Sharan et al. BMC Urology (2018) 18:10 https://doi.org/10.1186/s12894-018-0322-y RESEARCH ARTICLE Open Access Characterizing the transcutaneous electrical recruitment of lower leg afferents in healthy adults: implications for non- invasive treatment of overactive bladder Eshani Sharan1, Kelly Hunter1, Magdy Hassouna3 and Paul B. Yoo1,2* Abstract Background: As a potential new treatment for overactive bladder (OAB), we investigated the feasibility of non- invasively activating multiple nerve targets in the lower leg. Methods: In healthy participants, surface electrical stimulation (frequency = 20 Hz, pulse width = 200 μs) was used to target the tibial nerve, saphenous nerve, medial plantar nerve, and lateral plantar nerve. At each location, the stimulation amplitude was increased to define the thresholds for evoking (1) cutaneous sensation, (2) target nerve recruitment and (3) maximum tolerance. Results: All participants were able to tolerate stimulation amplitudes that were 2.1 ± 0.2 (range = 2.0 to 2.4) times the threshold for activating the target nerve. Conclusions: Non-invasive electrical stimulation can activate neural targets at levels that are consistent with evoking bladder-inhibitory reflex mechanisms. Further work is needed to test the clinical effects of stimulating one or more neural targets in OAB patients. Keywords: Transcutaneous electrical nerve stimulation, Bladder neuromodulation, Overactive bladder, Tibial nerve, Saphenous nerve, Plantar nerve Background neuromodulation [6]. However, long-term therapeutic Overactive bladder (OAB) is characterized by symptoms efficacy can be limited. Up to 80% of patients discon- of frequency and urgency that may or may not result in tinue drugs within the first 6 months [7], Botox injection urinary incontinence [1]. Unlike cases of neurogenic can cause urinary retention, and sacral neuromodulation bladder with known etiology (e.g., spinal cord injury or is an expensive and relatively invasive treatment option. multiple sclerosis), OAB is commonly diagnosed in As an alternative, patients may be provided with per- otherwise healthy individuals. OAB can affect up to 16% cutaneous tibial nerve stimulation (PTNS) therapy, of adults and can adversely affect an individual’s ability which is a procedure performed in a clinical setting. It to perform everyday tasks, social interactions, and sleep- involves the insertion of a 34G stainless needle above ing habits, all of which can be quantified by significant the medial malleolus, through which electrical pulses are decreases in quality of life measures [2, 3]. Widely ac- used to stimulate the tibial nerve. Nerve activation is cepted clinical therapies include behavioural modifica- confirmed by movement of the toes or a sensation radi- tion [4], drugs, intravesical Botox [5], and sacral ating along the sole of the foot. Weekly clinical visits are repeated for 3 months, and if the patient responds to * Correspondence: [email protected] treatment, maintenance PTNS is provided every 3 weeks 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto, thereafter [8, 9]. 164 College Street, Room 407, Toronto, ON M5S 3G9, Canada 2Department of Electrical and Computer Engineering, University of Toronto, Studies suggest that transcutaneous electrical nerve Toronto, ON, Canada stimulation (TENS) of the tibial nerve (TN) could also Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sharan et al. BMC Urology (2018) 18:10 Page 2 of 7 Fig. 1 Captured images of surface electrodes used to target the 4 neural targets. a The tibial nerve (TN) configuration involved the cathode being placed 3 finger widths above and 1 finger width posterior to the medial malleolus, and the anode placed at the midsole of the foot. b The medial plantar nerve (MPN) was targeted by placing both electrodes along the medial side of the plantar foot surface: the cathode is placed at the base of the hallux and the anode is placed 2 finger widths from the cathode. c The lateral plantar nerve (LPN) was targeted by placing both electrodes along the lateral side of the foot. d The saphenous nerve (SAFN) configuration involved positioning the cathode 2 finger widths below the medial condyle of the tibia, and the anode 2 fingers widths inferior to the cathode provide an effective means of treating OAB. It is non- invasive, relatively inexpensive, and could allow patients to self-administer treatment at home. Since the first clin- ical report on the therapeutic effects of TN stimulation [10], multiple studies have demonstrated the feasibility of using TENS in OAB patients. For example, Ammi et al. showed that daily TENS applied near the ankle can significantly improve the quality of life in patients [11], and Manriquez et al. demonstrated that TENS applied twice a week can