4th ICI Lecture Series: Neural control (Committee 3)

Presented by Lori Birder, MD, Marcus Drake, MD, et al., at the Fourth International Consultation on Incontinence (ICI) - July 5 - 8, 2008. Palais des Congres, Paris, France.



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 Neural Neural Control of the  Bladder  Lori Birder and Marcus Drake  Lori Birder, William de Groat, Marcus  Drake, Clare Fowler, Derek Griffiths,  Emeran Mayer, Ian Mills, John Morrison,  Julian Paton and Karl Thor Higher Centers and Pathophysiology  - Clinical relevance of basic science   - Influence of higher brain centers on normal (& abnormal) bladder and bowel function  - Discussion of functional brain imaging in humans  4th International Consultation on  Incontinence  The Periphery   - Sensory properties of the urothelium  - Properties of afferents  - Cross-talk between colon and urinary bladder: relevance to co-morbid disorders  - Innervation and neural control of outlet (bladder and bowel)  OVERVIEW This involves reflexes organized at the spinal and  brainstem level  Lower Urinary Tract Innervation  Functions of the Lower  Urinary Tract  1. Urine storage          - Reservoir:  Bladder  2. Urine release          - Outlet:  Urethra  Bladder  Urethra  4th International Consultation on  Incontinence Urothelium  (UT):  Multilayered structure  (transitional epithelium)  consisting of apical,  intermediate and basal cells  Umbrella Cell  Intermediate  Cell  Basal Cell  Basal Lamina  The urothelium is able to maintain high resistance (i.e., barrier role)- due to expression  of tight junctions between the apical or “umbrella” cells  Apical Urothelial Cells  4th International Consultation on  Incontinence  Apodaca Traffic 5:117-128, 2004;  Lewis  AJP 278:F867-874, 2000 Though the urothelium maintains a tight barrier to ion/solute flux, a number  of factors (tissue pH, trauma, infection) can modulate this barrier function  ?  H+; High K+; Irritants  When the barrier is compromised, it can result in passage of toxic substances into the  underlying tissue resulting in urgency, frequency and pain during distension  4th International Consultation on  Incontinence The Urothelium Maintains the Barrier as the Bladder Undergoes Cycles of  Filling/Voiding  •  This “accommodation” reflects ability of the urothelial  surface to unfold during filling.  •  The epithelial surface area is increased---due to fusion of  vesicles with membrane.  •  This process of vesicular movement is termed “trafficking”  and maintains the barrier function of the urothelium.  4th International Consultation on  Incontinence More than just a barrier:  The urothelium functions as a primary  transducer of physical and chemical stimuli  4 Lines of evidence lend support for involvement of the urothelium in visceral sensation:  (1) Expression of “neuronal-like” receptors/ion channels  (2) Release of transmitters/mediators  (3) Location in close proximity to bladder nerves  (4) Plasticity in signaling functions induced by pathological conditions  There is also evidence that urothelial vesicle movement:  • may regulate the composition of cell-surface receptors  • may be linked with release of transmitters  4th International Consultation on  Incontinence  Dye-filled  Urothelial  Vesicles Sensory Roles of the Urothelium  Urothelial cells express receptors/ion channels similar to  mechanoreceptive and nociceptive afferent nerves  4th International Consultation on  Incontinence  P2X3  TRPV1  TRPM8  Wang et al JCI 115:2412-15 2005  Birder et al Nat Nsci 5:856-86 2002  Apostolidis et al Urology 65:400-5, 2005 Expression of various receptors enable the  urothelium to:  respond to increased stretch during bladder  filling or  chemical mediators (many found in the urine)  This can lead to secretion of chemical substances  forming the basis of a “chemical-cross talk” within  a number of cell-types in the bladder wall  Multiple mechanisms (such as urothelial-afferent  chemical interactions) could contribute to the  sensation of urgency  Urothelial cells can receive and integrate multiple stimuli---providing an  important “link” in the transfer of information from the urinary bladder to  the nervous system  4th International Consultation on  Incontinence Distension-evoked ATP release from the urothelium:  •   Is involved in autocrine/paracrine signaling  •   Is decreased in the absence of TRPV1  Full Bladder  Sensory Nerve  Ending  Stretched  Epithelium  P2X3  Channel  ATP  Signal about Bladder Pain; Distension  Cook and McCleskey  Nature, 407:951-952, 2000.  