Brain Responses to Visceral and Somatic Stimuli in
Patients With Irritable Bowel Syndrome With and
Lin Chang, M.D., Steve Berman, Ph.D., Emeran A. Mayer, M.D., Brandall Suyenobu, Ph.D.,
Stuart Derbyshire, Ph.D., Bruce Naliboff, Ph.D., Brent Vogt, Ph.D., Leah FitzGerald, R.N., and
Mark A. Mandelkern, M.D., Ph.D.
C.N.S. Center for Neurovisceral Sciences & Women’s Health, Departments of Medicine, Physiology, and
Psychiatry & Biobehavioral Sciences, and Brain Research Institute, David Geffen School of Medicine at
UCLA, Los Angeles, California; University of Pittsburgh Medical Center, MR Research Facility, Pittsburgh,
Pennsylvania; Cingulum NeuroSciences Institute, Syracuse, New York; GLA VA Healthcare System,
Department of Nuclear Medicine, Irvine; and Departments of Biomathematics & Biostatistics and Physics,
University of California, Irvine, California
OBJECTIVE: Symptoms of irritable bowel syndrome (IBS)
and fibromyalgia (FM) commonly coexist. We hypothesized
that one of the mechanisms underlying this comorbidity is
increased activation of brain regions concerned with the
processing and modulation of visceral and somatic afferent
information, in particular subregions of the anterior cingu-
late cortex (ACC).
METHODS: Regional cerebral blood flow (rCBF) was as-
sessed in age-matched female IBS (n ? 10) and IBS ? FM
(n ? 10) subjects using H2
phy during noxious visceral (rectal) and somatic pressure
15O positron emission tomogra-
RESULTS: GI symptom severity was significantly higher in
the IBS patients compared with the IBS ? FM patients (p ?
0.05). In addition, IBS ? FM patients rated somatic pain as
more intense than their abdominal pain (p ? 0.05). Whereas
the somatic stimulus was less unpleasant than the visceral
stimulus for IBS patients without FM, the somatic and
visceral stimuli were equally unpleasant in the IBS ? FM
group. Group differences in regional brain activation were
entirely within the middle subregion of the ACC. There was
a greater rCBF increase in response to noxious visceral
stimuli in IBS patients and to somatic stimuli in IBS ? FM
CONCLUSION: Chronic stimulus-specific enhancement of
ACC responses to sensory stimuli in both syndromes may be
associated with cognitive enhancement of either visceral
(IBS) or somatic (IBS ? FM) sensory input and may play a
key pathophysiologic role in these chronic pain syndromes.
(Am J Gastroenterol 2003;98:1354–1361. © 2003 by Am.
Coll. of Gastroenterology)
Irritable bowel syndrome (IBS) and fibromyalgia (FM) are
syndromes characterized by chronic visceral and chronic
somatic pain and discomfort, respectively. Patients affected
by both disorders are commonly seen in tertiary referral
centers for functional GI disorders and frequently pose a
considerable therapeutic challenge. Epidemiologic studies
have confirmed the clinical impression that these two func-
tional disorders frequently overlap in the same patient, sug-
gesting shared pathophysiologic mechanisms (1). A study of
80 patients demonstrated that 70% of FM patients also had
symptoms of IBS, and 65% of IBS patients suffered from
FM symptoms (2). Although unequivocal demonstration of
peripheral tissue changes underlying the pain is lacking in
both syndromes, local pain elicited at known tender points
is considered the hallmark physical finding of FM, whereas
tenderness of the sigmoid colon during palpation or endo-
scopic manipulation is characteristic in IBS. In IBS, several
studies have demonstrated lower perceptual thresholds for
pain and discomfort during colorectal balloon distension
(3–5). In FM, several studies have demonstrated decreased
pain thresholds both at tender points and at control sites
Although the pathophysiology for both conditions is in-
completely understood, an alteration in central nervous sys-
tem (CNS) function has been suggested by several obser-
vations in both conditions: 1) the majority of patients
associate stressful life events with the initiation or exacer-
bation of symptoms (13, 14), 2) psychotherapy and behav-
ioral therapies (including hypnotherapy and relaxation tech-
niques) are efficacious in treating symptoms (15–17), 3)
low-dose tricyclic antidepressant medication can improve
symptoms of FM (18, 19) and IBS (20), most likely by their
CNS-mediated effect (21–23), and 4) altered regional cere-
THE AMERICAN JOURNAL OF GASTROENTEROLOGY
© 2003 by Am. Coll. of Gastroenterology
Published by Elsevier Inc.
Vol. 98, No. 6, 2003
bral responses to visceral and somatic stimulation have been
demonstrated in FM (24) and IBS (24–26). Consistent with
such a CNS-based shared pathophysiology, Whitehead et al.
recently suggested, based on an extensive review of pub-
lished studies, that the strong comorbidity between IBS and
FM suggests a common psychological feature important to
their expression (1).
