Transcranial Focal Stimulation Using Concentric Ring Electrodes

RESEARCH

October 2019

Walter G. Besio

• Statement of the challenge/opportunity: gaps, opportunities, and drivers

About 12 in 100 people worldwide, or 800 million, are suffering from neurological disorders such as epilepsy (having multiple recurrent seizures which are uncontrollable electrical activity of the brain), chronic pain, Parkinson’s Disease, etc. [1]. Around 450 million people worldwide are affected by psychiatric disorders [1]. Despite decades of research, new drugs, and advances in surgical therapy, 30% or more of the patients with epilepsy or psychiatric disorders do not respond to medical treatment or suffer from its severe side effects [2]. Epilepsy surgery and devices can control seizures in some patients with drug-resistant epilepsy but require advanced and often invasive diagnostic neurophysiology techniques. New solutions are needed for alternatives to drugs and to more invasive and expensive surgeries.
Growing prevalence of neurological and psychiatric disorders has led to a new era of medical treatment or therapy. There is increasing evidence that electrical neuromodulation (electrically altering the states of nerves) may be used as a potential therapy for neurological and psychiatric conditions that do not respond to conventional treatments. By directly targeting a specific neural region or circuit, electrical neuromodulation enables adjustable and reversible modulation of disease symptoms, both of which are lacking with con¬ventional surgery. Additionally, electrical neuromodulation avoids many adverse effects that are typically associated with systemic medications [3]. Today, the potential of electrical neuromodulation is largely untapped, and the technology has much to improve. Implantable stimulators can focus the delivery of the electric current, but require surgery, are highly invasive and costly. External stimulators have much lower risk and cost, but mostly lack accuracy and activate unwanted tissue.

• Technological innovation/advances with some good simple illustrations. What is the state-of-the-art? What are emerging or pivotal? Why is this novel and important?

We propose a novel, noninvasive method for neuromodulation: transcranial (from outside the head) focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCREs, Figure 1) on the scalp surface. Tripolar means we use three electrodes grouped together. Key advantages of TFS include its combination of focality, noninvasiveness, and cost-effectiveness.

A noninvasive and focal stimulation solution may potentially change the current paradigms for alternative or additive therapy for epilepsy, neuropsychiatric disorders, depression, Alzheimer’s, Parkinson’s, chronic pain, stroke, opioids, etc. The TFS device, envisioned as a compact battery-powered external stimulator, would cost only a fraction of the price of an implantable neuromodulation device and will eliminate the complication and risk of surgical implantation.
TFS has shown significant promise with successful efficacy and safety results in extensive animal studies and safety evidence on humans. We have demonstrated the effect of TFS in various animal models of seizures [4] [5] [6] [7] [8] [9] [10], epileptogenisis (the development of epilepsy) [11], Parkinson’s, and pain. TFS is the only reported method that selectively modulated GABA and glutamate [12] (the culprit for many neurological and psychiatric disorders). We proved that TFS does not cause pain, was safe on the scalp [13] [14], in the hippocampus [15], and does not cause memory loss on animals and humans [16] [14].
In our recent paper [11] we showed that our focal stimulation was able to protect cat brains from becoming epileptic. When strong electrical stimulation is applied directly to the brain day-after-day it causes the brain to become epileptic generating seizures originating from the location where the strong stimulation was applied. We applied our TFS for two-minutes, from outside the skull, immediately after the strong electrical stimulation was applied in the brain. We reasoned this would be like detecting a seizure and automatically turning the TFS on, like what we had already proven was possible [9]. What was unique about our results was that the TFS prevented the brains from becoming epileptic if we applied the TFS after the strong electrical stimulation in the brain. After 40-days we no longer applied the TFS, only the strong electrical stimulation in the brain. To our surprise we found that the brains were protected completely for another 20-days and it took 50-days for the brains to become epileptic. This was in sharp contrast to the control animals, not receiving TFS but getting the strong electrical stimulation in the brain, that became epileptic within 25 days. This proved that TFS had long-lasting affects.

• Why is this important and high potential?

There are multiple reasons that the results of [11] are important. First, it may be possible to provide people that have their first seizure with a TFS device that would be used manually to apply a dose of TFS each day in hopes of protecting the brain from becoming epileptic. Second, for people that have epilepsy and uncontrolled seizures, it may be possible to detect their seizure and automatically apply TFS to stop the seizure similar to what we showed in [9]. Further, since we have shown that we can prevent, terminate, and weaken seizures [4] [5] [6] [7] [8] [9] [10], the patient may be able to apply the TFS manually once or twice a day, similar to taking a medication to keep their seizures in check, applying TFS each day on a schedule as a prophylaxis. Also, since we showed that TFS has long-lasting affects [11], the patient may be able to go some length of days without having to apply TFS before starting the regimen again. Overabundance of glutamate has been implicated as a neurotoxin in Alzheimer’s [17], Parkinson’s [18], Huntington’s [19] diseases, traumatic brain injury, and OCD [20], and since we have shown we decrease glutamate noninvasively [12] there is hope that TFS will be beneficial for other diseases besides epilepsy.

• Process/how to get it deployed/implemented

We are currently conducting human TFS testing to determine if we are able to modulate the human brain. We are confident that we can, but we might have to change some parameters such as: size of the electrodes, intensity of the current applied, the width of the pulses or frequency applied compared to the parameters we used in animals. Once we have proven that we can modulate human brain, we will seek resources to perform human clinical efficacy testing in areas such as epilepsy and Parkinson’s Disease. In the meantime, researchers are able to get TFS components and perform animal research [21].

References

[1] World Health Organization (WHO), “Mental disorders affect one in four people,” 2001. [Online]. Available: http://www.who.int/whr/2001/media_centre/press_release/en/.

[2] B. M. Kwan P, “Early identification of refractory epilepsy.,” N Engl J Med., vol. 5, no. 342, pp. 314-319, 2000.

[3] B. Chen, H. Choi, L. J. Hirsch, A. Katz, A. Legge, R. Buchsbaum and K. Detyniecki, “Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy,” Epilepsy & Behavior, vol. 76, pp. 24-31, 11 2017.

[4] W. G. Besio, K. Koka and A. Cole, “Feasibility of non-invasive transcutaneous electrical stimulation for modulating pilocarpine-induced status epilepticus seizures in rats,” Epilepsia, vol. 48, no. 12, p. 2273–2279, 2007.

[5] W. Besio, M. Cuellar-Herrera, H. Luna-Munguia, S. Orozco-Suárez and L. Rocha, “Effects of transcranial focal electrical stimulation alone and associated with a sub-effective dose of diazepam on pilocarpine-induced status epilepticus and subsequent neuronal damage in rats.,” Epilepsy & behavior : E&B, vol. 28, no. 3, pp. 432-6, 9 2013.

[6] W. G. Besio, K. S. Gale and A. Medvedev, “Possible Therapeutic Effects of Trancutaneous Electrical Stimulation via Concentric Ring Electrodes, Xth Workshop on Neurobiology of Epilepsy (WONOEP 2009),” Epilepsia, vol. 51, no. 3, p. 85–87, 2010.

[7] W. G. Besio, X. Liu, L. Wang, A. Medvedev and K. Koka, “Transcutaneous Focal Electrical Stimulation Via Concentric Ring Electrodes Reduces Synchrony Induced By Pentylenetetrazole In Beta And Gamma Bands In Rats,,” IJ Neural Systems, vol. 21, no. 2, pp. 1-11, 2011.

[8] W. Besio, A. Makeyev, A. Medvedev and K. Gale, “Effects of transcranial focal electrical stimulation via tripolar concentric ring electrodes on pentylenetetrazole-induced seizures in rats,” Epilepsy Research, vol. 105, no. 1-2, pp. 42-51, 2013.

