Multitier Network Analysis Using Resting-state Functional MRI for Epilepsy Surgery

Abstract

Resting-state functional MRI (rs-fMRI) has been utilized to visualize large-scale brain networks. We evaluated the usefulness of multitier network analysis using rs-fMRI in patients with focal epilepsy. Structural and rs-fMRI data were retrospectively evaluated in 20 cases with medically refractory focal epilepsy, who subsequently underwent surgery. First, structural changes were examined using voxel-based morphometry analysis. Second, alterations in large-scale networks were evaluated using dual-regression analysis. Third, changes in cortical hubs were analyzed and the relationship between aberrant hubs and the epileptogenic zone (EZ) was evaluated. Finally, the relationship between the hubs and the default mode network (DMN) was examined using spectral dynamic causal modeling (spDCM). Dual-regression analysis revealed significant decrease in functional connectivity in several networks including DMN in patients, although no structural difference was seen between groups. Aberrant cortical hubs were observed in and around the EZ (EZ hubs) in 85% of the patients, and a strong degree of EZ hubs correlated to good seizure outcomes postoperatively. In spDCM analysis, facilitation was often seen from the EZ hub to the contralateral side, while inhibition was seen from the EZ hub to nodes of the DMN. Some cognition-related networks were impaired in patients with focal epilepsy. The EZ hub appeared in the vicinity of EZ facilitating connections to distant regions in the early phase, which may eventually generate secondary focus, while inhibiting connections to the DMN, which may cause cognitive deterioration. Our results demonstrate pathological network alterations in epilepsy and suggest that earlier surgical intervention may be more effective.

Keywords: default mode network; epilepsy; large-scale network; preoperative evaluation; resting-state functional MRI.

Fig. 1

Representative networks showing decrease in functional connectivity in epilepsy patients compared to controls. The center of the cursor represents the regions with statistically significant decrease (FWE, p <0.05): (A) bilateral middle prefrontal cortex in the default mode network, (B) right inferior parietal lobule in the salience network, (C) left prefrontal cortex in the left executive control network, and (D) precuneus in the precuneus network. Upper row is the coronal section, middle row is the axial section, and lower row is the sagittal section. FWE: family-wise error.

Fig. 2

Results of hub analysis in 20 patients with focal epilepsy. The cortical hubs, clusters with z-values >3, are overlaid on top of the anatomical image of each patient. In panel A, the patients obtained Engel class 1 outcome. In panel B, the patients obtained class 2 or 3 outcome. The number represents case number as shown in Tables 1 and 2. Yellow arrows indicate identified EZ hubs. White outlines indicate the resected area. All 14 cases showed EZ hub in and around the resected area in panel A, whereas 3 out of 6 cases had no EZ hub in panel B. The contralateral hubs can also be seen in all cases except for cases 4, 5, 7, and 18. EZ: epileptogenic zone.

Fig. 3

A diagram illustrating the hypothesized mechanism underlying the alterations observed in large-scale networks in focal epilepsy patients. (A) Early disease stage and (B) late disease stage. Circle, intensity of regional connectivity (=hub, large means strong intensity); white arrow, driving connection; black arrow, inhibiting connection; and dotted line, surgical resection. Driving connection appears from the EZ to distant areas including the contralateral region in the early disease stage. Inhibiting connection to the core regions of the DMN also appears. (A, upper). Epilepsy surgery is effective in such early stage (A, lower). However, secondary focuses start to manifest in connected distant areas over time (B, upper), and epilepsy surgery is less effective for these cases (B, lower). EZ: epileptogenic zone.