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October 25, 2005; 65 (8) Articles

Abnormal forebrain activity in functional bowel disorder patients with chronic pain

C. L. Kwan, N. E. Diamant, G. Pope, K. Mikula, D. J. Mikulis, K. D. Davis
First published October 24, 2005, DOI: https://doi.org/10.1212/01.wnl.0000180971.95473.cc
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Abstract

Background: Abnormal cortical pain responses in patients with fibromyalgia and conversion disorder raise the possibility of a neurobiologic basis underlying so-called “functional” chronic pain.

Objective: To use percept-related fMRI to test the hypothesis that patients with a painful functional bowel disorder do not process visceral input or sensations normally or effectively at the cortical level.

Methods: Eleven healthy subjects and nine patients with irritable bowel syndrome (IBS) underwent fMRI during rectal distensions that elicited either a moderate level of urge to defecate or pain. Subjects continuously rated their rectal stimulus–evoked urge or pain sensations during fMRI acquisition. fMRI data were interrogated for activity related to stimulus presence and to specific sensations.

Results: In IBS, abnormal responses associated with rectal-evoked sensations were identified in five brain regions. In primary sensory cortex, there were urge-related responses in the IBS but not control group. In the medial thalamus and hippocampus, there were pain-related responses in the IBS but not control group. However, pronounced urge- and pain-related activations were present in the right anterior insula and the right anterior cingulate cortex in the control group but not the IBS group.

Conclusions: Percept-related fMRI revealed abnormal urge- and pain-related forebrain activity during rectal distension in patients with irritable bowel syndrome (IBS). As visceral stimulation evokes pain and triggers unconscious processes related to homeostasis and reflexes, abnormal brain responses in IBS may reflect the sensory symptoms of rectal pain and hypersensitivity, visceromotor dysfunction, and abnormal interoceptive processing.

Irritable bowel syndrome (IBS) is a disorder characterized by chronic visceral pain1 and rectal hypersensitivity,2 exemplified as a reduced rectal pain threshold.3–6 IBS patients also perceive rectal stimuli to be more unpleasant than do healthy subjects,7 are hypervigilant of visceral sensations,8 and have a higher level of anxiety and somatization associated with rectal distension.9–12 Given the evidence of peripheral13–18 and CNS19,20 abnormalities, we propose that a dysfunction in brain–gut interactions underlies chronic pain in IBS.

Neuroimaging during rectal stimulation in healthy subjects consistently reports cortical activations in primary somatosensory (S1), secondary somatosensory (S2), anterior insular, dorsolateral prefrontal, and orbitofrontal cortices,21–28 yet neuroimaging results in IBS have been inconsistent.21,24,29–33 These previous studies have not considered the variety of rectal-evoked sensations (e.g., urge to defecate, pain, and unpleasantness).34–36 Rectal distension triggers widespread brain activity, some of which may be involved in conscious perception of these different sensations and some of which may not be perceived but could relate to homeostatic, visceromotor, or reflexive functions. We have shown that the perceptual responses to rectal stimuli are time locked to the stimulus period in healthy subjects but are dissociated from the duration and intensity of rectal stimuli in IBS patients.6,37 Therefore, we sought to use percept-related fMRI38,39 to identify in IBS patients abnormal cortical activations evoked by rectal distension and abnormal cortical activation associated with urge or pain perception. Some data from this study have been briefly presented in abstract form.40

Methods.

Subjects.

Prior to study entry, each subject’s suitability for either the control or the patient group was assessed using an inclusion/exclusion criteria questionnaire, and informed consent was acquired according to ethics guidelines of the University Health Network. None of the control subjects had a medical history of chronic pain, bowel disturbance, or visceral disease. IBS patients were recruited from the Gastrointestinal Unit of the Toronto Western Hospital and satisfied the following inclusion criteria: 1) positive diagnosis of IBS in accordance with the Rome II Criteria1 by a trained gastroenterologist and 2) standard clinical investigations to exclude the presence of organic disease. IBS patients were required to cease taking all medications at least 1 week prior to the study. The control group consisted of 11 healthy subjects (7 women and 4 men; age range 24 to 49 years, mean ± SD age 31.7 ± 7.4 years), whereas the patient group consisted of 9 IBS patients (6 women and 3 men; age range 23 to 55 years, mean ± SD age 37.8 ± 10.5 years). The average age of the two groups was not different (p = 0.15, Student t test). Each subject fasted for at least 9 hours prior to the experiment and self-administered a Fleet enema (C.B. Fleet, Lynchburg, VA) 2 hours prior to the functional neuroimaging experiment. Experiments in women were performed between 3 and 10 days after menstruation (i.e., during early follicular phase) to reduce the variability in pain ratings across the menstrual cycle.41,42

Rectal stimulus and evoked sensations.

An infinitely compliant polystyrene balloon catheter (10 cm long and 800-mL capacity; Mui Scientific, Mississauga, Ontario, Canada) connected to a computer-controlled barostat (Distender Series II; G &J Electronics, Toronto, Ontario, Canada) was used to deliver isobaric distensions of the rectum at an inflation rate of 40 mL/s. The balloon was positioned in the rectum with its base 10 cm from the anal verge prior to entry of the MRI suite. Subjects were required to lie in a supine position on the MRI platform, and a foam pad was placed underneath the subject’s hip to prevent excessive bending of the tube connecting the balloon catheter and barostat. Balloon pressure and volume and on-line perception ratings were continuously sampled (5 Hz) using a data acquisition program (Labview; National Instruments, Austin, TX). During each fMRI scanning session, subjects continuously rated the magnitude of either urge to defecate or pain evoked by the rectal stimuli using a computer-presented 100-point Visual Analog Scale (VAS). Subjects used a mirror system to view the computerized VAS, which was back-projected onto a screen placed at the foot of the MRI platform. All subjects used their left index finger to manipulate a trackball device that controlled the movement of a cursor along the VAS.38 We have previously considered the impact of these ratings38 and found little, if any, spurious motor activations produced by the slight (<5-mm) movement of a single finger. The word anchors for both the urge and pain intensity scales were adapted from the work of Gracely et al.43 and described as weak (1 to 20), mild (21 to 40), moderate (41 to 60), strong (61 to 80), and intense (81 to 100).

