ORIGINAL RESEARCH published: 06 February 2020 doi: 10.3389/fnsys.2020.00001 Transcutaneous Electrical Spinal Cord Neuromodulator (TESCoN) Improves Symptoms of Overactive Bladder Evgeniy Kreydin 1,2 , Hui Zhong 2,3 , Kyle Latack 1,2 , Shirley Ye 1,2 , V. Reggie Edgerton 2,3,4,5,6,7,8 and Parag Gad 1,2,3,8* 1 Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States, 2 Rancho Research Institute, Rancho Los Amigos National Rehabilitation Center, Downey, CA, United States, 3 Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA, United States, 4 Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United States, 5 Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, United States, 6 Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, United States, 7 Institut Guttmann, Hospital de Neurorehabilitació, Institut Universitari adscrit a la Universitat Autònoma de Barcelona, Barcelona, Spain, 8 The Centre for Neuroscience and Regenerative Medicine, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia Neuromodulation is a therapeutic technique that is well-established in the treatment of idiopathic Lower urinary tract (LUT) dysfunction such as overactive bladder (OAB). We have recently developed a novel neuromodulation approach, Transcutaneous Electrical Spinal Cord Neuromodulation (TESCoN) and demonstrated its acute effects on LUT dysfunction after spinal cord injury (SCI) during urodynamic studies. We found that TESCoN can promote urinary storage and induce urinary voiding when delivered during urodynamic studies. The objective of this study was to determine whether TESCoN can retrain the spinal neural networks to induce chronic improvement in the LUT, such that positive changes can persist even in the absence of stimulation. In addition, we wished Edited by: to examine the effect of TESCoN on LUT dysfunction due to multiple pathologies. To Ronaldo M. Ichiyama, achieve this objective, 14 patients [SCI = 5, stroke = 5, multiple sclerosis (MS) = 3, University of Leeds, United Kingdom and idiopathic OAB (iOAB) = 1] completed 24 sessions of TESCoN over the course of Reviewed by: Michelle Hook, 8 weeks. Patients completed urodynamic studies before and after undergoing TESCoN Texas A&M University, United States therapy. Additionally, each subject completed a voiding diary and the Neurogenic Kyle Baumbauer, University of Kansas Medical Center, Bladder Symptom Score questionnaire before and after receiving TESCoN therapy. We United States found that TESCoN led to decreased detrusor overactivity, improved continence, and *Correspondence: enhanced LUT sensation across the different pathologies underlying LUT dysfunction. Parag Gad This study serves as a pilot in preparation for a rigorous randomized placebo-controlled paraggad@ucla.edu trial designed to demonstrate the effect of TESCoN on LUT function in neurogenic and Received: 21 September 2019 non-neurogenic conditions. Accepted: 06 January 2020 Published: 06 February 2020 Citation: NEW AND NOTEWORTHY Kreydin E, Zhong H, Latack K, Non-Surgical modality to reduce incidence of urinary incontinence and improve Ye S, Edgerton VR and Gad P (2020) Transcutaneous Electrical Spinal Cord neurogenic bladder symptom scores (NBSS) in individuals with neurogenic bladder due Neuromodulator (TESCoN) Improves to spinal cord injury or stroke. Symptoms of Overactive Bladder. Front. Syst. Neurosci. 14:1. Keywords: non-invasive spinal cord stimulation, spinal cord injury, stroke, multiple sclerosis, neurogenic bladder, doi: 10.3389/fnsys.2020.00001 over active bladder urodynamics Frontiers in Systems Neuroscience | www.frontiersin.org 1 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder INTRODUCTION at a high frequency; on the other hand, when stimulation was delivered at a low frequency subjects demonstrated improved The lower urinary tract (LUT, consisting of the bladder and voiding efficiency. These changes in LUT function were only bladder outlet) serves two main roles: to store and empty urine. noted during active stimulation. In this study we wished to LUT dysfunction occurs when either storage or voiding are determine whether repetitive stimulation over the course of impaired, resulting in urinary incontinence or retention. LUT several weeks can retrain the spinal neural networks to relearn dysfunction is common in patients with neurological disease and timely storage and voiding. In addition, given the similarities the general population (de Groat, 1997; Jeong et al., 2010). In in storage LUT symptoms and physiologic phenomena (e.g., the case of neurological disease, LUT dysfunction occurs because detrusor overactivity) across multiple conditions, we wished to the normal pathways responsible for communication between the