Dissociated multimodal hubs and seizures in temporal lobe epilepsy

Abstract

Objective: Brain connectivity at rest is altered in temporal lobe epilepsy (TLE), particularly in "hub" areas such as the posterior default mode network (DMN). Although both functional and anatomical connectivity are disturbed in TLE, the relationships between measures as well as to seizure frequency remain unclear. We aim to clarify these associations using connectivity measures specifically sensitive to hubs.

Methods: Connectivity between 1000 cortical surface parcels was determined in 49 TLE patients and 23 controls with diffusion and resting-state functional magnetic resonance imaging. Two types of hub connectivity were investigated across multiple brain modules (the DMN, motor system, etcetera): (1) within-module connectivity (a measure of local importance that assesses a parcel's communication level within its own subnetwork) and (2) between-module connectivity (a measure that assesses connections across multiple modules).

Results: In TLE patients, there was lower overall functional integrity of the DMN as well as an increase in posterior hub connections with other modules. Anatomical between-module connectivity was globally decreased. Higher DMN disintegration (DD) coincided with higher anatomical between-module connectivity, whereas both were associated with increased seizure frequency. DD related to seizure frequency through mediating effects of anatomical connectivity, but seizure frequency also correlated with anatomical connectivity through DD, indicating a complex interaction between multimodal networks and symptoms.

Interpretation: We provide evidence for dissociated anatomical and functional hub connectivity in TLE. Moreover, shifts in functional hub connections from within to outside the DMN, an overall loss of integrative anatomical communication, and the interaction between the two increase seizure frequency.

Figure 1

Schematic representation of analysis pipeline. Raw rsfMRI and DTI data underwent standard preprocessing and were coregistered to anatomical images (B), after which time series were extracted from the rsfMRI data (A) and projected onto the cortical surface. A 1000 parcel surface parcellation was used (D), and Pearson's correlation coefficients were calculated to obtain a connectivity matrix per subject (E), which contained 40% of the highest connections. Deterministic tractography was performed on voxelwise tensors calculated from the DTI images (C), and results were also projected to the surface parcellation. The number of connecting fibers per parcel (normalized for surface area size) was transformed into a connectivity matrix per subject. Weighted network analysis was performed on individual matrices per modality, yielding between a modularity index, and measures of within-module and between-module connectivity (G). Also, a group-averaged connectivity matrix (i.e., one for patients, one for controls) was calculated per modality, after which modularity analysis was run on these average matrices to obtain the benchmark modular structure per group and modality (F).

Figure 2

Modular topology in patients and controls. (A) Functional benchmark modules in healthy controls. Crimson red indicates the default mode network (DMN+), green indicates the sensorimotor module (SMM), and blue refers to the parieto-occipital module (POM). In temporal lobe epilepsy (TLE) patients (B), violet refers to the anterior default mode network (aDMN+) and crimson red to the posterior default mode network (pDMN+). (C) Displays anatomical benchmark modules in healthy controls, whereas (D) depicts average modular structure in TLE patients.

Figure 3

Within-module DMN+ connections in patients versus controls. Purple nodes indicate the aDMN+ and pDMN+, blue nodes are the parcels outside of the DMN+. (A) Depicts all within-module connections in healthy controls, (B) displays those within-module connections in TLE patients. aDMN+/pDMN+, anterior/posterior default mode newtork; TLE, temporal lobe epilepsy.

Figure 4

Group differences in modular connectivity. All displayed results are significant with P < 0.05 after false discovery rate (FDR)-correction for multiple testing and correction for covariates. (A) Displays differences in functional between-module connectivity in patients as compared to controls. Warm colors indicate higher connectivity in patients, cool colors signify higher connectivity in controls. (B) Indicates functional within-module connectivity in patients versus controls, whereas (C) shows differences in regular functional connectivity per parcel. In (D), anatomical between-module differences are depicted. There were no significant parcel-based differences between groups in within-module or regular anatomical connectivity after correcting for confounders and multiple testing.

Figure 5

Correlation between modular default mode network (DMN+) disintegration and anatomical between-module connectivity. TLE lateralization is depicted separately, with right temporal lobe epilepsy (RTLE) patients showing lower anatomical between-module connectivity than left temporal lobe epilepsy (LTLE) patients. The association between functional modular DMN+ disintegration and anatomical between-module connectivity is present in the sample as a whole, and the two groups separately.

Figure 6

Mediation analyses of the associations between functional default mode network (DMN+) shift, anatomical between-module connectivity loss, and monthly seizure frequency. *P < 0.05, **P < 0.01. Numbers next to arrows are normalized coefficients in regression models, with the normalized coefficients when taking the mediator into account in parentheses.