Abstracts

Rationale: Absence seizures are the most common seizure type across generalized epilepsy syndromes, consisting of behavioral arrest with concurrent widespread EEG spike-and-wave discharges (SWDs). They are the defining seizure type of childhood and juvenile absence epilepsy, syndromes which may be associated with developmental and cognitive impairments. Neural mechanisms of seizure initiation and propagation are far from completely understood, and first-line pharmaceutical therapeutics are only ~50% effective. Consequently, an improved understanding of these mechanisms is required, and the variation in degree of behavioral impairment observed between seizures (within an individual) offers a promising route for their investigation. We have explored this variation in a polygenic rat model of absence epilepsy by studying its local and global hemodynamic and electrophysiological correlates in multiple modalities. Methods: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) between 3 and 12 months were divided into groups to study variation in hemo- and neurodynamics, and in behavioral severity between absence seizures. Both groups were implanted with frontoparietal EEG screw electrodes to facilitate comparison according to SWD parameters. The hemo- and neurodynamics group was habituated to body and head restraint by incremental introduction, while the behavioral group was trained in stimulus detection and discrimination tasks in an operant chamber. Neuronal activity and local cerebral blood flow (CBF) were measured using simultaneous local field potential and multiunit (MUA) recordings and laser Doppler flowmetry. Results: Local MUA in deep layers of multiple cortical regions increased (RMS voltage) to ~120% of pre-seizure baseline during the first 2 seconds of seizure, before gradually decreasing to ~90% of baseline (n=8, p < 0.05). This was accompanied by a similar dynamic of CBF, increasing to ~105% before decreasing to ~95% (n=8, p < 0.05). This pattern closely matches seizure start-related dynamics of blood oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) in humans. It disagrees, however, with prolonged increases in CBF, BOLD and neuronal activity in anesthetized animal models of SWDs. The relationship between SWD parameters (potentially indicative of seizure severity, as seen in clinical absence seizures) and local activity was also investigated, showing that the amplitude of the transient peaks and prolonged troughs in both CBF and MUA were greater for seizures of increased duration (P < 0.05 in all cases), and that increased SWD power (relative to baseline) was associated with seizures of greater MUA peak amplitude (P < 0.001). GAERS were successfully trained in stimulus detection with an auditory response task. Conclusions: Similarities of local activity transients with hemodynamics of clinical absence seizures, and contrasts with local activity in sedated rat models of SWDs, suggest that the latter is unsuitable as a means of studying the mechanisms of absence seizures. The relationship between transient local changes and seizure duration indicate that initial state of the brain may be a significant determinant of seizure duration. Correlation of the intensity of local activity with EEG parameters suggest that GAERS may recapitulate the variation in behavioral severity observed in patients with absence seizures. Further investigations in this model may reveal the neuronal basis of absence seizure initiation and the determinants of seizure severity, potentially leading to improved treatments for this disorder. Funding: Epilepsy Foundation & American Epilepsy Society: Post-Doctoral Research Training Fellowship, Award Number: 337053 NIH Grant 5R21NS083783-02