Impact of Bioelectronic Medicine on the Neural Regulation of Pelvic Visceral Function
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Neuromodulation elicited by electrical stimulation of peripheral or spinal nerves is a U.S. Food and Drug Administered (FDA)-approved therapy for treating disorders of the pelvic viscera, including urinary urgency, urgency-frequency, nonobstructive urinary retention and fecal incontinence. The technique is also being tested experimentally for its efficacy in treating interstitial cystitis, chronic constipation and pelvic pain. The goal of neuromodulation is to suppress abnormal visceral sensations and involuntary reflexes and restore voluntary control. Although detailed mechanisms underlying the effects of neuromodulation are still to be elucidated, it is generally believed that effects are due to stimulation of action potentials in somatic afferent nerves. Afferent nerves project to the lumbosacral spinal cord, where they release excitatory neurotransmitters that activate ascending pathways to the brain or spinal circuits that modulate visceral sensory and involuntary motor mechanisms. Studies in animals revealed that different types of neuromodulation (for example, stimulation of a sacral spinal root, pudendal nerve or posterior tibial nerve) act by releasing different inhibitory and excitatory neurotransmitters in the central nervous system. In addition, certain types of neuromodulation inhibit visceral smooth muscle by initiating reflex firing in peripheral autonomic nerves or excite striated sphincter muscles by initiating reflex firing in somatic efferent nerves. This report will provide a brief summary of (a) neural control of the lower urinary tract and distal bowel, (b) clinical use of neuromodulation in the treatment of bladder and bowel dysfunctions, (c) putative mechanisms of action of neuromodulation on the basis of animal experiments and (d) new approaches using combination therapies to improve the efficacy of neuromodulation.
Disorders of the lower urinary tract and distal bowel, such as overactive bladder syndrome (OAB), nonobstructive urinary retention, constipation and fecal incontinence, are commonly treated with behavioral therapy or drugs (4); however, when patients are refractory to these first-line treatments or when treatment has to be terminated because of side effects, neuromodulation elicited by electrical stimulation of spinal nerve roots or peripheral nerves is often used (5,6). Sacral neuromodulation is a U.S. Food and Drug Administered (FDA)-approved therapy that involves permanent implantation of electrodes on spinal nerves at the sacral level along with implantation of a stimulator and battery at a more distant site (7). Stimulation is usually applied continuously to obtain the optimal beneficial effects. Another type of FDA-approved office-based minimally invasive therapy involves stimulation of the posterior tibial nerve with electrodes inserted percutaneously for each treatment (8). Stimulation is applied for 30 min every week for 12 wks followed by 30-min booster treatments at 2- to 4-wk intervals.
Experimental neuromodulation methods include (a) transcutaneous posterior tibial nerve stimulation with electrodes applied to the surface of the leg (9), (b) pudendal nerve stimulation with implanted or percutaneous electrodes (10), (c) transcutaneous foot stimulation with electrodes applied to the plantar surface (11), (d) electrical stimulation of the bladder via electrodes inserted through the urethra into the bladder lumen (12), (e) electrical stimulation of the urethra via electrodes inserted into the urethral lumen (13) and (f) electrical stimulation of the dorsal genital nerve (14,15). Sacral anterior root stimulation via permanently implanted electrodes, a technique developed by Brindley in the 1970s, is used to elicit emptying of the bladder or colon or penile erection in people with complete suprasacral spinal cord injuries (16).
Although the detailed mechanisms underlying the effects of commonly used neuromodulation methods are still to be elucidated; it is generally believed that beneficial effects are due to the initiation of action potentials in somatic afferent nerves. Afferent nerves then project to the lumbosacral segments of the spinal cord, where they release neurotransmitters that modulate abnormal visceral sensations and/or involuntary motor mechanisms by activating either spinal reflex circuits or ascending pathways to the brain. This report will provide a brief overview of the neural control of the pelvic viscera with a particular focus on bladder and bowel, how neural control is altered in pathological conditions and the putative mechanisms that underlie the normalization of bladder and bowel functions by neuromodulation.
