Novel Evidence for Hypersensitivity of Visceral Sensory Neural Circuitry in Irritable Bowel Syndrome Patients

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1 GASTROENTEROLOGY 2006;130:26 33 Novel Evidence for Hypersensitivity of Visceral Sensory Neural Circuitry in Irritable Bowel Syndrome Patients ADEYEMI LAWAL, MARK KERN, HARJOT SIDHU, CANDY HOFMANN, and REZA SHAKER Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin See editorial on page 267. Background & Aims: Visceral hypersensitivity in irritable bowel syndrome (IBS) patients has been documented by evaluation of perceived stimulations that can reflect abnormalities of both sensory neurocircuitry and cognitive processes. The presence of actual neurohypersensitivity in human beings has not been documented separately. Because subliminal stimulations are free from the influence of stimulus-related cognitive processes, functional magnetic resonance imaging (fmri) cortical response to these stimuli can be considered a measure of activity of the neural circuitry alone. The aim of this study was to compare quantitatively the cerebral cortical fmri activity response to equal subliminal stimulations between IBS patients and age-matched controls. Methods: We studied 10 IBS patients and 10 healthy controls using a computerized barostat-controlled rectal distention device. fmri activity volume and percent maximum signal intensity change for equal subliminal distention pressures were compared between controls and patients. Results: Three levels of subliminal distention pressures (eg, 10, 15, and 20 mm Hg), were represented in both controls and patients and were analyzed for fmri response. In all 3 distention levels the fmri activity volume in IBS patients was significantly larger than age- and sex-matched controls (P <.05). The percent maximum signal intensity change was similar between IBS patients and controls. Conclusions: The volume of cerebral cortical activity response to equal subliminal distention pressures in IBS patients is significantly larger than in controls, documenting the existence of hypersensitivity of the neural circuitry in this patient group irrespective of stimulus-related cognitive processes. Abnormally responsive peripheral visceral receptors, 1 visceral afferents, 2,3 spinal cord synaptic alterations, 4 descending pain modulatory responses, 5 and cortical hypervigilance, 6 or a combination of these and other hitherto unknown factors, can contribute to the hypersensitivity of the gut shown to exist in irritable bowel syndrome (IBS) patients. The mechanisms for this phenomenon that forms the basis of the notion of allodynia and/or hyperalgesia in IBS patients remains poorly understood, but studies have suggested abnormalities of either or both afferent neural circuitry and cortical processing. 7 9 The evidence for the existence of this hypersensitivity stems from the finding of lower perception thresholds (volume or pressure) for rectal distention or lower pain thresholds among IBS patients compared with controls The finding of a lower threshold for perception and pain, however, does not specifically identify the component of the gut sensory function responsible for the hypersensitivity; rather it represents the sum effect of all of the elements involved. One of the confounding factors in defining the specific reason for hypersensitivity in IBS patients is the influence of cognitive processes associated with perception of the stimuli commonly used for studies. To date, there are little objective data separating the contribution of the neural sensitization and changes in cognitive processing of the tested stimulus in IBS patients. With the recent reports of cerebral cortical registration of subliminal stimuli, 7,17 evaluation of the afferent/sensory neurocircuitry of the gut without the influence of cognitive processes related to experimental stimulus (such as rectal distention) has now become possible. By using the method of subliminal stimulation, the aim of this study was to determine the presence or absence of visceral sensitization in IBS patients by comparing the cerebral cortical functional magnetic resonance imaging (fmri) activity response to subliminal (unperceived) rectal distention between IBS patients and age-/sex-matched healthy controls. We tested the hypothesis that application of similar subliminal pressure stimuli will result in a significantly larger volume of fmri activity in IBS patients compared with Abbreviations used in this paper: fmri, functional magnetic resonance imaging; IBS, irritable bowel syndrome by the American Gastroenterological Association /06/$32.00 doi: /j.gastro

