CHAPTER 1
Neurophysiology of voiding

Oreoluwa Ogunyemi and Hsi-Yang Wu

Lucile Packard Children's Hospital, Stanford, CA, USA

Anatomy of the lower urinary tract

The three main components of the bladder are the detrusor smooth muscle, connective tissue, and urothelium. The detrusor constitutes the bulk of the bladder and is arranged into inner longitudinal, middle circular, and outer longitudinal layers [1]. Elastin and collagen make up the connective tissue, which determines passive bladder compliance [2]. Elevated type III collagen and decreased elastin are associated with poorly compliant bladders [2]. Active compliance is determined by the detrusor, which is able to change its length over a wider range than skeletal muscle, allowing for a wide variation in bladder volume while maintaining a low pressure [2]. The detrusor maintains a baseline tension, which is modulated by hormones, local neurotransmitters, and the autonomic nervous system. Impedance studies reveal that compared to other smooth muscles, the detrusor is not electrically well coupled. This decreases the likelihood of detrusor overactivity (DO) during filling [2].

The urothelium has multiple layers, consisting of basal cells, intermediate cells, and luminal umbrella cells. The umbrella cells have tight junction complexes, lipid molecules, and uroplakin proteins that contribute to barrier function. A sulfated polysaccharide glycosaminoglycan layer covers the lumen of the bladder and defends against bacterial infection. Although the urothelium was previously thought to be an inert barrier, we now know that urothelial cells participate in afferent signaling. Bladder nerves terminate close to, as well as on urothelial cells. Urothelial cells have pain receptors and mechanoreceptors, which can be modulated by ATP to activate or inhibit sensory neurons. Abnormal activation of these channels by inflammation can lead to pain responses to normally nonnoxious stimuli. Urothelial cells release factors such as acetylcholine, ATP, prostaglandins, and nitric oxide that affect sensory nerves [3].

The internal and external urethral sphincters (EUS) are vital for urinary continence. The internal urethral sphincter functions as a unit with the bladder base and trigone to store urine. The EUS is comprised of inner smooth muscle surrounded by outer skeletal muscle. It is omega shaped, with the majority of its muscle anterior to the urethra, and the opening of the omega sitting posteriorly. The smooth muscle is comprised of a thick longitudinal layer and an outer circular layer. The smooth muscle of the female EUS has less sympathetic innervation than that of the male, and the male EUS is larger in size. The skeletal muscle of the EUS has both slow and fast twitch fibers, of which the slow twitch fibers are more important in maintaining tonic force in the urethra. Contraction of the EUS, coaptation of the mucosa, as well as engorgement of blood vessels in the lamina propria contribute to urinary continence [2].

The lower urinary tract (LUT) is innervated by both the autonomic and somatic nervous systems. Sympathetic nervous system control of the LUT travels via the hypogastric nerve (T10-L2) (Figure 1.1, sympathetic preganglionic nucleus in thoracolumbar spinal cord), while parasympathetic control travels via the pelvic nerve (S2-4) (Figure 1.1, Gert's nucleus in sacral spinal cord) [4, 5]. The somatic motor neurons control the skeletal muscle of the EUS via the pudendal nerve (S2-4) [4]. Its motor neurons are found in Onuf's nucleus (Figure 1.1, sacral spinal cord). The sympathetic and somatic nervous systems promote storage, while the parasympathetic system promotes emptying.

Figure 1.1 Storage function. a-AR, a adrenergic receptor; ß-AR, ß adrenergic receptor; nAChR, nicotinic acetylcholine receptor.

Source: Beckel and Holstege [4]. Reproduced with permission from Springer.

Afferent mechanisms

The sensation of bladder fullness is carried by two types of afferent fibers via the pelvic, hypogastric, and pudendal nerves. A-delta (Ad) fibers, which are activated at low thresholds, are myelinated large diameter nerves that conduct action potentials quickly [3]. C-fibers are high threshold, unmyelinated nerves that conduct signals more slowly, and usually transmit pain sensations. Normal bladder sensations are carried by Ad fibers, whereas C-fibers become more important in diseased bladders [3]. In humans, C-fibers are found in the urothelial and suburothelial layers, whereas Ad fibers are found in the smooth muscle [6]. A certain population of C-fibers is called silent afferents, because they normally respond to chemical or irritative stimuli. While these stimuli are uncommon in the bladder, chemical irritation can sensitize the bladder, to cause abnormal responses to normal stretch [3]. The transient receptor potential vanilloid type 1 (TRPV1) receptor responds to pain, heat and acidity. Vanilloids, such as resiniferatoxin, desensitize C-fibers and suppress painful sensation [7]. Although initial studies suggested that resiniferatoxin may improve neurogenic DO, it is currently being studied as a treatment for cancer related pain [8], rather than as a treatment of DO.

Although we have long known that acetylcholine (muscarinic agonist) and ATP (purinergic agonist) act via the parasympathetic nervous system to cause bladder contraction, they have been shown to play a role in afferent sensation as well. Muscarinic acetylcholine receptors are found on urothelial cells, suburothelial interstitial cells of Cajal, and on afferent nerves. The urothelium releases acetylcholine and ATP in response to stretch, both of which enhance spontaneous activity in interstitial cells of Cajal, to cause bladder smooth muscle contractions. This enhancement of spontaneous contractions may cause an increase in "afferent noise" that may be interpreted as urgency [9]. In spinalized rats, botulinum toxin lowers ATP release from the urothelium and blocks detrusor contraction [2]. Another mechanism of botulinum toxin's action is by decreasing afferent firing from the bladder [10].

Adjacent pelvic organs such as the colon and uterus can affect urinary continence [2]. This may be due to a common afferent system via the hypogastric nerve, or intermediary neurons allowing for cross talk between pelvic organs [3]. Distension of the colon from constipation is a well-recognized cause of urinary incontinence in children. This is likely due to changes in bladder afferent signaling arising from a chronically distended colon, which prevents the child from recognizing a full bladder [11].

Spinal cord and brainstem

During bladder storage, afferent signals from the hypogastric nerve and pelvic nerve travel to the thoracolumbar and sacral spinal cord, respectively (Figure 1.1). The hypogastric nerve sends signals via the sympathetic nervous system to block bladder contraction and contact the internal urethral sphincter. Onuf's nucleus maintains contraction of the EUS, which is coordinated with bladder storage by the pontine micturition center (PMC) in the medial pons (Figure 1.1, L-region).

Once the bladder pressure threshold is exceeded, afferent signals travel via the pelvic nerve to synapse on interneurons in Gert's nucleus in the S1-2 spinal cord [4] (Figure 1.2). These interneurons send projections up to the periaqueductal gray (PAG) in the midbrain to initiate voiding, which occurs if the cerebral cortex determines that it is appropriate to void. The PAG sends caudal projections to the PMC, which is the final efferent center of the LUT. The PMC sends projections caudally to the sacral parasympathetic nucleus, activating the neurons, which cause bladder contraction and EUS relaxation [4] (Figure 1.2).

Figure 1.2 Emptying function. mAChR, muscarinic acetylcholine receptor.

Source: Beckel and Holstege [4]. Reproduced with permission from Springer.

Although the mechanism of sacral or pudendal neuromodulation remains unclear, the two likely locations would be the peripheral nervous system (including the autonomic nervous system efferents) or the brainstem (PAG and PMC) and cortex [12, 13]. Positron emission tomography imaging shows that sacral neuromodulation restores normal afferent midbrain activity in women with Fowler's syndrome, which is characterized by EUS overactivity. Prior to neuromodulation, they exhibit continuous EUS activity and lack of bladder afferent activity reaching the PAG or PMC. After neuromodulation and reestablishment of normal bladder afferent activity, they regain control of EUS activity [14]. Functional MRI evaluation confirms that neuromodulation reduced deactivation in the PAG, suggesting that exaggerated EUS afferent activity is capable of blocking normal bladder afferent sensation from reaching the cortex [15]. Inhibition of DO is also believed to result from inhibition of abnormal afferent activity. Pudendal nerve neuromodulation represents a more peripheral means to stimulate S2-4 and inhibit the voiding reflex, decreasing uninhibited detrusor contractions and increasing bladder capacity [12].

Cortex

The role of the cerebral cortex in controlling voiding function has recently been described using PET scanning and functional MRI, to...