Sacral neuromodulation for the treatment of urinary bladder dysfunction: mechanism of action and future directions

Transcription

1 For reprint orders, please contact: Sacral neuromodulation for the treatment of urinary bladder dysfunction: mechanism of action and future directions Bertil FM Blok *,1 1 Department of Urology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands * Author for correspondence: b.blok@erasmusmc.nl Symptoms of overactive bladder affect a large portion of the world population, especially the elderly. Sacral neuromodulation (SNM) is an effective third-line therapy in patients with overactive bladder. The working mechanism of SNM can be explained by the neural connections of the lower urinary tract. It is proposed that SNM does not work directly on the central components of the micturition reflex, but on cortical and subcortical areas, which in turn inhibits the micturition reflex components in the caudal brainstem. The clinical use and outcomes of SNM are described for several forms of bladder dysfunction. Furthermore, some recent new developments in SNM are discussed, such as expanded indications, more effective use of existing nonrechargeable neuromodulators and the introduction of a rechargeable device. First draft submitted: 22 August 2017; Accepted for publication: 8 November 2017; Published online: 14 December 2017 Keywords: bladder pain nerve stimulation overactive bladder underactive bladder urge and frequency urgency urinary incontinence urinary retention Conservative treatment of overactive bladder (OAB) with or without urinary incontinence consists of pelvic floor exercises, medication and lifestyle intervention, including fluid restriction and timely voiding. If these conservative interventions fail, it is possible to offer electrical stimulation therapies, such as sacral neuromodulation (SNM). In patients suffering from urinary urgency, frequency and urgency incontinence, electrical stimulation of the sacral nerve significantly reduces urinary symptoms and improves patient quality of life. SNM is also used effectively for other forms of bladder dysfunction, such as underactive bladder and bladder pain syndrome (BPS). The increased use of minimally invasive SNM has decreased the need for more open surgical procedures such as ileocystoplasty and urinary diversion. SNM uses an implanted electrode to the third or fourth sacral spinal nerve to deliver a nonpainful electrical stimulus. The brain of the patient perceives this stimulus and, in turn, effectively restores bladder function and alleviates the patients symptoms. Due to the system-oriented, and not organ-oriented, approach, SNM not only treats urinary disorders, but may also have a beneficial effect on bowel and sexual dysfunction as well as on pelvic pain. Normal control of the lower urinary tract In order to understand the role of the brain in the control of the urinary bladder and its sphincter, one can make a distinction between structures and axonal tracts in the caudal brainstem and spinal cord, which are intrinsic part of the micturition and continence reflex, and structures and pathways, located in the forebrain and mesencephalon, which modulate these micturition and continence areas. Most of the clinical therapies aimed at functional bladder disorders are not specifically targeted to the micturition reflex areas, but influence cortical and subcortical brain areas, which, in turn, modulate the micturition reflex components. Examples of such therapies are pelvic floor physiotherapy, biofeedback, transcutaneous electrical nerve stimulation, posterior tibial nerve stimulation and SNM. Currently, there is no effective behavioral, chemical or electrical treatment which works directly and specifically on the central components of the micturition reflex /bem C 2017 Future Medicine Ltd Bioelectron. Med. (2018) 1(1), ISSN

2 Blok Cortical and subcortical areas controlling the micturition reflex components Periaqueductal gray Caudal brainstem Pontine micturition center Pontine continence center Secondary afferents GABA/glycine interneurons Bladder motoneurons Sphincter motoneurons Sacral cord Primary afferents Bladder External urethal sphincter Figure 1. Ascending and descending pathways of the micturition reflex. Primary afferents from the bladder and urethra are terminating on interneurons in the dorsal horn and intermediate zone of the lumbosacral spinal cord. Secondary afferents are relayed to the periaqueductal gray. When voiding can start, the pontine micturition center activates directly bladder motoneurons and inhibits indirectly the sphincter motoneurons. This results in a contraction of the bladder preceded