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Neural Control of Micturition

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Neural Control of Micturition

  2. 2. INTRODUCTION • Two main functions of LUT - storage and periodic elimination of urine • Two functional units in the LUT: • Reservoir - urinary bladder • Outlet - bladder neck, urethra, urethral sphincter • Coordination between these organs - mediated by a complex neural control system located in the brain, spinal cord, and peripheral ganglia
  3. 3. PERIPHERAL NERVOUS SYSTEM - Efferent innervation • Bilateral efferent innervation from the thoracic and lumbosacral segments of the spinal cord • Three sets of peripheral nerves: • Sympathetic innervation - thoracolumbar outflow of the spinal cord - hypogastric nerves and sympathetic chain • Parasympathetic and somatic innervation originates in the sacral segments of the spinal cord • sacral parasympathetic - pelvic nerves • sacral somatic nerves - primarily the pudendal nerves
  4. 4. • Preganglionic axons carrying information from the spinal cord to the bladder synapse with autonomic ganglion cells widely distributed: • Pelvic plexus • Prevertebral sympathetic ganglia (inferior mesenteric ganglia) • Paravertebral sympathetic chain ganglia • Ganglia on the serosal surface and in the wall (intramural ganglia) of the organs
  5. 5. Efferent pathways of the lower urinary tract
  6. 6. SYMPATHETIC POSTGANGLIONIC NERVES • Sympathetic preganglionic pathways – • Arise from the T11–L2 spinal segments • Pass to the paravertebral sympathetic chain ganglia and then to prevertebral ganglia in the inferior mesenteric, superior hypogastric and pelvic plexus • Postganglionic fibers travel through the hypogastric and pelvic nerves
  7. 7. • Sympathetic postganglionic nerves release NA • Inhibitory input to smooth muscle in the body of the bladder • β adrenergic inhibitory receptors in the detrusor muscle to relax the‑ bladder • Excitatory input to smooth muscle of the urethra and bladder base • α adrenergic excitatory receptors in the urethra and the bladder neck‑
  8. 8. PARASYMPATHETIC POSTGANGLIONIC NERVES • Sacral parasympathetic outflow • Through the pelvic nerves • Provides the major excitatory input to the urinary bladder • Preganglionic neurons - located in the intermediolateral region of the S2, S3, and S4 sacral spinal cord segments • Axons pass through the pelvic nerves, synapse at ganglia in the pelvic plexus and wall of the bladder
  9. 9. • Parasympathetic postganglionic nerves release both cholinergic (ACh) and non-adrenergic, non-cholinergic transmitters • Cholinergic transmission - M3 muscarinic receptors - detrusor contraction and consequent urinary flow • Non-cholinergic excitatory transmission - ATP actions on P2X purinergic receptors in the detrusor muscle • Parasympathetic input to the urethra induces relaxation during voiding • mediated by nitric oxide (NO)
  10. 10. SACRAL SOMATIC NERVES • Somatic cholinergic motor nerves • Arise in S2–S4 motor neurons in Onuf’s nucleus • Reach the periphery through the pudendal nerves • Supply the striated muscles of the external urethral sphincter (EUS) (i.e., rhabdosphincter)
  11. 11. Afferent pathways • Three sets of nerves carry afferent axons • Sensations of bladder fullness are conveyed to the spinal cord by the pelvic and hypogastric nerves • Sensory input from the bladder neck and the urethra is carried in the pudendal and hypogastric nerves • consist of A delta (thinly myelinated) and C (unmyelinated) fibers
  12. 12. • A delta fibres - located within the detrusor muscle • Respond to passive distention - known as “tension receptors” • C fibers - dispersed more widely in the detrusor and suburothelium • Insensitive to physiological filling - “silent” fibers • Respond to noxious stimuli, provide nociception, and are sensitive to changes in temperature and pH • Thought to be important in the pathogenesis of urgency and the Overactive Bladder (OAB)
  13. 13. • Cell bodies of these nerves - found in the dorsal root ganglia (DRG) of the S2–S4 and T11–L2 dorsal roots • Axons enter the dorsal horn, where they may • Synapse with interneurons and either transmit impulses to higher brain centers • Synapse with neurons involved in spinal reflexes • Thought to lie in the lateral part of the lateral column
  14. 14. GROSS ANATOMY OF THE LOWER URINARY TRACT • Bladder can be divided into two parts: • Body - lies above the ureteral orifices • Base - consists of the trigone and bladder neck • detrusor muscle - smooth muscle with fibers arranged in spiral, longitudinal, and circular bundles around the hollow viscus • Bladder outlet - composed of the bladder base, urethra, and striated urethral sphincter (i.e., rhabdosphincter) • external urethral sphincter - striated muscle at the level of the membranous urethra and is under voluntary control • Internal urethral sphincter - extension of the smooth muscle fibers of the detrusor muscle and is not under voluntary control
  15. 15. Anatomy of the bladder and its outlet.