Because visceral and somatic afferents are jointly pro-
cessed and modulated in some areas of the brain, we hy-
pothesized that patients with chronic visceral (IBS) and
somatic (FM) symptoms may be characterized by altered
activity in regions where afferent inputs overlap, or where
pain-modulating mechanisms are shared. Joint pain process-
ing regions include the dorsal horn of the spinal cord (27),
thalamic nuclei (and associated primary and secondary so-
matosensory cortices) (28–30), caudal anterior cingulate
cortex (ACC), and anterior insular cortices (29–35). An
important pain modulation network, which is likely to affect
the perception of both visceral and somatic noxious stimuli,
involves brainstem structures, such as the periaqueductal
gray, the parabrachial nucleus, and the ventromedial me-
dulla (36). This pontine network receives modulatory input
from the prefrontal cortex and more rostral aspects of the
ACC, and these inputs have been thought to play an impor-
tant role in mediating emotional and attentional influences
on pain perception (37, 38). Based on a meta-analysis of
recent human pain imaging studies, Petrovic and Ingvar
suggested that the ACC may be divided into three functional
subregions: a caudal portion, which is preferentially acti-
vated during painful stimuli; an adjacent, and slightly more
rostral region (middle ACC), which is activated during
attentional tasks; and the most rostral part (“perigenual”),
which is activated by emotional tasks and is part of central
opioid networks (39,40).
There have been few neuroimaging studies performed in
patients with IBS or FM that have employed visceral and
somatic pain stimuli. We and others have published studies
comparing brain activation responses to rectal distension in
IBS patients and healthy controls (25, 31, 32, 41). In most
studies, alterations in the activation of ACC subregions were
found in the IBS patients compared with the controls. There
have been two studies evaluating resting cerebral blood flow
in FM patients with single-photon-emission CT (42, 43).
Although these studies were done under baseline conditions,
and patients with psychological distress symptoms were not
excluded, these studies demonstrated only decreased blood
flow in subcortical regions (e.g., thalamus, caudate nucleus,
and pontine tegmentum) in the FM patients. The presence of
comorbid IBS was not assessed in these patients. A more
recent study that employed functional magnetic resonance
imaging compared brain activations in response to a somatic
pain stimulus in 16 FM patients and 16 healthy control
subjects (44). The authors found that when a stimulus of
identical pressure was applied to the thumbnail, the FM
group showed greater activation of the ACC in addition to
12 other regions, compared with the control group.
The goal of the present study was to compare the changes
in rCBF produced by a visceral compared with a somatic
pressure stimulus in IBS patients with and without FM. We
aimed to answer two general questions: 1) Do IBS and IBS
? FM patients show altered activation in brain regions
receiving viscerosomatic afferent input (somatosensory cor-
tex, caudal ACC, insula, and thalamus)? and 2) Do these
two patient groups show altered activation of cortical re-
gions involved in cognitive and emotional pain modulation
(prefrontal cortex and more rostral ACC subregions)? Part
of these results has been published in abstract form (24).
MATERIALS AND METHODS
IBS PATIENTS. Ten female IBS patients (mean age 42 ?
10 yr) were recruited from advertisements and the Univer-
sity of California, Los Angeles (UCLA) Functional Bowel
Disease Clinic. Selection criteria included a positive diag-
nosis by the Rome I criteria (45), a clinical diagnosis of IBS
made by a gastroenterologist experienced in the diagnosis of
functional bowel disorders, and the exclusion of inflamma-
tory or other structural intestinal disease based on clinical
and endoscopic evidence. Four IBS patients were constipa-
tion-predominant, one was diarrhea-predominant, and five
had alternating bowel habits. None had evidence of FM or
other nonvisceral chronic pain conditions.
IBS PATIENTS WITH FM. Ten female patients with IBS
? FM (mean age 46 ? 11 yr) were recruited from adver-
tisements and the UCLA Functional Bowel Disease Clinic.
All study subjects met selection criteria for IBS (see above).
Two of these patients were constipation-predominant, three
were diarrhea-predominant, and five had alternating bowel
habits (similar to patients with IBS alone). In addition, all
subjects were examined for and met the diagnostic criteria
for FM according to the 1990 American College of Rheu-
matology criteria (8) and were previously diagnosed with
FM by a rheumatologist.
There were no significant differences in mean age be-
tween the patients with IBS alone and coexistent IBS and
FM. None of the study subjects were taking medications,
including peripherally acting treatments for IBS, centrally
acting drugs (anxiolytics, antidepressants, narcotics), or
nonsteroidal anti-inflammatory medications for at least 2 wk
before the study. All study subjects underwent a pregnancy
test before the test, and all tests were negative. Although
including patients with FM alone would have been prefer-
able for this study, our experience has been that it is very
difficult to recruit this patient group with the following
criteria: 1) no centrally acting drugs, 2) no analgesic agents
including narcotics, and 3) willingness to undergo the study.
Verbal and written consent was obtained from each subject.
The VA Greater Los Angeles Healthcare System Research
and Development Committee and Committee on Human
Studies approved this study.
AJG – June, 2003
Cerebral Responses in IBS and Fibromyalgia
SYMPTOM RATINGS. At the start of the study, IBS pa-
tients were asked to rate the intensity and unpleasantness of
their abdominal pain for both the past 6 months (chronic)
and the past 24 h (acute), using validated verbal descriptor
anchored visual analog scales (see description below). The
patients with co-existent FM were also asked to rate their
somatic pain, using these same scales.
Bowel Symptom Questionnaire
All subjects completed a UCLA bowel symptom questionnaire
on encounter with the center. The bowel symptom question-
naire (4) distinguishes abdominal symptoms and bowel habits
as well as the presence of extra-intestinal symptoms.
