Abstract
Neuromodulation elicited by electrical stimulation of peripheral or spinal nerves is a US Food and Drug Administration–approved therapy for treating several disorders of the pelvic viscera. Although the detailed mechanisms underlying the effects of neuromodulation are still to be elucidated, it is generally believed that its beneficial effects are due to activation of somatic afferent nerves, which induces the release of neurotransmitters in the central nervous system, leading to modulation of abnormal visceral sensory and motor mechanisms. Studies in animals have revealed that different types of neuromodulation act by releasing different inhibitory and excitatory neurotransmitters. This chapter will provide a summary of neural control of the lower urinary tract and distal bowel, the clinical use of neuromodulation for the treatment of bladder and bowel dysfunctions, putative mechanisms of action of neuromodulation based on animal studies and new experimental approaches using combination therapies to improve the efficacy of neuromodulation.
Keywords
Colon, Glutamic acid, Micturition, Opioid peptides, Pontine micturition center, Pudendal nerve, Serotonin, Spinal cord, Striated sphincters, Urinary bladder, γ-Aminobutyric acid
Outline
Introduction 221
Neural Control of Lower Urinary Tract and Distal Bowel 223
Putative Mechanisms of Neuromodulation 225
Clinical Studies of the Mechanisms of SNS 225
Does SNS Target Efferent or Afferent Axons? 225
Importance of Proximity of Spinal Neuromodulatory Pathways and Pelvic Visceral Reflex Circuitry 225
Does Neuromodulation Target Normal or Pathologic Mechanisms? 226
Experimental Studies of Neuromodulation in Animal Models 227
Sacral Nerve Stimulation 227
Mechanisms Underlying the Enhancement of Urine Storage by SNS 227
Mechanisms of SNS Modulation of Bowel Function 228
Modulation of Bladder Function by Peripheral Nerve Stimulation 229
Experimental Models in Cats and Rats 229
Properties of the Different Types of Neuromodulation 229
Site of Action 229
Role of CNS GABA and Opioid Peptides in Neuromodulation 230
Role of Glutamatergic Mechanisms in Neuromodulation 230
Role of Serotonergic Mechanisms in PNS 230
Drug–Neuromodulation Combination Therapy 231
Treatment of LUT Dysfunction After SCI 231
Future Directions 231
References 233
Introduction
The pelvic visceral organs perform essential excretory functions that are mediated by complex neural circuitry in the brain and spinal cord. Accordingly, injuries or diseases at various sites in the nervous system can produce prominent changes in micturition and defecation. The pelvic organs have a similar peripheral efferent innervation that originates in the lumbosacral spinal cord ( Fig. 19.1D ) ( ). The organs also exhibit unique properties not shared by other visceral organs, including (1) functions that are initiated in an all-or-none or switchlike manner and that are completely dependent on central neural control, (2) functions that are dependent on coordination between multiple smooth and striated muscles, and (3) voluntary control of micturition and defecation in contrast to the involuntary control of most other visceral organs.
Disorders of the lower urinary tract (LUT) and distal bowel such as overactive bladder (OAB) syndrome, nonobstructive urinary retention, constipation, and fecal incontinence are commonly treated with behavioral therapy or drugs ( ); however, when patients are refractory to these first-line treatments or when treatment has to be terminated due to side effects, neuromodulation, elicited by sacral nerve stimulation (SNS) or peripheral nerve stimulation, is often used ( ). SNS is a US Food and Drug Administration (FDA)-approved therapy that involves permanent implantation of electrodes on spinal nerves at the sacral level ( ). 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 tibial nerve with electrodes inserted percutaneously (percutaneous tibial nerve stimulation, PTNS) for multiple treatments ( ).
Experimental neuromodulation methods include (1) transcutaneous, posterior tibial nerve stimulation with electrodes applied to the surface of the leg ( ), (2) pudendal nerve stimulation (PNS) with implanted or percutaneous electrodes ( ), (3) transcutaneous foot stimulation with electrodes applied to the plantar surface ( ), and (4) electrical stimulation of pudendal nerve afferents via electrodes inserted into the urethral lumen or applied to the sex organs ( ).
Although the detailed mechanisms underlying the effects of commonly used neuromodulation methods are still to be elucidated; it is generally believed that the beneficial effects are due to the initiation of action potentials (APs) in somatic afferent nerves, which then propagate to the lumbosacral segments of the spinal cord, where they release neurotransmitters ( Fig. 19.1C ) that modulate abnormal visceral sensations and/or involuntary motor mechanisms by activating either spinal reflex circuits or ascending pathways to the brain. This chapter will review the putative mechanisms that underlie the normalization of bladder and bowel functions by neuromodulation.
