Multifocal Initiation of Spreading Depolarization by Generalized Tonic-Clonic Seizures

Epileptic seizures are self-terminating events, yet the precise mechanisms underlying their cessation and the subsequent postictal suppression remain incompletely understood. Spreading depression (SD)-a traveling wave of intense depolarization and electrical silence-has emerged as a potential mechanism of focal seizure termination. Given that generalized tonic-clonic seizures involve widespread hyperexcitation of brain networks, we suggested that the seizures promote multifocal triggering of SD. Using a pentylenetetrazole seizure model and in vivo electrophysiology, we examined the occurrence of SD in different regions of the cortex and hippocampus in response to acute tonic-clonic seizures in freely behaving rats. We found that the seizures always induced SD within the first 20-40 s of ictal activity. SD was detected nearly simultaneously in all distant regions of the cortex and hippocampus. Most seizures were brief and culminated in SD. If the ictal discharge was long, cortical SD appeared mid-ictally. In the hippocampus, seizure-induced SD was partially blocked and spatially limited. Our findings support the idea that the awake brain rapidly responds to acute generalized seizures with multifocal initiation of SD in the cortex and hippocampus. We suggest that the seizure-induced SD contributes to seizure termination in the cortex but not in the hippocampus.