Aberrant fast spiking interneuronal activity precedes seizure transitions in humans
Merricks, E. M.; Deshpande, S. S.; Agopyan-Miu, A. H.; Smith, E. H.; Schlafly, E. D.; McKhann, G. M.; Goodman, R. R.; Sheth, S. A.; Greger, B.; House, P. A.; Eskandar, E. N.; Madsen, J. R.; Cash, S. S.; Trevelyan, A. J.; van Drongelen, W.; Schevon, C. A.
Show abstract
There is active debate regarding how GABAergic function changes during seizure initiation and propagation, and whether interneuronal activity drives or impedes the pathophysiology. Here, we track cell-type specific firing during spontaneous human seizures to identify neocortical mechanisms of inhibitory failure. Fast-spiking interneuron activity was maximal over 1 second before equivalent excitatory increases, and showed transitions to out-of-phase firing prior to local tissue becoming incorporated into the seizure-driving territory. Using computational modeling, we linked this observation to transient saturation block as a precursor to seizure invasion, as supported by multiple lines of evidence in the patient data. We propose that transient blocking of inhibitory firing due to selective fast-spiking interneuron saturation--resulting from intense excitatory synaptic drive--is a novel mechanism that contributes to inhibitory failure, allowing seizure propagation.
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