Gastroenterology Clinics of North America pptx

Preface
Henry P. Parkman, MD
Guest Editor
T
his issue of Gastroenterology Clinics of North America focuses on an important
area in gastroenterology for both clinicians and researchers: neurogas-
troenterology and gastrointestinal (GI) motility disorders. GI motility
and functional GI disorders are common reasons for patients to see physicians.
Knowledge of GI motility disorders, including the evaluation and treatment of
these disorders, is important for gastroenterologists, clinicians, and health care
providers to appropriately care for these frequently seen patients in clinical
practice.
Gastrointestinal motility can be defined as motor activity in the digestive tract
that mixes ingested food with digestive juices and moves luminal contents of
the gastrointestinal tract in an aboral direction from the mouth toward the
anus. A better understanding of the pathophysiology of GI motility disorders
has revealed a crucial role of the enteric, autonomi c, and central nervous sys-
tem. In fact, the term neurogastroenterology was introduced in the early 1990s to
account for the study of these processes. As with any new term, there was re-
sistance to its introduction. The breakthrough came when the editorial board of
the Journal of Gastrointestinal Motility changed its name to Neurogastroenterology and
Motility in 1994. The European Society changed its name in 1996; recently, the
American Society became the American Neurogastroenterology and Motility
Society, and the International Group became the International Society of Neu-
rogastroenterology. Neurogastroenterology emphasizes clinical and experimen-
tal gastroenterology embracing the concept of brain–gut interactions and refers
to motor disorders of the gastrointestinal tract attributable to neural control
mechanisms, includin g the psychophysiology of clinical disorders of visceral
perception and motor function. As defined in the free online encyclopedia
Wikipedia, ‘‘neurogastroenterology is a research area in the field of

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doi:10.1016/j.gtc.2007.07.011 gastro.theclinics.com
Gastroenterol Clin N Am 36 (2007) xiii–xiv
GASTROENTEROLOGY CLINICS
OF NORTH AMERICA
gastroenterology which regards interactions of the central nervous system
(brain) and the gut—the so-called brain–gut axis. Important research focuses
upon upward (sensory) and downward (motor and regulatory) neural connec-
tions and upon endocrine influences on gut function and the enteric nervous
system in itself. Clinical researc h deals on many levels involving GI motility
disorders and functional bowel disorders.’’
The articles in this issue discuss key aspects of GI motility disorders, focus-
ing on how they relate to practicing gastroenterologists, clinical investigators,
and other health care providers. Curren t knowledge in the area as well as
evolving concepts from clinical investigations and translational research from
basic sciences is discussed. The rapid explosion of new technology used in
the evaluation of patients is also addressed.
Most of the articles in this issue were written by members of the American
Neurogastroenterol ogy and Motility Society, formerly known as the American
Motility Society. The mission of the American Neurogastroenterology and Mo-
tility Society (ANMS) is to advance the study of neurogastroenterology, GI mo-
tility, and related enteric sciences; to promote the training of basic scientists and
clinician investigators; to translate the scientific advances to patient care; and to
disseminate the knowledge to patients and caregivers to improve the diagnosis
and treatment of patients with GI motility and functional GI disorders.
I hope you enjoy this edition of the Gastroenterology Clinics of North America!It
was a pleasure putting it together.
Henry P. Parkman, MD
Gastroenterology Section
Department of Medicine

Temple University Hospital
3401 North Broad Street
Philadelphia, PA 19104, USA
E-mail address:
xiv PREFACE
Overview of Neurogastroenterology-
Gastrointestinal Motility and Functional
GI Disorders: Classification, Prevalence,
and Epidemiology
Ann Ouyang, MD
a
, G. Richard Locke III, MD
b,
*
a
Division of Gastroenterology and Hepatology, Hershey Medical Center,
500 University Drive, Hershey, PA 17033, USA
b
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine,
200 First Street SW, Rochester, MN 55905, USA
‘‘
T
he times they are a-changing.’’ This famous title from a Bob Dylan track
and album sums up state of the understanding of functional gastrointes-
tinal disorders and motility disorders. Advancing technology, the in-
creased application of pharmacogenomics, and an expansion of an
integrative approach to understanding disease pathophysiology has led to sig-
nificant changes in how clinicians view the conditions that are encompassed by
the term ‘‘neurogastroenterology and motility disorders,’’ which is being in-
creasingly applied to these conditions. Classically, these conditions have been

described as functional gastrointestinal disorders (FGIDs) if patients complain
of symptoms related to the gastrointestinal tract in the absence of anatomic and
biochemical abnormalities [1] or motility disorders when a distinct and measur-
able alteration of motor function occurs (eg, achalasia, scleroderma, gastropa-
resis). The overlap between these two groups of conditions has caused
significant confusion in both nomenclature and in the literature. The rationale
and genesis of the Rome classification resulted from a need to change the focus
from a group of conditions serving as a catch-all diagnosis after exclusion of
organic conditions to ones with a positive diagnosis [1,2] and has been helpful
toward achieving this goal. This classification has been a useful tool for clinical
studies to decrease the heterogeneity of subjects recruited and to improve gen-
eral acceptance that these conditions are clustered in a manner that suggests
that there is a common pathophysiology that can be determined with time
and appropriate study. The last decade has resulted in tremendous advances
in understanding the pathophysiology related to these conditions. It is
*Corresponding author. E-mail address: (G.R. Locke III).
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doi:10.1016/j.gtc.2007.07.009 gastro.theclinics.com
Gastroenterol Clin N Am 36 (2007) 485–498
GASTROENTEROLOGY CLINICS
OF NORTH AMERICA
anticipated that the next decade will move these conditions from being symp-
tom based to pathophysiology based.
The term ‘‘neurogastroenterology’’ was introduced to include the processing
of information between the viscera and the brain [3]. Research in the ensuing
decade has shown overlap between conditions affecting the end organ and the
brain-gut axis. The term ‘‘neurogastroenterology and motility disorders’’ en-
compasses the organ systems that contribute to the symptom constellation
that are experienced by patients with these disorders: the central nervous sys-
tem (CNS), contributing to the sensory and motor control of the gastrointesti-

