Exploring individual fixel-based white matter abnormalities in epilepsy

Abstract

Diffusion MRI has provided insight into the widespread structural connectivity changes that characterize epilepsies. Although syndrome-specific white matter abnormalities have been demonstrated, studies to date have predominantly relied on statistical comparisons between patient and control groups. For diffusion MRI techniques to be of clinical value, they should be able to detect white matter microstructural changes in individual patients. In this study, we apply an individualized approach to a technique known as fixel-based analysis, to examine fibre-tract-specific abnormalities in individuals with epilepsy. We explore the potential clinical value of this individualized fixel-based approach in epilepsy patients with differing syndromic diagnoses. Diffusion MRI data from 90 neurologically healthy control participants and 10 patients with epilepsy (temporal lobe epilepsy, progressive myoclonus epilepsy, and Dravet Syndrome, malformations of cortical development) were included in this study. Measures of fibre density and cross-section were extracted for all participants across brain white matter fixels, and mean values were computed within select tracts-of-interest. Scanner harmonized and normalized data were then used to compute Z-scores for individual patients with epilepsy. White matter abnormalities were observed in distinct patterns in individual patients with epilepsy, both at the tract and fixel level. For patients with specific epilepsy syndromes, the detected white matter abnormalities were in line with expected syndrome-specific clinical phenotypes. In patients with lesional epilepsies (e.g. hippocampal sclerosis, periventricular nodular heterotopia, and bottom-of-sulcus dysplasia), white matter abnormalities were spatially concordant with lesion location. This proof-of-principle study demonstrates the clinical potential of translating advanced diffusion MRI methodology to individual-patient-level use in epilepsy. This technique could be useful both in aiding diagnosis of specific epilepsy syndromes, and in localizing structural abnormalities, and is readily amenable to other neurological disorders. We have included code and data for this study so that individualized white matter changes can be explored robustly in larger cohorts in future work.

Keywords: diffusion MRI; epilepsy; fixel-based analysis; individual analysis; white matter.

Graphical abstract

Figure 1

Methodology for individual tract-based FDC analysis. 1. A measure of FDC is quantified at each WM fixel in template space, for all healthy control participants and individuals with epilepsy. 2. Mean FDC is computed within select tracts-of-interest. 3. ComBat data harmonization is performed on the tract data to adjust for any scanner effects. 4. Assumptions of normality are tested across the control cohort. 5. The mean and SD are computed across the healthy control cohort for each tract. 6. Tractwise Z-scores are computed for each patient. INT, inverse normal transformation.

Figure 2

Exemplar spider plot display for tract z-scores in an individual patient (patient 1). Z-scores are plotted for an individual patient (n = 1) in a spider plot display. Each data point represents the Z-score for a given tract in the individual patient, with Z-scores for left hemisphere tracts shown on the lower layer (in blue) and Z-scores for right hemisphere tracts shown on the upper layer (in red). The inner dotted line (and corresponding data points in black) reflects a Z-score of −1.96, and outer solid line reflects the healthy control mean. The solid grey lines correspond to Z-scores of −1, −2, −3 and −4, with greater magnitude (more negative) scores toward the centre of the plot. The CC is included at the top centre, and the Z-score for this tract is included in both left and right hemisphere spider plots. Tracts with a Z-score of <−1.96 in either hemisphere are labelled in bold. AF, arcuate fasciculus; CC, corpus callosum; CG, cingulum; CST, corticospinal tract; FX, fornix; IFOF, inferior fronto-occipital fasciculus; SCP, superior cerebellar peduncles; SLF, superior longitudinal fasciculus; UF, uncinate fasciculus.

Figure 3

Tract- and fixel-level results for four patients with TLE. (A) Two patients with HS: Patient 1 is an individual who has left TLE with HS (L TLE-HS); Patient 2 is an individual with right TLE with HS (R TLE-HS). (B) Two patients with LN TLE: Patient 3 is an individual with MRI-negative or LN-RTLE; and Patient 4 is an individual with LN-LTLE. In all cases, spider plots on the left show Z-scores for FDC measures in each tract-of-interest (see Fig. 2 for interpretation). Fixel-level Z-score maps are shown on the right, with fixels exhibiting a Z-score of −1.96 or greater. Axial slices are placed at 10 mm increments. AF, arcuate fasciculus; CC, corpus callosum; CG, cingulum; CST, corticospinal tract; FX, fornix; IFOF, inferior fronto-occipital fasciculus; SCP, superior cerebellar peduncles; SLF, superior longitudinal fasciculus; UF, uncinate fasciculus.

Figure 4

Results in syndromic epilepsies. (A) Patient 5 is an individual with PME. (B) Patient 6 is an individual with Dravet syndrome. As with Fig. 3, spider plots are displayed on the left, showing tract-based Z-scores, while fixel Z-maps are displayed on the right (see Fig. 2 for spider plot interpretation). Axial slices are placed at 15 mm increments. AF, arcuate fasciculus; CC, corpus callosum; CG, cingulum; CST, corticospinal tract; FX, fornix; IFOF, inferior fronto-occipital fasciculus; SCP, superior cerebellar peduncles; SLF, superior longitudinal fasciculus; UF, uncinate fasciculus.

Figure 5

Results in lesional epilepsies. (A) Pane shows individual-level results for two patients with PVNH, one with additional PMG. In both cases, lesions were unilateral, with Patient 7 exhibiting left-sided PVNH, and Patient 8 exhibiting right-sided PVNH and PMG. (B) Panel shows individual-level results for two patients with BOSD: Patient 9 had a small BOSD in the right precentral sulcus; Patient 10 had a BOSD in the right post-central sulcus. See Fig. 2 for spider plot interpretation for Panels A and B. (C) Panel shows the lesion locations for all patients (Patients 7–10) on a single axial slice from a T1-weighted image in each subject’s own space.