The superficial white matter in temporal lobe epilepsy: a key link between structural and functional network disruptions

Abstract

Drug-resistant temporal lobe epilepsy is increasingly recognized as a system-level disorder affecting the structure and function of large-scale grey matter networks. While diffusion magnetic resonance imaging studies have demonstrated deep fibre tract alterations, the superficial white matter immediately below the cortex has so far been neglected despite its proximity to neocortical regions and key role in maintaining cortico-cortical connectivity. Using multi-modal 3 T magnetic resonance imaging, we mapped the topography of superficial white matter diffusion alterations in 61 consecutive temporal lobe epilepsy patients relative to 38 healthy controls and studied the relationship to large-scale structural as well as functional networks. Our approach continuously sampled mean diffusivity and fractional anisotropy along surfaces running 2 mm below the cortex. Multivariate statistics mapped superficial white matter diffusion anomalies in patients relative to controls, while correlation and mediation analyses evaluated their relationship to structural (cortical thickness, mesiotemporal volumetry) and functional parameters (resting state functional magnetic resonance imaging amplitude) and clinical variables. Patients presented with overlapping anomalies in mean diffusivity and anisotropy, particularly in ipsilateral temporo-limbic regions. Diffusion anomalies did not relate to cortical thinning; conversely, they mediated large-scale functional amplitude decreases in patients relative to controls in default mode hub regions (i.e. anterior and posterior midline regions, lateral temporo-parietal cortices), and were themselves mediated by hippocampal atrophy. With respect to clinical variables, we observed more marked diffusion anomalies in patients with a history of febrile convulsions and those with longer disease duration. Similarly, more marked diffusion alterations were associated with seizure-free outcome. Bootstrap analyses indicated high reproducibility of our findings, suggesting generalizability. The temporo-limbic distribution of superficial white matter anomalies, together with the mediation-level findings, suggests that this so far neglected region serves a key link between the hippocampal atrophy and large-scale default mode network alterations in temporal lobe epilepsy.

Keywords: functional network; mediation analysis; multimodal MRI; superficial white matter.

Temporal lobe epilepsy is a systems level disorder. Using multi-modal MRI, Liu et al. reveal temporolimbic anomalies in the superficial white matter (SWM) immediately below the cortex. The SWM is pivotal to maintaining corticocortical connectivity, and changes in this region may link hippocampal atrophy with large-scale default mode network alterations.

Figure 1

Surface-based mapping of SWM diffusion in TLE. (A) After generating the inner (white matter–grey matter, green) and outer (grey matter–CSF, red) cortical surfaces, we computed a Laplacian potential field between the white matter–grey matter interface and the ventricular walls to guide placement of a surface running 2 mm below the white matter–grey matter boundary (SWM, yellow). Fractional anisotropy (FA) and mean diffusivity (MD) were sampled on this surface. (B) and (C) show uni- and multivariate SWM diffusion anomalies in left (left TLE) and right (right TLE) patients relative to controls. To correct for multiple comparisons, findings were thresholded at P_FWE < 0.05, using random field theory for non-isotropic images (cluster threshold P < 0.01).

Figure 2

Spatial relationship between multivariate diffusion changes and cortical thinning as well as decrease of the resting state ALFF in left TLE (A, LTLE) and right TLE (B, RTLE) relative to controls. For a given TLE cohort, small maps show significant cortical thinning/ALFF reduction relative to controls, while yellow clusters on the multivariate maps represent the surface-based intersections between reduction in cortical thickness/ALFF and SWM changes. FA = fractional anisotropy; MD = mean diffusivity.

Figure 3

Relation of superficial white matter (SWM) to hippocampal volume (A) and function (B) in TLE. The maps represent the extent of SWM diffusion anomalies and amplitude of low frequency fluctuations (ALFF). Relationships and causality are shown in the correlation (middle) and mediation (right) graphs, respectively. In A, the degree of SWM diffusion anomalies negatively correlate with hippocampal volume ipsilateral to the focus in patients, but not controls. Hippocampal volume partially mediates SWM diffusion changes (P = 0.04). In B, decreased resting-state ALFF in patients relative to controls negatively correlates with the degree of diffusion anomalies in patients, but not controls. Moreover, diffusion anomalies mediate the abnormal function (P = 0.01). Numbers in mediation graphs represent path coefficients and standard errors. Asterisks denote significant coefficients with P < 0.05.