SUMMARY

Epilepsy is the second most frequent  chronic neurological disorder worldwide with more than 50 million patients and around 2 million new cases every year. Although the majority of patients are successfully treated with antiepileptic medication, around 30 percent of patients are drug resistant and continue to suffer from seizures in spite of correct medical treatment. This category of patients overcame, for instance in USA (where data was available), the cumulated number of patients with Parkinson disease and multiple sclerosis. Mortality in this group of patients is estimated 7 times higher comparative with the general population. (WHO, April 2011)
Temporal lobe (TL) epilepsy is considered the most common epilepsy syndrome in adult population. Virtually all patients have partial seizures, very often associated with impairment of consciousness .

When antiepileptic medication fails to control seizures (more than 50% of cases), surgery consisting in anterior temporal lobectomy is the procedure of choice. (Engel J., 2001).

Epilepsy surgery for temporal lobe epilepsy is a safe and efficient procedure and increase in quality adjusted life expectancy by 7.5 years. (Choi H., 2008)

Presurgical evaluation should be considered in all patient suffering from focal, drug resistant epilepsy. The goal of the evaluation is to define the epileptogenic zone (EZ) which is  the cortical area essential for seizures generation that should be completely removed or disconnected to render the patient seizure free. Part of the EZ, the seizure onset zone (SOZ) is represented by the area where the initial ictal discharge is recorded, provided that fulfils two requirements: a)  occurs prior to the first ictal clinical sign (visible modification of patients behavior or warning that he/she is feeling an aura); b) consists in a fast synchronizing discharge (low voltage fast activity or recruiting fast discharge of spikes) with some variations depending on the recording region (Kahane P, 2004).

Epileptic seizures were generally assumed to result from excessive synchronized firing of large neuronal aggregates. However, recent studies by Truccolo et al (2011) show that the neuronal spiking activity during seizure initiation and spread is highly heterogeneous, not hypersynchronous, as shown in figure 1.  That suggests complex interactions among different neuronal groups leading to the oscillatory behavior evidenced in the surface, cortical or depth macroelectrodes. Several frequency bands are of interest for characterizing the oscillatory activity, the lower end of the spectrum being well represented in standard EEG recordings performed with macroelectrodes, while the upper end can only be explored through the use of microelectrodes. Studies using microwire electrodes (Worrell 2008) highlight the importance of the oscillatory activity in the ripple (80 - 250Hz) and fast ripple (250 - 1000Hz) frequency range, which may be signatures of epileptogenic areas.  In addition, robust multi-unit bursts of activity (600 - 6000Hz) were shown to be synchronized with the lower frequency (<1000 Hz) ripples.  By moving up the frequency spectrum, into single-unit domain, converging information indicates that single unit activity may exhibit specific patterns of activity providing information regarding mechanisms of seizure generation. Very few human studies have gone beyond macroscopic scalp and intracranial EEG signals to examine neuronal spiking underlying seizures (Halgren et al 1977, Wyler et al 1982, Babb et al 1987, Engel et al 2005, Keller et al, 2010, Truccolo et al 2011). Therefore, the behavior of single neurons in human epilepsy remains largely unknown.

Standard procedure for localizing the seizure onset zone (SOZ) includes pre-surgical placement of scalp and depth electrodes and recording the EEG signal in the low frequency range, representing the averaged activity of many neurons, during several significant ictal episodes taking place over several days. The single-unit dynamics is not accessible using such electrodes. Large arrays of up to 96 microelectrodes, as used by Truccolo et al (2011) capable of discriminating individual neurons can only access the cortical surface, not the depth structures. Microwire depth electrodes (Worrell 2008) can potentially discriminate single units due to small contact area, however due to the fact that their position cannot be adjusted to bring the tip of the microwires in the close proximity of the active neurons, their single-unit yield is very small. Therefore, they are typically providing local field potentials (LFP’s) and  multi-unit activity in the high-frequency range (>500Hz). One of the few effective methods for isolating single units in depth is to intra-operatively slowly advance metal microelectrodes using microdrives (Wyler and Ward 1981, Wyler et al 1982) and stop when encountering a neuron. However, this acute recording inherently provides information about inter-ictal activity only. In order to probe neuronal excitability, direct cortical stimulation can be used (Wyler and Ward 1981, Kinoshita et al 2005). Electrical stimulation can evoke a multitude of neuronal responses, ranging from direct excitation when using low frequencies and high amplitudes (Wyler and Ward 1981) to neuronal inhibition when using lower amplitudes and higher frequencies (Kinoshita et al 2005). As a matter of fact, the modern widespread method of Deep Brain Stimulation (DBS), based on neuronal inhibition as a result of high-frequency stimulation, has been discovered and introduced by Benabid et al (1989) as a result of accidentally setting the stimulator frequency to a value higher than normally used during those procedures (Talan 2009).  To our knowledge, no study involving direct stimulation in depth, right in the SOZ, while recording single-unit activity has been performed, to date. By using standard surgical and electrophysiological equipment commonly used for functional mapping in DBS, we plan on record LFP’s, multi-unit and single-unit activity while applying electrical stimulation, in the SOZ. That will allow characterization of the excitability of the single neurons in the epileptogenic foci, provide information about single-neuron dynamics during epileptic seizures and open the path for establishing deep stimulation methods that could prevent development of epileptic seizures.