Neural Control of Lower Urinary Tract and Distal Bowel
The anatomy and major functions of the LUT and distal bowel are similar, such as storage of body waste (urine and fecal content) in reservoirs (the bladder and colon) and periodic elimination of waste (micturition and defecation) through the urethra and anal canal. These functions require both reflex and voluntary neural control organized in the central nervous system (CNS) and transmitted bilaterally from the lumbosacral spinal cord to the organs via three sets of peripheral nerves, which contain afferent as well as efferent axons ( ) ( Fig. 19.1D ). The efferent innervations of the LUT and distal bowel are similar. Sympathetic axons promote storage by relaxing smooth muscle of the reservoirs and contracting smooth muscle of the urethral and anal outlets. Parasympathetic axons promote emptying by contracting smooth muscle of the reservoirs and relaxing the outlets. Somatic motor axons in the pudendal nerves promote storage by contracting the external urethral sphincter (EUS) ( Fig. 19.1D ) or external anal sphincter (EAS).
Although the lumbosacral autonomic and somatic motor pathways to the LUT and distal bowel are similar, other aspects of the neural control are markedly different. For example, the bowel also has an intrinsic nervous system (the enteric plexus) that can function independently of the CNS to regulate bowel motility and secretion ( ). In addition, the proximal colon receives an efferent and afferent innervation via the vagus nerve from the brainstem and nodose ganglion, respectively ( ), whereas the bladder does not receive a vagal innervation. Central nervous control is also different. Micturition is mediated by parasympathetic excitatory input to the bladder, which is dependent on activation of a pontine micturition center (PMC) in the brainstem ( Fig. 19.2D ) ( ), while defecation is mediated by parasympathetic excitatory reflex mechanisms located in the sacral spinal cord ( ).
Afferents that innervate the bladder and distal bowel are divided into two populations: small myelinated (Aδ) and unmyelinated C-fibers that are mechanosensitve and/or chemosensitive ( ). Micturition is initiated by Aδ afferents ( ); while defecation is initiated by C-fiber afferents ( ). The pudendal nerves also contain larger-diameter myelinated afferents that innervate the striated sphincters and sex organs ( ).
Efficient urine storage, which requires a quiescent bladder and a closed urethral outlet, is promoted by spinal reflexes that activate sympathetic inhibitory input to the bladder and sympathetic excitatory input to the urethra in parallel with pudendal nerve excitatory input to the EUS ( Figs. 19.1D and 19.2D ) ( ). During micturition, these spinal storage reflexes are inhibited by input from the brain in parallel with activation of the sacral parasympathetic excitatory pathway to the bladder, mediated by descending projections from the PMC ( Fig. 19.2D ) ( ). The supraspinal mechanism functions as an ON-OFF switching circuit ( ) that changes the motor control of the LUT in an all-or-none manner from storage to voiding.
Storage of feces is facilitated by tonic contraction of the external anal sphincter (EAS) in concert with lumbar sympathetic inhibitory control of the colon and excitatory control of the smooth muscle of the anal canal ( ). Defecation is mediated by a spinal reflex mechanism that has an afferent limb in the pelvic nerve activated by colorectal distention and an efferent limb in the pelvic nerve that carries sacral parasympathetic excitatory input to the colorectal smooth muscle and myenteric plexus ( ). Defecation is facilitated by input from neurons in the region of the PMC ( ) but persists after transection of the spinal cord at a suprasacral level that eliminates the descending input ( ), whereas micturition is initially eliminated after cord transection that interrupts the supraspinal pathway ( ). However, reflex bladder contractions recover several weeks after cord transection due to reorganization of spinal circuitry ( ). In view of these differences in neural control, it would not be unexpected if some bladder and bowel dysfunctions have different etiologies and if neuromodulation used to treat these dysfunctions acts via different mechanisms. More detailed discussions of the neural control of LUT and gastrointestinal tract are presented in Chapter 114 , Chapter 121 .
Putative Mechanisms of Neuromodulation
Neuromodulation of pelvic organ functions induced by electrical stimulation of sacral spinal nerve roots or peripheral nerves is attributable to activation of APs 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 ( ). These observations indicate that neuromodulation must be mediated by activation of large afferent axons that innervate muscle, skin, or other nonvisceral tissues.