expand the application of TESCoN to LUT dysfunction due LUT and the neural micturition centers become disrupted. While to stroke, MS and iOAB. Finally, our objective was to provide the mechanism of idiopathic LUT dysfunction is not as obvious, a clinical assessment of the effect of TESCoN on the LUT the nervous system is thought to be at least partially implicated by examining changes in voiding diaries and validated clinical in the majority of cases. LUT dysfunction has profound effects questionnaire following a course of the therapy. which range from endangering patients’ health [as the case of poorly managed LUT dysfunction after spinal cord injury (SCI)] to significantly impacting patients’ quality of life [as in the MATERIALS AND METHODS case of idiopathic over active bladder (iOAB) and post-stroke LUT dysfunction]. Patient Recruitment While it is often assumed that paralyzed individuals prioritize This study was approved by the Institutional Review Board recovery of ambulation, multiple studies have demonstrated that of Rancho Research Institute, the research arm of Rancho restoration of bladder function is ranked among the top 2–3 Los Amigos National Rehabilitation Center, Downey, CA, priorities, above goals such as regaining lower extremity function United States. All research participants signed an informed (Anderson, 2004). Likewise, urinary incontinence after stroke consent form before the start of the study and consented to is a well-known risk factor for long-term disability, depression their data being used in future publications and presentations. and institutionalization (Panfili et al., 2017). Current therapy Five patients (four males and one female) with stable (greater for LUT focuses on managing these complications without than 1-year post diagnosis) SCI at T8 or above who used clean addressing the underlying cause or attempting to normalize or intermittent catheterization (CIC), five patients (three males and restore function (Stohrer et al., 2009). Urinary incontinence, two females) with stable cortical stroke (greater than 1-year post frequency and urgency present across diseases such as SCI, diagnosis), three female patients with progressive MS symptoms stroke, multiple sclerosis (MS) and iOAB. While the reasons for at least 1 year and one female patient with idiopathic OAB for this may vary, detrusor overactivity (or uninhibited detrusor were recruited (Table 1). All patients experienced symptoms contractions) is a common physiologic phenomenon observed of urinary incontinence and sensate (i.e., non-SCI) patients in these conditions. Multiple therapies exist for correcting reported urinary frequency and urgency. urinary storage function; however, they are not always suitable populations (e.g., anticholinergic medications in patients with Initial Assessment cognitive impairment; intravesical botulinum toxin in patients at Each patient underwent a detailed medical history and physical risk for retention) and they do not attempt to restore normal LUT examination and completed an assessment of LUT symptoms function. On the other hand, the premise of neuromodulation using the Neurogenic Bladder Symptom Score (NBSS). A baseline is to correct the underlying neurological deficit and thus urodynamic study was performed in SCI and stroke subjects restore function to an end organ. Some neuromodulation according to International Continence Society (ICS) guidelines techniques are well-established in iOAB including sacral nerve using a Goby Urodynamics System from Laborie (Ontario, stimulation (Dasgupta et al., 2005) and percutaneous tibial nerve Canada). In order to mimic a clinical setting where patients stimulation (Peters et al., 2010). We have recently developed may not be evaluated with urodynamics prior to therapy, a novel neuromodulation approach, Transcutaneous Electrical MS and idiopathic OAB subjects were assessed only with Spinal Cord Neuromodulation (TESCoN) a novel non-invasive a detailed history and physical, a voiding diary, and the neuromodulation technique to facilitate functional restoration NBSS. Following the initial visit, each subject completed a after neurological injury (Gad et al., 2019). This modality engages 4-day voiding diary. the automaticity and the feedforward (Gerasimenko et al., 2017) features of the spinal neural networks to activate the intrinsic Delivery of Spinal Stimulation control of the spinal networks that is sufficient to enable recovery Stimulation was delivered using a proprietary TESCoN device of voluntary control. We have previously demonstrated that (spineX, Inc.) (Gad et al., 2019). The stimulation waveform acute TESCoN facilitates urinary storage and promotes bladder consisted of two alternating pulses