by a relaxation of the sphincter. The central components of the micturition reflex consist of sacral spinal interneurons and their ascending sensory pathway to the periaqueductal gray (PAG) and the pontine micturition center (PMC) in the caudal brainstem, and the PMC and its descending motor pathway to the sacral cord (Figure 1). The afferent thin myelinated Aδ nerves from the urothelium, suburothelium and detrusor muscle in the bladder wall convey bladder filling information via the pelvic and hypogastric nerves to the lumbosacral spinal cord. The afferent information from the bladder neck and urethra is conveyed via the pudendal and hypogastric nerves to the lumbosacral spinal cord [1,2]. These lower urinary tract afferents terminate on interneurons in the lateral aspect of the dorsal horn and in the intermediate zone of the lumbosacral cord. Most of the interneurons make intraspinal connections for proprioception, but other spinal interneurons send ascending fiber tracts to specific areas in the pons and midbrain. Some of these interneurons are involved in conveying information on bladder filling. Other lumbosacral interneurons relay information to forebrain structures, including the thalamus and the 86 Bioelectron. Med. (2018) 1(1) future science group

3 Sacral neuromodulation Review hypothalamus [3,4]. The spinothalamic and spinohypothalamic tracts are thought not to play a specific role in the basic micturition reflex, but are involved in sensory processes such as sensation of urogenital pain, temperature, touch and conscious awareness of bladder filling and voiding. The sensory cortex is constantly informed about the fullness of the urinary bladder via the spinothalamic tract [5]. In OAB patients there is an overawareness of bladder filling, which can be suppressed by therapies, such as medication, pelvic floor physiotherapy or SNM. In patients with complete spinal cord injury it is possible that the brain receives bladder fullness information via the vagal nerve [6]. The motor part of the micturition reflex is composed of the PMC and its descending pathway to the sacral cord (Figure 1). The PMC is located in the dorsolateral pons and its descending axons make direct contact via their excitatory terminal boutons with the preganglionic motoneurons in the intermediolateral cell column in the sacral cord [7]. These excitatory terminals contain the neurotransmitter glutamate [8]. The cholinergic parasympathetic preganglionic motoneurons send their axons to the postganglionic neurons in the bladder wall [2]. The descending pathway from the PMC makes also direct excitatory glutaminergic contact with inhibitory interneurons in the sacral intermediomedial cell column. These inhibitory interneurons contain GABA and glycine [9,10] and send their axons to the motoneurons of the external urethral sphincter (EUS) [11]. Stimulation of the sacral intermediomedial cell column of the cat results in a strong relaxation of the EUS mimicking the relaxation of the sphincter during micturition [12]. In mammals, activation of the PMC results in urethral sphincter relaxation via the indirect pathway to the inhibitory sacral interneurons, followed by a bladder contraction via the direct pathway to the bladder motoneurons. The PMC is the final common pathway or micturition switch for both the relaxation phase involving the EUS and the contraction phase involving the smooth detrusor muscle of the urinary bladder. The thoracolumbar segments T10 to L2 contain sympathetic preganglionic motoneurons, which are involved in the relaxation of the bladder wall. Efferent nerves travel within the hypogastric nerve via the thoracolumbar sympathetic ganglionic chain to the bladder wall. The sympathetic tone keeps the intravesical pressure low during bladder filling. The sympathetic nerves to the bladder only start to fire at about 60% of bladder capacity [13]. The PMC receives input from the mesencephalic PAG, which is thought to be a crucial component of the micturition reflex in higher mammals. The PAG is a midbrain area known for its role in pain modulation [14]. In recent years it has become clear that this dense neuronal matter around the aqueduct of Sylvius is essential for many vital basic functions, including respiration, aggression, mating, defecation and micturition. In the cat, anterogradely labeled fibers from the lumbosacral spinal cord form a dense terminal field particularly in the lateral PAG [15]. Furthermore, bladder and pelvic nerve stimulation evokes activation of the PAG [16]. The importance of the PAG in the cat is exemplified by the observation that electrical stimulation of the lateral PAG results in in micturition