Abstracts

Rationale: Since its discovery by Leao, the role of spreading depolarization (SD) in the underlying pathophysiological processes of neuronal/glial dysregulation has been extensively studied. SD has been shown to play a crucial role in several human pathological conditions including migraine, stroke, and traumatic brain injury (Dreier et al., 2018). Within epilepsy research the study of SD has been mostly focused on slice electrophysiology experiments (Harreveld et al., 1954; Somjen et al., 2009) or genetic and induced models of seizures (Aiba and Noebels, 2015; Loonen et al., 2019).In vivo animal studies such as Aiba et al. and Loonen et al. have brought to light the pivotal role of SD in sudden unexplained death in epilepsy (SUDEP). However spatiotemporal dynamics of SD with respect to spontaneous seizures in the epileptic brain remains unknown. To determine the relationship between spontaneous seizures and SD we analyzed continuous long-term DC sensitive EEG measurements from two fundamentally different animal models of chronic acquired epilepsy. Methods: We measured seizure-associated SD in two dorsal hippocampal sites in retrospective analysis of recordings collected in the development of a murine model of post-cerebral malaria (post-CM) epilepsy (Ssentongo et al., 2017). To better characterize SD occurrence and propagation as well as its relationship with seizures, we used the rat tetanus toxin model of temporal lobe epilepsy ( Sedigh-Sarvestani et al., 2014). To allow observation of the propagation pattern of spreading depression animals were implanted bilaterally with multiple hippocampal electrodes extending along the rostral-caudal axis of both hippocampi. We have extended our previous recording system (Ssentongo et al., 2017) to provide 16 channels of wide-band biopotential recording plus head acceleration in rats. We utilized this technology for experimental measurements of cortical activity and hippocampal local field potentials in the tetanus toxin model of temporal lobe epilepsy in rats. Results: We found frequent instances of spontaneous seizure associated SD in two chronic animal models of epilepsy: the rat tetanus toxin (TeTX) model of temporal lobe epilepsy (TLE) and the murine model of post-cerebral malaria (post-CM) epilepsy. Collectively SDs were associated with approximately one third of the seizures in each animal model. Further, we found that in epileptic rats SD propagates across hippocampus with velocities ranging from 6 to 40 mm/min. We hypothesize that in epileptic conditions, the tissue is primed to support faster propagation analogous to the way that seizure propagation speeds can be parametrically modulated via neuronal excitability (Pinto and Ermentrout, 2001).Our findings indicate that hippocampal SD coincides with prolonged suppression of both ECoG and hippocampal activity. We demonstrate that quieting of ECoG may be an analogue for SD. This facilitates identification of the electrophysiological correlates of SD in human recordings with less costly and invasive ECoG measurements. Conclusions: Our findings provide a platform for mechanistic investigation of seizure-SD dynamics in chronic epilepsy and cases of sudden unexplained death in epilepsy (SUDEP) that may lead to new intervention and treatment approaches. Funding: Cure Epilepsy Foundation; NIH R01EB019804