nal tract; and the gastrointestinal functional unit, which includes the enteric
nerves and smooth muscle. Most of the motor and sensory function of the
gut occurs subconsciously and cerebral cortical activity is a key to the percep-
tion of gastrointestinal activity. The patient’s experience of visceral activity is
influenced by psychologic context, which can affect both the severity of the
sensation and the degree of unpleasantness of the sensations.
This issue highlights some of the advances in the understanding of these con-
ditions and how to translate this knowledge into the diagnosis and manage-
ment of patients. This article focuses on the classification and epidemiology
of these conditions.
CLASSIFICATION OF NEUROGASTROENTEROLOGY
DISORDERS
The Rome III classification of FGID is outlined below [4]. In comparison with
the Rome II criteria, the current classification has expanded the pediatric cate-
gories and provided more restrictive criteria for functional disorders of the gall-
bladder and sphincter of Oddi. In addition, functional abdominal pain was
separated from functional bowel disorders and placed into its own category
as recognition that this was primarily related to disorders of CNS functioning,
which results in a perceived sensation of pain in the presence of normal visceral
signals. These changes in the classification imply an acceptance that the classi-
fication will eventually change to one based on pathophysiology rather than
symptom complexes.
A. Functional esophageal disorders
A1. Functional heartburn
A2. Functional chest pain of presumed esophageal origin
A3. Functional dysphagia
A4. Globus
B. Functional gastroduodenal disorders
B1. Functional dyspepsia
B1a. Postprandial distress syndrome

B1b. Epigastric pain syndrome
B2. Belching disorders
B2a. Aerophagia
B2b. Unspecified excessive belching
B3. Nausea and vomiting syndromes
486 OUYANG & LOCKE
B3a. Chronic idiopathic nausea
B3b. Functional vomiting
B3c. Cyclic vomiting syndrome
C. Functional bowel disorders
C1. Irritable bowel syndrome
C2. Functional bloating
C3. Functional constipation
C4. Functional diarrhea
C5. Unspecified functional bowel disorder
D. Functional abdominal pain syndrome
E. Functional gallbladder and sphincter of Oddi disorders
E1. Functional gallbladder dysfunction
E2. Functional biliary sphincter of Oddi disorder
E3. Functional pancreatic sphincter of Oddi disorder
F. Functional anorectal disorders
F1. Functional fecal incontinence
F2. Functional anorectal pain
F2a. Chronic proctalgia
F2a1. Levator ani syndrome
F2a2. Unspecified functional anorectal pain
F3. Functional defecation disorders
F3a. Dyssynergic defecation
F3b. Inadequate defecatory propulsion
G. Functional disorders: neonates and toddlers

G1. Infant regurgitation
G2. Infant rumination syndrome
G3. Cyclic vomiting syndrome
G4. Infant colic
G5. Functional diarrhea
G6. Infant dyschezia
G7. Functional constipation
H. Functional disorders: children and adolescents
H1. Vomiting and aerophagia
H1a. Adolescent rumination syndrome
H1b. Cyclic vomiting syndrome
H1c. Aerophagia
H2. Abdominal pain-related functional gastrointestinal disorders
H2a. Functional dyspepsia
H2b. Irritable bowel syndrome
H2c. Abdominal migraine
H2d. Childhood functional abdominal pain
H2d1. Childhood functional abdominal pain syndrome
H3. Constipation and incontinence
H3a. Functional constipation
H3b. Nonretentive fecal incontinence
Table 1 provides a classification of the conditions that are considered neuro-
gastroenterology and motility disorders based on the current understanding of
the neuroanatomic level at which dysfunction can be recognized. This includes
487OVERVIEW OF NEUROGASTROENTEROLOGY
the end organ (at the gut level, which includes the enteric nerves, interstitial
cells of Cajal, and smooth muscle); sensory dysfunction alone (including the
afferent pathway from the gut and CNS processing); and disorders in which
there is a combined sensory and motor dysfunction. This classification is pos-
sible because of the development of technologies to assess these pathways sep-

arately. Examples of these technologies include the electrogastrogram, which
allows an assessment of motor activity in the stomach; advances in interpreta-
tion of videofluoroscopy and measurements of motor activity [5]; the barostat,
Table 1
Neurogastroenterology and motility disorders: classification based on brain-gut axis model
Location
Evidence for GI
dysmotility
Both motor and
sensory dysfunction
Primarily
sensory
Primarily CNS
processing
Esophagus Achalasia Diffuse esophageal
spasm
Functional
heartburn
Globus
Scleroderma Nutcracker
esophagus
Functional
dysphagia
Hypotensive
LES-GERD
Hypertensive LES
GERD-normal LES
Stomach Gastroparesis Dumping
syndrome
Functional

dyspepsia
Tachygastria Cyclic vomiting
syndrome
Functional
nausea
Scleroderma Rumination
syndrome
Belching disorders
Biliary tract Gallbladder
dysmotility
Sphincter of Oddi
dysfunction
Intestine and
colon
Chronic idiopathic
intestinal
pseudo-
obstruction
Irritable bowel
syndrome
Functional
bloating
Functional
abdominal
pain
Colonic inertia Bacterial
overgrowth
Scleroderma Functional
diarrhea
Functional

constipation
Anorectal Hirschsprung’s
disease
Functional
constipation
Functional
proctalgia
Pelvic floor
dyssynergia
Functional
anorectal pain
Functional
defecation
disorders
Abbreviations: CNS, central nervous system; GERD, gastroesophageal reflux disease; GI, gastrointestinal;
LES, lower esophageal sphincter.
488 OUYANG & LOCKE
which allows a measurement of the sensory pathway [6] particularly if used in
conjunction with pharmacologic blockade of motor activity; and a variety of
CNS imaging modalities including positron emission tomography scans and
functional MRI [7].
In the future, the next level of classification will be based on the underlying
pathophysiology, which might include a combination of factors including prior
inflammatory conditions with peripheral sensitization of the visceral pain path-
way. Such a classification will necessarily depend on the ability to detect such
alterations in the immune and cytokine pathways and assessment of the neuro-
transmitter function in the brain and gut [8–11].
One Disease or Many
Although a classification system based on physiology is the goal for the future,
the Rome criteria are the accepted classification scheme of the present for