Experimental protocol.

The intensities of rectal stimulation used during fMRI sessions were 1) baseline pressure and 2) pressures that elicited either a moderate intensity of urge to defecate or moderate pain intensity. These pressures were initially determined in a psychophysical experiment conducted at least 1 week prior to the fMRI study using an ascending stepwise distension protocol.6,37 On the day of the fMRI study, these pressures were tested and adjusted just prior to the scanning sessions to set a level that evoked moderate intensities (50/100 on a verbal rating scale) of urge or pain. These set pressures were used throughout the scanning session. During the fMRI scanning, rectal stimulation evoked average peak urge and pain ratings (using the online VAS system) in the IBS group (mean ± SEM urge rating 39.1 ± 6.5, pain rating 36.6 ± 4.7) that were not different compared with the control group (urge rating 30.6 ± 3.9, pain rating 31.4 ± 2.9) (for urge ratings, p = 0.26; for pain ratings, p = 0.34; Student t tests). Although IBS patients have lower pain thresholds than controls,6 the pressures used to evoke moderate urge or moderate pain were not different (for urge pressure, p = 0.55; for pain pressure, p = 0.65; Student t tests) between the IBS group (urge pressure 23.6 ± 1.9 mm Hg, pain pressure 32.9 ± 2.7 mm Hg) and the control group (urge pressure 25.4 ± 2.2 mm Hg, pain pressure 36.9 ± 3.1 mm Hg).

During each fMRI run, a set of 12 20-second duration rectal distensions were interleaved with baseline distensions of varying duration (either 10, 20, or 30 seconds). The purpose of baseline distensions of varying duration was to prevent anticipation of higher intensity urge- or pain-eliciting distensions. The distensions used in the first scan were delivered at a pressure that elicited a moderate intensity of the perception of urge, and subjects were instructed to continuously rate the sensation of urge (figure 1). The distensions used in the second scan were delivered at a pressure that elicited a moderate intensity of pain and subjects were instructed to continuously rate the sensation of pain (see figure 1).

Figure

Figure 1. Examples of rectal stimulus waveforms and continuous ratings (convolved to the hemodynamic response function) of urge during low-pressure rectal distensions that elicited moderate level of urge (A) or pain during high-pressure rectal distensions that elicited moderate level of pain (B) from a control subject and an IBS patient. In each graph, the left y-axis represents the scale for normalized pressure and the right y-axis represents the scale for rating intensity (see Methods).

MRI parameters.

Brain images were obtained using a standard quadrature head coil on a 1.5 T echo speed MRI system (GE Medical Systems, Milwaukee, WI). A standard T1-weighted three-plane localizer was initially obtained to ascertain the proper coordinates for acquisition of anatomic images. A T1-weighted three-dimensional inversion recovery–prepped fast spoiled gradient-recalled sequence (echo time [TE] = 5 milliseconds, repetition time [TR] = 25 milliseconds, flip angle = 45°) was used to generate 124 1.5-mm-thick sagittal anatomic images (256 × 256 matrix size, field of view = 24 × 24 cm, in-plane resolution = 1.17 × 1.17 mm) that covered the entire head. Twenty-five 4-mm-thick axial functional images covering the entire head were acquired using a T2*-weighted gradient echo spiral sequence through K-space44 (one shot, TE = 40 milliseconds, TR = 2,000 milliseconds, field of view = 20 × 20 cm, in-plane resolution = 3.125 × 3.125 mm). Each functional imaging session consisted of a total of 270 volumes for a total acquisition time of 9 minutes.

Processing and statistical analysis of brain images.

The processing of anatomic and functional brain images was performed using Brain Voyager 4.9 (Brain Innovation b.v., Maastricht, the Netherlands). Preprocessing of anatomic images involved resampling to a resolution of 1 × 1 × 1 mm and transformation into a standard stereotaxic space.45 Preprocessing of functional images first included correction for differences in time–slice acquisition, co-registration of functional images into three-dimensional stereotaxic space, and resampling of images to a resolution of 3 × 3 × 3 mm. These images subsequently underwent further preprocessing, including 1) removal of linear trends from the time course of each voxel, 2) correction of motion artifacts using a three-dimensional motion correction algorithm, 3) spatial smoothing using a 6-mm full width at half-maximum (FWHM) Gaussian kernel to accommodate intersubject variations in brain anatomy, 4) temporal smoothing of the time series of each voxel using a 1.4 frame FWHM Gaussian kernel, and 5) temporally smoothing using a high-pass filter (period > 273 seconds) to remove slow nonlinear drifts in the time series.

Data from individual subjects within each group (IBS, controls) were averaged and analyzed using a general linear model (GLM) to examine brain activity changes (activation). Two analyses were performed using either the normalized stimulus (rectal pressure) waveform or raw sensory ratings waveform as the predictor curve. As a major objective was to determine brain activity correlated to the temporal profile of the stimulus curve, the pressure curve was normalized by scaling pressure values between the minimum pressure, which was set to a value of 0, and the maximum pressure, which was set to a value of 1. Predictor curves were generated from either the normalized stimulus or the ratings waveforms convolved with a standard hemodynamic (gamma variate) reference function (BrainVoyager 4.9). Therefore, the resultant activations are referred to as “stimulus related,” “urge related,” or “pain related.” A further analysis was carried out to examine significant differences in brain activity between groups using a GLM in which data from IBS patients were contrasted to data from control subjects using predictor curves generated from stimulus or ratings waveforms.

The threshold of activation maps was based on a combination of voxel-wise p value (p < 0.0001) and cluster size (150 mm3) that was previously validated.38,46,47 Furthermore, we used Alphasim software (B. Douglas Ward, Biophysics Research Institute, Medical College of Wisconsin, Madison, WI) to create Monte–Carlo simulations of parameters particular to our scanning and processing protocol to verify that the above threshold would result in an image-wide corrected p value of p < 0.05. Overlap maps showing thresholded activations (see above) from both IBS and control groups during specific conditions were generated using in-house software.

