Effects of Transcranial Focal Electrical Stimulation via Concentric Ring Electrodes on Seizure Activity



Epilepsy affects approximately one percent of the planets population. There does not appear to be any single therapy that works for all types of epilepsy. As an alternative we have been developing a noninvasive, or minimally invasive, transcranial focal electrical stimulation (TFS) based on the novel tripolar concentric ring electrode (TCRE). By applying biphasic, charge balanced, constant current, pulses noninvasively through the TCRE we have realized acute seizure attenuation in rats. We found that the TFS significantly reduced penicillin-induced myoclonic jerks. There was also a significant improvement in survival for the TFS-treated animals compared to those without application of TFS due to the pilocarpine-induced status epilepticus (SE). Long-lasting control of SE, without antiepileptic drugs, provided positive proof that TFS had antiseizure effects. We also found that TFS via TCREs significantly reduced Pentylenetetrazole (PTZ)-induced hypersynchrony at the beta and gamma frequencies as quantified from cross channel coherence performed on the electroencephalograms (EEGs) recorded from the TCREs. Further, we developed a noninvasive automated seizure control system utilizing TFS and EEG signals from the TCREs. The automatically triggered TFS significantly reduced the power of the EEG. We have also performed safety testing, applying TFS once or multiple times. The histological analysis on scalp, cortex, and hippocampal areas suggests there is no significant difference between the controls and the TFS-treated samples. In conclusion we have found TFS to be effective at attenuating acute seizures from three different rat models and safe. In the future we need to test if TFS is effective in models of pharmacoresistant epilepsy.


Transcranial focal electrical stimulation (TFS) Tripolar concentric ring electrode (TCRE) Noninvasive Seizure Penicillin Pilocarpine Pentylenetetrazole (PTZ) 


  1. Ben-Haim S, Asaad WF, Gale JT, Eskandar EN. Risk factors for hemorrhage during microelectrode-­guided deep brain stimulation and the introduction of an improved microelectrode design. Neurosurgery. 2009;64:754–62.PubMedCrossRefGoogle Scholar
  2. Ben-Menachem E, Manon-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, Mirza W, et al. Vagus nerve stimulation therapy for treatment of partial seizures, 1: a controlled study of effect on seizures. Epilepsia. 1994;35:616–26.PubMedCrossRefGoogle Scholar
  3. Besio WG, Chen T. Tripolar Laplacian electrocardiogram and moment of activation isochronal mapping. Physiol Meas. 2007;28:515–29.Google Scholar
  4. Besio WG, Fasiuddin M. Quantizing the depth of bioelectrical sources for non-invasive 3D imaging. J Bioelectromagn. 2005;7:90–3.Google Scholar
  5. Besio WG, Koka K, Aakula R, Dai W. Tri-polar concentric electrode development for high resolution EEG Laplacian electroencephalography using tri-polar concentric ring electrodes. IEEE Trans Biomed Eng. 2006;53:926–33.Google Scholar
  6. Besio WG, Koka K, Cole A. Feasibility of non-invasive transcutaneous electrical stimulation for modulating pilocarpine-induced status epilepticus seizures in rats. Epilepsia. 2007;48:2273–9.Google Scholar
  7. Besio WG, Cao H, Zhou P. Application of tripolar concentric electrodes and pre-feature selection algorithm for brain–computer interface. IEEE Trans Neural Syst Rehabil Eng. 2008;16:191–4.Google Scholar
  8. Besio WG, Koka K, Gale KS, Medvedev AV. Preliminary data on anticonvulsant efficacy of transcutaneous electrical stimulation via novel concentric ring electrodes. In: Schachter SC, Guttag JV, Schiff SJ, Schomer DL, Summit Contributors. Advances in the application of technology to epilepsy: the CIMIT/NIO Epilepsy Innovation Summit, Boston, May 2008. Epilepsy Behav. 2009;16:3–46.Google Scholar
  9. Besio WG, Gale KS, Medvedev A. Possible therapeutic effects of transcutaneous electrical stimulation via concentric ring electrodes. Epilepsia. 2010a;51:85–7.Google Scholar
  10. Besio WG, Sharma V, Spaulding J. The effects of concentric ring electrode electrical stimulation on rat skin. Ann Biomed Eng. 2010b;38:1111–8.Google Scholar
  11. Besio WG, Liu X, Wang L, Medvedev A, Koka K. Transcutaneous focal electrical stimulation via concentric ring electrodes reduces synchrony induced by pentylenetetrazole in beta and gamma bands in rats. IJ Neural Syst Spec Iss Neuromodulat Epilepsy. 2011a;21:1–11.Google Scholar
  12. Besio WG, Liu X, Liu Y, Sun YL, Medvedev AV, Koka K. Algorithm for automatic detection of pentylenetetrazole-induced deizures in rats. Proceedings of 33rd annual international conference of the IEEE EMBS, Boston, USA, 30 August to 3 September; 2011b. p. 8283–6.Google Scholar
  13. Bhatia R, Dalton A, Richards M, Hopkins C, Aziz T, Nandi D. The incidence of deep brain stimulator hardware infection: the effect of change in antibiotic prophylaxis regimen and review of the literature. Br J Neurosurg. 2011;25:625–31.PubMedCrossRefGoogle Scholar
  14. Chabardes S, Kahane P, Minotti L, Koudsie A, Hirsch E, Benabid AL. Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic Disord. 2002;4:83–93.Google Scholar
  15. Chanpattana W, Sackeim HA. Electroconvulsive therapy in treatment-resistant schizophrenia: prediction of response and the nature of symptomatic improvement. J ECT. 2010;26:289–98.PubMedCrossRefGoogle Scholar
  16. Corda MG, Orlandi M, Lecca D, Carboni G, Frau V, Giorgi O. Pentylenetetrazol-induced kindling in rats: effect of GABA function inhibitors. Pharmacol Biochem Behav. 1991;40:329–33.Google Scholar