FGID. Still, the question remains as to whether 27 separate adult and 13 sep-
arate pediatric disorders exist. Some of these disorders are symptom com-
plexes, whereas others are single symptoms. One might argue whether or
not a single symptom should qualify as a unique disorder. The hope was
that homogeneity would lead to better studies of pathogenesis and therapy.
These disorders occur within the human body, however, and many similar-
ities exist from esophagus to stomach to small and large intestine. Patients
often present with multiple symptoms from different regions of the body.
Disorders of sensorimotor function might affect multiple sites along the gastro-
intestinal tract. For example, half of people with irritable bowel syndrome
(IBS) also have symptoms of reflux [12]. Symptoms may change over time
and a patient may have IBS symptoms one year and then dyspepsia symptoms
the next year [13]. One approach is to split these into separate conditions and
manage them separately. An alternative, however, is to think of the patient as
having one ‘‘pan-gut’’ or systemic disorder and manage the patient
accordingly.
In the future, much will be learned about the prevalence and epidemiology
of these pathophysiologic abnormalities. This will shed light on the appropriate
classification scheme. At present clinicians must continue to rely on symptoms
to define many of the neurogastroenterology and motility disorders. These
symptom-based diagnoses have been used extensively over the past 20 years
to understand the epidemiology of these conditions.
EPIDEMIOLOGY
Neurogastroenterology and motility disorders include the currently accepted
FGIDs and other primarily motor disorders, such as achalasia. FGIDs are ex-
tremely common conditions [14,15]. Studies have shown that many people
with FGIDs do not seek care. The decision to seek care introduces bias in
clinic-based research [16]. For this reason, population-based research has
been used to evaluate fully the epidemiology and clinical symptoms in individ-
uals with FGIDs. Many gender- and age-related issues arise related to the

489OVERVIEW OF NEUROGASTROENTEROLOGY
FGIDs. Extensive epidemiologic data exist for IBS, dyspepsia, heartburn, consti-
pation, and fecal incontinence, but less is known about the other neurogastroen-
terology conditions. For many FGIDs, such as globus, rumination, and sphincter
of Oddi dysfunction, the onlydata on prevalence by age come from a single study
[14]. Similarly, other motility disorders, such as achalasia and gastroparesis,
which are defined by physiologic or anatomic criteria, do not lend themselves
to epidemiologic studies except in small, very well characterized populations
[17,18]. To date, theepidemiologicstudieshave been conductedprimarilyinwest-
ern populations; data from other areas of the world are limited but growing [19].
Esophageal Disorders
The functional esophageal disorders include globus, rumination syndrome,
functional chest pain, functional heartburn, and functional dysphagia. Studies
have shown that these functional esophageal disorders are all quite common
[14,20]. Globus sensation is reported by 7% to 12.5% of the population
[14,20] and is more common in women. Rumination syndrome is reported
by 10.9% of the population [14]. No difference in gender has been reported.
The prevalence estimates of functional chest pain have varied between
12.5% and 23.1% [14,20,21]. These population-based estimates have relied
on the person’s self-report of not having cardiac disease. Still, noncardiac chest
pain and functional chest pain of esophageal origin are not synonymous.
People with noncardiac chest pain can have many underlying causes [22].In
the community, noncardiac chest pain has an equal gender prevalence
[14,20,21], but a higher female-to-male ratio in tertiary care referral centers
[23]. The prevalence of most of these disorders decreases with age. Specifically,
globus, rumination syndrome, and self-reported functional chest pain are all
more common in younger people [14,20,21].
Many of the symptoms of functional esophageal disorders are experienced
by people with gastroesophageal reflux disease [20]. Estimating the true prev-
alence of functional heartburn in the community is quite difficult. In popula-

tion-based studies, pH monitoring is not a real option because invasive
studies greatly reduce response rates [24]. The data are on symptoms rather
than a diagnosis. The prevalence of heartburn does not vary by gender and
is similar among people ages 25 to 74 [20].
Dysphagia is reported by 7% to 13% of the population [14,20]. Whether dys-
phagia is associated with gender is not clear. One study found that a difference
of 6.3% in men and 8.5% in women was statistically significant [14], whereas in
another study, the difference between 12.4% of men and 14.6% of women was
not statistically significant [18]. A gender effect may exist but it is small. The
prevalence of dysphagia increases with age, most notably in participants in
the 65- to 74-year category [18]. The proportion of these people who have func-
tional dysphagia versus another esophageal disorder (eg, esophageal obstruc-
tion or a motility disorder) is not known. Many conditions that affect motor
function of the oropharynx and esophagus, such as stroke and Parkinson’s
disease, are more prevalent in the elderly [25].
490 OUYANG & LOCKE
Esophageal motility disorders, which primarily involve the end organ (eg,
achalasia), are defined by the abnormal motility pattern of aperistalsis and im-
paired lower esophageal relaxation. Clearly, a population-based study that in-
volves an invasive diagnostic test is not feasible. Studies of the prevalence of
achalasia have often relied on hospital admissions and are retrospective. Stud-
ies from Iceland and Great Britain indicate an incidence of about 0.55 cases per
100,000 population per year [17,18].
Gastroduodenal Disorders
Dyspepsia is not a condition; it is a symptom complex. Dyspepsia can be de-
fined as persistent or recurrent abdominal pain or abdominal discomfort cen-
tered in the upper abdomen [26]. The term ‘‘discomfort’’ includes symptoms
of nausea, vomiting, early satiety, postprandial fullness, and upper abdominal
bloating. Symptoms are typically associated with eating but not with bowel
movements. In early studies, the symptoms of heartburn and acid regurgitation

were often included as symptoms of dyspepsia. Yet, if these symptoms are the
main symptoms, the patient should be considered to have reflux rather than
dyspepsia. Right upper quadrant pain or epigastric pain radiating to the back
should not be included in the dyspepsia definition.
Functional dyspepsia can then be defined as dyspepsia symptoms of more
than 3 months’ duration without an anatomic or biochemical abnormality
[26]. Typically, this means negative blood tests and a negative evaluation of
the upper gastrointestinal tract with either an endoscopy or barium radiograph.
Defining a negative endoscopy, however, can be difficult. Does this include
biopsies of the esophagus for esophagitis or biopsies of the stomach for gastritis
or Helicobacter pylori? Are erythema, erosions, or histologic inflammation mean-
ingful findings? These are somewhat controversial issues. What about other
tests like ultrasounds, CT scans, gastric emptying studies, or ambulatory pH
monitoring? Do these have to be done before making a diagnosis of functional
dyspepsia? These are issues that still need to be resolved.
Many surveys have evaluated how many people experience symptoms of
dyspepsia in the community. The rates vary in large part because of the defi-
nitions used. The surveys that include the symptom of heartburn in the defini-
tion of dyspepsia report a prevalence of 40% [27]. Other surveys exclude
subjects with symptoms of heartburn or IBS and report prevalence rates below
5% [14]. Nonetheless, it is reasonable to say that 15% (about one in seven) of
the adult population has dyspepsia [28]. Not all these people with dyspepsia
have functional dyspepsia. In one study, a random sample of the population
with dyspepsia underwent endoscopy [29]. Only 53% had a normal endoscopy.
The abnormal findings were esophagitis, peptic ulcer disease, duodenitis, and
duodenogastric reflux. Only 66% of the asymptomatic controls in this study,
however, had normal endoscopy. Peptic ulcer disease and duodenitis were
more common in the dyspepsia cases than the controls, but the other findings,
such as gastritis, were seen in similar numbers of cases and asymptomatic
controls.

