| Seizures have both local and remote effects on nervous system function. While propagated seizures are known to disrupt cerebral activity, how do partial seizures that do not propagate affect distant cortical regions involved in consciousness? Human focal temporal-lobe seizures demonstrate remote changes including slow oscillations on electroencephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex. Ictal neocortical slow waves have been interpreted as seizure propagation, however we hypothesize that they reflect a depressed cortical state resembling sleep or coma. To investigate, we performed multi-modal studies of limbic seizures in rats. Video/EEG monitoring of spontaneous seizures revealed ictal neocortical slow waves in the frontal cortex during mild partial seizures that were associated with behavioral arrest, contrasted with fast poly-spike activity during convulsive secondarily-generalized seizures. Seizures induced by hippocampal stimulation produced a similar pattern, and were recorded using functional magnetic resonance imaging (fMRI), demonstrating increased signals in the hippocampus, thalamus and septum, but decreases in the orbitofrontal, cingulate, and retrosplenial cortices during partial seizures; and increases in all these regions during propagated seizures. Combining these results with electrical recordings and CBF measurements, we related neocortical slow waves to reduced neuronal activity and cerebral metabolism during partial seizures, but found increased neuronal activity and metabolism during propagated seizures. Mechanistic studies revealed that stimulation of the lateral septum in the absence of a seizure produced both neocortical slow waves and behavioral arrest which closely resembled effects seen during ictal neocortical slow activity. Furthermore, neocortical slow oscillations and associated behavioral changes during partial limbic seizures were prevented in animals with lesions disrupting hippocampal-septal connections. Systemic administration of the acetylcholine agonist pilocarpine also prevented slow activity in the neocortex during partial seizures. It is thus possible that lateral septal involvement in partial limbic seizures contributes to ictal neocortical slow rhythms, perhaps by disrupting normal acetylcholinergic activation of the cortex. These findings suggest that ictal neocortical slow waves represent an altered cortical state of depressed function in patients with temporal lobe epilepsy, resulting from aberrant subcortical activity. This remote effect of partial seizures may cause impaired cerebral function, including loss of consciousness. |