Because all primary afferents are known to release excitatory neurotransmitters, it is assumed that the second step in the initiation of neuromodulation involves excitatory synaptic transmission and chemical activation of second-order spinal neurons ( Fig. 19.1C ) ( ). The third step would involve multiple downstream mechanisms that include (1) inhibition or excitation of visceral reflex circuitry in the same segments of the cord leading to changes in the motor outflow to the viscera ( ), (2) modulation of transmission of visceral sensory information to other segments of the spinal cord ( Fig. 19.2D ) or to the brain to modulate supraspinal pathways controlling pelvic viscera ( Fig. 19.2D ) ( ), and (3) initiation of reflexes in lumbosacral sympathetic or somatic efferent nerves that in turn change pelvic organ function ( Fig. 19.2D ) ( ).
Clinical Studies of the Mechanisms of SNS
Does SNS Target Efferent or Afferent Axons?
Various clinical studies have provided insights into the site of action (SOA) and mechanisms underlying the effects of SNS. The target for SNS was initially uncertain because the sacral spinal roots contain motor as well as sensory axons. Direct activation of motor pathways was initially considered to be an important factor; and the proper positioning of the stimulating electrodes in the intervertebral foramen was evaluated by the efficacy of stimulation to elicit a contraction of the EAS (the anal wink) or limb/foot muscles. conducted experiments to determine if SNS directly activates motor axons or activates the motor pathways reflexively by stimulating afferent axons. Recordings of EMG activity in the EAS revealed that the latencies of responses evoked by the lowest intensities of SNS were consistent with reflex activation rather than direct stimulation of motor axons. These data also suggested that, at the stimulus intensities commonly used to treat pelvic organ dysfunction, the beneficial effects are due to stimulation of afferent axons and activation of circuitry in the CNS. Subsequent studies by , which showed that SNS enhances the cortical potentials evoked by PNS, provided more direct evidence that SNS acts centrally to alter sensory pathways. In addition, it has been proposed that SNS activates somatosympathetic reflexes, which inhibit bladder and bowel activity and contract smooth muscle sphincters ( ). Many responses evoked by SNS are elicited by low intensities of stimulation, indicating that it targets low-threshold large-diameter A-type somatic afferent axons. However, treatment of different disorders may require activation of different types of afferent axons. For example, to increase the frequency of colonic propulsive slow waves in patients with slow transit constipation requires suprasensory intensities of SNS while subsensory stimulus intensities are ineffective ( ). On the other hand, fecal incontinence can be treated with subsensory stimulation at intensities below a conscious level of detection that can still activate proprioceptive afferent axons ( ).
Importance of Proximity of Spinal Neuromodulatory Pathways and Pelvic Visceral Reflex Circuitry
The efficacy of SNS in modulating pelvic organ dysfunction is also influenced by the segmental level of the stimulation and the proximity of the targeted afferent pathways to the S2–S4 spinal autonomic centers controlling the pelvic viscera. This suggests that convergence of somatic afferent pathways activated by SNS with visceral pathways in the spinal cord is an important factor in neuromodulation.
Bladder and bowel are midline organs that receive a bilateral innervation from both sides of the spinal cord; while SNS is usually applied unilaterally. This suggests that the influence of SNS is distributed bilaterally in the cord or that SNS affects supraspinal circuitry that coordinates autonomic activity on both sides of the sacral spinal cord. However, when unilateral SNS fails, bilateral stimulation is often effective, suggesting that the afferent input from a single spinal root is not sufficient to normalize all types of bladder and bowel dysfunctions and/or that the effects of neuromodulation occur primarily ipsilaterally and therefore afferent input to both sides of the spinal cord is necessary to elicit a significant therapeutic response ( ).
Does Neuromodulation Target Normal or Pathologic Mechanisms?
A recent detailed review of the literature concluded that SNS influences anorectal function by acting at the level of the pelvic afferent neurons or in the CNS ( ). Actions at these sites are also thought to play a major role in the treatment of urinary incontinence by SNS ( ). Furthermore, it is speculated that when SNS is used to treat OAB and urinary incontinence, it selectively targets pathologic changes in central control mechanisms because it reduces urinary urgency/frequency and normalizes bladder storage function without affecting voiding efficiency. Thus, SNS does not seem to target neural circuitry required for voluntary voiding or the normal sensations of bladder filling but seems to selectively suppress circuitry involved in involuntary voiding and abnormal bladder sensory mechanisms. Because voluntary and involuntary voiding are likely to use the same motor pathways in the spinal cord and PNS, it is also reasonable to speculate that SNS acts upstream of the parasympathetic preganglionic neurons and selectively suppresses pathologic mechanisms in the afferent limb of involuntary voiding reflexes.