  16. 16. THE NEUROLOGICAL CONTROL OF THE BLADDER • Micturition is under voluntary control, and is a learned process • Develops with the maturing nervous system • Neural pathways - organized as simple on–off switching circuits • Maintain a reciprocal relationship between the urinary bladder and urethral outlet • Maintains the bladder and sphincter in the storage mode for approximately 99.8% of life • Switches to the voiding mode when socially appropriate
  17. 17. Storage phase • Bladder functions as a reservoir, storing urine and providing continence • achieved by inhibition of parasympathetic activity • active process of relaxation of the detrusor resulting in “bladder compliance • intravesical pressure is maintained below 10 cmH2O • sympathetic and pudendal-mediated tonic contraction of the sphincters ensures urinary continence
  18. 18. Sympathetic storage reflex - Vesicosympathetic reflex • Sympathetic reflex activity • triggered by vesical afferent activity in the pelvic nerves • Stimulates the sympathetic outflow to the bladder outlet and the pudendal outflow to the external urethral sphincter • Inhibits contraction of the detrusor muscle • NA - inhibitory β-adrenergic receptors on the bladder body and excitatory α-adrenergic receptors on the urethral sphincter and bladder neck • Enhances urine storage and suppresses voiding
  19. 19. Urine storage reflexes
  20. 20. Voiding phase • Storage phase - can be switched to the voiding phase either involuntarily or voluntarily • First event is relaxation of the pelvic floor muscles and external and internal urethral sphincters • Achieved by inhibition of pudendal and sympathetic activity • Followed by parasympathetic mediated detrusor contraction • Coordinated activity between the detrusor and urethral sphincters • Subject to modulatory influences of higher function
  21. 21. Voiding responses
  22. 22. Model of CNS Lower Urinary Tract Control • Switch of LUT function between storage and voiding • Mediated by a long-loop spino-bulbo-spinal voiding reflex • Forebrain circuits modulate this reflex • Brainstem contains two principal nuclei concerned with voiding • PAG and PMC [“M region” or “Barrington’s nucleus”] • Storage - PAG is activated and PMC is inactive • Voiding - Enhanced PAG activity and PMC activation • L-region / pontine urine storage centre - excitation of this region - tighten the urethral sphincter
  23. 23. Voiding reflexes
  24. 24. • Ascending afferent input from the spinal cord pass through PAG before reaching the PMC • Efferents from the PMC - project to • Parasympathetic motor neurons of the detrusor in the sacral cord • Inhibitory interneuronal activity - suppression of activity of sympathetic and motor neurons in Onuf’s nucleus • Reciprocal synergistic contraction of the detrusor muscle and relaxation of the sphincter
  25. 25. Forebrain neural circuits involved in human voiding • Normal adults - can postpone or hasten the micturition • Ensure urination occurs only if it is consciously desired, emotionally safe and socially appropriate • PAG – projects to many parts of the forebrain, receives ascending afferent activity from the bladder, and sends efferent signals back to the bladder and urethra • PAG - occupies a pivotal location between brain and bladder - so as to suppress or enhance storage or voiding
  26. 26. Forebrain Regulation Of Micturition • Decision to void or to postpone voiding • Depends on forebrain processing of signals transmitted by bladder afferents • together with information from other organ systems • circumstances that might influence the desirability of voiding • Altering the input to the PAG - manipulate the strength of its activation • If activation of the PAG increases and approaches the set level, the switch to voiding is advanced, and vice versa
  27. 27. A simple working model of the lower urinary tract control system
  28. 28. Circuit 1 • Is voiding socially appropriate? • Social aspects are primarily dealt with in the prefrontal cortex, especially the medial prefrontal cortex (mPFC) • Voiding can be initiated voluntarily by exciting the mPFC - inflow into the PAG increases • Voiding can be suppressed by deactivating the mPFC – reduces inflow into the PAG • mPFC can either delay or advance voiding by reducing (deactivating) or increasing (activating) the flow of excitation along the pathway from the mPFC to PAG
  29. 29. Circuit 2 • Is voluntary voiding emotionally appropriate? • This limbic circuit includes the dorsalACC and the nearby SMA. • It probably includes the anterior insula also (previously assigned to circuit 1) • activation of insula and dACC/SMA • evokes strong desire to void or urgency • sympathetic motor output to the LUT