of opposite polarities emptying in individuals with SCI during urodynamic studies separated by a 1 µS delay to form a delayed biphasic waveform. (Gad et al., 2018a). Patients experienced decreased detrusor The pulses consisted of a high frequency biphasic carrier pulse overactivity, exhibited increased bladder capacity and improved (10 KHz) combined with a low frequency (30 Hz) burst pulse detrusor-sphincter dyssynergia when stimulation was delivered each with a pulse width of 1 ms. Stimulation was applied using Frontiers in Systems Neuroscience | www.frontiersin.org 2 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder TABLE 1 | Table summarizing 14 patients, their pathology (n = 5 SCI, 5 Stroke, n = 3 MS and n = 1iOAB) location of injury, severity of injury, months post injury, current bladder management technique, LUT symptoms and current medications. Pt# Age (yrs) Gender Pathology Location Severity Months Bladder Lower urinary tract Lower urinary tract post management symptoms medications P1 25–35 M SCI T4 AIS A 18 m CIC Incontinence None P2 25–35 F SCI T6 AIS A 29 m CIC Incontinence Mirabegron 50 mg P3 40–50 M SCI C4 AIS C 20 m CIC Urge Incontinence None P4 35–45 M SCI T5 AIS A 135 m CIC Urge Incontinence Tolterodine LA 4 mg P5 50–60 M SCI T9 AIS C 48 m CIC Urgency/Incontinence Solifenacin 10 mg P6 40–50 M CVA L Basal Ganglia 50 m Volitional Urgency/Nocturia Tolterodine LA 4 mg P7 40–50 M CVA R Basal Ganglia 36 m Volitional Urgency/urge incontinence Tolterodine LA 4 mg P8 55–65 F CVA L Centrum Semiovale 78 m Volitional Urge incontinence Tolterodine LA 4 mg P9 55–65 F CVA L Basal Ganglia 75 m Volitional Urge incontinence Oxybutynin 5 mgTID P10 55–65 M CVA LMCA 75 m Volitional Urgency/Frequency None P11 20–30 F MS 48 m Volitional Urge incontinence None P12 55–65 F MS 240 m Volitional Incontinence None P13 35–45 F MS 24 m Volitional Urge incontinence Tolterodine LA 4 mg, Tamsulosin 0.8 mg P14 55–65 F iOAB 48 m Volitional Urge None Incontinence/Frequency SCI, spinal cord injury; CVA, cerebral vascular accident; MS, multiple sclerosis; CIC, clean intermittent catheterization. an adhesive electrode over the interspinous ligaments of T11 Post-stimulation Assessment and L1 serving as the cathode and two adhesive electrodes Within 1 week after the last stimulation session, SCI and stroke over the iliac crests as the anodes. The frequencies were patients completed another clinical urodynamic study in the selected based on our previous findings demonstrating greatest absence of TESCoN. All patients also completed the NBSS at this reduction in incontinence and increase in bladder capacity time and submitted a voiding diary starting 4 days prior to the (Gad et al., 2018a). final assessment. Identification of Stimulation Parameters Data and Statistical Analysis Patients with SCI and stroke underwent formal evaluation for The following urodynamic variables were collected in SCI and selection of stimulation parameters as previously published stroke subjects: (1) Bladder capacity, (2) Voiding efficiency, (3) (Gad et al., 2018a). In brief, a urodynamic two-port urethral Maximum detrusor pressure during voiding contraction, (4) catheter and a urodynamic rectal catheter were placed to Change in urethral sphincter pressure during filling and voiding measure intravesical (Pves ), external urethral sphincter (Pura ) contraction, (5) volume at first sensation and (6) time between and abdominal (Pabd ) pressures, respectively. Stimulation was bladder capacity and beginning of voiding contraction. “1Pura delivered as described above. Dose response curves were Filling” was defined as the change in pressure observed in Pura constructed for each parameter with incremental increase in during the filling cycle. “Pura Baseline” was defined as the pressure stimulation intensity. The stimulation intensity that generated in the Pura prior to start of filling. “1Pdet void” and “1Pura void” a noticeable change in Pura with little to no change in Pdet were defined as the change in pressures observed in Pdet and was selected (Figure 1). This stimulation intensity did not 1Pura , respectively, between bladder capacity and voiding. The cause any discomfort to the patients. Urodynamic studies were paired t-test was used to determine the significance of differences then performed according to ICS guidelines with concurrent in urodynamic parameters, NBSS scores of participants and TESCoN stimulation. Again, to mimic a clinical setting which number of daily voids and incontinence episodes with and precludes such an assessment, subjects with MS and idiopathic without TESCoN and before and after therapy. OAB were stimulated at a preselected frequency (30 Hz) and location (T11 and L1). Stimulation