There are 50 million epileptic patients in the world and more than 30% of them are still suffering from drug-resistant refractory epilepsy; therefore, development of a new non-pharmaceutical therapy is needed. We have previously developed a closed-loop transcranial electrical stimulation (TES) technique to intervene absence (petit mal) seizures using rats (ref 1,2). Non-invasive and time-targeting natures of the closed-loop TES technique will diminish risks associated with intracranial electrode implantations and disturbance of normal brain functions, respectively.
We have also developed a new non-pharmaceutical technique for controlling secondary generalized grand-mal seizures of temporal lobe epilepsy (TLE) using a ‘proxy’ intervention strategy (ref 3). As seizure generator networks of TLE are widely distributed over bilateral hippocampi and para-hippocampal structures, direct interventions on these structures are difficult. Thus, we stimulated the medial septum (MS) to modulate highly-synchronous hippocampal oscillations in seizures of TLE because the MS has diffuse anatomical connections to the hippocampi and para-hippocampal structures bilaterally governing oscillatory activities there. We found that closed-loop MS electrical stimulation significantly alleviated electrographic and motor seizures of hippocampally-kindled freely-moving rats whereas open-loop MS stimulation did not. Cell-type specific optogenetic stimulation of MS neural populations revealed that phase-specific alternating excitations of MS glutamatergic and GABAergic neurons could underlie the MS-mediated anti-seizure effects. To promote clinical applications of these seizure intervention techniques, we have then developed a new TES technology to spatially target any brain regions: Intersectional Short Pulse (ISP) stimulation (ref 4). To focus intensity of electrical stimulation to an intracranial region, we placed multiple pairs of stimulus electrodes over the head of rats, cadavers, and healthy volunteers. We found that the focused electrical stimulation could successfully modulate neural activities in the focused brain region and oscillation patterns on electroencephalograms. Our seizure intervention techniques with non-invasive, time-, spatial-, and proxy-targeting natures would be useful to control refractory epilepsies.

References
1. Berényi A, Belluscio M, Mao D, and Buzsáki G. (2012) Closed-loop control of epilepsy by transcranial electrical stimulation. Science 337: 735–737.
2. Kozák G and Berényi A. (2017) Sustained efficacy of closed loop electrical stimulation for long-term treatment of absence epilepsy in rats. Sci Rep 7: 6300.
3. Takeuchi Y, Harangozó M, Pedraza L, Földi T, Kozák G, and Berényi A. (2018) Closed-loop stimulation of the medial septum alleviates temporal lobe epilepsy in rats. The 49th NIPS International Symposium, Dec5-8, 2018, Okazaki, Japan.
4. Vöröslakos M, Takeuchi Y, Brinyiczki K, Zombori T, Oliva A, Fernández-Ruiz A, Kozák G, Kincses ZT, Iványi B, Buzsáki G, and Berényi A. (2018) Direct effects of transcranial electric stimulation on brain circuits in rats and humans. Nat Commun 9: 483.