Controlling seizures is not controlling epilepsy: A parametric study of deep brain stimulation for epilepsy Berend Feddersen, a,b,1 Laurent Vercueil, b Soheyl Noachtar, a,1 Olivier David, b Antoine Depaulis, b and Colin Deransart b, ⁎ a University of Munich, Klinikum Grosshadern, Department of Neurology, Marchioninistr. 15, 81377 Munich, Germany b Grenoble Institut des Neurosciences, Centre de Recherche INSERM U 836-UJF-CEA-CHU, Equipes 5 et 9, 2280 Rue de la Piscine-BP 53, 38041 Grenoble Cedex 9, France Received 12 February 2007; revised 10 May 2007; accepted 16 May 2007 Available online 24 May 2007 Pharmacological inhibition and high-frequency stimulation (HFS) of the substantia nigra pars reticulata (SNr) suppress seizures in different animal models of epilepsy. The aim of the present study was to determine the optimal parameters of HFS to control spontaneous seizures in a genetic model of absence epilepsy in the rat. Single SNr stimulation that was bilateral, bipolar and monophasic at 60 Hz frequency and with 60-μs pulse width was optimal. However, when used for repeated stimulations, long-term suppression did not occur and even the number of seizures increased. A delay of at least 60 s between stimulations was necessary to be fully effective. Although single HFS of the SNr can be used to suppress ongoing seizures, repeated HFS is ineffective and could even aggravate seizures in our model. Thus investigations of accurate stimulation procedures are still needed. © 2007 Elsevier Inc. All rights reserved. Keywords: High-frequency stimulation; Deep brain stimulation; Parameters; Epilepsy; Substantia nigra; Animal model Introduction About one third of epileptic patients are resistant to antiepileptic drugs (AED), and only 30% are candidates for resective surgery (Hauser and Hesdorffer, 1990; Semah et al., 1998; Wiebe et al., 2001). Deep brain stimulation (DBS) has been considered as an alternative therapy since subcorticals networks are assumed to control cortical excitability. Several structures have been targeted for the neuromodulation of seizures (Theodore and Fisher, 2004; Chabardes et al., 2002; Deransart et al., 2006). Recently, the subthalamic nucleus (STN) has attracted attention because of neurological expertise developed in the treatment of movement disorders (Benabid, 2003; Perlmutter and Mink, 2006), as well as experimental studies suggesting that the basal ganglia control several types of seizures (Deransart and Depaulis, 2002; Gale, 1985; Depaulis et al., 1994). In particular, it was shown that pharmacological inhibition of the STN has an antiepileptic effect in different animal models (Deransart et al., 1996; Veliskova et al., 1996; Dybdal and Gale, 2000) and that high-frequency stimula- tions (HFS) of the STN interrupt seizures (Vercueil et al., 1998; Lado et al., 2003). Therefore, a few clinical studies have explored the effects of STN-HFS in patients with drug-resistant epilepsy (Chabardes et al., 2002; Benabid et al., 2002; Loddenkemper et al., 2001; Handforth et al., 2006) with encouraging results. However, seizures were suppressed in only some patients, but not in others. This difference may be due to the heterogeneity of the population studied but also to the non-optimal nature of the conditions. Indeed, so far there are no data supporting the view that the STN is the optimal target for DBS in epilepsy or that the HFS protocols used for movement disorders should be applied. The need to determine optimal target, stimulation modes and parameters for DBS in epilepsy is further motivated by the fact that, unlike Parkinsonian symptoms which can be investigated in the surgery room (Limousin et al., 1995, 1998; Rizzone et al., 2001; Moro et al., 2002), epileptic seizures are less frequent and the impact of optimal and safe stimulation parameters is critical (Theodore and Fisher, 2004; Deransart et al., 2006). The substantia nigra pars reticulata (SNr) is an interesting alternative target for DBS in epilepsy. As the main output of the basal ganglia, it was shown to be a key structure for the control of seizures in different models (Deransart and Depaulis, 2002; Gale, 1985; Depaulis et al., 1994; Velisek et al., 2002). Moreover, electrode contacts close to the SNr were reported to be the most effective at suppressing seizures in epileptic patients (Chabardes et al., 2002). Therefore, the aim of the present study was to examine the SNr as a potential target for DBS in epilepsy and to determine the optimal modes and parameters of stimulation to suppress generalized seizures in an animal model of chronic epilepsy with spontaneous recurrent seizures, the Generalized www.elsevier.com/locate/ynbdi Neurobiology of Disease 27 (2007) 292 – 300 ⁎ Corresponding author. Fax: +33 4 76 63 54 15. E-mail address: colin.deransart@ujf-grenoble.fr (C. Deransart). 1 Fax: +49 89 7095 3677. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2007.05.005