The main aim of this study was to delineate differences in cortical processing associated with rectal stimulation and with the sensations evoked by the stimulation in patients with IBS compared with healthy control subjects. Differences in fMRI responses between the IBS and control groups may arise owing to differences in the magnitude of responses or the location and spatial extent of activations. A popular method of showing differences between two subject groups is to subtract (i.e., contrast) one set of group data from the other. However, interpreting the resultant activations is complex. For example, an apparent activation in a Group A-B contrast can arise when 1) there is activation in Group A but not Group B; 2) there is activation in Groups A and B, but A is significantly greater than B; 3) there is no activation in Group A and a deactivation in Group B; 4) both Group A and B are deactivated, but Group B is more strongly deactivated; 5) Group A and Group B responses are subthreshold in terms of either magnitude or extent, but the difference between them is significantly above threshold; 6) activations in Groups A and B are similar in magnitude but differ in spatial extent. Therefore, we constructed individual group maps in addition to the group difference maps so that these possibilities could be considered: activations occurring 1) uniquely in the control group are displayed in green, 2) uniquely in the IBS group are displayed in red, and 3) common to both groups are displayed in yellow (figures 2 and 3). The between-group contrast maps (see figures E-1 and E-2 on the Neurology Web site; go to www.neurology.org) indicate brain activity that was significantly higher in the IBS group than the control group (shown in orange hues) or significantly lower in the IBS group than the control group (shown in blue hues).

Figure

Figure 2. Brain maps showing the spatial extent of stimulus-related (A) and urge-related (B) activations in both control and irritable bowel syndrome (IBS) groups during low-pressure rectal distensions that elicited a moderate level of urge. Control activations are displayed in green, IBS activations are displayed in orange, and regions of overlap are displayed in yellow. Maps show 18 contiguous 4-mm-thick axial slices from 58 mm above to 10 mm below the anterior–posterior commissure line and 4 contiguous 5-mm-thick sagittal slices centered at midline. All activations shown at a corrected map-wise threshold of p < 0.05 (also see Methods).

Figure

Figure 3. Brain maps showing the spatial extent of stimulus-related (A) and pain-related (B) activations in both control and irritable bowel syndrome (IBS) groups during high-pressure rectal distensions that elicited a moderate level of pain. Control activations are displayed in green, IBS activations are displayed in orange, and regions of overlap are displayed in yellow. Maps show 18 contiguous 4-mm-thick axial slices from 58 mm above to 10 mm below the anterior–posterior commissure line and 4 contiguous 5-mm-thick sagittal slices centered at midline. All activations shown at a corrected map-wise threshold of p < 0.05 (also see Methods).

Results.

Psychophysical measurements during fMRI.

Figure 1 shows examples of psychophysical ratings of rectal-evoked urge and pain and normalized stimulus (pressure) waveforms (convolved with the hemodynamic response function) emphasizing the temporal profile relationship between ratings and stimulus curves. The temporal profile of ratings acquired from IBS patients differed from that in control subjects during both urge-eliciting and pain-eliciting distensions. In control subjects, the sensation ratings curve followed the general temporal profile of the stimulus (pressure) curve but with a slight delay. In IBS patients, the sensation ratings did not tightly follow the temporal profile of the stimulus curve. A notable difference between groups is that in the control subjects, as the sensation ratings decreased to zero after each stimulus, they typically remained elevated in the IBS patients. A detailed report of the psychophysical profile differences between IBS and control subjects was recently published.6

Brain activations during low-pressure rectal distensions that elicit urge.

Stimulus-related activations during rectal distensions at pressures that evoked a moderate urge sensation were mostly confined to the prefrontal cortex and insula (table 1; see figure 2A and also table E-1 on the Neurology Web site). Although distinctly separate prefrontal activations (Brodmann area [BA] 9, 10, 44, and 46) appeared in the left hemisphere between groups, activations considerably overlapped in BA9 in the right hemisphere (see tables 1 and E-1 [on the Neurology Web site]; also figure 2A). Stimulus-related activations appearing prominently in control but not IBS subjects were located in the right primary motor cortex (M1), right supplementary motor area (SMA), and left anterior insula (see tables 1 and E-1 [on the Neurology Web site]; also figure 2A). The M1 and SMA activations could be due to the left finger movements used to rate the urge sensation, which were more temporally related to the stimulus in the control subjects than in the IBS group. Conversely, prominent stimulus-related activations found in the IBS group, but not control group, were located in right BA44, the left caudate nucleus (see tables 1 and E-1 [on the Neurology Web site]; also figure 2A.

View this table:

Table Major activations during low- and high-pressure rectal distensions

Urge-related activations were more widespread and spatially extensive than low-pressure stimulus–related activations, particularly in the control group (see tables 1 and E-1 [on the Neurology Web site]; also figure 2B). A large anterior cingulate cortex (ACC; right BA24 and 32) activation was identified in the control group, but in the IBS group only a very small region of the left ACC was activated (see figure 2B). Again, urge-related activations appearing in both control and IBS groups were located in both prefrontal cortices and right inferior parietal cortex, but these were more extensive in controls (see tables 1 and E-1 [on the Neurology Web site]; also figure 2B). Although urge-related activations in the right temporoparietal junction (which consists of BA22, 39, and 40) overlapped in control and IBS groups, this activation was much larger in the control group (see figure 2B). Prominent urge-related activations in the anterior insular cortex bilaterally and in the left basal ganglia (caudate, putamen, and pallidum) were found only in the control group but not the IBS group (see figure 2B). Finally, urge-related activations unique to the control group were found bilaterally in S2 and in the right premotor cortex (see tables 1 and E-1 [on the Neurology Web site]; also figure 2B). Conversely, a prominent urge-related activation that appeared in the IBS but not the control group was located in the right S1 (see tables 1 and E-1 [on the Neurology Web site]; also figure 2B).

The contrast maps of IBS vs control group data revealed additional regions (medial thalamus, hippocampus, posterior cingulate cortex [PCC], precuneus) where brain activity during low-pressure distensions was apparently higher in IBS than control subjects (see figure E-1 on the Neurology Web site), but as these regions did not appear in the individual group maps (see figure 2), the meaning of these findings is complex (see Methods). For stimulus-related contrast map, the IBS group had higher brain activity bilaterally in both medial thalamus and hippocampus, in left medial prefrontal cortex, in left precuneus, bilaterally in PCC, and in the right caudate nucleus (see figure E-1A on the Neurology Web site). For the urge-related contrast map, higher activity in the IBS group was located in the left PCC and bilaterally in the caudate nucleus (see figure E-1B on the Neurology Web site). Brain regions where activity was lower in the IBS than the control group (see figure E-1 on the Neurology Web site) coincided with the location of activations of the control group for stimulus- or urge-related activations (see figure 2).

