Neurotrauma Reports Volume 2.1, 2021 DOI: 10.1089/neur.2020.0061 SHORT COMMUNICATION Open Access Home-Based SCONETM Therapy Improves Symptoms of Neurogenic Bladder Parag Gad,1–3,* Hui Zhong,1,2 V. Reggie Edgerton,1,4–6 and Evgeniy Kreydin1,2,7 Abstract A wide range of dysfunction can occur after a stroke including symptoms such as urinary urgency, frequency, and urge incontinence. The Spinal Cord Neuromodulator (SCONETM) reactivates and retrains spinal neural networks. The present case study introduces initial evidence that home-based, self-administered SCONE therapy may be a safe and effective method of delivering this neuromodulation modality and may have the ability to minimize clinic visits, which is especially salient in today’s public health environment. Keywords: non-invasive spinal cord stimulation; neurogenic bladder; overactive bladder; stroke; urodynamics Introduction safe, well-tolerated, easily administered, and effective. Each component of the nervous system plays a role in As a therapy aimed at restoring normal neural func- the control of the lower urinary tract (LUT) with the tion, non-invasive self-delivered neuromodulation may brain classically thought to exert an inhibitory influ- meet these criteria. ence.1 In the case of cerebral stroke, LUT dysfunction Recently, we developed a non-invasive Spinal Cord occurs because the input to the LUT from the brain Neuromodulator (SCONETM) to reactivate and retrain is either completely lost or disrupted. A wide range spinal neural networks with the goal of restoring func- of dysfunction can occur after a stroke, but patients tion in patients with neurological disease, such as spi- most commonly develop storage symptoms such as nal cord injury, stroke, and multiple sclerosis.4 This urinary urgency, frequency, and urge incontinence approach consists of using specific neuromodulatory characterized by detrusor overactivity and resulting parameters that transform dysfunctional neural net- in a significant impact on health and quality of life.2 works of the spinal cord to functionally physiological Several current therapies that target the LUT have ad- states. We hypothesized that SCONE engages the auto- verse effects that limit their acceptability in the stroke maticity and the feed-forward5 features intrinsic to spi- population: for example, anticholinergics may have nal neural networks to enable recovery of voluntary an adverse effect on post-stroke cognitive function control of continence4 and voiding.6,7 In addition, un- and botulinum toxin may lead to urinary retention in like existing neuromodulation modalities (sacral and the most common type of stroke victim—the elderly tibial) this approach has the unique feature of deliv- male.3 Because stroke is one of the most prevalent ering stimulation to the spinal cord directly without causes of long-term disability in the world and often relying on peripheral intervention. Traditionally, non- affects the already-frail members of the population, invasive delivery of an electrical stimulus to deep ner- there exists a significant need for therapies that are vous structures, such as the spinal cord, has been a 1 Department of Neurobiology, 4Department of Neurosurgery, 5Brain Research Institute, Keck School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. 2 Rancho Research Institute, Rancho Los Amigos National Rehabilitation Center, Downey, California, USA. 3 SpineX, Inc., Los Angeles, California, USA. 6 Institut Guttmann, Hospital de Neurorehabilitació, Institut Universitari adscrit a la Universitat Autònoma de Barcelona, Barcelona, Badalona, Spain. 7 Department of Urology, University of Southern California, Los Angeles, California, USA. *Address correspondence to: Parag Gad, PhD, Department of Neurobiology, University of California, Los Angeles, Terasaki Life Sciences Building, 610 Charles E. Young Drive East, Los Angeles, CA 90095-1527, USA; E-mail: paraggad@ucla.edu ª Parag Gad et al., 2021; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (CC-BY) (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 165 Gad et al.; Neurotrauma Reports 2021, 2.1 166 http://online.liebertpub.com/doi/10.1089/neur.2020.0061 FIG. 1. Schematic representation of a stroke patient receiving Spinal Cord Neuromodulator (SCONETM) therapy. Note changes occur at multiple levels: 1) activation of local lumbosacral spinal neural networks, 2) changes in sensation and control at the cortical level, and 3) increase in voluntary control of urethra and reduction in urge and urge urinary incontinence. challenge due to cutaneous discomfort caused by incontinence at a low volume (68 mL). The detrusor high current levels required to reach these structures. overactivity contraction was at 53 cm H2O and a flow SCONE circumvents this issue by delivering a combina- of 14 mL/sec, suggesting that no bladder outlet obstruc- tion of multiple frequencies that render high-amplitude tion was present. A trial of anticholinergic