Abstracts

Rationale: Interictal spikes are electroencephalographic discharges occurring in or near brain regions that generate epileptic seizures. These spikes are observed far more frequently than seizures in epileptic patients and may appear in both the same and different brain areas where seizures originate. Interictal spikes alone have been shown to significantly affect cognition and behavior adversely in both patients and animal models. While the precise relationship between interictal spiking and seizures remains unclear, they are considered part of the initial pathological cascade leading to seizure development and represent a viable therapeutic target to prevent both seizures and behavioral abnormalities.


Methods: We optimized a tetanus toxin-induced neocortical epilepsy model in male Sprague–Dawley rats (n=5). This model was designed to produce spikes with or without seizures. Long-term video-electroencephalography (EEG) recordings were conducted over six months at six cortical sites, including the motor and somatosensory cortices in both hemispheres, accompanied by behavioral activity monitoring. Each rat received a single, unilateral injection of tetanus toxin (from 70-250 ng/µl) into either the somatosensory or motor cortex. Automated algorithms were employed to quantify spikes and seizures.


Results: Both somatosensory and motor cortex-injected animals developed progressive spike networks involving ipsilateral and contralateral hemispheres. In the first month after surgery, somatosensory cortex-injected animals primarily exhibited ipsilateral focal spikes that were dose dependent. These ipsilateral spikes progressed to propagating spikes after four months and to synchronized spikes involving both the sensory and motor cortices up to six months. Conversely, animals receiving the injection into the motor cortex predominantly developed contralateral spiking. For both groups, polyspikes initially developed contralaterally but disappeared after one month in all motor cortex-injected animals. In somatosensory cortex-injected animals, but not motor cortex-injected animals, these polyspikes were replaced by short duration seizures that after one month evolved into longer duration seizures that became synchronized across both hemispheres over time.


Conclusions: Through transient GABA inhibition, TeNT-induced interictal spiking can help understand the development of complex, bilateral spike and seizure networks that can be modified both by TeNT dose and injection site without significant brain injury seen in other models. The insights gained will enhance our understanding and provide useful models for testing therapeutics to target the development of epileptic networks.


Funding: This research was funded by National Institutes of Health grant R01NS109515 (JAL)