Impact of Bioelectronic Medicine on the Neural Regulation of Pelvic Visceral Function

Abstract

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.

Figures

Figure 1

Diagram shows the peripheral pathways for afferent innervation of the pelvic viscera in the cat. Neurons in the sacral dorsal root ganglia send axons into the pelvic and pudendal nerves. The pelvic nerves innervate exclusively the viscera, whereas the pudendal nerves innervate visceral as well as somatic structures such as the anal and urethral sphincters and the perineum. Neurons in the lumbar dorsal root ganglia send axons into the lumbar colonic nerve (LCN) and hypogastric nerve (HGN). The latter axons pass through the sympathetic chain ganglia (SCG) and then the inferior splanchnic nerves (ISN) to the inferior mesenteric ganglia (IMG). The HGN passes caudally to join the pelvic nerve.

Figure 2

Efferent pathways of the lower urinary tract. (A) Innervation of the female lower uri-nary tract. Sympathetic fibers (shown in blue) originate in the T11–L2 segments in the spinal cord and run through the inferior mesenteric ganglia (inferior mesenteric plexus [IMP]) and the hypogastric nerve [HGN]) or through the paravertebral chain to enter the pelvic nerves at the base of the bladder and urethra. Parasympathetic preganglionic fibers (shown in green) arise from the S2–S4 spinal segments and travel in sacral roots and pelvic nerves (PEL) to ganglia in the pelvic plexus (PP) and in the bladder wall. This is where the postganglionic nerves that supply parasympathetic innervation to the bladder arise. Somatic motor nerves (shown in yellow) that supply the striated muscles of the EUS arise from S2–S4 motor neurons and pass through the pudendal nerves. (B) Efferent pathways and neurotransmitter mechanisms that regulate the lower urinary tract. Parasympathetic postganglionic axons in the pelvic nerve release acetylcholine (ACh), which produces a bladder contraction by stimulating M3 muscarinic receptors in the bladder smooth muscle. Sympathetic postganglionic neurons release noradrenaline (NA), which activates β3 adrenergic receptors to relax bladder smooth muscle and activates α1 adrenergic receptors to contract urethral smooth muscle. Somatic axons in the pudendal nerve also release ACh, which produces a contraction of the external sphincter striated muscle by activating nicotinic cholinergic receptors. Parasympathetic postganglionic nerves also release ATP, which excites bladder smooth muscle, and nitric oxide, which relaxes urethral smooth muscle (not shown). L1, first lumbar root; S1, first sacral root; SHP, superior hypogastric plexus; SN, sciatic nerve; T9, ninth thoracic root. Reprinted with permission from (20): Fowler CJ, Griffiths D, de Groat WC. (2008) The neural control of micturition. Nat. Rev. Neurosci. 9:453–66.

Figure 3

Primary afferent and spinal interneuronal pathways involved in micturition. (A) Primary afferent pathways to the L6 spinal cord of the rat project to regions of the dorsal commissure (DCM), the superficial dorsal horn (DH) and the sacral parasympathetic nucleus (SPN) that contain parasympathetic preganglionic neurons. The afferent nerves consist of myelinated (Aδ) axons, which respond to bladder distension and contraction, and unmyelinated (C) axons, which respond to noxious stimuli. (B) Spinal interneurons that express c-fos after the activation of bladder afferents by a noxious stimulus (acetic acid) to the bladder are located in similar regions of the L6 spinal segment. (C) Spinal interneurons involved in bladder reflexes (labeled by transneuronal transport of pseudorabies virus injected into the urinary bladder) are localized to the regions of the spinal cord that contain primary afferents and c-fos. Some of these interneurons provide excitatory and inhibitory inputs to the parasympathetic preganglionic neurons located in the SPN. (D) The laminar organization of the cat sacral spinal cord, showing the location of parasympathetic preganglionic neurons in the intermediolateral region of laminae V and VII (shaded area). CC, central canal; IL, intermediolateral nucleus; LT, Lissauer tract; VM, ventromedial nucleus (Onuf nucleus). Reprinted with permission from (20): Fowler CJ, Griffiths D, de Groat WC. (2008) The neural control of micturition. Nat. Rev. Neurosci. 9:453–66.

