Abstracts

Rationale: Tonic-clonic seizures cause widespread physiological changes throughout the brain. We utilized a rodent model to study these episodes by systemically injecting bicuculline, a GABA-A receptor antagonist, into normal Wistar rats and non-invasively measuring the resulting physiological changes with combined blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Our aim was to observe and describe the spatial localization and timing of BOLD signal changes during the pre-ictal, ictal and post-ictal phases. Methods: We studied changes in BOLD-fMRI signal at 9.4 T in anesthetized Wistar rats (n=13) during bicuculline-induced generalized tonic-clonic seizures (n=17). Seizure activity on EEG appeared as high amplitude, high-frequency polyspike discharges followed by lower frequency, clonic paroxysmal activity with total electrographic seizure duration of 348.71 ± 25.78 s (mean ± SEM). The BOLD-fMRI images we obtained were spatially aligned by rigid body transformation using BioImage Suite. We created group t-maps comparing fMRI signal at various times against 30 s baseline signal (height threshold t>2.00) across all seizures and superimposed these t-maps on high resolution FLASH anatomical images. Results: In the 30 seconds before seizure onset according to EEG we observed significant BOLD increases in focal areas of cortex and thalamus. In the ictal period we saw large BOLD signal increases across the cortex, brainstem and thalamus and decreases in the hippocampus. Post-ictally we found a widespread decrease in BOLD signal persisting for several minutes. Conclusions: Our pre-ictal findings suggest that early localized hemodynamic changes may precede the earliest electrophysiological changes measurable through EEG. The BOLD signal increases we observed ictally represent increases in neuronal activity. Although BOLD decreases were found in the hippocampus, we have previously observed increased electrical activity in this region during bicuculline induced tonic-clonic seizures suggesting a local dissociation between hemodynamics and electrophysiology in the hippocampus. The post-ictal BOLD signal decreases suggest a generalized state of depressed neuronal activity. These findings show that so-called “generalized” tonic-clonic seizures induced by bicuculline appear to have a focal bilateral onset, and to involve specific cortical and subcortical networks. This rodent model may elucidate the pathophysiology of similar abnormal paroxysmal discharges and seizure activity in humans and merits further study. Supports: RO1NS049307 (H.B.); P30 NS052519, R01MH067528 (F.H.); The Betsy and Jonathan Blattmachr family.