Abstracts

Rationale: Absence seizures are the most common generalized seizure and the defining seizure type of Childhood Absence Epilepsy (CAE), a syndrome associated with significant psychosocial and developmental difficulties. Recent evidence suggests that improved pharmacological therapies are required, in turn necessitating greater understanding of the neuronal activity underlying these seizures. Previous mechanistic studies have been primarily conducted in sedated animal models, whereas reproduction of absence seizure behavior and fMRI hemodynamics requires un-drugged conditions. Methods: We used Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established and characterized polygenic model of absence epilepsy, to investigate behavior, neuronal activity, and hemodynamics associated with absence seizures. For behavioral experiments, GAERS undertook sensory detection and discrimination tasks as well as a task-free natural behavior paradigm, to contrast behavior within seizures and between seizure and baseline conditions. Neuronal and hemodynamic investigations took place in GAERS gradually habituated to body and head restraint, using single tungsten electrodes and a high-field magnet (9.4T), respectively. Fronto-parietal EEG was acquired in all conditions to detect and characterize seizures. Results:  BOLD fMRI signal during absence seizures followed dynamics qualitatively similar to those of human absence seizures, demonstrating a brief increase and prolonged decrease in cortex along with a prolonged increase in thalamic regions. Similar patterns were observed in cerebral blood flow. Initial evidence from cortical multi-unit activity demonstrates a transient peak in frequency at the start of spike-wave discharge oscillations, with longer seizures (in duration) having higher initial frequencies. Initial behavioral experiments confirmed an impairment of task-free licking during seizure, relative to control periods, and a decreased response rate to conditioned auditory stimuli. Conclusions: These data provide evidence that un-drugged conditions are necessary for the preservation of the hemodynamics and behavior of absence seizures. Further, they confirm impairment of beneficial behavior in this model which, similarly to human patients, may be related to electrophysiological seizure severity. Our un-drugged paradigm provides the opportunity to investigate the neuronal mechanisms underlying behavioral impairment and hemodynamic alterations and should facilitate future interventions for seizure prevention or interruption. Funding: Epilepsy Foundation Postdoctoral Research and Training Fellowship