Optimised induction of on-demand focal hippocampal and neocortical seizures by electrical stimulation

Epilepsy is a common neurological disorder affecting over 60 million people globally, approximately a third of whom are refractory to pharmacotherapy. Surgical resection of the epileptogenic zone is frequently unsuitable or ineffective, particularly for individuals with focal neocortical or mesial temporal lobe epilepsy. Therefore, there is a need to develop animal models for elucidating the mechanisms of focal epilepsies and evaluating novel treatment strategies.

We present two adapted in vivo seizure models, the neocortical and hippocampal epileptic afterdischarge models, that enable stereotyped seizures to be induced on demand by electrical stimulation in anaesthetised, neurologically intact rats. The stimulation parameters and anaesthetic were optimised to generate electrographically reproducible, self-sustaining seizures with a well-defined focal origin.

Neocortical or hippocampal seizures were consistently generated under fentanyl-isoflurane anaesthesia by stimulating the sensorimotor cortex or perforant path, respectively, with 100 Hz trains of biphasic square-wave pulses. The induced seizures were suppressed by propofol, an established antiseizure anaesthetic, thus validating the clinical responsiveness of the developed models.

The high degree of reproducibility in seizure presentation, predictable seizure induction and ability to operate in anaesthetised animals renders these models overall less laborious and more cost-effective than most conventionally used seizure models.

The proposed models provide an efficient method for the high-throughput screening of novel antiseizure therapies, including closed-loop stimulation paradigms, and are well-suited to in vivo investigations that require tight regulation of seizure timing under anaesthetised conditions, particularly neuroimaging studies aimed at understanding the development of epileptogenic networks.