Effect of topiramate and zonisamide on fMRI cognitive networks

Abstract

Objective: To investigate the effects of topiramate (TPM), zonisamide (ZNS), and levetiracetam (LEV) on cognitive network activations in patients with focal epilepsy using an fMRI language task.

Methods: In a retrospective, cross-sectional study, we identified patients from our clinical database of verbal fluency fMRI studies who were treated with either TPM (n = 32) or ZNS (n = 51). We matched 62 patients for clinical measures who took LEV but not TPM or ZNS. We entered antiepileptic comedications as nuisance variables and compared out-of-scanner psychometric measures for verbal fluency and working memory between groups.

Results: Out-of-scanner psychometric data showed overall poorer performance for TPM compared to ZNS and LEV and poorer working memory performance in ZNS-treated patients compared to LEV-treated patients. We found common fMRI effects in patients taking ZNS and TPM, with decreased activations in cognitive frontal and parietal lobe networks compared to those taking LEV. Impaired deactivation was seen only with TPM.

Conclusions: Our findings suggest that TPM and ZNS are associated with similar dysfunctions of frontal and parietal cognitive networks, which are associated with impaired performance. TPM is also associated with impaired attenuation of language-associated deactivation. These studies imply medication-specific effects on the functional neuroanatomy of language and working memory networks.

Classification of evidence: This study provides Class III evidence that in patients with focal epilepsy, TPM and ZNS compared to LEV lead to disruption of language and working memory networks.

Figure 1. Group activation and deactivation maps during the verbal fluency task

One-sample t tests of fMRI activation and deactivation maps for the 3 different patient groups on levetiracetam, zonisamide, and topiramate are demonstrated on a surface-rendered brain template. Task-relevant regions (red) include bilateral inferior and middle frontal gyrus (left > right), bilateral supplementary motor area, and the left dorsolateral parietal region. Areas of task-related deactivations (blue) include the bilateral precuneus, posterior cingulate, angular gyrus, and medial prefrontal and lateral temporal cortex. p < 0.005, 20-voxel threshold extent.

Figure 2. Group differences in fMRI activation maps during the verbal fluency task

Significant group differences between patients on levetiracetam (LEV), topiramate (TPM), and zonisamide (ZNS) are demonstrated. Patients on TPM and ZNS have less activation in frontal and parietal cognitive networks than patients on LEV. In patients on TPM, activation is reduced in the left middle frontal gyrus (MFG) and left dorsal parietal region (A). In patients on ZNS, activation is reduced in the left MFG and bilateral inferior frontal gyrus (IFG), as well as the left dorsal parietal region (B). In terms of task-relevant deactivation networks, bilateral lateral temporal regions and rolandic opercula and the right inferior parietal lobule and supramarginal gyrus are less deactivated (blue) in patients on TPM compared to those on LEV (C). Compared to ZNS, TPM shows increased activation in the IFG, insular cortex, and rolandic operculum on the left and the insular cortex, inferior parietal lobule, supramarginal gyrus, superior temporal gyrus, and rolandic operculum on the right. Differences in the left are due mainly to increased activation of task-relevant regions as shown in red (inclusively masked with LEV activation maps); on the right, activated regions lie mainly within task-negative areas, i.e., are due to impaired deactivation as shown in blue (inclusively masked with LEV and ZNS deactivation maps) (D). p < 0.005, 20-voxel threshold extent.