Symptom Checklist 90
All subjects completed the Symptom Checklist 90 (46). This
instrument is a reliable and valid measurement of current
psychological function, including detection of significant
psychological symptomatology. This instrument was used
to examine the presence of significant psychological symp-
toms based on the general symptom index (t score ? 63).
Somatic and Visceral Pressure Stimuli
The somatic stimulus device consisted of a 7.5-lb weight
attached to a syringe plunger with a contact head whose
surface area was equal to 1.54 cm2. This device was used to
apply pressure on the two designated somatic points. The
mechanical stimulus was applied for 1 min separately to the
active (2 cm distal to the left epicondyle) and control so-
matic point (dorsal distal third of the left forearm). The left
epicondyle somatic point is a standard tender point, however
several studies have demonstrated decreased pain thresholds
both at tender points and at control sites in FM patients (6-12).
Visceral pressure stimulation of the rectum was accom-
plished using a computer-driven pump (barostat), which
allowed for controlled inflations. The rectal balloon catheter
consisted of a single latex balloon (external diameter, 5 cm;
length of each balloon, 11 cm) attached to a Silastic elas-
tomer tube (external diameter 18 Fr) at both proximal and
distal ends (MAK-LA, Los Angeles, CA). Before and after
each procedure, each balloon was inflated repeatedly to rule
out any leak and to measure intrinsic compliance. The
lubricated balloon catheter was inserted into the rectum so
that the distal end was 4 cm from the anal orifice. The
catheter was secured with tape. The balloon was inflated at
a rapid volume rate (870 ml/min) and held at constant
pressure plateaus by the barostat for the duration of the trial.
A 12-h fast and application of two Fleet enemas (C.B. Fleet,
Lynchburg, VA) preceded the rectal balloon placement.
Positron Emission Tomography
The subjects were scanned using a positron emission to-
mography (PET) scanner, Siemens/CTI 953 tomograph (Si-
emens-Computer Technology, Knoxville TN), collecting 31
contiguous data planes corresponding to an axial depth of
3.375 mm each, in a 128 ? 128 image matrix. Each subject
was positioned in the scanner so that the axis of the scanner
was approximately parallel to the glabellar–inion line. An
automatic procedure outlined the scalp, and the well-known
bulk attenuation coefficient was used to correct the emission
scans. rCBF in each subject was measured by recording the
distribution of cerebral radioactivity after intravenous bolus
infusion of the freely diffusible positron emitting15O-la-
beled tracer, H2
commenced at the onset of a 25-mCi bolus injection of
to the rectal wall or arm, respectively, when the visceral or
somatic stimulus conditions were applied. Twelve minutes
passed between injections to allow background radiation to
decay to less than 10% of the recorded peak. Six rCBF
measurements were completed in a single session lasting
approximately 2 h.
The PET protocol is shown in Figure 1. Experimental
stimulation studies commenced 30 min after balloon place-
ment. Patients closed their eyes during all scans, and extra-
neous auditory stimuli were excluded by headphones,
through which a recorded message provided a general ex-
planation of the distention protocol. A baseline scan was
first obtained without balloon inflation. PET scans were
attempted during the subsequent visceral and somatic con-
ditions shown in Figure 1. However, an insufficient number
of adequate 45-mm Hg PET scans were recorded. There-
fore, this condition was excluded from the image analysis. A
rectal distension of moderate (45 mm Hg) or intense (60 mm
Hg) pressure was delivered by the computerized barostat for
60 s each, with a 12-min interim deflation. During the “no
inflation” conditions before and after the 60-mm Hg rectal
distension, the subjects were told that they might receive a
rectal distension, but none was delivered (anticipation). The
15O. For each measurement, a 120-s scan
15O. Scan onset also coincided with the onset of pressure
Figure 1. PET protocol. The amount of pressure given during the
visceral (rectum, mm Hg) or somatic (arm, lb) conditions is shown
on the y axis and numerically above each condition. The scan
number is given after the condition label. Note that the 20 mm Hg
visceral stimulus condition was not scanned, and there were in-
sufficient number of 45 mm Hg scans to be included in the
analysis. The order of the two somatic stimuli was randomized to
the active or control tender point on the left arm.
1356Chang et al.
AJG – Vol. 98, No. 6, 2003
last two PET scans were acquired during the application of
the two separate somatic conditions described previously,
counterbalanced for order.
Subjective Stimulus Ratings
Subjective sensory intensity and unpleasantness of each
visceral and somatic stimulus was assessed with similar
descriptor anchored visual analog scales as described for
symptom assessment (47). The sensory intensity scale con-
sisted of descriptors of increasing intensity, ranging from
“no sensation” to “extremely intense,” arrayed along a 20
cm vertical bar. The unpleasantness scale consisted of de-
scriptors of increasing unpleasantness, ranging from “neu-
tral” to “very intolerable.” Ratings were assessed after each
stimulus. Each stimulus was also rated on a 10-cm visual
analog scale of anxiety (anchored by “no anxiety” and
“greatest anxiety imaginable”).
