B.), the Stanford Stroke Center (M. S. B.), and NINDS, P30 center core grant NS069375 (M. S.). Conflict of Interest The authors have no conflict of interest to declare.

Electrical stimulation of deep structures in the brain has been used successfully for treatment of movement disorders, such as Parkinson’s disease. Recently, deep brain stimulation (DBS) has gained more attention as an alternative treatment for refractory epilepsy such as temporal lobe epilepsy (TLE). DBS has advantages as a reversible, less invasive treatment with fewer complications compared to temporal lobectomy; it offers a promising option for patients who are not eligible candidates for resective surgery.

Extensive Inhibitors,research,lifescience,medical evidence has shown that the hippocampus is pivotal in seizure generation (Swanson 1995; Spencer 2002). DBS, especially high frequency stimulation (HFS), has been applied to the hippocampus to control seizures in patients (Velasco et al. 2000a,b, 2001, 2007; Vonck et al. 2002; AZD5363 manufacturer Osorio et al. 2005; Tellez-Zenteno

et al. 2006; Boon et al. 2007) and in animal models (Bragin Inhibitors,research,lifescience,medical et al. 2002; Cuellar-Herrera et al. 2006; Wyckhuys et al. 2007, 2010a). The rational for HFS is that it is associated with desynchronization Inhibitors,research,lifescience,medical of neuronal activities and thereby might achieve therapeutic effects (Boon et al. 2007). Stimulation can be delivered at a predefined stimulation protocol, that is, scheduled stimulation, independent of the neurophysiological state of the brain. In contrast, responsive stimulation is delivered directly in response to electrographic epileptic activities. Inhibitors,research,lifescience,medical Considering that the occurrence of seizures can be irregular and intermittent, responsive stimulation has the potential advantages of targeting seizure dynamics with high temporal and spatial specificity and is less likely to cause tissue damage due to exposure of neuronal tissue to stimulation (Sunderam et al. 2010). Experimental studies indeed showed a reduction of spontaneous seizures by delivering high

frequency responsive stimulation to the epileptogenic zone or to the anterior nucleus of thalamus in Inhibitors,research,lifescience,medical each four patients with inoperable TLE (Osorio et al. 2005). Additionally, afterdischarges were terminated or shortened by responsive brief bursts of pulse stimulation (Lesser et al. 1999; Motamedi et al. 2002) and seizures were altered or Thiamine-diphosphate kinase suppressed by responsive cortical stimulation in patients (Kossoff et al. 2004). Recently, implantable responsive neurostimulator (RNS; NeuroPace, Inc., Mountain View, CA) has been developed to detect real-time seizures and deliver responsive stimulation to patients with medically intractable partial-onset epilepsy. The safety and efficacy of this system has been assessed in a multicenter, double-blinded, randomized study in adults with medically refractory epilepsy (Morrell 2011). High frequency hippocampal stimulation was delivered during the preictal period on predicted spontaneous seizures in the status epilepticus (SE) rat model (Nair et al. 2006).