An unusual and seemingly paradoxical property of SNS is its efficacy in treating constipation and idiopathic urinary retention (Fowler syndrome) using stimulation at the same location and with the same stimulus parameters that are effective in treating fecal and urinary incontinence ( ). Thus, SNS seems to normalize functions. In constipated patients, SNS increases the frequency and amplitude of colonic anterograde propagating waves ( ), whereas in fecal incontinent patients, SNS has the opposite effect to inhibit propulsive colonic motility, to increase the number of retrograde propagating waves and decrease rectal hypersensitivity ( ). This suggests that pathophysiology can alter the responses evoked by SNS ( ).
The selectivity of SNS for abnormal versus normal pelvic visceral functions is also demonstrated by the efficacy of SNS in treating Fowler syndrome. This disorder, which occurs mainly in women, is characterized by painless urinary retention associated with spasticity of the EUS and inability to voluntarily empty the bladder ( ). Cystometry, in Fowler syndrome, demonstrates a large-capacity bladder without the usual sensations during the filling phase. Brain imaging during bladder infusion reveals smaller functional magnetic resonance imaging (fMRI) signals in the periaqueductal gray (PAG) ( Fig. 19.2D ) and in higher brain centers consistent with the defect in bladder sensations. SNS for Fowler syndrome restores bladder sensations and the ability to void and increases bladder distention evoked fMRI signals in the PAG ( ). Thus, SNS can enhance normal sensory pathways that are tonically suppressed in patients with Fowler syndrome, in contrast to its effects in other patients with OAB, where it suppresses abnormal bladder sensations.
A pathophysiologic mechanism that might contribute to Fowler syndrome and that might be the target for SNS has been proposed based on animal experiments, which show that contractions of the EUS or EAS activates afferents in the pudendal nerve, which, in turn, inhibit reflex bladder activity ( ). This observation led to the hypothesis that spasticity of the striated sphincter muscles in women with Fowler syndrome induces a similar inhibition of bladder sensory and motor pathways in the sacral spinal cord ( ). Thus, SNS may suppress the putative sphincter–bladder inhibitory pathway at the level of the sacral spinal cord and normalize function. The ability of SNS to unmask normal bladder sensations, and voiding in these patients supports the hypothesis that SNS targets spinal pathways contributing to abnormal functions but does not affect CNS sensory and motor pathways responsible for normal voiding.
Unfortunately, other evidence for a spinal SOA of SNS in humans is weak or incomplete. Although SNS clearly is effective in treating nonneurogenic bladder and bowel dysfunctions in patients with intact spinal cords; SNS is not FDA approved nor has it been extensively tested as a treatment for bladder dysfunction after spinal cord injury (SCI) or other types of neurologic disorders. A systematic review and meta-analysis of 26 studies consisting of 357 patients with neurogenic bladder dysfunctions resulting from various causes concluded that SNS may be effective and safe ( ). However, only 61 of the patients had neurogenic LUT dysfunction due to SCI and only a small number were identified as having complete spinal injuries. Although the success rate was high (56%–100%) in the neurogenic bladder population, the review concluded that randomized controlled trials (RCTs) in larger populations of patients are needed before definitive conclusions can be drawn regarding the efficacy of SNS for neurogenic LUT dysfunction after SCI. If future studies are successful in demonstrating such an effect, this would provide direct evidence for an action of SNS on spinal reflex pathways.
One study ( ), which used SNS early during the spinal shock phase in patients with complete SCI, showed that the treatment prevented the subsequent development of detrusor overactivity and urinary incontinence. This study raises the possibility that early intervention with SNS may suppress the neuroplasticity and remodeling of the spinal circuitry that has been identified in animal spinal injury models to underlie the recovery of bladder reflexes and generation of bladder overactivity ( ). However, in the absence of convincing clinical evidence for an action of SNS on spinal bladder and bowel reflex circuits after separation from supraspinal controls, the question about site of SNS action (i.e., spinal cord, brain, or both) remains unanswered.
A similar uncertainty exists about the site and MOA of neuromodulation elicited by other types of somatic nerve stimulation (i.e., PNS and PTNS) and whether different types of neuromodulation act at the same site and via similar mechanisms. Clinical observations suggesting different mechanisms include (1) PNS is effective in treating OAB symptoms in patients in which SNS failed ( ) and (2) PTNS, which is administered intermittently for 30 min once a week for 12 weeks and which produces a reduction in symptoms that persists for several weeks after termination of the treatments ( ), is clearly different than SNS and PNS, which require continuous stimulation to maintain efficacy ( ). These findings suggest that the three types of neuromodulation (SNS, PNS, and PTNS), which send afferent signals to the sacral spinal cord, suppress bladder and bowel dysfunctions via different mechanisms.
