Functional brain imaging studies have demonstrated that neurological control of the bladder in humans is essentially similar to that demonstrated in experimental animals. A number of positron emission tomography (PET) and, more recently, functional magnetic resonance imaging (fMRI) studies have investigated human control of urinary storage and voiding. The initial PET experiments of Blok and colleagues identified the brain centers activated during attempted micturition (Blok et al., 1997, 1998). In those able to void during the scanning, activity was shown in a region of the medioposterior pons called the M-region. In those subjects unable to void, a distinct region in the ventrolateral pontine tegmentum was activated, the L-region. Although it had been demonstrated in cats that separate pontine nuclei exist for the storage and voiding phases of bladder activity, subsequent experiments have failed to consistently demonstrate activity in this distinct L-region. In the cortex, the PET scans showed significant activity in the right inferior frontal gyrus and the right anterior cingulate gyrus during voiding that was not present during the withholding phase. Nour and associates then corroborated these findings with their own PET study of 12 healthy male volunteers, showing activity in a number of brain areas including the cerebellum (Nour et al., 2000). Other areas that show activation in fMRI during bladder filling include the anterior cingulate gyrus and right insula; fMRI has shown that the medial prefrontal cortex, responsible for complex cognitive and socially appropriate behavior, plays an important role in voiding. A recent article reviews the functional imaging studies evaluating bladder functions and their contributions to our understanding of bladder control (Fowler and Griffiths, 2010).

Bowel and Its Neurological Control

The processing of rectal sensation is relevant in bladder function because unlike other gut organs, it has an important sensory role, and the rectum is a visceral organ that contains both unmyelinated C fibers and thinly myelinated Aδ afferents. In contrast, the anal canal has somatic innervation from the pudendal nerve. The study by Hobday and associates has highlighted the differences in its cortical representation from that of the rectum. The various brain imaging studies of visceral stimulation, including the foregoing report, have been reviewed (Derbyshire, 2003). When different visceral stimuli—esophageal distension, esophageal pain, rectal distension, or the mechanisms operative in irritable bowel syndrome—were analyzed, esophageal stimulation was found to activate the insula most consistently, with other commonly involved areas including somatosensory and motor cortices. Considerable variation was observed in whether the periaqueductal gray was activated or not. Lower GI stimuli predominantly activated the prefrontal and orbitofrontal cortices as well as the insula, with variability in cingulate activation. Overall, esophageal stimulation involved a more central sensory and motor neural circuit, whereas lower GI stimulation activated areas with projections to autonomic and affective control centers such as the brainstem and amygdala.

Sexual Function and Its Neurological Control

Physiological sexual response in men and women has been divided classically into four phases: excitement, plateau, orgasm, and resolution. Excitation occurs in response to either physical or psychological stimulation and results in penile or clitoral tumescence and erection or vaginal lubrication. The plateau phase is accompanied by the various physical changes of high sexual arousal in anticipation of orgasm. Orgasm, an intensely sensory event, usually is associated with rhythmic contraction of the pelvic floor and culminates with ejaculation in men. During resolution, the increased genital blood flow resolves. A modification of this model of sexual response was the three-phase model proposed by Kaplan, consisting of desire, arousal, and orgasm.

Much remains to be discovered about cortical control of sexual function. Although it is thought that cerebral processing determines libido and desire, the ability to effect a sexual response is determined by spinal autonomic reflexes. Libido is hormone dependent with a major hypothalamic component, and loss of libido may be the earliest symptom of a pituitary tumor. In experimental animals, the deep anterior midline structures that form the limbic system have been shown to be important for sexual responses, and the medial preoptic–anterior hypothalamic area has an integrating function (Andersson, 2001). Functional brain imaging experiments including five PET studies and seven fMRI studies have highlighted the key areas of brain activity associated with sexual functioning—for example, the role of the hypothalamus in reproductive function, regulation of human sexuality, and regulation of erection through medial preoptic area, or the roles of the insula and claustrum in autonomic regulation and visceral sensory processing. The aspects of sexual function covered include penile sexual stimulation (Arnow et al., 2002; Georgiadis and Holstege, 2005), male ejaculation (Holstege et al., 2003), and visual sexual stimuli (Karama et al., 2002).

Male Sexual Response

Erection results from increased blood flow into the corpora cavernosa caused by relaxation of the smooth muscle in the cavernosal arteries and a reduction in venous return. The major peripheral innervation determining this is parasympathetic, which arises from the S2-S4 segments and travels to the genital region in the pelvic nerves. Sympathetic input is also important: sympathetic innervation of the genital region originates in the thoracolumbar chain (T11-L2) and travels through the hypogastric nerves to the confluence of nerves that lies on either side of the rectum and the lower urinary tract—the pelvic plexus.

