Thalamic arousal network disturbances in temporal lobe epilepsy and improvement after surgery

Abstract

Objective: The effects of temporal lobe epilepsy (TLE) on subcortical arousal structures remain incompletely understood. Here, we evaluate thalamic arousal network functional connectivity in TLE and examine changes after epilepsy surgery.

Methods: We examined 26 adult patients with TLE and 26 matched control participants and used resting-state functional MRI (fMRI) to measure functional connectivity between the thalamus (entire thalamus and 19 bilateral thalamic nuclei) and both neocortex and brainstem ascending reticular activating system (ARAS) nuclei. Postoperative imaging was completed for 19 patients >1 year after surgery and compared with preoperative baseline.

Results: Before surgery, patients with TLE demonstrated abnormal thalamo-occipital functional connectivity, losing the normal negative fMRI correlation between the intralaminar central lateral (CL) nucleus and medial occipital lobe seen in controls (p < 0.001, paired t-test). Patients also had abnormal connectivity between ARAS and CL, lower ipsilateral intrathalamic connectivity, and smaller ipsilateral thalamic volume compared with controls (p < 0.05 for each, paired t-tests). Abnormal brainstem-thalamic connectivity was associated with impaired visuospatial attention (ρ = -0.50, p = 0.02, Spearman's rho) while lower intrathalamic connectivity and volume were related to higher frequency of consciousness-sparing seizures (p < 0.02, Spearman's rho). After epilepsy surgery, patients with improved seizures showed partial recovery of thalamo-occipital and brainstem-thalamic connectivity, with values more closely resembling controls (p < 0.01 for each, analysis of variance).

Conclusions: Overall, patients with TLE demonstrate impaired connectivity in thalamic arousal networks that may be involved in visuospatial attention, but these disturbances may partially recover after successful epilepsy surgery. Thalamic arousal network dysfunction may contribute to morbidity in TLE.

Keywords: epilepsy surgery; functional connectivity; functional neuroimaging; partial seizures; temporal lobe epilepsy.

Figure 1

Patients lose negative thalamo-occipital functional connectivity seen in controls. (A) Mean thalamo-occipital functional connectivity ismore positive in patients with TLE compared with control subjects while no difference in thalamo-cortical connectivity is detected for frontal, parietal ,or temporal lobes. (B) Cortical surface views are shown, demonstrating functional connectivity increases in the medial occipital lobe in patients with TLE seeded from bilateral thalami. Data represent seed-to-voxel functional connectivity maps (bivariate correlation) comparing preoperative patients versus matched control subjects fMRI (paired t-test, cluster threshold level p<0.05, FDR correction). Positive contrasts are shown, no connectivity decreases were observed in grey matter on negative contrasts. fMRIs are oriented with respect to epileptogenic side for patients with TLE and matched controls were flipped accordingly. N=26 patients with TLE before surgery and 26 matched control subjects. *p<0.01 paired t-test with Bonferroni-Holm correction. Centre bar shows median value, bottom and top of box designate 25th and 75th percentiles, respectively, and whiskers indicate data extremes. A: anterior; C: contralateral; FDR: false discovery rate; I: ipsilateral; P: posterior; TLE, temporal lobe epilepsy.

Figure 2

Thalamic atlas shown here is the active shape modelthalamic atlas with all 23 bilateral intrathalamic nuclei (46 total nuclei) volumetrically rendered in the top left. Four nuclei with masks smaller than two voxels (mean across participants) were excluded, and 19 bilateral (38 total) nuclei were used for analyses. MRI coronal, sagittal, and axial slices show the same atlas overlaid on a standard Montreal Neurological Institute space brain with each nucleus outlined in colour. In the coronal, sagittal, and axial slices, the CL intralaminar thalamic nuclei are highlighted in solid blue and green. For analyses involving the whole thalamus, the Harvard-Oxford atlas entire thalamus was used, whereas for connectivity analyses using CL the highlighted nuclei were used. CL, central lateral.

Figure 3

Patients with TLE exhibit perturbed thalamic connectivity and decreased ipsilateral thalamic volume. (A) Patients exhibit loss of negative connectivity between CL intralaminar thalamic nucleus and medial occipital lobe when compared with control subjects. (B) Patients exhibit abnormally increased functional connectivity between CL and MR/PBC as compared with control subjects. (C) Compared with control subjects, patients exhibit decreased intrathalamic connectivity and (D) decreased thalamic volume, on the side ipsilateral to the epileptogenic temporal lobe but not the contralateral side. (E, F) For patients, but not control subjects, higher thalamic volume is correlated with higher intrathalamic connectivity. N=26 patients with TLE before surgery and 26 matched control subjects. *p<0.01 paired t-test, **p<0.05 paired t-test with Bonferroni-Holm correction, and ***p<0.05 Spearman’s Rho with Bonferroni-Holm correction. Centre bar shows median, bottom and top of box designate 25th and 75th percentiles, respectively, and whiskers indicate data extremes. CL: central lateral; MR: median raphe; PBC: parabrachial complex; TLE, temporal lobe epilepsy.

Figure 4

Postoperative patients with TLE with improved seizures exhibit partial recovery of thalamic arousal network connectivity. (A) Cortical surface views are shown, demonstrating functional connectivity decreases in the medial occipital lobe in postoperative patients with TLE seeded from bilateral thalami. Data represent seed-to-voxel functional connectivity maps (bivariate correlation) comparing fMRI of postoperative versus preoperative patients with TLE (paired t-test, cluster threshold level p<0.05, FDR correction). Two-sided contrasts are shown. fMRIs are orientedwith respect to epileptogenic side for patients with TLE and matched controls were flipped accordingly. (B) Postoperative patients were foundto have some recovery of functional connectivity between CL and medial occipital lobe but connectivity values did not quite reach control subject values (left). However, postoperative patients’ functional connectivity between MR/PBC and CL are decreased compared with their preoperative connectivity with no difference found between postoperative and control subject connectivities (right). N=18 postoperative patients with TLE with improved seizures after surgery, the same 18 patients before surgery, and 18 matched control subjects. *p<0.01 analysis of variance with post-hoc Fisher’s least significant difference procedure. Centre bar shows median, bottom and top of box designate 25th and 75th percentiles, respectively, and whiskers indicate data extremes. A: anterior; C: contralateral; CL: central lateral; FDR: false discovery rate; I: ipsilateral; MR: median raphe; P: posterior; PBC: parabrachial complex; Post-Op: postoperative patients; Pre-Op: preoperative patients; TLE, temporal lobe epilepsy.