Abstracts

Rationale: In drug-resistant partial epilepsies, interictal events such as high frequency oscillations (Fast Ripples, FRs) and interictal epileptic spikes (IES) represent clinically relevant biomarkers, characteristic of the underlying epileptogenic networks, and generally admitted to be produced by synchronous hyperexcitable cells. However, the precise neuro- and patho-physiological mechanisms leading to either FR or IES, and the functional link between these two interictal events remain unclear. Moreover, the relationship between FR, IES and seizures is still a matter of a debate.Methods: Our computational model of CA1 hippocampal network (cellular level, including main pyramidal cells and interneurons) targeted by CA3 pyramidal cells was used to simulate realistic FRs and IESs as compared to our in vivo data (recorded in human hippocampus and in a mouse kainate model of temporal lobe epilepsy). We also developed a new index, referred to as the Fast Ripple Ratio (FRR), to quantify FRs. Based on the discrete wavelet transform, the FRR allowed us to characterize the signal energy in the fast ripple frequency band and to quantitatively compare real and simulated signals.Results: Modeling results showed that quasi-synchronous discharge patterns of pyramidal cells are a common feature of these two events, with however a weaker synchronization in the case of FRs. Subtle changes in the balance of GABAergic and Glutamatergic currents at network level were also found to lead either to FRs or IES. Regarding this point, in vitro experiments verified that pharmacologically-induced alterations in GABAergic and glutamatergic transmission could favor either the apparition of FRs or IESs, as predicted by the model. In addition, differences could be revealed in terms of spatial features of hyperexcitability (uniformly vs. clustered increased excitability), the number of hyperexcitable cells involved, drift of GABA reversal potential, as well as the degree of synchronicity of pyramidal cells. The model could also predict an influence of the electrode size, which can impact the recording of FRs.Conclusions: We suggest that the degree of alteration of the synaptic transmission as well as the spatio-temporal features of the hyperexcitability, are responsible for the progressive switch from FR to IES and ultimately to seizure activity.