A mechanical model for axon pathfinding in a folding brain

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Abstract Understanding the processes of axonal growth and pathfinding during cortical folding in the brain is crucial to unravel the mechanisms underlying brain disorders that disturb connectivity throughout human brain development. However, this topic remains incompletely understood, highlighting the need for further investigation. Here, we propose and evaluate a diffusion based-mechanistic model to understand how axons grow and navigate in the folding brain. To do so, a bilayer growth model simulating the brain was devised involving a thin gray matter overlying a thick white matter. Innovatively, the stochastic model of axonal growth was linked with the stress and deformation fields of the folding bilayer system. The results showed that the modulus ratio of the gray matter to the white matter and the axonal growth rate are two potentially critical parameters that significantly influence axon pathfinding in the folding brain. The model demonstrated robust predictability in identifying axonal termination points and offered a potential mechanism explaining why axons settle more in gyri (ridges) than sulci (valleys) of the brain. Importantly, the results explain how alterations in the mechanical properties of the folding system can impact the underlying connectivity patterning. This mechanistic insight not only enhances our understanding of brain connectivity development during the fetal stage but also sheds light on brain disorders characterized by linked abnormalities in cortical folds and disruptions in connectivity.