Summary

The lack of an adequate model of posttraumatic epilepsy (PTE) in which, similarly to the human condition, chronic spontaneous focal seizures follow a single episode of traumatic brain injury (TBI), has hampered the identification of clinically-relevant epileptogenic mechanisms and the development of effective therapies. We studied the electrophysiological, behavioral and structural consequences of a clinically relevant model of closed head injury, the lateral fluid percussion injury (FPI) in the rat. We found that a single episode of severe FPI is sufficient to cause PTE. Chronic electrocorticography (ECoG) demonstrated spontaneous chronic seizures that were partial, originated from the neocortex at the site of injury, and progressively worsened and spread over time. The cases of epilepsy in the posttraumatic population increased over time following injury. Post-FPI epileptic rats exhibited pauses in their behavior, facial automatisms and myoclonus at the time of epileptiform ECoG events. In-vitro local field-potential recordings demonstrated persistent hyperexcitability of the neocortex at and around the site of injury that was associated with intense glial reactivity. These results for the first time demonstrate persistent hyperexcitability of the injured neocortex and define an useful model for pathophysiological studies of basic mechanisms of spontaneous epileptogenesis and for preclinical screening of effective antiepileptogenic drugs.

Low-voltage rapid discharges (or fast EEG ictal activity) constitute a characteristic electrophysiological pattern in focal seizures of human epilepsy. They are characterized by a decrease of signal voltage with a marked increase of signal frequency (typically beyond 25 Hz). They have long been observed in stereoelectroencephalographic (SEEG) signals recorded with intra-cerebral electrodes, generally occurring at seizure onset and simultaneously involving distinct brain regions. Spectral properties of rapid ictal discharges as well as spatial correlations measured between SEEG signals generated from distant sites before, during and after these discharges were studied. Cross-correlation estimates within typical EEG sub-bands and statistical tests performed in ten patients suffering from partial epilepsy (frontal, temporal or fronto-temporal) reveal that SEEG signals are significantly de-correlated during the discharge period compared to periods that precede and follow this discharge. These results can be interpreted as a functional decoupling of distant brain sites at seizure onset followed by an abnormally high re-coupling when the seizure develops. They lead to the concept of “disruption” that is complementary of that of “activation” (revealed by significantly high correlations between signals recorded during seizures), both giving insights into our understanding of pathophysiological processes involved in human partial epilepsies as well as in the interpretation of clinical semiology.