Stress Landscape of Folding Brain Serves as a Map for Axonal Pathfinding

Understanding the mechanics underlying the connections between cortical folding and the development of brain connectivity is crucial, especially given that many brain disorders exhibit abnormal folding patterns and disrupted connectivity. Despite the importance of this relationship, existing models fail to explain how growing axon bundles navigate the stress field within a folding brain, or how this bidirectional and dynamic interaction shapes the resulting surface morphologies and connectivity patterns. Here, we propose the concept of “axon reorientation” in the folding brain and formulate a mechanical model to uncover the dynamic multiscale mechanics of the linkages between cortical folding and connectivity development. Simulations incorporating axon bundle reorientation and stress-induced growth reveal the potential mechanical mechanisms that lead to higher axon bundle density in gyri (ridges) compared to sulci (valleys), offering a more accurate representation than previous models. In particular, the degree of gyrification is shown to correlate strongly with the density, growth rate, and mechanical properties of underlying axon bundles. Model predictions are supported by in vivo diffusion tensor imaging of the human brain. Our findings suggest that mechanics plays a far more significant role in the healthy development of cortical folds and connectivity than previously recognized.