therapy for waveforms comfortable even in fully able-bodied 6 months was not beneficial. An intravesical injection individuals.8 of onabotulinumtoxinA 100 units was attempted but this resulted in incomplete bladder emptying and exac- Case Study erbation of his symptoms. Approximately 1 year after Our earlier pilot study provided promising preliminary the onabotulinumtoxinA injection, he completed 12 data that SCONE administered in the clinic setting may sessions of percutaneous tibial nerve stimulation have a significant beneficial effect on stroke-related (PTNS). This therapy resulted in mild improvement LUT dysfunction.4 In the present case study, we sought of his symptoms: his nocturia decreased to 5–6 epi- to explore the feasibility, safety, and efficacy of SCONE sodes a night and he noted a subjective improvement when it is self-administered in the home environment. in urgency. However, most of his LUTS returned to C.H.P. is a 49-year-old male with a history of left baseline levels within a few weeks of completing PTNS. basal ganglia hemorrhagic cerebrovascular accident Between September 2018 and November 2018, the that occurred 6 years prior to study initiation. The pa- patient completed a course of SCONE therapy in the tient developed right hemiparesis, speech impediment, clinic (3 times per week for 8 weeks), after which and storage LUT symptoms as a result of this event. he reported a reduction in neurogenic bladder symp- Lower urinary tract symptoms (LUTS) consisted of se- tom score (NBSS) by 8 points (23 to 15 points, vere urinary frequency (up to 10–12 times a day), noc- p < 0.05), a reduction in daytime frequency (10.35 to turia (up to 6–8 times per night), urinary urgency, and 7.5 times per day, p < 0.05), and a reduction in nocturia occasional urge incontinence. Initial urodynamic eval- (6.4 to 4.25 times per night, p < 0.05), as reported ear- uation revealed detrusor overactivity with associated lier.4 There were no changes in bladder capacity during Gad et al.; Neurotrauma Reports 2021, 2.1 167 http://online.liebertpub.com/doi/10.1089/neur.2020.0061 urodynamic studies compared with his baseline. How- der sensation.9 On the other hand, the premise of ever, he reported improvement in controlling the sud- neuromodulation is to deliver a low-level electrical den urge to void, that is, the ability to hold urine at stimulation to change the excitability of neural net- capacity prior to voluntarily initiating voiding. This ob- works involved in LUT control. Thus, restoration of servation was validated during the urodynamic study function and correction of dysfunction are the basis by a longer time window between reaching bladder of neuromodulation approaches to the LUT. We hy- capacity and involuntary initiation of voiding. On pothesize that spinal cord stimulation modulates the follow-up, the patient sustained the improved level of interneuronal networks and transforms both afferent functionality for 3–4 months. After this period, LUTS and efferent networks into more functional states. Neu- returned to the patient’s pre-stimulation state. romodulation alters the responsiveness of spinal net- Between August 2020 and October 2020, the patient works to bladder filling and emptying and increases completed a course of SCONE therapy at home the conscious awareness of these states. After chronic (5 times a week for 12 weeks), after which he reported SCONE therapy, patients have reported improved a reduction in NBSS by 5 points (19 to 14 points, bladder sensation and decreased urinary urgency.4 In p < 0.05), a reduction in daytime frequency (9.25 to addition, the case patient in the present study was ca- 7.75 times per day, p < 0.05), and a reduction in night- pable of sustaining the level of functionality for several time frequency (2.5 to 1.75 times per night, p < 0.05). months post-therapy. Together, these findings suggest A small increase in average voided volume (from 98 that parts of the central nervous system (CNS) responsi- to 112 mL) was observed at the end of 8 weeks. In ad- ble for conscious sensation in the brain may have been dition, he also reported a reduction in average urge re-engaged along with re-activation and/or re-training prior to voiding (1.08 to 0.55, p < 0.05), a reduction of local spinal centers controlling the LUT, reflecting a in frequency of occurrence of urge levels of 2 (on a highly significant level of functional neural plasticity. scale of 0 [no urge] to 4 [about to leak]) or greater (3.75 to 2, p < 0.05), and an increase in frequency of Conclusion voiding without any urge (4 to 7.5, p < 0.05). The The present case study introduces initial evidence that changes in behavior were not due to a decrease in home-based, self-administered SCONE therapy may fluid consumed as recorded from the 4-day average be a safe and effective method of delivering this neu- voiding diary: 1788 mL versus 1837 mL. The intensity romodulation modality. The ability to minimize