Abstracts

Rationale: Resting-state functional connectivity (FC) is altered in baboons with GGE (EPI) compared to healthy controls (CTL). We evaluated whether antiepileptic therapy with valproic acid (VPA) would normalize FC in the abnormal networks. Methods: Twenty baboons (10 EPI and 10 CTL), matched for age and weight, were scanned in two MRI sessions. In the first MRI session, baseline scans were acquired, then each animal received a 20 mg/kg intravenous loading dose of VPA, and a second (post VPA) resting-state fMRI scan was acquired. For the next week, each animal received daily dosages of 20-80 mg/kg. The final mean trough VPA level was 13 (range 5 to 22) mcg/ml. After one week of VPA treatment, a final resting-state fMRI was acquired for each animal. All images were pre-processed using the most current rs-fMRI techniques. Independent component analysis (ICA)?"using an automatic estimation of the number of components?"was used to determine the baboon's major brain networks. A data-driven approach was utilized to evaluate functional connectivity so that our results would not be influenced/limited by our seed selection. Each network mask was then thresholded (50% of max z-score), then used to assess group-wise FC differences between baseline and treatment states. Finally, differences between EPI and CTL groups were correlated with the final VPA levels. We controlled for age, gender, and VPA dose effects. Results: At baseline, the EPI group demonstrated increased FC in the basal ganglia, amygdalar, frontoparietal convexity, brainstem, and orbitofrontal networks, and decreased connectivity in the precuneus, frontoparietal operculum, bilateral parietal, temporoparietal, and left visuomotor networks. After VPA administration, areas initially demonstrating increases in FC were reversed in the amygdalar, frontoparietal (Figures 1 and 2), and orbitofrontal networks; areas initially exhibiting decreases in FC were reversed in the right parietal, temporoparietal and visuomotor networks. A significant VPA level effect was noted in the amygdalar, orbitofrontal and temporoparietal networks. Conclusions: FC in EPI baboons receiving VPA appears to be decreased in regions participating in the presumed epileptic network and increased in temporal, parietal and occipital connectivity. Most of the reversals in FC are correlated with VPA levels reflecting a direct therapeutic effect. While our findings do not account for all potential FC changes at therapeutic levels of VPA, resting-state functional MRI demonstrates a treatment response, which may also provide insight into mechanisms of action of antiepileptic medications. Funding: NIH/NINDS R21 NS 084198-01