Seizure-associated spreading depression is a major feature of ictal events in two animal models of chronic epilepsy

Abstract

Spreading depression is characterized by slow, propagating wave of cellular depolarization (SD) and is wildly associated with migraine, stroke, and traumatic brain injury. Seizures and spreading depression (or spreading depolarization, SD) have long been reported to coincide in acute seizure induction experiments. However, SD has not been observed associated with spotaneous seizures in animal or clinical recordings. Recently, advances in acquisition systems for neurointensive care units have made routine observations of SD possible. In clinical epilepsy, SD has been suggested as a candidate mechanism for migraine/headache like events following seizures as well as for post-ictal generalized suppression. In animal models of epilepsy, seizure-induced brainstem SD has also been demonstrated as a mechanism of sudden unexplained death in epilepsy (SUDEP). The interplay between seizures and SD has also been suggested in computational models, where the two are components of the repetoir of neuronal activity.However, the spatiotemporal dynamics of SD with respect to spontaneous seizures in chronically epileptic brain remains ambigous. We analyzed continuous long-term DC sensitive EEG measurements from two fundamentally different animal models of chronic epilepsy. We found that SD was associated with approximately one-third of all spontaneous seizures in each model. Additionally, SDs participated in the organization of seizure clusters. These findings demonstrate that the underlying dynamic of epileptic events is broader than seizures alone.Significance StatementSpreading depression is characterized by slow, propagating wave of cellular spreading depolarization (SD) and is wildly associated with migraine, stroke, and traumatic brain injury. Although recently the linkage between SD and induced seizures has been recognized, the mechanistic relationship between SD and spontaneous seizures remains poorly understood. Here, we utilized long-term, stable, near-DC measurements of the brain activity in two fundamentally different animal models of epilepsy to investigate the SD-seizure interplay. We found that SD is a frequent phenomenon in the epileptic brain, in these models is associated with more than a third of all seizures, and appears to connect seizures in seizure clusters. Although in one model SD stereotypically propagates out from a single focus in the hippocampus, depression of the field-potentials is observed synchronously across much of the hippocampus. These observations highlight the value of stable DC measurements for accurate understanding of SD and its propagation. We found that spontaneous ictal events that include both seizures and SD are frequent in animal models of epilepsy. These findings suggest that SD could be a valuable target for treatment and control of epilepsy.

Spreading depression as an innate antiseizure mechanism

“…Profound shifts in extracellular concentrations of most if not all ions, elevated levels of numerous neurotransmitters and neuromodulators, metabolic and hemodynamic alterations, and morphological and gene expression changes, can all contribute to the antiseizure effect to some extent. It has been proposed that the concept of the ictus in epilepsy could be broadened to include a trajectory of seizures terminated by SD, seen in spontaneous epilepsy 7 and predicted by biophysics 9,10 . Given the overlapping cellular and electrophysiological mechanisms of seizures and SD, it is not easy to find an intervention that directly and selectively blocks SD occurrence without affecting the seizures to dissect the causality between these two phenomena and their mechanisms.…”

“…Both are also known to predispose to seizures. Moreover, seizures and SD share common triggers 1 , and seizures can culminate in SD both in experimental animals 6,7 and in humans 8 . Indeed, a mixed dynamic of seizure and SD is predicted by an extended Hodgkin-Huxley model incorporating cell volume changes and oxygen availability, suggesting that seizures and SD represent a dynamic continuum of neuronal membranes 9,10 .…”

Preventing neuronal edema increases network excitability after traumatic brain injury

“…secondary brain insults following TBI (14,15). Although SDs are more prevalent than seizures in human recordings after brain injury (53% SD prevalence vs. ~15% seizure prevalence) (17,74,75), both have the potential to exacerbate tissue damage (13,25,26), and both occur together in animal models (19)(20)(21)(22)(23)(24) and in humans after TBI (17). Importantly, both SDs and seizures in patients with TBI are correlated with poorer clinical outcomes (14,27) and are being considered as measurable biomarkers of injury (76).…”

“…In experimental models, SDs are observed immediately after injury, with electrophysiological depression lasting almost 3 hours after injury (18). SDs and seizures are also seen together in experimental preparations (19)(20)(21)(22)(23)(24). When either SDs or seizures occur in the injured brain, they impose a substantial metabolic burden that exacerbates tissue damage (13,25,26).…”

Development of Mechanistic Neural Mass (mNM) Models that Link Physiology to Mean-Field Dynamics

“…Mortality in persons with epilepsy are nearly two times that of the population at large ( Thurman et al, 2017 ). In 2015, Aiba and Nobels demonstrated that spreading depolarization (SD) invading the brainstem could cause autonomic shutdown, and therefore might be one of the mechanisms of SUDEP ( Aiba and Noebels, 2015 ), and once looked for, spontaneous seizure-associated SD has been observed in animal models of epilepsy ( Ssentongo et al, 2017 ; Bahari et al, 2018 ; Loonen et al, 2019 ).…”