Neuromodulation in Experimetal Animal Models of Epilepsy

Epilepsy is the most common serious brain disorder affecting 0.5-1% of the general population. This neurological disorder consists of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Despite the pharmacological development of new treatments, still one third of the epilepsy patients does not respond sufficiently to anti-epileptic drugs (AED) and are called refractory patients. Hence, there is a constant impetus to search for other treatment strategies like epilepsy surgery, vagus nerve stimulation and deep brain stimulation. Besides the ongoing research on the efficacy of anti-epileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic changes in the epileptic network and in this way have a modulating effect. The impact of such therapies cannot be overlooked, because they may slow down processes underlying epilepsy, might prevent or even cure epilepsy. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. Acute application of both treatment options can be very effective. LEV can act rapidly on seizures in both animals and humans. In addition, preclinical studies suggest that LEV may have anti-epileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in animals and patients with in addition a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations (age, course of the epilepsy, type of epilepsy, AED regime and genetic background) and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two models mimicking epilepsy in humans. They are both chronic models with seizures evolving from true, genetically-driven epileptogenesis. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that these treatments can be considered as neuromodulatory: changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals