ORIGINAL RESEARCH published: 17 February 2022 doi: 10.3389/fnins.2022.816106 The Effect of Non-invasive Spinal Cord Stimulation on Anorectal Function in Individuals With Spinal Cord Injury: A Case Series Evgeniy Kreydin 1,2,3 , Hui Zhong 2,4 , Igor Lavrov 5,6 , V. Reggie Edgerton 4,7,8,9 and Parag Gad 2,3,4* 1 Keck School of Medicine, Institute of Urology, University of Southern California, Los Angeles, CA, United States, 2 Rancho Los Amigos National Rehabilitation Center, Rancho Research Institute, Downey, CA, United States, 3 SpineX Inc., Los Angeles, CA, United States, 4 Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA, United States, 5 Department of Neurology, Department of Biomedical Engineering, Mayo Clinic, Rochester, NY, United States, 6 Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia, 7 Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, United States, 8 Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, United States, 9 Institut Guttmann, Hospital de Neurorehabilitació, Institut Universitari Adscrit a la Universitat Autònoma de Barcelona, Barcelona, Spain Spinal cord injury (SCI) is a devastating condition that impacts multiple organ systems. Edited by: Neurogenic bowel dysfunction (NBD) frequently occurs after a SCI leading to reduced Arun Sridhar, sensation of bowel fullness and bowel movement often leading to constipation or fecal Independent Researcher, Milton incontinence. Spinal Neuromodulation has been proven to be a successful modality Keynes, United Kingdom to improve sensorimotor and autonomic function in patients with spinal cord injuries. Reviewed by: Victor Pikov, The pilot data presented here represents the first demonstration of using spinal Medipace Inc., United States neuromodulation to activate the anorectal regions of patients with spinal cord injuries Robert A. Gaunt, University of Pittsburgh, United States and the acute and chronic effects of stimulation. We observed that spinal stimulation *Correspondence: induces contractions as well as changes in sensation and pressure profiles along the Parag Gad length of the anorectal region. In addition, we present a case report of a patient with a paraggad@ucla.edu SCI and the beneficial effect of spinal neuromodulation on the patient’s bowel program. Specialty section: Keywords: non-invasive spinal cord stimulation, spinal cord injury, stroke, multiple sclerosis, neurogenic bladder, This article was submitted to overactive bladder urodynamics Autonomic Neuroscience, a section of the journal Frontiers in Neuroscience INTRODUCTION Received: 16 November 2021 Accepted: 20 January 2022 Neurogenic bowel dysfunction (NBD) is a significant source of morbidity after a spinal cord injury Published: 17 February 2022 (SCI). After an SCI, many patients develop the inability to empty the bowels spontaneously and Citation: become reliant on onerous and time-consuming bowel programs to manage constipation and Kreydin E, Zhong H, Lavrov I, stool retention. Others may develop stool incontinence secondary to obstipation or anal sphincter Edgerton VR and Gad P (2022) The weakness. As a result, NBD has a marked deleterious effect on patients’ health and quality of life. Effect of Non-invasive Spinal Cord Indeed, several survey studies of SCI patients have demonstrated that recovery of bowel function Stimulation on Anorectal Function in Individuals With Spinal Cord Injury: is one of the top rehabilitation priorities in this population (Anderson, 2004; Bloemen-Vrencken A Case Series. et al., 2005; Ditunno et al., 2008). Front. Neurosci. 16:816106. Despite such significant impact on a patient’s life, treatment options for NBD are limited. doi: 10.3389/fnins.2022.816106 Rectal suppositories and oral stool softeners and laxatives are the mainstays of therapy but have Frontiers in Neuroscience | www.frontiersin.org 1 February 2022 | Volume 16 | Article 816106 Kreydin et al. Neurogenic Bowel Mapping With Neuromodulation a limited efficacy in decreasing the time devoted to bowel monophasic pulse at 0.5 Hz with a high frequency carrier programs and do little to normalize bowel function and stool frequency (10 KHz) with a pulse width of 1 ms. The therapeutic transit. Surgical interventions, such as creation of colostomy waveform consisted of two alternating pulses of opposite or Malone Antegrade Continence Enema (MACE) are morbid polarities separated by a 1 uS delay forming a delayed biphasic and can have a negative impact on an already-impaired body waveform. The pulses consisted of a high frequency biphasic image in patients with SCI (Waddell et al., 2020). More recently, carrier pulse (10 KHz) combined with a low frequency (30 Hz) neuromodulation has begun to be explored as a therapy for burst pulse each with a pulse width of 1 ms. Stimulation NBD. Techniques such as functional electrical stimulation, was applied using an adhesive electrode over the interspinous magnetic stimulation, sacral nerve stimulation, dorsal genital ligaments of T11 and L1 serving as the cathode and two adhesive nerve stimulation and transcutaneous interferential electrical electrodes over the iliac crests as the anodes (Figure 1). The stimulation have been attempted as a therapy for NBD in adults intensity of stimulation during acute mapping studies (0.5 Hz) (SCI) and children (myelomeningocele) with promising results were set at a supra sensory and motor threshold, i.e., the lowest (Deng et al., 2018; Parittotokkaporn et al., 2020). intensity at which contractions were visible on the pressure We have developed and implemented a novel Spinal Cord probes. At this intensity all patients also noted contractions of Neuromodulator (SCONETM , SpineX Inc., Los Angeles, CA, several lower extremity muscles. The intensity of stimulation United States) as a non-invasive stimulation modality to facilitate during therapeutic stimulation (30 Hz) was set at a supra-sensory functional recovery after SCI. This approach delivers an electrical and sub-motor threshold level, i.e., at 80% of the intensity stimulation to the spinal cord without eliciting significant that generated a visible contraction on the pressure probes. At cutaneous discomfort by incorporating a high-frequency carrier this intensity, patients could feel the stimulation but did not current. We have previously demonstrated that non-invasive note any lower extremity muscles contractions and tolerated the spinal cord neuromodulation can improve lower (Gad et al., stimulation well. 2015; Gerasimenko Y. P. et al., 2015; Parag Gad and Reggie Edgerton, 2019), upper extremity (Gad P. et al., 2018; Inanici Anorectal Manometry and Mapping et al., 2018), trunk stability (Rath et al., 2018), respiratory Acute stimulation patients were asked to perform an enema (Gad et al., 2020) and lower urinary tract function (Gad P. at home at least 6 h prior to the study. Anorectal manometry N. et al., 2018; Kreydin et al., 2020; Gad et al., 2021b) in (ARM) probe was placed in the anorectal region. The probe patients with SCI. In this study, we used anorectal manometry consisted of four sensors around the periphery of the tip. (ARM) to determine the effect of acute SCONETM stimulation A balloon was positioned at the proximal end of the catheter. on anorectal physiology in three chronically paralyzed patients The anorectum was mapped by positioning the catheter at and the effect of chronic stimulation on bowel program specific distances from the anal verge starting at 2 cm and times in one patient. continuing up to 10 cm in increments of 1 cm. At each catheter location, stimulation test pulses were delivered starting at 10 mA and increasing to 200 mA in increments of 10 mA. MATERIALS AND METHODS A minimum of five pulses were delivered at each intensity. A minimum of 3 mins pause was taken prior to moving the Patient Recruitment catheter to the next position. Anorectal profiles were created This study was approved by the Institutional Review Board by slowly withdrawing the catheter at a constant speed of of Rancho Research Institute, the research arm of Rancho 0.5–1 cm/s. These profiles were created with the patient in a Los Amigos National Rehabilitation Center, Downey, CA, relaxed position (relax) and while attempting to generate a bowel United States. The research participants signed an informed movement (squeeze) on command. Following test stimulation, consent form before the start of the study and consented to the tonic submotor stimulation was applied and anorectal pressure data being used in future publications and presentations. The profiles were generated in an identical manner. Finally, to test patient demographics and injury characteristics were as follow: anorectal sensation, the catheter was placed at 5 cm from the Acute Stimulation Patient 1 (ASP1) was a 39-year-old male who anal verge, the