intensity was set as the highest current that did not cause cutaneous discomfort or cause any muscle activation in pelvic floor muscles or lower RESULTS extremity muscles. Urodynamic Assessment of SCI and TESCoN Therapy Course Stroke Patients Following the baseline evaluation, the patients were invited to During baseline urodynamics, SCI patients demonstrated return for an 8-week long course of TESCoN Subjects received detrusor overactivity at low volumes, low voiding efficiency and stimulation for 90 min. Each subject completed three stimulation detrusor sphincter dyssynergia during voiding. Stroke patients sessions a week. demonstrated low bladder capacity, detrusor overactivity, Frontiers in Systems Neuroscience | www.frontiersin.org 3 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder FIGURE 1 | Changes in detrusor and urethral pressures with changing parameters of TESCoN. Representative patient demonstrating the protocol to identify parameters of TESCoN that generates minimal change in Pdet along with a change in Pura. In this case stimulation at L1 at 100 mA (yellow box) generated no change in Pdet while Pura increased from ∼25 to 32 cm of H20 (green arrows) between TESCoN On and TESCoN off. Note the increase in both the Pura and Pdet at L1 120 mA. and appropriate voiding efficiency (Figure 2; Weld and Dmochowski, 2000; Weld et al., 2000). Acute delivery of TESCoN in SCI patients reduced detrusor overactivity, increased bladder capacity, improved coordination between detrusor and the external urethral sphincter and increased voiding efficiency (Figure 3), consistent with our earlier observations (Gad et al., 2018a). In contrast, stroke patients did not demonstrate a change in bladder capacity or voiding efficiency. However, stroke patients exhibited an increase in the volume at first bladder sensation, and a significant increase in the ability to delay urination, as measured by the time between reaching bladder capacity and initiation of voiding (P < 0.05) (Figure 4). After completing the 8-week therapeutic intervention, both sets FIGURE 2 | Changes in urodynamic studies without and with TESCoN. Representative urodynamic study for a stroke patient, (A) before therapy of patients (n = 5 Stroke and n = 5 SCI) demonstrated (PreTherapy) without and (B) with TESCoN and (C) after therapy an increased bladder capacity (P < 0.05, Figures 5A,F) (PostTherapy) and spinal cord injured (SCI) (D) before therapy (PreTherapy) (without TESCoN); however, no change in voiding efficiency without and (E) with TESCoN and (F) after therapy (PostTherapy). Note the was observed in either group (Figures 5B,G). The average increased bladder capacity (time prior to detrusor contraction), improved flow, improved detrusor and sphincter coordination and increase in urethral baseline pressure recorded at the urethral port (Pura ) pressure during filling both with TESCoN at PreTherapy and PostTherapy and the change in Pura during the filling phase of the (without TESCoN). Black arrow marks the occurrence of detrusor overactivity. urodynamic cycle were higher (P < 0.05) after compared to before therapy (Figures 5C,D,H,I). Detrusor pressure (Pdet ) during voiding did not change before vs. after Figure 6A). The mean score in the NBSS decreased from therapy (Figures 5E,J). 35.9 ± 2.6 to 26.6 ± 3.1 (P < 0.05) with the highest change being 34 points and the lowest being 0 (Figures 6C,D). Note Clinical Assessment of Patients that significant decrease in NBSS scores were observed in all All patients underwent a clinical assessment in the form of pathologies (Figure 6E). The distribution of NBSS decrease a 4-day voiding diary and NBSS. Eleven (n = 4 SCI, n = 5 among the different underlying pathologies showed no obvious Stroke and n = 2 MS) out of thirteen neurogenic patients trends. All patients also reported a significant decrease in reported at least a five-point decrease (minimal clinically the number of incontinence episodes/day (∼68% reduction important difference, MCID) in the NBSS (Welk et al., 2018; in leaks, P < 0.05) (Figure 7A), a reduction (12%) in the Frontiers in Systems Neuroscience | www.frontiersin.org 4 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder FIGURE 3 | Changes in urodynamic parameters during acute stimulation in FIGURE 4 | Changes in urodynamic parameters during acute stimulation in SCI subjects. Mean ±SE (n = 5 SCI) without (white bar) and with (red bar) stroke subjects. Mean ±SE (n = 5 Stroke) (A) bladder capacity, (B) Voiding acute delivery of TESCoN. (A) bladder capacity, (B) Voiding efficiency, (C) efficiency, (C) volume at first sensation during urodynamic study without (white changes in pressure during filling vs. voiding to demonstrate the