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Yao-Zong
Yuan, Ran-Jun Tao, Bin Xu, Jing Sun, Jia-Yu Xu, Department of
Gastroenterology, Ruijin Hospital, Shanghai Second Medical
University, Shanghai 200025, China
Ke-Min Chen, Fei Miao, Zhong-Wei Zhang, Department of Radiology,
Ruijin Hospital, Shanghai Second Medical University, Shanghai
200025, China
Correspondence to: Dr. Yao-Zong Yuan, Department of
Gastroenterology, Ruijin Hospital, Shanghai Second Medical
University, Shanghai 200025, China.
yyz28@hotmail.com
Telephone: +86-21-64370045-665242
Fax: +86-21-64150773
Received: 2002-11-19
Accepted: 2003-01-02
Abstract
AIM: Irritable bowel syndrome (IBS) is characterized by
abdominal pain and changes in stool habits. Visceral
hypersensitivity is a key factor in the pathophysiology of IBS. The
aim of this study was to examine the effect of rectal
balloon-distention stimulus by blood oxygenation level-dependent
functional magnetic resonance imaging (BOLD-fMRI) in visceral pain
center and to compare the distribution, extent, and intensity of
activated areas between IBS patients and normal controls.
METHODS:
Twenty-six patients with IBS and eleven normal controls were tested
for rectal sensation, and the subjective pain intensity at 90 ml and
120 ml rectal balloon-distention was reported by using Visual
Analogue Scale. Then, BOLD-fMRI was performed at 30 ml, 60 ml, 90
ml, and 120 ml rectal balloon-distention in all subjects.
RESULTS:
Rectal distention stimulation increased the activity of anterior
cingulate cortex (35/37), insular cortex (37/37), prefrontal cortex
(37/37), and thalamus (35/37) in most cases. At 120 ml of rectal
balloon-distention, the activation area and percentage change in MR
signal intensity of the regions of interest (ROI) at IC, PFC, and
THAL were significantly greater in patients with IBS than that in
controls. Score of pain sensation at 90 ml and 120 ml rectal
balloon-distention was significantly higher in patients with IBS
than that in controls.
CONCLUSION:
Using fMRI, some patients with IBS can be detected having visceral
hypersensitivity in response to painful rectal balloon-distention.
fMRI is an objective brain imaging technique to measure the change
in regional cerebral activation more precisely. In this study, IC
and PFC of the IBS patients were the major loci of the CNS
processing of visceral
perception.
Yuan
YZ, Tao RJ, Xu B, Sun J, Chen KM, Miao F, Zhang ZW, Xu JY.
Functional brain imaging in irritable bowel syndrome with rectal
balloon-distention by using fMRI. World J Gastroenterol
2003; 9(6): 1356-1360
http://www.wjgnet.com/1007-9327/9/1356.asp
INTRODUCTION
Irritable bowel syndrome (IBS) is the most common disorder seen
in gastroenterological practice[1,2]. The disorder
affects approximately 15 % to 20 % of the world's population and is
predominately found in women[2]. It comprises a group of
functional bowel disorders in which abdominal discomfort or pain is
associated with defecation or a change in bowel habit, and with
features of disordered defecation[3,4]. The
pathophysiology of the symptom remains unclear, and visceral
hypersensitivity or decreased pain thresholds to distension of the
gut is considered to be a biologic marker for IBS and is present in
most patients with this gastrointestinal disorder[5].
Possibly, there are dysfunctions in the processing of sensory
stimuli in the "brain-gut" axis that may cause visceral
hypersensitivity and secondary motility changes[6]. The
central nervous system is believed to play a strong modulatory or
etiological role in the pathophysiology of the disease[7].
In
animals, the perception of somatovisceral pain is derived from the
expression of the immediate early gene c-fos[8-11].
Numerous positron emission tomography (PET)[12-15] or
functional magnetic resonance imaging (fMRI)[16-18]
studies have dealt with the central processing of somatic pain in
humans. In contrast, the neural networks involved in the perception
of visceral pain in humans, especially rectal pain, have been the
subjects of a limited number of functional brain imaging studies[19-23].
Previous
studies of somatic pain using PET scanning to measure the regional
cerebral blood flow have suggested that the anterior cingulate
cortex (ACC), prefrontal cortex (PFC), insular cortex (IC), and
thalamus (THAL) are important loci in pain perception[12,24].
