1 1 1 1 1 1 0 1 0 Possible therapeutic effects of transcutaneous electrical stimulation via concentric ring electrodes *Walter G. Besio, ykaren N. Gale, and zandrei V. Medvedev *Department of Electrical, Computer and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, U.S.A.; ypharmacology and Interdisciplinary Program in Neuroscience, Gegetown University, Washington, District of Columbia, U.S.A.; and zdepartment of Neurology, Gegetown University, Washington, District of Columbia, U.S.A. SUMMARY E P I 1 B Even with the latest advancements in antiepileptic drugs (AEDs) there are still many persons whose seizures are not controlled. There are also side effects repted associated with the AEDs. Electrical stimulation of the brain has shown promise toward controlling seizures. However, most brain stimulation techniques involve invasive procedures to implant electrodes and electronic stimulats. There are no conclusive descriptions of where to place the implanted electrodes to Dispatch:.. Journal: EPI CE: R.Balaji Journal Name Manuscript No. Auth Received: No. of pages: PE: Saravanan Epilepsia, (Suppl. ):, 0 doi:./j.1-.0.01.x Address crespondence to Walter G. Besio, University of Rhode Island, East Alumni Ave, Kingston, RI 01, U.S.A. E-mail: besio@ ele.uri.edu Wiley Periodicals, Inc. ª 0 International League Against Epilepsy WONOEP 00 control seizures. Noninvasive electrical stimulation does not require the risks of implantation, and the electrodes can be moved easily as needed to determine where they may be the most effective in reducing seizure activity. Herein we review the progress of our group in the development of noninvasive electrical stimulation via concentric ring electrodes to control seizures in rats induced by penicillin G, pilocarpine, and pentylenetetrazole (PTZ). KEY WORDS: Epilepsy, Penicillin G, Pentylenetetrazole, Pilocarpine, Seizure. Brain stimulation is a promising new technology f the treatment of medically intractable epilepsy. However, the majity of brain stimulation techniques currently practiced expled are invasive [f a review on various brain stimulation techniques f epilepsy see (Theode & Fisher, 00)]. Electrical stimulation of the brain has a prolonged histy. Over the last 0 years, applications have included cerebellar stimulation (Davis, 000), vagus nerve stimulation (VNS) (Gege et al., 000; Patwardhan et al., 000), which does not directly stimulate the brain, and me recently, deep brain stimulation (DBS), targeting sites such as the subthalamic nucleus (Chabardes et al., 00), mesial tempal structures (Vonck et al., 00), and the anteri thalamic nucleus. Other techniques have included trigeminal (DeGigio et al., 00) and glossopharyngeal nerve stimulation (Patwardhan et al., 00). Effts have also been undertaken to interrupt epileptic seizures noninvasively via transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tdcs), and using electroconvulsive therapy (ECT). TMS applies magnetic fields to the cranium, producing electric fields in the brain. TMS has been studied extensively over the last decade with mixed results f controlling seizures. In a recent study TMS showed effectiveness where the seizure focus could be localized in the neoctex f malfmations of ctical development (Fregni et al., 00a). In a recent pilot study (Fregni et al., 00b) on patients with malfmations of ctical development and refracty epilepsy it has been shown that tdcs decreased epileptic discharges. However, the decrease in seizures due to tdcs was not significant f patients with multiple foci. In ECT, a controlled seizure is induced by applying electrical pulses to the patient s head. A case study repted that ECT acutely controlled seizures in two children (Griesemer et al., 1). We have been developing transcutaneous electrical stimulation (TcES) via concentric ring electrodes as an alternative/complementary therapy f seizure control. This innovative noninvasive stimulation technique demonstrated excellent efficacy with both penicillin and pilocarpine (PILO) induced rat seizure models (Besio et al., 00, 00).