491OVERVIEW OF NEUROGASTROENTEROLOGY
The prevalence of dyspepsia does not vary by gender [14,30]. Distinct sub-
groups of dyspepsia have been defined: ulcer-like dyspepsia, dysmotility-like
dyspepsia, and unspecified dyspepsia [26]. The prevalence of the ulcer-like
and dysmotility-like dyspepsia subgroups also do not vary by gender. Some
studies have suggested that the prevalence of dyspepsia decreases with age
[31–33]. The distribution of subtypes (ulcer-like and dysmotility-like), however,
does not vary by age.
The prevalence of aerophagia has been estimated to be 23.4% to 29%
[14,34]. Men are slightly more likely to report aerophagia than women. Young
people are slightly more likely to report aerophagia than older people.
The overall prevalence of functional vomiting is 2.3%, but there is no asso-
ciation with gender. In general, more men than women reported vomiting, but
this is not a statistically significant difference [30,31]. Vomiting decreases with
age.
The prevalence of gastroparesis, as defined by delayed gastric emptying, is
unclear. Although delayed gastric emptying has been recognized as a conse-
quence of systemic conditions, such as diabetes mellitus and systemic sclerosis,
it is also reported in functional dyspepsia and gastroesophageal reflux [35]. The
true prevalence is unknown because, in its strictest sense, the diagnosis depends
on a study that, although relatively noninvasive, is not applicable to a large
population. The issues related to gastroparesis are discussed elsewhere in
this issue.
Bowel Disorders Affecting Small Intestine and Colon
IBS is the best studied of all the FGIDs and can be defined as a constellation of
recurrent or chronic abdominal pain that is associated with defecation and
a chronically altered bowel habit [2]. How common is IBS? The answer de-
pends greatly on the definition used. In an early study, a representative random
sample of the United States population was asked if they had active symptoms
of spastic colon or mucous colitis. The prevalence varied by age and gender but

overall was roughly 20 per thousand [36]. This study, however, required that
the patient needed to know if they in fact had one of these diagnoses. Because
not everyone with IBS goes to the doctor and receives a diagnosis, an alterna-
tive strategy to determining prevalence was required. Many population-based
surveys have assessed the individual symptoms of IBS. The survey responses
are then used to make a diagnosis of IBS. The prevalence rates in these studies
have varied between 8 and 22 per hundred [14,15,37–39]. Note the 10-fold dif-
ference in prevalence rates between asking about a diagnosis and asking about
the symptoms of IBS. Why do the prevalence rates from the IBS-specific symp-
tom surveys vary threefold? Although this may represent true differences in
populations, it more likely reflects differences in the IBS definition. Higher
prevalence rates are identified using a threshold of two of six Manning criteria
[40]. Lower prevalence rates are identified using more specific criteria, whether
by increasing the threshold of Manning criteria necessary to make the diagnosis
or using the Rome criteria. In a direct comparison, prevalence using standard
492 OUYANG & LOCKE
Rome criteria is comparable with using a threshold of three of six Manning
criteria [40].
In clinic-based studies, IBS is strongly associated with gender. Of interest,
however, the female to male ratio in the community is approximately 2:1. Gen-
der may have a role in the onset of IBS but also has a role in health care seeking
behavior [16]. Gender may also play a role in symptom severity. In a study of
patients having general examinations in a health maintenance organization,
overall 68% of those with IBS symptoms were female. In those with mild symp-
toms (<3 Manning criteria), 65% were female, and in those with more severe
symptoms (!3 Manning criteria), 80% were female [41]. In another study,
symptom severity was compared in IBS patients from primary care clinics
with those from university internal medicine outpatient clinics [42]. Women
attending the outpatient clinics had a higher severity score than did men attend-
ing the same clinics, but women and men attending the primary care clinics had

the same severity. The prevalence rates for pain-related symptoms in IBS are
similar by gender [43], but a greater female predominance is seen in non–
pain-associated symptoms of constipation, bloating, and extraintestinal mani-
festations. In contrast, men reported higher levels of diarrhea [44,45].
The prevalence of IBS does decrease slightly with age. New-onset symptoms
may occur in the elderly [14,46]. Among the elderly, however, the prevalence
of IBS was found to increase with age from 8% among those 65 to 74 years to
over 12% for those over 85 [46]. Data regarding racial differences are increas-
ing with studies now available from around the globe [17]. The prevalence of
IBS seems to be lower in non-Western countries. This difference may reflect
a true cultural or biologic phenomenon or stem from methodologic differences,
such as the difficulties in performing population studies in some of these coun-
tries [17].
In contrast to IBS, much less is known about the epidemiology of functional
abdominal bloating. One study found that women were more likely than men
to report bloating or abdominal distention. The prevalence in women was 19%
versus 10% in men [47]. Another study, however, found that men were more
likely than women to report bloating (34% versus 27%) [14]. The existing lit-
erature is also discordant in regard to the changes in the estimates of bloating
by age [14,47].
Studies evaluating gender differences in the prevalence of functional consti-
pation and functional diarrhea have reported a female predominance in func-
tional constipation but similar rates in men and women with functional
diarrhea [14,31,48–50]. Chronic constipation is a common condition that has
been self-reported in 20.8% of women and 8% of men [49]. A more recent
study of more than 10,000 individuals reported the prevalence of constipation
in 16% of women and 12% of men [50]. The female-to-male ratio was elevated
for both the outlet type and the combined IBS-outlet type of functional consti-
pation. In one study, women with functional constipation were more likely to
seek medical care compared with men (36% versus 19.5%) at all ages except for

