This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: Childhood absence epilepsy is associated with impaired quality of life, including cognitive, psychosocial and learning deficits that may persist after seizure suppression. Understanding neuronal mechanisms that impair behavior during absence seizures requires animal models, but previous studies showed behavioral and hemodynamic discrepancies between some models and human seizures. Here we characterize seizure hemodynamics and associated behavior in awake, non-sedated animals, and investigated electrophysiological differences between physiologically and behaviorally mild and severe spike-wave discharges (SWDs). Methods: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) were used. Rats aged 4-8 months were habituated to body and head restraints, allowing for awake functional MR imaging. 9.4 tesla fMRI was performed in awake, drug-free animals with simultaneous skull carbon-electrode electroencephalography (EEG) for detection of SWDs. Separately, rats implanted with skull electrodes were trained on one of two behavioral tasks. A goal-oriented sensory detection task involved an 8kHz tone played at one to two-minute intervals to signify reward availability of 20% sucrose water. A repetitive spontaneous licking task involved the same 20% sucrose water rewarded at varying intervals without the tone, encouraging the rats to randomly check for rewards. Single unit thalamocortical recordings were acquired with 32-channel silicon probes and the OpenEphys acquisition system, sampled at 30 kHz. Neurosuite software was used for preprocessing. MATLAB and python scripts were used for analyses. Results: fMRI was obtained from 18 animals and 1,906 SWDs. We observed a decrease in blood oxygen level dependent (BOLD) signal in multiple cortical regions during SWDs and an increase in the thalamus. In the sensory detection task (17 rats and 5,836 SWDs), the correct response occurred in < 1% of tones played during ictal periods and 90.05% during baseline periods (p< 0.0001), with a rapid recovery of responsiveness post-SWD. In contrast, in 24 rats and 18,797 seizures in the spontaneous licking task, the degree of impairment varied between SWDs: rats continued to lick during 285 SWDs, and ceased during 2367. Behavioral impairment on the spontaneous licking task correlated with SWD properties including duration (p< 0.01) and vRMS (p< 0.0001). Recordings in 15 animals showed heterogeneous cortical and thalamic individual neuronal firing patterns during SWDs. The degree of change in firing activity, including both transient and sustained increases and decreases in spiking, were more pronounced in longer duration seizures. Conclusions: Non-sedated GAERS SWDs featured cortical and thalamic hemodynamics and behavior consistent with human absence seizures. GAERS displayed overall behavioral impairment during SWDs, with approx. 10% having some preserved behavior. EEG properties correlated with the degree of behavioral impairment. Cortical and thalamic neurons showed a variety of changes during seizure activity providing mechanistic insights into behavioral impairment during seizures. Funding: Please list any funding that was received in support of this abstract.: NIH R37 NS100901. Postdoctoral Fellowship 337053, Epilepsy Foundation.