2 January 2006 EVIDENCE FOR HYPERSENSITIVITY IN IBS 27 controls, indicating hypersensitivity of afferent neural circuitry. Materials and Methods A total of 10 diarrhea-predominant female IBS patients (age, y) and 10 age-matched healthy female controls were studied. The Human Research Review Committee of the Medical College of Wisconsin approved the study protocol and all participants gave written informed consent before their studies. IBS patients were identified by symptoms and clinical evaluation conforming to the Rome II criteria. 18 Healthy controls completed a detailed health-related questionnaire before each study and did not report any present or previous history of gastrointestinal-related diseases. All participants were studied within 1 week of their last menstrual period. Evaluation of Cortical Activity During Subliminal (Unperceived) Rectal Distentions Rectal distention protocol. All IBS patients and controls participated in the following paradigm-driven rectal distention protocol, using a commercially available computercontrolled barostat (G and J Electronics, Willowdale, Ontario, Canada). A catheter-affixed polyethylene bag was positioned in the rectum before MRI scanning. The polyethylene bag was cylindric in shape with a length of 10 cm and a fully inflated diameter of 8 cm. The maximum bag volume was 500 ml and was infinitely compliant up to its distensible limit. The barostat device was kept outside of the scanner suite and was connected to the bag by a 30-foot long polyethylene tube (3-mm outer diameter, 1.8-mm inner diameter). After the catheter-affixed bag was inserted into the rectum, the perception threshold for each individual participant was determined. To achieve this, the barostat was programmed to deliver rapid phasic distention of the rectal bag to a constant plateau pressure for 10 seconds. At each pressure step, the participants were asked whether they felt anything. The balloon was deflated completely after each tested pressure. The distention pressure was increased phasically by using a previously described method 19 in increments of 5 mm Hg until perception was reported. The procedure was repeated twice and the barostat pressure recorded at this level was deemed to reflect the perception threshold for rectal distention for that particular participant. By using this approach, the perception threshold pressure was reproduced reliably in all tested participants. During the experimental scans, the rectal bag was inflated and deflated at the maximum flow rate of 60 ml/s to maintain the desired distention pressure or nondistention (zero) pressure. Before every MR scan, the rectal bag was inflated to a minimal static pressure of 3 5 mm Hg followed by deflation so that the pressure in the bag was zero relative to atmospheric pressure. Thus, before each scan the rectal bag was preloaded with air up to the volume at which a nominal pressure was measured. During fmri recording we tested rectal distention pressures starting at 5 mm Hg and increasing increments of 5 mm Hg up to the perception pressure for each participant. Participants also were queried regarding their sensation after each distention scan. MRI scanning protocol. MRI data were acquired during 105-second scan sessions of 15-second intervals of sustained distention alternated with 15 seconds of no distention. Two scans were performed at each distention level. There was a 1-minute interval between each distention scanning session. Cerebral cortical activity response to rectal distentions was monitored in all participants by using the blood oxygenation level dependent fmri technique. We acquired 11 contiguous sagittal slices (12-mm thick) spanning the whole brain volume using an MRI echo planar imaging technique. MRI scanning was performed on a 3-T Bruker Scanner (Bruker Medical, Karlsruhe, Germany). The scanner was equipped with a custom 3-axes head coil designed for rapid gradient field switching and a shielded, transmit/receive birdcage radiofrequency coil to acquire a time course of echo planar imaging across the entire brain volume with the desired slice specifications. Echo planar imaging, resolved to pixels/slice at a repetition time of 1 second and an echo time of 40 ms, was obtained. High-resolution spoiled gradientrecalled acquisition anatomic images also were acquired for subsequent superposition of activation color maps indicating regions of stimulus-related cortical activity. All image data were mapped stereotaxically to the Talairach Tournoux coordinate system for comparison purposes. Data analysis. All fmri signal analysis was performed by using the Analysis of Functional Neuro-Imaging software. 20 Subtle changes in head position during MRI scanning sessions were corrected using 3-dimensional volume registration that corrects motions of a few millimeters and rotations of a few degrees using first-order Taylor series at each point in the 6 motion parameters (3 shifts, 3 angles) and Fourier interpolation. 