April 25, 2022

Hippocampal Position and Orientation as Prognostic Biomarkers for Post-Traumatic Epileptogenesis – an Experimental Study in Rat Lateral Fluid-Percussion Model

Abstract found on Wiley Online Library

Objective: To identify prognostic biomarkers for post-traumatic epileptogenesis derived from parameters related to the hippocampal position and orientation.

Methods: Data was derived from two pre-clinical magnetic resonance imaging (MRI) follow-up studies: EPITARGET (156 rats) and EpiBioS4Rx (UEF Cohort 43 rats). Epileptogenesis was induced with lateral fluid-percussion induced traumatic brain injury (TBI) in adult male Spraque-Dawley rats. In the EPITARGET cohort, ??2T2?-weighted MRI was performed at 2 d, 7 d and 21 d and in the EpiBioS4Rx cohort at 2 d, 9 d, 30 d, and 5 months post-TBI. Both hippocampi were segmented using convolutional neural networks. The extracted segmentation mask was used for a geometric construction, extracting 39 parameters that described the position and orientation of the left and right hippocampus. In each cohort, we assessed the parameters as prognostic biomarkers for post-traumatic epilepsy (PTE) both individually, using repeated measure ANOVA, as well as in combination using random forest classifiers.

Results: The extracted parameters were highly effective in discriminating between sham-operated and TBI rats in both the EPITARGET and EpiBioS4Rx cohorts at all timepoints (t) (balanced accuracy > 0.9). The most discriminating parameter was the inclination of the hippocampus ipsilateral to the lesion at ?=2t=2 d and the volumes at ??7t?7 d after TBI. Furthermore, in the EpiBioS4Rx cohort, we could effectively discriminate epileptogenic vs. non-epileptogenic animals with a longer MRI follow-up, at ?=150t=150 d (AUC 0.78, balanced accuracy 0.80, p=0.0050), based on the orientation of both hippocampi. We found that the ipsilateral hippocampus rotated outward on the horizontal plane, while the contralateral hippocampus rotated away from the vertical direction.

Significance: We demonstrate that assessment of TBI-induced hippocampal deformation by clinically translatable MRI methodologies detects subjects with prior TBI as well as those at high-risk of PTE, paving the way towards subject stratification for antiepileptogenesis studies.