Fetal brain growth portrayed by a spatiotemporal diffusion tensor MRI atlas computed from in utero images

Abstract

Altered structural fetal brain development has been linked to neuro-developmental disorders. These structural alterations can be potentially detected in utero using diffusion tensor imaging (DTI). However, acquisition and reconstruction of in utero fetal brain DTI remains challenging. Until now, motion-robust DTI methods have been employed for reconstruction of in utero fetal DTIs. However, due to the unconstrained fetal motion and permissible in utero acquisition times, these methods yielded limited success and have typically resulted in noisy DTIs. Consequently, atlases and methods that could enable groupwise studies, multi-modality imaging, and computer-aided diagnosis from in utero DTIs have not yet been developed. This paper presents the first DTI atlas of the fetal brain computed from in utero diffusion-weighted images. For this purpose an algorithm for computing an unbiased spatiotemporal DTI atlas, which integrates kernel-regression in age with a diffeomorphic tensor-to-tensor registration of motion-corrected and reconstructed individual fetal brain DTIs, was developed. Our new algorithm was applied to a set of 67 fetal DTI scans acquired from healthy fetuses each scanned at a gestational age between 21 and 39 weeks. The neurodevelopmental trends in the fetal brain, characterized by the atlas, were qualitatively and quantitatively compared with the observations reported in prior ex vivo and in utero studies, and with results from imaging gestational-age equivalent preterm infants. Our major findings revealed early presence of limbic fiber bundles, followed by the appearance and maturation of projection pathways (characterized by an age related increase in FA) during late 2nd and early 3rd trimesters. During the 3rd trimester association fiber bundles become evident. In parallel with the appearance and maturation of fiber bundles, from 21 to 39 gestational weeks gradual disappearance of the radial coherence of the telencephalic wall was qualitatively identified. These results and analyses show that our DTI atlas of the fetal brain is useful for reliable detection of major neuronal fiber bundle pathways and for characterization of the fetal brain reorganization that occurs in utero. The atlas can also serve as a useful resource for detection of normal and abnormal fetal brain development in utero.

Plot of individual subject FA at multiple ROIs.

Plot of individual subject MD at multiple ROIs.

Fig. 1:

Block diagram representing the T2-weighted (T2w) structural image processing pipeline. Multiple anisotropic T2w images are acquired in orthogonal views. A slice-to-volume registration approach used within an iterative model-based super-resolution framework is employed to reconstruct an isotropic T2w image (T₂S). The reconstructed image is brain-extracted, registered with a preexisting image (at the corresponding age) from the fetal brain atlas to bring it into a standard space.

Fig. 2:

Block diagram representing diffusion-weighted imaging processing pipeline: For each DWI scan, 1 b=0 and 12 b≠0 images are acquired. All non-diffusion-sensitive images (b=0) from multiple scans are merged using a superresolution approach shown in Fig. 1 to construct a composite isotropic C0 image. C1 image is similarly computed using b≠0 images. C0 or C1 image is registered to the isotropic reconstructed T2-weighted image (T₂S) of the same fetus; the resulting transformation is stored as Tr_B0→S. Subsequently, all slices from b=0 and b≠0 images are registered to the C0 and C1 images respectively and the resulting transformations are stored as Tr_b=0→C0. Finally, all DWI slices are transformed using a composite Tr _b=0→A) transform and a pointspread-function (PSF) based tensor fitting approach is used to compute the DTI for the fetal subject.

Fig. 3:

An illustration on regression of tensor-valued data on a manifold M using kernel-regression approach. Steps involved in the computation have been presented in Algorithm 1.

Fig. 4:

Number of fetal scans used in atlas construction at different gestational age points.

Fig. 5:

Region-of-interest (ROI) selection for fractional anisotropy sampling: 27 voxels of relatively high intensity on FA images were chosen within each ROI. The ROIs are shown over a template from the atlas. Label descriptions are available in the ‘Abbreviations’ subsection under Methods.

Fig. 6:

Axial, coronal, and sagittal views of fractional anisotropy (grayscale) and color fractional anisotropy templates from the in-utero DTI atlas. Gestational age in weeks is mentioned below the images.

Fig. 7:

Color fractional anisotropy maps showing various fiber-rich structures labeled at the end of the 2^nd trimester at GA-27w (a), and at the end of the 3^rd trimester at GA-38w (b) respectively. Label descriptions are available in the ‘Abbreviations’ section.

Fig. 8:

Fractional Anisotropy (FA) (y-axis, unitless) plotted against the gestational age (x-axis, in weeks) for major fiber pathway structures. The FA values and trends observed in our atlas are in agreement with previously published ex vivo, preterm infant and in utero studies. The abbreviation used in the figure for fiber structures have been described in the Methods section.

Fig. 9:

Fractional Anisotropy (FA) and mean diffusivity (MD) in the cortical plate, plotted against gestational age (in weeks). While FA shows decreasing trend with gestational age, MD reaches a peak between 28 and 32 gestational weeks.

Fig. 10:

A panel of primary eigenvectors of diffusion tensors projected on the right-half coronal plane located in the vicinity of genu of the internal capsule, with inferior section in the temporal lobe and superior section at the boundary of frontal and parietal lobe. Age in gestational weeks is shown below each image. Initial radial organization of cortical plate and subplate, indicated by the primary eigenvectors of the diffusion tensors directed towards the ventricles at 22w, gradually disappears with an increase in gestational age. The reduction in the radial coherence appears to affect various brain regions differently; reduction in inferior region (temporal lobe) appears near-complete at 36 weeks, as compared to the superior region (fronto-parietal lobe) which appears to have significantly reduced radial coherence at GA-34w. Moreover, note that the radial coherence of cortical plate and subplate in central regions, marked at 22w, starts to disappear in regions of deep subplate zone first (26–28w). The reduction in radial coherence parallels appearance of long association fibers (arrows). The borders between transient fetal zones (CP, SP, IZ) were identified in the underlying FA images, and are marked by an oblique line. Abbreviations: cortical plate (CP), subplate (SP), intermediate zone (IZ), and fetal white matter (WM). Borders are approximate and were identified visually on the underlying FA and T2 images by a neuro-anatomist (LV) with expertise in delineating transient fetal zones on MR and histology images.

Fig. 11:

Medial migratory steam of inhibitory neurons migrating from anterior tip of the lateral ventricle to the medial prefrontal cortex has been shown (on the right) on a color FA template computed at GA-33w. The zoomed in view on the left shows the projection of principal eigenvectors of the diffusion tensors in this area on the sagittal plane visualized in this figure. The red bounding line was hand drawn over the medial migratory stream.