Brain activations during high-pressure painful rectal distensions.

High-pressure stimulus-related activations were more widespread in the IBS group (figure 3A), whereas pain-related activations were more widespread in the control group (see figure 3B).

Stimulus-related activations were found for both the control and IBS groups bilaterally in the temporal, frontal, and anterior insular cortices, the right SMA, the left S2, and the right ventral M1 (see tables 1 and E-2 [on the Neurology Web site]; also figure 3A). The IBS group had a larger activation of the left anterior insula than controls during painful rectal distension, although the dorsal aspect of the right anterior insula was activated only in the control group (see figure 3A). Stimulus-related activations that appeared only in the IBS group were located in many regions including the right hippocampus, right posterior insular cortex, left medial thalamus, right pallidum, left putamen, and bilaterally in the precuneus (see tables 1 and E-2 [on the Neurology Web site]; also figure 3A).

Large pain-related activations in the control group, and to a lesser extent in the IBS group, were found bilaterally in the prefrontal and inferior parietal cortices and the right temporal cortex (see tables 1 and E-2 [on the Neurology Web site]; also figure 3B). Pain-related activations common to both control and IBS groups were also found in left anterior insular cortex, right S1, and left S2 (see tables 1 and E-2 [on the Neurology Web site]; also figure 3B). Although there was significant overlap of activations between groups in these regions, activations in right temporoparietal junction, right prefrontal cortex, bilateral anterior insular cortex, left S2, bilateral ACC, and basal ganglia were much larger in spatial extent in the control group (see figure 3B). Also, conspicuously large activations spanned BA32 and BA24 in the right ACC in the control but not IBS group (see figure 3B). Also of note were the large activations situated in the middle and dorsal portions of the right anterior insula found in the control group and not IBS group (see figure 3B). Finally, pain-related activations in the hippocampus appeared only in the IBS group (see tables 1 and E-2 [on the Neurology Web site]; also figure 3B).

Contrast maps of IBS vs control group constructed for pain-eliciting high-pressure distensions revealed additional regions where brain activity appeared to be greater in IBS than control subjects (see figure E-2 on the Neurology Web site); yet these regions were not identified in the single-group activation maps, and so their meaning is unclear (see above and Methods). For the stimulus-related contrast map, the IBS group had higher brain activity in left hippocampus and left medial prefrontal cortex (see figure E-2A on the Neurology Web site). Conspicuously large regions of bilateral precuneus and PCC also had higher activity in the IBS compared with the control group (see figure E-2A on the Neurology Web site). For the pain-related contrast map, higher activity in the IBS group was found in the left amygdala and left hippocampus, and bilaterally in the precuneus (see figure E-2B on the Neurology Web site). Similar to the contrast maps constructed for low-pressure distensions, brain regions where activity was lower in the IBS compared to control group (see figure E-2 on the Neurology Web site) coincided with the location of activations of the control group for stimulus- or pain-related activations (see figure 3).

Discussion.

These data demonstrate that the brain response to rectal distension is different in IBS compared with healthy control subjects. Five key brain areas were differentially activated in IBS vs healthy individuals: S1 and four components of the medial pain system (medial thalamus, hippocampus, anterior insula, and ACC)48 (figure 4). These findings may reflect abnormal sensory and affective–emotional processing of visceral input, interoception, and visceromotor regulation in IBS.

Figure

Figure 4. Major sites of activation differences between irritable bowel syndrome (IBS) and healthy control subjects. Brain maps indicate urge-related activations (as indicated by the yellow arrow) within S1 and pain-related activations in medial thalamus and hippocampus that appear only in the IBS group, whereas control group images show the absence of activation in analogous brain regions (as indicated by the green circle). Conversely, the control group shows prominent pain-related activations within the dorsal anterior insula and anterior cingulate cortex but not in the IBS group. Right (R) and left (L) sides of the brain are indicated in axial and coronal brain images; sagittal images were from the right hemisphere.

Interpreting abnormal brain activation during rectal distension in IBS patients requires consideration of both conscious events (i.e., perceptual responses) and unconscious processing (e.g., homeostatic and/or motor/reflex responses) of the stimulus. Percept-related activations were more extensive than stimulus-related activations in control subjects, likely owing to a better temporal “fit” with the percept compared with the stimulus pressure curve. However, this was not always the case for the IBS group during high-pressure distension, highlighting a possible index of abnormal conscious and unconscious rectal perception and brain–gut relationships. Although IBS patients are not uniform in their perceptual abnormalities, we have previously demonstrated6 that they all show some form of abnormal perceptual urge and pain responses to rectal distension, in terms of either temporal fit (e.g., prolonged responses) or increased response intensity. As rectal distension evokes a variety of sensations including urge to defecate and pain,34–37 our findings underscore the importance of monitoring perceptual responses during fMRI. For example, a ventrolateral S1 activation was detected by correlating the fMRI data to the temporal dynamics of the urge sensation but not to the low pressure stimulus in the IBS group.

A heightened sensitivity in the sensory processing of rectal distension in IBS could be reflected by the activation of S1 in IBS (but not control) subjects during low-pressure rectal distensions. This activation was located in the inferolateral aspect of S1, a region associated with the processing of visceral input.49,50 As the control subjects only activated S1 during high-pressure distension, these findings suggest that the threshold for S1 activation is lower in IBS and that painful rectal stimuli may normally be required for the activation of this cortical area. Therefore, the S1 activation in the IBS group may reflect visceral allodynia. These findings are consistent with one fMRI study,27 but contrary to another.25 Nonetheless, S1 activation produced by low-pressure distension in controls may still be a point of contention because another fMRI study27 also failed to find S1 activation with this type of stimulation. More importantly, our finding of S1 activation during low-pressure rectal distension in IBS and not control subjects supports psychophysical observations that patients with IBS are hypersensitive to visceral stimuli as well as have abnormal rectal perception.2,7–9 We have also reported that low-pressure distensions eliciting a level of moderate urge were also felt as mildly painful in IBS patients.6 The finding that both painful cutaneous and visceral stimuli have been shown to activate common regions of the insular cortex in IBS patients28 suggests that this region is responsible for the processing of both types of pain in IBS patients. As the lateral S1 region is specifically activated by intra-abdominal but not cutaneous stimuli,51,52 our lateral S1 activation observed only during low-pressure rectal stimulation in IBS suggests that this region may play a specific and important role in visceral hyperalgesia in IBS.