in cats which includes an initial relaxation of the EUS followed by a bladder contraction [17,18]. Disconnection of the PAG from the PMC results in an extreme form of urge urinary incontinence where the bladder empties completely after minimal filling [19]. The forebrain controls the PAG and the PMC like a switch. Lesions rostral to the mesencephalic PAG result in the loss of control of the timing of micturition, but the micturition reflex remains intact. A pivotal role for the PAG and PMC in bladder control has been described in humans using positron emission tomography and functional magnetic imaging [20 23]. Afferent information from the bladder and urethra is relayed via the thalamus to the cingular and insular cortices. These areas help to take the decision whether it is safe to start voluntary voiding via the prefrontal cortex [20]. Urinary continence is controlled by the pontine continence center or L-region [1,2]. The pontine continence center continuously excites the EUS during continence (Figure 1). This tonic contraction is interrupted six- to seven-times per day by the relaxation of the sphincter by the PMC during micturition. Possible mechanism of action of SNM Proposed theories for the working mechanism of SNM have usually focused on one component of the lower urinary tract and its innervation. Nevertheless, the working mechanism of SNM is probably similar to that of other modes of urogenital neuromodulation, such as posterior tibial nerve stimulation (PTNS), transcutaneous electrical nerve stimulation (TENS), dorsal genital nerve stimulation and pudendal nerve stimulation. The main difference with those alternative therapies is that the SNM recruits 1000-times more axons by stimulating the sacral root and not a small nerve or some nerve fibers. Moreover, SNM provides continuous stimulation and as opposed to once per 1 2 weeks, and offers more flexibility in stimulation parameters. Neuromodulation is also used for other diseases, like epilepsy, depression and chronic pain. The working mechanism in these other diseases may have similarities to SNM for bladder dysfunction. future science group 87

4 Blok Interstim 1994 Interstim II 2006 Axonics 2016 Figure 2. Anterior fluoroscopy view of implanted the three marketed sacral neuromodulators and the year of obtaining CE Mark. Arrowheads point to the course of the lead with four electrodes. The electrodes of the Interstim devices are placed on the right S3 nerves. The electrodes of the Axonics device are placed on the left S3 nerve. The main paradigm of the early theories on SNM assumed that stimulation of motor nerves resulted in pelvic muscle contraction. This muscle contraction relaxed the bladder wall via intramural ganglion cells [24]. This early theory was abolished, because SNM also works when there is no muscle contraction. Furthermore, activation of exclusive sensory nerves like the dorsal clitoral and dorsal penile nerves results in similar effects on the bladder as SNM [25]. Later, higher brain areas were also incorporated into relevant theories. Cortical sensory areas of the brain might be altered by SNM. Positron emission tomography showed differences in regional cerebral blood flow during acute and chronic SNM [26]. The primary and associative sensory cortices were not the only areas modulated during SNM; modulation was also seen in areas important for attention and alertness. The results also suggested that chronic SNM induces neuroplasticity [26]. At present, it is thought that SNM activates afferent pathways which modulate forebrain structures involved in awareness and alertness. This modulation in OAB patients results in less firing of the PMC, thereby, restoring normal urinary continence. Patients with an underactive bladder lack an effective sensation of bladder filling, which does not lead to activation of the PMC switch. SNM results in an increased awareness of bladder filling and pelvic floor contraction state. This awareness makes it possible for the patient to turn on the micturition switch and effectively relax the EUS via the PMC. In my view, SNM exerts its beneficial effect in underactive bladder mainly via relaxing the striated sphincter and much less via contracting the smooth muscle of the bladder. Current indications & outcomes for SNM The European Association of Urology and American Urological Association recommend SNM as a third-line treatment option when first-line lifestyle intervention and pelvic floor exercises and second-line medication have failed in patients with idiopathic OAB symptoms. The first sacral neuromodulator, Interstim from Medtronic, received a CE Mark in Europe in 1994 for the treatment of functional