50 to 64 years where probability rates were similar [51]. The prevalence of
493OVERVIEW OF NEUROGASTROENTEROLOGY
constipation clearly increases with advancing age [52–54]. Pathophysiologic
studies in patients with constipation classify patients based on underlying con-
ditions, which include medication-related constipation; constipation related to
a systemic disorder; and neurogastroenterology conditions, which include co-
lonic inertia and pelvic floor dyssynergy. These disorders are discussed else-
where in this issue.
The prevalence estimates of self-reported diarrhea vary from 1.6% to 27%
[14,31,55]. Some people with diarrhea may be alternating, however, and indi-
vidual diarrhea symptoms do not correlate well to an overall self-report of
diarrhea. One study identified decreasing rates of diarrhea with age [36].
The prevalence of functional abdominal pain has been estimated to be 1.7%
[14]. The rate was higher in women and decreased slightly with age.
Disorders of the Biliary Tract and Pancreas
As opposed to studies of IBS, which allow for symptoms to be assessed by
questionnaire, the diagnosis of sphincter of Oddi dysfunction requires invasive
testing. Very little epidemiologic data exist. One study estimated the prevalence
of sphincter of Oddi dyskinesia to be 0.8%. The rate was much higher in
women (2.3% versus 0.6%) and increased with age [14].
Anorectal Disorders
Prevalence rates of fecal incontinence have varied from 3% to 11%
[14,52,56,57]. The role of gender in fecal incontinence has varied by study.
Among nursing home residents, incontinence has been reported to be more
common in men [58], whereas among older people living at home, the reported
rates are higher in women [59,60]. Men are more likely to report soiling of
underclothes [56]. Fecal incontinence clearly increases with age [14,52,56,57].
Relatively little data exist on the epidemiology of functional anorectal pain.
The estimated prevalence is 11.3% with no difference in gender, but decreasing
rates with age [14].

Pelvic floor dysfunction is a recognized cause of constipation. The preva-
lence of outlet delay has varied from 4.6% [47] and 11% [61] and was more
common in women. In the one study that attempted to estimate the prevalence
of dyschezia, the rate was 13% with higher rates in women [14]. The prevalence
of rectal outlet delay does not vary by age [61]. Outlet delay is more common
in women. Finally, prevalence of dyschezia has been reported to be similar by
age.
SUMMARY
Symptoms of neurogastroenterologic and motility disorders are quite prevalent
in the community. The epidemiologic data for FGIDs are summarized in Table
2. In general, women report these symptoms more than men. Women are more
likely to report globus, IBS, bloating, constipation, chronic functional abdomi-
nal pain, sphincter of Oddi dysfunction, fecal incontinence, and pelvic floor
dysfunction. In contrast, women and men report similar rates of functional
esophageal symptoms and dyspepsia. Most of the high-quality epidemiologic
494 OUYANG & LOCKE
studies have been conducted in Western populations with IBS, constipation,
heartburn, and dyspepsia but not the other FGID. Some FGID increase with
age, whereas others decrease. The challenge is that these studies do not include
diagnostic tests and they measure symptom reporting rather than being true
estimates of the prevalence of the FGIDs. Exclusions are often done based
on self-report but this is not entirely accurate. Any shift in classification to
a pathophysiologic basis requires different approaches to determine the
prevalence.
Most of the studies have been of middle-aged populations. More recently
studies have been more focused on patients at the two extremes of age, children
and the elderly. The presence of FGIDs in children is well recognized [62].
Only recently, however, have studies begun to examine the relationship be-
tween gastrointestinal symptoms in children and adults. The exact age of onset
of FGIDs remains to be determined.

The classification of FGID and motility disorders is in a state of transition.
Over time, the emphasis will likely shift from symptoms to pathophysiology.
Nonetheless, the epidemiology of these conditions is based on symptom
surveys. This article reviewed the epidemiology of these common disorders
from the esophagus to the anorectum.
Table 2
Prevalence by gender and change with age for the functional GI disorders
FGID Prevalence by gender Change with age
Esophageal
Globus F >M #
Rumination F ¼ M #
Functional chest pain F ¼ M #
Functional heartburn F ¼ M ¼
Dysphagia F >M "
Gastroduodenal
Dyspepsia F ¼ M #
Aerophagia M >F #
Functional vomiting ¼#
Biliary tract F "
Lower GI tract
IBS F #
Functional constipation F "
Functional diarrhea M >F #
Functional bloating Discordant studies Discordant studies
CFAP F >M #
Fecal incontinence F >M (at home) "
M >F (nursing homes)
Functional anorectal pain F >M #
Outlet delay F ¼
Of note, some of the data in this table are based on single studies or multiple small-scale studies and should

be interpreted with caution.
Abbreviations: CFAP, chronic functional abdominal pain; FGID, functional gastrointestinal disorder; GI,
gastrointestinal; IBS, irritable bowel syndrome.
495OVERVIEW OF NEUROGASTROENTEROLOGY
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498 OUYANG & LOCKE
Evolving Concepts in the Cellular

Control of Gastrointestinal Motility:
Neurogastroenterology
and Enteric Sciences
Amelia Mazzone, PhD
a,b
, Gianrico Farrugia, MD
a,b,
*
a
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine,
200 First Street SW, Rochester, MN 55905, USA
b
Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine,
200 First Street SW, Rochester, MN 55905, USA
T
he function of the gastrointestinal tract is controlled by a dynamic inter-
action between different cell types that interact directly, or through a large
number of signaling molecules. Enteric neural integrity is essential for
normal gastrointestinal motility, as is a constant communication between the
enteric and the central nervous system (CNS). Smooth muscle cells form an
electrical syncytium within the gut and are innervated, directly or indirectly,
by neurons. Not only are smooth muscle cells the final effector cells that result
in gastrointestinal motility, but recently they have been found also to have an
active role in the control of motility. The basic electrical rhythm of the gut, the
slow waves, originates from a complex network of cells known as ‘‘interstitial
cells of Cajal’’ (ICC). ICC not only generates the slow wave but is also in-
volved in effective neurotransmission and in the control of smooth muscle
membrane potential. Other cellular elements, such as the immune system
and enteric glia, are now increasingly understood actively to be involved in
the modulation of intestinal functions. The study of the complex interaction

