High frequency oscillations (80-500 Hz) in the preictal period in patients with focal seizures

Approximately one-third of epileptic patients have inadequate seizure control through anticonvulsant medications. For these patients the unforeseeable way in which seizures occur represents the most disabling and dangerous aspect of their disease. Even if seizures seem to occur suddenly and without warning in most patients, there has been a longstanding discussion on whether seizures may be building up slowly in the hours or minutes before the clinical event (Le Van Quyen et al., 1999; Lehnertz et al., 1999; Litt et al., 2001). Some patients describe unspecific premonitory symptoms hours before the seizure (Schulze-Bonhage et al., 2006; Haut et al., 2007), and several studies detected electroencephalography (EEG) changes during the preictal period (for review see Mormann et al., 2007). However, the presence and time-frame of consistent EEG changes prior to seizures remain uncertain and no method of seizure prediction can consistently predict seizures in different patients (Schelter et al., 2006; Mormann et al., 2007). The conventional range of EEG analysis involves frequencies below 100 Hz, but studies over the last decade suggest that localized higher frequencies may also be important. Frequencies above 100 Hz have been extensively characterized in human epileptic mesial temporal structures using depth microelectrodes. Whereas 100–200 Hz oscillations appear related to physiologic memory processing, higher frequencies, between 200 and 500 Hz, are associated with epileptogenic tissue (Bragin et al., 1999). These high frequency oscillations (HFOs) have been termed ripples (80–250 Hz) and fast ripples (250–500 Hz). Recently depth macroelectrodes and spectral and visual analysis techniques have also revealed focal HFOs in humans during interictal (Urrestarazu et al., 2006, 2007; Jacobs et al., 2008; Worrell et al., 2008) and ictal recordings (Jirsch et al., 2006; Ochi et al., 2007; Ramachandrannair et al., 2008). Discrete HFOs occurred mainly in regions of seizure onset and rarely in regions of secondary spread in mesial temporal as well as neocortical seizures. Moreover, no ictal high frequency activities occurred in the seizures of patients with poor localization (Jirsch et al., 2006). In animal studies, a clear relationship between the presence of HFOs and their degree of activity with spontaneous seizures could be shown (Bragin et al., 2004). In an in vitro model of low-Mg2+ seizures, an increase of HFOs preceded seizure activity (Khosravani et al., 2005). In rats, an increase of ripple and fast ripple bands could be observed within the dentate gyrus 1 s before seizure onset (Bragin et al., 2005). The behavior of HFOs in the preictal period in epilepsy patients has been evaluated in only one study (Khosravani et al., 2008), which found changes in the seconds preceding seizures. The possibility that HFOs may reflect basic epileptogenic processes and changes during the preictal period bears scientific and clinical interests. For instance, potential therapies involving EEG-triggered anticonvulsant injections or electrical stimulation could result in seizure control. Such antiseizure therapies may have greater chance of success if seizures could be predicted from the interictal EEG (Elger, 2001; Osorio et al., 2005). We hypothesized that HFOs in the range of 80–500 Hz measured using depth macroelectrodes in patients with intractable temporal and extratemporal epilepsy change in frequency of occurrence during the preictal state. Visual and spectral analyses techniques were used to assess HFO rates and band power in the 15 min prior to seizure onset. These two methods were chosen to detect changes in high frequency power in general but also in distinct HFOs. Distinct HFOs are very short events and, therefore, a change in their rate may not be detectable with spectral analysis.