Zhong et al. Bioelectronic Medicine (2022) 8:5 https://doi.org/10.1186/s42234-022-00087-x Bioelectronic Medicine SHORT REPORT Open Access Noninvasive spinal neuromodulation mitigates symptoms of idiopathic overactive bladder Hui Zhong1,2, Emilie Liu1,2,3, Priya Kohli2,4, Laura Perez2,4, V. Reggie Edgerton1,5,6,7, David Ginsberg2,4, Parag Gad1,2,3* and Evgeniy Kreydin2,4 Abstract Background: Overactive bladder (OAB) affects 12 to 30% of the world’s population. The accompanying urinary urgency, frequency and incontinence can have a profound effect on quality of life, leading to depression, social isola- tion, avoidance of sexual activity and loss of productivity. Conservative measures such as lifestyle modification and pelvic floor physical therapy are the first line of treatment for overactive bladder. Patients who fail these may go on to take medications, undergo neuromodulation or receive injection of botulinum toxin into the bladder wall. While effective, medications have side effects and suffer from poor adherence. Neuromodulation and botulinum toxin injec- tion are also effective but are invasive and not acceptable to some patients. Methods: We have developed a novel transcutaneous spinal cord neuromodulator (SCONE™,) that delivers multifre- quency electrical stimulation to the spinal cord without the need for insertion or implantation of stimulating elec- trodes. Previously, multifrequency transcutaneous stimulation has been demonstrated to penetrate to the spinal cord with idiopathic overactive bladder, who underwent 12 weeks of SCONE™ therapy. and lead to motor activation of detrusor and external urethral sphincter muscles. Here, we report on eight patients Results: All patients reported statistically significant clinical improvement in multiple symptoms of overactive blad- der, such as urinary urgency, frequency and urge incontinence. In addition, patients reported significant symptomatic improvements as captured by validated clinical surveys. Conclusion: SCONE™ therapy represents the first of its kind therapy to treat symptoms of urgency, frequency and urge urinary incontinence in patients with OAB. Trial registration: The study was listed on clinicaltrials.gov (NCT03​753750). Keywords: Non-invasive spinal cord stimulation, Urge urinary incontinence, Overactive bladder, Lower urinary tract, Urodynamics Introduction Although not inherently dangerous or life threatening, Overactive bladder (OAB) is a highly prevalent condi- OAB has far-reaching implications for overall health, tion characterized by urinary frequency, urgency and quality of life and health economics. Highly effective urge incontinence (Ouslander 2004; Homma et al. 2006). therapies for OAB exist and include pelvic floor physi- cal therapy, oral medications, neuromodulation tech- niques and intravesical botulinum toxin injection (Wein *Correspondence: parag@spinex.co 3 2003; Hartmann et al. 2009). Despite their effectiveness, SpineX Inc., 19509 Astor Pl, Northridge, Los Angeles, CA 91324, USA Full list of author information is available at the end of the article these therapies have their respective weaknesses and © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. Zhong et al. Bioelectronic Medicine (2022) 8:5 Page 2 of 9 shortcomings, such as low adherence, invasiveness and (Gad et al. 2020b). Finally, SCONE™ has shown prom- requirement for frequent office visits. Therefore, a need ise in improving locomotor capabilities in children with exists for additional treatment options for OAB. cerebral palsy (Gad et al. 2021; Edgerton et al. 2021). The conceptual foundation for the work done here In our previous neurogenic bladder studies (Krey- was established by our ability to restore locomotor din et al. 2020), we noted an improvement in bladder function using lumbosacral epidural spinal stimulation capacity and for sensate subjects - a decrease in urinary (Harkema et al. 2011; Angeli et al. 2014; Grahn et al. urgency and frequency. Since noninvasive spinal neuro- 2017). We found that patients also began regaining vol- modulation resulted in reduced symptoms of urgency, untary control of urinary voiding (Harkema et al. 2011). frequency and decreased incontinence episodes even In parallel, we developed epidural stimulation proto- in patients with a compromised nervous system, we cols to initiate voiding in an spinal cord injury (SCI) rat hypothesized that similar improvement could be model, which normally requires manual expression of observed in patients suffering from idiopathic over- urine from the bladder (Gad et al. 2014). Our team and active bladder that have an intact neuraxis. Thus, the noninvasive spinal neuromodulation using SCONE™ in several others have previously demonstrated the impact objective of this study was to assess the effectiveness of of spinal neuromodulation in controlling and improv- ing bladder function in rodents (Horst et al. 2013; Gad treating the symptoms of overactive bladder. et al. 2014, 2016; Abud et al. 2015; Hoey et al. 2021), nonhuman primates (Havton et al. 2019) and patients with paralysis (Gad et al. 2018b; Herrity et al. 2018). Methods More recently, we have developed and implemented a Patient recruitment noninvasive spinal cord neuromodulation technology This study was approved by the Institutional Review that delivers a sufficient electrical signal non-invasively Board of Rancho Research Institute, the research arm to activate the neural structures of the spinal cord with- of Rancho Los Amigos National Rehabilitation Center, out significant cutaneous discomfort (Gerasimenko Downey, CA. The study was listed on clinicaltrials.gov et al. 2015a, b, 2016). To date, we have demonstrated (NCT03753750). Eight patients (7F, 1 M) were recruited that this modality can enable recovery of voluntary for the study. The patient demographic and biometric movement (Gerasimenko et al. 2015b; Gad et al. 2017) characteristics are summarized in Table 1. The inclu- of upper (Gad et al. 2018a; Inanici et al. 2018) and sion criteria included: 1) Age between 18 and 80 years lower limbs (Gad et al. 2019), improved trunk function and 2) Known diagnosis of overactive bladder, confirmed (Rath et al. 2018) and self-assisted standing (Sayenko by either urge urinary incontinence episodes or pres- et al. 2018). In addition to motor function, noninvasive ence of urinary frequency (> 8/day) or high urge prior to spinal cord neuromodulation can lead to significant void (captured by the voiding diary). Exclusion criteria and meaningful levels of normalization of autonomic included: 1) Presence of lower urinary tract symptoms parameters after SCI, such as cardiovascular (Phillips suggestive of urinary retention or obstruction, 2) Find- et al. 2018) and lower urinary tract (LUT) function ing of an elevated post-void residual (> 100 ml) on an (Gad et al. 2018b), function in patients with neurogenic ultrasonographic bladder scan, 3) History of spinal cord bladder due to stroke, spinal cord injury and multiple injury, spina bifida, multiple sclerosis, stroke or other sclerosis (Kreydin et al. 2020; Gad et al. 2021a, b), nor- neurological disease, 4) Acute or current urinary tract malize breathing and coughing after spinal cord injury infection, and 5) Current or planned pregnancy. Table 1 Patient demographics Patient ID Age Height (cm) Weight (kg) Waist (cm) Belly (cm) BMI P1 53 160.0 79.5 90 96 31 P2 48 134.6 44.1 79 84 24.3 P3 69 160.0 90.5 107 114 35.2 P4 55 157.5 79.5 91 100.5 32 P5 48 165.1 90.9 122 131 33.3 P6 51 155 61.4 86 92 25.5 P7 60 142.2 46.8 89 78 33.3 P8 49 157.5 85.0 100 113 34.2 Zhong et al. Bioelectronic Medicine (2022) 8:5 Page 3 of 9 Clinical evaluation channel was always maintained at a suprasensory but All patients were weaned off anticholinergic or B3 ago- sub-motor threshold intensity, i.e., no visible contractions nist medication for a period of at least 7 days prior to were observed on abdominal, pelvic or lower extrem- study initiation. All patients completed a 4-day voiding ity muscles. The intensity for each channel was adjusted diary (2 weekdays and 2 weekend days) and all clinical individually daily based on patient comfort; i.e. amplitude surveys prior to initiation of spinal stimulation therapy of stimulation was increased until the patient could toler- and within 2 days of finishing spinal stimulation therapy. ate it, to identify the threshold. The stimulation was low- The voiding diary captured data that included: frequency ered to 80% of the tolerable threshold and used for the of voids, frequency of incontinence episodes, urgency duration of the session. The intensities used across all rating for each void (self-classified by the patient on a patients ranged from 40 to 100 mA and did not change scale of 0 to 4, as follows: 0 = No urge, 1 = Minimal urge significantly over the course of the 12 weeks of therapy. (Can wait 10 min or more), 2 = Moderate urge (Can wait Skin temperature and blood pressure and heart rate were 1 to 5 min), 3 = Strong urge (Can wait less than 1 min) monitored before and after stimulation. None of the and 4 = (About to leak)). If any incontinence episodes patients reported any pain or discomfort due to the stim- occurred, they were classified on a scale of 0 to 3, where ulation or otherwise during the course of the therapy. 