[9] O. Makeyev, X. Liu, H. Luna-Munguía, G. Rogel-Salazar, S. Mucio-Ramirez, Y. Liu, Y. L. Sun, S. M. Kay and W. G. Besio, “Toward a noninvasive automatic seizure control system in rats with transcranial focal stimulations via tripolar concentric ring electrodes.,” IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society, vol. 20, no. 4, pp. 422-31, 7 2012.

[10] O. Makeyev, H. Luna-Munguía, G. Rogel-Salazar, X. Liu and W. Besio, “Noninvasive transcranial focal stimulation via tripolar concentric ring electrodes lessens behavioral seizure activity of recurrent pentylenetetrazole administrations in rats,” IEEE Transactions on Neural Systems and Rehabilitation Engineering, vol. 21, no. 3, pp. 383-390, 2013.

[11] A. Valdés-Cruz, B. Villasana-Salazar, B. Williams, D. Martínez-Vargas, V. M. Magdaleno-Madrigal, S. Almazán-Alvarado and W. G. Besio, “Transcranial focal electrical stimulation via concentric ring electrodes in freely moving cats: Antiepileptogenic and postictal effects,” Experimental Neurology, vol. 320, p. 113012, 10 10 2019.

[12] C. E. Santana-Gomez, D. Alcantara-Gonzalez, H. Luna-Munguia, I. Banuelos-Cabrera, V. Magdaleno-Madrigal, M. Tamayo, L. L. Rocha and W. G. Besio, “Transcranial focal electrical stimulation reduces seizure activity and hippocampal glutamate release during status epilepticus,” in 37th Annual International IEEE EMBS Conference, August 25 – 29, 2015, Milan, Italy, 2015.

[13] W. Besio, V. Sharma and J. Spaulding, “The effects of concentric ring electrode electrical stimulation on rat skin.,” Annals of biomedical engineering, vol. 38, no. 3, pp. 1111-8, 20 3 2010.

[14] L. M. McCane, P. Steele, J. Mercier, D. J. McFarland and W. G. Besio, “Safety of transcranial focal stimulation (TFS) via tripolar concentric ring electrodes (TCREs) in people: initial results,” in Proceedings of the SfN 2018 Annual Meeting, San Diego, 2018.

[15] S. Mucio-Ramirez and O. Makeyev, “Mucio-Ramirez S., Makeyev O., Safety of the transcranial focal electrical stimulation via tripolar concentric ring electrodes for hippocampal CA3 subregion neurons in rats,” J Healthcare Eng, vol. 2017, 2017.

[16] G. Rogel-Salazar, H. Luna-Munguia, K. Stevens and W. and Besio, “Transcranial focal electrical stimulation via tripolar concentric ring electrodes does not modify the short- and long-term memory formation in rats evaluated in the novel object recognition test,” Epilepsy & Behavior, vol. 27, pp. 154-158, 2013.

[17] R. Wang and P. H. Reddy, “Role of Glutamate and NMDA Receptors in Alzheimer’s Disease,” Journal of Alzheimer’s Disease, 2016.

[18] A. Q. Farrand, R. A. Gregory, C. M. Bäckman and K. L. Helke, “Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson’s disease,” September 2016.

[19] D. J. Wright, L. J. Gray, D. I. Finkelstein, P. J. Crouch, D. Pow, T. Y. Pang, S. Li, Z. M. Smith, P. S. Francis, T. Renoir and A. J. Hannan, “N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington’s disease,” Human Molecular Genetics, May 2016.

[20] M. A. Richter, D. R. de Jesus, S. Hoppenbrouwers, M. Daigle, J. Deluce, L. N. Ravindran, P. B. Fitzgerald and Z. J. Daskalakis, “Evidence for Cortical Inhibitory and Excitatory Dysfunction in Obsessive Compulsive Disorder,” Neuropsychopharmacology, vol. 37, no. 5, pp. 1144-1151, 14 4 2012.

[21] A. Khatoun, B. Asamoah and M. Mc Laughlin, “Investigating the Feasibility of Epicranial Cortical Stimulation Using Concentric-Ring Electrodes: A Novel Minimally Invasive Neuromodulation Method.,” Frontiers in neuroscience, vol. 13, p. 773, 2019.

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