Abstracts

Rationale: The canonical view of epilepsy is based on the notion of imbalance between excitatory and inhibitory activity. There are several theories, based on slice and animal experiments, proposing that a decrease in inhibition is a necessary prerequisite of epileptic activity. However, there are competing theories that suggest a dramatic increase in inhibition is necessary to synchronize the activity of excitatory cells into epileptiform discharges. It is also unclear what happens to the firing of inhibitory neurons as a seizure progresses. The activity of human inhibitory interneurons during seizures has never been comprehensively described. Here, we attempt to clarify the role of these neurons in human seizures by characterizing the role of human inhibitory interneuron activity during different phases of focal seizures with secondary generalization. Methods: Four patients were implanted with intracranial grid electrodes as part of the clinical process of identifying the site of origin of their drug-resistant epilepsy. A 4x4 mm Neuroport microarray (Blackrock Microsystems) was also placed in a region of the neocortex that was expected to be in the resection site. We used these arrays to simultaneously record the activity of dozens of individual neurons during ictal activity. We then identified putative inhibitory neurons using well-established criteria, including action potential shape. These neurons most-likely correspond to the class of fast-spiking, parvalbumin-expressing inhibitory interneurons. Results: We show that interneuron activity initially parallels that of excitatory cells as the seizure first spreads to the neocortex, a finding consistent with what is known about feedforward drive of both inhibition and excitation. Unexpectedly, however, we also find that putative inhibitory neurons switch off well before the end of a seizure. This cessation of inhibitory firing is accompanied by a dramatic increase in the amplitude of local spike-and-wave events. We present evidence based on a novel set of analyses that suggests that these inhibitory interneurons stop firing because they enter depolarization block, where most sodium channels are inactivated and incapable of sustaining another action potential. Conclusions: Our results show that there is some degree of inhibitory-excitatory balance during the first part of human focal seizures but a complete lack of inhibition towards the end - when seizure symptoms are sometimes at their worst. This cessation likely results from inhibitory interneurons entering depolarization block well before the termination of the seizure. Strikingly, this absence of inhibitory activity is accompanied by large increases in the amplitude of the local field potential. These results suggest that it may be possible to alter or prevent seizures by using pharmacological manipulations that prevent inhibitory interneurons from entering depolarization block. This represents a potentially novel therapeutic avenue in the treatment of human epilepsy. This research was funded by an Epilepsy Foundation Fellowship (222178) to OJA and by NIH grant NS062092 to SSC.