disorders of the pelvis and lower urinary or intestinal tract. In 1997 Interstim was approved by the US FDA for the treatment of urinary urgency incontinence, and in 1999 for urinary urgency-frequency and urinary retention. The updated neuromodulator Interstim II received CE mark in 2006 and the new rechargeable neuromodulator from Axonics received the CE mark in 2016 (Figure 2). The terminologies urinary urgency incontinence and urinary urgency-frequency are combined in the terminology OAB with or without incontinence. This combination seems more logical since urgency for voiding may eventually result in urinary leakage when the bathroom is not reached in time [27]. This leakage happens much more frequently in the less mobile elderly person than in younger individuals. The definition of success in SNM refers to an improvement in symptoms of 50% or more during the test period of 1 2 weeks. OAB with or without urinary incontinence The International Continence Society definition of OAB with urinary incontinence is any involuntary urinary leakage which is preceded or accompanied by urgency, a sudden compelling desire to pass urine that is difficult to defer [28]. It is generally accepted that seven-times per 24 h is the upper limit of the normal voiding frequency. OAB 88 Bioelectron. Med. (2018) 1(1) future science group

5 Sacral neuromodulation Review without urinary incontinence in other words, urinary urgency and frequency is then defined as eight-times voiding or more per 24 h. In addition, is the notation that there exists urgency for voiding, which is difficult to defer. It is obvious that the voiding frequency very much depends on the fluid intake. Therefore, it is important to obtain frequency voiding by charting before starting any treatment for OAB. Other causes, like urinary tract infection, underactive bladder with significant post void residue, bladder stones and bladder cancer have to be ruled out. Urodynamic investigation in patients with OAB may or may not demonstrate detrusor overactive contractions during the filling phase of the micturition cycle. Several studies demonstrated no association between detrusor overactivity and successful treatment with chronic SNM [29,30]. Multiple studies have shown the efficacy of SNM in the short- and long-term but the definition of success varies considerably among the studies. A recent prospective randomized trial in 147 OAB patients with mild to moderate symptoms compared SNM with standard medical treatment [31]. Intention to treat analysis demonstrated a 61% success rate for neuromodulation and 42% success for standard medical treatment at 6 months of treatment. In another prospective randomized study, over 6 months, 34 implanted patients were observed and 42 patients, who received standard medical therapy, comprised the control group [32]. Voiding and incontinence parameters were significantly better in the SNM group compared with the control group with 76% success, including 47% completely without incontinence. Another recent prospective randomized trial compared onabotulinumtoxina to SNM in 381 women [33]. The mean number of incontinence episodes decreased more in the onabotulinumtoxina group than in the SNM group (- 3.9 vs -3.3 episodes per day) at 6 months. Unfortunately, in this study the amount of 200 U of onabotulinumtoxina was twice as high as the registered and reimbursed dose for idiopathic OAB and not the standard of care for this third-line therapy. This alternative dose of 200 U was used off label before the compound was registered for idiopathic OAB, but this is not clinical practice at present due to higher chance of adverse events like urinary retention and urinary tract infection [34]. The registered dose of onabotulinumtoxina for idiopathic OAB is 100 U, which was significantly more effective than placebo at 4 months [35]. Two prospective cohort studies on OAB and SNM had a follow-up of at least 5 years. The study groups comprised of 96 patients of both men and women and 60 female patients [36,37]. Significantly less incontinence episodes were found in 58 and 50% of the patients, respectively, and in 61 and 53% significant less use of pads. Nonobstructive chronic underactive bladder Nonobstructive chronic underactive bladder is defined as a nonpainful bladder with a chronic high post void residual which necessitates regular drainage of the bladder. The amount of clinically accepted residue after voiding is usually a maximum of 100 ml. An underactive bladder is as a rule also hyposensitive with larger than normal maximum capacity of > 500 ml. Clinically, it is important whether it is necessary to drain the bladder, since this is the only