Abstracts

Rationale: Because of their wide availability and relatively low expense, rodent models of epilepsy are by far the most common substrate for studying tonic-clonic activity in-vivo. While seizures observed in rats reliably mimic the electrographic morphology and behavioral manifestations seen in humans, the relative simple development of the rodent cortex makes neuroimaging studies difficult to interpret. This study attempts to correct this deficiency by using a bicuculline-induced, ferret model of tonic-clonic seizures. Compared to rodents, ferrets have a closer evolutionary link to humans and share many of the same anatomical structures in cortical and subcortical regions. Functional neuroimaging data during ictal periods may elucidate the networks involved in seizure propagation and provide some insight on focality of tonic-clonic activity in humans. Methods: Simultaneous measurements of scalp EEG and Blood Oxygen Level Dependent (BOLD) signal were collected during ictal periods in ferrets. Seizures were induced through intravenous injections of bicuculline solution, which is a strong GABAA receptor antagonist. All ferrets were female and ranged in weight from 300 to 700 grams. BOLD measurements were recorded with a 9.4T Varian magnet while the animal was under ketamine / xylazine anesthesia. Recordings of scalp EEG were collected using two carbon-filament electrodes. To reduce movement artifact during fMRI recordings, each animal was paralyzed with d-tubocurarine-Cl and artificially ventilated through a tracheostomy. Heart rate and blood pressure were monitored through an arterial line attached to an analogue-to-digital pressure transducer. Blood gas levels were periodically measured to ensure appropriate physiology, and corresponding adjustments were occasionally made to respiration rate and tidal volume. Results: All collected data was processed with in-house fMRI analysis software used in previous studies from our lab. A two-sample t-test was performed to determine significant changes in blood-oxygenation between baseline and seizure periods (as defined by EEG activity). The results revealed widespread increases in BOLD signal for both cortical and sub-cortical regions during ictal periods. A time-course analysis of neuroimaging data showed progressive spread of hemodynamic increases as the seizure propagated from its initial onset zone. Functional increases during ictal periods were followed by large post-ictal decreases in cortical and sub-cortical areas. This correlated closely with the cortical suppression seen on EEG during this time period. Conclusions: Using simultaneous recordings of scalp EEG and functional neuroimaging, a new model of tonic-clonic seizures was investigated. Regions involved in the initiation and spread of seizures in ferrets have closer anatomical correlates to human patients, and discoveries made using this model could guide more targeted therapy in humans suffering from this disorder. Future work could further characterize the time-course of fMRI changes during the ictal period, and may include electrophysiology experiments that better describe neuronal activity.