Figure 4

Neural circuits that control continence and micturition. (A) Urine storage reflexes. During the storage of urine, distention of the bladder produces low-level vesical afferent firing. This in turn stimulates the sympathetic outflow in the hypogastric nerve to the bladder outlet (the bladder base and the urethra) and the pudendal outflow to the EUS. These responses occur by spinal reflex pathways and represent guarding reflexes, which promote continence. Sympathetic firing also inhibits contraction of the detrusor muscle and modulates neurotransmission in bladder ganglia. A region in the rostral pons (the pontine storage center) might increase striated urethral sphincter activity. (B) Voiding reflexes. During the elimination of urine, intense bladder-afferent firing in the pelvic nerve activates spinobulbospinal reflex pathways (shown in blue) that pass through the pontine micturition center. This stimulates the parasympathetic outflow to the bladder and to the urethral smooth muscle (shown in green) and inhibits the sympathetic and pudendal out-flow to the urethral outlet (shown in red). Ascending afferent input from the spinal cord might pass through relay neurons in the PAG before reaching the pontine micturition center. Note that these diagrams do not address the generation of conscious bladder sensations, or address the mechanisms that underlie the switch from storage to voluntary voiding, both of which presumably involve cerebral circuits above the PAG. R, receptors on afferent nerve terminals. Reprinted with permission from (20): Fowler CJ, Griffiths D, de Groat WC. (2008) The neural control of micturition. Nat. Rev. Neurosci. 9:453–66.

Figure 5

Computer model of PMC-PAG switching circuits. Diagram illustrating the putative pathways in the PAG and PMC that contribute to urine storage and voiding. This circuitry shows the neuronal elements and connections used in the computer model. The right side illustrates the ascending afferent limb of the spinobulbospinal micturition reflex that projects to the PAG, and the left side shows the descending limb that connects the PMC direct neuron to the bladder efferent neuron in the sacral spinal cord. During urine storage, as the bladder slowly fills, a low level of afferent activity activates an excitatory neuron (E) in the PAG, which relays information (pathway A) to an inverse neuron (I) in the PMC that in turn provides inhibitory input to the type 1 direct neuron (D) to maintain continence. Bladder afferent input is also received by a second neuron in the PAG (E) that is on the excitatory pathway (pathway B) to the PMC type 1 direct neuron (D) and to a transiently active PMC neuron (T) that fires at the beginning of micturition. However, the PAG excitatory relay neuron (E) is not activated during the early stages of bladder filling because it is inhibited by a tonically active independent neuron (I). The PMC type 1 direct neuron is also inhibited by a tonically active independent neuron (I) located in the PMC. Bladder afferent firing gradually increases during bladder filling, which increases feed-forward inhibition of the direct neuron via the PAG-PMC inverse neuron pathway. However, at a critical level of afferent firing, excitatory input to the PAG excitatory relay neuron surpasses the tonic inhibition and sends signals to the PMC transient neuron. This process briefly inhibits the inverse neuron, reducing inhibitory input to the direct neuron, allowing it to overcome tonic inhibition and fire action potentials that activate by an axon collateral (pathway C), a reciprocal inhibitory neuron (R) that suppresses the inverse neuron (I) and further reduces inhibition of the direct neuron (D). The direct neuron then switches into maximal firing mode and sends excitatory input to the spinal efferent pathway to the bladder, inducing a large bladder contraction and more afferent firing, which further enhances synaptic transmission in the PAG-PMC micturition reflex pathways. The reflex circuitry returns to storage mode as the bladder empties and afferent firing declines. Excitatory neurons are green and inhibitory neurons are red. Reprinted with permission from (31): de Groat WC, Wickens C. (2013) Organization of the neural switching circuitry underlying reflex micturition. Acta Physiol. (Oxf). 207:66–84.