0 = no leak or dry pad/diaper, 1 = Small leak, 2 = Mod- erate leak and 3 = Heavy leak. The Minimal Clinical Statistical analysis Important Difference (MCID) for 1) urge urinary incon- All data are reported as mean ± SE. Paired t-tests were tinence episodes has been defined as 50% reduction, 2) used to compare the group mean data before and after urgency as 50% reduction and 3) frequency as 50% (or 8 stimulation. All statistical significance is reported at voids or lower) by FDA’s guidance for devices to address P < 0.05. urge urinary incontinence. The clinical surveys consisted of ICIQ-B (Cotterill et al. 2011), ICIQ-UI SF (Lim et al. Results 2017) and OAB-q SF (Coyne et al. 2002, 2015). At the end Voiding diaries and questionnaire responses were con- of the study, participants’ overall impression of symptom sistent with the diagnosis of overactive bladder for all improvement was measured on the PGI-I scale (Peters participants. Minimum daytime frequency reported was et al. 2010), ranging from 1 (very much better) to 7 (very 8 voids, and minimum nighttime frequency was 3 voids much worse). Skin temperature was monitored using a at the start of therapy (Fig. 2A). Five of seven patients clinical grade infrared camera (PerfectPrime IR0280H). reported urge incontinence (Fig. 2B-C), with strong urgency (rated as 2 or greater) being common (Fig. 2D & F), occurring in 92.5% of voiding episodes across all the Chronic spinal neuromodulation participants. Only 5% of voids were urge-free (Fig. 2E). Voiding diary findings were accompanied by high OAB using SCONE™, a proprietary electrical neuromodula- Noninvasive spinal neuromodulation was delivered questionnaire scores. All patients also reported high tion device (SpineX Inc., Los Angeles, CA). All patients scores in their ICIQ-B surveys, suggesting concurrent completed 24 sessions at a rate of 2 sessions a week with bowel dysfunction. Patients were encouraged to maintain each session lasting for 60 mins. During each session, the their normal lifestyle with respect to fluid consumption patients were comfortably seated in a regular office chair while in the study (Fig. 3). and were given ~ 3–5 min to ramp up the stimulation Patients began to report symptom changes by week 3 intensity and to allow for accommodation. The therapeu- of the study. In most cases, the changes observed began tic waveform consisted of two alternating pulses of oppo- with improvement in urge and decrease in night-time site polarities separated by a 1uS delay forming a delayed frequency. By week 6-7, all patients also reported sub- biphasic waveform (Fig. 1C). The pulses consisted of jective improvement in lower urinary tract symptoms a rectangular high frequency biphasic carrier pulse through the entire day. At week 12, all patients reported (10KHz) combined with a low frequency (30 Hz) burst a decrease in both daytime and night-time frequency pulse, each with a pulse width of 1 ms. Two independent along with an overall decrease in daily voiding fre- channels of stimulation were applied using self-adhesive quency (Fig. 2A). In addition, six out of seven patients hydrogel electrodes (1.25″ round, Axelgard) between the reported improved control in the ability to plan voiding interspinous ligaments of T11-T12 and L1-2 serving as cycles with fewer high urge voids (73% at pretherapy to the cathodes and two self-adhesive rectangular hydro- 45% at post therapy) and an increase in urge free voids gel electrodes (3”× 5” rectangular electrodes, Axelgard) (5% at pretherapy to 47% at post therapy) (P = 0.11). five bilaterally over the iliac crests as the common anodes to out of seven patients that had urge urinary incontinence both channels (Fig. 1). The stimulation intensity for each at baseline reported a > 50% decrease in the number of Zhong et al. Bioelectronic Medicine (2022) 8:5 Page 4 of 9 Fig. 1 A Schematic representation of experimental setup. B Step by step representation of position