The pelvic plexus also receives input from the pelvic nerves. It is from the pelvic plexus that the cavernous nerves arise and innervate the corpora cavernosa. Although erection is induced by parasympathetic activity, nitric oxide has been identified as important in causing relaxation of the corporeal blood vessels and the increase in penile blood flow that causes erection. Psychogenic erection requires cortical activation of spinal pathways, and the preservation of this type of responsiveness in men with low spinal cord lesions suggests that sympathetic pathways can mediate it. Reflex erections occur as the result of cutaneous genital stimulation. Preservation of reflex erections in men with lesions above T11 indicates that the response is the result of spinal reflexes, with afferent signals conveyed in the pudendal nerve and S2-S4 roots, and efferent signals through the same sacral roots. In health, reflex and psychogenic responses are thought to reinforce one another. In men, orgasm and ejaculation are not the same process; ejaculation is the release of semen, and orgasm consists of the sensory changes accompanied by pelvic floor contractions. Ejaculation involves emission of semen from the vas and seminal vesicles into the posterior urethra and closure of the bladder neck. The latter processes are under sympathetic control, whereas contraction of the pelvic floor muscles is under somatic nerve control, innervation being from the perineal branch of the pudendal nerve. After ejaculation, a period of resolution is necessary before sexual activity can be reinitiated.

Female Sexual Response

The neurological control of sexual function in women is less well understood than that in men, but similarities exist. The main parasympathetic innervation is from the pelvic nerves, sympathetic innervation from the hypogastric nerves, and bilateral somatic innervation from the pudendal nerves. The finding of acetylcholinesterase-positive nerves around blood vessels in the vagina points to parasympathetic control of vaginal vasodilation and secretomotor function. It seems likely that increased vaginal blood flow, erection of the cavernous tissue of the clitoris and around the outer part of the vagina, and lubrication are brought about through neural mechanisms similar to those that control erection in men. The lubrication that occurs as part of sexual arousal results from transudation through the vaginal walls and fluid from Bartholin glands.

During orgasm, a series of synchronous contractions of the sphincter and vaginal muscles may occur. As many as 20 consecutive contractions have been registered, lasting for 10 to 50 seconds. The accompanying sensory experiences generally are described as an intensely pleasurable pelvic event.

Neurogenic Bladder Dysfunction

Lesions of the nervous system, central or peripheral, can result in characteristic patterns of bladder dysfunction depending upon the level of the lesions in the neurological axis (Panicker et al., 2010). The storage function of the bladder is affected following suprapontine or infrapontine/suprasacral lesions. This results in involuntary spontaneous or induced contractions of the detrusor muscle (detrusor overactivity), which can be identified during the filling phase of urodynamics. The voiding function of the bladder can be affected by infrapontine lesions. Following spinal cord damage, there is simultaneous contraction of the external urethral sphincter and detrusor muscle, detrusor-sphincter dyssynergia, which results in incomplete bladder emptying and abnormally high bladder pressures. Following lesions of the conus medullaris or cauda equina, voiding dysfunction can be due to poorly sustained detrusor contractions and possibly non-relaxing urethral sphincters (Table 38.1).

Table 38.1 Diagnostic Findings in Patients with Suspected Neurogenic Bladder Dysfunction

Cortical Lesions

The role of hormonal dysfunction has yet to be fully determined. On the basis of measurements of sex hormones and pituitary function, it has been suggested that the hyposexuality of TLE results from a subclinical hypogonadotropic hypogonadism, and that dysfunction of medial temporal lobe structures may dysmodulate hypothalamopituitary secretion (Murialdo et al., 1995). Erectile dysfunction (ED) with preservation of libido can occur in men with temporal lobe damage with or without epilepsy and may be characterized by loss of nocturnal penile tumescence. Surgery for epilepsy rarely restores erectile function, although a survey of operated patients showed a higher level of satisfaction with sexual function among those who were free of seizures. Sexual dysfunction is common after head injury, particularly in patients who demonstrate cognitive damage. Hypersexual behavior may occur after frontal lobe damage. Lesions of the frontal lobes, the basal-medial part in particular, may lead to loss of social control, which also may affect sexual behavior.

Basal Ganglia Lesions

Bladder Dysfunction

Bladder symptoms in Parkinson disease (PD) correlate with neurological disability (Araki and Kuno, 2000) and stage of disease; both findings appear to support a link between dopaminergic degeneration and symptoms of urinary dysfunction. In line with current thinking about staging of PD in terms of underlying neuropathology (Braak et al., 2004), it appears that bladder dysfunction does not occur until some years after the onset of motor symptoms, and the dysfunction is correlated with the extent of dopamine depletion (Sakakibara et al., 2001b). This means that the underlying pathological process is likely to have extended into the neocortex and explains why the clinical context in which bladder dysfunction is seen in PD is common in patients with cerebral symptoms, as well as with adverse effects of long-standing treatment with dopaminergic agents.