improvement bar) and with (red bar) acute TESCoN and (D) time window between bladder in Detrusor-Sphincter Dyssynergia (DSD) without (black) and with TESCoN capacity and voiding in stroke patients. * statistically significant from without (red). * statistically significant from without TESCoN at P < 0.05. TESCoN at P < 0.05. Frontiers in Systems Neuroscience | www.frontiersin.org 5 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder number of voiding/CIC episodes per day (Figure 7B) and a significant reduction (∼37%) in night time voiding/CIC episodes as recorded on the voiding diary (Figure 7C). No Adverse Events (AE) were reported. All patients reported to be satisfied with the therapy and would have continued beyond the 8 weeks if the therapy was offered. DISCUSSION Neuromodulation Enables Restoration of Sensation and Motor Control of LUT Multiple components of the nervous system play a role in LUT control. Thus, when one or more components of the nervous system are affected by a disease, LUT dysfunction can ensue. Although modern management techniques have ensured that LUT dysfunction is rarely dangerous, it almost inevitably has a marked impact on patients’ quality of life. Some current therapies for LUT dysfunction in neurogenic and idiopathic situations are effective for preventing incontinence (e.g., anticholinergics, beta-agonists, botulinum toxin injection) but they do not restore normal bladder sensation or voiding function and sometimes achieve continence at their expense. On the other hand, spinal neuromodulation is a technique whose premise is to restore neural control functions by delivering a sub-motor threshold electrical stimulus that can transform the controlling neural networks into more functional physiological states. After 8 weeks of non-invasive spinal cord stimulation, bladder capacity increased. SCI patients also demonstrated improved detrusor-sphincter dyssynergia during detrusor contractions. All patients reported an improved sensation of bladder fullness and an increased latency time between sensation of urgency and the first episode of detrusor overactivity (or volitional voiding contraction). These effects appeared to be durable as they were observed even 1 week after therapy was concluded. A commons question in the field of neuromodulation is, how epidural and transcutaneous spinal stimulation compare? Some of the more Important comparisons are (1) the ability to deliver the desired stimulation parameters to the most functionally effective neuronal networks for a given target organ system, (2) patient acceptability and ease and accessibility of delivery of the intervention (3) cost of the intervention and (4) safety of the intervention. To date, there is insufficient knowledge to weigh the advantages, but it seems reasonably safe to conclude that both approaches should continue to be developed and tested. Given the data to date, it seems almost inevitable that the best choice of approach FIGURE 5 | Changes in urodynamic parameters after a 8-week course of will be based on the net result of pros and cons for stimulation. mean ±SE (n = 5 SCI patients) (A) bladder capacity, (B) Voiding a given patient as judged by the patient, the physician efficiency (C) baseline Pura prior to filling, (D) 1Pura during bladder filling, (E) 1Pdet during voiding as observed during clinical urodynamic studies at and the caregivers. Pre-Therapy and Post-Therapy without TESCoN. mean ±SE (n = 5 stroke To briefly expand on some of these points, it is obvious patients) (F) bladder capacity, (G) Voiding efficiency (H) baseline Pura prior to that using the transcutaneous approach, multiple organ systems filling, (I) 1Pura during bladder filling, (J) 1Pdet during voiding as observed can be targeted simply by moving the electrode along the during clinical urodynamic studies at Pre-Therapy and Post-Therapy without TESCoN. ∗ Significantly different from Pre-Therapy at P < 0.05. length of the spinal cord (Gad et al., 2018a,b; Gad P. et al., 2018; Inanici et al., 2018; Phillips et al., 2018; Rath et al., Frontiers in Systems Neuroscience | www.frontiersin.org 6 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder FIGURE 6 | Changes in NBSS parameters after TESCoN therapy (A) Neurogenic Bladder Symptom Score (NBSS) at Pre-Therapy and Post-Therapy for the 14 patients tested. (B) Mean ± SE (n = 14 patients) NBSS scores at Pre-Therapy and Post-Therapy. (C) Distribution of NBSS score decrease across the 14 patients tested, note only 5 SCI patients are plotted since 5th patient observed a change of 0, (D) decrease in NBSS scores relative to the initial NBSS scores, (E) mean ±SE (n = 5 SCI patients, n = 5 stroke and n = 3 MS) NBSS scores at Pre-Therapy and Post-Therapy. MCID, minimal clinically important difference. ∗ statistically significant from Pre-therapy at P < 0.05. 