the anode and cathode and C Electrical waveforms used in the current study incontinence episodes (Fig. 2B, overall average decrease 60 mins of stimulation. In addition, the no significant of 64%) and a decrease in the size of leaks (1.84 to 0.92, changes in blood pressure or heart rate were observed on a scale of 0 to 3) (Fig. 2C). (Table 2). No adverse events were observed, and none Clinical questionnaire changes were consistent with were reported by the patients. the changes noted on the voiding diary, with a mean decrease in OAB-q by 72.66 ± 16.9 points and mean Discussion decrease in ICIQ-UI by 8.33 ± 2.97 points. All patients’ In this pilot study we demonstrate that noninvasive spi- ICIQ-B scores also decreased by a mean of 15.5 ± 16.32 nal cord neuromodulation has a beneficial effect on points, suggesting a significant improvement in bowel patients with idiopathic OAB. After completing 12 weeks function (Fig. 3). The improvement in symptoms of over- of therapy, patients reported improved OAB question- active bladder was also reflected in urodynamic stud- naire scores, and decreased urinary frequency, urgency ies with patients reporting 1st desire and strong desire and incontinence. All patients reported high levels of to void at higher volumes at post-therapy compared to satisfaction with the therapy. We recognize the absence pre-therapy even in the absence of active spinal neuro- of a sham arm as a weakness of the study and intend to modulation. A representative tracing of the urodynamic implement a sham control in the pivotal trial that will study at pre-therapy and post-therapy is shown in Fig. 4. follow these preliminary results. We also recognize that Seven patients reported to be much better on the PGI-I the small number of participants in the study may pre- scale, while one reported to be a little better (Fig. 5). The clude the generalizability of the results. However, we average temperature did not change immediately after are encouraged by the ability to detect a statistically and the stimulation was initiated and increased by < 1 °C after Zhong et al. Bioelectronic Medicine (2022) 8:5 Page 5 of 9 Fig. 2 Voiding diary characteristics. A Mean ± SE (n = 8) total voiding frequency, B Mean ± SE (n = 7) urge urinary incontinence episodes per day, C Mean ± SE (n = 7) size of each incontinence episodes per day (Incontinence episodes were classified on a scale of 0 to 3, where 0 = no leak or dry pad/diaper, 1 = Small leak, 2 = Moderate leak and 3 = Heavy leak), D Mean ± SE (n = 8) Average urgency prior to voiding, E Mean ± SE (n = 8) frequency of zero urge voids and F Mean ± SE (n = 8) voiding frequency with high urge (levels 2 or higher; urgency rating for each void self-classified by the patient on a scale of 0 to 4, as follows: 0 = No urge, 1 = Minimal urge (Can wait 10 min or more), 2 = Moderate urge (Can wait 1 to 5 min), 3 = Strong urge (Can wait less than 1 min) and 4 = About to leak) Fig. 3 Survey scores. A Mean ± SE (n = 8) OAB-q survey, B Mean ± SE (n = 8) ICIQ-UI survey and C Mean ± SE (n = 8) ICIQ-B survey clinically meaningful difference in LUT symptoms even tibial nerve and the ventral ramus of the S3 spinal nerve. in such a small group of randomly selected participants. The S3 spinal nerve carries sensory and motor fibers that Neuromodulation is a well-established therapeutic distally give rise to the pudendal nerve innervating the technique in OAB (Amend et al. 2011). Two main tar- urethral sphincter and the pelvic nerve that innervates gets for neuromodulation are currently employed: the the detrusor muscle. Proximally, S3 fibers arise from Zhong et al. Bioelectronic Medicine (2022) 8:5 Page 6 of 9 Fig. 4 A representative Urodynamic study from a patient before and after 12 weeks of therapy. Note the while the overall bladder capacity remained the same, the changes in 1st desire and strong desire relative to beginning of voiding demonstrates the increased bladder and sphincter control Table 2 Changes in skin temperature and cardiovascular function before and after therapy Range Pre Therapy Stim On Post Therapy Skin Temperature max 98.9 99.7 99.8 (°F) min 98.4 99.2 99.5 Systolic (mm Hg) max 103 Not recorded 113 min 99 108 Diastolic (mm Hg) max 77 82 min 71 75 Fig. 5 Distribution of the Patient Global Improvement Index (PGI-I), Heart Rate (BPM) max 69 80 ranging from 1 (very much better) to 7 (very much worse) min 62 72 Zhong et