No abstract

The human brain has a highly complex structure both on the microscopic and on the macroscopic scales. Increasing evidence has suggested the role of mechanical forces for cortical folding – a classical hallmark of the human brain. However, the link between cellular processes at the microscale and mechanical forces at the macroscale remains insufficiently understood. Recent findings suggest that an additional proliferating zone, the outer subventricular zone (OSVZ), is decisive for the particular size and complexity of the human cortex. To better understand how the OSVZ affects cortical folding, we establish a multifield computational model that couples cell proliferation in different zones and migration at the cell scale with growth and cortical folding at the organ scale by combining an advection-diffusion model with the theory of finite growth. We validate our model based on data from histologically stained sections of the human fetal brain and predict 3D pattern formation. Finally, we address open questions regarding the role of the OSVZ for the formation of cortical folds. The presented framework not only improves our understanding of human brain development, but could eventually help diagnose and treat neuronal disorders arising from disruptions in cellular development and associated malformations of cortical development.

The human brain has a highly complex structure both on the microscopic and macroscopic scales. Increasing evidence has emphasized the role of mechanical forces for cortical folding – a classical hallmark of the human brain. However, the link between cellular processes at the microscale and mechanical forces at the macroscale remains insufficiently understood. Recent findings suggest that an additional proliferating zone, the outer subventricular zone (OSVZ), is decisive for the particular size and complexity of the human cortex. To better understand how the OSVZ affects cortical folding, we establish a multifield computational model that couples cell proliferation and migration at the cell scale with growth and cortical folding at the organ scale by combining an advection-diffusion model with the theory of finite growth. We validate our model based on data from histologically stained sections of the human fetal brain. Finally, we address open questions regarding the role of the OSVZ for the formation of cortical folds. The presented framework not only improves our understanding of human brain development, but could eventually help diagnose and treat neuronal disorders arising from disruptions in cellular development and associated malformations of cortical development.

The human brain has a complex structure on both cellular and organ scales. This structure is closely related to the brain's abilities and functions. Disruption of one of the biological processes occurring during brain development on the cellular scale may affect the cortical folding pattern of the brain on the organ scale. However, the link between disruptions in cellular brain development and associated cortical malformation remains largely unknown. From a mechanical perspective, the forces generated during development lead to mechanical instability and, eventually, the mergence of cortical folds. To fully understand mechanism underlying malformations of cortical development, it is key to consider both the events that occur on the cellular scale and the mechanical forces generated on the organ scale. Here we present a computational model describing cellular division and migration on the cellular scale, as well as growth and cortical folding on the tissue or organ scale, in a continuous way by a coupled finite growth and advection‐diffusion model. We introduce the cell density as an independent field controlling the volumetric growth. Furthermore, we formulate a positive relation between cell density and cortical layer stiffness. This allows us to study the influence of the migration velocity, the cell diffusivity, the local stiffness, and the local connectivity of cells on the cortical folding process and mechanical properties during normal and abnormal brain development numerically. We show how an increase in the density of the neurons increases the layer's mechanical stiffness. Moreover, weWe validate our simulation results through the comparison with histological sections of the fetal human brain. The current model aims to be a first step towards providing a reliable platform to systematically evaluate the role of different cellular events on the cortical folding process and vice versa.