Abstracts

Rationale: Complex partial seizures can cause loss of consciousness to devastating effect. Patients with surgically refractory epilepsy have no clinical option to prevent loss of consciousness during seizures. Human patients with complex partial seizures have ictal neocortical slow oscillations during impaired consciousness. We have previously developed a rodent model of complex partial limbic seizures, which mimics the human EEG. In our rodent model, the brainstem cholinergic system is suppressed and the intralaminar thalamic nuclei are disrupted. There are previous reports that stimulation of the intralaminar thalamic nuclei has restored consciousness to patients in minimally conscious state. In this study, we investigated the efficacy of stimulating the intralaminar thalamic nuclei in our rodent model of complex partial seizures with the goal of restoring consciousness.Methods: To optimize our stimulation paradigm and determine the downstream effects of stimulation, we stimulated the intralaminar centrolateral nucleus under anesthesia (ketamine/xylazine 90/15 mg/kg) while recording blood oxygen level dependent (BOLD) fMRI. BOLD fMRI images were recorded at 9.4 T. Next, we recorded local field potential and multiunit activity in the orbital frontal cortex while stimulating the thalamus under anesthesia in order to convert anesthesia-induced slow oscillations into normal cortical activity. Finally we stimulated the thalamus during limbic seizures in order to convert ictal neocortical slow oscillations to normal cortical activity. Seizures were induced by a 2-second, 60 Hz electrical stimulus in the dorsal hippocampus. In each experiment, the thalamic stimulation parameters were a 2 second stimulus of 100 Hz. Stimulus amplitude varied (0.2-2mA). Results: We observed BOLD fMRI increases during thalamic stimulation under anesthesia in the thalamus, cingulate, and frontal cortex, the same regions which show BOLD decreases during limbic seizures. Cortical electrophysiological recordings during intralaminar thalamic stimulation under anesthesia revealed conversion of cortical low-frequency slow oscillations to high-frequency fast activity which persisted for several seconds after stimulation. Finally, we stimulated the intralaminar nuclei during limbic seizures and converted ictal neocortical slow waves as well as post-ictal slow waves into normal fast activity.Conclusions: Thalamic stimulation to restore consciousness during complex partial is a novel therapeutic approach to improving the lives of patients suffering from surgically-refractory epilepsy. In the future, we will extend our studies to awake recordings, with a goal of restoring both normal electrophysiological activity as well as normal behavior. If thalamic stimulation prevents loss of consciousness in an animal model, we hope to extend our studies to human therapeutic trials.