Figure 6

A simple working model of the lower urinary tract control system, showing the voiding reflex and brainstem (green) and forebrain circuits 1, 2 and 3 (red/blue, yellow and blue, respectively). Circuit 1 includes the thalamus (th) and insula, which is regarded as the homeostatic afferent cortex. The insula processes visceral sensations and sends information about the state of the bladder to the medial prefrontal cortex (mPFC), which is thought to provide modulatory feedback to PAG-PMC circuits. Lesions in the mPFC can induce incontinence. Circuit 2 includes the dorsal anterior cingulate cortex (dACC) and the supplementary motor area (SMA), which are thought to be involved in motivation and modulation of body arousal states. These areas are activated when patients experience a sense of urinary urgency and are thought to trigger responses of the urethral outlet to postpone voiding. Circuit 3 is thought to be concerned with the emotional aspects of voiding. lPFC, lateral prefrontal cortex. Reprinted with permission from (1): de Groat WC, Griffiths D, Yoshimura N. (2015) Neural control of the lower urinary tract. Compr. Physiol. 5:327–96. doi: 10.1002/cphy.c130056.

Figure 7

Changes in the organization of the parasympathetic excitatory reflex pathway to the detrusor muscle after spinal cord injury. This scheme is based on results from electro-physiological studies in cats. In spinal intact animals, micturition is initiated by a supraspinal reflex pathway that passes through a center in the brainstem. The pathway is triggered by myelinated afferents (Aδ-fibers), which are connected to the tension receptors in the bladder wall. Injury to the spinal cord above the sacral segments interrupts the connections between the brain and spinal autonomic centers and initially blocks micturition. However, after cord injury, a spinal reflex mechanism (shown in green) emerges that is triggered by unmyelinated vesical afferents (C-fibers); the A-fiber afferent inputs are ineffective. The C-fiber reflex pathway is usually weak or undetectable in animals with an intact nervous system. Stimulation of the C-fiber bladder afferents by instillation of ice water into the bladder (cold stimulation) activates voiding responses in patients with spinal cord injury. Capsaicin (20–30 mg, subcutaneously) blocks the C-fiber reflex in cats with spinal lesions but does not block micturition reflexes in spinal intact cats. Intravesical capsaicin also suppresses detrusor hyperreflexia and cold-evoked reflexes in patients with neurogenic bladder dysfunction. Reprinted with permission from (20): Fowler CJ, Griffiths D, de Groat WC. (2008) The neural control of micturition. Nat. Rev. Neurosci. 9:453–66.

Figure 8

Model showing putative circuitry and neurotransmitters involved in the inhibition of reflex bladder overactivity elicited by pudendal nerve stimulation (PNS) in an acute spinal cord transected cat (T9/T10). Bladder overactivity was elicited by intravesical infusion of dilute acetic acid. Pudendal nerve afferents (right side) activate a GABA inhibitory interneuron via the release of glutamate and stimulation of metabotropic glutamate receptor 5 (mGluR5). The GABA interneuron can suppress the C-fiber afferent–mediated spinal micturition reflex by inhibiting transmission at the level of an excitatory interneuron or the preganglionic neuron. Note the supraspinal micturition reflex activated by Aδ afferents is eliminated by spinal cord transection. GABA activates GABAA receptors, which are blocked by picrotoxin. Excitatory glutamatergic transmission at the pudendal afferent terminal or in the micturition reflex pathway (*) is blocked by MTEP, an mGluR5 antagonist.

Figure 9

Model showing putative circuitry and neurotransmitters involved in inhibition of reflex bladder overactivity elicited by TNS in a cat with an intact spinal cord. Bladder overactivity is elicited by intravesical infusion of dilute acetic acid and is mediated by both spinal and supraspinal pathways triggered by both Aδ and C-fiber bladder afferents. Note that TNS does not inhibit reflex bladder activity in the acute spinal cord transected preparation shown in Figure 8. It is likely that the inhibition occurs at a supraspinal site. Tibial nerve afferents activate (presumably by the releases of glutamate and stimulation of glutamatergic receptors) a spinal tract neuron that transmits information to the brain (left side). The receptors may be mGluR2/3 subtypes because LY341495, an mGluR2/3 antagonist, suppresses TNS inhibition. Because naloxone, an opioid receptor antagonist, blocks TNS inhibition, it is likely that the inhibition of the supraspinal micturition reflex pathway occurs at the level of the PAG-PMC and is mediated by release of an opioid peptide. Activation of opioid receptors in the brain with drugs suppresses reflex bladder activity, and intracerebroventricular injection of naloxone enhances bladder reflexes, indicating that the reflexes are tonically suppressed by endogenously released opioid peptides. *Excitatory glutamatergic transmission at the tibial nerve afferent terminal or in the micturition reflex pathway in the spinal cord.