1 1 1 1 1 1 0 1 0 W. G. Besio et al. Penicillin F penicillin G induced seizures myoclonic jerks began within 1. min after the injection of the convulsant, and when the myoclonic jerks reached, on average, per min, monophasic positive pulses, ma, at 00 Hz f a duration of one minute were applied multiple times. The main result was that the first administration of TcES reduced the myoclonic jerk rate in half. In all instances, after TcES, myoclonic jerks stopped f a few minutes and then returned with a weaker amplitude and a lower frequency. In of the 1 cases, repeated stimulation led to complete cessation of myoclonic jerks. In the control group (n = ), the myoclonic jerks were continuous with a maximum average rate of 0 per min. Pilocarpine F the PILO-induced seizures, min after the onset of SE, TcES was delivered from a tripolar concentric ring electrode centered on the top of the head. Immediately after the application of TcES, attenuation of electrographic seizure activity was evident in all eight treated rats. In some cases, the EEG still resembled the baseline activity, even h after the administration of TcES, whereas the PILO was still active. The behavial activity of the control group (n = ) progressed to significantly higher Racine sces than the experimental group (mean R =. vs. R =., where R =, wild running fit was the maximum possible sce). The behavial manifestations of the treated rats indicate that TcES halted the progression of the seizures. There also was a significant difference between the survival times of the controls and TcES-treated rats. These findings suggest that TcES administered min after SE onset has a significant effect on PILO-induced SE electrographic and behavial activity, and the effect appears to be long lasting. Pentylenetetrazole To evaluate possible therapeutic effects of TcES on seizures induced by pentylenetetrazole (PTZ) in rats, male Sprague-Dawley rats weighing 0 g were briefly anesthetized, shaved, and concentric ring electrodes were attached to their scalp 1 day befe the experiment. PTZ ( mg/kg) was given intraperitoneally. Laplacian EEG was recded from tripolar concentric electrodes on the scalp. TcES ( ma, 00 Hz, 00 ls f min) was applied directly after the first myoclonic jerk (R = ). Control rats were prepared and treated the same way, except that no current was passed through the electrodes. Behavi was sced as follows: the stages are: R = 0, no seizure activity; R = 1, al-facial movements only; R =, head nodding; R =, myoclonic jerks; R =, felimb clonus; R =, rearing (Racine, 1). The duration Epilepsia, (Suppl. ):, 0 doi:./j.1-.0.01.x Table 1. Duration of myoclonic activity Duration (min) Experiment Control TcES 1.00.00.00.0..00.00 0....00 1.1.... 1.... 1...00 0. 0. 1. 1.. 1. NA 1.00 NA 1.00 NA 1.00 NA 1. NA 0 1.0 NA 1. NA Mean 1.. SD.1.0 SD, standard deviation. of the behavial signs of seizure activity was measured as time elapsed between the first and last myoclonic jerk. F a within-subjects comparison, the TcES-treated rats were also tested as controls 1 days after the TcES treatment. In the PTZ control group, the rats exhibited myoclonic jerks (R = ) with a latency of less than min and then progressed from myoclonic jerks through rearing with felimb clonus; repeated seizure episodes were observed over a 0-min period. Electrographic signs of seizure activity (sht high-frequency bursts in EEG) preceded the behavial activity and typically continued f over an hour after the behavial seizure activity had ceased. The duration over which myoclonic jerks occurred (Table 1) was compared between the control group and the TcEStreated group. There was a significant (p = 0.001) reduction in this duration as a result of treatment: TcES treated, min (n = ) versus controls, 1 min (n = 1). After TcES, no behavial activity was evident in six treated rats and only a few myoclonic jerks were observed in the remaining treated rats. In most of the treated rats, the electrographic seizure activity was significantly reduced within 1 min after TcES application. Discussion TcES applied through the scalp via concentric ring electrodes significantly attenuated seizures induced by
