Role of axonal fibers in the cortical folding patterns: A tale of variability and regularity

Abstract Cortical folding is one of the most complex processes that occur during the normal development of the human brain. Despite variability in folding patterns of different individuals, there are a few specific types of preserved folding patterns within individuals or across species. The origin and formation mechanism of variable or regular folding patterns in the human brain yet remains to be thoroughly explored. This study aims to delineate how the interplay between the differential tangential growth of cerebral cortex and axonal fiber tension induces and regulates the folding patterns in a developing human brain. To achieve this aim, an image-based multiscale mechanical model on the basis of the embedded nonlinear finite element method is employed to investigate a set of growth and folding scenarios. Our results show that the differential growth between cortical and subcortical layers is the main inducer of cortical folding. In addition, the gyrification of the cortex pulls the areas with a high density of stiff axonal fiber bundles towards gyri rather than sulci; therefore, axonal fiber bundles induce symmetry breaking, and regulate the folding patterns. In particular, spatial distribution of axonal fiber bundles is the determinant factor to control the locations of gyri and sulci. In conclusion, we propose that neural wiring might be the main regulator of folding patterns responsible for the formation of regular cortical folding patterns. This study provides a deeper understanding of cortical folding and its morphogenesis which are the key to interpreting normal brain development and growth. Statement of Significance There is a vital need to discover the role of axonal fibers of the brain’s connectivity on the formation and modulation of folding patterns in the developing human brain. The lack of knowledge of the physical interplay between cortical folding and neural wiring is a critical barrier to the fundamental understanding of the relationship between cortical folding, brain connectivity, and brain function in different neurodevelopmental stages. This study by using image-based multiscale mechanical models investigates the role of the differential tangential growth of cerebral cortex and axonal fibers in the formation and regulation of the folding patterns in the developing human brain. This is the first study to explain why despite variation in folding patterns, there are some specific types of regular shapes within individuals or across species and why axonal fibers connected to gyri in the human brain are typically denser than those connected to sulci. The study has a positive impact on the deeper understanding of cortical folding and its morphogenesis that is the key to interpreting the normal development of the human brain during the early stages of growth.