The most frequent complaints are of nighttime frequency, urgency, and difficulty voiding (Sakakibara et al., 2001a), and the most common abnormality in urodynamic studies is detrusor overactivity (Araki et al., 2000). Of the several possible explanations for this finding, the hypothesis most widely accepted is that in healthy persons, the basal ganglia has an inhibitory effect on the micturition reflex, and with neuronal loss in the substantia nigra, detrusor overactivity develops. Studies on anesthetized cats demonstrated that rhythmic bladder contractions were inhibited by intracerebroventricular administration of a dopamine D₁ receptor agonist but were not affected by a D₂ receptor agonist. From this evidence, it was concluded that the D₁ receptor provides the main inhibitory influence on the micturition reflex (Yoshimura et al., 2003). Clinical studies that have looked at the effect of l-dopa or apomorphine on bladder behavior in patients with PD have, however, produced conflicting results. In patients demonstrating the on/off phenomenon, cystometry done after taking l-dopa showed improvement of overactivity in some and worsening in others. The unpredictable effect of antiparkinsonian medications on urinary symptoms has not been definitively shown to correlate with age or stage of disease (Winge and Fowler, 2006). Many patients with PD have nocturnal polyuria as well, which contributes to bladder symptoms and would not be expected to improve with antimuscarinics. In addition to neurogenic bladder dysfunction, benign prostatic obstruction may occur concomitantly in some men with PD and contribute to bladder dysfunction. A recent study suggests that contrary to previous teaching, transurethral prostate resection may be successful in carefully selected PD men and is associated with minimal risk of incontinence (Roth et al., 2009).

In a patient with severe urinary symptoms but mild parkinsonism, a diagnosis of multiple system atrophy (MSA) should be considered. The onset of urogenital symptoms in MSA may precede overt neurological involvement; ED and bladder symptoms begin on average 4 to 5 years before diagnosis and 2 years before more specific neurological symptoms appear. The neuronal degeneration of MSA affects the central nervous system (CNS) at several locations that are important for bladder control, which probably explains why urinary complaints occur so early and are so severe in this condition. It is thought that detrusor overactivity is caused by neuronal loss in the pontine region, whereas incomplete bladder emptying is caused by loss of parasympathetic innervation of the detrusor after neuronal degeneration in the intermediolateral cell columns of the spinal cord. In addition, anterior horn cell loss in the Onuf nucleus results in denervation of the urethral sphincter so that the patient has a combination of detrusor overactivity, incomplete bladder emptying, and a weak sphincter. Bladder dysfunction may change during the progression of MSA, and serial studies have shown that the mean postmicturition residual volume increases as the condition progresses (Ito et al., 2006). Bladder symptoms in other parkinsonian syndromes are less prominent than in MSA, and although they may occur as part of the patient’s general disability, they rarely are as severe as in MSA and do not occur at a stage of the disease when a neurological cause is not evident.

Bowel Dysfunction

Constipation is now thought to be a preclinical manifestation of PD, and a symptom questionnaire showed that this was considered to be the most bothersome nonmotor symptom for PD patients (Sakakibara et al., 2001a). Several possible causes for constipation are recognized: a slow colonic transit time has been demonstrated in a number of studies; this finding may be secondary to a reduction in dopaminergic myenteric neurons. An abnormality of the defecation process has also been demonstrated in some patients with PD, with paradoxical contraction of the external anal sphincter and pubococcygeus causing outlet obstruction. This phenomenon can result in anismus and is thought to be a form of focal dystonia. Bowel dysfunction appears earlier and progresses faster in patients with MSA than in those with PD (Stocchi et al., 2000).

Sexual Dysfunction

Experimental evidence from animals and humans shows that dopaminergic mechanisms are involved in determining libido and inducing penile erection. In animal studies, the medial preoptic area of the hypothalamus has been shown to regulate sexual drive, and selective stimulation of dopamine D₂ receptors in this region increases sexual activity in rats (Andersson, 2001). An increase in libido in some patients with PD treated with dopamine agonists and l-dopa as part of the “hedonistic homeostatic dysregulation” syndrome (Giovannoni et al., 2000) is a well-recognized phenomenon, although its incidence is uncertain. The cause of ED in PD is unclear, but it is a significant problem and in one study was shown to affect 60% of a group of men with PD, compared with 37.5% of age-matched healthy men. ED usually affects men later in the course of PD, with onset years after the diagnosis of neurological disease has been established. A survey of relatively young patients with PD (mean age, 49.6 years) and their partners revealed a high level of sexual dysfunction, with the most severely affected couples being those in which the patient was male.

ED may be the first symptom in men with MSA, predating the onset of any other neurological symptoms by several years. The disorder appears to be chronologically distinct from the development of postural hypotension. The reason for the apparently early selective involvement of neural mechanisms for erection is not known. Preserved erectile function in a man with parkinsonism strongly contradicts the diagnosis of MSA. The available literature on female sexual problems in movement disorders is limited (Jacobs et al., 2000; Oertel et al., 2003).

Brainstem Lesions

Voiding difficulty is a rare but recognized symptom of a posterior fossa tumor and has been reported in series of patients with brainstem disorders (Fowler, 1999). In an analysis of urinary symptoms of 39 patients who had had brainstem strokes, lesions that resulted in micturition disturbance usually were dorsally situated (Sakakibara et al., 1996)—a finding consistent with the known location of the brainstem centers involved in bladder control. The proximity in the dorsal pons between the pontine micturition center and medial longitudinal fasciculus means that a disorder of eye movements, such as an internuclear ophthalmoplegia (INO), is highly likely in patients with a pontine disorder causing a voiding difficulty.