of different kind of cells is known as ‘‘neurogastroenterology,’’ a subspecialty
of gastroenterology that focuses on understanding the control of the sensory
and motor function of the gastrointestinal tract in health and disease.
ENTERIC NERVOUS SYSTEM
The enteric nervous system (ENS) regulates most of the physiologic and path-
ophysiologic processes in the gastrointestinal tract. These include control of
This work was supported by grants DK17238, 57061, and 68055 from the National Institutes of Health.
*Corresponding author. Division of Gastroenterology and Hepatology, Mayo Clinic College
of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail address: farrugia.
(G. Farrugia).
0889-8553/07/$ – see front matter ª 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.gtc.2007.07.003 gastro.theclinics.com
Gastroenterol Clin N Am 36 (2007) 499–513
GASTROENTEROLOGY CLINICS
OF NORTH AMERICA
motor functions for the transpo rt of luminal content, regulation of blood flow
and of secretion and absorption, and modulation of the immune response
against pathogens. The ENS consists of a netwo rk of enteric neurons organized
in ganglia interconnected by nerve fiber bu ndles surrounded by support cells.
These neural circuits are able to exchange and integrate information in a way
similar to the CNS, including generation of reflexes; the ENS often is referred
to as the ‘‘little brain.’’
The ENS is made up of two major components. The submucosal plexus is
located between the inner layer of the circular muscle and the submucosa
and is more developed in the small and large intestine. Its role is mainly in
the regulation of mucosal and vascular functions in responses to nutrients. In
large mammals, submucosal ganglia form two distinct, but interconnected,
plexuses that are defined as inner and outer submucosal plexus [1]. The myen-
teric plexus lies between the inner circular and outer longitudinal smooth
muscle layers along the entire gastrointestinal tract and it is mainly involved

in the coordination of the activity of the muscle layers. In the small intestine
a deep muscular plexus is also present, made up of nerve bundles (without
cell bodies). The deep muscular plexus lies between the most inner circular
smooth muscle cells and the rest of the circular muscle layer.
Work on identification and classification of enteric neurons has been per-
formed mostly in the guinea pig small intestine [2], but the overall organization
and function of neurons is applicable to larger mammals, including humans.
Based on morphology, electrophysiologic properties, function, and neurochem-
istry, enteric neurons can be classified in intrinsic primary afferent neurons
(IPANs), interneurons, motor neurons, and intestinofugal neurons (Fig. 1).
IPANs respond to mechanical and chemical stimuli and regulate the physio-
logic function of the gastrointestinal tract by transmitting information to other
neurons. IPANs initiate intestinal reflexes. The somewhat laborious name
given to these neurons rather than the more commonly used term ‘‘sensory
neurons’’ is because of the fact that IPANS do not usually convey sensation
from the intestine, as demonstrated by Kirchgessner and colleagues [3]. There
are no nerve endings that directly reach the lumen of the gut; sensation occurs
through enterochromaffin cells, located in the enteric epithelium, which work
as sensory transducers [4]. IPANS are found in both plexi [5] and are choliner-
gic neurons [6].
Motor neurons are either excitatory or inhibitory and innervate the muscle
layers of the digestive tract and blood vessels and glands. The cell bodies of
motor neurons that supply the muscle layers are located in the myenteric gan-
glia, but there is evidence that there are a few cell bodies that innervate the
muscle layers in submucosal ganglia [7]. The primary transmitters of the excit-
atory motor neurons are acetylcholine and tachykinins, such as substance P
and neurokinin A. Inhibitory neurons use a larger spectrum of transmitters in-
cluding nitric oxide, vasoactive intestinal pol ypeptide, c-aminobutyric acid,
ATP, carbon monoxide, and pituitary adenyl cyclase–activating polypeptide
[8]. Regulation of secretion of water and electrolytes and of blood flow in

500 MAZZONE & FARRUGIA
the gut occurs by secretomotor and vasomo tor neurons, respectively. The cell
bodies of these neurons reside in the submucosal plexus [9].
Interneurons are defined as ascending or descending based on whether their
processes run orally or anally. They integrate information from IPANs and, in
general, relay the information to enteric motor neurons. At least one type of
ascending and three types of descending interneurons have been described in
the small intestine of guinea pig [10]. Ascending interneurons are mainly cho-
linergic, whereas descending motor neurons have a varied and complex neuro-
chemistry [11]. Ascending interneurons and the three types of the descending
ones participate in local motility reflexes. A fourth type of descending interneu-
ron conducts the migrating myenteric complexes (MMC). Ascending interneu-
rons project to other myenteric neurons, whereas descending interneurons also
innervate the submucosal plexus.
A fourth class of enteric neurons, intestinofugal afferent neurons (IFANs),
have their cell bodies within the myenteric plexus but send their processes
out of the gut wall to form synapses with the inferior and superior mesente ric
ganglia and the celiac ganglion (collectively known as ‘‘prevertebral ganglia’’)
[12]. IFANs carry efferent signals from the gut and they work as mechanore-
ceptors that detect changes in gut volume [12]. Primary IFANs transmit directly
to the prevertebral ganglia without synaptic interruption, whereas another
Fig. 1. Types of neurons in the enteric nervous system. 1. interneuron; 2. excitatory longitudi-
nal muscle motor neuron; 3. myenteric intrinsic primary afferent neuron; 4. inhibitory longitu-
dinal muscle motor neuron; 5. intestinofugal neuron; 6. myenteric plexus interstitial cell of
Cajal; 7. excitatory circular muscle motor neuron; 8. inhibitory circular muscle motor neuron;
9. circular muscle interstitial cell of Cajal; 10. cholinergic secretomotor (nonvasodilator)
neuron; 11. cholinergic secretomotor neuron; 12. noncholinergic vasomotor neuron; 13.
submucosal intrinsic primary afferent neuron; 14. mucosal cell; 15. enterochromaffin cell.
PVG, prevertebral ganglia. (Adapted from Furness JB. The enteric nervous system. Blackwell
Publishing: Oxford, UK; 2006; p. 30; with permission.)

