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bioRxiv · 10.1101/2025.01.22.634312

Large Animal Epilepsy Model Platform: Kainic Acid Porcine Model of Mesial Temporal Lobe Epilepsy

Mivalt, F.·Maltais, D.·Kim, I.·Kim, J.·Began, P.·Duque Lopez, A.·Krakorova, V.·Winter, B.·Gregg, N. M.·Montonye, D.·Gow, C.·Miller, K. J.·Van Gompel, J.·Leyde, K.·Kremen, V.·Worrell, G. A.
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Abstract

Translational large-animal models that can accommodate human-scale implantable devices are essential for advancing neuromodulation therapies in epilepsy. This study establishes a kainic acid (KA)-induced porcine model of mesial temporal lobe epilepsy (mTLE) using clinical imaging, stereotactic surgery, and a fully implantable neural stimulation and recording (INSR) device designed for humans. Seven pigs (six KA-treated and one saline control) underwent MRI-guided stereotactic implantation of electrodes targeting bilateral hippocampus (HPC) and anterior thalamus (ANT), followed by intra-hippocampal KA or saline infusion. Local field potentials (LFP) were recorded continuously with synchronized video monitoring. Seizures and LFP interictal epileptiform-like discharges (IEDs) were quantified using validated automated detectors. Histology was performed in the saline control and the longest surviving KA-treated pig. Intra-hippocampal KA infusion induced acute status epilepticus in all (6/6) treated pigs. Four animals survived to chronic monitoring with spontaneous seizures observed in three pigs (2,733 seizures; mean duration of 27.2 {+/-} 17.6 seconds). IEDs were observed in bilateral HPC of all animals, including saline control, with higher rates in the lesioned HPC (p <0.0001). While the IED morphology is consistent with epileptiform activity; IEDs alone are not specific for epilepsy and physiological transients (e.g. sharp-wave ripples) and injury-related hyperexcitability or strain-specific hyperexcitability cannot be excluded. Histological analysis revealed patchy neuronal loss and cytoarchitectural changes in HPC. This porcine model reproduces electrophysiological features of human mTLE. This approach provides a powerful translational bridge for developing and testing next-generation INSR and neuromodulation strategies in freely behaving large animals.

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Mivalt, F., Maltais, D., Kim, I., Kim, J., Began, P., Duque Lopez, A., Krakorova, V., Winter, B., Gregg, N. M., Montonye, D., Gow, C., Miller, K. J., Van Gompel, J., Leyde, K., Kremen, V., Worrell, G. A.. 2025-01-22. Large Animal Epilepsy Model Platform: Kainic Acid Porcine Model of Mesial Temporal Lobe Epilepsy. https://doi.org/10.1101/2025.01.22.634312

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