Meta-regression of sulcal patterns, clinical and environmental factors on neurodevelopmental outcomes in participants with multiple CHD types.

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change ß = 0.7, false discovery rate P = 0.004; ß = 4.1, false discovery rate P = 0.03; and ß = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.

The role of cortical structural variance in deep learning-based prediction of fetal brain age.

Background: Deep-learning-based brain age estimation using magnetic resonance imaging data has been proposed to identify abnormalities in brain development and the risk of adverse developmental outcomes in the fetal brain. Although saliency and attention activation maps have been used to understand the contribution of different brain regions in determining brain age, there has been no attempt to explain the influence of shape-related cortical structural features on the variance of predicted fetal brain age. Methods: We examined the association between the predicted brain age difference (PAD: predicted brain age-chronological age) from our convolution neural networks-based model and global and regional cortical structural measures, such as cortical volume, surface area, curvature, gyrification index, and folding depth, using regression analysis. Results: Our results showed that global brain volume and surface area were positively correlated with PAD. Additionally, higher cortical surface curvature and folding depth led to a significant increase in PAD in specific regions, including the perisylvian areas, where dramatic agerelated changes in folding structures were observed in the late second trimester. Furthermore, PAD decreased with disorganized sulcal area patterns, suggesting that the interrelated arrangement and areal patterning of the sulcal folds also significantly affected the prediction of fetal brain age. Conclusion: These results allow us to better understand the variance in deep learning-based fetal brain age and provide insight into the mechanism of the fetal brain age prediction model.

Automatic cortical surface parcellation in the fetal brain using attention-gated spherical U-net.

Cortical surface parcellation for fetal brains is essential for the understanding of neurodevelopmental trajectories during gestations with regional analyses of brain structures and functions. This study proposes the attention-gated spherical U-net, a novel deep-learning model designed for automatic cortical surface parcellation of the fetal brain. We trained and validated the model using MRIs from 55 typically developing fetuses [gestational weeks: 32.9 ± 3.3 (mean ± SD), 27.4-38.7]. The proposed model was compared with the surface registration-based method, SPHARM-net, and the original spherical U-net. Our model demonstrated significantly higher accuracy in parcellation performance compared to previous methods, achieving an overall Dice coefficient of 0.899 ± 0.020. It also showed the lowest error in terms of the median boundary distance, 2.47 ± 1.322 (mm), and mean absolute percent error in surface area measurement, 10.40 ± 2.64 (%). In this study, we showed the efficacy of the attention gates in capturing the subtle but important information in fetal cortical surface parcellation. Our precise automatic parcellation model could increase sensitivity in detecting regional cortical anomalies and lead to the potential for early detection of neurodevelopmental disorders in fetuses.

A Prospective Multi-Institutional Study Comparing the Brain Development in the Third Trimester between Opioid-Exposed and Nonexposed Fetuses Using Advanced Fetal MR Imaging Techniques.

BACKGROUND AND PURPOSE: While the adverse neurodevelopmental effects of prenatal opioid exposure on infants and children in the United States are well described, the underlying causative mechanisms have yet to be fully understood. This study aims to compare quantitative volumetric and surface-based features of the fetal brain between opioid-exposed fetuses and unexposed controls by using advanced MR imaging processing techniques. MATERIALS AND METHODS: This is a multi-institutional IRB-approved study in which pregnant women with and without opioid use during the current pregnancy were prospectively recruited to undergo fetal MR imaging. A total of 14 opioid-exposed (31.4 ± 2.3 weeks of gestation) and 15 unexposed (31.4 ± 2.4 weeks) fetuses were included. Whole brain volume, cortical plate volume, surface area, sulcal depth, mean curvature, and gyrification index were computed as quantitative features by using our fetal brain MR imaging processing pipeline. RESULTS: After correcting for gestational age, fetal sex, maternal education, polysubstance use, high blood pressure, and MR imaging acquisition site, all of the global morphologic features were significantly lower in the opioid-exposed fetuses compared with the unexposed fetuses, including brain volume, cortical volume, cortical surface area, sulcal depth, cortical mean curvature, and gyrification index. In regional analysis, the opioid-exposed fetuses showed significantly decreased surface area and sulcal depth in the bilateral Sylvian fissures, central sulci, parieto-occipital fissures, temporal cortices, and frontal cortices. CONCLUSIONS: In this small cohort, prenatal opioid exposure was associated with altered fetal brain development in the third trimester. This adds to the growing body of literature demonstrating that prenatal opioid exposure affects the developing brain.

Association between placental oxygen transport and fetal brain cortical development: a study in monochorionic diamniotic twins.

Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors, environmental factors in fetal life can modify the gene expression associated with brain development. As the placenta plays a vital role in shaping the fetal environment, affecting fetal growth through the exchange of oxygen and nutrients, placental oxygen transport might be one of the environmental factors that also affect early human cortical growth. In this study, we aimed to assess the placental oxygen transport during maternal hyperoxia and its impact on fetal brain development using MRI in identical twins to control for genetic and maternal factors. We enrolled 9 pregnant subjects with monochorionic diamniotic twins (30.03 ± 2.39 gestational weeks [mean ± SD]). We observed that the fetuses with slower placental oxygen delivery had reduced volumetric and surface growth of the cerebral cortex. Moreover, when the difference between placenta oxygen delivery increased between the twin pairs, sulcal folding patterns were more divergent. Thus, there is a significant relationship between placental oxygen transport and fetal brain cortical growth and folding in monochorionic twins.

Morphological Features of Language Regions in Individuals with Tuberous Sclerosis Complex.

A significant number of individuals with tuberous sclerosis complex (TSC) exhibit language difficulties. Here, we examined the language-related brain morphometry in 59 participants (7 participants with TSC and comorbid autism spectrum disorder (ASD) (TSC + ASD), 13 with TSC but no ASD (TSC-ASD), 10 with ASD-only (ASD), and 29 typically developing (TD) controls). A hemispheric asymmetry was noted in surface area and gray matter volume of several cortical language areas in TD, ASD, and TSC-ASD groups, but not in TSC + ASD group. TSC + ASD group demonstrated increased cortical thickness and curvature values in multiple language regions for both hemispheres, compared to other groups. After controlling for tuber load in the TSC groups, within-group differences stayed the same but the differences between TSC-ASD and TSC + ASD were no longer statistically significant. These preliminary findings suggest that comorbid ASD in TSC as well as tuber load in TSC is associated with changes in the morphometry of language regions. Future studies with larger sample sizes will be needed to confirm these findings.

Comprehensive quantitative analyses of fetal magnetic resonance imaging in isolated cerebral ventriculomegaly.

Isolated cerebral ventriculomegaly (IVM) is the most common prenatally diagnosed brain anomaly occurs in 0.2-1 % of pregnancies. However, knowledge of fetal brain development in IVM is limited. There is no prenatal predictor for IVM to estimate individual risk of neurodevelopmental disability occurs in 10 % of children. To characterize brain development in fetuses with IVM and delineate their individual neuroanatomical variances, we performed comprehensive post-acquisition quantitative analysis of fetal magnetic resonance imaging (MRI). In volumetric analysis, brain MRI of fetuses with IVM (n = 20, 27.0 ± 4.6 weeks of gestation, mean ± SD) had revealed significantly increased volume in the whole brain, cortical plate, subcortical parenchyma, and cerebrum compared to the typically developing fetuses (controls, n = 28, 26.3 ± 5.0). In the cerebral sulcal developmental pattern analysis, fetuses with IVM had altered sulcal positional (both hemispheres) development and combined features of sulcal positional, depth, basin area, in both hemispheres compared to the controls. When comparing distribution of similarity index of individual fetuses, IVM group had shifted toward to lower values compared to the control. About 30 % of fetuses with IVM had no overlap with the distribution of control fetuses. This proof-of-concept study shows that quantitative analysis of fetal MRI can detect emerging subtle neuroanatomical abnormalities in fetuses with IVM and their individual variations.

Quantification of sulcal emergence timing and its variability in early fetal life: Hemispheric asymmetry and sex difference.

Human fetal brains show regionally different temporal patterns of sulcal emergence following a regular timeline, which may be associated with spatiotemporal patterns of gene expression among cortical regions. This study aims to quantify the timing of sulcal emergence and its temporal variability across typically developing fetuses by fitting a logistic curve to presence or absence of sulcus. We found that the sulcal emergence started from the central to the temporo-parieto-occipital lobes and frontal lobe, and the temporal variability of emergence in most of the sulci was similar between 1 and 2 weeks. Small variability (< 1 week) was found in the left central and postcentral sulci and larger variability (>2 weeks) was shown in the bilateral occipitotemporal and left superior temporal sulci. The temporal variability showed a positive correlation with the emergence timing that may be associated with differential contributions between genetic and environmental factors. Our statistical analysis revealed that the right superior temporal sulcus emerged earlier than the left. Female fetuses showed a trend of earlier sulcal emergence in the right superior temporal sulcus, lower temporal variability in the right intraparietal sulcus, and higher variability in the right precentral sulcus compared to male fetuses. Our quantitative and statistical approach quantified the temporal patterns of sulcal emergence in detail that can be a reference for assessing the normality of developing fetal gyrification.