Our study also suggests that brain regions associated with the affective–emotional dimension of pain are altered in IBS.53,54 For example, the medial thalamus (an integral pain-processing center55–59) activated only in the IBS patients during high-pressure (painful) rectal distension. Medial thalamus was noted in previous studies for both IBS and control subjects during painful rectal distension,24,28 whereas we observed a large medial thalamic activation in IBS patients but little activation in this area in control subjects during painful rectal distension. These differences could be due to the conservative statistical threshold used in our image analysis that could exclude a weaker medial thalamic activation in the control group. Consistent with this view is the finding of a much larger medial thalamic activation in IBS patients compared with controls.24 Indeed, when the statistical threshold was lowered to p < 0.05 (uncorrected) or cluster threshold was lowered to below 50 mm3, there was a weak activation of the left dorsomedial thalamus in control subjects (data not shown). The hippocampus is also associated with the affective–motivational processing of pain,60–65 and this region was only activated in the IBS group during painful rectal distension. Activation of both medial thalamus and hippocampus by painful rectal distension is consistent with observations that IBS patients display a great aversion to visceral stimuli66 and perceive rectal distension as highly unpleasant7 and suggests that rectal distension in IBS patients evokes a high level of affect and anxiety.62,67 On the other hand, a lack of activation in these two brain areas in controls suggests relatively less affective processing associated with moderately painful rectal distension. This concept is supported by the findings that pain intensity and unpleasantness are comparable in control subjects at most rectal distension intensities.7,8,37 The amygdala plays a key role in the affective–motivational dimension of pain through the processing of fear associated with the pain experience.68–72 Although we did not identify statistically significant amygdala activations in either group, the IBS minus control contrast did reveal amygdala activity. However, the meaning of this activation is complex and could be due to a combination of subthreshold activities (see Methods).

Perhaps the most remarkable difference in activation between IBS patients and control subjects is within insular cortex, an important brain area for the integration of visceral and somatosensory input.73,74 Painful rectal distension produced left anterior insular cortical activation in IBS patients both in our study and in others.28,32 Our study highlights the finding that regardless of distension level, there is activation in the dorsal pole of the right anterior insula in control subjects but not patients with IBS. The absence of activation in this region in IBS may suggest a “ceiling” effect whereby this region is already highly activated at basal state (i.e., in a chronic pain state) and thus cannot be further activated during rectal distension.75,76 However, lower activity in the right dorsal anterior insula in IBS compared with control subjects found in our contrast map analysis would suggest that this region inherently has low activity in IBS. This region has been implicated as critically important for interoception77–80 and has connections to posterior insula, higher cortical centers such as S2, and subcortical areas such as thalamus, amygdala, and hippocampus.73,74,81–83 Furthermore, the anterior insula is important for the regulation of visceral motor responses as shown by the different types of gustatory and cardiovascular responses elicited by electrical stimulation of this region.84 Therefore, the lack of right anterior insular activation in IBS patients may indicate a deficit in interoceptive processing but, on the other hand, may signal a disruption in the formation of a proper homeostatic or visceral reflex response to painful rectal distension. As electrical stimulation of the anterior insula is capable of eliciting visceromotor activity,85 a dysfunction of visceromotor control can conceivably result in rectal motor physiology abnormalities such as decreases in dynamic compliance,13–15 static volume–pressure relationship,16,17 and rate of rectal relaxation.17,18

The ACC is a key brain area implicated in the attentional and emotional components of pain.86 Previous fMRI studies in patients with IBS have demonstrated rostral ACC activations during painful28 and both nonpainful and painful rectal distension.24,32 Our study found a large activation in the midrostral ACC during painful rectal distension in the control group. In the IBS group, we found a distinct rostral ACC activation during painful high-pressure distensions but did not observe any activation in this region during low-pressure rectal distension. Such findings suggest that attentional engagement is higher in controls vs IBS patients. It is difficult to interpret and reconcile the differences across studies, but given the well-known role of the rostral ACC in emotion, previous activations may be related to general limbic function. Regardless, activation during painful rectal distension in both our study and others’24,32,28 indicates that this region likely plays a role in the processing of painful visceral stimuli in IBS. Consistent with this concept is that ACC activation can be abolished with the resolution of IBS symptoms by behavioral intervention87 and that pharmacological treatment with a 5-HT3 receptor antagonist reduces pain intensity and unpleasantness ratings during painful rectal distension as well as decreases blood flow in the ACC.88 Although percept-related fMRI used in the current study was especially relevant to identifying differences in ACC processing in IBS patients, this approach additionally revealed central substrates of visceral allodynia (hypersensitivity) and differential visceromotor activity that can impact on the sensory, attentional, or affective–emotional dimensions of pain processing in IBS.

Footnotes

  • Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the October 25 issue to find the title link for this article.

    *These authors contributed equally as senior authors.

    Supported by the Canadian Institutes of Health Research and the Canadian Research Chair Program. C.L.K. was supported by a Canadian Institutes of Health Research/Canadian Pain Society/Janssen–Ortho Doctoral Research Award.

    Disclosure: The authors report no conflicts of interest.

    Received March 1, 2005. Accepted in final form July 19, 2005.

