Neurophysiology of the GI Tract

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Neurophysiology of the GI Tract

• Klaus Bielefeldt

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Starting Point

• 51 year-old Caucasian woman complains about a new
  onset of severe RUQ pain associated with nausea.
• The pain started about 1 day ago and appears to
  worsen with food intake.
• The pain radiates to the right shoulder.
• She does not have fever or other symptoms.

What do you think?
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Patient Care and Neurogastroenterology
Afferent Pathways Sensation / Perception

• Pain
• Location
• Character
• Radiation
• Nausea

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Case 2

• 21 year-old man complains about 6 months of
  dysphagia for liquids and solids.
• He experiences chest pressure located in the
  retrosternal area and radiating to his neck.
• He occasionally regurgitates food.
• He lost about 3 kg within the last 3 months.

Disruption of normal esophageal function
(motility).
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Patient Care and Neurogastroenterology
Nerves Regulate Function

• Motility
• Secretion
• Blood flow
• Immunity

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Why Should You Care?

• UNDERSTANDING DISEASES
• DIAGNOSING DISEASES
• TREATING DISEASES
• YOU CHANGE NEUROMUSCULAR GUT FUNCTION
• Vagotomy
• Diuretics (hypokalemia)
• Calcium channel blockers
• Anticholinergics
• SSRI
• ISDN

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Nerves for the Gut
Nerve fibers can be found in all layers of the GI
tract. There are INTRINSIC and EXTRINSIC fibers.
Gastric CGRP fiber
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Gut Level Feelings

• Intrinsic Nerves
• Afferent nerves (input)
• Processing within the gut wall
• Efferent nerves (output)
• Encodes and modulates patterns
• Motility
• Secretion
• Blood flow

• Extrinsic Nerves
• Afferent nerves (input)
• Processing outside of the gut wall (CNS)
• Efferent nerves (output)
• Modulates patterns
• Rapid communication between brain and gut
  (perception).

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ENS Basic Structure
Neuroscience 198051
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Brain-Gut Axis
Vagus / Parasympathetics - afferents -
efferents Sympathetics / Spinal - afferents -
efferents
Division into sympathetic and parasympathetic
nerves should only be used for efferents.
Autonomic Neuroscience 851, 2000
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Starting Point Input Signals

• Mucosal fibers
• Chemosensation
• Mechanosensation
• Muscle fibers
• Stretch (distension)
• Tension (muscle tone)

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Direct Activation of Sensory Neurons
But there is more to activation of visceral
afferents.
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Special Case Serotonin
Chen et al., J Neurosci 2001
95 of the bodies serotonin is found in the GI
tract. Most of this serotonin is in
enteroendocrine cells.
Endocrine Reviews 24 571-599, 2003
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STIMULUS
5-HT
5-HT
Intrinsic Neuron
Extrinsic Neuron
Motility
Secretion
Motility Secretion
Sensation
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Not Always Precise
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More on PrecisionSpinal Divergence
Somatic afferent
Visceral afferent
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Peripheral Afferents

• Activation by mechanical (stretch muscle
  tension) and different chemical signals.
• Indirect activation through specialized
  epithelial cells (e.g. 5-HT in enteroendocrine
  cells).
• Visceral afferents may have many receptive fields
  and spread their information over several levels
  at the spinal cord (lack of precision).

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Viscero-somatic Convergence
Gallbladder
Right shoulder
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Convergence So What?

• Pain referral as a diagnostic criterion

Yamada et al (ed.) Textbook of Gastroenterology,
2003
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Where Does it Go?
Sensory motor cortex Insula (anterior gt
posterior) Anterior cingulate cortex Prefrontal
cortex BASICALLY MUCH IS IN MIDLINE STRUCTURES

• American Journal of Gastroenterology
  20039812-20.

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More About the Neighborhood
Nature Reviews Neuroscience 6 533-544 2005
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Does it Matter?
Visceral sensation triggers stronger emotional
response than somatic input.
Pain 97 235-246, 2002
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Bottom Line

• Visceral input is less precise (location,
  modality).
• Visceral input often projects to somatic areas
  (referral pain).
• Visceral input triggers strong emotional
  reactions.

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Pain GI Tract
More on this topic later.
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Output Signals
Chemical Signaling (Neurotransmitter)
Cytosol







Interstitium


Electrical Signaling (Action Potential)
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Synaptic Transmission Acetylcholine (muscarinic
receptors)
ACh
200
160
2
Ca
120
Calcium Channel Blockers
80
40
0
20
40
60
100
80
Time (s)
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Back to Case 2

• 21 year-old man complains about 6 months of
  dysphagia for liquids and solids.
• He experiences chest pressure located in the
  retrosternal area and radiating to his neck.
• He occasionally regurgitates food.
• He lost about 3 kg within the last 3 months.