2018; Hofstoetter et al., 2019; Sayenko et al., 2019). Epidural has a greater advantage because of a more encompassing stimulation has been effective in treating both autonomic combination of networks that can be modulated to multiple (Harkema et al., 2018; Herrity et al., 2018; Hubscher et al., organ systems. The activation of a broader network may 2018) and motor functions (Grahn et al., 2017; Angeli et al., enable multiple muscle groups and rely of the automaticity 2018; Gill et al., 2018; Wagner et al., 2018) while maintaining and feedforwardness of the spinal cord (Gerasimenko et al., the overall location of the implant even though the scope 2017). A disadvantage of the transcutaneous approach is of the neural networks being neuromodulated may be more the inconvenience to frequently don and doff the electrodes limited compared to transcutaneous stimulation. Evidence to and the lower spatial resolution compared to the epidural date suggest that the transcutaneous approach in general approach. While only a side-by-side comparison in the same Frontiers in Systems Neuroscience | www.frontiersin.org 7 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder FIGURE 7 | Changes in voiding diary parameters after TESCoN therapy. (A) Number of urinary incontinence at Pre-Therapy and Post-Therapy for the 14 patients tested, mean ± SE percent decrease in incontinence episodes for the 4 patient groups and all patients (n = 14 patients) tested, (B) mean ± SE percent decrease in number of voids for the 4 patient groups and all patients (n = 14 patients) tested and (C) mean ±SE percent decrease in number of night time voiding/CIC episodes during the night (10pm to 6am) for the 4 patient groups and all patients (n = 14 patients) tested. ∗ Significanatly different from pretherapy at P < 0.05. patient may provide more definitive answers, the transcutaneous of life). The ability of NBSS to detect a meaningful clinical approach definitely can help screen potential responders and change has been recently shown in a pilot study of SCI and provide insights regarding effective sights for stimulation. multiple sclerosis patients, receiving botulinum toxin injections One could proceed from the transcutaneous approach to the for neurogenic urinary incontinence (Fragala et al., 2015). Over Implantation strategy if this would be viewed as a more 85% of the neurogenic bladder patients in our study reported long-term solution. The reverse approach, however, would be a statistically significant and clinically meaningful improvement more problematic. in the overall NBSS score after TESCoN therapy was completed. Among the various domains of the questionnaire, there was improvement in the incidence of incontinence, quality of life and Clinically Significant Levels of LUT voiding/storage domains of the NBSS. As expected, there was no Function Can Be Restored significant change in the consequences domain of the NBSS as the As important as the physiological changes observed on questions in this section of the questionnaire represent chronic urodynamic testing were the clinical improvements assessed problems related to the urinary tract (e.g., bladder and kidney by the voiding diary and the NBSS. The NBSS is a validated stones), that would not be expected to improve immediately questionnaire (Welk et al., 2018) that addresses common with positive change in LUT function. However, all patients also urological complaints in patients with neurological disease (e.g., reported either a significant decrease in the number of urinary incontinence, frequency, urgency and their impact on quality incontinence episodes per day or a decrease in the number of Frontiers in Systems Neuroscience | www.frontiersin.org 8 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder night time voiding cycles. Similar to the responses observed networks controlling the LUT seem to not only persist post in the NBSS scores, no obvious trends were observed across injury, but also have the potential to undergo transformation the pathologies. to a more functional state. These observations are consistent with our studies of non-invasive spinal cord stimulation in other applications such as lower extremity (Gerasimenko et al., 2015; Mechanistic Factors That Contribute to Gad et al., 2017), and upper extremity functional rehabilitation Restoration of LUT Functions (Gad P. et al., 2018; Inanici et al., 2018), where we have Although the mechanistic details of how spinal neuromodulation consistently observed some restoration of voluntary control in can improve bladder function is not known, multiple but individuals clinically