achieve clinical efficacy that is compar- able to bladder medication [12]. Despite these findings, optimal therapeutic use of TENS remains unclear [13]. As a potential solution for improving the clinical effi- cacy, we have begun to investigate the feasibility of using TENS to electrically activate multiple nerve targets. Bladder-inhibitory responses evoked by TN stimulation is a well-documented phenomenon that has been dem- onstrated in anesthetized animals [14–16], and also in human participants subjected to surface stimulation of the plantar surface of the foot [17, 18]. It has also been Fig. 2 Shaded anatomical plot of the sensation perceived during TN shown in anesthetized rats that electrical stimulation of stimulation. The color of each square within the grid represents the the medial and lateral plantar nerves can evoke reflexes cumulative number of participants that felt stimulation at that location. Progressive spread of the perceived sensation occurred as that (1) inhibit the bladder during electrical stimulation the stimulation amplitude was increased: (a)Tskin,(b)Tnerve, and (c) (i.e. acute effect) or (2) cause bladder inhibition that is Tlimit. There were increases in the ‘activated’ areas both on the sustained even after the stimulus has been turned off plantar foot surface and the medial aspect of the lower leg. It is (i.e., prolonged effect), respectively [19]. In addition, noted that the color scale (1 to 14) indicates that not all 15 there is evidence that electrical stimulation of the saphe- participants shaded in the same pixels in response to stimulation. (same as in Fig. 3) nous nerve (SAFN) can also modulate bladder function. Sharan et al. BMC Urology (2018) 18:10 Page 3 of 7 healthy participants (10 female, age = 23.9 ± 2.5 years, range = 19–28 years) who provided written consent prior to beginning each experiment. Participants were re- cruited using posters placed around the university cam- pus, and e-mails sent to the students and faculty at the University of Toronto. The experiment involved a one-hour session, during which a total of 11 stimulation trials were conducted. Following skin sterilization with alcohol wipes, a pair of 5 cm × 5 cm self-adhesive surface electrodes (STIM- CARE, DJO Global, Vista, California) were placed on the lower leg to activate different neural targets (Fig. 1): tib- ial nerve (TN), medial plantar nerve (MPN), the lateral plantar nerve (LPN), and the saphenous nerve (SAFN). Both electrodes were connected to a hand-held TENS unit (Empi Continuum™, DJO Global, Vista, California), where the stimulation frequency (20 Hz) and pulse width (200 μs) were set at constant values. The electrical activation of each neural target involved a series of 3 stimulation trials, where the amplitude was increased from 0 mA up to a pre-defined endpoint. The first trial was terminated at the cutaneous sensory Fig. 3 Shaded anatomical plot of the sensation perceived during (a) threshold, where the participant felt the stimulation at SAFN, (B) LPN, and (c) MPN. As the amplitude was increased during the surface electrode (Tskin). The second trial was termi- SAFN stimulation from Tskin to Tlimit, the evoked sensation spread across the entire medial aspect of the lower leg, down to the ankle. nated at the threshold for activating the target nerve As shown for LPN and MPN stimulation, the perceived area of (Tnerve), where the participant for example began to feel sensation at Tlimit was generally consistent with the innervation paresthesia radiate distally along the medial surface of pattern of the lateral and plantar nerves, respectively the leg. Finally, the third trial was terminated when the participant could no longer tolerate TENS stimulation By implanting a nerve cuff electrode around the SAFN (Tlimit). The 4 neural targets were tested in randomized (immediately below the knee) in anesthetized rats [20], order by conducting a set of stimulation trials on one we showed that prolonged bladder-inhibitory responses leg (e.g., TN + right leg) and then switching to the can be evoked in a frequency-dependent manner (10 Hz contralateral leg to test another nerve (e.g., MPN + left to 20 Hz). And in a small cohort of OAB patients [21], leg). Any potential carry-over effects of stimulation were we have observed significant improvements in both minimized by alternating neural targets between each OAB symptoms and quality of life measures following leg. The nerve activation threshold (Tnerve) was con- 12 weeks of percutaneous SAFN stimulation. firmed by either a foot motor response (TN, LPN, and In this study, we investigated the feasibility of using MPN) or a cutaneous sensation that radiated down the TENS to selectively activate multiple nerve targets lo- medial aspect of the lower leg (SAFN).