balloon was slowly filled with air using an external sustained a SCI at C5 (AIS A) 9 years prior to study. ASP2 was a syringe at a rate of 60 ml/min without and with sub-motor 29-year-old male who sustained a SCI at T6 (AIS A) 5 years prior threshold stimulation. The patient was asked to report when they to the study. ASP3 was a 28-year-old female who sustained a SCI experienced rectal sensation and the 1st volume, at which this at T6 (AIS A) 2 years prior to the study. Finally, the patient who occurred, was recorded. underwent chronic stimulation [Chronic Stimulation Patient 1 (CSP1)] was a 32-year-old female who sustained a SCI at T6 (AIS Chronic Spinal Stimulation A) 2 years prior to the study. The chronic stimulation patient (CSP1) was recruited to study the effect of chronic spinal stimulation on bowel function. Spinal Stimulation This patient needed external digital stimulation to assist bowel Spinal stimulation was delivered using a proprietary SCONETM movement and relied on rectal suppositories to move her device (SpineX Inc., Los Angeles, CA, United States). The bowels every 1–2 days. She was asked to monitor the duration stimulation was delivered either as single test pulses or as of her bowel program for the duration of the study. The therapeutic pulses. The test pulse waveform consisted of a therapeutic waveform consisted of two alternating pulses of Frontiers in Neuroscience | www.frontiersin.org 2 February 2022 | Volume 16 | Article 816106 Kreydin et al. Neurogenic Bowel Mapping With Neuromodulation (30 Hz) burst pulse each with a pulse width of 1 ms (Figure 1). A Stimulation was applied using an adhesive electrode over the interspinous ligaments of T11 and L1 serving as the cathode and two adhesive electrodes over the iliac crests as the anodes. She received 1 h of stimulation 5 days a week for 5 weeks. On the days that the patient had a bowel program, she completed the bowel program 1–3 h prior to receiving stimulation. For the first 18 days, stimulation was delivered at a therapeutic level whereas during the last 18 days, stimulation intensity was reduced to an amplitude not expected to generate any physiological response based on our previous studies (sham stimulation). The patient was blinded by the intensity of stimulation at all times. RESULTS Acute Stimulation Single pulses delivered over the lumbosacral spinal cord generated contractions in the anorectum of all three acute stimulation patients. The latency of contraction varied from 100 to 200 ms post stimulation pulse. The response amplitude varied based on the location. In addition, responses between 4 and 6 cm demonstrated a more complex response consisting of a second component with a longer latency (200–300 ms) (Figure 2A). However, location that generated the maximal B amplitude occurred either between 1 and 3 cm or between 4 and 6 cm (Figure 2B). The pressure profile across the anorectal region peaked between 4 and 6 cm (Figure 3) in all patients while the patients were relaxed and while they attempted to push as if to attempt a bowel movement. With tonic sub-motor threshold stimulation at T11 and L1, the pressure profile demonstrated a more consistent curve with high responses occurring between 3 and 8 cm. In addition, while the patient attempted to empty their bowels, the C amplitude of response further increased between 3 and 8 cm. The change in pressure across the profile was higher while the patient was attempting to defecate and with the stimulation On (Figure 3). Without stimulation, one patient was able to sense a filled balloon in the rectum, whereas two patients were unable to sense it up to a volume of 300 ml, which was established as a safe upper limit by the clinician (Figure 4A). Upon initiation of tonic sub- motor threshold stimulation at T11 and L1, the sensate patient reported rectal sensation at a lower balloon volume, and one of the insensate patients reported new onset sensation with balloon FIGURE 1 | (A) Experimental setup demonstrating the stimulation electrodes distention of the rectum (Figure 4B). over T11-12 and L1-2 vertebral levels and return electrodes over the iliac crests. (B) Test pulses showing the train of monophasic pulses including the Chronic Stimulation high frequency (10 KHz) pulses on for a period of 1 ms and low frequency The chronic stimulation patient was asked to record the amount (0.5 Hz, repeating every 2 