Patients with focal temporal lobe seizures often experience transient episodes of impaired awareness with behavioral arrest, but the precise mechanism remains unknown. The Network Inhibition Hypothesis attributes these deficits to a loss of cholinergic input to the cortex. This is presumed to result from increased activation of inhibitory regions that suppress subcortical arousal, giving rise to cortical delta wave activity. Recently, this hypothesis has been tested in animal experiments, where triggering dorsal hippocampal seizures is associated with behavioral arrest. To further test this hypothesis in animals - and, more specifically, to characterize the relationship between propagated discharge, cortical delta waves and behavioral arrest - we performed partial kindling studies in three different limbic sites in rats. We found that seizure discharge took longer to spread from the amygdala than the hippocampus, and took more stimulations to elicit behavioral arrest. In addition, the onset of propagated discharge in subcortical and cortical sites did not always match with the onset of behavioral arrest. Importantly, the activity seen in the cortex did not resemble the slow waves seen in deep sleep. Together, these findings suggest that limbic discharge triggers epileptic discharge in downstream pacemakers, including the cortex, and that these secondarily cause behavioral arrest.

Patients with focal temporal lobe seizures often experience transient episodes of impaired awareness with behavioural arrest, but the precise mechanism remains unknown. The Blumenfeld hypothesis attributes these deficits to a loss of cholinergic input to the cortex. This is presumed to result from increased activation of inhibitory regions that suppress subcortical arousal, giving rise to slow wave activity. To investigate this hypothesis – and more specifically, to characterize the relationship between propagated discharge, cortical slow waves and behavioural arrest – we performed kindling studies in rats. We found that seizure discharge took longer to spread from the amygdala than the hippocampus, and took more kindling stimulations to elicit behavioural arrest. In addition, the onset of propagated discharge in subcortical and cortical sites did not always match with the onset of behavioural arrest. Importantly, the activity seen in the cortex did not resemble the slow waves seen in deep sleep. Together, these findings suggest an additional mechanism – other than the Blumenfeld hypothesis – to explain how temporal lobe seizures may produce behavioural arrest and impair awareness.

Complex partial seizures – which often arise in the temporal lobes – are the most common seizures in adults and are often drug resistant. They involve transient episodes of impaired consciousness with behavioural arrest. Identifying the neural substrate for these common and drug-resistant attacks will be valuable not only for understanding epileptogenic networks, but also for evolving new pharmacologic or stimulation paradigms designed for complex partial seizures. Dr. Hal Blumenfeld at Yale University has offered a testable hypothesis concerning the neural substrate of complex partial seizures. Blumenfeld postulates (2012): (1) that focal discharge arises somewhere in the brain, typically in the temporal lobes; (2) that the focal discharge spreads to subcortical structures that have strong inhibitory outputs, such as the septal nuclei; and (3) that the discharge in these structures suppresses activity in the arousal systems of the upper brain stem and diencephalon. Suppression of the arousal systems leads to unconsciousness, which is signaled by the onset of behavioural arrest and slow waves in the neocortical EEG. Blumenfeld’s hypothesis has not yet been tested in the amygdala-kindling model – the most widely used and drug-validated animal model of complex partial seizures. Tests involving the Blumenfeld hypothesis and amygdala-kindled rats are now underway in our laboratory. We predict that behavioural arrest in kindled animals will correlate with the onset of slow waves in the rat neocortex. We also predict that the behavioural arrest will not be suppressed by anti-epileptic drugs (AEDs), since AEDs do not suppress complex partial seizures in patients or the kindled amygdala focus in rats (Albright and Burnham, 1980).

Seizures that impair consciousness and cardiorespiratory function have a significant, negative impact on patient safety and quality of life. If uncontrolled, such seizures can limit a patient's driving ability, productivity at school and work, or worse, lead to death ([Blumenfeld, 2012][1]). Sudden

The network mechanisms underlying loss of consciousness during temporal lobe complex partial seizures (CPS) are not well understood. The Blumenfeld hypothesis states that unconsciousness results not from epileptic hyper-excitation of the neocortex — which was the traditional view — but from secondary inhibition of the cortex due to the suppression of subcortical arousal systems. To investigate this hypothesis – and more specifically, to characterize the major inhibitory structures involved – we have performed local stimulation experiments and hippocampal kindling studies in rats. We have found that 10 Hz stimulation of the lateral septal nuclei and the nucleus accumbens shell causes behavioural arrest and slow waves in the cortex. Preliminary hippocampal kindling studies have also revealed that the occurrence of propagated discharge in the lateral septum and the nucleus accumbens shell is highly correlated with the presence of neocortical slow waves but not the onset of behavioural arrest. These findings identify the lateral septum and nucleus accumbens shell as key subcortical structures underlying seizure-related neocortical deactivation. Future studies will be needed to determine the role of other possible candidates.