al. Bioelectronic Medicine (2022) 8:5 Page 7 of 9 autonomic (sacral parasympathetic nucleus) and somatic diminished detrusor overactivity. Prior to its applica- (Onuf ’s nucleus) nuclei of the sacral spinal cord (de Groat tion in humans, spinal neuromodulation was dem- et al. 2015). Thus, a possible mechanism for S3 neuro- onstrated to affect LUT function in murine and modulation is to electrically stimulate the central struc- non-human primate animal models (Gad et al. 2014; tures of LUT neural control in a retrograde fashion (Gill Abud et al. 2015; Chang et al. 2018). In those studies, et al. 2017). Although the mechanism for tibial nerve spinal cord neuromodulation resulted in partial nor- neuromodulation is less obvious, the underlying princi- malization of voiding in spinal cord injured animals ple is the same: the tibial nerve is partially formed by S3; (Gad et al. 2018c; Havton et al. 2019). In addition to the thus, supra-motor threshold electrical stimulation of the LUT, spinal neuromodulation has been shown to effect LUT function. Like these modalities, SCONE™ appears tibial nerve is thought to affect S3 fibers responsible for changes in locomotor, cardiovascular and respiratory function both in able-bodied humans and patients with to modulate the neural structures responsible for LUT neurological injuries or disease (Gerasimenko et al. function, with the key difference being the stimulation 2016; Inanici et al. 2018; Gad et al. 2020a). nervous system, SCONE™ stimulation is delivered to the site: whereas existing modalities stimulate the peripheral This study represents the initial evaluation of spinal neuromodulation for the treatment of an idiopathic spinal cord, a component of the central nervous system. condition (OAB) in a cohort of able-bodied individuals. Whether this difference leads to any functional differ- The etiology of OAB is multifactorial, but subclinical ences in LUT function remains to be determined; how- neurological dysfunction almost certainly plays a role. ever, our early observations suggest improvement and Functional brain imaging studies have demonstrated restoration of LUT sensation as a unique property of spi- that women with urge incontinence have distinct pat- nal cord neuromodulation (Kreydin et al. 2020; Gad et al. terns of brain activation compared to women without 2021a, b). OAB (Tadic et al. 2012). Furthermore, neuromodula- In addition, we hypothesize that the mechanism of tion with well-established techniques, such as SNS, was transcutaneous spinal neuromodulation is by direct stim- shown to alter brain activity patterns in regions of the ulation of spinal cord networks involved in LUT control. brain involved in LUT control, such as the insula and By positioning the stimulating electrodes between verte- the cingulate cortex (Weissbart et al. 2018). We hypoth- bral levels T11-12 and L1-2, the electrical signal is deliv- esize that transcutaneous spinal cord neuromodulation ered to spinal levels corresponding to the sympathetic has a similar effect on micturition-associated brain chain and the sacral nuclei of the spinal cord respec- activity, potentially normalizing activation of brain tively. We hypothesized that by stimulating these centers, regions important for LUT function. SCONE would elicit a response similar to sacral and tibial Sacral transcutaneous electrical nerve stimulation nerve stimulation. The results reported here support this (TENS) has been previously studied in adults (Okada hypothesis with the functional improvements of OAB et al. 1998) and is an established therapeutic tech- symptoms being similar or better compared to previously nique in children, where it has been demonstrated to published results for these established neuromodulation be effective for bowel and bladder dysfunction by mul- modalities. Specifically, PTNS demonstrated 45% (Peters tiple groups (Malm-Buatsi et al. 2007; Sillen et al. 2014; et al. 2009) to 69% (Kobashi et al. 2019) reduction in urge Hoffmann et al. 2018). Signal transduction to the sacral urinary incontinence episodes. Sacral Neuromodulation nerve in adults may not be as effective, because of the reported a 57% (Siegel et al. 2000) to 76% (Hoen et al. greater amount of overlying fat and subcutaneous tis- 2017) reduction in urge urinary incontinence episodes, sue. On the other hand, dual frequency stimulation whereas our current data demonstrate ~ 65% reported