The central nervous system control of micturition in cats and humans
Bertil F.M. Blok *, Gert Holstege Department of Anatomy and Embryology, Faculty of Medical Sciences, Uni6ersity of Groningen, Oostersingel 69, 9713 EZ Groningen, The Netherlands Abstract Recent ndings concerning the central control of micturition in cats are compared to ndings obtained from dynamic imaging studies in humans. In the cat, three areas in the brainstem and diencephalon are specically implicated in the control of micturition: (1) Barringtons nucleus or the pontine micturition center in the dorsomedial pontine tegmentum directly excites bladder motoneurons and indirectly inhibits, via inhibitory interneurons in the medial sacral cord, urethral sphincter motoneu- rons; (2) the periaqueductal grey receiving bladder lling information; and (3) the pre-optic area of the hypothalamus possibly involved in determining the beginning of micturition. According to PET-scan studies, in humans the same supraspinal regions are active during micturition. In the cat another area, located in the ventrolateral pontine tegmentum and is called the L-region, which controls the motoneurons of the pelvic oor, including the external urethral sphincter. This region might be considered as the pontine storage center. In humans the L-region is especially active in volunteers who tried but did not succeed to micturate. The results suggest that in cats and humans at the brainstem and diencephalic levels micturition is organized in the same way. 1998 Elsevier Science B.V. All rights reserved. Keywords: Pontine micturition center; Periaqueductal grey; Hypothalamus; Urge incontinence 1. Introduction The kidneys produce urine continuously, which, for practical reasons, is rst collected in the bladder where it is stored until disposal is possible. Since the individ- ual animal is relatively vulnerable during the release of urine, micturition only takes place when the environ- ment is relatively safe. Furthermore, in many animals urine is used as a marker for territorial demarcation or sexual attraction (a female lets the males know that she is in estrus by leaving a scent trace). Thus, micturition does not take place at random, but is part of a rather complicated behavior, directly related to the survival of the individual or species. This means that spinal cord micturition control must be under the emotional motor system regulation [5,16]. This paper will discuss the bladder and bladder sphincter regulation by the sacral cord and will give an overview of how the sacral cord centers are regulated by emotional motor system cen- ters in the brainstem, diencephalon and cortex. Micturi- tion depends on the co-ordinated action between the smooth (detrusor) muscle of the bladder and the stri- ated external urethral sphincter (EUS), which closes the bladder. During the storage of urine, the detrusor mus- cle remains relaxed and the EUS is tonically contracted. When micturition takes place, this activation pattern is reversed: the EUS relaxes and the bladder contracts, resulting in the expulsion of urine. The motoneurons of both bladder and EUS are located in the sacral spinal cord. However, the co-ordi- nation between these two motoneuronal cell groups in adult animals seems not to take place in the spinal cord, but in the pontine tegmentum in the brainstem. Interruption of the descending bers from the pons to the sacral cord, e.g. in patients with a transection of the spinal cord, results in dyssynergic micturition. In such patients the contraction of the bladder is accompanied Abbre6iations: PAG, periaqueductal grey; PET, positron emission tomography; PMC, pontine micturition center; rCBF, regional cere- bral blood ow. * Corresponding author. Tel.: +31 50 3632460; fax: +31 50 3632461; e-mail: b.f.m.blok@med.rug.nl 0166-4328/98/$19.00 1998 Elsevier Science B.V. All rights reserved. PII S0166-4328(97)00184-8 B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 120 Fig. 1. Schematic drawing of the location of the nucleus of Onuf in various mammals. Note the motoneurons in the rat innervating the external urethral (U) and anal (A) sphincters are located at different sites in the ventral horn, while they are present in the same nucleus in cat, dog, monkey and man. In the pig the anal sphincter motoneurons are not located in the ventral horn but dorsolateral from the central canal. The species and the spinal segments, in which the nucleus of Onuf is present, are indicated below the drawings. by the simultaneous contraction of the sphincter. This means that, in order to expel urine through the toni- cally closed urethral sphincter, the bladder has to pro- duce an extremely high intravesical pressure. The result is a thick bladder wall and a small bladder capacity, the so-called overow bladder. Patients with brain lesions rostral to the pons never show bladder-sphincter dyssynergia. However, such patients might suffer from urge incontinence, i.e. hyperactivity of the bladder and an inability to delay voiding. Apparently, centres in the pons co-ordinate micturi- tion as such, but centers rostral to the pons determine the beginning of micturition act. 2. Efferent systems 2.1. Micturition motoneurons The smooth detrusor muscle of the bladder is inner- vated by parasympathetic postganglionic bers, of which the ganglion cells are located in the bladder wall. The parasympathetic preganglionic motoneurons reside in the sacral intermediolateral cell group in the sacral cord segments and their axons reach the bladder via the pelvic nerve. In cats the parasympathetic preganglionic motoneurons are located in the S 1 S 3 segments [28], and in humans in S 2 S 4 [25]. The striated EUS forms part of the pelvic oor musculature, and is innervated by the pudendal nerve. In the cat its motoneurons are located in the ventrolat- eral part of the so-called nucleus of Onuf in the ventral horn at the level S 1 S 2 of the spinal cord [36]. The dorsomedial part of Onufs nucleus is occupied by motoneurons innervating the external anal sphincter (EAS). The same situation exists in the dog, monkey and human, where the motoneurons of the anal and urethral sphincters are also located in Onufs nucleus ([24,32,35,40]; Fig. 1). However, in the rat the motoneu- rons of the anal and urethral sphincters are located in two separate nuclei, the dorsolateral and the dorsome- dial nucleus, respectively, at the levels L 5 L 6 [21,27,37]. Remarkably, the motoneurons of the EAS in the do- mestic pig [9] and the Mongolian gerbil [41] are not located in the ventral horn, but in the intermediate zone just dorsolateral to the central canal (Fig. 1). 2.2. Brainstem-spinal cord pathways co-ordinate bladder and sphincter motoneurons In young kittens De Groat et al. [10] demonstrated that the sacral cord in itself is capable of producing a micturition reex, but it needs to be elicited by the mother licking the perineum of the kittens. This behav- ior stops after approximately 4 weeks post partum, after which the supraspinal centers play an essential role. From the work of Barrington [2] it is known that a crucial structure of the micturition reex is located in dorsolateral pontine tegmentum, because bilateral le- sions in this area in the cat results in urinary retention. In the cat two different pontine projection systems have been identied ([17,18]; Fig. 2). A group of neurons in the medial part of the dorsolateral pons projects to the parasympathetic bladder motoneurons in the sacral in- termediolateral cell column. Neurons in the lateral part of the dorsolateral pons specically project to the nu- cleus of Onuf. The medial cell group was called M-re- gion (M=medial), and the lateral cell group L-region (L=lateral). The M-region is also called the pontine micturition center or PMC or Barringtons nucleus. Ultrastructurally, Blok and Holstege [6] have demon- strated that the projection from the PMC to the blad- der parasympathetic motoneurons in the sacral cord is monosynaptic and excitatory. B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 121 Fig. 2. A schematic overview of the spinal and supraspinal structures involved in the efferent control of micturition. The solid lines represent excitatory projections; the dashed line from sacral inhibitory interneurons to the nucleus of Onuf represents an inhibitory pathway. Pathways are indicated on one side only. Abbreviations: BC, brachium conjunctivum; CA, anterior commissure; IC, inferior colliculus; OC, optic chiasm; PON, pontine nuclei; SC, superior colliculus; S2, second sacral segment. In accordance with these ndings, electric and chemi- cal stimulation in the PMC in the cat produces a steep rise in the intravesical pressure [17,26], it also produces an immediate and sharp decrease in the urethral pres- sure and pelvic oor electromyogram. This decrease cannot be caused by a direct PMC projection to the nucleus of Onuf, because such a projection does not exist [17,18], and the PMC does not project to the L-region (Blok and Holstege, unpublished observa- tions). In this respect, the PMC projection to interneu- rons in the sacral intermediomedial cell column [17,26] might play a crucial role. Retrograde tracing studies with the pseudorabies virus have shown that this area contains interneurons projecting to the nucleus of Onuf [30] and electrical stimulation in the intermediomedial cell column results in an inhibition of the EUS via GABAergic interneurons in the IMM (Blok and Hol- stege, unpublished observations). Bilateral lesions in the PMC result in total urinary retention leading to depressed detrusor activity and increased bladder capacity [14,17]. Unilateral chemical lesions of the PMC attenuate the bladder response [26]. Stimulation in the L-region results in strong excitation of the pelvic oor musculature and an increase in the urethral pressure [17]. Bilateral lesions in the L-region give rise to an inability to store urine; bladder capacity is reduced and urine is expelled prematurely by exces- sive detrusor activity accompanied by urethral relax- ation. Outside the episodes of detrusor activity, the urethral pressure is not depressed below normal values B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 122 Fig. 3. Horizontal sections showing brain areas where activity showed a signicant positive correlation with micturition. Functional PET results are displayed at threshold of Z=2.58 (PB0.005), superimposed for anatomical reference, upon a T1-weighted magnetic resonance imaging scan normalized into stereotactic space. Section numbers refer to the coordinates relative to the intercommissural plane. (a) M-region or pontine micturition center; (b) periaqueductal grey; (c) hypothalamus; (d) inferior frontal gyrus; and (e) anterior cingulate gyrus. L, left side; and R, right side of the brain. Fig. 4. Horizontal sections showing brain areas where activity showed a signicant positive correlation with the condition during which the volunteers were trying to micturate, but did not succeed. (a) L-region or pontine storage center; and (b) inferior frontal gyrus. L, left side; R, right side of the brain. [26]. These observations suggest that during the lling phase the L-region has a continuous excitatory effect on the nucleus of Onuf resulting in inhibition of ure- thral relaxation coupled with detrusor contraction. Re- cently, a positron emission tomography (PET) study has provided evidence that there also exists a PMC and a L-region in humans [7]. A group of ten right handed male volunteers were able to micturate during scanning. In this group an increase in regional blood ow during micturition was found in the dorsomedial part of the pons close to the fourth ventricle (Fig. 3). The location of this area in humans is similar to that of the PMC described in the cat. In the same PET study there was a second group of seven right handed volunteers, who were not able to micturate during scanning. In this group there was no activation in the dorsomedial, but in the ventrolateral pons, as predicted on the basis of the location of the L-region in cats (Fig. 4). Apparently, B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 123 the volunteers in this not successful micturition group, probably because of emotional reasons, contracted their urethral sphincter and withheld their urine, al- though they had a full bladder and tried to urinate. 3. Afferent systems 3.1. Peripheral afferent ner6es Most afferent bers from the bladder enter the sacral cord via the pelvic nerve. The peripheral bers of the dorsal root ganglia neurons of the pelvic nerve contact the bladder wall mechanoreceptors. The prox- imal bers enter Lissauers tract and terminate mainly in Rexeds [34] laminae I, V, VII and X of the lum- bosacral spinal cord at segments L 4 S 2 [29] in the cat. The majority of these afferents are thin myelinated and unmyelinated axons, and their conduction veloc- ities are in the Al- and C-ber range, respectively [19]. Most Al-bers originate from slowly adapting mechanoreceptors in the bladder wall, because excita- tion of these bers results in activation of the micturi- tion reex. In all likelihood, the Al-bers are the peripheral afferent bers for this reex [11,26], be- cause the unmyelinated C-bers in the pelvic nerve do not respond to distension and contraction of the uri- nary bladder [20]. 3.2. Spinal cord-brainstem pathways in6ol6ed in the micturition reex Obviously, bladder lling information from sensory neurons in the sacral cord must nally reach the PMC in order to empty the bladder at an appropriate time. However, Blok et al. [8] have demonstrated that the lumbosacral cord does not project strongly to PMC neurons. This raises the question, what other area relays bladder lling information to the PMC. The micturition reex is not abolished by precollicular decerebration [39], which means that lumbosacral pro- jections to forebrain areas, as thalamus and hypotha- lamus, are not essential for this reex. However, the very strong projections from the lumbosacral cord to the lateral and dorsal parts of the mesencephalic peri- aqueductal grey (PAG) probably play a much more important role ([8]; Fig. 5). The lateral PAG is the only caudal brainstem structure known to project spe- cically to the PMC ([4]; Fig. 5). Moreover, stimula- tion of afferent bladder nerves in the rat evokes short latency potentials (1393 ms) in the most caudal PAG, while much longer latency potentials (4297 ms) are found in the PMC [31]. In the cat electrical stimulation of the PAG has been shown to evoke complete micturition ([38]; Blok, personal observa- tion), facilitate bladder reexes, and reduce bladder capacity [22]. The PAG has also been implicated in the control of micturition in humans, because in the previously discussed PET study the regional cerebral blood ow (rCBF) in the PAG was signicantly in- creased during micturition ([7]; Fig. 3). 4. Forebrain involvement in the control of micturition Although, the forebrain is not essential for the ba- sic micturition reex (see previous paragraph), clinical observations suggest that it determines the beginning of micturition [3]. In the cat, stimulation of forebrain structures, such as the anterior cingulate gyrus, pre- optic area of the hypothalamus, amygdala, bed nu- cleus of the strict terminalis and septal nuclei, elicits bladder contractions [12,13]. Although most of these regions send bers to the brainstem [16], only the pre-optic area projects to the PMC [15]. Our PET study suggests that this might also be true in humans, because the hypothalamus, including the pre-optic area, showed an increased rCBF during micturition ([7]; Fig. 3). The direct projection of the pre-optic area to the PMC is the tool needed by the emotional motor system to control the PMC and thus to deter- mine the beginning of micturition. The emotional mo- tor system uses this tool for giving a safe signal to the PMC to start micturition, but also to use micturi- tion for sexual behavior and territorial marking. 5. Cortex The human PET scan results of Blok et al. [7] point to two cortical areas involved in micturition. The right dorsolateral prefrontal cortex is active when mic- turition takes place (Fig. 3), but also when micturition is allowed but does not take place (Fig. 4). The rCBF in the right anterior cingulate gyrus was signicantly decreased during the voluntary withholding of urine. Possibly, activation of the prefrontal cortex and the anterior cingulate gyrus are not specically involved in micturition, but in general mechanisms, such as attention and response selection [33]. Forebrain le- sions including the anterior cingulate gyrus are known to cause urge incontinence [1], which might be due to an attention decit that interferes with the patients ability to recognize a lled bladder. A striking observation of the PET study on mictu- rition of Blok et al. [7] was that the control areas were found predominantly on the right side of the brain and the brainstem (cortex and pons), which cor- responds with studies reporting that urge incontinence is correlated with lesions in the right hemisphere [23]. B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 124 Fig. 5. A schematic overview of the spinal and supraspinal structures involved in the afferent information concerning bladder lling. Pathways are indicated on one side only. For abbreviations see Fig. 2. 6. Conclusions The organization of the central nervous system con- trol of the basic micturition reex is probably the same in humans and cats. Several levels of the central nervous system (CNS) are involved in the control of micturition. Sensory information concerning bladder lling is relayed, via the pelvic nerve and dorsal root ganglion cells, to the sacral cord, where second order sensory neurons are located. These neurons convey the information to the caudal PAG where it is pro- cessed and ltered. When the amount of urine in the bladder makes voiding desirable, PAG neurons acti- vate the premotor interneurons in the M-region, which, via long descending bers to the bladder mo- toneurons in the sacral cord, let micturition take place. The direct projection from the pre-optic area to the M-region may determine the beginning of micturi- tion. References [1] Andrew J, Nathan PW. Lesions of the anterior frontal lobes and disturbances of micturition and defaecation. Brain 1964;87:233 62. [2] Barrington FJF. The effect of lesions of the hind- and mid-brain on micturition in the cat. Q J Exp Physiol Cogn Med 1925;15:81102. [3] Blaivas JG. The neurophysiology of micturition: a clinical study of 550 patients. J Urol 1982;127:95863. [4] Blok BFM, Holstege G. Direct projections from the periaque- ductal grey to the pontine micturition center (M-region). An anterograde and retrograde tracing study in the cat. Neurosci Lett 1994;166:936. B.F.M. Blok, G. Holstege / Beha6ioural Brain Research 92 (1998) 119125 125 [5] Blok BFM, Holstege G. Neuronal control of micturition and its relation to the emotional motor system. Prog Brain Res 1996;107:11326. [6] Blok BFM, Holstege G. Ultrastructural evidence for a direct pathway from the pontine micturition center to the parasympa- thetic preganglionic motoneurons of the bladder of the cat. Neurosci Lett 1997;222:1958. [7] Blok BFM, Willemsen ATM, Holstege G. A PET study on the brain control of micturition in humans. Brain 1997;120:11121. [8] Blok BFM, DeWeerd H, Holstege G. Ultrastructural evidence for the paucity of projections from the lumbosacral cord to the M-region in the cat. A new concept for the organization of the micturition reex with the periaqueductal grey as central relay. J Comp Neurol 1995;359:3009. [9] Blok BFM, Roukema G, Geerdes B, Holstege G. Location of external anal sphincter motoneurons in the sacral cord of the female domestic pig. Neurosci Lett 1996;216:2036. [10] De Groat WC, Nadelhaft I, Milne RJ, Booth AM, Morgan C, Thor K. Organization of the sacral parasympathetic reex path- ways to the urinary bladder and large intestine. J Auton Nerv Syst 1981;3:13560. [11] De Groat WC, Booth AM, Milne RJ, Roppolo JR. Parasympa- thetic preganglionic neurons in the sacral spinal cord. J Auton Nerv Syst 1982;5:2343. [12] Gjone R. Excitatory and inhibitory bladder responses to stimula- tion of limbic, diencephalic and mesencephalic structures in the cat. Acta Physiol Scand 1966;66:91102. [13] Gjone R, Setekleiv J. Excitatory and inhibitory bladder responses to stimulation of the cerebral cortex in the cat. Acta Physiol Scand 1963;59:33749. [14] Grifths D, Holstege G, De Wall H, Dalm E. Control and coordination of bladder and urethral function in the brain stem of the cat. Neurourol Urodyn 1990;9:6382. [15] Holstege G. Some anatomical observations on the projections from the hypothalamus to brainstem and spinal cord: an HRP and autoradiographic tracing study in the cat. J Comp Neurol 1987;260:98126. [16] Holstege G. Descending motor pathways and the spinal motor system: limbic and non-limbic components. Prog Brain Res 1996;107:307421. [17] Holstege G, Grifths D, de Wall H, Dalm E. Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat. J Comp Neurol 1986;250:44961. [18] Holstege G, Kuypers HGJM, Boer RC. Anatomical evidence for direct brain stem projections to the somatic motoneuronal cell groups and autonomic preganglionic cell groups in cat spinal cord. Brain Res 1979;171:32933. [19] Hulsebosch CE, Coggeshall RE. An analysis of the axon popula- tions in the nerves to the pelvic viscera in the rat. J Comp Neurol 1982;211:110. [20] Janig W, Morrison JF. Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Prog Brain Res 1986;67:87114. [21] Jordan CL, Breedlove SM, Arnold AP. Sexual dimorphism and the inuence of neonatal androgen in the dorsolateral motor nucleus of the rat lumbar spinal cord. Brain Res 1982;249:30914. [22] Kruse MN, Noto H, Roppolo JR, De Groat WC. Pontine control of the urinary bladder and external urethral sphincter in the rat. Brain Res 1990;532:18290. [23] Kuroiwa Y, Tohgi H, Ono S, Itoh M. Frequency and urgency of micturition in hemiplegic patients: relationship to hemisphere laterality of lesions. J Neurol 1987;234:1002. [24] Kuzuhara S, Kanazawa I, Nakanishi T. Topographical localiza- tion of the Onufs nuclear neurons innervating the rectal and vesical striated sphincter muscles: a retrograde uorescent double labeling in cat and dog. Neurosci Lett 1980;16:12530. [25] Lue TF, Zeineh SJ, Schmidt RA, Tanagho EA. Neuroanatomy of penile erection: its relevance to iatrogenic impotence. J Urol 1984;131:27380. [26] Mallory BS, Ropollo JR, De Groat WC. Pharmacological mod- ulation of the pontine micturation center. Brain Res 1991;546: 31020. [27] McKenna KE, Nadelhaft I. The organization of the pudendal nerve in the male and female rat. J Comp Neurol 1986;248:53249. [28] Morgan C, Nadelhaft I, De Groat WC. Location of bladder preganglionic neurons within the sacral parasympathetic nucleus of the cat. Neurosci Lett 1979;14:18995. [29] Morgan C, Nadelhaft I, De Groat WC. The distribution of visceral primary afferents from the pelvic nerve to Lissauers tract and the spinal grey matter and its relationship to the sacral parasympa- thetic nucleus. J Comp Neurol 1981;201:41540. [30] Nadelhaft I, Vera PL. Neurons in the rat brain and spinal cord labeled after pseudorabies virus injected into the external urethral sphincter. J Comp Neurol 1996;375:50217. [31] Noto H, Roppolo JR, Steers WD, De Groat WC. Electrophysio- logical analysis of the ascending and descending components of the micturition reex pathway in the rat. Brain Res 1991;549:95 105. [32] Onufrowicz B. Notes on the arrangement and function of the cell groups in the sacral region of the spinal cord. J Nerv Mental Dis 1899;26:498504. [33] Pardo JV, Pardo PJ, Janer KW, Raichle ME. The anterior cingulate cortex mediates processing selection in the Stroop attentional conict paradigm. Proc Natl Acad Sci USA 1990;87:2569. [34] Rexed B. A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol 1954;100:297380. [35] Roppolo JR, Nadelhaft I, De Groat WC. The organization of pudendal motoneurons and primary afferent projections in the spinal cord of the rhesus monkey revealed by horseradish perox- idase. J Comp Neurol 1985;234:47588. [36] Sato M, Mizuno N, Konishi A. Localization of motoneurons innervating perineal muscles: a HRP study in cat. Brain Res 1978;140:14954. [37] Schrder HD. Organization of the motoneurons innervating the pelvic muscles of the rat. J Comp Neurol 1980;192:56787. [38] Skultety FM. Relation of periaqueductal grey matter to stomach and bladder motility. Neurology 1959;9:1907. [39] Tang PC, Ruch TC. Localization of brain stem and diencephalic areas controlling the micturition reex. J Comp Neurol 1956;106:21345. [40] Ueyama T, Mizuno N, Nomura S, Konishi A, Itoh K, Arakawa H. Central distribution of afferent and efferent components of the pudendal nerve in cat. J Comp Neurol 1984;222:3846. [41] Ulibarri C, Popper P, Micevych PE. Motoneurons dorsolateral to the central canal innervate perineal muscles in the Mongolian gerbil. J Comp Neurol 1995;356:22537. .