diagnosed with complete motor and sensory highly linked mechanisms probably contribute to the observed paralysis. We hypothesize that neuromodulation enables activity- improvements. We postulate that stimulation modulates both dependent mechanisms that transform functionally incompetent afferent and efferent spinal networks into a more functional spinal and supraspinal networks to higher functional states. The state. Neuromodulation may alter the responsiveness of spinal idea that neuromodulation can affect a part of the CNS remote networks to bladder filling and emptying and increase the from the site of stimulation is supported by data from other conscious awareness of these states. After chronic TESCoN groups. For example, sacral nerve stimulation (a peripheral nerve therapy, subjects reported improved bladder sensation and neuromodulation modality commonly employed for idiopathic decreased urinary urgency. Together, these findings suggest overactive bladder) is known to generate changes in brain that parts of the CNS responsible for conscious sensation in signaling even during acute delivery of stimulation (Dasgupta the brain may have been re-engaged along with re-activation et al., 2005). The encouraging findings that TESCoN can improve and/or retraining of local spinal centers controlling the LUT, LUT symptoms in a variety of disease states encourages the reflecting a highly significant level of functional neural plasticity. exploration of its use in other brain pathologies associated with It is interesting to note that despite the varied pathology, LUT dysfunction (e.g., Parkinson’s disease, cerebral palsy), thus location and severity of injury, the spinal control of detrusor expanding the potential impact of this technology to a wider and urethral sphincter muscles were intact and could be range of diseases. transformed using a non-invasive modality. Our finding that voiding efficiency after 8 weeks of treatments did not change when urodynamic test was repeated in absence TESCoN suggests CONCLUSION that the parasympathetic system, that drives bladder emptying, may require ongoing stimulation in order to induce a functional We have successfully demonstrated that TESCoN can (1) reduce change. On the other hand, it appears that TESCoN can induce detrusor overactivity, increase bladder capacity and reduce long standing neuroplasticity in the sympathetic and somatic episodes of incontinence in patients with SCI, stroke, multiple system, which drives bladder storage, as evidenced by our finding sclerosis and idiopathic over active bladder, (2) functional that bladder capacity and Pura showed improvement even in the transformation of the sensory component of bladder control to absence of stimulation. improve sensation of fullness bladder and awareness by delaying Despite the potential shortcomings of the limited number of the time between reaching bladder capacity and initiation of patients and lack of sham stimulation which will be addressed voiding, and (3) significantly reduce the number of incontinence in future randomized controlled clinical trials, these data episodes and night time voids that also reflects in the changes demonstrate the ability to transform the neural control of bladder in NBSS scores. These observations suggest that the level of function from a dysfunctional to a functional state using non- functional autonomy that is intrinsic to the neural circuitry that invasive spinal neuromodulation. Our previous results have controls bladder function. This is a highly attractive clinical demonstrated improvement in multiple functions (locomotion target for regaining greater levels of function in SCI and other and autonomic function) with spinal neuromodulation during etiologies of neurogenic bladder because it is a non-invasive function rehabilitation (Gerasimenko et al., 2015; Gad et al., form of neuromodulation that can re-engage and restore, via 2017; Gad P. et al., 2018). In this study, however, since the activity-dependent mechanisms, the automaticity intrinsic to the patients were seated while receiving TESCoN therapy, minimal autonomic control of the LUT. improvements in locomotor function were observed. TESCoN could prove to be a critical component of in our clinical toolbox while designing rehabilitation therapies for patients that suffer DATA AVAILABILITY STATEMENT from multiple organ dysfunction (autonomic and motor) due to paralysis. In addition, future studies will also identify potential All datasets generated for this study are included in the chronic changes in the cortex during simultaneous functional article/supplementary material. MRI recordings during urodynamic studies. These data allow us to speculate about multiple neural