Resting state functional connectivity patterns associated with pharmacological treatment resistance in temporal lobe epilepsy

Abstract

There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well-controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance.

Keywords: Biomarker; Epilepsy; Resting State fMRI; Temporal lobe epilepsy; Treatment response; fMRI.

Conflict of interest statement

Conflicts of Interest and Affirmation

The authors report no conflicts of interest.

Copyright © 2018 Elsevier B.V. All rights reserved.

Figures

Figure 1.

Processing steps per case, a) parcellation of T1-weigthed anatomical MRI data into 164 pre-defined (Harvard Oxford Atlas) regions of interest (ROIs), b) mean Fisher-transformed Z-scores of Resting State Functional Connectivity (RsFC) correlation between all 164×164 ROI-to-ROI connections shown in one connectivity matrix, c) extraction of RsFC connectivity Z-scores of interest.

Figure 2.

Mean Fisher-transformed Z-scores of Resting State Functional Connectivity (RsFC) correlations between the left thalamus and left hippocampus, and between the right thalamus and right hippocampus in healthy controls (Controls, green, n=13), treatment-resistant left TLE patients (trTLE, red, n=8), and well-controlled left TLE patients (cTLE, blue, n=7). Error bars indicate the 95% confidence interval.

Figure 3.

Subject level analysis of functional connectivity shows individual differences in Fisher-transformed Z-scores of Resting State Functional Connectivity (RsFC) correlations between the left thalamus and the left hippocampus. Healthy controls (Controls, green, n=13), treatment-resistant left TLE patients (trTLE, red, n=8), well-controlled left TLE patients (cTLE, blue, n=7).

Figure 4.

Scatterplot showing individual measurements in 2-dimensional feature space, containing of ipsilateral thalamo-hippocampal RsFC measures bilaterally (left Thalamus to left Hippocampus (HC)). Showing two clearly distinguishable clusters of well-controlled and treatment-resistant left-TLE cases, with one clear outlier, one medically tractable case falling among the cluster of treatment-resistant cases. The Mahalanobis distance (MD) is computed between the two cluster-centers, seen here visualized with a Gaussian mixture distribution. Contour lines are added representing the probability distribution function (min-max).

Figure 5.

The Mahalanobis distance between the two group clusters (for bilateral thalamo-hippocampal connectivity, see Figure 4) was randomized (10,000x bootstrap – with replacement). Randomization was performed once on subject data assigned to the correct groups (trTLE and cTLE, green) and once when subject data was randomly assigned to one of the two groups (blue). The histogram results of the bootstrapping are shown for both real and random groups. With random groups approaching zero, or no significant Mahalanobis distance. Real group distances ranged from 1 to over a 100 (shown here for the range 0 to 50).