Neural Circuitry Controlling the Pelvic Viscera
Peripheral Nervous System
Excitatory parasympathetic neuroeffector transmission in the bladder and bowel is mediated by acetylcholine acting on postjunctional muscarinic receptors (Figure 2B) (1,20), whereas parasympathetic input to the penis inducing penile erection is mediated by nitric oxide (3). Nitric oxide is also involved in parasympathetic nerve-induced relaxation of the smooth muscle of the urethra (1,20) and anal canal (2). Sympathetic nerves relax bladder and colonic smooth muscle by releasing norepinephrine, which activates β adrenergic receptors and contracts smooth muscle of the urethra, anal canal and vas deferens by activating α adrenergic receptors (Figure 2B) (1, 2, 3).
Afferent axons in the pelvic, hypogastric and pudendal nerves transmit information from the pelvic organs to second-order neurons in the lumbosacral spinal cord. Afferents that innervate the lower urinary tract and distal bowel originate in caudal lumbosacral dorsal root ganglia (DRG) (Figure 1) and are divided into two populations: small myelinated (Aδ) and unmyelinated C-fibers (21). The pudendal nerves also contain larger-diameter myelinated afferents that innervate the penis, clitoris and striated sphincters (3,19).
Mechanisms of Neuromodulation
Neuromodulation of pelvic organ functions induced by electrical stimulation of sacral spinal nerve roots or peripheral nerves originating in the lumbosacral segments of the spinal cord is attributable to activation of action potentials in afferent axons that propagate into the spinal cord. Based on the electrical thresholds for inducing neuromodulation, it is likely that large diameter myelinated afferent axons are the target of stimulation rather small myelinated Aδ and C fiber visceral afferent axons that have high electrical thresholds exceeding the stimulus intensities used for neuromodulation (37). These observations indicate that neuromodulation must be mediated by activation of large afferent axons that innervate muscle, skin or other nonvisceral tissues.
Support for these mechanisms has been obtained in both animal and human studies. For example, experiments in patients with fecal incontinence have revealed that sacral spinal nerve root stimulation (SNS) inhibits propulsive colonic motility and decreases rectal hypersensitivity, whereas in normal individuals, it enhances external sphincter excitability and increases anal electromyographic responses to cortical stimulation (2). A recent and detailed review of the literature concluded that SNS influences anorectal function by acting at the level of the pelvic afferents or in the central nervous system (6). Actions at these sites are also thought to play a major role in the treatment of urinary incontinence by SNS (5,10,43, 44, 45).
An unusual and seemingly paradoxical property of SNS is its efficacy in treating constipation and idiopathic urinary retention (Fowler syndrome) by using stimulation at the same location and with the same stimulus parameters that are effective in treating bowel and bladder incontinence (46,47). Fowler syndrome, which occurs mainly in women, is characterized by a loss of bladder sensations and the inability to voluntarily empty the bladder. It is associated with abnormal EUS activity and failure of the sphincter to relax during micturition. It is thought that tonic afferent firing arising in the sphincter inhibits the transmission of normal bladder sensory information to the brain (48). Functional magnetic resonance imaging (fMRI) studies revealed that SNS removes the inhibition and restores normal sensations and voiding (48). Thus, the actions of SNS can be influenced by pathological conditions. SNS can suppress abnormal sensory pathways in patients with overactive bladder but can enhance normal sensory pathways that are tonically suppressed in patients with urinary retention.
