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The discovery of the pontine micturition centre by F. J. F. Barrington

2008; Wiley; Volume: 93; Issue: 6 Linguagem: Inglês

10.1113/expphysiol.2007.038976

1469-445X

J. Morrison,

Urological Disorders and Treatments

Experimental PhysiologyVolume 93, Issue 6 p. 742-745 Free Access The discovery of the pontine micturition centre by F. J. F. Barrington John F. B. Morrison, John F. B. Morrison Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, POB 17666, Al Ain, United Arab EmiratesSearch for more papers by this author John F. B. Morrison, John F. B. Morrison Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, POB 17666, Al Ain, United Arab EmiratesSearch for more papers by this author First published: 28 June 2008 https://doi.org/10.1113/expphysiol.2007.038976Citations: 9 Corresponding author J. F. B. Morrison: Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, POB 17666, Al Ain, United Arab Emirates. Email: [email protected] AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Neuro-urology is a well-established field of study today, and Frederick James Fitzmaurice Barrington (1884–1956) was the first surgeon–physiologist to realize the importance of the association between the brainstem and the lower urinary tract. His famous 1925 paper entitled 'The effect of lesions of the hind- and mid-brain on micturition in the cat' is highly cited and was the first major paper on the location within the brainstem of an area concerned with the control of the lower urinary tract. Barrington's own conclusion stated: 1 Destruction of a small part of the brain just ventral to the internal edge of the superior cerebellar peduncle from the level of the middle of the motor nucleus of the fifth nerve behind to the level of the anterior end of the hind brain in front is followed by a permanent inability to empty the urinary bladder if the lesion is bilateral, but not if it is unilateral. 2 Destruction of the mid-brain from the ventral half of the side of the posterior end of the aqueduct outwards to just beyond the mesencephalic root of the fifth nerve is followed when the lesion is bilateral by a permanent loss of consciousness of wanting to micturate or defaecate, but does not impair the performance of either of these functions. 3 A lesion in the position of the last, but rather more extensive, produces frequency of micturition as well as the effects observed in 2. The first of these regions has subsequently been called 'Barrington's nucleus', the 'pontine micturition centre' (PMC), or the 'M-region' (De Groat, 1975; Loewy et al. 1979), and has been shown to contain neurons that have an essential role in the control of bladder contraction. Neurons in the PMC of the cat provide direct synaptic inputs to sacral parasympathetic preganglionic neurones, as well as to neurons in the sacral dorsal commissure (Blok & Holstege, 1997). The former neurons innervate the bladder (via the pelvic ganglia), while the latter are thought to have an important inhibitory influence on motoneurons that control the external urethral sphincter (Blok et al. 1998b). As a result of these connections, the PMC can promote co-ordinated reciprocal activity in the bladder and urethral sphincter. Sensory information arising from the lower urinary tract reaches the PMC in the cat and the primate (Roppolo et al. 1985), and there is recent evidence that the afferent pathway to the PMC is first processed in the periaqueductal grey matter (PAG; Liu, 1983; Blok & Holstege, 1994; Blok et al. 1995). The first indication of a bladder reflex pathway involving the brainstem, and probably the PMC (de Groat & Ryall, 1969), was an important step in our understanding of spinal injuries, viz. that spinal cord transection can interfere with bladder emptying, because it destroys sensory and motor pathways between the sacral spinal cord and the PMC. In humans, the first studies using positron emission tomography on the regulation of bladder function looked at brainstem activation during voiding. The pioneering studies of Blok and his colleagues showed that during voiding there was increased blood flow in an area in the right dorsomedial pontine tegmentum close to the fourth ventricle, and this was presumed to be the location of PMC in humans (Blok et al. 1997, 1998a). Thus, the impact of Barrington's study has been immense, and remains central to our understanding of neuro-urology in humans and animals. Background to F. J. F. Barrington, urologist and physiologist In 1925, when Barrington published this celebrated paper, his academic position was as surgeon for genito-urinary diseases to University College Hospital. Barrington's experiments were made possible because of the development of the Horsley–Clarke stereotaxic instrument, which was developed by Victor Horsley, the Professor of Surgery, together with Robert Henry Clarke. Barrington borrowed the first of these instuments for these experiments. Barrington collated the individual case histories of lesioned animals; it is not clear how long the total series of experiments took, but since the study of individual cases sometimes took many months, the duration of the whole project must have lasted several years. Barrington's 1925 paper in the Quarterly Journal of Experimental Physiology Barrington borrowed the first Horsley–Clarke apparatus to position lesions in the midbrain and hindbrain of approximately 84 cats under chloroform anaesthesia; these animals (probably mainly female) recovered and then lived in his work room, where they were observed daily, sometimes over a period of many months. Residual volume of urine and 'desire to void' There is no Methods section in the 1925 paper, but Barrington classified the lesioned cats on the basis of: (a) residual volume, i.e. the volume of urine remaining in the bladder after voiding, which was estimated by palpation and measurements of the volume of urine that could be expressed manually; and (b) estimates of a conscious desire to void, which were deduced from observations of feline behaviour around the time of voiding. If a lesioned cat would scratch around, circle or squat before micturition, Barrington concluded that the animal had a desire to void. At the other extreme, there were animals that appeared to have no conscious knowledge that micturition was occurring, either during sleep or when standing or even when drinking milk; they seemed oblivious to the fact that micturition was occurring and made no attempt to go through the normal feline performance described above. Three 'syndromes' Barrington described three 'syndromes' based on his records of individual animals, linked to the behaviour, clinical signs, functional disturbances, estimates of bladder volume and the location of the causative electrolytic lesions in the brainstem. In Barrington's Group 1, cats had a large residual volume but appeared to have a normal desire to void; seven animals developed permanent changes in residual volume while eight showed recovery after several weeks. In Group 2, there was a clear loss of consciousness of a desire to micturate, but no permanent change in residual volume; three cats developed permanent changes, while in four others the changes were transient. In Group 3, there were three cats that had both a loss of conscious desire to void and an increased residual volume that persisted for at least 8 weeks. The brainstem lesions In Figs 1 and 2 of his paper, Barrington displayed drawings showing bilateral lesions in his Group 1 animals, arranged according to the quantity of the residual urine. Measurements were made to the nearest 0.1 mm of brain tissue, and he concluded that 'the common part of the lesions [that caused permanent elevation of residual urine] extends from just behind the level of the anterior end of the motor nucleus of the fifth nerve forwards for rather more than a millimetre to the extreme end of the hindbrain, stopping immediately behind the posterior end of the aqueduct: the decussation of the fourth nerves in the velum is present in the section containing it.' The lesions that gave rise to the sensory changes observed in Barrington's Group 2 animals were characterized by more extensive lesions beginning anteriorly at the level of the posterior parts of the colliculi but not extending as far posteriorly as the motor nucleus of the fifth nerve. Some of the Group 3 animals had extensive lesions similar to those found in Group 2. Therefore, by 1925 he believed that there were two important regions of the brainstem, one necessary for normal bladder emptying, and resulting in an increased residual volume when lesioned; and a second region that, following rather more extensive lesions, resulted in loss of any desire to void and, on occasions, an enlarged bladder. Barrington did not mention the word sphincter in this paper, but did refer on several occasions to urethral resistance (to flow during manual expression of urine) and to urethral contraction, although no measurements of this were made. Modern knowledge Much of the older literature was reviewed by Torrens & Morrison (1987), and more recent reviewers include Shefchyk, (2001), Morrison et al. (2005) and de Groat (2006). Today it is clear that a PMC is present in rats, cats, dogs, guinea-pigs, pigs and humans. Two separate regions are now recognized within the rostral dorsolateral pons, one projecting to the parasympathetic neurones innervating the bladder, and the other more lateral area concerned with the control of the external urethral sphincter. The region lateral to the PMC, just ventral to the brachium conjunctivum, is now recognized as having some importance in the regulation of the external urethral sphincter and has been designated the 'L-region' to distinguish it from more medial neurones concerned with the bladder and micturition (the 'M-region'; see Fig. 1). The L-region contains neurons that send a prominent input to sphincteric motoneurones in Onuf's nucleus (a distinct nucleus in the sacral cord containing the cell bodies of pudendal nerve motoneurones), as well as a projection to the thoracolumbar preganglionic neurones (Holstege et al. 1979, 1986). Bilateral lesions of the L-region in cats have been reported to induce bladder hyperreflexia and incontinence (Holstege et al. 1986). Barrington also reported that urinary frequency seen in some of his Group 2 animals appeared to be closely related to 'an affection of the skeletal muscles.' He also comments that 'the bladder seemed in a state of greater and the urethra weaker contraction than normal.' A more modern interpretation would be that the L-region appears to be part of a larger, less specific area that regulates sphincter tone during changes in intra-abdominal pressure, such as occurs during respiration, coughing and sneezing, or sexual activity (Griffiths, 2002). Figure 1Open in figure viewerPowerPoint Modern views of the motor effects of Barrington's pontine micturition centre Barrington defined the location of the pontine micturition centre by making lesions in the rostral dorsolateral pons and observing their effects on behaviour and the residual volume of urine in the bladder. Nowadays we recognize that this centre projects to the sacral cord and excites the bladder parasympathetic neurones in the intermediolateral column. In addition, the descending pathway excites interneurones adjacent to the central canal that inhibit sphincteric motoneurones in Onuf's nucleus; these connections mediate the normal reciprocal relationship between bladder contraction and sphincteric relaxation. Functional imaging investigations in humans support the view that the PAG is an important relay station of bladder afferent activity. Although in the first PET imaging studies PAG activation was seen in the withholding phase prior to micturition in men but not women (Blok et al. 1997, 1998a), subsequent studies focusing on the storage phase in healthy male volunteers showed increasing activation in the PAG with increasing bladder volumes (Athwal et al. 2001), and a study which looked at activation during natural filling to capacity showed activation of the PAG with the same brain co-ordinates (Matsuura et al. 2002). Conclusion Barrington's paper certainly did not conform to modern editorial concepts of how to write a scientific paper, but the impact of this celebrated work has nevertheless been momentous for urologists and neuroscientists interested in the control of the bladder. Many problems remain, and the search for solutions to the urological problems faced by paraplegic individuals is, and should be, the focus of further research. The role of Barrington's pontine micturition centre will remain central to these studies. References Athwal BS, Berkley KJ, Hussain I, Brennan A, Craggs M, Sakakibara R, Frackowiak RS & Fowler CJ (2001). Brain responses to changes in bladder volume and urge to void in healthy men. Brain 124, 369– 377. Barrington FJF (1925). The effect of lesions of the hind- and mid-brain on micturition in the cat. Q J Exp Physiol 15, 81– 102. Blok BF, De Weerd H & Holstege G (1995). Ultrastructural evidence for a paucity of projections from the lumbosacral cord to the pontine micturition center or M-region in the cat: a new concept for the organization of the micturition reflex with the periaqueductal gray as central relay. J Comp Neurol 359, 300– 309. Blok BF & Holstege G (1994). Direct projections from the periaqueductal gray to the pontine micturition center (M-region). An anterograde and retrograde tracing study in the cat. Neurosci Lett 166, 93– 96. Blok BF & Holstege G (1997). Ultrastructural evidence for a direct pathway from the pontine micturition center to the parasympathetic preganglionic motoneurons of the bladder of the cat. Neurosci Lett 222, 195– 198. Blok BF, Sturms LM & Holstege G (1997). A PET study on cortical and subcortical control of pelvic floor musculature in women. J Comp Neurol 389, 535– 544. Blok BF, Sturms LM & Holstege G (1998a). Brain activation during micturition in women. Brain 121 ( Pt 11 ), 2033– 2042. Blok BF, Van Maarseveen JT & Holstege G (1998b). Electrical stimulation of the sacral dorsal gray commissure evokes relaxation of the external urethral sphincter in the cat. Neurosci Lett 249, 68– 70. De Groat WC (1975). Nervous control of the urinary bladder of the cat. Brain Res 87, 201– 211. De Groat WC (2006). Integrative control of the lower urinary tract: preclinical perspective. Br J Pharmacol 147 Suppl 2 , S25– S40. De Groat WC & Ryall RW (1969). Reflexes to sacral parasympathetic neurones concerned with micturition in the cat. J Physiol 200, 87– 108. Griffiths DJ (2002). The pontine micturition centres. Scand J Urol Nephrol Suppl 210 , 21– 26. Holstege G, Griffiths D, De Wall H & Dalm E (1986). Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in cats. J Comp Neurol 250, 449– 461. Holstege G, Kuypers HG & Boer RC (1979). Anatomical evidence for direct brain stem projections to the somatic motoneuronal cell groups and autonomic preganglionic cell groups in cat spinal cord. Brain Res 171, 329– 333. Liu RPC (1983). Laminar origins of spinal projection neurons to the periaqueductal gray of the rat. Brain Res 264, 118– 122. Loewy AD, Saper CB & Baker RP (1979). Descending projections from the pontine micturition center. Brain Res 172, 533– 538. Matsuura S, Kakizaki H, Mitsui T, Shiga T, Tamaki N & Koyanagi T (2002). Human brain region response to distention or cold stimulation of the bladder: a positron emission tomography study. J Urol 168, 2035– 2039. Morrison J, Fowler C, Birder L, Craggs M, De Groat W, Downie J, Drake M & Thor K (2005). Neural control of the bladder. In Incontinence, ed. P Abrams, L Cardozo, S Khoury & A Wein, pp. 363– 422. Health Publications Ltd, Paris . Roppolo JR, Nadelhaft I & De Groat WC (1985). The organization of pudendal motoneurons and primary afferent projections in the spinal cord of the rhesus monkey revealed by horseradish peroxidase. J Comp Neurol 234, 475– 488. Shefchyk SJ (2001). Sacral spinal interneurones and the control of urinary bladder and urethral striated sphincter muscle function. J Physiol 533, 57– 63. Torrens M & Morrison JFB (1987). The Physiology of the Lower Urinary Tract. Springer-Verlag, London . Acknowledgements I would like to acknowledge the help of Dr Tilli Tansey in finding source material and Professor Wim Lammers for his comments on the manuscript. Photo of F. J. F. Barrington reproduced with kind permission from UCL Library services. Citing Literature Volume93, Issue6June 2008Pages 742-745 FiguresReferencesRelatedInformation