The central control of micturition and continence: implications for urology

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1 BJU International (1999), 83, Suppl. 2, 1 6 The central control of micturition and continence: implications for urology B.F.M. BLOK and G. HOLSTEGE Department of Anatomy and Embryology, Faculty of Medical Sciences, University of Groningen, Groningen, The Netherlands Keywords Pontine micturition centre, overactive bladder, Barrington s area, pontine storage centre, urethral sphincter, bladder Introduction Micturition and continence are independently Bladder control problems in the elderly is a major organized in the brain problem; #30% of the population older than 60 years Micturition depends on a coordinated action between and more than half of those resident in a nursing home the smooth muscle of the bladder (the detrusor) and the sucer from bladder control problems, in particular over- striated external urethral sphincter (EUS). During the active bladder [1]. The costs related to urinary incontinence storage of urine, the bladder muscle remains relaxed and in 1995 were estimated to be US$26.3 billion or the EUS is tonically contracted. When micturition takes US$3565 per patient [2]. Although it is well known that place, this activation pattern is reversed; the EUS relaxes the brain plays a crucial role in the control of micturition and the bladder contracts, resulting in the expulsion of and urinary continence (see [3]), until recently the urine. Motoneurones of both bladder and EUS are located location of the structures involved was unknown. This in the sacral spinal cord. However, the coordination is surprising, as a large proportion of bladder control between these two motoneuronal cell groups in adult problems in the elderly is probably related to a dysfunc- animals and humans does not to take place in the spinal tion of the brain [4]. To identify the specific brain cord, but in the pons of the caudal brainstem. structures involved in micturition it is important to Interruption of the descending fibres from the pons to emphasize its importance for survival. the sacral cord, e.g. in patients with a transection of the The kidneys continuously produce urine which is spinal cord, results in dyssynergic micturition. In such collected in the urinary bladder and stored until disposal patients the contraction of the bladder is accompanied is possible at the appropriate place and time. As an by simultaneous contraction of the sphincter. Patients individual is vulnerable during voiding, micturition only with brain lesions rostral to the pons never show bladder- takes place when the environment is relatively safe. In sphincter dyssynergia [4]. However, such patients might many animals urine is important for territorial demarcation sucer from bladder overactivity and/or an inability to or sexual signalling. Urine odour from neonatal delay voiding. rats stimulates the mother to lick their perineum and Apparently, centres in the pons coordinate micturition thus initiate micturition; isolated neonatal rats die as such, but centres rostral to the pons determine the because they cannot empty their bladders. Thus, micturition beginning of micturition. Recent experiments in the cat does not take place at random, but is part of a have provided evidence that the pontine micturition complex behaviour, directly related to the survival of the centre (PMC) and the pontine storage centre (PSC) are individual or species. This means that micturition must not interconnected at the level of the brainstem [6]. be under close regulation by brain structures important Therefore, the central control of micturition and urinary for survival. These structures belong to the so-called continence will be discussed separately. emotional motor system [5]. The regulation of the urinary bladder and the external urethral sphincter by the caudal spinal cord and the caudal brainstem will be The micturition circuit discussed, and an overview given of how these sacral The smooth detrusor muscle of the bladder is innervated cord and brainstem centres are controlled by structures by parasympathetic postganglionic fibers, of which the in the diencephalon and cerebral cortex belonging to the ganglion cells are located in the bladder wall (Fig. 1). emotional motor system. The parasympathetic preganglionic motoneurones reside in the sacral intermediolateral cell group in the sacral cord segments and their axons reach the bladder via the 1999 BJU International 1

2 2 B.F.M. BLOK and G. HOLSTEGE Micturition pathways ( ) IC Micturition centre GABA-ergic neurones Bladder motoneurones S2 Bladder Urethral sphincter motoneurones [12]. Electrical and chemical stimulation in the PMC in the cat produces a steep rise in the intravesical pressure, and an immediate and sharp decrease in the urethral pressure and pelvic floor electromyogram [12,13]. The increase in bladder pressure is caused by the monosynaptic and excitatory PMC projection to bladder motoneurones [14]. The relaxation of the EUS during micturition is caused by the excitatory PMC projection to GABA-ergic interneurones in the DGC in the spinal cord [15]. This is corroborated by the observation that electrical stimulation of the sacral DGC results in a sharp decrease in the intraurethral pressure [16]. Bilateral lesions in the PMC result in total urinary retention, leading to depressed detrusor activity and increased bladder capacity [17]. Unilateral chemical lesions of the PMC attenuate the bladder response [13]. Recent positron emission tomography (PET) studies provided evidence that there is also a PMC in humans [18,19]. In men and women who were able to micturate during scanning, there was an increase in regional blood flow in the dorsomedial part of the pons close to the fourth ventricle (Fig. 2). The location of this area in humans is similar to that of the PMC described in the cat. The information on bladder filling from sensory neurones in the lumbosacral cord must finally reach ( ) Urethral sphincter relaxation Fig. 1. Schematic diagram of the spinal and supraspinal structures and their pathways involved in micturition. Pathways are indicated on one side only. IC, inferior colliculus; S2, second sacral segment. pelvic nerve. In cats, the parasympathetic preganglionic motoneurones are located in the S1-S3 segments [7] and in humans, in S2 S4 [8]. The striated EUS forms part of the pelvic floor musculature and is innervated by the pudendal nerve. In the cat and human its motoneurones are located in the so-called nucleus of Onuf in the ventral horn at the level S1 S2 of the spinal cord [9,10]. Since the work of Barrington [11] it has been known that a crucial structure of the micturition reflex is located in the dorsolateral pontine tegmentum, because bilateral lesions in this area in the cat result in urinary retention. This area is known as the PMC, Barrington s nucleus or M-region. The PMC is located in the medial part of the dorsolateral pons, and projects to the sacral intermediolateral cell column and to the sacral intermediomedial cell column or dorsal grey commissure (DGC) Fig. 2. A horizontal PET section showing significant activation in the pontine micturition centre during micturition. The section number (z= 28 mm) refers to the coordinates relative to the plane through the anterior and posterior commissure. The colour scale on the left corresponds with the level of significance. L=left side; R=right side of the brain.

3 CENTRAL CONTROL OF MICTURITION AND CONTINENCE 3 the PMC so that the bladder can be emptied at an appropriate time. It has been shown that in the cat the lumbosacral cord projects only weakly to the PMC [20]. On the other hand, the micturition reflex is not abolished by recollicular decerebration. Apparently, lumbosacral projections to forebrain areas, such as the thalamus and hypothalamus, are not essential for this reflex [21]. This observation, together with the finding that there are only very weak sacral cord projections to the PMC, leads to the conclusion that another brainstem region must serve as a relay for the sacral cord PMC. The best candidate for such a relay centre is the mesencephalic periaqueductal grey (PAG). The PAG is the only caudal brainstem structure known to project specifically to the PMC [22] and stimulation of the PAG elicits complete micturition [23]. The importance of the PAG is further emphasized by the observation that interruption of some of the fibres from the PAG to the PMC results in a low-capacity bladder, which already contracts when filled with a few millilitres of urine [21]. PET studies showed that the PAG is activated during micturition in men and women [18,19]. A role for the PAG in micturition control is also suggested by clinical observations [24]. Continence circuit Another group of neurones in the pons is involved in the storage of urine during continence (Fig. 3). These neurones are located more ventrally and more laterally in the pontine tegmentum than the PMC. This cell group is known as the PSC or l-region, and projects to the motoneurones of the urethral sphincter in the nucleus of Onuf [12]. Stimulation of the PSC results in strong excitation of the pelvic floor musculature and an increase in urethral pressure [12]. Bilateral lesions in the PSC cause an inability to store urine [17]; bladder capacity is reduced and urine is expelled prematurely by excessive detrusor activity, accompanied by urethral relaxation. Outside the episodes of detrusor activity, the urethral pressure is not depressed below normal values. These observations suggest that during the filling phase the PSC has a continuous excitatory ecect on the nucleus of Onuf, resulting in inhibition of urethral relaxation coupled with detrusor contraction. Recently, PET scanning has provided evidence that there is also a PSC in humans [18,19] (Fig. 4). In volunteers who were unable to micturate during scanning, there was no activation in the dorsomedial pons, but was in the ventrolateral pons, as predicted on the basis of the location of the PSC in cats. Apparently, the volunteers who were unable to micturate (probably because of emotional reasons) contracted their urethral sphincter and withheld their urine, although they had a full bladder and tried to urinate. Storage centre Urinary continence pathways IC S2 Bladder Urethral sphincter motoneurones Urethral sphincter contraction Fig. 3. Schematic diagram of the spinal and supraspinal structures and their pathways involved in bladder control problems. Fig. 4. A horizontal PET section showing significant activation in the pontine storage centre during the withholding of urine. For details see Fig. 2.

4 4 B.F.M. BLOK and G. HOLSTEGE Forebrain involvement in the control of Species diverences in the control of micturition micturition Micturition control is important in all mammals, but Although the forebrain is not essential for the basic there are considerable variations in motor patterns, e.g. micturition reflex, clinical observations suggest that it when rats are stressed by being taken out of their cage, determines the beginning of micturition [3,4]. In the they immediately urinate. In contrast, cats, like humans, cat, stimulation of forebrain structures, e.g. the anterior urinate very seldom in stressful situations. It is possible cingulate gyrus, preoptic area of the hypothalamus, that these dicerences are reflected by a dicerent neuronal amygdala, bed nucleus of the stria terminalis and septal control system. Recent light microscopy investigations nuclei, elicits bladder contractions [25]. Many of these by Ding et al. [28] suggest that in the rat the sensory regions send fibres to the brainstem, but only one neurones in the lumbosacral cord project directly onto region (the preoptic area) projects to the PMC [26]. The neurones in the PMC. Preliminary ultrastructural results PET studies on micturition in humans suggest that this (BFM Blok, unpublished observations) on direct lumbosacral is probably also true in humans, because during projections to the PMC of the rat confirm this micturition the hypothalamus, including the preoptic observation. Apparently, micturition control is more area, showed an increased regional cerebral blood flow simply organized in lower mammals (like rodents) than (rcbf) [18,19]. This preoptic area, similar to the PAG, in higher mammals, including cats and humans, which is known to play an important role in sexual behaviour is then reflected in dicerent behaviour. and contains many oestrogen- and androgen-receptor immunoreactive cells. Recent observations [27] show that in the preoptic area of the uncastrated male cat, a The role of the cerebral cortex in micturition substantial number of the neurones containing andro- The human PET scan results indicate two cortical areas gen receptors project to the PMC. The importance of involved in micturition. The right dorsolateral prefrontal the preoptic area, which is better known for its role in cortex is active when micturition takes place, but also sexual behaviour, is further shown by the observation when micturition is allowed but does not take place. The that it receives a substantial projection from the sacral rcbf in the right anterior cingulate gyrus was significantly cord (BFM Blok, unpublished observations). The direct decreased during the voluntary withholding of projection of the preoptic area to the PMC could be urine. Forebrain lesions including the anterior cingulate regarded as the final pathway for the emotional motor gyrus are known to cause bladder overactivity [3]. It system to control the PMC and thus micturition. In this remains to be elucidated how the prefrontal cortex and respect, it must be remembered that micturition is an the anterior cingulate gyrus are precisely connected with important tool in territorial demarcation and urine is a the brainstem and hypothalamic micturition areas. A message in the context of sexual behaviour. striking observation in the PET studies on micturition Fig. 5. Horizontal PET sections indicating (arrowheads) significant activation in the primary motor cortex during pelvic straining (left) and during abdominal straining (right).

5 which will be activated or deactivated during scanning. These studies may eventually lead to improved patient selection criteria. Androgen and oestrogen supplementation in patients with an overactive bladder could be used to test the involvement of sex hormones in the central control of micturition. PET scanning with oes- trogen and androgen ligands could be used test whether these hormones cause functional changes in the brain structures that malfunction in bladder overactivity. was that the cortical and pontine control areas are predominantly on the right side [18,19], which corresponds with studies reporting that bladder overactivity is correlated with lesions in the right hemisphere [29]. Studies of lesions in the cat reported no dicerence in importance between the left and right PMC [13,17]. The classic motor areas of the brain are the primary and secondary motor cortex, the motor thalamic nuclei and the cerebellum. All these areas were found to be activated during voluntary straining of the pelvic floor and abdomen [30]. The part of the primary motor cortex involved in the voluntary control of the pelvic floor is located in the superomedial part of the precentral gyrus, and the part involved in abdominal straining in the superolateral part (Fig. 5). It is likely that the structures involved in voluntary motor control are not essential for involuntary micturition. CENTRAL CONTROL OF MICTURITION AND CONTINENCE 5 Acknowledgements The research was supported by a CBR grant entitled Neuronal control of micturition from the Faculty of Medical Sciences, University of Groningen. References Main conclusions 1 Resnick NM, Yalla SV, Laurino E. The pathophysiology of urinary incontinence amongst institutionalized elderly Some important conclusions can be drawn from these persons. N Engl J Med 1989; 320: 1 7 observations in animals and humans: (i) Animal experinence 2 Wagner TH, Hu TW. Economic costs of urinary inconti- ments, especially in the cat, are directly relevant in in Urology 1998; 51: understanding the neural pathways involved in micturand 3 Andrew J, Nathan PW. Lesions of the anterior frontal lobes disturbances of micturition and defaecation, Brain ition in humans. (ii) Processing of sensory input from 1996; 87: the bladder to the brainstem is more complex than 4 Blaivas JG. The neurophysiology of micturition: a clinical previously recognized, and is relayed, in part, by the study of 550 patients. J Urol 1982; 127: PAG. The thalamus does not have an essential role in 5 Blok BFM, Holstege G. Neuronal control of micturition and normal micturition. (iii) The integration between bladder its relation to the emotional motor system. Prog Brain Res and sphincter is not mediated by direct connections 1996; 107: between the PMC and PSC in the brainstem, but by 6 Blok BFM, Holstege G. The two pontine micturition centers projections to the spinal cord. 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Brain Intrathecal injection of Baclofen (a GABA agonist) is Res 1978; 140: used to induce relaxation of the EUS in paraplegic 10 Onufrowicz B. Notes on the arrangement and function of patients with dyssynergia [31]. This therapy can have the cell groups in the sacral region of the spinal cord. serious side-ecects, such as systemic hypotension. Local J Nerv Mental Dis 1899; 26: application of Baclofen in the region of the inhibitory 11 Barrington FJF. The ecect of lesions of the hind- and mid- neurones in the DGC could be more ecective and reduce brain on micturition in the cat. Quart J Exp Physiol Cogn Med 1925; 15: the side-ecects. The source of the beneficial ecect of the 12 Holstege G, GriBths D, De Wall H, Dalm E. Anatomical sacral nerves in patients with bladder overactivity is and physiological observations on supraspinal control of unknown [32]. This beneficial ecect could originate in bladder and urethral sphincter muscles in the cat. 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6 6 B.F.M. BLOK and G. HOLSTEGE 14 Blok BFM, Holstege G. Ultrastructural evidence for a direct stimulation of limbic, diencephalic and mesencephalic pathway from the pontine micturition center to the structures in the cat. Acta Physiol Scand 1966; 66: parasympathetic preganglionic motoneurons of the bladder 26 Holstege G. Some anatomical observations on the projections of the cat. Neurosci Lett 1997; 222: from the hypothalamus to brainstem and spinal cord: 15 Blok BFM, De Weerd H, Holstege G. The pontine micturition an HRP and autoradiographic tracing study in the cat. center projects to sacral cord GABA immunoreactive J Comp Neurol 1987; 260: neurons in the cat. Neurosci Lett 1997; 233: Blok BFM, Holstege G. Androgen receptor immunoreactive 16 Blok BFM, Van Maarseveen JTPW, Holstege G. Electrical neurons in the preoptic area of the hypothalamus project stimulation of the sacral dorsal gray commissure evokes to the pontine micturition center in the male cat. Neurourol relaxation of the external urethral sphincter in the cat. Urodynam 1998; 17: 53 Neurosci Lett 1998; 249: Ding YQ, Zheng HX, Gong LW, Lu Y, Zhao H, Qin BZ. 17 GriBths D, Holstege G, De Wall H, Dalm E. Control and Direct projections from the lumbosacral spinal cord to coordination of bladder and urethral function in the brain Barrington s nucleus in the rat: a special reference to stem of the cat. Neurourol Urodynam 1990; 9: micturition reflex. J Comp Neurol 1997; 389: Blok BFM, Willemsen ATM, Holstege G. A PET study on 29 Kuroiwa Y, Tohgi H, Ono S, Itoh M. Frequency and brain control of micturition in humans. Brain 1997; urgency of micturition in hemiplegic patients: relationship 120: to hemisphere laterality of lesions. J Neurol 1987; 234: 19 Blok BFM, Sturms LM, Holstege G. Brain activation during micturition in women. Brain 1998; in press 30 Blok BFM, Sturms LM, Holstege G. A PET study on cortical 20 Blok BFM, De Weerd H, Holstege G. Ultrastructural evidence and subcortical control of pelvic floor musculature in for the paucity of projections from the lumbosacral cord to women. J Comp Neurol 1997; 389: the M-region in the cat. A new concept for the organization 31 Leyson JF, Martin BF, Sporer A. Baclofen in the treatment of the micturition reflex with the periaqueductal gray as of detrusor-sphincter dyssynergia in spinal cord injury central relay. J Comp Neurol 1995; 359: patients. J Urol 1980; 124: Tang PCF, Ruch TC. Localization of brain stem and 32 Tanagho EA, Schmidt RA. Bladder pacemaker: scientific diencephalic areas controlling the micturition reflex. J Comp basis and clinical future. Urology 1982; 20: Neurol 1956; 106: Blok BFM, Holstege G. Direct projections from the periaqueductal gray to the pontine micturition center M-region. An anterograde and retrograde tracing study in the cat. Authors Neurosci Lett 1994; 166: 93 6 B.F.M. Blok 23 Skultety FM. Relation of periaqueductal gray matter to G. Holstege stomach and bladder motility. Neurology 1959; 9: Correspondence: B.F.M. Blok, Department of Anatomy and 24 Sakakibara R, Hattori T, Yasuda K, Yamanishi T, Tojo M, Embryology, Faculty of Medical Sciences, University of Mori M. Micturitional disturbance in Wernicke s encepha- Groningen, Oostersingel 69, 9713 EZ Groningen, The lopathy. Neurourol Urodynam 1997; 16: Netherlands 25 Gjone R. Excitatory and inhibitory bladder responses to E mail: b.f.m.blok@med.rug.nl

University of Groningen. Neuronal control of micturition Kuipers, Rutger

University of Groningen. Neuronal control of micturition Kuipers, Rutger University of Groningen Neuronal control of micturition Kuipers, Rutger IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the