Epilepsy has been classically seen as a brain disorder resulting from abnormally enhanced neuronal excitability and synchronization. Although it has been described since antiquity, there are still significant challenges achieving the therapeutic goal of seizure freedom. Deep brain stimulation of the anterior nucleus of the thalamus has emerged as a promising therapy for focal drug-resistant epilepsy; the basic mechanism of action, however, remains unclear. Here, we show that desynchronization is a potential mechanism of deep brain stimulation of the anterior nucleus of the thalamus by studying local field potentials recordings from the cortex during high-frequency stimulation (130 Hz) of the anterior nucleus of the thalamus in nine patients with drug-resistant focal epilepsy. We demonstrate that high-frequency stimulation applied to the anterior nucleus of the thalamus desynchronizes ipsilateral hippocampal background electrical activity over a broad frequency range, and reduces pathological epileptic discharges including interictal spikes and high-frequency oscillations. Furthermore, high-frequency stimulation of the anterior nucleus of the thalamus is capable of decoupling large-scale neural activity involving the hippocampus and distributed cortical areas. We found that stimulation frequencies ranging from 15 to 45 Hz were associated with synchronization of hippocampal local field potentials, whereas higher frequencies (>45 Hz) promoted desynchronization of ipsilateral hippocampal activity. Moreover, reciprocal effective connectivity between the anterior nucleus of the thalamus and the hippocampus was demonstrated by hippocampal-thalamic evoked potentials and thalamic-hippocampal evoked potentials. In summary, high-frequency stimulation of the anterior nucleus of the thalamus is shown to desynchronize focal and large-scale epileptic networks, and here is proposed as the mechanism for reducing seizure generation and propagation. Our data also demonstrate position-specific correlation between deep brain stimulation applied to the anterior nucleus of the thalamus and patients with temporal lobe epilepsy and seizure onset zone within the Papaz circuit or limbic system. Our observation may prove useful for guiding electrode implantation to increase clinical efficacy.

Objective: To investigate the generation, spectral characteristics, and potential clinical significance of brain activity preceding interictal epileptiform spike discharges (IEDs) recorded with intracranial EEG.Methods: Seventeen adult patients with drug-resistant temporal lobe epilepsy were implanted with intracranial electrodes as part of their evaluation for epilepsy surgery. IEDs detected on clinical macro-and research microelectrodes were analyzed using time-frequency spectral analysis.Results: Gamma frequency oscillations (30-100 Hz) often preceded IEDs in spatially confined brain areas. The gamma-IEDs were consistently observed 35 to 190 milliseconds before the epileptiform spike waveforms on individual macro-and microelectrodes. The gamma oscillations associated with IEDs had longer duration (p , 0.001) and slightly higher frequency (p 5 0.045) when recorded on microelectrodes compared with clinical macroelectrodes. Although gammaIEDs comprised only a subset of IEDs, they were strongly associated with electrodes in the seizure onset zone (SOZ) compared with the surrounding brain regions (p 5 0.004), in sharp contrast to IEDs without preceding gamma oscillations that were often also detected outside of the SOZ. Similar to prior studies, isolated pathologic high-frequency oscillations in the gamma (30-100 Hz) and higher (100-600 Hz) frequency range, not associated with an IED, were also found to be associated with SOZ. Conclusions:The occurrence of locally generated gamma oscillations preceding IEDs suggests a mechanistic role for gamma in pathologic network activity generating IEDs. The results show a strong association between SOZ and gamma-IEDs. The potential clinical application of gammaIEDs for mapping pathologic brain regions is intriguing, but will require future prospective studies. Neurology ® 2015;84:602-608 GLOSSARY HFO 5 high-frequency oscillation; IED 5 interictal epileptiform discharge; iEEG 5 intracranial EEG; SOZ 5 seizure onset zone.Interictal epileptiform spike discharges (IEDs) manifest as sharp-wave deflections in the local field potential recorded within the "irritative zone" of epileptic brain.1 The irritative zone is distinct from the seizure onset zone (SOZ), where the ictal discharge is first observed. The relationship between the 2 zones or between IEDs and seizures remains unclear (for review, see de Curtis and Avanzini 2 ). In particular, the processes underlying IED generation are not well understood, and on a cellular level, recordings show a heterogeneous profile of increased, decreased, or unchanged neuronal firing during IEDs.3,4 Furthermore, the spatial extent of IEDs and their association with SOZ has long been recognized to be highly variable. 2Network local field potential oscillations that can be detected with intracranial EEG (iEEG) provide a powerful window into synchronized activity of neuronal populations. Oscillations in the gamma frequency range (30-100 Hz) were recently implicated in the neuronal network generation of ictal-like discharges in an in vitro...