title: Distinct hyperexcitability mechanisms underlie fast ripples and epileptic spikes.
abstract: OBJECTIVE
  In partial epilepsies, interictal epileptic spikes (IESs) and fast ripples (FRs) represent clinically relevant biomarkers characteristic of epileptogenic networks. However, their specific significance and the pathophysiological changes leading to either FRs or IESs remain elusive. The objective of this study was to analyze the conditions in which hyperexcitable networks can generate either IESs or FRs and to reveal shared or distinct mechanisms that underlie both types of events.
  
  
  METHODS
  This study is the first to comparatively analyze mechanisms that induce either IESs or FRs using an approach that combines computational modeling and experimental data (in vivo and in vitro). A detailed CA1 hippocampal network model is introduced. A parameter sensitivity analysis was conducted to determine which model parameters (cell related and network related) allow the most accurate simulation of FRs and IESs.
  
  
  RESULTS
  Our model indicates that although FRs and IESs share certain common mechanisms (shifted gamma-aminobutyric acid [GABA]A reversal potential, altered synaptic transmission), there are also critical differences in terms of number of pyramidal cells involved (small vs large), spatial distribution of hyperexcitable pyramidal cells (clustered vs uniform), and firing patterns (weakly vs highly synchronized). In vitro experiments verified that subtle changes in GABAergic and glutamatergic transmission favor either FRs or IESs, as predicted by the model.
  
  
  CONCLUSIONS
  This study provides insights into the interpretation of 2 interictal markers observed in intracerebral electroencephalographic data. Depending on the degree and spatiotemporal features of hyperexcitability, not only IESs or FRs are generated but also transitions between both types of events.
authors.affiliation: INSERM, U642, University of Rennes 1, LTSI, and Neurology Department, University Hospital, Rennes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Demont-Guignard
authors.forename: Pascal
authors.initials: P
authors.lastname: Benquet
authors.forename: Urs
authors.initials: U
authors.lastname: Gerber
authors.forename: Arnaud
authors.initials: A
authors.lastname: Biraben
authors.forename: Benoit
authors.initials: B
authors.lastname: Martin
authors.forename: Fabrice
authors.initials: F
authors.lastname: Wendling
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D016571:Neural Networks, Computer; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D007608:Kainic Acid