SUBJECTIVE SYMPTOMS. The following were com-
pared between the IBS and IBS ? FM groups: acute and
chronic ratings of the intensity and unpleasantness of cur-
rent abdominal pain and discomfort, subjective response to
the visceral and somatic stimuli during the PET scanning
sessions, and Symptom Checklist 90 psychological general
symptom scores. In addition, acute and chronic ratings of
abdominal compared with somatic pain were compared in
the IBS ? FM group. These comparisons were made using
Student t test. Perceptual ratings of the 60-mm Hg visceral
stimulus and the somatic stimulus (average ratings of the
two somatic stimuli) were compared for each group using a
t test. Statistical significance was assessed at the p ? 0.05
level. All analyses were conducted with the SPSS statistical
software package (SPSS, Chicago, IL.).
IMAGE DATA ANALYSIS. The following procedures
were carried out using SPM99 (Wellcome Trust Center
(London, UK) for the Study of Cognitive Neurology), de-
scribed in detail elsewhere (48, 49). All scans within each
individual subject were corrected for head movement by
alignment with the first scan. Each realigned set of scans
was then registered into the standardized anatomic space of
the average magnetic resonance image provided by the
Montreal Neurological Institute. To increase the signal-to-
noise ratio and accommodate variability in functional anat-
omy, each image was smoothed in x, y, and z dimensions
with a Gaussian filter of 12 mm (full width half maximum).
At each voxel, a standard parametric statistical model
used multiple linear regression to partition variability in
blood flow, measured as normalized radioactive counts, in
terms of experimental effects, confounds, and residual vari-
ance. Subject main effects were defined as confounds, with
global activity removed by proportional scaling. Linear ef-
fects of scan order were removed as confounds through use
of subject-specific covariates. Voxel-by-voxel one-tailed t
tests then assessed the effects of visceral and somatic pres-
sure and displayed them as statistical parametric maps.
The object of these studies was to compare brain activa-
tion (rCBF) between IBS and IBS ? FM patients in re-
sponse to rectal compared with somatic pressure. Prelimi-
nary investigations did not detect significant differences
between individual visceral pressures, individual somatic
pressures, or between the three different scans in which no
pressure was applied. However, it is possible that with
greater statistical power, differences between these condi-
tions could have been demonstrated. Alternatively, the lack
of detectable differences to individual visceral or somatic
stimuli may be due to a greater variability of brain responses
to fixed pressure stimuli as compared to using individual-
ized pressure levels equated for subjective sensory ratings.
Because we were primarily interested in the unique effects
of visceral and somatic pressure stimuli, we maximized
statistical power by contrasting scans recorded during each
type of pressure with all of the scans not featuring this type
was assessed by contrasting scans 5-6 with scans 1-4 (Figure
1). Likewise, the response to visceral stimulus was assessed by
contrasting scan 3 with scans 1, 2, 4, 5, and 6. Therefore, these
comparisons were insensitive to rCBF changes that occurred
during both visceral and somatic pressure.
Differences between IBS and IBS ? FM patients were
assessed as group ? condition interactions. The effects of
visceral and somatic pressure were separately analyzed in
the two groups of IBS patients and used to mask the inter-
action contrast to rule out effects due solely to deactivations.
That is, to ensure proper interpretation, interactions were
masked at the p ? 0.01 height level by the relevant activa-
tion in the patient group where that activation was being
interpreted. In other words, any reported activation repre-
sents significantly increased activation in the designated
patient group (and not solely a deactivation of the other
group) and a significant difference between the two groups.
For statistical parametric map display purposes, any clus-
ter larger than 23 voxels (extent threshold ? 0.05) with a
signal intensity corresponding to a threshold of p ? 0.01 is
depicted. This follows other work with functional imaging
and pain or visceral distension (25, 50, 51) and reduces the
possibility of false-negative reporting (52). However, to
reduce the risk of over-interpreting false-positive findings,
clusters are tabled only if they were significantly activated
after correction for total brain volume, or if there is a clear
a priori reason to expect activation. Because this study
seeks to analyze differences between two clinical sub-
groups, the brain activation responses to the somatic and
visceral stimuli are presented using between-group differ-
ences and are shown in the figures to demonstrate the
significant areas of activation in the medial structures.
Determination of the subregion of the ACC that was
significantly activated was made by superimposing the co-
ordinates of the region onto the schematic of the three
subregions of the ACC as illustrated in a recent review by
Petrovic and Ingvar (37).
AJG – June, 2003
Cerebral Responses in IBS and Fibromyalgia
Subjective Symptom Ratings
Subjective ratings of acute and chronic abdominal pain were
higher in the IBS patients compared with the IBS ? FM
patients for both intensity and unpleasantness (p ? 0.05 for
chronic [6-month] ratings; Table 1). Comparing the symp-
tom ratings of somatic pain with those of abdominal pain in
the IBS ? FM patients, chronic somatic pain was rated as
more intense than chronic abdominal pain (p ? 0.02). These
ratings suggest that IBS ? FM patients perceive their ab-
dominal pain to be less intense than their somatic pain, and
less intense than that perceived by patients with IBS alone.
With regard to psychological symptom scores, only one IBS
patient and two IBS ? FM patients had elevated general
symptom index scores (p ? ns).
Differences in Brain Activation Between IBS and IBS ?
IBS GROUP: GREATER ACTIVATION OF THE MID-
DLE ACC TO NOXIOUS VISCERAL DISTENSION.