During distension, ATP release from urothelium—and via activation of suburothelial  afferents--may trigger sensations of fullness, pain or changes in bladder activity  Localization of  urothelial ATP  TRPV1-putative chemo-  mechanical transducer  4th International Consultation on  Incontinence  Birder et al Nat Neurosci  5:856-860, 2002 C-afferents  (unmyelinated)  • Contain peptides  •  Close proximity with urothelium as well  as intramural ganglia  • Some are ‘silent’ (not responsive to  normal distension)  Silent fibers---becomes active during  inflammation  A-δ afferents (myelinated)  • most sensitive receptors for distension  • ‘in series’ with smooth muscle  •  Sense bladder volume, respond to  distension and contraction  New information regarding properties of bladder afferents:  receptive fields / physiology / pharmacology  Finely Myelinated Aδ  axons are rare in the  mucosa  Urothelium  Smooth  Muscle  C  A-δ  4th International Consultation on  Incontinence  Peptidergic-  Fiber  Peptidergic-  Fiber  Intramural Ganglia  Urothelium  Gillespie Cell Tiss Res 325:33-45, 2006 Functional Classes of Bladder Mechanoreceptors  High and Low-threshold Stretch Sensitive Afferents  •  Receptive fields located within smooth muscle and muscle / suburothelium  Respond to light brushing  Urothelial Afferents  •  Receptive fields within the suburothelium  •  Identified by light brushing (sensitivity to filling not tested)  •  Some only activated with inflammation (silent C fibers)  Urothelium Removed  Mechanosensitive pelvic nerve receptive fields are  distributed throughout the bladder  4th International Consultation on  Incontinence  Xu and Gebhart J Neurophysiol 99:244-253, 2008 Bladder afferents can be sensitized by chemical (“inflammatory”) mediators  C-fibers can be activated by a variety of neurotransmitters and chemical mediators:  – ATP  – Nerve Growth Factor  – Histamine, 5-HT, adenosine and PGE2  – Some of these occur physiologically, others during inflammation  Significance:  Mechanosensitive afferents may contribute to discomfort & pain  (generated by normal bladder filling in circumstances such as PBS/IC).  Control  + Inflammatory Soup  4th International Consultation on  Incontinence  Xu and Gebhart J Neurophysiol 99:244-253, 2008 • Recent reports show that stress  enhances mechanical hyperalgesia  • May be mediated by increases in  immune mediators ; activation of  hypothalamic pituitary adrenal  (HPA) axes and autonomic nervous  system  The activity of these afferents may be enhanced by  emotional stress  Stress Exacerbates Pain Syndromes such as PBS/IC  4th International Consultation on  Incontinence  Khasar  J Nsci  28:5721-30 2008    Irritation/inflammation in one pelvic organ can evoke hypersensitivity in a non-irritated structure     May be due to convergence of colon and bladder afferent inputs at the level of DRG / Spinal cord-  -% of afferents involved may be low  Chemical “cross-talk” between pelvic viscera may influence a  number of functional pain syndromes  Noxious  Stimulus  Effect of  noxious colon  stimulus:  Bladder  overactivity Bladder-colon  convergence  onto second  order neurons  4th International Consultation on  Incontinence  Ustinova et al, AJP 292:F123-130, 2007  Rudick et al, AJP 293:R1191-98, 2007. Chronic pelvic pain can develop following inflammation/irritation of  individual pelvic organs but also can involve:  •  associated sphincters  •  muscular structure of the pelvic floor  •  components of the abdominal wall  Both fecal and urinary incontinence likely to be mediated by either  (a) overactivity, or (b) weakness of outlet (urethral or anal  sphincter)  New information as to how outlet controlled / innervated  4th International Consultation on  Incontinence Urethral Sphincter, Anal Sphincter and Levator Ani (pelvic floor muscle)-  regulated by a group of motoneurons within (or dendritic projections in)  Onuf’s nucleus  LA motoneurons are of 2 types α and γ  AS motoneurons are a single population –α  dorsal  ventral  cc  α  γ  Onufʼs nucleus  α  γ  Onufʼs nucleus  Onuf!s nucleus  Pierce L; Am. J. Obst. Gynecol. 192: 1506 (2005)  Barber et al AmJOG 187:64-71,2002 Levator Ani  Nerve  The LA muscle  is important in maintenance of pelvic floor support, urinary and fecal  continence  Denervation or injury of this muscle and its connective tissue is associated with pelvic  organ prolapse (POP), urinary and fecal incontinence  Recent evidence reveals that levator ani nerve damage alone not sufficient for POP  4th International Consultation on  Incontinence Patch-clamp recordings  Lumbar spinal cord  Urethra  Urethral  Sphincter  Bladder  Adult  intraurethral  DLN  Pudendal  nerve  Neonatal  ischiorectal  fossa  These motoneurons are modulated by descending inputs from monoaminergic  (5HT; NE) systems  Studies using patch-clamp recording (from identified rhabdosphincter motoneurons) have  shown that these transmitters have an excitatory effect  4th International Consultation on  Incontinence These findings elaborate on the concept that monoaminergic compounds  (may be useful in the treatment of stress urinary incontinence) regulate the bladder  outlet via an excitatory effect on sphincter motoneurons  During voiding, pathways passing through the PMC (via the  dorsal grey commissure) inhibit Onuf’s nucleus (pudendal  outflow to the urethral outlet)  4th International Consultation on  Incontinence Urinary  Bladder  Changes in DRG:  Neurochemical &  Electrical properties  Changes in Urothelium:  • Receptor expression  •  Sensitivity to  chemical/mechanical  stimuli  • Barrier function  Both Neural and Non-Neural