Folding, But Not Surface Area Expansion, Is Associated with Cellular Morphological Maturation in the Fetal Cerebral Cortex

Abstract

Altered macroscopic anatomical characteristics of the cerebral cortex have been identified in individuals affected by various neurodevelopmental disorders. However, the cellular developmental mechanisms that give rise to these abnormalities are not understood. Previously, advances in image reconstruction of diffusion magnetic resonance imaging (MRI) have made possible high-resolution in utero measurements of water diffusion anisotropy in the fetal brain. Here, diffusion anisotropy within the developing fetal cerebral cortex is longitudinally characterized in the rhesus macaque, focusing on gestation day (G85) through G135 of the 165 d term. Additionally, for subsets of animals characterized at G90 and G135, immunohistochemical staining was performed, and 3D structure tensor analyses were used to identify the cellular processes that most closely parallel changes in water diffusion anisotropy with cerebral cortical maturation. Strong correlations were found between maturation of dendritic arbors on the cellular level and the loss of diffusion anisotropy with cortical development. In turn, diffusion anisotropy changes were strongly associated both regionally and temporally with cortical folding. Notably, the regional and temporal dependence of diffusion anisotropy and folding were distinct from the patterns observed for cerebral cortical surface area expansion. These findings strengthen the link proposed in previous studies between cellular-level changes in dendrite morphology and noninvasive diffusion MRI measurements of the developing cerebral cortex and support the possibility that, in gyroencephalic species, structural differentiation within the cortex is coupled to the formation of gyri and sulci.

Dynamic patterns of cortical expansion during folding of the preterm human brain

“…At the individual level, we observed highest cortical expansion in areas undergoing the most dramatic folding (Fig. 3), consistent with previous reports in ferret (16,20). To quantify change in preterm folding, we analyzed non-dimensional mean curvature, defined as K ú = KL where L =  SA/4fi and SA = total cortical surface area (20).…”

“…Furthermore, subtle or localized folding abnormalities have been linked to disorders such as epilepsy, autism, and schizophrenia (11)(12)(13). To address this issue and attain more detailed measures, several groups have analyzed user-delineated regions of interest (ROIs) (14)(15)(16). However, manual definition of ROIs may introduce bias or error and typically requires labor-intensive editing.…”

Abnormal microstructural development of the cerebral cortex in neonates with congenital heart disease is associated with impaired cerebral oxygen delivery

“…Increasing cytoarchitecture complexity also restricts water diffusion more evenly in all directions, with a consequent reduction in FA 40,50 . The link between diffusion imaging studies and underlying tissue biology is supported by prior evidence that NODDI-derived dispersion measures match their histological counterparts in adult postmortem specimens 53 , and by correlations found between maturation of dendritic arbors at the cellular level and loss of diffusion anisotropy with cortical development in the rhesus macaque 16 and fetal sheep 54 .…”

“…Thirdly, ascending aorta oxygen saturations have been found to be 10% lower in human fetuses with mixed CHD compared to healthy controls, with saturation measurements that correlated with fetal brain size 5 . Finally, microstructural maturation of the cortex, measured using both histology and diffusion anisotropy, has been demonstrated to occur in parallel with macrostructural development 16 .…”

Identification of in vivo Sulci on the External Surface of Eight Adult Chimpanzee Brains: Implications for Interpreting Early Hominin Endocasts

“…The mechanical folding model, on the other hand, suggests that tangential expansion of the cerebral cortex generates compression that leads to the development of cortical sulci [Tallinen et al, 2016]. A recent study of developing cortex in rhesus monkey fetuses suggests that maturation of dendrites within the cortex may be linked to the formation of sulci, which may be more consistent with the mechanical folding model [Wang et al, 2017]. Although these discussions about the mechanisms of how sulci form during development may seem somewhat tangential to the present paper, the shape of the developing brain (endocast) modulates the mechanical factors that influence the placement and orientations of sulci so that, in real brains, the "primary convolutions are consistently reproducible in their location" [Tallinen et al, 2016, p. 591].…”