Abstracts

Rationale: Epileptic seizures involve a series of wavefronts traveling across the cortex. The neuronal mechanisms underlying this propagation are not well understood. This is especially true in humans. A more detailed knowledge of how epileptiform activity propagates may provide crucial clues towards an improved delineation of epileptogenic cortex and provide a clear rationale for novel treatment methods to prevent the initiation or propagation of seizures. Here, we present the first description of how human inhibitory and excitatory single neurons behave as epileptic seizure waves travel across the neocortex of epilepsy patients.Methods: Four patients were implanted with intracranial grid electrodes as part of the clinical process of identifying the precise 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 from layer 3 of the neocortex. We then identified putative inhibitory and excitatory neurons using well-established criteria. The inhibitory neurons most likely correspond to the class of fast-spiking inhibitory interneurons.Results: We observed rapid waves of epileptiform activity sweeping through the high resolution electrode arrays during the seizure. These fast epileptic waves changed direction several times during the initial and middle part of the seizures, often manifesting as spiral waves. However, as inhibitory neurons stopped firing during the last half of the seizure, the waves became far more stereotyped in both direction and speed. This supports the hypothesis that inhibitory neurons interfere with and alter the propagation of seizure waves through the cortex. Excitatory neurons were phase locked to the local spike and wave oscillations recorded on the same electrode, but their spiking was phase shifted with respect to oscillations on distant electrodes. Surprisingly, however, many neurons showed stronger phase-locking to the wave at downstream electrode locations. This suggests that the firing of local excitatory neurons plays an active role in pushing the wave along.Conclusions: We have shown that a cessation of inhibitory neuron firing midway through the seizure leads to dramatically more stereotyped traveling waves that remain regular until the end of the seizure, suggesting that inhibition exerts a powerful control over wave propagation. Our results also suggest that traveling waves are not just inherited from distant input but are actively propagated by local excitatory neuronal activity. These findings point towards the possibility of being able to use small surgical lesions to prevent the spread of epileptic seizures, potentially reducing the comorbidity associated with the removal of large brain regions in the treatment of intractable epilepsy.