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In utero exposure to maternal stress, anxiety, and depression has been associated with reduced cortical thickness (CT), and CT changes, in turn, to adverse neuropsychiatric outcomes. Here, we investigated global and regional (G/RCT) changes associated with fetal exposure to maternal psychological distress in 265 brain MRI studies from 177 healthy fetuses of low-risk pregnant women. GCT was measured from cortical gray matter (CGM) voxels; RCT was estimated from 82 cortical regions. GCT and RCT in 87% of regions strongly correlated with GA. Fetal exposure was most strongly associated with RCT in the parahippocampal region, ventromedial prefrontal cortex, and supramarginal gyrus suggesting that cortical alterations commonly associated with prenatal exposure could emerge in-utero. However, we note that while regional fetal brain involvement conformed to patterns observed in newborns and children exposed to prenatal maternal psychological distress, the reported associations did not survive multiple comparisons correction. This could be because the effects are more subtle in this early developmental window or because majority of the pregnant women in our study did not experience high levels of maternal distress. It is our hope that the current findings will spur future hypothesis-driven studies that include a full spectrum of maternal mental health scores.

Recent advances in functional magnetic resonance imaging (fMRI) have helped elucidate previously inaccessible trajectories of early-life prenatal and neonatal brain development. To date, the interpretation of fetal–neonatal fMRI data has relied on linear analytic models, akin to adult neuroimaging data. However, unlike the adult brain, the fetal and newborn brain develops extraordinarily rapidly, far outpacing any other brain development period across the life span. Consequently, conventional linear computational models may not adequately capture these accelerated and complex neurodevelopmental trajectories during this critical period of brain development along the prenatal-neonatal continuum. To obtain a nuanced understanding of fetal–neonatal brain development, including nonlinear growth, for the first time, we developed quantitative, systems-wide representations of brain activity in a large sample (>500) of fetuses, preterm, and full-term neonates using an unsupervised deep generative model called variational autoencoder (VAE), a model previously shown to be superior to linear models in representing complex resting-state data in healthy adults. Here, we demonstrated that nonlinear brain features, that is, latent variables, derived with the VAE pretrained on rsfMRI of human adults, carried important individual neural signatures, leading to improved representation of prenatal-neonatal brain maturational patterns and more accurate and stable age prediction in the neonate cohort compared to linear models. Using the VAE decoder, we also revealed distinct functional brain networks spanning the sensory and default mode networks. Using the VAE, we are able to reliably capture and quantify complex, nonlinear fetal–neonatal functional neural connectivity. This will lay the critical foundation for detailed mapping of healthy and aberrant functional brain signatures that have their origins in fetal life.

An important step in the preprocessing of resting state functional magnetic resonance images (rs-fMRI) is the separation of brain from non-brain voxels. Widely used imaging tools such as FSL’s BET2 and AFNI’s 3dSkullStrip accomplish this task effectively in children and adults. In fetal functional brain imaging, however, the presence of maternal tissue around the brain coupled with the non-standard position of the fetal head limit the usefulness of these tools. Accurate brain masks are thus generated manually, a time-consuming and tedious process that slows down preprocessing of fetal rs-fMRI. Recently, deep learning-based segmentation models such as convolutional neural networks (CNNs) have been increasingly used for automated segmentation of medical images, including the fetal brain. Here, we propose a computationally efficient end-to-end generative adversarial neural network (GAN) for segmenting the fetal brain. This method, which we call FetalGAN, yielded whole brain masks that closely approximated the manually labeled ground truth. FetalGAN performed better than 3D U-Net model and BET2: FetalGAN, Dice score = 0.973 ± 0.013, precision = 0.977 ± 0.015; 3D U-Net, Dice score = 0.954 ± 0.054, precision = 0.967 ± 0.037; BET2, Dice score = 0.856 ± 0.084, precision = 0.758 ± 0.113. FetalGAN was also faster than 3D U-Net and the manual method (7.35 s vs. 10.25 s vs. ∼5 min/volume). To the best of our knowledge, this is the first successful implementation of 3D CNN with GAN on fetal fMRI brain images and represents a significant advance in fully automating processing of rs-MRI images.