s) pulses and (C) Therapeutic pulses showing the train of biphasic pulses including the high frequency (10 KHz) pulse on for a of time needed to complete her bowel program. Prior to initiation period of 1 ms and low frequency (30 Hz, repeating every 33.33 ms) pulses. of the study and during the first few days, her bowel program time was consistently approximately 75 mins. After completing 1 week of daily stimulation, her bowel program time reduced to 15 mins. Over the course of the next 18 days, sham stimulation opposite polarities separated by a 1 uS delay forming a delayed was delivered, and her bowel program time increased to between biphasic waveform. The pulses consisted of a high frequency 45 and 65 mins (Figure 5). No adverse effects of stimulation were biphasic carrier pulse (10 KHz) combined with a low frequency reported by the patient or noted by the study staff. Frontiers in Neuroscience | www.frontiersin.org 3 February 2022 | Volume 16 | Article 816106 Kreydin et al. Neurogenic Bowel Mapping With Neuromodulation A FIGURE 3 | Anorectal pressure profile without (black) and with (ref) SCONETM at T11 from the three SCI patients while the patients were relaxed (light) or B squeezing (bold) their anus trying to assist a bowel movement. A B FIGURE 2 | (A) Average (n = 5) pulses spinally evoked pressure change with singe pulses at 150 mA in the anorectal region 10 cm to 2 cm from the anus from a representative SCI (P1) patient. (B) Pressure changes across the anorectal region 10 cm to 2 cm from the anus from the three patients enrolled in the study. FIGURE 4 | (A) Anorectal pressure recorded while manually filling the rectal balloon with air without (black) and with (red) spinal stimulation at T11 in a DISCUSSION representative SCI patient (P1) AIS A at C5 without and with SCONETM . Note the sensation of filling appears at lower volume with compared to without In this pilot study we demonstrate that spinal neuromodulation SCONETM (190 ml vs. 220 ml). (B) Threshold of sensation without and with SCONETM from the three patients enrolled in the study. ∞ represents a case can acutely change motor and sensory function of the anorectum. when the patient was unable to detect the filled air (mm Hg). Additionally, in a case report of one patient, we show that spinal neuromodulation delivered over the course of several weeks may improve bowel function by decreasing the time required to perform a bowel program. SCONETM is a non-invasive overactivity (Gad P. N. et al., 2018; Kreydin et al., 2020). neuromodulation modality initially developed to promote lower Although the bowel and the bladder differ markedly in function extremity functional recovery after SCI. In our previous work, and control, their spinal and peripheral innervation share we have demonstrated that SCONETM also appears to facilitate common origins. Parasympathetic innervation of both the changes in lower urinary tract function in SCI individuals, anorectum and lower urinary tract (LUT) originates in the sacral promoting higher bladder capacity and decreasing detrusor parasympathetic nucleus located at the S2–S5 levels of the spinal Frontiers in Neuroscience | www.frontiersin.org 4 February 2022 | Volume 16 | Article 816106 Kreydin et al. Neurogenic Bowel Mapping With Neuromodulation one participant exhibited the strongest pressure response in a more rostral location of the rectum, 6 cm above the anal verge. This location is considerably proximal to the skeletally innervated puborectalis and EAS, suggesting that this increase in pressure may be mediated by excitation of the autonomic nerves responsible for rectal function. Morren et al. (2001) also noted changes in rectal pressure (i.e., proximal to the puborectalis and the EAS) with transcutaneous magnetic stimulation and hypothesized that this was likely due to a reflex arc, whereby stimulation of large caliber somatic sensory nerves led to the excitation of autonomic fibers at the level of the lumbosacral FIGURE 5 | Time required to complete bowel program (blue) in an SCI patient spine. (T4 AIS A) over 35 therapy days with varying intensities of stimulation (red). While the exact neural structure, with which spinal Note the decrease in bowel time over the first 18 days during higher intensity neuromodulation interacts, remains to be determined, the therapeutic stimulation (red region). However, the bowel program time relatively