Objective Inflammatory cerebrovascular damage occurs in epilepsy. Here, we tested the hypothesis that a pericyte‐glia scar forms around the outer wall of hippocampal capillaries in a model of temporal lobe epilepsy associated with hippocampal sclerosis. We studied the participation of stromal cells expressing platelet‐derived growth factor receptor beta (PDGFRβ) and extracellular matrix modifications to the perivascular scar during epileptogenesis. Methods We used NG2DsRed/C57BL6 mice and induced status epilepticus (SE) followed by epileptogenesis and spontaneous recurrent seizures (SRS) by means of unilateral intrahippocampal injection of kainic acid (KA). For pharmacological assessment, we used organotypic hippocampal cultures (OHCs) where ictal electrographic activity was elicited by KA or bicuculline. Results NG2DsRed pericytes, GFAP astroglia, and IBA1 microglia are reactive and converge to form a pericapillary multicellular scar in the CA hippocampal regions during epileptogenesis and at SRS. The capillaries are leaky as indicated by fluorescein entering the parenchyma from the peripheral blood. Concomitantly, PDGFRβ transcript and protein levels were significantly increased. Within the regional scar, a fibrotic‐like PDGFRβ mesh developed around the capillaries, peaking at 1 week post‐SE and regressing, but not resolving, at SRS. Abnormal distribution or accumulation of extracellular matrix collagens III/IV occurred in the CA regions during seizure progression. PDGFRβ/DAPI cells were in direct contact with or adjacent to the damaged NG2DsRed pericytes at the capillary interface, consistent with the notion of stromal cell reactivity or fibroblast formation. Inducing electrographic activity in OHCs was sufficient to augment PDGFRβ reactivity around the capillaries. The latter effect was pharmacologically mimicked by treating OHCs with the PDGFRβ agonist PDGF‐BB and it was diminished by the PDGFRβ inhibitor imatinib. Significance The reported multicellular activation and scar are traits of perivascular inflammation and hippocampal sclerosis in experimental epilepsy, with an implication for neurovascular dysfunction. Modulation of PDGFRβ could be exploited to target inflammation in this chronic disease setting.

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.