Experimental Studies of Neuromodulation in Animal Models
Mechanisms Underlying the Enhancement of Urine Storage
The neurotransmitter mechanisms involved in neuromodulation have been studied extensively in animals by using cystometry to record reflex bladder activity. In chloralose anesthetized cats with an intact central nervous system (45) and in decerebrate, unanesthetized (30) or spinal cord-transected cats (42,49), bladders were infused with saline to elicit normal reflexes (50) or infused with dilute acetic acid to induce overactivity (51). The experiments compared different types of neuromodulation elicited by electrical stimulation of (a) the sacral spinal nerve root (SNS) (45), (b) the pudendal nerve (38,40), (c) the posterior tibial nerve (37,52), (d) the posterior cutaneous femoral nerve (53) and (e) the distal branches of tibial nerve on the plantar surface of the foot (51,54). The experiments revealed that neuromodulation increases bladder capacity without altering the amplitude of reflex bladder contractions, indicating that neuromodulation suppresses the sensory/afferent limb of the micturition reflex pathway and delays the gating of the micturition switching circuit without changing the efferent limb of the reflex pathway downstream of the PAG-PMC switch (Figure 5) (31). This result is consistent with clinical data indicating that neuromodulation reduces urgency sensations and frequency of voiding without reducing voiding efficiency.
It is clear that neuromodulation of reflex bladder activity in cats depends on the action of multiple neurotransmitters in the central nervous system and that different types of neuromodulation can be identified based on stimulation parameters, site of action in the central nervous system (Figures 8 and 9) and responses to drugs. For example, pudendal nerve stimulation (PNS) and SNS neuromodulation are frequency-dependent and are effective at low frequencies of stimulation (5–10 Hz) but not at higher frequencies (20–30 Hz) (45,55), whereas posterior tibial nerve stimulation (TNS) or foot stimulation is effective across a broader range of frequencies (5–30 Hz) (50,51). PNS neuromodulation is only effective during the period of stimulation and the effect is lost within a few minutes after termination of the stimulation (38,56,57), whereas the inhibitory effect of TNS or foot stimulation persists for at least 2 h after termination of the stimulation but only in normal bladders and not in irritated bladders (58,59).
The effect of PNS neuromodulation depends in part on inhibitory transmission in the spinal cord mediated by gamma aminobuyric acid (GABA) (Figure 8) and is suppressed by a GABAA receptor antagonist (picrotoxin) (39,40) but not by an opioid receptor antagonist (naloxone) (42,56,60). However, the effect of tibial nerve stimulation or foot stimulation on bladder overactivity is suppressed by naloxone, an opioid receptor antagonist, and therefore involves opioid receptor mechanisms (54,61). In addition, the inhibitory effect of TNS on normal bladder activity is not suppressed by naloxone, indicating that the mechanism of modulation by TNS can be altered by pathological conditions (50). The inhibitory effect of PNS exists in acute and chronic spinal transected animals (T8–T9) (39, 40, 41,55,57), whereas the effect of TNS is not detectable in acute spinal transected animals (41) but is present in decerebrate animals, raising the possibility that TNS suppresses micturition by an action on the PAG-PMC circuits (Figure 9). Thus, the two types of inhibition target different sites in the central nervous system. The effect of PNS is reduced by transecting the hypogastric nerves or administration of a nonselective β adrenergic receptor antagonist (42,62), whereas the effect of SNS is not affected by these procedures (45), indicating that PNS inhibition but not SNS inhibition is mediated in part by reflex activation of sympathetic inhibitory pathways to the bladder.
PNS neuromodulation that remains after propranolol treatment is also suppressed by administration of MTEP, a metabotropic glutamate receptor 5 (mGluR5) antagonist (38,56). This effect occurs in both spinal cord intact and acute spinal cord transected animals, indicating as shown in Figure 8 that pudendal neuromodulation may be mediated by a spinal disynaptic inhibitory pathway consisting of an initial mGluR5 excitatory synapse that activates GABAergic inhibitory input to the spinal micturition reflex pathway. TNS inhibition is reduced by an mGluR2/3 antagonist (LY341495), indicating that a different type of glutamatergic excitatory transmission is necessary for activation of the TNS opioid inhibitory mechanism (61).
