Stress landscape of folding brain serves as a map for axonal pathfinding.

Understanding the mechanics linking cortical folding and brain connectivity is crucial for both healthy and abnormal brain development. 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" 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 potential mechanical mechanisms that lead to higher axon bundle density in gyri (ridges) compared to sulci (valleys). In particular, the connectivity patterning resulting from cortical folding exhibits a strong dependence on the growth rate and mechanical properties of the navigating axon bundles. Model predictions are supported by in vivo diffusion tensor imaging of the human brain.