Regional brain development in fetuses with Dandy-Walker malformation: A volumetric fetal brain magnetic resonance imaging study.

Dandy-Walker malformation (DWM) is a common prenatally diagnosed cerebellar malformation, characterized by cystic dilatation of the fourth ventricle, upward rotation of the hypoplastic vermis, and posterior fossa enlargement with torcular elevation. DWM is associated with a broad spectrum of neurodevelopmental abnormalities such as cognitive, motor, and behavioral impairments, which cannot be explained solely by cerebellar malformations. Notably, the pathogenesis of these symptoms remains poorly understood. This study investigated whether fetal structural developmental abnormalities in DWM extended beyond the posterior fossa to the cerebrum even in fetuses without apparent cerebral anomalies. Post-acquisition volumetric fetal magnetic resonance imaging (MRI) analysis was performed in 12 fetuses with DWM and 14 control fetuses. Growth trajectories of the volumes of the cortical plate, subcortical parenchyma, cerebellar hemispheres, and vermis between 18 and 33 weeks of gestation were compared. The median (interquartile range) gestational ages at the time of MRI were 22.4 (19.4-24.0) and 23.9 (20.6-29.2) weeks in the DWM and control groups, respectively (p = 0.269). Eight of the 12 fetuses with DWM presented with associated cerebral anomalies, including hydrocephalus (n = 3), cerebral ventriculomegaly (n = 3), and complete (n = 2) and partial (n = 2) agenesis of the corpus callosum (ACC); 7 presented with extracerebral abnormalities. Chromosomal abnormalities were detected by microarray analysis in 4 of 11 fetuses with DWM, using amniocentesis. Volumetric analysis revealed that the cortical plate was significantly larger in fetuses with DWM than in controls (p = 0.040). Even without ACC, the subcortical parenchyma, whole cerebrum, cerebellar hemispheres, and whole brain were significantly larger in fetuses with DWM (n = 8) than in controls (p = 0.004, 0.025, 0.033, and 0.026, respectively). In conclusion, volumetric fetal MRI analysis demonstrated that the development of DWM extends throughout the brain during the fetal period, even without apparent cerebral anomalies.

Optimal Method for Fetal Brain Age Prediction Using Multiplanar Slices From Structural Magnetic Resonance Imaging.

The accurate prediction of fetal brain age using magnetic resonance imaging (MRI) may contribute to the identification of brain abnormalities and the risk of adverse developmental outcomes. This study aimed to propose a method for predicting fetal brain age using MRIs from 220 healthy fetuses between 15.9 and 38.7 weeks of gestational age (GA). We built a 2D single-channel convolutional neural network (CNN) with multiplanar MRI slices in different orthogonal planes without correction for interslice motion. In each fetus, multiple age predictions from different slices were generated, and the brain age was obtained using the mode that determined the most frequent value among the multiple predictions from the 2D single-channel CNN. We obtained a mean absolute error (MAE) of 0.125 weeks (0.875 days) between the GA and brain age across the fetuses. The use of multiplanar slices achieved significantly lower prediction error and its variance than the use of a single slice and a single MRI stack. Our 2D single-channel CNN with multiplanar slices yielded a significantly lower stack-wise MAE (0.304 weeks) than the 2D multi-channel (MAE = 0.979, p < 0.001) and 3D (MAE = 1.114, p < 0.001) CNNs. The saliency maps from our method indicated that the anatomical information describing the cortex and ventricles was the primary contributor to brain age prediction. With the application of the proposed method to external MRIs from 21 healthy fetuses, we obtained an MAE of 0.508 weeks. Based on the external MRIs, we found that the stack-wise MAE of the 2D single-channel CNN (0.743 weeks) was significantly lower than those of the 2D multi-channel (1.466 weeks, p < 0.001) and 3D (1.241 weeks, p < 0.001) CNNs. These results demonstrate that our method with multiplanar slices accurately predicts fetal brain age without the need for increased dimensionality or complex MRI preprocessing steps.

Abnormal Right-Hemispheric Sulcal Patterns Correlate with Executive Function in Adolescents with Tetralogy of Fallot.

Neurodevelopmental disabilities are the most common noncardiac conditions in patients with congenital heart disease (CHD). Executive function skills have been frequently observed to be decreased among children and adults with CHD compared with peers, but a neuroanatomical basis for the association is yet to be identified. In this study, we quantified sulcal pattern features from brain magnetic resonance imaging data obtained during adolescence among 41 participants with tetralogy of Fallot (ToF) and 49 control participants using a graph-based pattern analysis technique. Among patients with ToF, right-hemispheric sulcal pattern similarity to the control group was decreased (0.7514 vs. 0.7553, P = 0.01) and positively correlated with neuropsychological testing values including executive function (r = 0.48, P < 0.001). Together these findings suggest that sulcal pattern analysis may be a useful marker of neurodevelopmental risk in patients with CHD. Further studies may elucidate the mechanisms leading to different alterations in sulcal patterning.

