Heterotopic connectivity of callosal dysgenesis in mice and humans

Abstract

The corpus callosum (CC), the largest brain commissure and the primary white matter pathway for interhemispheric cortical connectivity, was traditionally viewed as a predominantly homotopic structure, connecting mirror areas of the cortex. However, new studies verified that most callosal commissural fibers are heterotopic. Recently, we reported that ~75% of the callosal connections in the brains of mice, marmosets, and humans are heterotopic, having an essential role in determining the global properties of brain networks. In the present study, we leveraged high-resolution diffusion-weighted imaging and graph network modeling to investigate the relationship between heterotopic and homotopic callosal fibers in human subjects and in a spontaneous mouse model of Corpus Callosum Dysgenesis (CCD), a congenital developmental CC malformation that leads to widespread whole-brain reorganization. Our results show that the CCD brain is more heterotopic than the normotypical brain, with both mouse and human CCD subjects displaying highly variable heterotopicity maps. CCD mice have a clear heterotopicity cluster in the anterior CC, while hypoplasic humans have strongly variable patterns. Graph network-based connectivity profile showed a direct impact of heterotopic connections on CCD brains altering several network-based statistics. Our collective results show that CCD directly alters heterotopic connections and brain connectivity.

Brain plasticity following corpus callosum agenesis or loss: a review of the Probst bundles

“…As these studies did not report a high-caudal to low-rostral gradient of cell death along the cortex, it is likely that additional mechanisms may contribute to the differing rostrocaudal axon densities observed between the corpus callosum and PBs. For example, PBs have increased axonal bifurcations in rostral areas (Rayêe et al, 2021), perhaps linked to the higher overall heterotopicity of projections recently reported in human and mouse brains with callosal malformations (Szczupak et al, 2023b) and contributing to differences in axonal bulk along the rostro-caudal axis.…”