PNS suppresses the bladder contractions elicited by electrical stimulation of the PMC, suggesting that the PNS inhibition influences the descending efferent limb of the spinal-brain-spinal micturition pathway (Figure 8). PNS inhibition is also modulated by bulbospinal serotonergic pathways because the inhibition can be suppressed by methysergide, an antagonist of serotoninergic 5HT2 receptors (63), and by ondansetron, an antagonist of 5HT3 receptors (64). Duloxetine, a serotonin/norepinephrine reuptake inhibitor known to increase serotonin levels in the raphe nuclei and enhance serotonin autoinhibition of raphe neuron firing by activation of 5HT1A receptors, also suppresses PNS inhibition (65). WAY100635, a 5HT1A receptor antagonist, reverses the duloxetine inhibitory effect and enhances PNS inhibition (65). These data suggest that tonic bulbospinal serotonergic input facilitates the PNS inhibitory pathway, and removal of this input suppresses the inhibitory pathway. A combination of duloxetine and WAY100635 also enhanced bladder inhibition elicited by foot stimulation (66). These studies demonstrate the potential complexity of neuromodulatory inhibitory mechanisms and show that to fully understand neuromodulation, it will be necessary to identify the contributions of multiple neurotransmitters.
Treatment of Lower Urinary Tract Dysfunction after Spinal Cord Injury
Spinal cord injury rostral to the lumbosacral level eliminates voluntary and supraspinal control of voiding, leading initially to an areflexic bladder and complete urinary retention, followed by slow development of automatic micturition and bladder overactivity mediated by spinal reflex pathways (Figure 7) (1,36). However, voiding is commonly inefficient because of simultaneous contractions of the bladder and urethral sphincter (detrusor-sphincter-dyssynergia [DSD]). Thus, the bladder does not store well or empty well after spinal injury.
Sacral anterior root stimulation in combination with sacral deafferentation was developed in the 1970s to treat this condition (16). Transection of the sacral posterior roots eliminates reflex contractions of the sphincter and DSD, while electrical stimulation of the anterior roots activates the parasympathetic efferent pathway to the bladder, producing bladder emptying. Stimulating electrodes are connected to a radio receiver positioned subcutaneously over the lower chest wall and activated by an external radio transmitter to induce micturition. The method has also been used to elicit defecation and penile erection. However, this device can only be used in individuals with complete suprasacal injuries because the stimulation produces pain when the spinal injury is incomplete. Another disadvantage that has limited widespread use is that posterior rhizotomy interrupts reflex functions of the pelvic viscera, including penile erections.
In people with complete suprasacral spinal cord injury, SNS has not been effective in reducing detrusor overactivity, suggesting that spinal reflex mechanisms are more resistant to this inhibition (67). However, a recent study (67) in which bilateral SNS was begun during the early acute bladder areflexic phase following complete spinal cord injury revealed that the SNS prevented the development of detrusor overactivity and urinary incontinence, normalized bladder capacity, reduced urinary tract infection rates and improved bowel function. The mean follow-up was 26 months. The beneficial effects did not occur with unilateral sacral neuromodulation. These results raise the possibility that early application of SNS influences the reorganization of spinal circuits that occurs after disruption of descending spinal tracts and reduces the neuroplasticity that underlies the emergence of neurogenic detrusor overactivity.
Experiments in chronic spinal cord-injured cats have evaluated the efficacy of different frequencies of PNS for promoting voiding (49,55,57). Whereas low frequencies (5–10 Hz) of stimulation suppress reflex bladder contractions, higher frequencies (20–40 Hz) produce large amplitude reflex contractions. Electrical stimulation of pudendal sensory nerve branches to the penis, clitoris or urethra also elicit reflex bladder contractions in animals and humans (13,68, 69, 70, 71, 72, 73, 74, 75). However, voiding efficiency is low (10%) because of simultaneous contractions of the EUS due to direct stimulation of sphincter motor axons in the pudendal nerve or EUS reflex responses induced by the rise in intravesical pressure and activation of bladder afferents. However, voiding can be improved considerably (to 90%) by blocking the motor input to the sphincter by applying ultrahigh frequency stimulation (5–20 kHz) to the pudendal nerve to block conduction in the sphincter motor axons distal to the site of the pudendal afferent stimulation used to elicit the bladder contractions (57,76). The axonal block induced by ultrahigh frequency stimulation is rapidly reversible and repeatable (77,78).