References

  1. 1.↵
    Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut 1999;45(suppl 2):II43–II47.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 1995;109:40–52.
    OpenUrlCrossRefPubMed
  3. 3.↵
    Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 1973;14:125–132.
    OpenUrlAbstract/FREE Full Text
  4. 4.
    Bradette M, Delvaux M, Staumont G, Fioramonti J, Bueno L, Frexinos J. Evaluation of colonic sensory thresholds in IBS patients using a barostat. Definition of optimal conditions and comparison with healthy subjects. Dig Dis Sci 1994;39:449–457.
    OpenUrlCrossRefPubMed
  5. 5.
    Bouin M, Plourde V, Boivin M, et al. Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology 2002;122:1771–1777.
    OpenUrlCrossRefPubMed
  6. 6.↵
    Kwan CL, Diamant NE, Mikula K, Davis KD. Characteristics of rectal perception are altered in irritable bowel syndrome. Pain 2005;113:160–171.
    OpenUrlCrossRefPubMed
  7. 7.↵
    Verne GN, Robinson ME, Price DD. Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain 2001;93:7–14.
    OpenUrlCrossRefPubMed
  8. 8.↵
    Naliboff BD, Munakata J, Fullerton S, et al. Evidence for two distinct perceptual alterations in irritable bowel syndrome. Gut 1997;41:505–512.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    Trimble KC, Farouk R, Pryde A, Douglas S, Heading RC. Heightened visceral sensation in functional gastrointestinal disease is not site-specific. Evidence for a generalized disorder of gut sensitivity. Dig Dis Sci 1995;40:1607–1613.
    OpenUrlCrossRefPubMed
  10. 10.
    Slepoy VD, Pezzotto SM, Kraier L, et al. Irritable bowel syndrome: clinical and psychopathological correlations. Dig Dis Sci 1999;44:1008–1012.
    OpenUrlPubMed
  11. 11.
    Drossman DA, Leserman J, Li Z, Keefe F, Hu YJ, Toomey TC. Effects of coping on health outcome among women with gastrointestinal disorders. Psychosom Med 2000;62:309–317.
    OpenUrlAbstract/FREE Full Text
  12. 12.
    Bouin M, Meunier P, Riberdy-Poitras M, Poitras P. Pain hypersensitivity in patients with functional gastrointestinal disorders: a gastrointestinal-specific defect or a general systemic condition? Dig Dis Sci 2001;46:2542–2548.
    OpenUrlCrossRefPubMed
  13. 13.↵
    Hammer J, Phillips SF, Talley NJ, Camilleri M. Effect of a 5HT3-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome. Aliment Pharmacol Ther 1993;7:543–551.
    OpenUrlPubMed
  14. 14.
    Slater BJ, Plusa SM, Smith AN, Varma JS. Rectal hypersensitivity in the irritable bowel syndrome. Int J Colorect Dis 1997;12:29–32.
    OpenUrlCrossRefPubMed
  15. 15.
    Steens J, Van Der Schaar PJ, Penning C, Brussee J, Masclee AA. Compliance, tone and sensitivity of the rectum in different subtypes of irritable bowel syndrome. Neurogastroenterol Motil 2002;14:241–247.
    OpenUrlCrossRefPubMed
  16. 16.↵
    Lembo T, Munakata J, Mertz H, et al. Evidence for the hypersensitivity of lumbar splanchnic afferents in irritable bowel syndrome. Gastroenterology 1994;107:1686–1696.
    OpenUrlPubMed
  17. 17.↵
    Kwan CL, Davis KD, Mikula K, Diamant NE. Abnormal rectal motor physiology in patients with irritable bowel syndrome. Neurogastroenterol Motil 2004;16:251–263.
    OpenUrlCrossRefPubMed
  18. 18.
    Munakata J, Naliboff B, Harraf F, et al. Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome. Gastroenterology 1997;112:55–63.
    OpenUrlCrossRefPubMed
  19. 19.↵
    Aziz Q, Thompson DG. Brain–gut axis in health and disease. Gastroenterology 1998;114:559–578.
    OpenUrlCrossRefPubMed
  20. 20.
    Mayer EA, Naliboff BD, Chang L. Basic pathophysiologic mechanisms in irritable bowel syndrome. Dig Dis 2001;19:212–218.
    OpenUrlCrossRefPubMed
  21. 21.↵
    Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997;112:64–72.
    OpenUrlCrossRefPubMed
  22. 22.
    Baciu MV, Bonaz BL, Papillon E, et al. Central processing of rectal pain: a functional MR imaging study. AJNR Am J Neuroradiol 1999;20:1920–1924.
    OpenUrlAbstract/FREE Full Text
  23. 23.
    Bouras EP, O’Brien TJ, Camilleri M, O’Connor MK, Mullan BP. Cerebral topography of rectal stimulation using single photon emission computed tomography. Am J Physiol 1999;277:G687–G694.
    OpenUrlPubMed
  24. 24.↵
    Mertz H, Morgan V, Tanner G, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000;118:842–848.
    OpenUrlCrossRefPubMed
  25. 25.↵
    Hobday DI, Aziz Q, Thacker N, Hollander I, Jackson A, Thompson DG. A study of the cortical processing of ano-rectal sensation using functional MRI. Brain 2001;124:361–368.
    OpenUrlAbstract/FREE Full Text
  26. 26.
    Kern MK, Jaradeh S, Arndorfer RC, Jesmanowicz A, Hyde J, Shaker R. Gender differences in cortical representation of rectal distension in healthy humans. Am J Physiol Gastrointest Liver Physiol 2001;281:G1512–G1523.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    Lotze M, Wietek B, Birbaumer N, Ehrhardt J, Grodd W, Enck P. Cerebral activation during anal and rectal stimulation. Neuroimage 2001;14:1027–1034.
    OpenUrlCrossRefPubMed
  28. 28.↵
    Verne GN, Himes NC, Robinson ME, et al. Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome. Pain 2003;103:99–110.
    OpenUrlCrossRefPubMed
  29. 29.
    Berman S, Munakata J, Naliboff BD, et al. Gender differences in regional brain response to visceral pressure in IBS patients. Eur J Pain 2000;4:157–172.
    OpenUrlCrossRefPubMed
  30. 30.
    Naliboff BD, Derbyshire SW, Munakata J, et al. Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation. Psychosom Med 2001;63:365–375.
