The Mechanical Fingerprint of Hippocampal Sclerosis Linking Neuronal Cell Loss and Gliosis to Tissue Stiffness

Hippocampal sclerosis (HS) is the most common pathology in drug-resistant temporal lobe epilepsy (TLE). However, clinical diagnosis, prevalent epileptogenicity, and drug drug-resistance in individuals with HS remain an ongoing challenge demanding multidisciplinary research efforts. In this study, we examined the mechanical properties of neurosurgically en bloc resected HS specimens (n=8) ex vivo under compression, tension, and torsional shear. We fitted a two-term Ogden hyperelastic model to the measured mechanical responses to quantify nonlinear mechanical tissue properties. The resulting parameters revealed higher strain stiffening under compression in HS compared to hippocampus obtained post mortem (n=7). The distinction was most noticeable in the large-strain regime, which has important implications for using mechanical tissue properties as valuable diagnostic biomarker. Furthermore, we correlated the tissue microstructure with mechanical parameters. We trained a deep-learning histopathology classifier to detect and classify neurons and glial cells from hematoxylin-stained whole slide images (WSI). We identified a strong association between the small-strain stiffness (shear modulus {micro}) and the overall cell density as well as the glial cell density. The negative relationship between the neuron-to-glia ratio and shear modulus is consistent with the hypothesis that neuronal cell loss and gliosis drives tissue stiffening, respectively. Magnetic resonance imaging (MRI) analysis of the specimens confirmed the previously reported negative association between MRI-derived fractional anisotropy and shear modulus {micro}. Taken together, our study establishes a direct link between tissue mechanics and microstructure, suggesting nonlinear continuum mechanics models as promising new tools for clinical diagnosis and novel research strategies.