objective parameter to measure success or failure of treatment. In 1999, the FDA approved isnm for the treatment of chronic urinary retention without obstruction. In a prospective randomized study, 68 out of 177 patients with urinary retention qualified for full SNM implantation after a test of 3 to 7 days. Of these 68 patients, 37 patients received SNM implantation and were compared with 31 patients who continued self-catherization [38]. After 6 months 69% of the SNM patients did not have to catheterize anymore compared with none in the control group. Another retrospective study in 21 men with chronic urinary retention demonstrated a similar success rate of 67% with the notation that men younger than 43 years of age were more likely to respond. Other indications SNM is not approved for BPS and neurogenic bladder dysfunction. In selected patients SNM might be offered, especially when there are also symptoms of OAB. Since measurement of change in pain perception is very subjective and strongly influenced by pain medication, the recording of OAB symptoms makes it possible to determine an objective improvement during the test phase. Most of the studies on SNM and BPS and chronic pelvic pain used a retrospective approach in a small number of selected patients. In a prospective study, 17 patients were treated with SNM for a mean of 14 months [39]. Mean voided volume increased from 111 to 264 ml and pain decreased from 5.8 to 1.6 on a 0 to 10 visual analog pain scale. Another study with a follow-up of a mean of 86 months reported a 64% reduction of pain in 30 patients who underwent SNM [40]. SNM might be effective for treating neurogenic bladder patients, but, as in BPS, the level of evidence is low [41]. A systematic review identified 224 patients in 22 studies whom underwent SNM. Patients with multiple sclerosis and spinal cord injury were most prevalent and had future science group 89

6 Blok mainly a mix of symptoms of OAB and urinary retention. The pooled success rate was 92% after a mean follow-up of 26 months. It was concluded that the effectiveness of SNM in non-neurogenic patients and neurogenic patients is comparable. SNM patient selection & implantation procedure The SNM implants are products of Medtronic and contain a lead with four electrodes and a neurostimulator, named Interstim II. The success of an implanted SNM depends to a large extent on a correct selection of the patient. Theoretically, it should be possible that a test stimulation is not necessary and that selected OAB patients receive immediate implantation of the complete SNM with a chance of success of at least 90%. However, clinical practice teaches that all candidate patients receive a stimulation test trial. The test may be done in the outpatient clinic known as peripheral or percutaneous nerve evaluation (PNE) or can be performed with a two staged implant in the operation room. The patient may get a complete implantation of SNM when there is 50% improvement or more in one or more of the voiding parameters frequency of voiding, voided volume and incontinence episodes. Comparing the baseline bladder diary filled out by the patient for 3 5 days before the test trial with a second bladder diary filled out during the test period constitutes the assessment. PNE test During a PNE, an insulated needle is introduced into the third or fourth sacral foramen under local anesthesia on the basis of bony landmarks, such as coccygeal bone, the iliac crest and the lumbosacral joint. Fluoroscopy may be used during or after placement but with respect to SNM the anatomical location is not fully correlated with the functional outcome. Correct placement during electrical stimulation by an external neurostimulator is confirmed by induction of perineal sensations. Usually, these sensory responses precede possible motor responses, like contraction of the external anal sphincter and flexion of the great toe. Subsequently, a temporary flexible test lead with an electrode at the tip is introduced via the needle, which is removed when the lead is in place. The lead is adhered to the skin and connected to a receiver in a belt. The receiver is wirelessly controlled by an external neurostimulator. When the patient is not distracted and is focused on the perineal area, he or she will feel a small perineal sensation which is not painful or annoying. The test phase lasts usually 5 to 7 days, during which a bladder diary is recorded. The PNE is assumed positive when one or more bladder diary parameters shows more than 50% improvement. In our clinic the PNE test is positive in 60% of the OAB patients. We do not use the PNE test for urinary retention, because of the high