Sex Differences in Axonal Dynamic Responses Under Realistic Tension Using Finite Element Models

Existing axonal finite element models do not consider sex morphological differences or the fidelity in dynamic input. To facilitate a systematic investigation into the micromechanics of diffuse axonal injury, we develop a parameterized modeling approach for automatic and efficient generation of sex-specific axonal models according to specified geometrical parameters. Baseline female and male axonal models in the corpus callosum with random microtubule (MT) gap configurations are generated for model calibration and evaluation. They are then used to simulate a realistic tensile loading consisting of both a loading and a recovery phase (to return to an initial undeformed state) generated from dynamic corpus callosum fiber strain in a real-world head impact simulation. We find that MT gaps and the dynamic recovery phase are both critical to successfully reproduce MT undulation as observed experimentally, which has not been reported before. This strengthens confidence in model dynamic responses. A statistical approach is further employed to aggregate axonal responses from a large sample of random MT gap configurations for both female and male axonal models (n = 10,000 each). We find that peak strains in MTs and the Ranvier node and associated neurofilament failures in female axons are substantially higher than those in male axons because there are fewer MTs in the former and also because of the random nature of MT gap locations. Despite limitations in various model assumptions as a result of limited experimental data currently available, these findings highlight the need to systematically characterize MT gap configurations and to ensure a realistic model input for axonal dynamic simulations. Finally, this study may offer fresh and improved insight into the biomechanical basis of sex differences in brain injury, and sets the stage for more systematic investigations at the microscale in the future, both numerically and experimentally.