  17. Cyberonics Inc. 2012. Press release obtained from Accessed 13 Sept 2012.
  18. Davis R. Cerebellar stimulation for cerebral palsy spasticity, function, and seizures. Arch Med Res. 2000;31:290–9.PubMedCrossRefGoogle Scholar
  19. DeGiorgio CM, Shewmon DA, Whitehurst T. Trigeminal nerve stimulation for epilepsy. Neurology. 2003;12:421–2.CrossRefGoogle Scholar
  20. Drislane FW, Blum AS, Lopez MR, Gautam S, Schomer DL. Duration of refractory status epilepticus and outcome: loss of prognostic utility after several hours. Epilepsia. 2009;50:1566–71.PubMedCrossRefGoogle Scholar
  21. Fisher R. Anterior thalamic nucleus stimulation: issues in study design. In: Luders H, editor. Deep brain stimulation and epilepsy. London: Martin Dunitz; 2003. p. 307–22.Google Scholar
  22. Fregni F, Otachi P, do Valle A, Boggio P, Thut G, Rigonatti S, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol. 2006a;60:447–55.PubMedCrossRefGoogle Scholar
  23. Fregni F, Thome-Souza S, Nitsche MA, Freedman SD, Valente KD, Pascual-Leone A. A controlled clinical trial of cathodal DC polarization in patients with refractory epilepsy. Epilepsia. 2006b;47:335–42.PubMedCrossRefGoogle Scholar
  24. George MS. Stimulating the brain. Sci Am. 2003;289:66–73.PubMedCrossRefGoogle Scholar
  25. George MS, Sackeim HA, Rush AJ, Marangell LB, Nahas Z, Husain MM, et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry. 2000;47:287–95.PubMedCrossRefGoogle Scholar
  26. Gigante PR, Goodman RR. Alternative surgical approaches in epilepsy. Curr Neurol Neurosci Rep. 2011;11:404–8.PubMedCrossRefGoogle Scholar
  27. Goodman J, Berger R, Theng T. Preemptive low-frequency stimulation decreases the incidence of amygdale-kindled seizures. Epilepsia. 2005;46:1–7.PubMedCrossRefGoogle Scholar
  28. Griesemer DA, Kellner CH, Beale MD, Smith GM. Electroconvulsive therapy for treatment of intractable seizures. Initial findings in two children. Neurology. 1997;49:1389–92.PubMedCrossRefGoogle Scholar
  29. Hallett M. Transcranial magnetic stimulation: a revolution in clinical neurophysiology. J Clin Neurophysiol. 2002;19:253–4.PubMedCrossRefGoogle Scholar
  30. Han D, Yamada K, Senzaki K, Xiong H, Nawa H, Nabeshima T. Involvement of nitric oxide in pentylenetetrazole-induced kindling in rats. J Neurochem. 2000;74:792–8.PubMedCrossRefGoogle Scholar
  31. Handforth A, DeGiorgio C, Schachter S, Uthman B, Naritoku D, Tecoma E, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology. 1995;51:48–55.CrossRefGoogle Scholar
  32. Ito T, Hori M, Yoshida K, Shimizu M. Effect of anticonvulsants on seizures developing in the course of daily administration of pentetrazol to rats. Eur J Pharmacol. 1977;45:165–72.CrossRefGoogle Scholar
  33. Kerrigan J, Litt B, Fisher R, Cranstoun S, Frence J, Blum D, et al. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia. 2004;45:346–54.PubMedCrossRefGoogle Scholar
  34. Koka K, Besio WG. Improvement of spatial selectivity and decrease of mutual information of tri-­polar concentric ring electrodes. J Neurosci Methods. 2007;165:216–22.Google Scholar
  35. Kossoff E, Ritzl E, Politsky J, Murro A, Smith J, Duckrow R, et al. Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia. 2004;45:1560–7.PubMedCrossRefGoogle Scholar
  36. Krumholz A, Sung GY, Fisher RS, Barry E, Bergey GK, Grattan LM. Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology. 1995;45:1499–504.PubMedCrossRefGoogle Scholar
  37. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–9.PubMedCrossRefGoogle Scholar
  38. Makeyev O, Liu X, Koka K, Kay SM, Besio WG. Transcranial focal stimulation via concentric ring electrodes reduced power of pentylenetetrazole-induced seizure activity in rat electroencephalogram. 33rd Annual international IEEE EMBS conference, Boston, USA, 30 August to 3 September; 1991. p. 7560–3.Google Scholar
  39. Makeyev O, Liu X, Luna-Munguia H, Rogel-Salazar G, Mucio-Ramirez S, Liu Y, et al. Toward a noninvasive automatic seizure control system in rats with transcranial focal stimulations via tripolar concentric ring electrodes. IEEE TNSRE. 2012a;20:422–31.Google Scholar
  40. Makeyev O, Luna-Munguía H, Rogel-Salazar G, Liu X, Besio WG. Noninvasive transcranial focal stimulation via tripolar concentric ring electrodes lessens behavioral seizure activity of recurrent pentylenetetrazole administrations in rats. IEEE TNSRE. 2012b. doi: 10.1109/TNSRE.2012.2198244.