Possible Therapeutic Effects of Transcutaneous Electrical Stimulation 1 1 1 1 1 1 1 0 1 0 PTZ. The TcES was administered after the first myoclonic jerk (R = ), which came well after the first signs of electrographic seizure activity. In each of the seizure models we have tested penicillin, PILO, and PTZ the TcES was administered after the seizure process had manifested itself by a clear change in behavial activity (R > 0). In our future studies we will include administering TcES befe PTZ administration and also at the first onset of PTZ-induced electrographic seizure activity. We also found that TcES did not cause mot contractions as is common with electroconvulsive therapy, another fm of transcranial electrical stimulation. The rats did not appear to be in pain when the TcES was applied. In a preliminary, unpublished, experiment TcES was applied ( ma, 00 Hz, ls, biphasic pulses) via concentric ring electrodes and conventional disc electrodes. The rats tolerated the concentric ring electrode TcES well and continued to roam around the cage while TcES was applied. In contrast, when the electrical stimulation was applied via conventional electrodes, the rats had vocalizations, escape behavi, and uncontrollable mot activity. The underlying mechanism that could explain such a contrast in the electrographic and behavial effects of the two different stimulation techniques is not yet clear, but we suggest that it is related to the spatial distribution of the electrical field caused by stimulation. With the concentric ring electrode stimulation the field effect is vertically concentrated below the center disc, whereas the conventional stimulation causes me parallel distribution of the field effects between both electrodes. Taken together with previous effects observed in models of status epilepticus induced by pilocarpine (Besio et al., 00) and penicillin (Besio et al., 00), these results indicate that the seizure control achieved with noninvasive TcES is applicable to diverse seizure types and mechanisms of seizure induction. These results also suggest that in the future TcES has the potential to be a viable noninvasive therapy f intractable epilepsy. Disclosure None of the auths has any conflict of interest to disclose. We confirm that we have read the Journal s position on issues involved in ethical publication and affirm that this rept is consistent with those guidelines. References Besio W, Nayak A, Koka K, Jiang W, Sahin M, Patwardhan R. (00) Localized transcutaneous electrical brain stimulation development. Proceedings of the 00 Annual International Conference of the BMES,. Besio W, Koka K, Cole A. (00) Feasibility of non-invasive transcutaneous electrical stimulation f modulating pilocarpine-induced status epilepticus seizures in rats. Epilepsia :. Chabardes S, Kahane P, Minotti L, Koudsie A, Hirsch E, Benabid AL. (00) Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic Disd (suppl ):S S. Davis R. (000) Cerebellar stimulation f cerebral palsy spasticity, function, and seizures. Arch Med Res :0. DeGigio CM, Shewmon DA, Whitehurst T (00) Trigeminal nerve stimulation f epilepsy. Neurology 1:1. Fregni F, Otachi P, do Valle A, Boggio P, Thut G, Rigonatti S, Pascual- Leone A, Valente K. (00a) A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refracty epilepsy. Ann Neurol 0:. Fregni F, Thome-Souza S, Nitsche MA, Freedman SD, Valente KD, Pascual-Leone A. (00b) A controlled clinical trial of cathodal DC polarization in patients with refracty epilepsy. Epilepsia :. Gege MS, Sackeim HA, Rush AJ, Marangell LB, Nahas Z, Husain MM, Lisanby S, Burt T, Goldman J, Ballenger JC. (000) Vagus nerve stimulation: a new tool f brain research and therapy. Biol Psychiatry :. Griesemer DA, Kellner CH, Beale MD, Smith GM. (1) Electroconvulsive therapy f treatment of intractable seizures. Initial findings in two children. Neurology :1. Patwardhan RV, Stong B, Bebin EM, Mathisen J, Grabb PA. (000) Efficacy of vagal nerve stimulation in children with medically refracty epilepsy. Neurosurgery : 1; discussion 1 1. Patwardhan RV, Tubbs RS, Killingswth CR, Rollins DL, Smith WM, Ideker RE. (00) Ninth cranial nerve stimulation f epilepsy control. Part 1: efficacy in an animal model. Pediatr Neurosurg :. Racine R. (1) Modification of seizure activity by electrical stimulation. II. Mot seizure. Electroencephalogr Clin Neurophysiol :1. Theode W, Fisher R (00) Brain stimulation f epilepsy. Lancet : 1. Vonck K, Boon P, Achten E, De Reuck J, Caemaert J. (00) Long-term amygdalohippocampal stimulation f refracty tempal lobe epilepsy. Ann Neurol :. Epilepsia, (Suppl. ):, 0 doi:./j.1-.0.01.x
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