Modulation of lower urinary tract function has also been induced by stimulation and block of pudendal nerve axons by using a wireless-controlled implantable stimulator in cats (79). Tripolar cuff electrodes were implanted bilaterally on the pudendal nerves to block motor pathways to the EUS, and a bipolar cuff electrode was implanted proximal to the tripolar electrodes to activate pudendal afferent input to the spinal cord. Continence promoting responses such as an increased bladder capacity and an increase in urethral pressure due to sphincter contractions were elicited by low-frequency (5 Hz) afferent and efferent stimulation. Responses that could be used to induce voiding such as an increase in intravesical pressure and sphincter relaxation were induced by 20–30 Hz stimulation of the bipolar electrode and 5–10 kHz stimulation of the blocking electrodes. Although the mechanisms involved in ultrahigh frequency axonal block are still uncertain (80, 81, 82, 83, 84, 85), it is likely that this method in combination with low frequency stimulation will be useful for modulating neurogenic lower urinary tract dysfunction. Other approaches for selectively modulating bladder and sphincter activity in individuals with spinal cord injury include activation of afferent nerves with different patterns of stimulation or stimulation of subpopulations of afferent axons in distal branches of the pudendal nerve that may have more specific reflex functions (68–70,73–75).
Questions to be addressed in future research include (a) can mechanisms of action of neuromodulation of pelvic organ dysfunction identified in anesthetized animal models be validated in humans, (b) do certain types of neuromodulation produce slowly developing, prolonged changes in neural control (that is, neuroplasticity) that persist after termination of the stimulation, (c) does neuromodulation only affect symptoms or can it alter the development or progression of pathophysiological mechanisms, (d) does stimulation of specific subpopulations of afferent axons in distal nerve branches in contrast to stimulation of heterogeneous afferent populations in large nerve trunks produce more effective control of symptoms, (e) can simultaneous stimulation of multiple nerves that act by different mechanisms produce greater efficacy, and (f) can a combination of drug therapy and nerve stimulation produce greater efficacy?
The possibility of combination therapies is theoretically appealing because the animal experiments revealed that diverse chemical signals (that is, neurotransmitters) are involved in neuromodulation. This raises the possibility that drugs targeting these chemical signaling mechanisms might be used to enhance the efficacy of neuromodulation. In addition, synergistic interactions between drugs and neuromodulation may enhance drug efficacy and thereby allow a reduction in drug dosage and side effects. The animal study in which WAY100635, a 5HT1A receptor antagonist, enhanced pudendal neuromodulation is an example of the potential benefits of combination therapy (65). Similarly, because GABA is an important inhibitory transmitter for pudendal neuromodulation (39,40), it is possible that drugs that increase GABA concentrations at the synapse by blocking GABA reuptake/metabolism or drugs that act allosterically with the GABAA receptors to enhance GABAergic inhibition would be useful in combination therapies. Similar approaches might be used to enhance neuromodulation induced by TNS or foot stimulation, which suppress bladder over-activity by activating opioid receptor mechanisms (54,61). Animal experiments showed that administration of tramadol, an opioid receptor agonist with monoamine reuptake inhibitor properties, enhances the bladder inhibitory effects of these two types of neuromodulation and unmasks a prolonged suppression of bladder overactivity that persists after termination of the electrical stimulation (86,87). Thus, future clinical studies should examine the interactions between pharmaceuticals and electroceuticals. Furthermore, if it is reasonable to assume that neuromodulation and drugs act by reversing pathological mechanisms, then these experiments may provide insights into the pathophysiology of pelvic visceral disorders and lead to the identification of molecular targets for new therapies.
The authors declare that they have no competing interests as defined by Bioelectronic Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.
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