prolonged latencies and the multipeak nature of the increased close to baseline during the second half of the study with sham stimulation (yellow region). pressure response suggest that the effect is not due to the direct stimulation of the pudendal nerve (causing anal sphincter contraction) but rather to a polysynaptic or reflex-mediated phenomenon. A similar response was noted by Fowler et al. cord (T12-L1 vertebral level). Onuf ’s nucleus, which serves as (2000) and Schurch et al. (2003), when the S3 nerve root was the origin of the pudendal nerve, is located at the same level of percutaneously stimulated in able-bodied and SCI participants, the spinal cord and provides innervation of the skeletal external respectively. A direct motor response would be expected to occur urethral and anal sphincters. Finally, sympathetic innervation of at a sub-10 ms timescale; on the other hand, the response we the anorectum and the LUT arises in the sympathetic chain at observed occurred at least 100 ms after pulse adminstration with spinal levels T11-L2 (vertebral levels T7–T11) (de Groat et al., a second component occurring up to 300 ms after. Similarly, a 2015; Callaghan et al., 2018). Thus, stimulation at levels T11 and pudendo-anal reflex would be expected to occur with a latency L1 exerts an effect on all three components of the nervous system of less than 40 ms (Cavalcanti Gde et al., 2007). Although involved in bladder and bowel regulation. Just as with locomotion latencies observed in this study could be mediated by an and LUT function, we hypothesize that spinal neuromodulation afferent spino-bulbospinal mechanism, this is less likely as the at these levels provides a signal to the relevant spinal centers, spinobulbar pathways are expected to be disrupted after an SCI. separated from the brain and brainstem by an injury, and allows Nonetheless, it is possible that spinal neuromodulation promotes acute and chronic changes to anorectal activity, that eventually communication along damaged but anatomically persistent lead to improvement in function. pathways. The other possibility is that the response we observed An increase in anorectal pressure in response to SCONETM is mediated by a reflex of spinal origin. The latter possibility is was an effect we observed in each participant, with two supported by the persistence of the response even in patents with participants exhibiting the strongest response in the region of AIS A injuries both with acute and chronic stimulation. the anal canal. This region is the location of the external (EAS) In other applications of spinal neuromodulation, it was and internal (IAS) anal sphincters, with the puborectalis muscle noted that stimulation improves not only motor activity, located more proximally and giving rise to the former (Kaiser but also sensory function in patients with SCI (Gerasimenko and Ortega, 2002). Thus, one of the two participants exhibited et al., 2016; Gad P. N. et al., 2018), stroke and multiple the strongest response at the level of the puborectalis (3.5 cm sclerosis (Kreydin et al., 2020), and children with cerebral palsy above the anal verge), while the other exhibited the strongest (Edgerton et al., 2021; Gad et al., 2021a). Here we observed a response at the level of the superficial EAS (0.5–2 cm above similar phenomenon, whereby rectal sensation changed during the anal verge), suggesting the pudendal nerve as the ultimate application of stimulation, enabling two of the three participants element that mediates the response as part of a spinal reflex arc to sense inflation of a rectal balloon at a lower volume (see discussion below). Other authors have demonstrated similar than in the absence of stimulation. The mechanism by which effects in response to transcutaneous magnetic stimulation of spinal neuromodulation alters conscious sensation is not fully the sacral regions of patients with SCI. Morren et al. (2001) understood. As in our experience with urinary storage and delivered transcutaneous magnetic stimulation laterally to the locomotion, however, we hypothesized that SCONETM may midline at S2–S4 vertebral levels, targeting the sacral spinal activate intact (but dormant) neural fibers at the injury site even nerves as they exit the sacral foramina, and hypothesized that in cases of functionally complete SCI and promote restoration the strong pressure response noted in the