Cells Exhibit Plasticity  Changes in Spinal  Cord:  To regions that  influence the  micturition pathway  Inflammation/injury can alter the properties of these cells which could  contribute to bladder hypersensitivity and pain  Neural Plasticity:  • Reorganization of  peripheral innervation  •Upregulation of P2X3  and TRPV1 (patients  with NDO)  •Increased NGF  sensitizes afferents  SHAM  NGF  4th International Consultation on  Incontinence  Spinal cord glial cells may play  important role in modulating  sensory processing • An emerging concept regarding the role of urothelial cells in sensory transduction  – Both afferents and urothelial cells can be sensitized by chemical mediators  – Both types of cells exhibit plasticity via changes in receptor expression/transmitter release  – Activity may be enhanced by autonomic nervous system  – New information that spinal cord “glial” cells can modulate sensory processing  Summary:  The Periphery  • New information regarding pelvic organ cross-sensitization  – May underlie a number of functional pain disorders  – May involve hormonal and/or neural (central/peripheral) mechanisms  • New findings regarding innervation/neural control of outlet (bladder & bowel)  – Differences emerging between innervation of urethral and anal sphincters and pelvic floor  muscle  – Role for levator ani innervation in maintenance of pelvic organ support  – Direct excitatory effect of 5HT/NE on motoneurons  4th International Consultation on  Incontinence The CNS hierarchy in LUT  and GI function  4th International Consultation on  Incontinence 4th International Consultation on  Incontinence 4th International Consultation on  Incontinence Brain centres  BJU International 2007; 99: 731  4th International Consultation on  Incontinence S2-4 in cauda equina  pelvic & pudendal ns  PAG  PMC PAG  PMC  MPFC  RI/LPFC  TH  ACG  4th International Consultation on  Incontinence PAG  PMC  MPFC  RI/LPFC  TH  ACG  4th International Consultation on  Incontinence PMC  S2-4 in cauda equina  pelvic & pudendal ns  Fowler C, et al. Nature Reviews Neuroscience 2008; 9: 453  4th International Consultation on  Incontinence Griffiths & Tadic 2007  4th International Consultation on  Incontinence Griffiths & Tadic 2007 Homeostatic afferent processing network   Mayer, et al. Gastroenterology 2006  GUT-BASED FACTORS:  Motility  Acid  Immune activation  Fluid handling  Microbe host interaction  VISCERAL AFFERENTS:  Peripheral sensitization  Central (spinal) sensitiz.  Microglia activation  EMOTIONAL FACTORS:  Anxiety  Sx related fears  Depression  COGNITIVE:  Coping  Expectation  Attention  No background perception  4th International Consultation on  Incontinence NO Perception  Homeostatic   Afferent Processing  Network  Physiologic Visceral  Stimulus  Most physiologic afferent  signals in health are part  of a hierarchial reflex  system and are NOT  consciously perceived  Food components  Microbiota  Intraluminal milieu  Motility  Secretion  Blood flow Brain responses to  expected and to  delivered rectal  distension (fMRI)  •Patients show greater  antINS activation during  expectation  •Patients show greater  activation in antINS,  dACC and dorsal pons  during distension  Berman, Mayer et al,  J. Neurosci 2008  4th International Consultation on  Incontinence Perception  Emotional  Arousal  Network  Visceral  Afferent Processing  Network  Tonic Pain  Inhibition/Facilitation  Network  Phasic Pain  Facilitation  Network  Phasic Pain  Inhibition  Network  Visceral  Stimulus  Cognition  Emotion  Reward  Network  Mayer et al, 2006  Copyright UCLA, 2002  4th International Consultation on  Incontinence Oral..  Oral.. …  …anal  anal  Furness J.  TIPS 2008;  28: 473  4th International Consultation on  Incontinence 4th International Consultation on  Incontinence  Hashitani, et al. McCloskey et al. van Mastrigt & Gillespie Desired  volume  Comparator                       Controller    Plant  (Detrusor) Actual  volume            Outlet resistance  Bladder ICs / neurones  PMC  Servo-assistance  Drake M. Ann Roy Coll Surg Eng 2007; 89: 580  4th International Consultation on  Incontinence Distortion  Stimulation of stretch receptors Sensation  Co-ordination  Most of bladder contracting Overactivity  ICs & neurones  Isolated areas contracting  Urgency  Excessive  Distortion  Intrinsic mechanisms; filling  4th International Consultation on  Incontinence Drake M, et al. BJU Int 2005; 95: 1002  2mm  30sec  Asymptomatic  Urgency Summary; central mechanisms  • Common ground between LUT and GI  • Midbrain and brainstem; PAG and PMC  • Higher centres; insula, ACC and PFC  • Homeostatic afferent processing network  • Central and peripheral mechanisms may  contribute or compensate for pathology  4th International Consultation on  Incontinence Issues raised  • Neuronal network function & hierarchies  • Basis of functional pain syndromes  • The contribution of peripheral structures  to normal LUT function  • Different species show marked  variations4th International Consultation on  Incontinence

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