Carbamazepine reduces memory induced activation of mesial temporal lobe structures: a pharmacological fMRI-study

We studied 21 consecutive patients with refractory TLE [11 women; mean age 35.7 years; SD 10.1; range 13 to 54 years) who underwent a comprehensive evaluation prior to epilepsy surgery at our institution. All patients fulfilled the following criteria: unilateral seizure onset of temporal lobe origin shown by continuous interictal and ictal video/EEG monitoring with scalp and sphenoidal electrodes, and unilateral lesions within the temporal lobes demonstrated by high resolution routine MRI. In 13 patients a right-sided and in eight patients a left-sided TLE was diagnosed. Ten patients had hippocampal sclerosis, three vascular lesions, two tumors, and six miscellaneous or cryptogenic temporal lobe lesions. The mean duration of epilepsy was 21.6 years (SD 9.4; range 1 to 35 years). Median seizure frequency was 3 complex partial seizures/month (range 0.1–180 seizures/month). The mean full scale IQ (WAIS-R, WCIS-R) was 96.3 (SD 20.6; range 51 to 126). Neither global nor selective cognitive impairment were a criterion for patient exclusion.

All patients received CBZ (mean serum level 7.5 mg / l; range 2.4 to 11.7). Two patients received gabapentine (GBP: 3.8; 2.3 mg / l) and three patients lamotrigine (LTG: 2.3; 3.2; 3.9 mg / l) as comedication.

Twenty healthy controls (10 women, mean age 31.7 years, SD 0.6) were also studied using fMRI.

The paradigm consisted of 10 activation blocks and 10 baseline blocks. Each block was introduced by spoken commands using the in-build communication device of the commercially available MR scanner. The duration of each block was 30 seconds. During each block, 10 sets of 16 coronal T2*-weighted MR-slices were obtained. During the activation block, retrieval from long-term memory without language was induced by self paced performance of Roland's Hometown Walking task [9, 10]. The task were explained to the subjects in detail before scanning. For each subject an individual hometown walk encompassing ten destinations was prepared. If a subject had recently moved, than the most familiar hometown was chosen. The walk started either at home or at a well known central point (e.g. place, station). Then the subjects were asked to select a familiar landmark as destination. This landmark served as starting point for the walk to the next destination. Subjects were instructed to seek destinations within a 300 to 400 meters range. After preparation of ten pairs of starting points and destinations the complete route was presented to the subject to ensure consistency and comprehension of the words denoting the route. During MR-scanning, subjects were asked to mentally navigate through the ten different routes and to imagine as many details as possible while navigating. Subjects were instructed to look around the destination if they reach the destination prior to the beginning of the baseline condition. After 30 seconds each route was interrupted by the baseline task. The baseline condition consisted of covertly counting odd numbers starting with 21. Children and mentally impaired patients counted consecutively if they had difficulties to count fluently odd numbers.

MRI scanning was performed on a 1.5 T scanner (Siemens Magnetom Symphony, Erlangen, Germany) equipped with a standard head coil. Scout and sagittal T1-weighted images were obtained in every subject to position the coronal T2*-weighted images perpendicular to the long axis of the hippocampus. For fMRI, 16 contiguous coronal T2*-weighted images covering the temporal lobes with a slice thickness of 5 mm were obtained using a standard EPI sequence (TR = 1600 msec, TE = 50 msec, field of view 192 mm, matrix 64 × 64).

Online image processing was performed using software provided with the commercially available scanner which recently has been compared to standard offline postprocessing software (SPM 99) [11]. The T2*-weighted images were corrected for subject movement using an algorithm for realignment in k-space. Images were smoothed using a Gaussian filter (width 2.0) to prepare statistical comparisons on a voxel-by-voxel basis. Voxel-by-voxel z tests were performed for each subject, identifying average signal intensity increases as measured during the activation phases, compared to the average signal intensity acquired during baseline conditions. The statistical threshold was chosen to be z > 4, P < 0.00003 for a single activated voxel. Statistical maps showing activated voxels were projected onto EPI images of the same patient thus using images for display purposes with geometric distortions similar to the fMRI data. To perform group data analysis, two investigators blinded to clinical data counted the numbers of voxels in a predefined region of interest over both MTL. The size of this region of interest was 600 to 800 voxels per person. Counting used the crus of the fornix as the posterior starting point and continued anteriorly until no activated voxels were found. Activated voxels were defined as those voxels that had neighboring activated voxels, i.e. at least one adjacent activated voxel in plane and one neighboring activated voxel on at least one adjacent MR-slice. Clustering removed small and scattered activated regions that were unlikely to represent genuine brain activation. Clustering further reduced the real type I error probability of a z > 4 threshold.

For each subject the absolute numbers of individual MTL voxel counts were determined. In patients, activated voxels for the MTL ipsilateral and contralateral to the seizure onset were counted. The total voxel number of both MTL was summed up. Spearman's rank correlation coefficients were computed between CBZ serum level, the ipsilateral, contralateral, and total number of activated voxels within MTL. A univariate analysis of variance (ANOVA) was used to study effects of the factor 'side of seizure onset' and of the covariates 'age', 'duration of epilepsy', and 'intelligence'. MTL activation contralateral to the seizure onset of patients was compared to averaged MTL activation of healthy controls using an univariate ANOVA with study group as factor, while age served as covariate. The influence of polytherapy and type of lesion on the number of activated voxels was compared.