mechanisms that can account for end-organ dysfunction in neurogenic and non-neurogenic ETHICS STATEMENT states (e.g., loss of connectivity between centers responsible for end organ control, formation of aberrant neural connections The studies involving human participants were reviewed resulting in abnormal function). However, the intrinsic spinal and approved by the Institutional Review Board Frontiers in Systems Neuroscience | www.frontiersin.org 9 February 2020 | Volume 14 | Article 1 Kreydin et al. Transcutaneous Spinal Neuromodulation of Overactive Bladder of Rancho Research Institute, the research arm of Rancho FUNDING Los Amigos National Rehabilitation Center, Downey, CA, United States. The patients/participants provided their written This research was funded in part by the Conquer Paralysis informed consent to participate in this study. Now Challenge award, Walkabout Foundation, Dana and Albert R. Broccoli Charitable Foundation, Nanette and Burt Forester, including matching by PwC LLP, and International Foundation AUTHOR CONTRIBUTIONS for Research in Paraplegia, Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU), and EK, PG, and VE designed the study. EK performed the initial Whittier Foundation. The authors declare that this study received medical evaluation and performed the urodynamic study. HZ, funding from PwC LLP. The funder was not involved in KL, and SY performed the day to day stimulation. PG analyzed the study design, collection, analysis, interpretation of data, the data. EK and PG wrote the manuscript. All authors edited the writing of this article, or the decision to submit it and approved the manuscript. for publication. REFERENCES Grahn, P. J., Lavrov, I. A., Sayenko, D. G., Van Straaten, M. G., Gill, M. L., Strommen, J. A., et al. (2017). Enabling task-specific volitional motor functions Anderson, K. D. (2004). Targeting recovery: priorities of the spinal cord- via spinal cord neuromodulation in a human with paraplegia. Mayo Clin. Proc. injured population. J. Neurotrauma 21, 1371–1383. doi: 10.1089/neu.2004.21. 92, 544–554. doi: 10.1016/j.mayocp.2017.02.014 1371 Harkema, S. J., Wang, S., Angeli, C. A., Chen, Y., Boakye, M., Ugiliweneza, B., et al. Angeli, C. 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Transcutaneous Spinal Neuromodulation of Overactive Bladder Stohrer, M., Blok, B., Castro-Diaz, D., Chartier-Kastler, E., Del Popolo, G., Kramer, Conflict of Interest: VE holds shareholder interest in NeuroRecovery G., et al. (2009). EAU guidelines on neurogenic lower urinary tract dysfunction. Technologies and hold certain inventorship rights on intellectual property Eur. Urol. 56, 81–88. doi: 10.1016/j.eururo.2009.04.028 licensed by The Regents of the University of California to NeuroRecovery Wagner, F. B., Mignardot, J. B., Le Goff-Mignardot, C. G., Demesmaeker, R., Komi, Technologies and its subsidiaries. VE and PG holds shareholder interest in spineX S., Capogrosso, M., et al. (2018). Targeted neurotechnology restores walking in Inc., and hold certain inventorship rights on intellectual property licensed by The humans with spinal cord injury. Nature 563, 65–71. doi: 10.1038/s41586-018- Regents of the University of California to spineX Inc. 0649-2 Weld, K. J., and Dmochowski, R. R. (2000). Association of level of injury and The remaining authors declare that the research was conducted in the absence of bladder behavior in patients with post-traumatic spinal cord injury. Urology 55, any commercial or financial relationships that could be construed as a potential 490–494. doi: 10.1016/s0090-4295(99)00553-1 conflict of interest. Weld, K. J., Graney, M. J., and Dmochowski, R. R. (2000). Clinical significance of detrusor sphincter dyssynergia type in patients with post-traumatic Copyright © 2020 Kreydin, Zhong, Latack, Ye, Edgerton and Gad. This is an open- spinal cord injury. Urology 56, 565–568. doi: 10.1016/s0090-4295(00) access article distributed under the terms of the Creative Commons Attribution 00761-5 License (CC BY). The use, distribution or reproduction in other forums is permitted, Welk, B., Lenherr, S., Elliott, S., Stoffel, J., Presson, A. P., Zhang, C., et al. (2018). provided the original author(s) and the copyright owner(s) are credited and that the The neurogenic bladder symptom score (NBSS): a secondary assessment of its original publication in this journal is cited, in accordance with accepted academic validity, reliability among people with a spinal cord injury. Spinal Cord 56, practice. No use, distribution or reproduction is permitted which does not comply 259–264. doi: 10.1038/s41393-017-0028-0 with these terms. Frontiers in Systems Neuroscience | www.frontiersin.org 11 February 2020 | Volume 14 | Article 1