Histological morphometric correlates of MRI-defined cortical thinning in temporal lobe epilepsy

Abstract

Large-scale MRI studies have consistently demonstrated progressive and age-accelerated neocortical thinning in temporal lobe epilepsy (TLE). These findings are frequently interpreted as evidence of cumulative neurodegeneration. However, the histopathological substrates underlying MRI-confirmed cortical thinning in epilepsy remain poorly defined. In particular, it is unknown whether cortical thinning reflects irreversible neuronal loss or potentially reversible epilepsy-related network alterations in cortical microstructure. We analysed the resected middle temporal gyrus from 117 individuals undergoing surgery for temporal lobe epilepsy, including cases with (n= 74) or without hippocampal sclerosis (HS) and 12 cases with additional temporal lobe sclerosis (TLS, or Focal Cortical Dysplasia IIIa), defined by a distinct pattern of cytoarchitectural reorganisation and gliosis involving superficial layers. All cases were stratified by the presence or absence of pre-operative MRI-defined cortical thinning of the middle temporal gyrus, quantified using CAT12 relative to healthy controls. On NeuN-immuno-labelled sections using automated image analysis we assessed neuronal spatial distributions relative to their size and packing density; relative cortical layer thickness and sulcal-gyral cytoarchitectural variation were also quantified. MRI-defined cortical thinning was not associated with diffuse neuronal loss. Instead, thinning correlated with increased neuronal density and altered cell-size spatial organisation in superficial and deep layers, particularly in right temporal lobe epilepsy cases with HS. There was limited evidence of layer-specific laminar thinning, being confined to layer VI in the right TLE/HS group only. Of note, TLS cases did not show either cortical thinning on MRI or laminar thinning on histology compared to cases without TLS but altered neuronal densities and composition that was not confined to the superficial cortex. MRI cortical thinning was also characterised by attenuation of normal sulcal/gyral cytoarchitectural variations suggesting disruption of cortical architectural gradients. In contrast, cases with HS but without MRI cortical thinning demonstrated loss of the expected inter-hemispheric cytoarchitectural asymmetry, indicating a distinct pathological process dissociated from thinning. Clinical-pathological correlations were lateralised, including age of onset, further supporting distinct mechanisms contributing to MRI cortical thinning between left and right TLE. These findings challenge the prevailing assumption that MRI-defined cortical thinning in epilepsy reflects progressive neuronal degeneration. Rather than laminar neuronal loss and atrophy, thinning was associated with altered neuronal packing and cell-size distributions between layers. This points towards altered neuropil volumes, including myelin content and dendritic remodelling, in turn suggesting potentially reversible dynamic seizure- or network-related processes.