Association between Quantitative MR Markers of Cortical Evolving Organization and Gene Expression during Human Prenatal Brain Development.

The relationship between structural changes of the cerebral cortex revealed by Magnetic Resonance Imaging (MRI) and gene expression in the human fetal brain has not been explored. In this study, we aimed to test the hypothesis that relative regional thickness (a measure of cortical evolving organization) of fetal cortical compartments (cortical plate [CP] and subplate [SP]) is associated with expression levels of genes with known cortical phenotype. Mean regional SP/CP thickness ratios across age measured on in utero MRI of 25 healthy fetuses (20-33 gestational weeks [GWs]) were correlated with publicly available regional gene expression levels (23-24 GW fetuses). Larger SP/CP thickness ratios (more pronounced cortical evolving organization) was found in perisylvian regions. Furthermore, we found a significant association between SP/CP thickness ratio and expression levels of the FLNA gene (mutated in periventricular heterotopia, congenital heart disease, and vascular malformations). Further work is needed to identify early MRI biomarkers of gene expression that lead to abnormal cortical development.

Abnormal Left-Hemispheric Sulcal Patterns in Adults With Simple Congenital Heart Defects Repaired in Childhood.

Background Children operated on for a simple congenital heart defect (CHD) are at risk of neurodevelopmental abnormalities. Abnormal cortical development and folding have been observed in fetuses with CHD. We examined whether sulcal folding patterns in adults operated on for simple CHD in childhood differ from those of healthy controls, and whether such differences are associated with neuropsychological outcomes. Methods and Results Patients (mean age, 24.5 years) who underwent childhood surgery for isolated atrial septal defect (ASD; n=33) or ventricular septal defect (VSD; n=30) and healthy controls (n=37) were enrolled. Sulcal pattern similarity to healthy controls was determined using magnetic resonance imaging and looking at features of sulcal folds, their intersulcal relationships, and sulcal graph topology. The sulcal pattern similarity values were tested for associations with comprehensive neuropsychological scores. Patients with both ASD and VSD had decreased sulcal pattern similarity in the left hemisphere compared with controls. The differences were found in the left temporal lobe in the ASD group and in the whole left hemisphere in the VSD group (P=0.033 and P=0.039, respectively). The extent of abnormal left hemispheric sulcal pattern similarity was associated with worse neuropsychological scores (intelligence, executive function, and visuospatial abilities) in the VSD group, and special educational support in the ASD group. Conclusions Adults who underwent surgery for simple CHD in childhood display altered left hemisphere sulcal folding patterns, commensurate with neuropsychological scores for patients with VSD and special educational support for ASD. This may indicate that simple CHD affects early brain development. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871881.

Regional Alterations in Cortical Sulcal Depth in Living Fetuses with Down Syndrome.

Down syndrome (DS) is the most common genetic cause of developmental disabilities. Advanced analysis of brain magnetic resonance imaging (MRI) has been used to find brain abnormalities and their relationship to neurocognitive impairments in children and adolescents with DS. Because genetic factors affect brain development in early fetal life, there is a growing interest in analyzing brains from living fetuses with DS. In this study, we investigated regional sulcal folding depth as well as global cortical gyrification from fetal brain MRIs. Nine fetuses with DS (29.1 ± 4.24 gestational weeks [mean ± standard deviation]) were compared with 17 typically developing [TD] fetuses (28.4 ± 3.44). Fetuses with DS showed lower whole-brain average sulcal depths and gyrification index than TD fetuses. Significant decreases in sulcal depth were found in bilateral Sylvian fissures and right central and parieto-occipital sulci. On the other hand, significantly increased sulcal depth was shown in the left superior temporal sulcus, which is related to atypical hemispheric asymmetry of cortical folding. Moreover, these group differences increased as gestation progressed. This study demonstrates that regional sulcal depth is a sensitive marker for detecting alterations of cortical development in DS during fetal life, which may be associated with later neurocognitive impairment.

Fetal Cortical Plate Segmentation Using Fully Convolutional Networks With Multiple Plane Aggregation.

