Structural connectivity changes in focal epilepsy: Beyond the epileptogenic zone

Abstract

Objective: Epilepsy is recognized increasingly as a network disease, with changes extending beyond the epileptogenic zone (EZ). However, more studies of structural connectivity are needed to better understand the behavior and nature of this condition.

Methods: In this study, we applied differential tractography, a novel technique that measures changes in anisotropic diffusion, to assess widespread structural connectivity alterations in a total of 42 patients diagnosed with medically refractory epilepsy (MRE), including 27 patients with focal epilepsy and 15 patients with multifocal epilepsy that were included to validate our hypothesis. All patients were compared individually to an averaged database constructed from 19 normal controls regressed by age and sex.

Results: Statistical analyses revealed specific distribution patterns of tracts with increased connectivity that were located in multiple subcortical structures across all patients including the arcuate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, uncinate fasciculus, fornix, and short U fibers. Conversely, pathways with a significant decrease in connectivity (p < .05) exhibited a more central distribution near mesial structures across all patients (corpus callosum, cingulum, corticospinal tract, and sensory fibers).

Significance: Our findings add to the growing evidence that focal epilepsy is not solely anatomically confined, but is rather a network disorder that extends beyond the EZ, and differential tractography shows strong potential as a clinical biomarker for assessing structural connectivity alterations in patients with epilepsy.

Keywords: biomarker; differential tractography; diffusion MRI; epileptogenic zone; medical refractory epilepsy; structural connectivity.

FIGURE 1

Conventional vs differential tractography. Left panel: (A, B) Whole brain fiber tracking shown in sagittal and axial views with colors representing diffusion directionality (blue, superior–inferior; red, left–right; green, anterior–posterior). (C, D) Tracts with only increased connectivity are shown in sagittal and axial views. (E, F) Tracts with only decreased connectivity are shown in sagittal and axial views. Right panel: (G, H) Axial view of whole brain fiber tracking overlay in T1 slices and 3D view of MRI slices and tracts. (I, J) Axial view of tracts with increased connectivity (blue) and decreased connectivity (red), and its corresponding 3D view of tracts with increased connectivity (blue) and tracts with decreased connectivity (red). (K, L) Axial view showing superposition of tracts with increased connectivity (blue) and decreased connectivity (red) along with its corresponding 3D view. MRI, magnetic resonance imaging; T1, T1‐weighted imaging.

FIGURE 2

Tracts with increased structural connectivity. Axial views of whole‐brain surface depicting tracts with increased fractional anisotropy (FA) and quantitative anisotropy (QA) connectivity across subjects (A–D) at 20%, 30%, and 40% differential tractography thresholds. Tracts exhibiting increased connectivity are situated predominantly in the peripheral cortical areas, with QA displaying more white matter fibers than FA, where fewer fibers are visible. Colors represent diffusion directionality (blue, superior–inferior; red, left–right; and green, anterior–posterior). FA, fractional anisotropy; QA, quantitative anisotropy.

FIGURE 3

Tracts with decreased structural connectivity. Axial views of the whole‐brain surface illustrating tracts with decreased fractional anisotropy (FA) and quantitative anisotropy (QA) connectivity across subjects (A–D) at 20%, 30%, and 40% differential tractography thresholds. Tracts demonstrating diminished connectivity are located predominantly in mesial structures, thalamic radiations, corpus callosum, cingulum, motor fibers, and brainstem pathways. QA reveals fewer white matter fibers than FA, where more fibers are visible. Colors represent diffusion directionality (blue, superior–inferior; red, left–right; and green, anterior–posterior). FA, fractional anisotropy; QA, quantitative anisotropy.

FIGURE 4

Illustrating that focal LEFT hemisphere drug‐resistance epilepsy involving changes in the bilateral hemisphere in one subject. (A) Frequent interictal activity was noted around the cavernoma regions as electrodes B′ and C′ lateral contacts (with a close view). (B) Illustrating seizure activity with interictal and ictal transition over the same electrodes on B′ and C′ (lateral contacts). (C) Electrode location over the Talairach grid showing the cavernoma (noted as a blue circle) between electrode B′ and C′. (D) The ipsilateral hemisphere (LEFT) decreased in structural connectivity. (E) The contralateral hemisphere (RIGHT) increased in structural connectivity. Colors represent diffusion directionality (blue, superior–inferior; red, left–right; and green, anterior–posterior).