Closed-loop neural stimulation for pentylenetetrazole-induced seizures in zebrafish

SUMMARY Neural stimulation can reduce the frequency of seizures in persons with epilepsy, but rates of seizure-free outcome are low. Vagus nerve stimulation prevents seizures by continuously activating noradrenergic projections from the brainstem to the cortex. Cortical norepinephrine then increases GABAergic transmission and increases seizure threshold. Another approach, responsive nervous stimulation, prevents seizures by reactively shocking the seizure onset zone in precise synchrony with seizure onset. The electrical shocks abort seizures before they can spread and manifest clinically. The goal of this study was to determine whether a hybrid platform in which brainstem activation triggered in response to impending seizure activity could prevent seizures. We chose the zebrafish as a model organism for this study because of its ability to recapitulate human disease, in conjunction with its innate capacity for tightly controlled high-throughput experimentation. We first set out to determine whether electrical stimulation of the zebrafish hindbrain could have an anticonvulsant effect. We found that pulse train electrical stimulation of the hindbrain significantly increased the latency to onset of pentylenetetrazole-induced seizures, and that this apparent anticonvulsant effect was blocked by noradrenergic antagonists, as is also the case with rodents and humans. We also found that the anticonvulsant effect of hindbrain stimulation could be potentiated by reactive triggering of single pulse electrical stimulations in response to impending seizure activity. Finally, we found that the rate of stimulation triggering was directly proportional to pentylenetetrazole concentration and that the stimulation rate was reduced by the anticonvulsant valproic acid and by larger stimulation currents. Taken as a whole, these results show that that the anticonvulsant effect of brainstem activation can be efficiently utilized by reactive triggering, which suggests that alternative stimulation paradigms for vagus nerve stimulation might be useful. Moreover, our results show that the zebrafish epilepsy model can be used to advance our understanding of neural stimulation in the treatment of epilepsy.

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