Fetal magnetic resonance imaging (MRI) has the potential to advance our understanding of human brain development by providing quantitative information of cortical plate (CP) development in vivo. However, for a reliable quantitative analysis of cortical volume and sulcal folding, accurate and automated segmentation of the CP is crucial. In this study, we propose a fully convolutional neural network for the automatic segmentation of the CP. We developed a novel hybrid loss function to improve the segmentation accuracy and adopted multi-view (axial, coronal, and sagittal) aggregation with a test-time augmentation method to reduce errors using three-dimensional (3D) information and multiple predictions. We evaluated our proposed method using the ten-fold cross-validation of 52 fetal brain MR images (22.9-31.4 weeks of gestation). The proposed method obtained Dice coefficients of 0.907 ± 0.027 and 0.906 ± 0.031 as well as a mean surface distance error of 0.182 ± 0.058 mm and 0.185 ± 0.069 mm for the left and right, respectively. In addition, the left and right CP volumes, surface area, and global mean curvature generated by automatic segmentation showed a high correlation with the values generated by manual segmentation (R 2 > 0.941). We also demonstrated that the proposed hybrid loss function and the combination of multi-view aggregation and test-time augmentation significantly improved the CP segmentation accuracy. Our proposed segmentation method will be useful for the automatic and reliable quantification of the cortical structure in the fetal brain.

An Atypical Sulcal Pattern in Children with Disorders of the Corpus Callosum and Its Relation to Behavioral Outcomes.

Hypogenesis (hCC) and dysgenesis (dCC) of the corpus callosum (CC) are characterized by its smaller size or absence. The outcomes of these patients vary considerably and are unrelated to the size of the CC abnormality. The aim of the current study was to characterize the sulcal pattern in children with hCC and dCC and to explore its relation to clinical outcome. We used quantitative sulcal pattern analysis that measures deviation (similarity index, SI) of the composite or individual sulcal features (position, depth, area, and graph topology) compared to the control group. We calculated SI for each hemisphere and lobe in 11 children with CC disorder (hCC = 4, dCC = 7) and 15 controls. hCC and dCC had smaller hemispheric SI compared to controls. dCC subjects had smaller regional SI in the frontal and occipital lobes, which were driven by a smaller SI in a position or a graph topology. The significantly decreased SI gradient was found across groups only in the sulcal graph topology of the temporal lobes (controls > hCC > dCC) and was related to clinical outcome. Our results suggest that careful examination of sulcal pattern in hCC and dCC patients could be a useful biomarker of outcome.

Spatiotemporal Differences in the Regional Cortical Plate and Subplate Volume Growth during Fetal Development.

The regional specification of the cerebral cortex can be described by protomap and protocortex hypotheses. The protomap hypothesis suggests that the regional destiny of cortical neurons and the relative size of the cortical area are genetically determined early during embryonic development. The protocortex hypothesis suggests that the regional growth rate is predominantly shaped by external influences. In order to determine regional volumes of cortical compartments (cortical plate (CP) or subplate (SP)) and estimate their growth rates, we acquired T2-weighted in utero MRIs of 40 healthy fetuses and grouped them into early (<25.5 GW), mid- (25.5-31.6 GW), and late (>31.6 GW) prenatal periods. MRIs were segmented into CP and SP and further parcellated into 22 gyral regions. No significant difference was found between periods in regional volume fractions of the CP or SP. However, during the early and mid-prenatal periods, we found significant differences in relative growth rates (% increase per GW) between regions of cortical compartments. Thus, the relative size of these regions are most likely conserved and determined early during development whereas more subtle growth differences between regions are fine-tuned later, during periods of peak thalamocortical growth. This is in agreement with both the protomap and protocortex hypothesis.

Temporal Patterns of Emergence and Spatial Distribution of Sulcal Pits During Fetal Life.

Sulcal pits are thought to represent the first cortical folds of primary sulci during neurodevelopment. The uniform spatial distribution of sulcal pits across individuals is hypothesized to be predetermined by a human-specific protomap which is related to functional localization under genetic controls in early fetal life. Thus, it is important to characterize temporal and spatial patterns of sulcal pits in the fetal brain that would provide additional information of functional development of the human brain and crucial insights into abnormal cortical maturation. In this paper, we investigated temporal patterns of emergence and spatial distribution of sulcal pits using 48 typically developing fetal brains in the second half of gestation. We found that the position and spatial variance of sulcal pits in the fetal brain are similar to those in the adult brain, and they are also temporally uniform against dynamic brain growth during fetal life. Furthermore, timing of pit emergence shows a regionally diverse pattern that may be associated with the subdivisions of the protomap. Our findings suggest that sulcal pits in the fetal brain are useful anatomical landmarks containing detailed information of functional localization in early cortical development and maintaining their spatial distribution throughout the human lifetime.

Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P < 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.