Abstracts

Rationale: The hippocampus is traditionally considered the disease epicentre of temporal lobe epilepsy (TLE), with hippocampal sclerosis (HS) as its pathological hallmark.¹ Despite extensive research revealing TLE-related genes,² their downstream effects rendering the hippocampus more vulnerable to seizures remain unclear. Here, we mapped morphological and microstructural alterations in TLE using structural and diffusion magnetic resonance imaging (MRI), and examined associations to TLE-specific risk gene expression.


Methods: Participants. We investigated multimodal MRI data (T1-weighted MRI, diffusion MRI) in 67 individuals with pharmaco-resistant unilateral TLE (mean [SD] age = 31.9 [12.0] years, 34 females, 32 left sided focus) and 92 age and sex-matched healthy controls (age = 31.7 [10.0] years, 51 females) recruited from three independent sites: Universidad Nacional Autonoma de Mexico, Nanjing Hospital, and Montreal Neurological Institute and Hospital.

Hippocampal morphology and microstructure. Employing HippUnfold,^3,4 an automated pipeline for hippocampal unfolding and novel surface-based registration, individualized hippocampal surfaces were generated and subsequently used to sample (i) hippocampal thickness (HT), (ii) fractional anisotropy (FA), and (iii) mean diffusivity (MD; Fig 1A). Surface-based linear models compared patients with TLE to healthy controls, while correcting for age and sex.

Relation to epilepsy risk gene expression. Microarray expression data of six deceased human donors from the Allen Human Brain Atlas, (AHBA) were aggregated and mapped to the hippocampus (Fig 2A).⁵ Based on previous genome-wide association studies (GWAS),² we derived transcriptomic maps for genes related to HS (C3orf33, GJA1, KCNAB1, SCN1A, SLC33A1). Spatial correlations correcting for autocorrelation examined correspondence between structural and gene expression maps.⁶ Assessing disease specificity, we repeated imaging-transcriptomic analyses with generalized epilepsy (GE) risk genes.


Results: Comparing groups, widespread patterns of structural compromise were observed in patients relative to controls, including HT decreases, FA decreases, and MD increases (Fig 1B). Imaging-transcriptomic correlations revealed strong and distinct associations between structure and disease risk genes: (i) HT correlated with GJA1 and KCNAB1, and (ii) FA and MD correlated with C3orf33, SLC33A1, and SCN1A (all p_{spin-corrected} < 0.05; Fig 2B). Little significant correlations were observed for risk genes associated with GE, suggesting possible specificity to HS.


Conclusions: Capitalizing on recent imaging-transcriptomic initiatives, we highlighted widespread hippocampal alterations in structure in pharmaco-resistant TLE. These morphological and microstructural changes were related to independent sets of risk genes specific to HS, pointing to parallel and disease-relevant pathways.

¹Blümcke et al. (2013) Epilepsia
²ILAE Consortium on Complex Epilepsies (2019) Nat Commun
³DeKraker et al. (2022). eLife
⁴DeKraker et al. (2023). eLife
⁵Hawrylycz et al. (2012). Nature
⁶Alexander-Bloch et al. (2018) Neuroimage


Funding: Canadian Institute of Health Research
Fonds de Recherche du Québec - Santé