The interaction of condition with presence or absence of FM
within IBS patients showed rCBF changes only in the mid-
dle subregion of the ACC, as depicted in Figure 2. The
largest site activated more in response to visceral distension
in the IBS group compared with the IBS ? FM group
consisted of 76 voxels in the middle ACC (peak voxel 10,
14, 38; t ? 2.89; uncorrected p ? 0.003). In response to the
visceral stimulus, there were no areas more activated in the
IBS ? FM group compared with the IBS group.
Table 1. Clinical Symptom Ratings in the IBS and IBS ? FM
Acute sensory intensity
Chronic sensory intensity 15.4 ? 0.8 cm
Acute sensory intensity
Chronic sensory intensity
(n ? 10)
IBS ? FM Patients
(n ? 10)
10.5 ? 1.8 cm
8.7 ? 1.9 cm
7.1 ? 1.7 cm
6.5 ? 1.5 cm
11.3 ? 1.6 cm*
10.3 ? 1.2 cm*14.2 ? 0.8 cm
10.0 ? 1.5 cm
7.8 ? 1.3 cm
13.5 ? 1.1 cm†
12.0 ? 1.2 cm
* p ? 0.05 compared with IBS patients.
† p ? 0.05 compared with chronic intensity rating of abdominal pain in IBS ? FM
Figure 2. Results for the interaction of type of stimulus (visceral, somatic), and clinical group (IBS and IBS ? FM). There was greater
activation of the middle ACC in IBS patients in response to visceral distension and in the IBS ? FM patients in response to somatic
1358 Chang et al.
AJG – Vol. 98, No. 6, 2003
IBS ? FM GROUP: GREATER ACTIVATION OF THE
MIDDLE ACC TO SOMATIC PRESSURE. In response to
the somatic stimulus, there were no areas more activated in
the IBS group compared with the IBS ? FM group. How-
ever, 217 voxels in the middle ACC showed a greater
activation in response to somatic pressure in the IBS ? FM
group than in the IBS group (peak voxel 12, 42, 36; t ?
3.35; uncorrected p ? 0.001), as shown in Figure 2. All of
these voxels were also activated at the p ? 0.01 level in the
IBS ? FM group considered alone. We also measured rCBF
in response to the somatic stimuli compared with the other
conditions excluding those with visceral distension (baseline
and two no inflation conditions), and there was greater
activation of the middle ACC extending to the perigenual
ACC (uncorrected p ? 0.001). The thalamus was also
activated (uncorrected p ? 0.05).
Subjective Stimulus Ratings During Viscerosomatic
Both sensory intensity (16.1 ? 0.8 vs 16.1 ? 0.7) and
unpleasantness (14.5 ? 1.1 vs 13.3 ? 1.1) ratings in re-
sponse to the 60-mm Hg rectal distension were similar in the
IBS and IBS ? FM groups, respectively. The visceral stim-
ulus was rated as “very intense” and “intolerable.” With
regard to the somatic stimulus, the IBS ? FM patients rated
the somatic stimuli similarly when compared with IBS pa-
tients without FM for both intensity (13.2 ? 1.0 vs 10.1 ?
1.6, p ? 0.13) and unpleasantness (11.0 ? 0.8 vs 8.7 ? 1.3,
p ? 0.15) comparing the subjective ratings to the active vs.
control somatic points, the IBS ? FM patients rated the
intensity (13.5 ? 0.7 vs. 12.9 ? 1.6) and unpleasantness
(11.8 ? 0.7 vs. 10.3 ? 1.4) of the active and control somatic
points similarly. However, the IBS patients rated the active
tender point as more unpleasant (9.5 ? 1.2 vs. 8.0 ? 1.5, p
? 0.05) but of similar intensity (10.1 ? 1.6 vs. 10.2 ? 1.8)
compared to the control point. The intensity ratings of the
visceral stimulus were significantly higher than the intensity
ratings of the somatic stimuli in both groups (p ? 0.05).
However, the unpleasantness ratings of the visceral stimulus
were only higher than those of the somatic stimulus in the
IBS group. IBS ? FM patients reported equivalent unpleas-
antness in response to the visceral and somatic stimuli.
Anxiety ratings to the visceral and somatic stimuli were not
different between the two groups.
This study considered the hypothesis that the high frequency
of symptom overlap between patients with IBS and FM may
be due in part to altered functions in brain regions involved
in processing and/or modulation of both visceral and so-
matic afferent inputs. We used potentially noxious mechan-
ical stimuli delivered either to the left forearm or to the
rectal wall to produce somatic and visceral pain, respec-
tively. Both IBS groups rated the visceral and somatic
stimuli similarly. However, whereas the visceral stimulus
produced greater unpleasantness than did the somatic stimulus
in the IBS group, there was no difference in unpleasantness
elicited by the two types of stimuli in the IBS ? FM group.
Patients with IBS (and greater GI pain symptom severity
than IBS ? FM) had greater activation of the ACC in
response to visceral distension than did patients with IBS ?
FM. This is consistent with our finding that IBS patients had
significantly higher ratings of abdominal pain over the past
6 months compared with the IBS ? FM patients. In contrast,
patients with IBS ? FM (and greater somatic pain symptom
severity) had greater activation of the same brain region in
response to somatic stimuli than did patients with IBS. This
is consistent with the presence of chronic somatic pain and
the fact that the somatic stimuli produced as much unpleas-
antness as the visceral stimulus in the IBS ? FM patients.
Thus, enhanced activation of the ACC by viscerosomatic af-
ferent input may play a role in the pathophysiology of altered
perception of visceral and somatic pain in both syndromes.