  41. Merton PA, Morton HB. Stimulation of the cereberal cortex in the intact human subject. Nature. 1980;285:227.PubMedCrossRefGoogle Scholar
  42. Mirski M, Rossell L, Terry J, Fisher R. Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat. Epilepsy Res. 1997;28:89–100.PubMedCrossRefGoogle Scholar
  43. Mucio-Ramirez S, Makeyev O, Liu X, Leon-Olea M, Besio WG. Cortical integrity after transcutaneous focal electrical stimulation via concentric ring electrodes. Society for neuroscience 41st annual meeting, abs. 672.20/Y19, Washington, DC, 12–16 November; 2011.Google Scholar
  44. Pouratian N, Reames DL, Frysinger R, Elias WJ. Comprehensive analysis of risk factors for seizures after deep brain stimulation surgery. J Neurosurg. 2011;115(2):310–5.CrossRefGoogle Scholar
  45. Sackeim HA. Convulsant and anticonvulsant properties of electroconvulsive therapy: towards a focal form of brain stimulation. Clin Neurosci Res. 2004;4:39–57.CrossRefGoogle Scholar
  46. Shorvon SD, Trinka E, Walker MC. The proceedings of the first London colloquium on status epilepticus. Epilepsia. 2007;48:1–3.CrossRefGoogle Scholar
  47. Sirven J, Waterhouse E. Management of status epilepticus. Am Fam Physician. 2003;68:469–76.PubMedGoogle Scholar
  48. Szyndler J, Rok P, Maciejak P, Walkowiak J, Czlonkowska A. Effects of pentylenetetrazol-induced kindling of seizures on rat emotional behavior and brain monoaminergic systems. Pharmacol Biochem Behav. 2002;73:851–61.Google Scholar
  49. Tassinari CA, Cincotta M, Zaccara G, Michelucci R. Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol. 2003;114:777–98.PubMedCrossRefGoogle Scholar
  50. The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology. 1995;45:224–30.CrossRefGoogle Scholar
  51. Theodore W, Fisher R. Brain stimulation for epilepsy. Lancet. 2004;3:111–8.CrossRefGoogle Scholar
  52. Theodore WH, Hunter K, Chen R, Vega-Bermudez F, Boroojerdi B, Reeves-Tyer P, et al. Transcranial magnetic stimulation for the treatment of seizures. A controlled study. Neurology. 2002;59:560–2.Google Scholar
  53. Thomas RK, Young CD. A note on the early history of electrical stimulation of the human brain. J Gen Psychol. 1993;120:73–81.PubMedCrossRefGoogle Scholar
  54. Usui N, Maesawa S, Kajita Y, Endo O, Takebayashi S, Yoshida J. Suppression of secondary generalization of limbic seizures by stimulation of subthalamic nucleus in rats. J Neurosurg. 2005;102:1122–9.PubMedCrossRefGoogle Scholar
  55. Van Oosterom A, Strackee J. Computing the lead field of electrodes with axial symmetry. Med Biol Eng Comput. 1983;21:473–81.Google Scholar
  56. Velasco AL, Velasco M, Velasco F, Menes D, Gordon F, Rocha L, et al. Subacute and chronic electrical stimulation of hippocampus on intractable temporal lobe seizures: preliminary report. Arch Med Res. 2000;31:16–328.Google Scholar
  57. Vonck K, Boon P, Achten E, De Reuck J, Caemaert J. Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy. Ann Neurol. 2002;52:556–65.PubMedCrossRefGoogle Scholar
  58. Wassermann E. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation. Electroencephalogr Clin Neurophysiol. 1998;108:1–16.PubMedCrossRefGoogle Scholar
  59. Wiley JD, Webster JG. Analysis and control of the current distribution under circular dispersive electrodes. IEEE Trans Biomed Eng. 1982a;29:381–5.Google Scholar
  60. Wiley JD, Webster JG. Distributed equivalent-circuit model for circular dispersive electrodes. IEEE Trans Biomed Eng. 1982b;29:385–9.Google Scholar
  61. Zangen A, Roth Y, Voller B, Hallett M. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-Coil. Clin Neurophysiol. 2005;116:775–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Department of Electrical, Computer, and Biomedical EngineeringRhode Island UniversityKingstonUSA

Personalised recommendations