501CONCEPTS IN THE CELLULAR CONTROL OF GI MOTILITY
population of intestinofugal neurons receives information arising from other
enteric neurons [13].
MOTOR PATTERNS
Coordinated activation of enteric neuronal circuits is respo nsible for the rhyth-
mic and regular contraction of the gastrointestinal muscle and the aboral trans-
port of the luminal content. Control of gastrointestinal motor function requires
the coordinated function of several cell types. Four fundamental patterns of
motility are present in the small intestine: (1) peristalsis, (2) segmentation, (3)
the migratory motor complex, and (4) the postprandial motor pattern.
Peristalsis consists of contraction waves that propagate along the gastrointes-
tinal tract that mix and propel content distally. Peristalsis is initiated by me-
chanical and chemical stimuli triggered by the presence of a bolus in the gut
lumen. These stimuli activate IPANs, which then activate ascending and de-
scending interneurons, which activate excitatory and inhibitory motor neurons.
Activation of excitatory motor neurons above the bolus results in contraction
of smooth muscle above the bolus. Activation of inhibitory motor neurons re-
sults in relaxation of smooth muscle below the bolus. Shortening of the muscle
immediately below the bolus also occurs as a result of descending excitation
[14]. The rhythmicity of peristalsis is determined by the electrical activity of
the ICC. Peristalsis is not affected by vago tomy or sympathetectomy, indicat-
ing it is mediated exclusively by the ENS. The ENS also initiates clusters of
contractions that are nonpropulsive. These segmental contractions have the
purpose of mixing chyme with digestive juices exposing it to the mucosa for
absorption [15].
The MMC is a specific pattern of motor activity identified in the stomach
and small intestine smooth muscle during fast ing in most mammalian species,
including human. The MMC clears the stomach and intestine of residual food
and mucosal debris and prevents microorganism overgrowth [16]. The MMC
is a periodic activity with a cycle time of about 1.5 to 2 hours in humans; it can

be divided into four phases. Phase I is a quiescent phase of about 45 to 60 min-
utes during which there are only rare action potentials and contractions that
progressively i ncrease in frequency, followed by an irregular phase II of 30
minutes characterized by random activity. In phase III, also called the activity
front, each slow wave is associated with spike potentials and resulting contrac-
tions, which consist of bands of quickly moving, evenly spaced contractions.
This phase lasts for about 5 to 15 minutes. In contrast to the digestive period,
the pylorus remains open during these peristaltic contractions, allowing many
indigestible materials to pass into the small intestine. Phase IV is a brief cycle of
irregular activity in between phase III and phase I. Extrinsic stimul i can
modulate the MMC but are not required for its initia tion or propagation.
The progression of the activity front is a result of sequential activation of a spe-
cialized class of descending interneurons. Followin g the ingestion of a meal, the
MMC is replaced by an irregular activity, similar to phase II, which in humans
lasts for 1 to 2 hours.
502 MAZZONE & FARRUGIA
Colon motility is irregular and complex and the neuronal control of colonic
patterns of motility is not yet well delineated. There are several distinct colonic
motor patterns. The baseline pattern is one of seemingly chaotic, irregular con-
tractile activity. Another pattern consists of high-amplitude propagated contrac-
tions. These often, but not always, propagate colonic content over long
segments of the colon and can be associated with the urge to defecate [17].
The occurrence of these contractions is not regulated by slow waves and their
duration in dogs is approximately 18 to 20 seconds [18]. Electrical activity that
underlies motor activity in the colon is also not as well delineated as in the
stomach and small bowel. Electrical activity recorded from the colonic myen-
teric plexus region is not in the form of electrical slow waves as in the small
intestine and stomach but is in the form of frequent oscillations in membrane
potential that originate near the myenteric border or within longitudinal mus-
cle, and conduct through most of the circular muscle [18], defined as myenteric

potential oscillations. Electrical slow waves do originate from submucosal
plexus ICC but their role in regulating smooth muscle contractile activity is
not yet established.
EXTRINSIC CONTROL OF ENTERIC NERVOUS SYSTEM
There is a close functional relationship between the ENS and the CNS in the
control of gut function. Extrinsic afferent and efferent pathways transfer stimuli
to and from the gut, respectively, providing a constant exchange of information
between CNS and ENS. Afferent neurons signal information to the CNS about
the chemical content of the gut lumen; about the mechanical status (tension or
relaxation) of the gut wall; and about the condition of tissues (inflammation,
pH, heat, cold). Efferent neurons transmit information from the CNS to the
ENS. CNS neurons do not dire ctly innervate smooth muscle cells. Both affer-
ent and efferent nerves follow two major pathways (spinal and vagal) (see [19]
for a review).
Extrinsic Efferents
The primary transmitter of sympathetic postganglionic neurons that supply the
gastrointestinal tract is norepinephrine. Efferent neuron s innervating the gut
originate from prevertebral or paravertebral ganglia. Most cell bodies of sym-
pathetic postganglionic neurons, located in paravertebral ganglia, control gas-
trointestinal blood vessels. Three other classes of neurons, whose cell bodies
reside in the prevertebral ganglia, control motility and secretion.
Several important roles of the upper gastrointestinal tract, such as gastric
fundic relaxation and gastric and pancreatic secretion, are mediated through
vagal neurons whose cell bodies lie within the brainstem. In contrast to the up-
per gut, the distal colon and rectum are innervated by pelvic nerves, not the
vagus. In general, vagal stimulation causes inhibition of gast rointestinal secre-
tion and motor activity, and contraction of gastrointestinal sphincters and
blood vessels. Conversely, spinal stimuli typically stimulate these digestive
activities.
503CONCEPTS IN THE CELLULAR CONTROL OF GI MOTILITY

Extrinsic Primary Afferents
Afferent innervation conveys sensory information from the gut to the CNS
activating spinal and vagal-pelvic reflexes. Extrinsic primary afferent neurons
(EPANs) are classified in vagal and spinal based on the physical location of
their cell bodies. Vagal primary afferent neurons have cell bodies in the nodose
and jugular ganglia and pro ject centrally to the brainstem, whereas the cell bod-
ies of the spinal EPANs are located in the dorsal root ganglia. Vagal afferent
pathways carry information about the physiologic state of the digestive organs
(eg, satiety and nausea) and regulate inflammatory responses, whereas spinal
afferents primarily mediate pain impulses [20]. Similar to vagal efferents, vagal
afferents are concentrated mainly in the upper gastrointestinal tract, whereas
pelvic afferents innervate mostly the lower bowel; spinal afferents are distrib-
uted throughout the gut by splanchnic nerves [21].
SENSATION OF THE GUT
Humans are usually not aware of the ongoing functions of the gastrointestinal
tract, such as contractile activity, digestion, and absorption. In health, physio-
logic stimuli from the gut induce motor reflexes, but these remain largely
unperceived, with the exception of those related to ingestion and excretion.
Although these processes generally do not reach a level of sensation unless
they go awry, they are closely monitored by specialized neurons in both the
enteric and extrinsic nervous systems of the gastrointestinal tract. Food intake,
contractile activity, and metabolic products of the enteric flora regulate diges-
tive motility through the brain-gut axis mediated by extrinsic nerves, intrinsic
neurons, and gastrointestinal hormones. These processes are also influenced by
the environment and emotions. Disturbed digestive motility often con tributes
to the generation of gastrointestinal symptoms in various diseases. Two types
of primary afferent neurons are involved in the detection of changes in the gas-
trointestinal environment: IPANs (whose cell bodies and processes never leave
the gut) and vagal and spinal EPANs (whose cell bodies reside outside the gut).
A third cell type, IFANs (whose cell body is within the gut but whose processes