clinic of SCONE delivered during therapy in the clinic and visits is especially salient in today’s public health envi- at home ranged between 60 and 80 mA. The patient ronment. We acknowledge that these findings cannot experienced no discomfort or pain due to the stimula- be interpreted to imply results from a large population tion. No adverse events were reported and the degree of patients. However, current and previous results pro- in symptom improvement was similar or better than vide a significant level of confidence that SCONE has what the patient experienced during Transcutaneous the potential to significantly ameliorate symptoms of Electrical Spinal Cord Neuromodulator (TESCoN) autonomic dysfunction such as neurogenic bladder4 therapy delivered in the clinic. and motor dysfunction such as paralysis.10 Subsequently, during the next 3 months of follow-up without SCONE therapy, the patient reported a sus- Funding Information tained level of functionality with an NBSS score of This research was funded in part by the Dana & Albert 12, an average urge prior of voiding of 0.3, a minimal R. Broccoli Charitable Foundation, Nanette and Burt change in frequency of occurrence of urge levels of 2 Forester, including matching by PwC LLP, Roberta or greater (once per day), with no change in nocturia Wilson, BEL13VE in miracles Jack Jablonski Founda- frequency (2.3) and frequency of voiding without any tion and Brain Recovery Project. urge (6.3). Due to impairment in hand function, the electrodes were placed on his back by his primary Author Disclosure Statement caregiver. Although self-placement of electrodes is a V.R.E. holds a shareholder interest in NeuroRecovery potential limiting factor to this approach, the benefits Technologies and holds certain inventorship rights observed outweigh the costs associated. on intellectual property licensed by The Regents of Oral medications and botulinum toxin improve the University of California to NeuroRecovery Tech- LUTS by diminishing bladder contractility and blad- nologies and its subsidiaries. V.R.E., P.G., and E.K. Gad et al.; Neurotrauma Reports 2021, 2.1 168 http://online.liebertpub.com/doi/10.1089/neur.2020.0061 hold shareholder interests in SpineX, Inc. and hold sensory, spinal, and volitional descending inputs in regulation of human locomotion. J. Neurophysiol. 116, 98–105. certain inventorship rights on intellectual property li- 9. Duthie, J.B., Vincent, M., Herbison, G.P., Wilson, D.I., and Wilson, D. (2011). censed by The Regents of the University of California Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database Syst. Rev., CD005493. to SpineX, Inc. 10. Gad, P., Gerasimenko, Y., and Edgerton, V.R. (2019). Tetraplegia to overground stepping using non-invasive spinal neuromodulation. References 9th Int. IEEE/EMBS Conf. on Neural Engineering (NER) 1. de Groat, W.C., Griffiths, D., and Yoshimura, N. (2015). Neural control (San Francisco, CA), 89–92. of the lower urinary tract. Compr. Physiol. 5, 327–396. 2. Burney, T.L., Senapati, M., Desai, S., Choudhary, S.T., and Badlani, G.H. (1996). Acute cerebrovascular accident and lower urinary tract dysfunction: a prospective correlation of the site of brain injury with urodynamic findings. J. Urol. 156, 1748–1750. Cite this article as: Gad, P, Zhong, H, Edgerton, VR, and Kreydin, 3. Sanford, M.T., and Suskind, A.M. (2016). Neuromodulation in neurogenic E (2021) Home-Based SCONETM therapy improves symptoms of bladder. Transl. Androl. Urol. 5, 117–126. neurogenic bladder. Neurotrauma Reports 2:1, 165–168, DOI:10.1089/ 4. Kreydin, E., Zhong, H., Latack, K.R., Ye, S., Edgerton, R., and Gad, P.N. neur.2020.0061. (2020). Transcutaneous Electrical Spinal Cord Neuromodulator (TESCoN) improves symptoms of overactive bladder. Front. Syst. Neurosci. 14, 1. 5. Gerasimenko, Y., Sayenko, D., Gad, P., Liu, C.T., Tillakaratne, N.J., Roy, R.R., Kozlovskaya, I., and Edgerton, V.R. (2017). Feed-Forwardness of spinal networks in posture and locomotion. Neuroscientist 23, 441–453. 6. Gad, P.N., Kreydin, E., Zhong, H., Latack, K., and Edgerton, V.R. (2018). Abbreviations Used Non-invasive neuromodulation of spinal cord restores lower urinary tract CNS ¼ central nervous system function after paralysis. Front. Neurosci. 12, 432. LBNS ¼ neurogenic bladder symptom score 7. Gad, P.N., Roy, R.R., Zhong, H., Lu, D.C., Gerasimenko, Y.P., and Edgerton, LUT ¼ lower urinary tract V.R. (2014). Initiation of bladder voiding with epidural stimulation in LUTS ¼ lower urinary tract symptoms paralyzed, step trained rats. PLoS One 9, e108184. PTNS ¼ percutaneous tibial nerve stimulation 8. Gerasimenko, Y., Gad, P., Sayenko, D., McKinney, Z., Gorodnichev, R., SCONE ¼ Spinal Cord Neuromodulator Puhov, A., Moshonkina, T., Savochin, A., Selionov, V., Shigueva, T., TESCoN ¼ Transcutaneous Electrical Spinal Cord Neuromodulator Tomilovskaya, E., Kozlovskaya, I., and Edgerton, V.R. (2016). 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