anal canal was due to of conscious sensation in a retrograde fashion. Alternatively, direct excitation of this nerve. An elevation in rectal pressure SCONETM may lead to the excitation of sympathetic fibers, thus was also seen with transcutaneous magnetic stimulation of the allowing rectal distention to elicit a sympathetic response at a cauda equina (L3–L5 vertebral levels) in studies by Lin et al. lower volume. The participant may then appreciate this response (2001) (both healthy controls and patients with SCI) and Shafik as “rectal sensation.” Although it is unclear why Participant 2 and El-Sibai (2000) (healthy individuals only). Interestingly, did not exhibit this change in sensation, it is possible that this Frontiers in Neuroscience | www.frontiersin.org 5 February 2022 | Volume 16 | Article 816106 Kreydin et al. Neurogenic Bowel Mapping With Neuromodulation individual had a more complete injury and the reflex arc between of magnitude as spinal neuromodulation and has been found rectal sensory fibers and the sympathetic chain/higher sensory to be effective in improving both clinical and physiological centers was more significantly disrupted. parameters of neurogenic bowel in pediatric patients with spina Finally, the finding that the participant who underwent bifida (Kajbafzadeh et al., 2012). daily SCONETM sessions noted a gradual decrease in the time While the results observed are significant, our study has from required to complete the bowel program suggests that SCONETM several limitations. First, the small number of patients limits stimulation may be a useful technique to promote functional the generalizability of the results. However, the activation of improvement in patients with NBD. Several previous studies the anorectum across all three participants, and similar findings have assessed neuromodulation as a means of improving bowel by other authors utilizing magnetic stimulation suggest that we function after SCI. Tsai et al. (2009) studied seven patients with observed a true physiologic effect. Secondly, our participants supraconal SCI and assessed the effect of a 3-week course of were fairly heterogeneous with varying levels and years post daily transcutaneous magnetic stimulation at T9 and L3 on bowel SCI. It is possible that with a more homogeneous cohort, more function. A statistically significant decrease in colonic transit consistent effects of SCONETM would have been observed. Future time and an improvement in questionnaire-measured bowel studies will need to determine how injury characteristics impact function were noted. Lin et al. (2001) reported similar findings SCONETM response and to identify biomarkers that modulate in subjects who underwent transcutaneous magnetic stimulation its effect. Finally, SCONETM mediated improvement in bowel of the cauda equina and exhibited a significant decrease in function after SCI requires further evaluation and confirmation colonic transit time. In addition, subjects reported restoration in a rigorous sham-controlled setting. of some sensory function and decreased reliance on digital stimulation to empty their bowels (Lin et al., 2001). Implantable sacral neuromodulation (Medtronic Interstim , Minnesota, MN, R DATA AVAILABILITY STATEMENT United States) was assessed as a means to improve bowel function in patients with incomplete SCI by Jarrett et al. (2005) The raw data supporting the conclusions of this article will be and was found to improve bowel continence and sensation of made available by the authors, without undue reservation. incomplete bowel emptying. Because patients with SCI suffer from abnormally prolonged bowel transit times and dyssenergic defecation, correction of these parameters would be expected to ETHICS STATEMENT reduce the time required to complete a bowel movement. While the mechanism by which neuromodulation achieves these effects The studies involving human participants were reviewed remains to be elucidated, we hypothesize that the stimulation and approved by the Rancho Research Institute. The signal interacts with neural fibers that remain after an injury to patients/participants provided their written informed consent correct or improve end organ function. to participate in this study. Traditionally, non-invasive electrical spinal stimulation has been thought to be ineffective for stimulation of neural structures in the spinal cord because, unlike