Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum

We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders

3D global and regional patterns of human fetal subplate growth determined in utero

The waiting period of subplate evolution is a critical phase for the proper formation of neural connections in the brain. During this time, which corresponds to 15 to 24 postconceptual weeks (PCW) in the human fetus, thalamocortical and cortico-cortical afferents wait in and are in part guided by molecules embedded in the extracellular matrix of the subplate. Recent advances in fetal MRI techniques now allow us to study the developing brain anatomy in 3D from in utero imaging. We describe a reliable segmentation protocol to delineate the boundaries of the subplate from T2-W MRI. The reliability of the protocol was evaluated in terms of intra-rater reproducibility on a subset of the subjects. We also present the first 3D quantitative analyses of temporal changes in subplate volume, thickness, and contrast from 18 to 24 PCW. Our analysis shows that firstly, global subplate volume increases in proportion with the supratentorial volume; the subplate remained approximately one-third of supratentorial volume. Secondly, we found both global and regional growth in subplate thickness and a linear increase in the median and maximum subplate thickness through the waiting period. Furthermore, we found that posterior regions—specifically the occipital pole, ventral occipito-temporal region, and planum temporale—of the developing brain underwent the most statistically significant increases in subplate thickness. During this period, the thickest region was the developing somatosensory/motor cortex. The subplate growth patterns reported here may be used as a baseline for comparison to abnormal fetal brain development

Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum

We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders

A spatio-temporal atlas of the developing fetal brain with spina bifida aperta

Background: Spina bifida aperta (SBA) is a birth defect associated with severe anatomical changes in the developing fetal brain. Brain magnetic resonance imaging (MRI) atlases are popular tools for studying neuropathology in the brain anatomy, but previous fetal brain MRI atlases have focused on the normal fetal brain. We aimed to develop a spatio-temporal fetal brain MRI atlas for SBA. Methods: We developed a semi-automatic computational method to compute the first spatio-temporal fetal brain MRI atlas for SBA. We used 90 MRIs of fetuses with SBA with gestational ages ranging from 21 to 35 weeks. Isotropic and motion-free 3D reconstructed MRIs were obtained for all the examinations. We propose a protocol for the annotation of anatomical landmarks in brain 3D MRI of fetuses with SBA with the aim of making spatial alignment of abnormal fetal brain MRIs more robust. In addition, we propose a weighted generalized Procrustes method based on the anatomical landmarks for the initialization of the atlas. The proposed weighted generalized Procrustes can handle temporal regularization and missing annotations. After initialization, the atlas is refined iteratively using non-linear image registration based on the image intensity and the anatomical land-marks. A semi-automatic method is used to obtain a parcellation of our fetal brain atlas into eight tissue types: white matter, ventricular system, cerebellum, extra-axial cerebrospinal fluid, cortical gray matter, deep gray matter, brainstem, and corpus callosum. Results: An intra-rater variability analysis suggests that the seven anatomical land-marks are sufficiently reliable. We find that the proposed atlas outperforms a normal fetal brain atlas for the automatic segmentation of brain 3D MRI of fetuses with SBA. Conclusions: We make publicly available a spatio-temporal fetal brain MRI atlas for SBA, available here: https://doi.org/10.7303/syn25887675. This atlas can support future research on automatic segmentation methods for brain 3D MRI of fetuses with SBA

A spatio-temporal atlas of the developing fetal brain with spina bifida aperta

Background: Spina bifida aperta (SBA) is a birth defect associated with severe anatomical changes in the developing fetal brain. Brain magnetic resonance imaging (MRI) atlases are popular tools for studying neuropathology in the brain anatomy, but previous fetal brain MRI atlases have focused on the normal fetal brain. We aimed to develop a spatio-temporal fetal brain MRI atlas for SBA. Methods: We developed a semi-automatic computational method to compute the first spatio-temporal fetal brain MRI atlas for SBA. We used 90 MRIs of fetuses with SBA with gestational ages ranging from 21 to 35 weeks. Isotropic and motion-free 3D reconstructed MRIs were obtained for all the examinations. We propose a protocol for the annotation of anatomical landmarks in brain 3D MRI of fetuses with SBA with the aim of making spatial alignment of abnormal fetal brain MRIs more robust. In addition, we propose a weighted generalized Procrustes method based on the anatomical landmarks for the initialization of the atlas. The proposed weighted generalized Procrustes can handle temporal regularization and missing annotations. After initialization, the atlas is refined iteratively using non-linear image registration based on the image intensity and the anatomical land-marks. A semi-automatic method is used to obtain a parcellation of our fetal brain atlas into eight tissue types: white matter, ventricular system, cerebellum, extra-axial cerebrospinal fluid, cortical gray matter, deep gray matter, brainstem, and corpus callosum. Results: An intra-rater variability analysis suggests that the seven anatomical land-marks are sufficiently reliable. We find that the proposed atlas outperforms a normal fetal brain atlas for the automatic segmentation of brain 3D MRI of fetuses with SBA. Conclusions: We make publicly available a spatio-temporal fetal brain MRI atlas for SBA, available here: https://doi.org/10.7303/syn25887675. This atlas can support future research on automatic segmentation methods for brain 3D MRI of fetuses with SBA

Current state of MRI of the fetal brain in utero.

In this article we provide an overview of fetal brain development, describe the range of more common fetal neuropathology, and discuss the relevance of in utero MR (iuMR). Although ultrasonography remains the mainstay of fetal brain imaging, iuMR imaging is both feasible and safe, but presents several challenges. We discuss those challenges, the techniques employed to overcome them, and new approaches that may extend the clinical applicability of fetal iuMR

Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth

Registration of 3D fetal neurosonography and MRI.

We propose a method for registration of 3D fetal brain ultrasound with a reconstructed magnetic resonance fetal brain volume. This method, for the first time, allows the alignment of models of the fetal brain built from magnetic resonance images with 3D fetal brain ultrasound, opening possibilities to develop new, prior information based image analysis methods for 3D fetal neurosonography. The reconstructed magnetic resonance volume is first segmented using a probabilistic atlas and a pseudo ultrasound image volume is simulated from the segmentation. This pseudo ultrasound image is then affinely aligned with clinical ultrasound fetal brain volumes using a robust block-matching approach that can deal with intensity artefacts and missing features in the ultrasound images. A qualitative and quantitative evaluation demonstrates good performance of the method for our application, in comparison with other tested approaches. The intensity average of 27 ultrasound images co-aligned with the pseudo ultrasound template shows good correlation with anatomy of the fetal brain as seen in the reconstructed magnetic resonance image

Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1 . We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2 , selected using World Health Organization recommendations for growth standards3 . Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5 . The atlas was produced using 1,059 optimal quality, three dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6–8 . The atlas corresponds structurally to published magnetic resonance images9 , but with finer anatomical details in deep grey matter. The between study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks’ gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks’ gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment