Committee 3 Neural Control Chair L. BIRDER (USA) Co-Chairman M. DRAKE (UK) Members W. DE GROAT (USA), C. FOWLER (U.K), E. MAYER (USA), J. MORRISON (UAE), J. PATON (U.K) Consultants D. GRIFFITHS (Canada), I. MILLS (U.K), K. THOR (USA) 167 CONTENTS OVERVIEW V. MIDBRAIN-BRAINSTEM CONTROL OF BLADDER FUNCTION LEVELS OF EVIDENCE 1. AFFERENT PATHWAYS TO THE BRAINSTEM I. THE UROTHELIUM 2. DEFINING BRAINSTEM CIRCUITRY REGULATING BLADDER FUNCTION 1. INTRODUCTION TO THE ANATOMY AND 3. THE PONTINE MICTURITION CENTER (PMC) BARRIER FUNCTION OF THE UROTHELIUM 4. BLADDER ‘FILLING’ NEURONES IN THE PMC 2. RESPONSE TO THE UROTHELIUM TO AND MEDIAL RETICULAR FOR-MATION: INJURY WHAT’S THEIR ROLE? 3. UROTHELIAL HETEROGENEITY 5. OFF-SWITCHING MICTURITION – THE 4. ROLES FOR UROTHELIAL CELLS IN PONTINE CONTINENCE CENTRE (PCC) VISCERAL SENSATION 6. THE PERIAQUEDUCTAL GREY (PAG): IS THIS AN ESSENTIAL REGION FOR 5. CLINICAL SIGNIFICANCE OF THE SENSORY SUPPRESSING THE MICTURITION WEB REFLEX? II. AFFERENT NEURONES 7. NEUROTRANSMITTERS & MODULATORS WITHIN BRAINSTEM NETWORKS 1. PROPERTIES OF BLADDER AFFERENT CONTROLLING BLADDER FUNCTION NEURONS VI. CORTEX AND BRAINSTEM 2. UROTHELIAL AFFERENTS CONTROL OF BLADDER FUNCTION 3. SENSITIVITY OF AFFERENT ENDINGS 4. SPINAL CORD 1. BACKGROUND 5. SPINAL CORD GLIAL CELLS AND 2. ROLE AND IMPORTANCE OF CEREBRAL CONTROL OF VOIDING MODULATION OF PELVIC AFFERENTS 3. CORTICAL AND SUBCORTICAL CENTRES III. NEURAL CONTROL OF FEMALE INVOLVED IN BLADDER CONTROL. PELVIC FLOOR MUSCLES AND EVIDENCE FROM OBSERVATIONS OF RHABDOSPHINCTERS LESIONS AND FROM FUNCTIONAL BRAIN IMAGING IN HUMANS 1. STRUCTURAL ELEMENTS OF THE PELVIC 4. WORKING MODEL OF BRAIN/BLADDER FLOOR CONTROL 2. INNERVATION OF THE FEMALE LEVATOR VII. ABNORMAL LOWER URINARY ANI MUSCLES TRACT FUNCTION 3. INNERVATION OF URETHRAL AND ANAL RHABDOSPHINCTERS 1. ABNORMALITIES INVOLVING 4. SPINAL URINE-STORAGE-REFLEX INFLAMMATION INHIBITORY CENTER (SUSRIC) 2. INVOLVING ABNORMAL URINE STORAGE 3. INVOLVING ABNORMAL VOIDING 5. PHARMACOLOGY OF URETHRAL AND ANAL RHABDOSPHINCTERS 4. CO-MORBID DISORDERS VIII. BRAIN-GUT INTERACTIONS IV. EFFERENT PATHWAYS TO THE BLADDER 1. BACKGROUND 2. ORGANIZATION OF HOMEOSTATIC 1. PREGANGLIONIC NEURONS REFLEXES: PROCESSING OF PELVIC 2. GANGLIA VISCERAL INFORMATION WITHIN 3. TERMINAL NERVE FIBRES HIERARCHICAL ORGANIZED 4. DESCENDING AND SPINAL SEGMENTAL HOMEOSTATIC REFLEXES INFLUENCES ON SPINAL AUTONOMIC 3. CONSCIOUS PERCEPTION OF INPUT FROM CENTRES THE BODY AS ASPECTS OF HOMEOSTASIS 5. NEURAL TRAFFIC 4. DESCENDING MODULATION OF HOMEO- STATIC REFLEXES AND FEELINGS 6. PELVIC ORGAN INTERACTIONS AT THE 5. BRAIN CIRCUITS ACTIVATED BY ACUTE EFFERENT NEURAL LEVEL VISCERAL STIMULI: EVIDENCE FROM 7. EFFERENT INHIBITION FUNCTIONAL BRAIN IMAGING STUDIES IN 8. PERIPHERAL EXCITATORY MECHANISMS HUMANS 168 Neural Control L. BIRDER, M. DRAKE, W. DE GROAT, C. FOWLER, E. MAYER, J. MORRISON, J. PATON Consultants D. GRIFFITHS, I. MILLS, K. THOR OVERVIEW LEVELS OF EVIDENCE This chapter deals with individual components This book attempts to use Levels of Evidence regulating the neural control of the urinary bladder. This throughout. The Oxford Centre for Evidence Based chapter has been completely remodeled and updated Medicine has laid down guidelines that apply to Levels with the focus on factors and processes involved in of Therapeutic Interventions and Grades of the two models of operation of the bladder: storage Recommendations to Patients; the existence of dispute and elimination. There has been significant new regarding each major conclusion should be information since the last consultation in a number of documented. However this advice does not really fields: apply to the basic sciences, where randomized controlled trials are not a common format of • The urothelium and its roles in sensor and investigation, and acute studies with internal controls transducer functions including interactions with are more common. other cell types within the bladder wall (‘sensory web’) Within this chapter we intend to be selective and report scientific evidence that has appropriate controls • The location and properties of bladder afferents and achieves statistical significance. Other categories including factors involved in regulating afferent of evidence, e.g. uncontrolled studies, anecdotal sensitization information, hypothesis or speculation will be referred • The neural control of the pelvic floor muscle and to as such. pharmacology of urethral and anal sphincters Of some importance in this field are species (focusing on monoamine pathways) differences, and efforts have been made to make it • Efferent pathways to the urinary bladder very clear when each new topic is introduced in which species the observation was made with special • Abnormalities in bladder function including emphasis as to the extent comparable data exists for mechanisms underlying co-morbid disorders humans. associated with bladder pain syndrome and incontinence In this report, we intend to indicate whether the conclusions are based on (A) peer-reviewed papers The next sections deal with the current understanding in reputable journals (B) evidence in book chapters of brainstem neuronal networks, which regulate lower or reviews, and (C) Abstracts: abstracts will only be urinary tract function (1-4). The importance is reflected mentioned if they refer to a systematic study with in the current advances in functional brain imaging good statistical methodology. (both positron emission topography or PET and functional magnetic resonance imaging or fMRI). These advances have had a major impact on understanding CNS control of the human bladder. This section has been completely revised to also include the recent advances in understanding of bidirectional brain-gut interactions in addition to discussion of homeostatic function and neural mechanisms underlying fecal and anal continence. 169 membrane, which reduce the permeability of the cells I. THE UROTHELIUM to small molecules (water, urea, protons) [5,11]. The apical surface of the urothelium is also covered with There is evidence that a number of functional pain a sulfated polysaccharide glycosaminoglycan (GAG) syndromes are associated with changes in the or mucin layer that is thought to act as a nonspecific epithelial layer. Alterations of bladder urothelium at the anti-adherence factor and as a defense mechanism molecular and structural levels have been reported in against infection [12-14]. In addition, during bladder both patients and animals modeled for various bladder filling the umbrella cells become flat and squamous disorders. It is likely that many therapies currently and this shape change is accompanied by vesicular used in the treatment of bladder disease may target traffic (i.e. exocytosis/endocytosis), adding membrane urothelial receptors and/or their release mechanisms. to the apical surface thereby increasing overall urinary bladder surface area [7,15,16]. There is evidence that 1. INTRODUCTION TO THE ANATOMY AND this stretch-induced exocytosis is dependent on BARRIER FUNCTION OF THE UROTHELIUM activation of epidermal growth factor receptor (EGFR) [17,18]. These processes allow the bladder to The urothelium is the epithelial lining of the lower accommodate increasing volumes of urine during urinary tract between the renal pelvis and the urinary filling without compromising the barrier function. bladder. Urothelium is composed of at least three Exocytosis/endocytosis (vesicular recycling) may also layers: a basal cell layer attached to a basement play an important role in modulating the release of a membrane, an intermediate layer, and a superficial or number of neurotransmitters/mediators as well as apical layer composed of large hexagonal cells regulation of the function of many receptors and ion (diameters of 25-250 µm) known as ‘umbrella cells’ channels in urothelial cells [19,20]. [5, 6] (Figure 1) The umbrella cells are interconnected by tight junctions (which are composed of multiple 2. RESPONSE OF THE UROTHELIUM TO proteins such as the claudins) and are covered on their INJURY apical surface (nearly 70-80%) by crystalline proteins called uroplakins that assemble into hexagonal plaques Basal cells, which are thought to be precursors for [7-10]. Uroplakins and other urothelial cellular other cell types, normally exhibit a low (3-6 month) differentiation markers, such as cytokeratin 20, are not turnover rate, in fact the slowest turnover of any expressed in the stratified epithelium of the urethra. mammalian epithelial cells [7,21]. It has been shown In some species, the umbrella cells and perhaps also that neither urine-derived factors nor cyclic mechanical the intermediate cells have projections to the basement changes contribute to urothelial proliferation and membrane [5]. differentiation; however accelerated proliferation can occur in pathology. For example, using a model The ability of the bladder to maintain the barrier (protamine sulfate) that selectively damages the function, despite large alterations in urine volume and umbrella cell layer, it has been shown that the increases in pressure during bladder filling and urothelium rapidly undergoes both functional and emptying, is dependent on several features of the structural changes in order to restore the barrier in umbrella cell layer. These features include tight- response to injury [22]. The initiation of urothelial junction complexes that reduce the movement of ions proliferation is thought to involve up-regulation of and solutes between cells and specialized lipid growth factors