delivered by SCONE appears to penetrate the overly- reduction in urge urinary incontinence episodes over the ing tissues of the spinal cord effectively and generate an same period of time (3 months). In addition, our results immediate and long term sensory and motor response demonstrate functional improvements in several other corresponding in location to the stimulated spinal level metrics extracted from the bladder diary such as the (Kreydin et al. 2020; Gad et al. 2021b) and leading to number of zero urge voids and average urgency which the observed clinical changes in LUT function. further strengthen our original hypothesis. We have previously demonstrated the effect of trans- cutaneous spinal neuromodulation on the LUT in Conclusion patients with neurogenic bladder due to spinal cord This first in human study demonstrates the feasibility of injury, stroke, and multiple sclerosis. Transcutane- mitigating symptoms of OAB using a noninvasive and ous spinal neuromodulation was shown to result in well-tolerated modality, thus potentially adding a new improved continence, increased bladder capacity and tool to the armamentarium of OAB therapies. Zhong et al. Bioelectronic Medicine (2022) 8:5 Page 8 of 9 Chang HH, Yeh JC, Ichiyama RM, Rodriguez LV, Havton LA. Mapping and neuromodulation of lower urinary tract function using spinal cord stimu- Abbreviations lation in female rats. Exp Neurol. 2018;305:26–32. LUT: Lower Urinary Tract; OAB: OverActive Bladder; SCI: Spinal Cord Injury; Cotterill N, Norton C, Avery KN, Abrams P, Donovan JL. Psychometric evalu- SCONE: Spinal Cord Neuromodulator; TENS: Transcutaneous Electrical Nerve ation of a new patient-completed questionnaire for evaluating anal Stimulation. incontinence symptoms and impact on quality of life: the ICIQ-B. Dis Colon Rectum. 2011;54:1235–50. Acknowledgements Coyne K, Revicki D, Hunt T, Corey R, Stewart W, Bentkover J, et al. Psychometric Not Applicable. validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res. 2002;11:563–74. Authors’ contributions Coyne KS, Thompson CL, Lai JS, Sexton CC. An overactive bladder symptom The author(s) read and approved the final manuscript. and health-related quality of life short-form: validation of the OAB-q SF. Neurourol Urodyn. 2015;34:255–63. Funding de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. This research was funded in part by NIH/NIDDK R44DK129164, NIH/NINDS Compr Physiol. 2015;5:327–96. 1U01NS113871-01, the Dana & Albert R. Broccoli Charitable Foundation, Nan- Edgerton VR, Hastings S, Gad PN. Engaging spinal networks to mitigate ette and Burt Forester, including matching by PwC LLP, Roberta Wilson and supraspinal dysfunction after CP. Front Syst Neurosci. 2021;15:409. BEL13VE in Miracles Jack Jablonski Foundation. Gad P, Gerasimenko Y, Zdunowski S, Turner A, Sayenko D, Lu DC, et al. Weight bearing over-ground stepping in an exoskeleton with non-invasive spinal Availability of data and materials cord neuromodulation after motor complete paraplegia. Front Neurosci. All raw data are available upon request. 2017;11:333. Gad P, Gerasimenko Y, Edgerton VR. Tetraplegia to overground stepping using non-invasive spinal neuromodulation. In: IEEE 9th International IEEE/ Declarations EMBS Conference on Neural Engineering (NER); 2019. p. 89–92. Gad P, Kreydin E, Zhong H, Edgerton VR. Enabling respiratory control after Ethics approval and consent to participate severe chronic tetraplegia: an exploratory case study. J Neurophysiol. The authors confirm that the study was approved by the institutional review 2020a;124:774–80. board of Rancho Research Institute and certify that the study was performed Gad P, Kreydin E, Zhong H, Edgerton VR. Training the bladder how to void: a in accordance with the ethical standards as laid down in the 1964 Declaration noninvasive spinal neuromodulation case study. In: 10th International of Helsinki and its later amendments. IEEE/EMBS Conference on Neural Engineering (NER); 2021a. Gad P, Hastings S, Zhong H, Seth G, Kandhari S, Edgerton VR. Transcutaneous Consent for publication spinal neuromodulation reorganizes neural networks in patients with This study was approved by the Institutional Review Board of Rancho cerebral palsy. Neurotherapeutics. 