Image-based axon model highlights heterogeneity in initiation of damage

Abstract

Head injury simulations predict the occurrence of traumatic brain injury by placing a threshold on the calculated strains for axon tracts within the brain. However, a current roadblock to accurate injury prediction is the selection of an appropriate axon damage threshold. While several computational studies have used models of the axon cytoskeleton to investigate damage initiation, these models all employ an idealized, homogeneous axonal geometry. This homogeneous geometry with regularly spaced microtubules, evenly distributed throughout the model, overestimates axon strength because, in reality, the axon cytoskeleton is heterogeneous. In the heterogeneous cytoskeleton, the weakest cross section determines the initiation of failure, but these weak spots are not present in a homogeneous model. Addressing one source of heterogeneity in the axon cytoskeleton, we present a new semiautomated image analysis pipeline for using serial-section transmission electron micrographs to reconstruct the microtubule geometry of an axon. The image analysis procedure locates microtubules within the images, traces them throughout the image stack, and reconstructs the microtubule structure as a finite element mesh. We demonstrate the image analysis approach using a C. elegans touch receptor neuron due to the availability of high-quality serial-section transmission electron micrograph data sets. The results of the analysis highlight the heterogeneity of the microtubule structure in the spatial variation of both microtubule number and length. Simulations comparing this image-based geometry with homogeneous geometries show that structural heterogeneity in the image-based model creates significant spatial variation in deformation. The homogeneous geometries, on the other hand, deform more uniformly. Since no single homogeneous model can replicate the mechanical behavior of the image-based model, our results argue that heterogeneity in axon microtubule geometry should be considered in determining accurate axon failure thresholds.