Gaining insight of fetal brain development with diffusion MRI and histology

Abstract

Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic levels. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns.

Keywords: Cerebral wall; Connectivity; DTI; Development; Fetal brain; Histology; Tractography; White matter.

Fig. 1

Striking morphological changes from the 4th wg to the 40th wg. The reconstruction of the 4th wg is adapted from the textbook (Chapter 2 of Nolte, 1999). Many questions on micro- and macroscopic structural changes from a “tubular” structure at the 4^th wg to an extremely complicated human brain at birth remain unanswered. The pink color indicates the cerebrum or corresponding prosencephalon at earlier stage. The light purple color indicates the brain stem and cerebellum or corresponding rhombencephalon at earlier stage.

Figure 2

Outline of DTI data acquisition, tensor fitting, DTI-derived quantification maps and DTI-based tractography of an in vivo preterm neonate brain at 32 weeks of gestation.

Figure 3

Coronal images of FA map (upper row) and mapping of FA on the cortical surface (middle row) of 13wg, 15wg, 17wg, 19wg and 21wg fetal brain from left to right. The three layers, marked with “1”, “2” and “3”, can be clearly differentiated from all cerebral wall of 13wg to 21wg fetal brains with FA contrasts. Layer 1, 2 and 3 indicate cortical plate, subplate and inner layer (the cerebral wall compartment between ventricle and subplate), respectively. The heterogeneous FA decrease patterns of three representative cortical regions, VFC, S1C and IPC, are shown in the lower row. The decrease line in the lower row is averaged from 11 cortical ROIs (Huang et al., 2013) covering major cortical areas across the cortical plate. The locations of these three ROIs are labeled in 21wg cortical FA map in the middle row.

Figure 4

GFAP histological (a, b) image of a 17wg fetal brain and the corresponding FA maps (c, d) are shown in the upper panel. The close-to-ventricle part of inner layer (layer 3) has clear radial fibers in GFAP images (a, b). Neurofilament histology image of 16wg fetal brain (e, f) and corresponding FA maps (g, h) are shown in the lower panel. Tangential fibers can be observed in the close-to-subplate part of inner layer (layer 3). The ROIs for FA measurements in (i) are shown in (d) and (h) as dashed boxes, which are consistent with those derived from histology contrasts in (b) and (f), respectively. The close-toventricle part has more uniformly distributed radial fibers and hence has a higher FA value than close-to-subplate region where tangential and radial fibers may cross to each other. Yellow lines in (b) and (f) indicate the orientations of the microstructures. Green lines in (b) point to the region where GFAP stain color changes and possibly the crossing of tangential and radial fibers takes place. Asterisk in (i) indicates p less than 0.001. Adapted with permission from Huang et al., 2012.

Figure 5

Maps of primary diffusion eigenvectors overlaid on maps of apparent diffusion coefficient maps from infants of 26 and 35 wg (a), diagrams depicting the ordered radial structures in the cerebral layer of 26 week brain (b) and 35 week brain (c). In the left image of (a), the directions of the vectors are oriented radially in cortex at 26 week of gestational age. By 35 weeks of gestational age, the radial structure is much less evident, shown in the right image of (a). At 26 week of gestational age (b), radial glial fibers and pyramidal neurons with prominent, radially oriented apical dendrites are shown. This organization has the effect of restricting water displacement parallel to the cortical surface more than displacement orthogonal to it, resulting in diffusion ellipsoids which are non-spherical with their major axes oriented radially, indicated by arrows. By 35 weeks of gestational age (c), prominent basal dendrites for the pyramidal cells and thalamocortical afferents have been added. This has the effect of restricting water displacement more uniformly in all directions. As a result, the diffusion ellipsoids are spherical, without a preferred orientation. Adapted with permission from McKinstry et al. 2002.

