Brainstem Seizures and Associated Cardiorespiratory Depression Following Intrahippocampal 4-AP Application in Freely Moving Rats

Cardiorespiratory dysfunction during or after seizures may contribute to hypoxic brain damage or, in some cases, sudden unexpected death in epilepsy (SUDEP). Disruption of lower brainstem cardiorespiratory systems by seizures are postulated to impair respiratory and cardiac function. Here, I explored the effects of brainstem seizures on cardiorespiratory function using a rat model of intrahippocampal 4-aminopyridine (4-AP)-induced acute recurrent seizures. I hypothesize that seizures, focally initiated in the hippocampus, become generalized and propagate into the brainstem, disrupting brainstem function leading to cardiorespiratory depression. Animal mortality is associated with brainstem seizures which cause respiratory arrest followed by cardiac arrest. Hippocampal, cortical and caudal dorsomedial brainstem electrographic recordings together with cardiorespiratory monitoring were conducted in freely moving rats. Increased respiration rate but unchanged heart rate occurred during the seizures in the hippocampus and cortex. Status epilepticus (SE) without brainstem seizures increased respiration and heart rates whereas SE with intermittent brainstem seizures induced repeated cardiorespiratory depression leading to death. Respiratory arrest prior to asystole was a terminal event. Phenytoin (100 mg/kg, i.p.) terminated brainstem seizure-induced cardiorespiratory depression and prevented death in 5/6 rats. Focal electrical stimulation of the brainstem also suppressed cardiorespiratory parameters. I conclude that seizure propagation to the brainstem produces cardiorespiratory depression related to mortality. Although cardiorespiratory depression was observed during SE, I hypothesize that the mechanisms causing death in my model are shared with spontaneous seizures associated with SUDEP. Finally cross frequency coupling and phase coherence features were able to identify different seizure states. These variables may help elucidate the network mechanisms that lead to brainstem seizure generation.