magnetic stimulation, AUTHOR CONTRIBUTIONS significant signal attenuation occurs when an electrical impulse is PG, EK, and VE designed the study. EK, PG, and HZ performed applied to highly resistant tissues, such as skin, fat and bone that the experiments. All authors edited and approved the manuscript. overlie the spinal cord. However, this study adds to the existing evidence that the unique dual frequency paradigm delivered by spinal neuromodulation can affect the function of neural FUNDING structures in the spinal cord (Gerasimenko Y. et al., 2015). We hypothesize that the relatively high amplitude of stimulation This research was funded in part by the NIH/NINDS afforded by spinal neuromodulation allows electrical charge to 1U01NS113871-01, NIH/NIDDK 01R44DK129164-01A1, and penetrate the investing tissues of the spinal cord and modulate NSF 2112366, the Dana and Albert R. Broccoli Charitable the activity of spinal reflex arcs important for limb, lower urinary Foundation, Nanette and Burt Forester, including matching tract, respiratory and bowel control. 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Neurosci. 12:432. doi: 10.3389/fnins.2018.00432 life after spinal cord injury: systematic review. BJS Open 4, 1054–1061. doi: Gerasimenko, Y., Gad, P., Sayenko, D., McKinney, Z., Gorodnichev, R., Puhov, A., 10.1002/bjs5.50339 et al. (2016). Integration of sensory, spinal, and volitional descending inputs in regulation of human locomotion. J. Neurophysiol. 116, 98–105. doi: 10.1152/jn. Conflict of Interest: VE holds shareholder interest in Onward and hold certain 00146.2016 inventorship rights on intellectual property licensed by The Regents of the Gerasimenko, Y., Gorodnichev, R., Moshonkina, T., Sayenko, D., Gad, P., and University of California to Onward. VE, EK, and PG holds shareholder interest in Reggie Edgerton, V. (2015). Transcutaneous electrical spinal-cord stimulation SpineX Inc., and hold certain inventorship rights on intellectual property licensed in humans. Ann. Phys. Rehabil. Med. 58, 225–231. by The Regents of the University of California to SpineX Inc. Gerasimenko, Y. P., Lu, D. C., Modaber, M., Zdunowski, S., Gad, P., Sayenko, D. G., et al. (2015). Noninvasive reactivation of motor descending control after The remaining authors declare that the research was conducted in the absence of paralysis. J. Neurotrauma 32, 1968–1980. doi: 10.1089/neu.2015.4008 any commercial or financial relationships that could be construed as a potential Inanici, F., Samejima, S., Gad, P., Edgerton, V. R., Hofstetter, C. P., and Moritz, conflict of interest. C. T. (2018). Transcutaneous electrical spinal stimulation promotes long-term recovery of upper extremity function in chronic tetraplegia. IEEE Trans. Neural Publisher’s Note: All claims expressed in this article are solely those of the authors Syst. Rehabil. Eng. 26, 1272–1278. doi: 10.1109/TNSRE.2018.2834339 and do not necessarily represent those of their affiliated organizations, or those of Jarrett, M. E., Matzel, K. E., Christiansen, J., Baeten, C. G., Rosen, H., Bittorf, B., the publisher, the editors and the reviewers. Any product that may be evaluated in et al. (2005). Sacral nerve stimulation for faecal incontinence in patients with this article, or claim that may be made by its manufacturer, is not guaranteed or previous partial spinal injury including disc prolapse. Br. J. Surg. 92, 734–739. endorsed by the publisher. doi: 10.1002/bjs.4859 Kaiser, A. M., and Ortega, A. E. (2002). Anorectal anatomy. Surg. Clin. North Am. Copyright © 2022 Kreydin, Zhong, Lavrov, Edgerton and Gad. This is an open-access 82, 1125–1138. article distributed under the terms of the Creative Commons Attribution License Kajbafzadeh, A. M., Sharifi-Rad, L., Nejat, F., Kajbafzadeh, M., and Talaei, H. R. (CC BY). The use, distribution or reproduction in other forums is permitted, provided (2012). Transcutaneous interferential electrical stimulation for management the original author(s) and the copyright owner(s) are credited and that the original of neurogenic bowel dysfunction in children with myelomeningocele. Int. J. publication in this journal is cited, in accordance with accepted academic practice. No Colorectal Dis. 27, 453–458. doi: 10.1007/s00384-011-1328-z use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Neuroscience | www.frontiersin.org 7 February 2022 | Volume 16 | Article 816106