    OpenUrlAbstract/FREE Full Text
  31. 31.
    Bonaz B, Baciu M, Papillon E, et al. Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study. Am J Gastroenterol 2002;97:654–661.
    OpenUrlCrossRefPubMed
  32. 32.
    Bernstein CN, Frankenstein UN, Rawsthorne P, Pitz M, Summers R, McIntyre MC. Cortical mapping of visceral pain in patients with GI disorders using functional magnetic resonance imaging. Am J Gastroenterol 2002;97:319–327.
    OpenUrlCrossRefPubMed
  33. 33.
    Sidhu H, Kern M, Shaker R. Absence of increasing cortical fMRI activity volume in response to increasing visceral stimulation in IBS patients. Am J Physiol Gastrointest Liver Physiol 2004;287:G425–G435.
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    Akervall S, Fasth S, Nordgren S, Oresland T, Hulten L. Rectal reservoir and sensory function studied by graded isobaric distension in normal man. Gut 1989;30:496–502.
    OpenUrlAbstract/FREE Full Text
  35. 35.
    Prior A, Maxton DG, Whorwell PJ. Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects. Gut 1990;31:458–462.
    OpenUrlAbstract/FREE Full Text
  36. 36.
    Hammer HF, Phillips SF, Camilleri M, Hanson RB. Rectal tone, distensibility, and perception: reproducibility and response to different distensions. Am J Physiol 1998;274:G584–G590.
  37. 37.
    Kwan CL, Mikula K, Diamant NE, Davis KD. The relationship between rectal pain, unpleasantness, and urge to defecate in normal subjects. Pain 2002;97:53–63.
    OpenUrlCrossRefPubMed
  38. 38.↵
    Davis KD, Pope GE, Crawley AP, Mikulis DJ. Neural correlates of prickle sensation: a percept-related fMRI study. Nat Neurosci 2002;5:1121–1122.
    OpenUrlCrossRefPubMed
  39. 39.
    Davis KD, Pope GE, Crawley AP, Mikulis DJ. Perceptual illusion of “paradoxical heat” engages the insular cortex. J Neurophysiol 2004;92:1248–1251.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    Kwan CL, Diamant NE, Mikula K, Davis KD. Percept-related fMRI of rectal-evoked sensations in irritable bowel syndrome. Soc Neurosci Abstr 2002;28.
  41. 41.↵
    Fillingim RB, Ness TJ. Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev 2000;24:485–501.
    OpenUrlCrossRefPubMed
  42. 42.
    Heitkemper MM, Cain KC, Jarrett ME, Burr RL, Hertig V, Bond EF. Symptoms across the menstrual cycle in women with irritable bowel syndrome. Am J Gastroenterol 2003;98:420–430.
    OpenUrlCrossRefPubMed
  43. 43.↵
    Gracely RH, McGrath P, Dubner R. Ratio scales of sensory and affective verbal pain descriptors. Pain 1978;5:5–18.
    OpenUrlCrossRefPubMed
  44. 44.↵
    Glover GH, Lai S. Self-navigated spiral fMRI: interleaved versus single-shot. Magn Res Med 1998;39:361–368.
    OpenUrlPubMed
  45. 45.↵
    Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. New York: Thieme Medical, 1988.
  46. 46.
    Downar J, Crawley AP, Mikulis DJ, Davis KD. A cortical network sensitive to stimulus salience in a neutral behavioral context across multiple sensory modalities. J Neurophysiol 2002;87:615–620.
    OpenUrlAbstract/FREE Full Text
  47. 47.
    Downar J, Mikulis DJ, Davis KD. Neural correlates of the prolonged salience of painful stimulation. Neuroimage 2003;20:1540–1551.
  48. 48.↵
    Treede RD, Kenshalo DR, Gracely RH, Jones AKP. The cortical representation of pain. Pain 1999;79:105–111.
    OpenUrlCrossRefPubMed
  49. 49.↵
    Ito S. Visceral region in the rat primary somatosensory cortex identified by vagal evoked potential. J Comp Neurol 2002;444:10–24.
    OpenUrlCrossRefPubMed
  50. 50.
    Ito S, Craig AD. Vagal input to lateral area 3a in cat cortex. J Neurophysiol 2003;90:143–154.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    Aziz Q, Thompson DG, Ng VW, et al. Cortical processing of human somatic and visceral sensation. J Neurosci 2000;20:2657–2663.
  52. 52.
    Strigo IA, Duncan GH, Boivin M, Bushnell MC. Differentiation of visceral and cutaneous pain in the human brain. J Neurophysiol 2003;89:3294–3303.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288:1769–1772.
    OpenUrlAbstract/FREE Full Text
  54. 54.
    Craig AD. Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 2003;26:1–30.
    OpenUrlCrossRefPubMed
  55. 55.↵
    Dostrovsky JO, Guilbaud G. Nociceptive responses in medial thalamus of the normal and arthritic rat. Pain 1990;40:93–104.
    OpenUrlCrossRefPubMed
  56. 56.
    Casey KL, Minoshima S, Berger KL, Koeppe RA, Morrow TJ, Frey KA. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994;71:802–807.
    OpenUrlAbstract/FREE Full Text
  57. 57.
    Shyu BC, Lin CY, Sun JJ, Chen SL, Chang C. BOLD response to direct thalamic stimulation reveals a functional connection between the medial thalamus and the anterior cingulate cortex in the rat. Magn Res Med 2004;52:47–55.
    OpenUrlCrossRefPubMed
  58. 58.
    Lorenz J, Cross DJ, Minoshima S, Morrow TJ, Paulson PE, Casey KL. A unique representation of heat allodynia in the human brain. Neuron 2002;35:383–393.
    OpenUrlCrossRefPubMed
  59. 59.
    Wang JY, Luo F, Chang JY, Woodward DJ, Han JS. Parallel pain processing in freely moving rats revealed by distributed neuron recording. Brain Res 2003;992:263–271.
    OpenUrlCrossRefPubMed
  60. 60.↵
    Derbyshire SWG, Jones AKP, Gyulai F, Clark S, Townsend D, Firestone LL. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997;73:431–445.
    OpenUrlCrossRefPubMed
  61. 61.