Figure 6

Isocortical versus allocortical diffusion anisotropy of an E90 baboon fetal brain. Coronal slices (a–h) of RA maps are shown for locations indicated on the surface models (i,j,k). Coronal slices f–h are enlargements of slices b–d to show details. The classification of surface structures used is illustrated on slices f–h. Isocortex is shown in blue, “other cortex” (including allocortex) in green, unassigned cortex in brown, and the “medial wall” (not containing cortex) in gray. The anisotropy color scale for “volume data” (a–h) differs from the surface anisotropy color scale (i–l); however, in both cases, yellow is most anisotropic. At the location of the isocortex/allocortex boundary, a dramatic change in cortical diffusion anisotropy (high-isocortex/low-allocortex) is observed. In the ventral view inset (l), a color code is used to show the location of proisocortical areas lai, lam, and 13a described by Ferry et al. (2000) using surface registration to the adult macaque atlas surface. Adapted with permission from Kroenke et al., 2007.

Figure 7

Three-dimensional depiction of developmental white matter fibers. (a) is a lateral view of limbic tracts where pink fibers in 13, 15 and 19 week brains are the fornix and stria terminalis and purple fibers in 19 week brain indicate the cingulum bundle. (b) is an oblique view of commissural fibers where pink and green fibers in 13, 15 and 19 week brains are the corpus callosum and the middle cerebellar peduncle. (c) is a lateral view of projection fibers where red and purple fibers in 13, 15 and 19 week brains are the cerebral peduncle and the inferior cerebellar peduncle, respectively. (d) is a lateral view of association tracts where blue fibers in 13 and 15 week brains are the external capsule and green and red fibers in a 19 week gestation brain are inferior longitudinal fasciculus/inferior fronto-occipital peduncle and uncinate fasciculus, respectively. For anatomical guidance, thalamus (yellow structure in a,b,c,d) and ventricle (gray structure in a,c,d) are also shown. Adapted with permission from Huang et al., 2009.

Figure 8

Development of thalamocortical fibers at mid-fetal period. At 21wg fibers from different thalamic nuclei/complex (ROI, b) are taking different routes (anterior, superior, inferior and posterior thalamic radiation) towards the “waiting compartment’ - subplate (a) and cortical plate. In c the waiting fiber bundles in subplate, originating from thalamus can be seen by DTI at 26wg. Accumulation of the growing front of thalamocortical fibers in superficial subplate is shown by AChE staining (f, X) embedding in extracellular matrix rich neuropil shown by fibronectin staining (e, X). In vivo T2 weighted image (d) are also useful in showing subplate part (d, +) due to the different T2 properties of the fetal laminae. Hippocampus and the enlarged marginal zone are showing similar T2 tissue properties in in vivo T2 weighted image (d, curved arrows). sp, subplate; ci, internal capsule. Adapted with permission from Vasung et al., 2010.

Figure 9

Tractography pathways at 19wg (A), 22wg (B), 26wg (C), 33wg (D) and 42wg (E). (A) Tractography at 19wg shows dominant radial pathways with immature forms of projection, limbic, and few emergent association pathways. (B) Tractography at 22wg shows dominant radial pathways and emerging long-range connectivity patterns. (C) Tractography at 26wg shows less predominant radial pathways in dorsal frontal, parietal and inferior frontal lobes, and emergent short-range corticocortical and long-range association pathways. (D) Tractography at 33wg shows less dominant radial pathways in the temporal and occipital lobes, emergent short-range corticocortical and long-range association pathways ventrally. (E) Tractography at 42wg shows no evident radial pathways, abundant complex, crossing short- and long-range corticocortical association pathways. Small letters in all panels indicate individual identifiable tracts and the names can be found in the legend of figure 2 in Takahashi et al., 2012. In all panels, tractography pathways passing through a sagittal slice in upper left corner is shown. In a coronal slice next to the upper left corner sagittal slice, the locations of the sagittal slice is shown as a yellow line. Only 70% of the tractography fibers that touched each sagittal slice and were more than 2mm in length were shown. Colors indicate orientation of the pathways. Red: left-right, blue: anterior-posterior, and green: dorsal-ventral orientation. Adapted with permission from Takahashi et al., 2012.