Neurovascular multiparametric MRI defines epileptogenic and seizure propagation regions in experimental mesiotemporal lobe epilepsy

Abstract

Objective: Improving the identification of the epileptogenic zone and associated seizure-spreading regions represents a significant challenge. Innovative brainimaging modalities tracking neurovascular dynamics during seizures may provide new disease biomarkers. Methods: With use of a multi-parametric magnetic resonance imaging (MRI) analysis at 9.4 Tesla, we examined, elaborated, and combined multiple cellular and cerebrovascular MRI read-outs as imaging biomarkers of the epileptogenic and seizurepropagating regions. Analyses were performed in an experimental model of mesial temporal lobe epilepsy (MTLE) generated by unilateral intra-hippocampal injection of kainic acid (KA). Results: In the ipsilateral epileptogenic hippocampi, tissue T 1 and blood-brain barrier (BBB) permeability to gadolinium were increased 48-72 hours post-KA, as compared to sham and contralateral hippocampi. BBB permeability endured during spontaneous focal seizures (4-6 weeks), along with a significant increase of apparent diffusion coefficient (ADC) and blood volume fraction (BVf). Simultaneously, ADC and BVf were augmented in the contralateral hippocampus, a region characterized by electroencephalographic seizure spreading, discrete histological neurovascular cell modifications, and no tissue sclerosis. We next asked whether combining all the acquired MRI parameters could deliver criteria to classify the epileptogenic from the seizure-spreading and sham hippocampi in these experimental conditions and over time. To differentiate sham from epileptogenic areas, the automatic multi-parametric classification provided a maximum accuracy of 97.5% (32 regions) 48-72 hours post-KA and of 100% (60 regions) at spontaneous seizures stage. To differentiate sham, epileptogenic, and seizure-spreading areas, the accuracies of the automatic classification were 93.1% (42 regions) 48-72 hours post-KA and 95% (80 regions) at spontaneous seizure stage. Significance: Combining multi-parametric MRI acquisition and machine-learning analyses delivers specific imaging identifiers to segregate the epileptogenic from the SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Boux F, Forbes F, Collomb N, et al. Neurovascular multiparametric MRI defines epileptogenic and seizure propagation regions in experimental mesiotemporal lobe epilepsy. Epilepsia.

Seizure activity triggers tau hyperphosphorylation and amyloidogenic pathways

“…Mice were monitored by video‐electroencephalography (EEG) during epileptogenesis and spontaneous seizures (12 h/week, one session starting in the morning; Figure 1A). 8 Figure provides examples of spontaneous seizure frequency, consistent with previous reports 10,11,13,14 …”

“…The reported expression of specific tau-related and amyloidogenic players directly integrates with the neuroinflammatory dynamics in the epileptogenic hippocampus. [8][9][10]30 Importantly, existing evidence showed learning and memory deficits in the MTLE setting, 13,31,32 an outcome consistent with the patterns of AD-relevant markers outlined here. Our F I G U R E 5 Cross-comparisons of long-term pathological trajectories in post-status epilepticus (SE), mesial temporal lobe epilepsy (MTLE), and J20 models.…”

“…Over time, the EEG pattern after generalized SE sharply contrasts with the MTLE model, the latter leading to epileptogenesis and recurrent focal seizures (Figure 1A). 8,11,14 …”

“…This model leads to epileptogenesis and the development of spontaneous focal seizures. [8][9][10][11] The KA-injected ipsilateral hippocampus is the epileptogenic zone presenting significant sclerosis. 9,12 The contralateral, noninjected, hippocampus is a seizure propagation zone devoid of lesion or sclerosis.…”

“…We used a model of mesial TLE (MTLE) based on unilateral intrahippocampal (ih) kainic acid (KA) injection in C57BL/6 mice. This model leads to epileptogenesis and the development of spontaneous focal seizures 8–11 . The KA‐injected ipsilateral hippocampus is the epileptogenic zone presenting significant sclerosis 9,12 .…”