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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.
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Stress landscape of folding brain serves as a map for axonal pathfinding
Abstract 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.
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- Award ID(s):
- 2123061
- PAR ID:
- 10569220
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 16
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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