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The role of paroxysmal depolarization in focal seizure activity.

A. Tryba,E. Merricks,Somin Lee,Tuan Pham,D. Nordli,Tahra L. Eissa,R. Goodman,G. Mckhann,R. Emerson,C. Schevon,W. van Drongelen

Published 2019 in Journal of Neurophysiology

ABSTRACT

We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays, as well as at the macroscale of standard clinical EEG. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell-size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a cm-sized cortical network. We summarize Wilson-Cowan type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin-Huxley formalism, to show how feed forward, feedback, PD and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD is not only a cellular marker or epiphenomenon, but actively contributes to seizure activity.

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