Studies of visceral pain have generally suggested that these brain
centers are important in sensation. fMRI is an alternative technique
to measure changes in regional cerebral activity during stimulation.
Using fMRI, the cerebral loci activated by rectal distention were
also characterized in healthy volunteers[22].
In this
study, we examined the effect of rectal balloon-distention stimulus
by blood oxygenation level-dependent functional magnetic resonance
imaging (BOLD-fMRI) in the visceral pain center and to compare the
distribution, extent, and intensity of activated areas between
irritable bowel Syndrome (IBS) patients and normal controls.
MATERIALS
AND METHODS
Subjects
Eleven normal right-handed control subjects (6 men and 5
women; age, 24-49 years; average age, 39 years) and twenty-six
right-handed patients with IBS (12 men and 14 women; age, 18-61
years; average age, 47 years) participated in the study. All
volunteers were free of any gastrointestinal complaint. The IBS
patients were all diagnosed in Ruijin Hospital, and met the Rome II
criteria for IBS[4], which include at least 12 weeks, not
necessarily to be consecutive in the preceding 12 months of
abdominal discomfort or pain that has two of the following three
features: (1) Relieved with defecation; (2) Onset associated with a
change in frequency of stool; (3) Onset associated with a change in
form (appearance) of stool. Each patient underwent a basic
evaluation to exclude organic disease including a history, physical
examination, and colonoscopy.
Distention
protocol
Subjects reclined on the magnetic resonance imaging (MRI) table with
head resting on a beanbag saddle that reduced head motion. A plastic
balloon (Medtronic Synectics, USA) was placed in rectum at 10-15 cm
from the anal margin. First, the subjects were tested for the rectal
sensation, including the thresholds for sensation of gas, defecation
and pain. Second, subjects reported the subjective pain intensity at
90 ml and 120 ml rectal balloon-distention by using visual analogue
scale (0=no pain, 10=unbearable pain). Then, fMRI scanning was
begun. Subjects were instructed to expect 4 series of rectal
stimuli. Each set of distention included 3 stimuli of the same
volume lasting 30 seconds each, with a 30-second rest period in
between. The balloon inflation and deflation for each stimulus
required an average of 6 seconds. The baseline volume during the
rest periods was 0 ml. The first series of stimulus volume was 30
ml, the second 60 ml, the third 90 ml, and the last 120 ml.
MRI
scanning
BOLD imaging was performed on a 1.5-T GE Signa MRI system.
Each scanning consisted of a T1-weighted (the parameters included TR/TE=400
ms/14 ms, matrix=256×256, NEX=1). Next, four 10-mm-thickslices
aligned at an approximately 20o angle above the anterior commissure-posterior
commissure line to include the ACC, IC, PFC, and THAL. A functional
scan was performed using echo planar imaging, and a matrix of 64×64,
NEX=1. The pulse sequence parameters included a 90o flip-angle with
a TR (image repetition rate)/TE (effective echo time) of 3 000 ms/60
ms. Each run consisted of 3 repetitions of 30 seconds of rest,
followed by 30 seconds of stimulus. In each 30-second period, 10
parameters were collected, 60 data during each series.
Data
processing and analysis
Data analysis was performed using correlation-coefficient
tool in Functional software (AW3.2, SUN workstation). The confidence
level was 0.05. Brain areas thought to mediate painful sensation
included the ACC, the IC, the PFC, and THAL. These regions of
interest (ROI) were identified and circled on the high-resolution
anatomic images by a radiologist, who was blind to the identity of
the patient and to the active pixels. The regional cerebral
activation was evaluated by the percentage area of ROI and the
percentage change in MR signal intensity of ROI. The percentage area
of ROI was calculated by the formula: the percentage area of ROI =
the pixels of ROI/the total pixels of selected pain center ×100 %.
The percentage change in MR signal intensity of ROI = (the MR signal
intensity during stimulation - the Mean baseline signal)/the mean
baseline signal ×100 %. The average percentage change in MR signal
intensity was calculated for each subject at each stimulus volume in
each ROI. To exclude the influence of balloon inflation and
deflation, the first and the tenth MR signal intensity of the rest
and stimulus phase were eliminated.