Greater activation of the ACC was seen in response to the
visceral stimulus in the IBS compared with the IBS ? FM
group and in response to somatic stimuli in the IBS ? FM
group compared with the IBS group. Although the somatic
stimulus was always presented after the visceral stimuli, an
order effect is unlikely to account for the finding of greater
middle ACC activation in both the IBS patients to visceral
pain and the IBS ? FM patients to somatic pain. Thus,
enhanced ACC activation occurs in both patient groups but
is associated with different classes of sensory stimuli.
Concepts regarding the specific role of the ACC in pain
perception have evolved from neuroanatomic studies in
animals to the observations derived from functional brain
imaging studies in humans (53). Considerable functional
and neuroanatomic evidence supports the concept that the
ACC has functionally distinct subregions. Based on a meta-
analysis of human studies using cognitive and emotional
stimuli, Bush et al. proposed a subdivision into the ventral
subregions (infralimbic, perigenual) primarily concerned
with regulation of emotion, and the dorsal subregions con-
cerned with cognitive functions, such as attentional demand
and response selection (40, 54). Based on a meta-analysis of
human pain studies, Petrovic and Ingvar (37) recently pro-
posed a similar subdivision into a more caudal portion of
ACC, which is consistently activated by stimulation of
somatic and visceral nociceptive afferents (31, 32, 35, 52).
Immediately rostral to this area is a middle ACC subregion
concerned with attentional processes, and the most rostral
ACC subregion (also referred to as perigenual ACC) is
concerned with emotional processes (37, 38). Increases in
cerebral blood flow in the middle ACC correlate with so-
matic pain ratings of unpleasantness (55, 56) and intensity
(56) during hypnotic suggestion. Considerable evidence
suggests that this brain region is not simply involved in the
processing of afferent information associated with negative
emotion (57, 58). Rather, subregions of the ACC seem to
play a prominent role in regulation of attention to afferent
information of both negative and positive valence, and the
AJG – June, 2003
Cerebral Responses in IBS and Fibromyalgia
subregions organize the most appropriate behavioral re-
sponse to sensory stimuli while taking into account its
affective component (56). One plausible explanation for the
greater activation of the middle ACC subregion in IBS
patients to a rectal distension and in IBS ? FM patients to
somatic pressure is that these findings may represent greater
attentional attribution and therefore increased conscious
processing of visceral and somatic stimuli in the two patient
groups, respectively. The fact that no significant group dif-
ferences in rCBF were observed in other areas receiving
viscerosomatic input and known to be involved in the pro-
cessing of painful stimuli, such as insula, thalamus, or
somatosensory cortex, makes it highly unlikely that the
differences in subjective symptom reports, as well as in
ACC activation, are related primarily to differences in af-
ferent input from sensitized visceral versus somatic afferent
pathways. This explanation is supported by Whitehead et al.
in their extensive review of the comorbidity of IBS with
other disorders, including FM (1). These authors suggest
that, although these disorders may be manifestations of
interacting physiologic and cognitive factors, they may be
distinct disorders and that their strong co-morbidity suggests
a common feature, which is most likely psychological.
Numerous functional imaging studies provide a platform
for informed speculation as to the role of ACC in the
pathophysiology of IBS, FM, and their extensive co-mor-
bidity. This region has been consistently activated in pa-
tients with IBS or FM compared with controls. Two studies
comparing IBS patients with healthy control subjects dem-
onstrated greater activation of the middle ACC (but not
thalamus and insula) by a rectal pressure stimulus (31, 32).
Interestingly, the same subregion of the ACC was activated
to a greater degree in FM patients compared with healthy
controls during a somatic pressure stimulus (44). The au-
thors of the latter study concluded that their findings sug-
gested that FM is characterized by central augmentation of
pain processing (44). Thus, the main differences between
patients with IBS or FM and healthy individuals, as well as
between the IBS subgroups, involves the attentional pro-
cessing of stimuli that are assessed as clinically relevant,
rather than differences in increased afferent input of noxious
visceral or somatic stimuli. This interpretation is consistent
with the hypothesis proposed by Whitehead et al. (1) for IBS
patients (i.e., that cognitive traits, such as selective attention,
may be important in the altered perception of visceral stim-
uli by these patients). In patients with chronic pain disor-
ders, such as IBS and/or FM, greater activation of the ACC
may initially occur in response to a potentially threatening
stimulus but subsequently become chronically activated ow-
ing to enhanced attentional processing. This could lead to
hypervigilance that might generalize to similar stimuli not
necessarily associated with the disease symptoms.
In summary, greater activation of the middle subregion of
the ACC in patients with IBS without FM in response to
visceral stimuli and in IBS ? FM patients in response to
somatic stimuli suggests an alteration of normal attentional
attribution to specific afferent information from different
body regions. Future studies using the rapidly advancing
functional neuroimaging techniques will help increase our
understanding of the central processing and modulation of
visceral and somatic sensory information and how alter-
ations in these processes might manifest as syndromes char-
acterized by chronic visceral and/or somatic discomfort and
pain, such as IBS and FM.
Reprint requests and correspondence: Lin Chang, M.D., UCLA/
CURE Clinical Research Center, West LA VA Medical Center,
C.N.S. Center for Neurovisceral Sciences & Women’s Heath,
Building 115, Room 223, 11301 Wilshire Boulevard, Los Angeles,
Received Aug. 19, 2002; accepted Dec. 30, 2002.