  30. 30. Circuit 3 • Is voiding safe? • This subcortical circuit includes the parahippocampal complex as well as the PAG and probably the hypothalamus • deactivation of parahippocampal regions tends to suppress voiding at the PAG • Hypothalamus might be part of this subcortical circuit, sending a ‘safe’ or ‘unsafe’ signal to the pontine micturition centre
  31. 31. • PAG activation • driven by afferent input from the sacral spinal cord • inhibitory or excitatory inputs from circuits one, two and three • Voiding reflex is triggered if PAG activity reaches a certain set level • PAG then activates the PMC
  32. 32. References • de Groat, W. C., Griffiths, D. & Yoshimura, N. Neural control of the lower urinary tract. Compr. Physiol. 5, 327–396 (2015) • Griffiths D. Neural control of micturition in humans: a working model. Nat Rev Urol. 2015 Dec;12(12):695-705 • de Groat WC, Yoshimura N. Anatomy and physiology of the lower urinary tract. Handb Clin Neurol 2015;130:61-108

Notas do Editor

  • Sympathetic fibres (shown in blue) originate in the T11–L2 segments in the spinal cord and run through the inferior mesenteric ganglia (inferior mesenteric plexus, IMP) and the hypogastric nerve (HGN) or through the paravertebral chain to enter the pelvic nerves at the base of the bladder and the urethra
    Parasympathetic preganglionic fibres (shown in green) arise from the S2–S4 spinal segments and travel in sacral roots and pelvic nerves (PEL) to ganglia in the pelvic plexus (PP) and in the bladder wall
    Somatic motor nerves (shown in yellow) that supply the striated muscles of the external urethral sphincter arise from S2–S4 motor neurons and pass through the pudendal nerves
    Parasympathetic postganglionic axons in the pelvic nerve release acetylcholine (ACh), which produces a bladder contraction by stimulating M3 muscarinic receptors in the bladder smooth muscle.
    Sympathetic postganglionic neurons release noradrenaline (NA), which activates β3 adrenergic receptors to relax bladder smooth muscle and activates α1 adrenergic receptors to contract urethral smooth muscle
    Somatic axons in the pudendal nerve also release Ach, which produces a contraction of the external sphincter striated muscle by activating nicotinic cholinergic receptors
  • Distention of the bladder produces low-level vesical afferent firing. This in turn stimulates the sympathetic outflow in the hypogastric nerve to the bladder outlet (the bladder base and the urethra) and the pudendal outflow to the external urethral sphincter. These responses occur by spinal reflex pathways and represent guarding reflexes, which promote continence.
    Sympathetic firing also inhibits contraction of the detrusor muscle and modulates neurotransmission in bladder ganglia.
    A region in the rostral pons (the pontine storage centre) might increase striated urethral sphincter activity
  • Combined cystometrograms and sphincter electromyograms
    A - Volume of urine exceeds the micturition threshold, increased afferent firing from tension receptors in the bladder produces firing in the sacral parasympathetic pathways and inhibition of sympathetic and somatic pathways. The expulsion phase consists of an initial relaxation of the urethral sphincter followed by a contraction of the bladder, an increase in bladder pressure, and flow of urine
    B, the start of sphincter relaxation, which precedes the bladder contraction by a few seconds, is indicated (“start”), a voluntary cessation of voiding (“stop”) is associated with an initial increase in sphincter EMG and detrusor pressure (a myogenic response), resumption of voiding is associated with sphincter relaxation and a decrease in detrusor pressure that continues as the bladder empties and relaxes
    C - paraplegic patient, the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, involuntary bladder contractions (detrusor overactivity) occur in association with sphincter activity. Each wave of bladder contraction is accompanied by simultaneous contraction of the sphincter (detrusor-sphincter dyssynergia), hindering urine flow. Loss of the reciprocal relationship between the bladder and the sphincter in paraplegic patients thus interferes with bladder emptying
  • During the elimination of urine, intense bladder afferent firing in the pelvic nerve activates spinobulbospinal reflex pathways (shown in blue) that pass through the pontine micturition centre.
    This stimulates the parasympathetic outflow to the bladder and to the urethral smooth muscle (shown in green) and inhibits the sympathetic and pudendal outflow to the urethral outlet (shown in red). Ascending afferent input from the spinal cord might pass through relay neurons in the periaqueductal gray (PAG) before reaching the pontine micturition centre
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