Abstracts

Rationale: One of the most significant components of morbidity and mortality in epilepsy is consciousness impairment during the ictal and postictal states. For patients suffering from medically and surgically refractory epilepsy, the use of deep brain stimulation (DBS) to improve consciousness during and after seizures would represent an alternative therapeutic resource of substantial impact on their quality of life. Some of our labs recent work in a rodent model of limbic seizures has shown that dual-site stimulation of the thalamic intralaminar central lateral nucleus (CL) and pontine nucleus oralis (PnO) applied bilaterally during the ictal and postictal periods improved behavioral arousal while restoring normal-appearing cortical electrophysiology. Using the same rodent model of limbic seizures, our aim is to further investigate the behavioral effect of this dual-site stimulation. Methods: Through the implementation of an operant behavioral task, we assess performance during and after focal seizures and evaluate the effect of the DBS on it. During successive sessions, animals are trained to respond at an instrumental port (nose-poking) to activate an adjacent reward port, where they can collect sucrose water rewards when signaled by a stimulus. After they complete training, electrodes are implanted bilaterally in CL and PnO, and unilaterally in the hippocampus and lateral orbitofrontal cortex. Animals are reevaluated in the task after recovering from surgery and retrained until they meet baseline performance criteria, at which point sessions with seizure trials begin. Within these sessions, seizures are induced by brief 2 second hippocampal stimulation at 60 Hz in some of the trials. Bilateral CL and PnO are stimulated, at 100 and 50 Hz respectively and with varying current intensities, while synchronously recording electrophysiology and behavior. Results: Focal limbic seizures were accompanied by frontal cortical slow wave activity and behavioral arrest as in our prior work. In addition, CL+PnO stimulation was capable of restoring normal appearing cortical physiology during and following seizures. In the training process, animals showed increased percentage of rewards collected, decreased response times, and increased selectivity in responding (n= 9). Task performance was significantly impaired during seizures with cortical slow wave activity (p < 0.05; n=12 seizures in 3 animals). Conclusions: We have developed a paradigm to evaluate behavioral responses during seizures in a rodent model which replicates human physiological and behavioral impairment during seizures. Through the implementation of these experiments, we expect to obtain results that will provide substantial information to further elucidate the potential benefits of using multi-site DBS to improve consciousness in patients with refractory epilepsy. This could accelerate the translation of preclinical data into the development of a clinical therapeutic resource. Funding: NIH R21 NS083783 NIH R01 NS066974