1. Whitehead WE, Palsson O, Jones KR. Systemic review of the
comorbidity of irritable bowel syndrome with other disorders:
What are the causes and implications? Gastroenterology 2002;
2. Veale D, Kavanagh G, Fielding JF, et al. Primary fibromyalgia
and the irritable bowel syndrome: Different expressions of a
common pathogenetic process. Br J Rheumatol 1991;30: 220–2.
3. Mertz H, Naliboff B, Munakata J, et al. Altered rectal percep-
tion is a biological marker of patients with irritable bowel
syndrome. Gastroenterology 1995;109:40–52.
4. Munakata J, Naliboff B, Harraf F, et al. Repetitive sigmoid
stimulation induces rectal hyperalgesia in patients with irrita-
ble bowel syndrome. Gastroenterology 1997;112:55–63.
5. Naliboff BD, Munakata J, Fullerton S, et al. Evidence for two
distinct perceptual alterations in irritable bowel syndrome. Gut
6. Scudds RA, Rollman GB, Harth M, et al. Pain perception and
personality measures as discriminators in the classification of
fibrositis. J Rheumatol 1987;14:563–9.
7. Tunks E, Crook J, Norman G, et al. Tender points in fibro-
myalgia. Pain 1988;34:11–9.
8. Wolfe F, Smythe HA, Yunus MB, et al. The American College
of Rheumatology criteria for the classification of fibromyalgia:
A report of the Multicenter Criteria Committee. Arthritis
9. Granges G, Littlejohn G. Pressure pain threshold pain-free
subjects, in patients with chronic regional pain syndromes, and
in patients with fibromyalgia syndrome. Arthritis Rheum
10. Gibson SJ, Littlejohn GO, Gorman MM, et al. Altered heat
pain thresholds and cerebral event-related potentials following
painful CO2laser stimulation in subjects with fibromyalgia
syndrome. Pain 1994;58:185–93.
11. Lautenbacher S, Rollman GB, McCain GA. Multi-method
assessment of experimental and clinical pain in patients with
fibromyalgia. Pain 1994;59:45–53.
12. McDermid AJ, Rollman GB, McCain GA. Generalized hyper-
vigilance in fibromyalgia: Evidence of perceptual amplifica-
tion. Pain 1996;66:133–44.
13. Ford MJ, Miller PM, Eastwood J, et al. Life events, psychiatric
illness and the irritable bowel syndrome. Gut 1987;28:160–5.
14. Goldenberg DL. Psychiatric and psychologic aspects of fibromy-
algia syndrome. Rheum Dis Clin North Am 1989;15:105–14.
15. Drossman DA, Thompson WG. The irritable bowel syndrome:
Review and a graduated multicomponent treatment approach.
Ann Intern Med 1992;116:1009–16.
1360 Chang et al.
AJG – Vol. 98, No. 6, 2003
16. Haanen HC, Hoenderdos HT, van Romunde LK, et al. Con-
trolled trial of hypnotherapy in the treatment of refractory
fibromyalgia. J Rheumatol 1991;18:72–5.
17. White KP, Nielson WR. Cognitive behavioral treatment of
fibromyalgia syndrome: A follow-up assessment. J Rheumatol
18. Gruber AJ, Hudson JI, Pope HGJ. The management of treat-
ment-resistant depression in disorders on the interface of psy-
chiatry and medicine. Fibromyalgia, chronic fatigue syn-
drome, migraine, irritable bowel syndrome, atypical facial
pain, and premenstrual dysphoric disorder. Psychiatr Clin
North Am 1996;19:351–69.
19. Goodnick PJ, Sandoval R. Psychotropic treatment of chronic
fatigue syndrome and related disorders. J Clin Psychiatry
20. Whitehead WE, Bosmajian L, Zonderman AB, et al. Symp-
toms of psychological distress associated with irritable bowel
syndrome. Gastroenterology 1988;95:709–14.
21. Mertz H, Fass R, Hirsh T, et al. Amitryptiline for functional
dyspepsia: Affect on symptoms, gastric sensitivity and sleep.
Gastroenterology 1995;108:A649 (abstract).
22. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel
syndrome: A technical review for practice guideline develop-
ment. Gastroenterology 1997;112:2120–37.
23. Clouse RE. Antidepressants for functional gastrointestinal
syndromes. Dig Dis Sci 1994;39:2352–63.
24. Chang L, Mayer EA, Munakata J, et al. Differences in left
prefrontal activation to visceral and somatic stimuli assessed
by O15-water PET in female patients with irritable bowel
syndrome (IBS) and fibromyalgia. Gastroenterology 1998;
25. Silverman DH, Munakata JA, Ennes H, et al. Regional cere-
bral activity in normal and pathological perception of visceral
pain. Gastroenterology 1997;112:64–72.
26. Naliboff B, Silverman DHS, Munakata J, et al. Altered re-
gional brain activity to rectal distension following repetitive
sigmoid stimulation in IBS. Gastroenterology 1998;114:A809.
27. Al-Chaer ED, Feng Y, Willis WD. Comparative study of
viscerosomatic input onto postsynaptic dorsal column and
spinothalamic tract neurons in the primate. J Neurophysiol
28. Schnitzler A, Volkmann J, Enck P, et al. Different cortical
organization of visceral and somatic sensation in humans.
