Abstracts

Rationale: Impaired consciousness during and following temporal lobe seizures has a major negative impact on quality of life for patients. One-sixth of patients cannot achieve seizure control with medications or surgical resection. Neurochemical, functional neuroimaging, and electrophysiological evidence suggests limbic seizures inhibit thalamic and brainstem arousal circuits, leading indirectly to widespread depressed cortical function and behavioral impairment. We designed a behavioral performance task to assess behavioral responses during and after induced limbic seizures in a rat model to promote further translational studies. Methods: Adult female rats were implanted with lateral orbitofrontal and dorsal hippocampal electrodes. Animals were food restricted to 85% body weight and trained to respond to a 2-second 100 Hz clicking sound with a lick response into a metal spout affixed to a photobeam lickometer. Click stimuli were randomly spaced 10-15 seconds. Appropriate lick response within 5 seconds of a click stimulus resulted in delivery of 40μL of 10% sucrose; inappropriate lick responses resulted in a 30-second timeout. Limbic seizures were induced with a 2-second 60 Hz hippocampal stimulation. Behavioral responses and simultaneous video-electrocorticography were measured during baseline, pre-ictal, ictal, and post-ictal states. Results: All implanted animals were successfully trained to respond to click stimuli to over 80% accurate response rate. Average response time in the final training session prior to any seizure induction was less than 2 seconds. Induced limbic focal and secondarily generalized seizures (electrographically determined) were elicited. Seizure epochs were compared with behavioral epochs without seizure.  The ictal and post-ictal performance was varied, ranging from complete abolition of behavioral responses or preservation of the lick response. Correct response rates decreased significantly during the ictal and post-ictal periods (p<0.001). Latency of first lick response after click stimuli also tended to increase in the ictal and post-ictal states. Initial analyses of cortical signals suggest that ictal and postictal impaired behavior is correlated with seizure physiological severity. Conclusions: We describe a novel behavioral and electrophysiological paradigm for assessment of consciousness in our animal model of human temporal lobe seizures. Just as in human TLE, some seizures have preserved behavior, while others lead to unresponsiveness. With these established baseline data, this model can be utilized to test innovative seizure treatments including subcortical nuclei stimulation (e.g central lateral thalamus) to reverse of loss of consciousness in refractory seizures. Funding: NIH-NINDS R01