Statistical
analysis
The data were expressed as means ±SEM. For comparison of
means, an unpaired Student's t test was used. The primary
comparisons were the thresholds for sensation and VAS score between
IBS patients and controls. Secondary analysis included the
percentage of ROI and the average percentage change in MR signal
intensity of ROI comparing IBS patients with controls. Statistically
significant differences by 2-tailed t tests were defined by P<0.05.
RESULTS
Rectal sensation test
In the control group, the average thresholds for sensation of gas,
defecation and pain were 28 ml, 127 ml, and 208 ml. They were 24 ml,
90 ml, and 150 ml respectively in IBS group. The thresholds for
sensation of defecation and pain were significantly lower in IBS
group than in control group (P<0.05, Figure 1).
Figure
1(PDF) Rectal
sensation test (the thresholds for sensation).
VAS
score
At 30 ml rectal distention, subjects generally sensed a
very-low-intensity stimulation, using the terms "gas",
"mildly felt". At 60 ml rectal distention, some IBS
patients expressed sensation of defecation. At 90 ml rectal
distention, a large number of IBS patients and some normal controls
expressed sensation of stool, associated with mild-moderate pain,
and VAS score was 4.42±2.00 vs 2.71±1.78. At 120 ml rectal
distention, most IBS patients reported moderate-severe painful
sensation, and VAS score was 5.90±1.84 vs 3.95±2.04. In this
study, three IBS patients could not tolerate 120 ml rectal
distention. The VAS score of 90 ml and 120 ml rectal distention
(painful rectal distention) was significantly higher in IBS patients
than in control (P<0.05, Figure 2).
Figure
2(PDF) Subjective
pain intensity.
Figure 3(PDF)
The percentage change in MR signal intensity time course of
PFC in response to 3 rectal distentions at 90 ml.
Functional
brain imaging
The time course of rectal stimulation sensation center
response indicated immediate increase and rapid decline in BOLD
signal in parallel with the mechanical distending stimulus (Figure
3). For both IBS patients and control subjects, rectal distention
stimulation increased the activity of anterior cingulate cortex
(35/37), insular cortex (37/37), prefrontal cortex (37/37), and
thalamus (35/37) in most cases.
In
patients with IBS, the average percentage area of ROI increased in
parallel with rectal distention volumes in the IC, PFC, and THAL,
only that in PFC had statistical significance (P<0.05). In
controls, this increasing tendency only occurred in the ACC (Figure
4). At 120 ml rectal distention, the average percentage area of ROI
and the average percentage change in MR signal intensity of ROI in
the IC, PFC, and THAL were significantly greater in patients with
IBS than in control subjects (P<0.05, Figure 5 and 6).
Figure
4 Functional brain map. The red area is the ROI.
Figure 5(PDF)
The average area of ROI at 120ml rectal distention.
Figure 6(PDF)
The percentage change in MR signal intensity of ROI at 120 ml
rectal distention.
DISCUSSION
FMRI is a useful technology to measure changes in regional CNS
blood oxygenation, which is in parallel with regional metabolic
activity[25-27]. The BOLD technology detects changes in
the ratio of deoxyhemoglobin to oxyhemoglobin. When brain-center
neurons are metabolically active, there is an increase in local
blood flow and a relative increase in the amount of oxyhemoglobin,
and an increase in magnetic resonance signal[25-29].
Accordingly, the magnetic resonance signal in a given pixel will
increase above baseline if the region is activated in response to
stimulation. FMRI offers advantages over PET such as direct anatomic
correlation, avoidance of radioisotopes, and acceptable
signal-to-noise ratio that do not require large numbers of stimuli.
fMRI images give similar results as PET[30,31].
It showed
that fMRI has adequate sensitivity to measure regional cerebral
blood flow changes in response to visceral - in this case rectal -
stimulation. Activity in the 4 selected CNS pain centers, ACC, IC,
PFC, and THAL, promptly increase with rectal distention stimulation.
The 4 selected pain centers are components of the brain's
pain-processing system[12,24,32,33]. Current studies
pointed to the THAL as a relay center, connecting afferent signals
from the spinothalamic tract and spinoreticular tracts to higher
centers such as the cingulate, prefrontal, and insular cortices[34,35].
