Poster Q3 - Stress Landscape of Folding Brain Serves as a Map for Axonal Pathfinding

Introduction: Understanding the interplay between cortical folding and the concurrent development of brain connectivity is critical, as many brain disorders feature linked abnormal folding morphologies and connectivity disruptions. This study proposes and evaluates a mechanical model to elucidate the multiscale mechanics of axonal growth in the folding brain, aiming to uncover the linkages between cortical folding and connectivity development. We explored how growing axon bundles respond to physical forces and navigate within a dynamic stress field. Our results demonstrate, for the first time, potential mechanical mechanisms by which the density of axon bundles is higher in gyri (ridges) than in sulci (valleys), a phenomenon previously unexplained. The degree of cortical gyrification strongly correlates with the density, growth rate, and mechanical properties of underlying axon bundles. This bidirectional linkage underscores the significance of mechanical factors in early brain development. Additionally, axon bundles navigating from the brain's core towards the cortical layer experience stress-induced growth and reorientation, primarily settling in gyri due to the stress field from cortical folding. Conversely, axon biophysical properties can influence the gyrification index and fold morphology, dynamically altering white matter properties and creating a heterogeneous stiffness map that may predict secondary and tertiary gyri and sulci locations. These findings have significant implications for understanding the origins of linked abnormal cortical folding and connectivity disruptions in brain disorders.

Materials and

Methods: we propose and evaluate a mechanical model to understand the multiscale mechanics of the interplay between brain folding and connectivity development. This modeling focuses on elucidating the growth and pathfinding mechanisms of axons destined to extend from white matter towards the gray matter. Indeed, we derived a constitutive model to simulate the reorientation of axons in response to mechanical stress. We incorporated a stress-dependent term to account for the influence of high-stress regions on axonal directionality. This term was derived from empirical observations indicating that axons tend to align themselves along the principal stress directions to minimize energy expenditure and enhance structural integrity. We then implemented the model in ABAQUS by using a VUMAT subroutine. To validate our simulations, we compared the results with imaging data obtained from high-resolution sMRI and dMRI scans. We specifically acquired scans from 10 healthy adult brains aged 22–35 years to analyze the organization of thalamocortical fiber tracts. These fibers extend from the thalamus to cortical regions, similar to the simulations in directing fibers from the core to the cortex.

Results, Conclusions, and Discussions: In this study, we proposed and evaluated a mechanical model to understand how growing axons navigate in a folding system, which simulates the interaction between cortical folding and axonal development (brain connectivity) in a developing brain. The results confirm the vital role of mechanical factors in determining cortical folding, connectivity development, and their bidirectional relationship. We studied key parameters such as the growth rate, stochastic behavior, density, and mechanical properties of axon bundles, as well as the stiffness ratio of cortex to white matter, to understand how axon bundles respond to the physical forces of the folding system and navigate within a complex deformation field. The results indicated that axon bundles destined to grow from the core of the brain towards the cortical layer potentially experience stress-induced growth and reorientation, which settle more in gyri than sulci. This observation arises from the stress field of the white matter induced by cortex folding. On the other hand, the biophysical properties of axons can alter the gyrification index and surface morphology of the folds. Developing axon bundles dynamically change the material properties of the white matter, which provide a heterogeneous substrate for cortex folding. This heterogeneous stiffness map may also help identify the locations of prospective secondary and tertiary gyri and sulci. The bidirectional linkage underscores the significance of mechanics in the healthy development of the human brain during the early stages. Future in vivo or in vitro studies are essential to provide feedback regarding the proposed model and its assumptions, limitations, and predictions. This will open new avenues to understand the origins of linked abnormal cortical folding and connectivity disruptions in brain disorders.

Acknowledgements (Optional): This work was supported by the National Science Foundation [CMMI: 2123061] awarded to M. J. Razavi. The authors would like to acknowledge Ali Gholipour from Harvard Medical School and Boston Children’s Hospital for sharing the longitudinal fetal brain scans.