leave the gut), also particip ates in detecting gut stimuli. No nerve cell processes
reach the enteric lumen. Sensation must be accomplished transepithelially by
means of specialized cells, enteroendocrine cells. The best characterized of
these sensory transducers are enterochromaffin cells that have been demon-
strated to respond not only to mechanical pressure [22] but also to nutrients
(eg, glucose or fatty acids) present in the intestinal lumen, by releasing chemical
mediators into the wall of the gut and initiating responses [23,24].
Mechanosensation
Mechanosensitivity, in particular that mediated by spinal afferents, can be
transduced by a wide range of chemical mediators released following detection
of mechanical stimuli inside the lumen of the gut. Par acrine mediators of dis-
tention include serotonin, cholecystokinin, gastrin, somatostatin, and peptide
YY. Release of peptides activates intrinsic and extrinsic afferent neurons
504 MAZZONE & FARRUGIA
present in the submucosal plexus. The intrinsic afferents provide the basis for
local reflexes that control and coordinate gastrointestinal function. Stretch-
sensitive IPANs also respond to tension in the muscle and to direct distortion
of their processes [25] and communicate the information by the discharge of
action potentials, through gating of mechan osensitive ion channels that are
expressed in neurons [26]. Mechanical stimuli are also detected by EPANs
and transferred to the CNS, to be processed and to evoke a reaction, through
the combined action of vagal and spinal pathways.
Vagal mechanosensitive EPANs are activated by low-intensity mechanical
stimuli and can be classified based on localization of the terminal ending receiv-
ing the stimulus. Mucosal stroking, but not distention, stimulates one class of
EPANs whose terminals innervate the gut mucosa. A second class responds
to food intake by reacting to gut wall tension within the physiologic range
(<10 mm Hg). These EPANs have endings in the muscle and mediate satiety
[27]. The third class of vagal nerves is in close association with ICC, suggesting
that ICC may be involved in afferent neural transduction [28].

Spinal afferents convey to the CNS discomfort and pain through nerve end-
ings that reside in the muscle wall. In contrast to vagal afferents, spinal afferents
also respond to intense stimuli that go beyond the ph ysiologic range. A subclass
of spinal afferents responds to distending pressures that exceed 30 mm Hg
(high threshold mechanoreceptors) and are considered as mechanonocirecep-
tors. They encode both physiologic and noxious levels of stimulation [20].
Intestinofugal processes, whose cell bodies are in the myenteric plexus,
project to the prevertebral ganglia. Mechanosensory IFANs function as volume
detectors, and unlike most vagal and spinal mechanosensitive afferent nerves,
are arranged ‘‘in parallel’’ with the circular muscle layer [12]. This arrangement
results in a decrease in synaptic input with a decrease of the colon
circumference.
Chemosensation
Chemosensation is also mediated by enteroendocrine cells, which act as the
sensory mediator between the mucosal epithelial cells and the neuronal system.
Immune cells also seem to play a role in the process of chemosensation in the
gut. Direct innervation of mast cells has been shown and also a functional
connection between mast cells and extrinsic afferent nerves by the release of
mediators, such as histamine and serotonin (see [29] for a review). Data gener-
ated from functional experiments that measured inhib ition of gastric motility or
acid secretion as a measure of activation of sensors have yielded useful infor-
mation about the mechanism by which nutrients are perceived by the intestinal
wall. Chemosensation is a separate process from osmotic or mechanical effects.
Also, the different nutrient groups activate distinct pathways and mechanisms.
Vagal and spinal EPANs are involved in the response to chemical stimulation
of the gastrointestinal tract wall and mediate inhib ition of gastric emptying and
secretion by generating satiety, nausea, and vomiting sensations. Chemical
mediators can also directly trigger the response of mechanosensitive afferent
505CONCEPTS IN THE CELLULAR CONTROL OF GI MOTILITY
nerves [30]. A subset of spinal chemosensitive receptors have been identified

that can only be activated after high threshold stimulations, such as inflamma-
tion. These receptors are considered silent nociceptors because they do not
normally respond to physiologic stimuli. Activators include inflammatory
mediators and a variety of neuronal released factors including nerve growth
factor [30].
INTERSTITIAL CELL OF CAJAL
ICC were tentatively identified in the 1890s by histochemical techniques using
methylene blue and silver staining [31]. They are mesenchymal cells, inter-
posed between enteric nerves and smooth muscle cells (Fig. 2), with small
cell bodies and several elongated processes and are classified based on their dis-
tribution. In most regions of the gastrointestinal tract, there is a network of ICC
cells lying between the longitudinal and circular layers in the myenteric region
(ICC-MY). This subclass of ICC is largest in the corpus and antrum of the
stomach and in the small intestine [32]. A second group of ICC has an intra-
muscular location (ICC-IM), with individual ICC being distributed among
the smooth muscle cells in the muscle layers. Intramuscular ICC are found
in all levels of the human gut, unlike smaller animals. In the small intestine,
ICC also form a second network between the innermost and outer circular
muscle cells, known as the ‘‘deep muscular plexus’’ (ICC-DMP). In the gastric
antrum, ICC-IM are widely distributed throughout the circular layer and only
very few are found in the longitudinal layer (see [33] for a review). In the fun-
dus, a myenteric network of ICC is absent, but ICC-IM are widely distributed
through both the circular and longitudinal muscle layers [32]. In the colon,
Fig. 2. Innervation of smooth muscle cells. Two mechanisms for neuronal innervation of gas-
trointestinal smooth muscle exist. Most innervation occurs through interstitial cells of Cajal.
Neurons can also directly innervate intestinal smooth muscle cells. ICC, interstitial cells of
Cajal.
506 MAZZONE & FARRUGIA