failure rate. When the patient passes the test, they may receive the complete SNM, which consists of the quadripolar lead and a neuromodulator. The advantage of PNE is that it is an incision-free procedure performed in the outpatient clinic under local anesthesia. The main disadvantage of the temporary PNE lead is that is prone to dislocation, which may lead to test failure. Staged implant procedure Patients who failed or could not tolerate PNE may be offered the two-staged procedure. In response to patients who had a positive PNE but a less favourable result with complete SNM, the two staged implant procedure was introduced [42]. The first stage comprises implantation of the permanent electrode (Figure 3). Originally, the lead wasplacedinthes3foramenduringanopenprocedureviaa10cmverticalincisionoverthesacralboneand after placement in the foramen fixed on the periosteum of the bone. Since 2003 such an invasive procedure is not necessary and the lead can be placed percutaneously in the relatively short time of about 30 min [43]. The permanent lead is coupled to a temporary extension wire which is placed subcutaneously towards the flank and connected in the same way as described for the PNE. The tunneling reduces the risk of infection, the lead is more precisely placed than the PNE lead, and the evaluation can be prolonged by up to 4 weeks while the neurostimulator program is optimized. Implantation of the neuromodulator at the buttock and removal of the extension wire follows in the second stage after 2 to 4 weeks in case of 50% of more improvement in one or more of the voiding parameters. In the case of test failure, the lead and extension wire are removed and alternative treatment options can be offered. The minimal invasive staged implant can be done under local anesthesia, sedation or general anesthesia. The staged procedure results in an increased rate of implants compared with the PNE test. In a retrospective study, 69 patients with OAB and 31 with urinary retention received a PNE test, followed by a staged implantion [44]. Success was observed in 47% after PNE and 69% after staged implantation. The Interstim II neuromodulator was introduced in It has a lithium battery (1.3 A-h at 3.2 V), which is covered by a titanium box ( mm). The neuromodulator weighs 22 g and it volume is 14 cc. 90 Bioelectron. Med. (2018) 1(1) future science group

7 Sacral neuromodulation Review CRANIAL DORSAL VENTRAL CAUDAL Figure 3. Lateral fluoroscopy view of the permanent tined quadripolar lead in the third sacral foramen. The voltage driven battery provides continuous or intermittent pulses from 2.1 to 130 Hz (in 49 steps) with a pulse width of μs (per 30 μs). The upper limit of voltage is 8.5 V. The much larger Interstim was the precursor of the Interstim II and has not been available since since July For bladder dysfunction, pulse width is set at 210 μs and rate at Hz. The amplitude is set around the threshold of urogenital or anal sensation. Programming of neuromodulator ensures the optimal stimulation with the best tolerable sensation at the lowest amplitude. Stimulation can be carried out in either unipolar or bipolar fashion. After implantation and the initial programming, the neuromodulator has to be adjusted on average three-times during the first year and 0.8 per year in the following years in patients with OAB [37]. The durability of Interstim was around 7 years, whereas that of the smaller Interstim II is on average 4.4 years [37]. A smaller neuromodulator will improve the comfort of the patient, but this comes at the high replacement rate and increased risk infection with the device and its lead around the time of operation. At our department of Urology, Erasmus Medical Center, in 2016, more than 50% of our SNM budget for 60 full implants was allocated to replacement of the Interstim II, leaving fewer resources for new patients. Conclusion Sacral neuromodulation is an effective treatment for refractory overactive bladder syndrome with or without incontinence. An overview is given of the indications and operation procedure. Furthermore, a new theory on the mechanism of action is presented and future developments, such as expanded indications, and the introduction of a rechargeable device are discussed. Future perspective No clear predictors of success have been identified and a positive response does not lead to a successful outcome in all patients in the long term [45]. Since SNM treatment is usually for life, other modes of battery use have been investigated. Constant versus intermittent stimulation SNM uses a continuous stimulation protocol. Other forms of electrical neuromodulation for OAB, like PTNS, use stimulation