    Khanna S. Dorsal hippocampus field CA1 pyramidal cell responses to a persistent versus an acute nociceptive stimulus and their septal modulation. Neuroscience 1997;77:713–721.
    OpenUrlPubMed
  62. 62.↵
    Ploghaus A, Tracey I, Clare S, Gati JS, Rawlins JNP, Matthews PM. Learning about pain: the neural substrate of the prediction error for aversive events. Proc Natl Acad Sci USA 2000;97:9281–9286.
    OpenUrlAbstract/FREE Full Text
  63. 63.
    McKenna JE, Melzack R. Blocking NMDA receptors in the hippocampal dentate gyrus with AP5 produces analgesia in the formalin pain test. Exp Neurol 2001;172:92–99.
    OpenUrlCrossRefPubMed
  64. 64.
    Saito K, Kanazawa M, Fukudo S. Colorectal distention induces hippocampal noradrenaline release in rats: an in vivo microdialysis study. Brain Res 2002;947:146–149.
    OpenUrlPubMed
  65. 65.
    Bingel U, Quante M, Knab R, Bromm B, Weiller C, Büchel C. Subcortical structures involved in pain processing: evidence from single-trial fMRI. Pain 2002;99:313–321.
    OpenUrlCrossRefPubMed
  66. 66.↵
    Lembo T, Naliboff B, Munakata J, et al. Symptoms and visceral perception in patients with pain-predominant irritable bowel syndrome. Am J Gastroenterol 1999;94:1320–1326.
    OpenUrlCrossRefPubMed
  67. 67.
    Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 2003;126:1079–1091.
    OpenUrlAbstract/FREE Full Text
  68. 68.↵
    Hebert MA, Ardid D, Henrie JA, Tamashiro K, Blanchard DC, Blanchard RJ. Amygdala lesions produce analgesia in a novel, ethologically relevant acute pain test. Physiol Behav 1999;67:99–105.
    OpenUrlCrossRefPubMed
  69. 69.
    Critchley HD, Mathias CJ, Dolan RJ. Fear conditioning in humans: the influence of awareness and autonomic arousal on functional neuroanatomy. Neuron 2002;33:653–663.
    OpenUrlCrossRefPubMed
  70. 70.
    Morris JS, deBonis M, Dolan RJ. Human amygdala responses to fearful eyes. Neuroimage 2002;17:214–222.
    OpenUrlCrossRefPubMed
  71. 71.
    Dilger S, Straube T, Mentzel HJ, et al. Brain activation to phobia-related pictures in spider phobic humans: an event-related functional magnetic resonance imaging study. Neurosci Lett 2003;348:29–32.
    OpenUrlCrossRefPubMed
  72. 72.
    Gao YJ, Ren WH, Zhang YQ, Zhao ZQ. Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats. Pain 2004;110:343–353.
    OpenUrlCrossRefPubMed
  73. 73.↵
    Hanamori T, Kunitake T, Kato K, Kannan H. Responses of neurons in the insular cortex to gustatory, visceral, and nociceptive stimuli in rats. J Neurophysiol 1998;79:2535–2545.
    OpenUrlAbstract/FREE Full Text
  74. 74.
    Jasmin L, Granato A, Ohara PT. Rostral agranular insular cortex and pain areas of the central nervous system: a tract-tracing study in the rat. J Comp Neurol 2004;468:425–440.
    OpenUrlCrossRefPubMed
  75. 75.↵
    Davis KD. Neurophysiological and anatomical considerations in functional imaging of pain. Pain 2003;105:1–3.
    OpenUrlCrossRefPubMed
  76. 76.
    Mailis-Gagnon A, Giannoylis I, Downar J, et al. Altered central somatosensory processing in chronic pain patients with “hysterical” anesthesia. Neurology 2003;60:1501–1507.
    OpenUrlAbstract/FREE Full Text
  77. 77.↵
    Craig AD. Interoception: the sense of the physiological condition of the body. Curr Opin Neurobiol 2003;13:500–505.
    OpenUrlCrossRefPubMed
  78. 78.
    Craig AD. Human feelings: why are some more aware than others? Trends Cogn Sci 2004;8:239–241.
    OpenUrlCrossRefPubMed
  79. 79.
    Critchley HD, Mathias CJ, Dolan RJ. Neuroanatomical basis for first- and second-order representations of bodily states. Nat Neurosci 2001;4:207–212.
    OpenUrlCrossRefPubMed
  80. 80.
    Critchley HD, Wiens S, Rotshtein P, Ohman A, Dolan RJ. Neural systems supporting interoceptive awareness. Nat Neurosci 2004;7:189–195.
    OpenUrlCrossRefPubMed
  81. 81.
    Krushel LA, van der KD. Visceral cortex: integration of the mucosal senses with limbic information in the rat agranular insular cortex. J Comp Neurol 1988;270:39–43.
    OpenUrlCrossRefPubMed
  82. 82.
    Allen GV, Saper CB, Hurley KM, Cechetto DF. Organization of visceral and limbic connections in the insular cortex of the rat. J Comp Neurol 1991;311:1–16.
    OpenUrlCrossRefPubMed
  83. 83.
    Shi CJ, Cassell MD. Cortical, thalamic, and amygdaloid connections of the anterior and posterior insular cortices. J Comp Neurol 1998;399:440–468.
    OpenUrlCrossRefPubMed
  84. 84.↵
    Yasui Y, Breder CD, Saper CB, Cechetto DF. Autonomic responses and efferent pathways from the insular cortex in the rat. J Comp Neurol 1991;303:355–374.
    OpenUrlCrossRefPubMed
  85. 85.↵
    Ostrowsky K, Isnard J, Ryvlin P, Guenot M, Fischer C, Mauguiere F. Functional mapping of the insular cortex: clinical implication in temporal lobe epilepsy. Epilepsia 2000;41:681–686.
    OpenUrlCrossRefPubMed
  86. 86.↵
    Vogt BA, Sikes RW. The medial pain system, cingulate cortex, and parallel processing of nociceptive information. Prog Brain Res 2000;122:223–235.
    OpenUrlPubMed
  87. 87.↵
    Drossman DA, Ringel Y, Vogt BA, et al. Alterations of brain activity associated with resolution of emotional distress and pain in a case of severe irritable bowel syndrome. Gastroenterology 2003;124:754–761.
    OpenUrlCrossRefPubMed
  88. 88.↵
    Mayer EA, Berman S, Derbyshire SW, et al. The effect of the 5-HT3 receptor antagonist, alosetron, on brain responses to visceral stimulation in irritable bowel syndrome patients. Aliment Pharmacol Ther 2002;16:1357–1366.
    OpenUrlCrossRefPubMed

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