Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation

Stimulation of the vagus nerve has become an effective method for desynchro nizing the highly coherent neural activity typically associated with epilep tic seizures. This technique has been used in several animal models of seiz ures as well as in humans suffering from epilepsy. However, application of this technique has been limited to unilateral stimulation of the vagus nerv e, typically delivered according to a fixed duty cycle, independently of wh ether ongoing seizure activity is present. Here, we report that stimulation of another cranial nerve, the trigeminal nerve, can also cause cortical an d thalamic desynchronization, resulting in a reduction of seizure activity in awake rats. Furthermore, we demonstrate that providing this stimulation only when seizure activity begins results in more effective and safer seizu re reduction per second of stimulation than with previous methods. Seizure activity induced by intraperitoneal injection of pentylenetetrazole was rec orded from microwire electrodes in the thalamus and cortex of awake rats wh ile the infraorbital branch of the trigeminal nerve was stimulated via a ch ronically implanted nerve cuff electrode. Continuous unilateral stimulation of the trigeminal nerve reduced electrographic seizure activity by up to 7 8%, and bilateral trigeminal stimulation was even more effective. Using a d evice that automatically detects seizure activity in real time on the basis of multichannel field potential signals, we demonstrated that seizure-trig gered stimulation was more effective than the stimulation protocol involvin g a fixed duty cycle, in terms of the percent seizure reduction per second of stimulation. In contrast to vagus nerve stimulation studies, no substant ial cardiovascular side effects were observed by unilateral or bilateral st imulation of the trigeminal nerve. These findings suggest that trigeminal n erve stimulation is safe in awake rats and should be evaluated as a therapy for human seizures. Furthermore, the results demonstrate that seizure-trig gered trigeminal nerve stimulation is technically feasible and could be fur ther developed, in conjunction with real-time seizure-predicting paradigms, to prevent seizures and reduce exposure to nerve stimulation.