THE JOURNAL OF COMPARATIVE NEUROLOGY 493:15–20 (2005)

Micturition and the Soul GERT HOLSTEGE* Department of Anatomy and Embryology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands

ABSTRACT There is a close connection between micturition and emotion. Several species use micturition to signal important messages as territorial demarcation and sexual attraction. For this reason, micturition is coordinated not in the spinal cord but in the brainstem, where it is closely connected with the limbic system. In cat, bladder afferents terminate in a cell group in the lateral dorsal horn and lateral part of the intermediate zone. Neurons in this cell group project to supraspinal levels, not to the thalamus but to the central periaqueductal gray (PAG). Neurons in the lateral PAG, not receiving direct sacral cord afferents, project to the pontine micturition center (PMC). The PMC projects directly to the parasympathetic bladder motoneurons and to sacral GABA-ergic and glycinergic premotor interneurons that inhibit motoneurons in Onuf’s nucleus innervating the external striated bladder sphincter. Thus, PMC stimulation causes bladder contraction and bladder sphincter relaxation, i.e., complete micturition. Other than the PAG, only the preoptic area and a cell group in the caudal hypothalamus project directly to the PMC. The ventromedial upper medullary tegmentum also sends projections to the PMC, but they are diffuse and also involve structures that adjoin the PMC. Neuroimaging studies in humans suggest that the systems controlling micturition in cat and human are very similar. It seems that the many structures in the brain that are known to influence micturition use the PAG as relay to the PMC. This basic organization has to be kept in mind in the fight against overactive bladder (OAB) and urge-incontinence. J. Comp. Neurol. 493:15–20, 2005. © 2005 Wiley-Liss, Inc. Indexing terms: urge-incontinence; overactive bladder; pontine micturition center; periaqueductal gray; nucleus of Onuf

What is the relation between micturition and the soul? The main function of micturition is to empty the bladder, thus to dispose of urine, a fluid that contains waste substances. In humans, the urine, once it is outside the body, does not play a role. A completely different situation exists in most other mammals, in which olfaction plays a much more important role in the context of the survival of the individual and of the species. Urine not only serves to dispose of waste substances from the body but it signals important messages such as the demarcation of territory of a specific individual or the fact that a female is in estrous, i.e., signals to males that mating is possible. These functions of urine also mean that micturition takes place not only to empty the bladder when it is full but also in the context of other survival mechanisms. Hence, micturition control in the central nervous system takes place not in the spinal cord but at supraspinal levels, with substantial input from areas involved in sexual behavior. Although in humans micturition does not play a role in territorial demarcation or sexuality, it is still controlled by supraspinal regions, which, in turn, are heavily influenced by those regions that take part in the other aspects of © 2005 WILEY-LISS, INC.

survival discussed in this special issue on the “Anatomy of the soul.” The fact that the brain and brainstem are so important in micturition control is also reflected in one of the great problems of modern society, overactive bladder (OAB) and urge-incontinence. OAB is a brain disease caused by lesions in those areas that influence the micturition control center in the pons, the pontine micturition center. Such lesions occur so frequently that OAB affects more than 16.6% of all men and women over 40 years of age. OAB is defined by three main symptoms: frequency, urgency, and urge-incontinence. Patients need to urinate with great frequency, often enough that work, socializing, and relationships all suffer. They may not get enough

*Correspondence to: Gert Holstege, Department of Anatomy and Embryology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: [email protected] Received 1 June 2005; Revised 1 August 2005; Accepted 10 August 2005 DOI 10.1002/cne.20785 Published online in Wiley InterScience (www.interscience.wiley.com).

16 sleep, as they wake up several times a night to empty their bladders. Urgency occurs because the detrusor muscle contracts suddenly, leaving OAB patients with little time to reach a bathroom. These sudden contractions can also cause urge-incontinence, where the bladder suddenly voids, often completely. Fear that this will happen in public leaves many OAB sufferers housebound. In the United States alone, the costs of OAB in the year 2000 amounted $12.6 billion and of urge-incontinence $19.5 billion, together more than $32 billion (Hu et al., 2004). In this paper wel give an overview of the brain organization of micturition and put forward the concept that OAB and urge-incontinence are the result of lack of inhibition of the central micturition control centers by forebrain systems that control basic survival mechanisms.

MOTONEURONS INNERVATING BLADDER AND BLADDER SPHINCTER Micturition is a combination of contraction of the detrusor muscle of the bladder and relaxation of the bladder sphincter. The bladder is innervated by parasympathetic preganglionic motoneurons, in humans located in sacral segments S2 and S3. These motoneurons send their fibers to the bladder via the pelvic nerve, where they contact the postganglionic motoneurons located in the bladder wall. Parasympathetic motoneurons belong to the so-called autonomic nervous system, which means that it is not possible to excite them voluntarily, for example, by way of the corticospinal tract. This is not so for the external sphincter of the bladder, which consists of striated muscles and is innervated by somatic motoneurons. These motoneurons are located in the ventrolateral part of the nucleus of Onuf (ON), also located in the upper sacral cord. The external striated bladder sphincter is a peculiar muscle, because on the one hand it can be contracted voluntarily, but on the other hand it must be precisely coordinated with bladder activity, which is a function of the autonomic motor system. Thus, for micturition to occur, a system is needed involving control of the somatic bladder sphincter motoneurons in ON as well as the parasympathetic bladder motoneurons in the sacral intermediolateral cell group. For this reason, the ON motoneurons innervating the external bladder sphincter occupy a position different from that of the other somatic motoneurons in the spinal cord, innervating, for example, neck, back, trunk, or limb muscles. In fact, although external bladder sphincter motoneurons in ON directly innervate the striated sphincter muscles and are under voluntary control of the motor cortex, albeit not directly (Iwatsubo et al., 1990), they also behave as autonomic motoneurons. For example, ON motoneurons are smaller than most other somatic motoneurons. They do not degenerate in patients suffering from amyotrophic lateral sclerosis (ALS), a fatal illness destroying all somatic motoneurons (Mannen et al., 1977), but do degenerate in patients suffering from Shy-Dra¨ger disease, which affects autonomic motoneurons (Mannen et al., 1982; Chalmers and Swash, 1987). Moreover, brain regions that specifically control autonomic motoneurons in general, such as the paraventricular hypothalamic nucleus, also project to ON (Holstege, 1987). Thus, ON motoneurons occupy a position between somatic and autonomic motoneurons. Sympathetic preganglionic motoneurons, located in the intermediolateral cell group of the upper lumbar cord

G. HOLSTEGE (L1–L4), also innervate the bladder. Their fibers run via the pelvic and hypogastric nerves to have direct access to the bladder or indirectly via connections with the paravesical ganglia of the parasympathetic system. Sympathetic fibers have inhibitory effects on the detrusor muscle and excitatory effects on the smooth musculature of the urethra and base of the bladder, perhaps via suppression of transmission between parasympathetic preganglionic and postganglionic neurons within the pelvic ganglia. The sympathetic bladder innervation is thought to allow bladder filling without causing reflexive contractions (for review see deGroat et al., 1999).

SPINAL PREMOTOR INTERNEURONS FOR BLADDER AND BLADDER SPHINCTER MOTONEURONS The parasympathetic bladder motoneurons are located in the sacral intermediolateral cell group (sacral IML) and the external bladder sphincter motoneurons in ON. Although the locations of these cells are in different regions of the sacral cord, their premotor interneurons are located in the same region, the so-called intermediomedial cell group (IMM), medial to the intermediolateral cell group in the sacral cord. The sacral IMM contains, among other cells, GABA-ergic and glycinergic neurons (Blok et al., 1997a; Sie et al., 2001), many of which innervate the ON motoneurons (Nadelhaft and Vera, 1996). There are no reports about the existence of other interneurons in the spinal cord that contact bladder or sphincter motoneurons. Although one would expect that the neurons in the sacral IMM can produce complete micturition by exciting the bladder motoneurons in IML and inhibiting the sphincter motoneurons in ON, they cannot. In cat, transection of the spinal cord results in dyssynergic micturition; i.e. when the bladder contracts, the sphincter contracts also, not allowing normal emptying of the bladder. A similar situation exists in patients suffering from a transection of the spinal cord. Such patients initially suffer urinary retention, so that artificial catheterization of the bladder is necessary. Ultimately this gives way to a spastic bladder that does not empty completely, and urinary tract morbidity ranks as the second leading cause of death in spinal cord-injured patients (Siroky, 2002). These observations indicate that supraspinal structures play a crucial role in normal micturition.

SUPRASPINAL CONTROL OF BLADDER AND BLADDER SPHINCTER MOTONEURONS Those supraspinal regions that contact all autonomic (sympathetic and parasympathetic) and somatic motoneurons in caudal brainstem and spinal cord also project to the bladder motoneurons and ON. Examples are the A11 dopaminergic cell group at the transition between mesand diencephalon, the noradrenergic neurons in the locus coeruleus and subcoeruleus, and the serotonergic and many other neurons in the ventromedial tegmentum of caudal pons and medulla, including the raphe nuclei (for review see Holstege, 1991). These projections seem to involve ON more than the other somatic motoneurons at sacral levels. As mentioned above, the hypothalamic paraventricular nucleus, which projects to all spinal autonomic

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preganglionic motoneurons (sympathetic and parasympathetic), also projects to ON motoneurons, which points to the strong relationship between ON and the autonomic motoneurons. The degree to which each of these descending systems plays a role in micturition control remains to be determined, but, because of their diffuse effects on all spinal neurons, it is unlikely that they will have a specific effect on micturition.

PONTINE MICTURITION CENTER There is one distinct cell group in the brainstem that specially controls the bladder motoneurons. This cell group is located in the dorsolateral pontine tegmentum, just ventral to the mesencephalic trigeminal tract and locus cueruleus and is called the pontine micturition center (PMC), M (⫽medial) region (Holstege et al., 1986), or Barrington’s nucleus, after Barrington’s 1925 description of a micturition control region in this area in the cat. Since 1979, tract tracing studies at the light and ultrastructural levels and electrophysiological studies in the cat (Holstege et al., 1979, 1986; Blok and Holstege, 1997; Sasaki, 2005; fig. 1) have revealed that neurons in the PMC indeed send direct excitatory projections to the bladder motoneurons in the sacral cord. These PMC fibers travel in the lateral and dorsolateral funiculus throughout the length of the spinal cord to terminate on the bladder motoneurons in the sacral IML as well as on neurons in the sacral IMM. In cat, bilateral lesions of the PMC were needed to cause complete retention for urine (Griffiths et al., 1990), but Komiyama et al. (1998) reported that a distinct lesion in only the right PMC in a 30-year-old man caused complete retention for 7 days. These observations indicate that the strong relationship between the PMC and micturition may become lateralized in humans. The neuroimaging study of Blok et al. (1997b, 1998b), who found activation of the PMC during micturition only on the right side, support this idea. Electrical stimulation of the PMC revealed that there is a direct connection between PMC stimulation and bladder contraction (Holstege et al., 1986). The immediate effect of PMC stimulation is an inhibition of the bladder sphincter, although there was no direct connection between PMC and ON motoneurons. Later studies revealed that this ON inhibition, resulting in bladder sphincter relaxation, is the result of PMC projections to GABA-ergic (Blok et al., 1997a) and glycinergic (Sie et al., 2001) interneurons in the sacral IMM that, in turn, have an inhibitory effect on ON motoneurons (Blok et al., 1998a). Thus, PMC neurons directly excite the parasympathetic preganglionic bladder motoneurons as well as the GABAergic and glycinergic interneurons that inhibit ON motoneurons, leading to bladder contraction and sphincter relaxation. The degree to which the PMC also plays a role in defecation remains to be determined.

OTHER SPECIFIC PROJECTIONS TO ON MOTONEURONS Urethral and anal sphincters not only are important for micturition and defecation but also form the floor of the pelvic cavity, together with some other muscles innervated by ON motoneurons. The so-called nucleus retroambiguus in the caudal medulla (Holstege and Tan, 1987) is

Fig. 1. Schematic overview of the micturition pathways in the cat, with the ascending and descending components. BC, brachium coniunctivum; CA, anterior commissure; CGL, corpus geniculatum laterale; F, fornix; IC, inferior colliculus; OC, optic chiasm; OT, optic tract; PC, pedunculus cerebri; PON, pontine nuclei; SC, superior colliculus.

involved in regulating muscles of the abdominal wall that control intraabdominal pressure, and its projections to ON probably play a role in this function. This retroambiguus-ON pathway, therefore, might play a role in stress incontinence, in which weakness of the bladder sphincter allows urine to be expelled during increased abdominal pressure because of physical exercise. It is doubtful, however, that the retroambiguus-ON pathway plays a role in the supraspinal control of micturition. Another specific projection to ON motoneurons originates from a cell group in the lateral part of the pontine tegmentum, which projects directly to ON motoneurons. This cell group is called the L (⫽lateral) region by Holstege et al. (1986) to differentiate it from the M region or PMC. Griffiths et al. (1990) have put forward the concept that the L region plays a role in keeping the sphincters closed continuously and introduced the term “continence center.” Their main argument was that bilateral lesions in the L region in the cat resulted in an extreme form of

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incontinence. Blok and Holstege (1999) were not able to demonstrate a direct connection between the L region and M region or PMC. The precise function of the L region, therefore, remains to be elucidated, and a role in fecal continence cannot be excluded.

HOW DO BLADDER AFFERENTS REACH THE BRAIN? Because the brainstem plays such a crucial role in micturition control, it needs very precise and continuous information about the amount of urine in the bladder. For this reason, afferent A␦ fibers from mechanoreceptors in the bladder wall reach the spinal cord via the pelvic nerve to terminate in a region just lateral to or in the lateral dorsal horn (Morgan et al., 1981; DeGroat et al., 1982). This region contains not only a great number of dendrites of the parasympathetic bladder motoneurons but also neurons that project to the mesencephalic periaqueductal gray (PAG; Blok et al., 1995; VanderHorst et al., 1996; Mouton and Holstege, 2000). In cat, no fibers from this lateral sacral cell group terminate in the PMC itself (Blok et al. 1995). Of all spinal projections to the PAG, the sacral cord projection is the strongest, with the exception of the upper cervical cord (Mouton and Holstege, 2000). In agreement with these results, in studies on humans using positron emission tomography (PET; Athwal et al., 2001; Matsuura et al., 2002) or fMRI (Griffiths et al., 2005), saline infusion in the bladder produced activation in the PAG. It cannot be ruled out that this projection from the lateral sacral cell group to the PAG also plays a role in the relay of information from the genitals in the framework of sexual function. Remarkably, this lateral sacral cell group does not project to the thalamus (Klop et al., 2005), which probably means that the information it relays does not reach consciousness directly. On the other hand, in all likelihood, there are relays between the PAG and the thalamus that provide information on bladder filling to the forebrain. In conclusion, the PAG receives a continuous stream of afferent information from the bladder. This stream is not interrupted in most people suffering from OAB or urgeincontinence, because their pelvic nerves, spinal cord, and brainstem are intact. Therefore, it is unlikely that OAB patients have a problem with the stream of information from the bladder to the brain. According to the concept of the current author, it is the inadequate communication between the forebrain and the brainstem that accounts for the “lack of warning” that OAB patients report. Whether influencing this afferent bladder information, as is done by sacral nerve stimulation, is the best way of treating OAB patients remains to be determined.

THE FUNCTION OF THE PAG IN MICTURITION As has been shown in the study of Holstege et al. (1986), there is a direct relationship between the PMC activation and micturition. Stimulation of the PMC results in micturition, and micturition does not take place when the PMC is not stimulated by other brain structures or artificially. A very important question, therefore, is what controls the PMC. As shown by Holstege and coworkers, the

PMC does not receive direct projections from the sacral spinal cord but is the target of very strong projections from the PAG (Blok et al., 1994, 1995; Kuipers et al., 2005). Indeed, the PAG plays a crucial part in the micturition reflex, even in humans, as shown by Yaguchi et al. (2004), who reported that a small lesion in the right PAG in a 31-year-old man caused acute urinary retention. It is important that, within the PAG, the central area that receives direct sacral cord projections differs from the more laterally located PAG area with cells that send projections to the PMC (see also Taniguchi et al., 2002). Thus, within the PAG, the bladder information is first processed before it is relayed to the PMC-projecting cells. We put forward the concept that, because of this processing, a great many other brain structures can influence the sacral cord-PAGPMC micturition system. In simple terms, the bladder, via the lateral cell group in the sacral cord, sends a continuous stream of information about bladder filling to the PAG, where it is decided whether the amount of urine in the bladder is such that PMC-projecting cells in the PAG will be activated. This decision, however, is influenced not only by the amount of bladder filling but also by the many other brain regions that have direct access to the PAG. Examples are the lateral, caudal, and anterior parts of the hypothalamus; the preoptic region (medial and lateral); the central nucleus of the amygdala; the bed nucleus of the stria terminalis; and large portions of the prefrontal cortex (Andrew and Nathan, 1964). All these brain regions take part in or are related to the limbic system and continuously verify whether the safety of the environment is such that micturition can take place. If safety is not guaranteed, these limbic structures will prevent the PAG from exciting the PMC neurons, even when other parts of the PAG receive a strong message from the sacral cord that the bladder is full and has to be emptied as soon as possible. The resolution of this simple conflict between cognitive-social-emotional intent and basic bodily needs lies at the core of the problem of the “soul,” and it is in simple circuitry such as exists at the level of the PAGPMC that the final behavioral pattern is resolved. Humans place remarkable social importance on this outcome, as judged by the acute embarrassment associated with wetting one’s pants when excited or frightened, from childhood onward. This social ostracism is also at the core of the discomfiture of OAB patients who lose the ability to maintain this control.

OTHER AFFERENTS TO THE PMC A recent study by Kuipers et al. (2005) shows that direct afferents to the PMC other than from the PAG are relatively scarce. Such afferents originate in the preoptic region (see also Holstege, 1987) and the caudal hypothalamus. The medial preoptic region is known for its role in sexual behavior, and one might speculate that its projection to PMC prevents micturition during sexual activity. Alternatively, in species for which pheromones play a prominent role in sexual communication, micturition may become an integral part of mate attraction. Similarly, the ventrolateral preoptic nucleus is involved in sleep control, and its projection to the PMC might suppress micturition during sleep. From the caudal brainstem, only the ventromedial caudal pontine and medullary tegmentum was found to project diffusely to the PMC as well as to its adjoining regions, similar to its diffuse

MICTURITION AND THE SOUL projections to brainstem and spinal cord (Kuipers et al., 2005). Neuroimaging studies strongly suggest that the central nervous system control of micturition in humans may be lateralized (i.e., the right side of the brain may have assumed more importance for this function than the left) but otherwise is not different from that in cat (Blok et al., 1997, 1998; Nour et al., 2000; see also Kavia and Fowler, 2005), which further emphasizes the importance of the results obtained in cats.

HOW DOES THE BRAIN CONTROL MICTURITION? As shown above, brain regions that are involved in micturition control need access to the PMC. Although there are some hypothalamic and preoptic regions that project directly to the PMC, it seems likely that the PAG is the major control center. It receives direct afferents from those neurons in the sacral cord that in turn receive bladder afferents. The PAG also receives a great many afferents from other brain regions, such as the amygdala, the bed nucleus of the stria terminalis, and various parts of the hypothalamus (for review see Holstege, 1991), but very dense projections also originate from the orbital and medial prefrontal cortex (Price, 1999; Kuipers et al., 2005; see also Price, 2005). Although none of these structures has direct access to the PMC, it is clear that they probably project to those cells in the PAG that in turn control the PMC. In a recent paper by Griffiths et al. (2005), it has been shown that the orbitofrontal cortex was strongly activated in human subjects with good bladder control after infusion of large volumes of saline into the bladder. However, the orbitofrontal cortex was only weakly activated in humans with poor bladder control, such as patients suffering from OAB and urge-incontinence. In these patients, exaggerated responses were found in several other parts of the cortex, possibly because of their anxiety over involuntarily starting micturition as a consequence of urgeincontinence.

CONCLUSIONS Micturition is controlled by a spinal-brainstem-spinal system, in which bladder filling information is conveyed to neurons in the lateral sacral cord, which in turn relay this information to the central parts of the PAG. Other cell groups in the dorsomedial, and especially the lateral, PAG activate the PMC when it is necessary to start micturition. The decision to initiate micturition is made in the PAG, based on afferent information from the sacral cord and from brain structures belonging to or associated with the limbic system and prefrontal cortex. In simple terms, although the PAG is continuously informed about the amount of bladder filling,its decision to initiate micturition is strongly influenced by the limbic system and prefrontal cortex that continuously evaluate the safety of the environment. This is important, because the act of micturition as such is a risky situation in animals, insofar as immediate fight or flight is not possible, and in humans, because, at least in the Western world, micturition in view of other people is not socially acceptable. In healthy people, these signals from the limbic system and prefrontal cortex are very powerful, but, in OAB patients, for reasons

19 that may differ from patient to patient (Griffiths et al., 2005; see also Kavia and Fowler, 2005), these signals are weak. In such patients, the strength of the “safety signals” might be so low that the spinal-brainstem-spinal micturition pathway acts more or less independently of the social environment, with feelings of urge and later urgeincontinence as a consequence. This concept also explains why reducing bladder activity with antimuscarinic drugs, at present the only drugs available to treat OAB and urge-incontinence, does not alleviate the symptoms in the long run. The same is true for interfering with the stream of afferent bladder information by means of stimulation of the pelvic nerve, because the afferent information from the bladder is not abnormal, and the bladder is not overactive by itself; rether, the overactivity is caused by lack of inhibition of the PAG-PMC pathway. Many elderly people suffer from diverse and often small lesions in the various limbic structures or their descending limbic pathways to the PAG, preventing the usual inhibitory “safety” signals from reaching the PAG properly. Thus, the problem in OAB or urge-incontinence is at the level of the PAG or PMC and their connections, and possible treatments for this condition should target the micturition pathways at that level.

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G. HOLSTEGE Mannen T, Iwata M, Toyokura Y, Nagashima K. 1982. The Onuf’s nucleus and the external anal sphincter muscles in amyotrophic lateral sclerosis and Shy-Drager Syndrome. Acta Neurophathol 58:255–260. Matsuura S, Kakizaki H, Mitsui T, Shiga T, Tamaki N, Koyanagi T. 2002. Human brain regions response to distention or cold stimulation of the bladder: a positron emission tomography study. J Urol 168:2035–2039. Morgan C, Nadelhaft I, De Groat WC. 1981. The distribution of visceral primary afferents from the pelvic nerve to Lissauer’s tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus. J Comp Neurol 201:415– 440. Mouton LJ, Holstege G. 2000. The segmental and laminar origin of the spinal neurons projecting to the periaqueductal gray (PAG) in the cat suggests the existence of at least five separate spino-PAG systems. J Comp Neurol 428:389 – 410. Nadelhaft I, Vera PL. 1996. Neurons in the rat brain and spinal cord labeled after pseudorabies virus injected into the external urethral sphincter. J Comp Neurol 376:502–517. Nour S, Svarer C, Kristensen JK, Paulson OB, Law I. 2000. Cerebral activation during micturition in normal men. Brain 123:781–789. Price JL. 1999. Prefrontal cortical networks related to visceral function and mood. Ann N Y Acad Sci 877:383–396. Sasaki M. 2005. The role of Barrington’s nucleus in micturition. J Comp Neurol (this issue). Sie JA, Blok BF, de Weerd H, Holstege G. 2001. Ultrastructural evidence for direct projections from the pontine micturition center to glycineimmunoreactive neurons in the sacral dorsal gray commissure in the cat. J Comp Neurol 429:631– 637. Siroky MB. 2002. Pathogenesis of bacteriuria and infection in the spinal cord injured patient. Am J Med 113(Suppl 1A):67S–79S. Taniguchi N, Miyata M, Yachiku S, Kaneko S, Yamaguchi S, Numata A. 2002. A study of micturition inducing sites in the periaqueductal gray of the mesencephalon. J Urol 168:1626 –1631. VanderHorst VGJM, Mouton LJ, Blok BFM, Holstege G. 1996. Somatotopical organization of input from the lumbosacral cord to the periaqueductal gray in the cat; possible implications for aggressive and defensive behavior, micturition, and lordosis J Comp Neurol 376:361– 385. Yaguchi H, Soma H, Miyazaki Y, Tashiro J, Yabe I, Kikuchi S, Sasaki H, Kakizaki H, Moriwaka F, Tashiro K. 2004. A case of acute urinary retention caused by periaqueductal grey lesion. J Neurol Neurosurg Psychiatry 75:1202–1203.

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