Temporal lobe epilepsy (TLE) is a common and relatively homogeneous form of epilepsy in which seizures originate in the mesial temporal regions including the hippocampus. The seizures propagate across temporal lobe networks and throughout the brain. When refractory to pharmacological therapy, seizures can occur in this manner over several years or decades over the duration of disease. Our working model consists of a temporal and cingulate network which evolves over years in both functional and structural connectivity. This work represents the first step in characterizing this network evolution using MRI.

We have currently recruited 26 TLE patients and 26 age (+/- 2 years) and gender matched controls. This cross sectional analysis included 20 TLE patients, 15 who were seizure free after resection of the temporal lobe or anterior temporal lobe (sz free group, 7F, 10 right TLE, duration 17.1 +/- 13.1 yrs) and 5 patients who had seizure recurrence (sz recur group, 4F, 5 right TLE, duration 18.4 +/- 16.3 yrs). Subjects were scanned on a 3T MRI scanner using resting state fMRI for functional connectivity (FC) (TR=2 s, 3x3x4 mm3, 300 vols) and diffusion weighted MRI for structural connectivity (SC) (b=1600 s/mm2, 92 directions, 2.5 x. 2.5 x 2.5 mm3, 3 averages).

The nodes of interest were defined ipsilateral and contralateral to seizure onset (hippocampus: HIPI, HIPC; insula: INSI, INSC; thalamus: THALI, THALC). In addition, two midline bilateral structures were defined (precuneus: PREC; midcingulate cortex: CING). For FC, the preprocessed time series were averaged across each node and pairwise correlations were determine and transformed to Z scores. For SC, the FSL probabilistic fiber tracking protocol was computed separately with each region as seed with the other seven regions as targets and terminations. The SC was computed as the percent of total fibers originating from the seed reaching the target. All patient FC and SC values were transformed to the percent change from age matched control. The sz free group was divided into those with less than 10 years (n=5) and greater than or equal to 10 years (n=10) disease duration. T-tests were used to determine difference from controls and between sz free and sz recur groups (p<0.01).

Figure 1 shows network diagrams with each node as a red circle. Paths with decreased connectivity from controls are indicated by dashed lines. There were no increases. Figure 2 shows the change from control for each sz free patient (FC blue, SC red) for two paths (INSI-CING, HIPI-HIPC) shown in Figure 1. Zero on the y-axis represents the age corrected value of the control subject. The 10 year line dividing the data in the left and right columns of Figure 1 is indicated on the x-axis. Figure 3 shows the path and the associated individual data of the path where the SC of the sz free group was increased over the sz recur group. There were no differences between groups in FC.

These results suggest an evolution of both FC and SC networks over years of duration in TLE. The decreases in FC in HIPI-HIPC and HIPI-PREC at durations 10 years or greater are consistent with the literature [1]. In addition, FC decreases from the INSI are also not surprising given the known role of the insula in TLE seizures [2]. In SC, the decreases in the sz free group were also generally consistent with other reports [3].

This work includes several novel concepts. The first is the age control correction of the patient data. We enrolled an individual age matched control for each patient. We then fit the controls vs. age and subtracted this fit from the patient and divided by it to get a percent change from age corrected control. Second, we grouped patients into sz free and sz recur groups and detected SC differences in bilateral hippocampal paths. Third, we investigated early and late changes in connectivity and found more significant changes later in duration. Finally, out of 28 paths investigated, we found 2 consistent ipsilateral paths with decreases in both FC and SC.

In summary, we found consistent decreases in ipsilateral hippocampus and insula FC and SC primarily after 10 years of duration of disease in TLE patients with seizure freedom after surgery. In those with seizure recurrence, there were more severe bilateral hippocampal SC decreases when compared to those with seizure freedom.