J Neurosci 1999;11:305–15.
29. Coghill RC, Talbot JD, Evans AC, et al. Distributed process-
ing of pain and vibration by the human brain. J Neurosci
30. Casey KL. Forebrain mechanisms of nociception and pain:
Analysis through imaging. Proc Natl Acad Sci U S A 1999;
31. Naliboff BD, Derbyshire SWG, Munakata J, et al. Cerebral
activation in irritable bowel syndrome patients and control
subjects during rectosigmoid stimulation. Psychosom Med
32. Mertz H, Morgan V, Tanner G, et al. Regional cerebral acti-
vation in irritable bowel syndrome and control subjects with
painful and nonpainful rectal distension. Gastroenterology
33. Derbyshire SW. Exploring the pain “neuromatrix.” Curr Rev
34. Peyron R, Laurent B, Garcı ´a-Larrea L. Functional imaging of
brain responses to pain. A review and meta-analysis. Neuro-
physiol Clin 2000;30:1752–61.
35. Aziz Q, Thompson DG, Ng VWK, et al. Cortical processing of
human somatic and visceral sensation. J Neurosci 2000;20:
36. Fields HL, Basbaum AI. Endogenous pain control mecha-
nisms. In: Wall PD, Melzack R, eds. Textbook of pain. New
York: Churchill Livingstone, 1989:206–19.
37. Petrovic P, Ingvar M. Imaging cognitive modulation of pain
processing. Pain 2002;95:1–5.
38. Villemure C, Bushnell MC. Cognitive modulation of pain:
How do attention and emotion influence pain processing? Pain
39. Petrovic P, Kalso E, Petersson KM, et al. Placebo and opioid
analgesia–imaging a shared neuronal network. Science 2002;
40. Bush G, Luu P, Posner MI. Cognitive and emotional influences
in anterior cingulate cortex. Trends Cogn Sci 2000;4:215–22.
41. Bernstein CN, Frankenstein UN, Rawsthorne P, et al. Cortical
mapping of visceral pain in patients with GI disorders using
functional magnetic resonance imaging. Am J Gastroenterol
42. Kwiatek R, Barnden L, Tedman R, et al. Regional cerebral
blood flow in fibromyalgia: Single-photon-emission computed
tomography evidence of reduction in the pontine tegmentum
and thalami. Arthritis Rheum 2000;43:2823–33.
43. Mountz JM, Bradley LA, Modell JG, et al. Fibromyalgia in
women. Arthritis Rheum 1995;38:926–38.
44. Gracely RH, Petzke F, Wolf JM, et al. Functional magnetic
resonance imaging evidence of augmented pain processing in
fibromyalgia. Arthritis Rheum 2002;46:1333–43.
45. Drossman DA, Thompson GW, Talley NJ, et al. Identification
of subgroups of functional gastrointestinal disorders. Gastro-
enterol Int 1990;3:159–72.
46. Derogatis LR. SCL-90R. Administration, scoring and proce-
dures manual–II. Towson, MD: NCS, 1983.
47. Gracely RH, McGrath P, Dubner R. Ratio scales of sensory
and affective verbal pain descriptors. Pain 1978;5:5–18.
48. Friston KJ, Holmes AP, Worsley KJ, et al. Statistical para-
metric maps in functional imaging: A general linear approach.
Hum Brain Mapp 1995;2:189–210.
49. Friston KJ, Price CJ, Fletcher P, et al. The trouble with
cognitive subtraction. Neuroimage 1996;4:97–104.
50. Derbyshire SW, Jones AK, Gyulai F, et al. Pain processing
during three levels of noxious stimulation produces differen-
tial patterns of central activity. Pain 1997;73:431–45.
51. Hsieh JC, Belfrage M, Stone-Elander S, et al. Central repre-
sentation of chronic ongoing neuropathic pain studied by
positron emission tomography. Pain 1995;63:225–36.
52. Derbyshire SWG. Meta-analysis of thirty-four independent
samples studied using PET reveals a significantly attenuated
central response to noxious stimulation in clinical pain pa-
tients. Curr Rev Pain 1999;3:265–80.
53. Vogt BA, Vogt LJ, Nimchinsky EA, et al. Primate cingulate
cortex chemoarchitecture and its disruption in Alzheimer’s dis-
ease. In: Bloom FE, Bjorklund A, Hokfelt T, eds. Handbook of
chemical neuroanatomy. New York: Elsevier, 1997:455–528.
54. Drevets WC, Raichle ME. Suppression of regional cerebral
blood during emotional versus higher cognitive implications
for interactions between emotion and cognition. Cogn Emo-
55. Rainville P, Duncan GH, Price DD, et al. Pain affect encoded
in human anterior cingulate but not somatosensory cortex.
56. Faymonville ME, Laureys S, Degueldre C, et al. Neural mech-
anisms of antinociceptive effects of hypnosis. Anesthesiology
57. Damasio AR, Grabowski TJ, Bechara A, et al. Subcortical and
cortical brain activity during the feeling of self-generated
emotions. Nat Neurosci 2000;3:1049–56.
58. Bartels A, Zeki S. The neural basis of romantic love. Neuro-
AJG – June, 2003
Cerebral Responses in IBS and Fibromyalgia