2021;18(3):1953–62. Research Institute, the research arm of Rancho Los Amigos National Rehabili- Gad P, Lee S, Terrafranca N, Zhong H, Turner A, Gerasimenko Y, et al. Non- tation Center, Downey, CA. Informed consent was obtained from all individual invasive activation of cervical spinal networks after severe paralysis. J participants included in the study. Patients signed informed consent regard- Neurotrauma. 2018a;35:2145–58. ing publishing their data. Gad P, Zhong H, Edgerton VR, Kreydin E. Home-based SCONETM therapy improves symptoms of neurogenic bladder. Neurotrauma Rep. Competing interests 2021b;2(1):165–8. V.R.E, holds shareholder interest in Onward and hold certain inventorship Gad PN, Kokikian N, Christe KL, Edgerton VR, Havton LA. Noninvasive neu- rights on intellectual property licensed by The Regents of the University of rophysiological mapping of the lower urinary tract in adult and aging California to Onward. rhesus macaques. J Neurophysiol. 2018c;119:1521–7. V.R.E, E.K, and PG hold shareholder interest in SpineX Inc. and hold certain Gad PN, Kreydin E, Zhong H, Edgerton VR. Enabling respiratory control after inventorship rights on intellectual property licensed by The Regents of the severe chronic tetraplegia: an exploratory case study. J Neurophysiol. University of California to SpineX Inc. 2020b;124(3):774–80. Gad PN, Kreydin E, Zhong H, Latack K, Edgerton VR. Non-invasive neuromodu- Author details lation of spinal cord restores lower urinary tract function after paralysis. 1 Department of Neurobiology, University of California, Los Angeles, CA 90095, Front Neurosci. 2018b;12:432. USA. 2 Rancho Research Institute, Rancho Los Amigos National Rehabilitation Gad PN, Roy RR, Zhong H, Gerasimenko YP, Taccola G, Edgerton VR. Neuro- Center, Downey, CA 90242, USA. 3 SpineX Inc., 19509 Astor Pl, Northridge, modulation of the neural circuits controlling the lower urinary tract. Exp Los Angeles, CA 91324, USA. 4 Institute of Urology, Keck School of Medicine Neurol. 2016;285:182–9. of University of Southern California, Los Angeles, CA 90033, USA. 5 Department Gad PN, Roy RR, Zhong H, Lu DC, Gerasimenko YP, Edgerton VR. Initiation of of Neurosurgery, University of California, Los Angeles, CA 90095, USA. 6 Brain bladder voiding with epidural stimulation in paralyzed, step trained rats. Research Institute, University of California, Los Angeles, CA 90095, USA. 7 Insti- PLoS One. 2014;9:e108184. tut Guttmann, Hospital de Neurorehabilitació, Institut Universitari adscrit a la Gerasimenko Y, Gad P, Sayenko D, McKinney Z, Gorodnichev R, Puhov A, et al. Universitat Autònoma de Barcelona, 08916 Badalona, Barcelona, Spain. Integration of sensory, spinal, and volitional descending inputs in regula- tion of human locomotion. J Neurophysiol. 2016;116:98–105. 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N Engl J Med. 2004;350:786–99. Peters K, Carrico D, Burks F. Validation of a sham for percutaneous tibial nerve stimulation (PTNS). Neurourol Urodyn. 2009;28:58–61. Peters KM, Carrico DJ, Perez-Marrero RA, Khan AU, Wooldridge LS, Davis GL, et al. Randomized trial of percutaneous tibial nerve stimulation versus Sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial. J Urol. 2010;183:1438–43. Ready to submit your research ? Choose BMC and benefit from: Phillips AA, Squair JW, Sayenko DG, Edgerton VR, Gerasimenko Y, Krassioukov AV. An autonomic neuroprosthesis: noninvasive electrical spinal cord • fast, convenient online submission stimulation restores autonomic cardiovascular function in individuals with spinal cord injury. J Neurotrauma. 2018;35:446–51. • thorough peer review by experienced researchers in your field Rath M, Vette AH, Ramasubramaniam S, Li K, Burdick J, Edgerton VR, et al. Trunk • rapid publication on acceptance stability enabled by noninvasive spinal electrical stimulation after spinal • support for research data, including large and complex data types cord injury. J Neurotrauma. 2018;35:2540–53. Sayenko DG, Rath M, Ferguson AR, Burdick JW, Havton LA, Edgerton VR, Gerasi- • gold Open Access which fosters wider collaboration and increased citations menko YP. Self-assisted standing enabled by non-invasive spinal stimula- • maximum visibility for your research: over 100M website views per year tion after spinal cord injury. J Neurotrauma. 2019;36(9):1435–50. Siegel SW, Catanzaro F, Dijkema HE, Elhilali MM, Fowler CJ, Gajewski JB, et al. At BMC, research is always in progress. Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and reten- Learn more biomedcentral.com/submissions tion. Urology. 2000;56:87–91.