Ictal neural oscillatory alterations precede sudden unexpected death in epilepsy

Abstract

Sudden unexpected death in epilepsy is the most catastrophic outcome of epilepsy. Each year there are as many as 1.65 cases of such death for every 1000 individuals with epilepsy. Currently, there are no methods to predict or prevent this tragic event, due in part to a poor understanding of the pathologic cascade that leads to death following seizures. We recently identified enhanced seizure-induced mortality in four inbred strains from the genetically diverse Collaborative Cross mouse population. These mouse models of sudden unexpected death in epilepsy provide a unique tool to systematically examine the physiological alterations during fatal seizures, which can be studied in a controlled environment and with consideration of genetic complexity. Here we monitored the brain oscillations and heart functions before, during, and after nonfatal and fatal seizures using a flurothyl-induced seizure model in freely moving mice. Compared to mice that survived seizures, non-survivors exhibited significant suppression of brainstem neural oscillations that coincided with cortical epileptic activities and tachycardia during the ictal phase of a fatal seizure. Non-survivors also exhibited suppressed delta (0.5–4 Hz)/gamma (30–200 Hz) phase-amplitude coupling in cortex but not in brainstem. A connectivity analysis revealed elevated synchronization of cortex and brainstem oscillations in the delta band during fatal seizures compared to nonfatal seizures. The dynamic ictal oscillatory and connectivity features of fatal seizures provide insights into sudden unexpected death in epilepsy and may suggest biomarkers and eventual therapeutic targets.

Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy

“…1A ). Flurothyl-induced seizures are typically generalized forebrain seizures; however in seizure-prone mouse models or in mice exposed to higher concentrations of flurothyl, mice can experience a suppression of brainstem oscillations followed by sudden death (Gu et al, 2022; Kadiyala et al, 2016). The B4gat1 M155T/M155T mutation was originally identified based on a hindbrain axon guidance phenotype, suggesting they may have currently unknown defects in brainstem development or circuitry that could render them more susceptible to fatal brainstem seizures (Wright et al, 2012).…”

“…1A). Flurothyl-induced seizures are typically generalized forebrain seizures; however in seizure-prone mouse models or in mice exposed to higher concentrations of flurothyl, mice can experience a suppression of brainstem oscillations followed by sudden death (Gu et al, 2022;Kadiyala et al, 2016).…”

Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy

“…9A). Flurothyl-induced seizures are typically generalized forebrain seizures; however in seizure-prone mouse models or in mice exposed to higher concentrations of flurothyl, mice can experience a suppression of brainstem oscillations followed by sudden death (84), (85) . The B4GAT1 M155T/M155T mutation was originally identified based on a hindbrain axon guidance phenotype, suggesting they may have currently unknown defects in brainstem development or circuitry that could render them more susceptible to fatal brainstem seizures (36) .…”

Perspectives on the basis of seizure-induced respiratory dysfunction

“…Likewise, excitatory synaptic transmission has been shown to facilitate SD in a seizure-related mouse model of familial hemiplegic migraine type-1 (Tottene et al, 2009 ). Furthermore, SUDEP-prone mouse lines showed cortical epileptic activity that correlated with abnormal brainstem electroencephalographic (EEG) oscillations and suppression of brainstem activity (Gu et al, 2022 ), suggesting cortical-brainstem connectivity facilitated SD propagation to the brainstem.…”