Disruption of normal esophageal function
(motility).
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Structure without Stricture
No tumor or stricture. BUT Aperistalsis No
LES relaxation
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Achalasia A Disease of Intrinsic Nerves
GASTROENTEROLOGY 111 648 1996
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Mimic Matters of NO
NO release by enteric neurons regulates
propagation along the smooth muscle portion of
the esophagus and LES relaxation.
Gastroenterology 19951091241-8
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ENS TASKSMotor Patterns Gut

• Stereotypical sequences of activity (motility).
• Deglutition (CNS)
• Esophageal peristalsis (CNS ENS)
• Migrating motor complex (ENS)
• Defecation (CNS ENS)
• State dependent (stomach small bowel)
• Fasting activity
• Fed activity

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Esophageal Peristalsis
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Migrating Motor Complex

• MMC (migrating motor complex)
• Duration about 90 120 min (longer at night)
• Maximal contraction frequency 12 / min

Phase I quiescent Phase II irregular
contractions Phase III activity front
Dig Dis Sci 42 873-877
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More then Movement

• Sphincters keep areas / compartments separated.
• Esophageal sphincters
• UES
• LES
• Pylorus
• Sphincter of Oddi
• Ileo-cecal valve
• Anal sphincter
• Accommodation prepares storage sites
• Stomach
• Gall bladder
• Rectum

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Take Home

• The enteric (intrinsic) nervous system regulates
  patterns (e.g. peristalsis).
• Acquired disruption or genetic defects causes
  disease.
• More on this from Dr. Moore

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Feeling Full

• A 27 year-old woman presents with severe
  abdominal pain and bloating after eating.
• She has 1 BM/week.
• She lost 5 kg / 6 months.
• Her examination shows a distended abdomen with
  sparse bowel sounds.

Intestinal Pseudo-Obstruction
Gut. 43117-22, 1998
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Biopsy ICC Problem
Normal
c-kit neuronal marker
c-kit
Loss of ICC impairs motility.
GASTROENTEROLOGY 200011814-21
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What are ICC?

• Interstitial Cells of Cajal are specialized
  mesenchymal cells.
• They form a network within the muscularis
  propria.
• They generate spontaneous electrical activity
  (pacemaker system).
• They have extensive connections with muscle cells.

Journal of Physiology 531 827, 2001
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Pacemaker in the Gut?
Loss of ICC loss of normal spontaneous activity
Journal of Physiology 531 827, 2001
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Why Do I Need to Know This?

• Muscle and other effector cells (e.g. ICC) are
  important.
• ICC generate spontaneous electrical activity
  necessary for normal motility.
• Rare inherited and acquired diseases are due to a
  loss of ICC.
• Drugs affect the ion channels underlying this
  spontaneous electrical (and resulting mechanical)
  activity (e.g. calcium channel blocker).

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Doc, I Cant Swallow!
A 72 year old man complains about daily episodes
of problems swallowing. Liquids and solids will
get stuck. He points at an area in the
mid-neck. His problem started immediately after
he suffered a stroke 2 weeks ago. Prior to this
acute event, he had no gastrointestinal problems.
He is recovering from pneumonia. The physical
examination demonstrates a left hemiparesis, a
wet voice and some crackles over the right base.
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Whats the Problem?
Retention
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Gut Dysfunction CNS

• Especially important in deglutition defecation.
  (processes are under voluntary control).
• Initiation of swallowing and defecation involves
  striated muscle
• Deglutition tongue, soft palate, hypopharynx,
  larynx, proximal esophagus
• Defecation external anal sphincter abdominal
  muscles.

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Postprandial Blues

• A 64 year-old woman complains about fullness and
  discomfort after eating.
• She has lost about 3 kg over the last 2 years.
• 20 years ago, she underwent a vagotomy for peptic
  ulcer disease.

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Vagus Gastric Emptying
Vagotomy
Aliment Pharmacol Ther, 11381-385
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Brain Gut Axis 2

• The CNS regulates / modulates GI function.
• Neurological diseases and / or intentional
  dissection of intestinal nerves affect GI
  function.

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The Real Bottom Line

• The innervation of the GI tract is complex.
• Changes in sensory and/or motor (secreto-motor)
  nerves contribute to disease.
• As physicians, we often intentionally or
  unintentionally alter structure / function of
  nerves within the GI tract.