for 30 min per 1 or 2 weeks. The effectiveness of this PTNS protocol suggests that intermittent SNM stimulation might have a beneficial effect on OAB symptoms. Indeed, a prospective randomized crossover trial showed no difference of the effects between continuous and cyclic stimulation with 16 s on and 8 s off [46]. Another prospective cohort study in 19 patients demonstrated no difference between SNM for 8 h on and 16 h off and continuous SNM [47]. Closed loop neurostimulation is also a future possibility for SNM in idiopathic OAB. In such a stimulation protocol the electrical stimulation is only necessary just before the OAB symptoms are present. The start of the stimulation could be set on the basis of a certain bladder volume at which the first future science group 91

8 Blok sensation is perceived by the patient or at the point that the bladder pressure increases. Both parameters bladder volume and increased bladder pressure could be measured directly by a microchip on the bladder or indirectly by measurement of afferent pelvic nerve activity. Rechargeable neurostimulator The need for different stimulation protocols such as intermittent and closed loop stimulation in order to save battery life is much less prominent with the recent introduction of a rechargeable neurostimulator by Axonics. Clinical results after three months for the treatment of OAB in 51 patients demonstrated success in 73% after implantation of the complete device without prior test stimulation (Neurourology and Urodynamics, accepted). It is claimed that the Axonics neurostimulator can last for more than 15 years. The use of a current driven stimulation protocol results in fewer adjustments of the stimulation parameters than a voltage-driven stimulation protocol as with the Interstim II neurostimulator. An additional advantage of the rechargeable device is that it can be switched to the Medtronic lead via an extension cable when the Interstim II battery is empty. Other issues Some publications suggested bilateral neuromodulation in the case of failing unilateral stimulation [48].Thisisnot clinical practice because of the lack of definitive evidence of superiority compared with unilateral stimulation and the potential of increased economic burden for the healthcare system. The Interstim II neurostimulator has FDA-approved labeling for 1.5 Tesla MRI head scans. The use of 3 or 7 Tesla MRI scans or MRI scans of the lower body including the lower back and pelvic region is contra-indicated. Executive summary The indications and procedure of sacral neuromodulation for bladder dysfunction are discussed in detail. Furthermore a new theory on the working mechanism and future developments are presented. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. References 1 Blok BF. Central pathways controlling micturition and urinary continence. Urology 59(5 Suppl. 1), (2002). 2 de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. Compr. Physiol. 5(1), (2015). 3 Giesler GJ Jr, Spiel HR, Willis WD. Organization of spinothalamic tract axons within the rat spinal cord. J. Comp. Neurol. 195(2), (1981). 4 Katter JT, Burstein R, Giesler GJ Jr. The cells of origin of the spinohypothalamic tract in cats. J. Comp. Neurol. 303(1), (1991). 5 ChandlerMJ,HobbsSF,FuQGet al. Responses of neurons in ventroposterolateral nucleus of primate thalamus to urinary bladder distension. Brain Res. 571(1), (1992). 6 Krhut J, Tintera J, Bilkova K et al. Brain activity on fmri associated with urinary bladder filling in patients with a complete spinal cord injury. Neurourol. Urodyn. 36(1): p (2017). 7 Blok BF, Holstege G. Ultrastructural evidence for a direct pathway from the pontine micturition center to the parasympathetic preganglionic motoneurons of the bladder of the cat. Neurosci. Lett. 222(3), (1997). 8 Matsumoto G, Hisamitsu T, de Groat WC. Role of glutamate and NMDA receptors in the descending limb of the spinobulbospinal micturition reflex pathway of the rat. Neurosci. Lett. 183(1 2), (1995). 9 Blok BF, de Weerd H, Holstege G. The pontine micturition center projects to sacral cord GABA immunoreactive neurons in the cat. Neurosci. Lett. 233(2 3), (1997). 10 Sie JA, Blok BF, de Weerd H, Holstege G. Ultrastructural evidence for direct projections from the pontine micturition center to glycine-immunoreactive neurons in the sacral dorsal gray commissure in the cat. J. Comp. Neurol. 429(4), (2001). 11 Konishi A, Itoh K, Sugimoto T et al. Leucine-enkephalin-like immunoreactive afferent fibers to pudendal motoneurons in the cat. Neurosci. Lett. 61(1 2), (1985). 92 Bioelectron. Med. (2018) 1(1) future science group

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