maturation with advancing gestation, with complete overlap of the mean gestational age and 95% CIs between the sexes for each development score. No differences in Sylvian fissure maturation between the right and left hemispheres were observed.
We present, for the first time, international standards for fetal cerebellar growth and Sylvian fissure maturation throughout pregnancy based on a healthy fetal population that exhibited adequate growth and development at 2 years of age. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.