The IC is believed to mediate primarily visceral sensations (taste,
smell, gastric, colonic, and other visceral inputs) including rectal
stimuli, whereas the ACC is thought to mediate the affective or
"emotional" content of sensory information. The insular
cortex neurons distributed between the taste area and the visceral
area receive convergent inputs from baroreceptor, chemoreceptor,
gustatory and nociceptive organs and may have roles in taste
aversion or in regulation of visceral responses[36].
Using positron emission tomography (PET), Craig's[37]
group found contralateral activity correlated with graded cooling
stimuli only in the dorsal margin of the middle/posterior insula in
humans. Furthermore, Krushel[38] referred to the region
of convergence in the agranular insular cortex as the visceral
cortex, and suggested its involvement in the efficient integration
of specific visceral sensory stimuli with correlated limbic or
motivational consequences. The visceral cortex may help regulate the
organism's visceral response to stress.
The
PFC is thought to exert higher executive functions in pain
perception[39]. There are several different functional
divisions of the PFC, including the dorsolateral, ventromedial, and
orbital sectors. Each of these regions plays some role in affective
processing that shares the feature of representing affect in the
absence of immediate rewards and punishments as well as in different
aspects of emotional regulation[40].
In
this study, the thresholds for sensation of defecation and pain were
significantly lower in IBS group than in control group, and VAS
score was significantly higher in IBS patients than in controls. The
results were similar to the previous studies[41]. Normal
volunteers and IBS patients had significant cerebral activation in
the 4 selected brain centers (ACC, IC, PFC, and THAL) during
distention stimulation at 30 ml, 60 ml, 90 ml, and 120 ml.
Significant differences in cerebral activation (both the percentage
area and the percentage change in MR signal intensity of ROI) were
found between IBS patients and controls. In IBS patients, there was
significantly greater area of ROI of the PFC with 120 ml distention
than with other volume distention. Conversely, in control subjects
there was no significant increase in activation of these areas with
120 ml distention compared with others. Furthermore, at 120 ml
rectal distention, there was significantly greater activation of the
IC, PFC, and THAL in patients with IBS than in control subjects. In
summary, by a variety of measures, it is possible that IC and PFC
responses to visceral pain in IBS are greater than that in controls.
There were
several studies about the CNS activity in response to visceral
stimulation by using PET and fMRI, but the results differed.
Silverman[20] found a lack of activation within the ACC
or PFC with nonpainful stimuli, and reported activation of PFC in
response to rectal pain only in IBS and the ACC only in normal
subjects. In contrast, more recently Mertz[23], using
fMRI, observed that pain led to a greater activation of the ACC than
nonpainful stimuli. In Bernstein's[42] study, they also
found that normal controls and subjects with IBD and IBS shared
similar loci of activations to visceral sensations of stool and
pain. A significantly higher percentage of pixels activated in the
anterior cingulate gyrus over both pain and stool conditions for the
control group than for the IBS group and for the IBS group than for
the IBD group (P<0.035). In another study, Bonaz et al
revealed significant deactivations within the right insula, the
right amygdala, and the right striatum[7]. There were
gender differences in cortical representation of rectal distension
in healthy humans. Male subjects showed localized clusters of fMRI
activity primarily in the sensory and parietooccipital regions,
whereas female subjects also showed activity in the anterior
cingulate and insular regions[43]. Thus, somatic and
visceral sensation including pain perception can be studied
noninvasively in humans with functional brain imaging techniques.
Positron emission tomography and functional magnetic resonance
imaging have identified a series of cerebral regions involved in the
processing of somatic pain, including the anterior cingulate,
insular, prefrontal, inferior parietal, primary and secondary
somatosensory, and primary motor and premotor cortices, the
thalamus, hypothalamus, brain stem, and cerebellum[44].
Experimental evidence supports possible specific roles for
individual structures in processing the various dimensions of pain[44].
In
conclusion, our data conform that fMRI is an objective brain imaging
technique to measure the change in regional cerebral activation
exactly. Using fMRI, some patients with IBS could be detected having
visceral hypersensitivity in response to painful rectal
balloon-distention. In this study, IC and PFC of IBS patients are
the major loci in CNS processing of
visceral perception.
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