Experimental Studies of Neuromodulation in Animal Models
Sacral Nerve Stimulation
The SOA and the neurotransmitter mechanisms involved in neuromodulation of bladder and bowel function have been studied in various animal models by recording intravesical ( Fig. 19.1A and B ) or intracolonic pressure to monitor organ activity before and after lesioning of central or peripheral neural pathways ( Fig. 19.1D ), before and after neuromodulation-induced changes in activity ( Fig. 19.1A and B ), and after systemic or local administration of drugs that target neurotransmitter receptors ( Fig. 19.2 ) ( ).
Bladder activity is examined by two methods: (1) cystometry, during which the bladder is slowly distended with fluid to evaluate storage and voiding functions by measuring bladder capacity and micturition pressure ( Fig. 19.1A ), and (2) isovolumetric recording at a constant bladder volume to induce repeated micturition reflex contractions ( Fig. 19.1B ) ( ). The bladder is filled with either saline solution to induce normal bladder activity or a solution containing an irritant (e.g., dilute acetic acid or turpentine oil) to sensitize bladder afferents and induce bladder overactivity ( ), which presents as a reduction in bladder capacity or an increase in the frequency of isovolumetric bladder contractions. SNS increases bladder capacity (i.e., the volume to induce a micturition reflex contraction, Fig. 19.1A ) and reduces the frequency or completely blocks the rhythmic isovolumetric bladder contractions ( Fig. 19.1B ).
Mechanisms Underlying the Enhancement of Urine Storage by SNS
Experiments in rats : The mechanisms involved in SNS were first studied in anesthetized female rats by Hassouna and colleagues. These experiments revealed that chronic bilateral SNS (20 Hz, S1 dorsal root, 8 h/day, for 3 weeks) reduced bladder hyperreflexia in chronic, spinal cord transected (SCT, T10) animals ( ) and decreased hyperactive voiding in a chemically induced cystitis model in spinal cord intact animals ( ). In both models, SNS also reduced the c- fos expression in spinal neurons induced by activation of bladder afferents. SNS also reduced the rise in neuropeptide content in the L6 dorsal root ganglia ( ) and the upregulation of TRPV1 expression in the spinal dorsal horn (DH) after spinal transection ( ). The authors concluded that SNS acts through inhibition of bladder C-fiber afferent activity. However, it is also possible that SNS acts in the spinal cord to suppress excitatory synaptic transmission between afferents and second-order spinal interneurons in the bladder reflex pathway and this, in turn, reduces bladder hyperreflexia.
The neurotransmitters involved in SNS have been studied in rats by using saline cystometry to examine modulation of normal voiding and using chemically induced cystitis to examine modulation of bladder hyperactivity. In a chronic cystitis model (10 days) in anesthetized female rats, the suppression of isovolumetric reflex bladder contractions by bilateral SNS (20 Hz) was blocked by the intrathecal administration of a non– N -methyl- d -aspartate (NMDA) glutamatergic receptor antagonist (CNQX) but not by an NMDA glutamatergic receptor antagonist ( ). It was concluded that glutamate is an important excitatory transmitter in the spinal pathways mediating SNS inhibition of bladder hyperactivity and that glutamate activates inhibitory interneurons that, in turn, suppress the bladder reflex pathway.
More recent studies ( ) have identified a role for endogenous opioid peptides in SNS inhibition of isovolumetric bladder contractions in an anesthetized rat model. Intravenous, intrathecal, or intracerebroventricular administration of naloxone methiodide, a nonselective opioid receptor antagonist, reduced the inhibition elicited by SNS, whereas administration of δ- or κ-selective opioid receptor antagonists was ineffective. It was concluded that SNS modulation of reflex bladder activity is dependent on the release of opioid peptides that act on μ-opioid receptors in the brain and spinal cord.
Experiments in cats : Experiments in anesthetized cats have confirmed the inhibitory effect of SNS on reflex bladder activity recorded under isovolumetric conditions ( Fig. 19.1B ) and under more physiologic isotonic conditions during bladder filling where the inhibitory effect of SNS is evident as an increase in bladder capacity ( Fig. 19.1A ) ( ). SNS increases bladder capacity when the bladder is filled with saline or when it is filled with dilute acetic acid to induce bladder overactivity. Long-duration SNS (30 min) also induces a poststimulation increase in bladder capacity that persists for at least 2 h during saline but not acetic acid cystometrograms ( ). The inhibitory effect occurs over a range of frequencies (5–30 Hz), and excitatory effects do not occur ( Fig. 19.3 ). Inhibition is elicited by stimulation of the S1 and S2 dorsal roots (DRTs) but minimally with S3 DRT stimulation.
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