Specific subcortical structures are activated during seizure-induced death in a model of sudden unexpected death in epilepsy (SUDEP): A manganese-enhanced magnetic resonance imaging study
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Abstract
Sudden unexpected death in epilepsy (SUDEP) is a major concern for patients with epilepsy.
In most witnessed cases of SUDEP generalized seizures and respiratory failure preceded
death, and pre-mortem neuroimaging studies in SUDEP patients observed changes in specific
subcortical structures. Our study examined the role of subcortical structures in the
DBA/1 mouse model of SUDEP using manganese-enhanced magnetic resonance imaging (MEMRI).
These mice exhibit acoustically-evoked generalized seizures leading to seizure-induced
respiratory arrest (S-IRA) that results in sudden death unless resuscitation is rapidly
instituted. MEMRI data in the DBA/1 mouse brain immediately after acoustically-induced
S-IRA were compared to data in C57 (control) mice that were exposed to the same acoustic
stimulus that did not trigger seizures. The animals were anesthetized and decapitated
immediately after seizure in DBA/1 mice and after an equivalent time in control mice.
Comparative T1 weighted MEMRI images were evaluated using a 14T MRI scanner and quantified.
We observed significant increases in activity in DBA/1 mice as compared to controls
at previously-implicated auditory (superior olivary complex) and sensorimotor-limbic
[periaqueductal gray (PAG) and amygdala] networks and also in structures in the respiratory
network. The activity at certain raphe nuclei was also increased, suggesting activation
of serotonergic mechanisms. These data are consistent with previous findings that
enhancing the action of serotonin prevents S-IRA in this SUDEP model. Increased activity
in the PAG and the respiratory and raphe nuclei suggest that compensatory mechanisms
for apnea may have been activated by S-IRA, but they were not sufficient to prevent
death. The present findings indicate that changes induced by S-IRA in specific subcortical
structures in DBA/1 mice are consistent with human SUDEP findings. Understanding the
changes in brain activity during seizure-induced death in animals may lead to improved
approaches directed at prevention of human SUDEP.