20 A nonbiased method of detecting cortical regions that show blood oxygenation level dependent changes was applied using a deconvolution (multiple regression) technique that computes the hemodynamic response function from the magnetic signal time series in each voxel and tests whether the response function differs from the response associated with random Gaussian variation of the signal. As reported in previous studies, 17,21 a threshold correlation coefficient of.7 was used as a limiting criterion for accepting an fmri time course as being correlated to the stimulus paradigm. In the present study, a correlation threshold of.7 with 105 images per scanning session and a pixel image resolution yielded a probability of for committing a type I error, which is considered to be a conservative standard for minimizing the chance of claiming a significant correlation when one did not actually exist. The percent fmri signal intensity change was calculated as previously described. 21 The volume of cortical activity was calculated by multiplying the number of activated voxels by the voxel volume. In the present study using a 12-mm slice thickness to include the whole cerebral cortex, 1 echo planar imaging voxel volume was

3 28 LAWAL ET AL GASTROENTEROLOGY Vol. 130, No. 1 mm mm 3. Total cortical activity volumes in response to the equal distending pressures were compared using a paired Student t test. All data are expressed as mean standard error of mean unless stated otherwise. A posteriori studies. To investigate the influence of the length of the barostat catheter system on participantreported perception pressure and to investigate the possibility of bias introduced by using the method of ascending limits for determining the perception threshold for rectal distention pressures as outlined earlier, we studied an additional 5 healthy volunteers. In these 5 healthy volunteers (age, y, 2 women), the perception threshold for rectal distention was evaluated using both the ascending method of limits and the forced choice method. 19,22 A catheter-affixed polyethylene bag identical to those described in the Materials and Methods section (cylindric shape, 10 cm in length, 8 cm fully inflated diameter) was secured in a fixed position within the rectum. Determination of the perception threshold for each participant was performed by connecting the polyethylene bag assembly to the computercontrolled barostat via a 30-foot long, 1.8-mm internal diameter tube identical to the tube described in the Materials and Methods section. The perception threshold then was established by using progressively increasing stepwise distentions starting at a 5 mm Hg barostat pressure reading, holding the pressure for 10 seconds, and precipitously increasing the distention pressure by increments of 5 mm Hg until the participant reported feeling the distention. After the report of perception, air was evacuated from the bag until zero pressure was measured and the participant rested for 2 minutes. The ascending method of limits was repeated for a total of 3 ascending sequences from 5 mm Hg to the perception threshold. Next, the participant s perception threshold was determined using the forced choice method, wherein the participant was presented with pairs of distention stimuli and was asked to choose which stimulus, if any, was perceived. Progressively higher distention pressures in 1 of the 2 choices were presented until the intensity at which the participant perceived the distention pressure at least 75% of the time was reached. 19 After establishing the perception threshold using the 2 earlierdescribed techniques, the 30-foot long tube connecting the barostat to the distention bag was replaced by a 3-foot long tube of the same internal diameter and the perception threshold experiments were repeated using both the ascending method of limits and the forced choice techniques. By using these measurements we also compared the perception pressure threshold for the 30-foot tube and the 3-foot tube configurations for both the ascending method of limits and the forced choice technique. Results The mean perception threshold pressure averaged mm Hg (range, mm Hg) and 25.8 mm Hg (range, mm Hg) in IBS patients and controls, respectively (P.007). Analysis of the fmri cortical response to the tested pressures showed that in addition to the threshold perceived pressure, a range of lower unperceived pressures also activated the cerebral cortex (Figure 1). Among these subliminal stimulations, 3 levels of distention pressures (10, 15, 20 mm Hg) were represented in both controls and patients and were used for analysis. At a distention pressure of 10 mm Hg, 7 IBS patients and 6 controls were represented. At a distention pressure of 15 mm Hg, 8 IBS patients and 10 controls were represented, and at a distention pressure of 20 mm Hg, 4 IBS patients and 9 controls were represented (Figure 1). Comparison of the fmri cortical activity volume between the 2 groups showed that for all 3 subliminal distention levels the cortical fmri activity volume in IBS patients was significantly larger than that of the agematched healthy controls (P.05) (Figure 2). Comparison of the total volume of cortical activity associated with the 3 levels of subliminal distention pressures in the healthy controls showed a direct relationship between stimulus intensity and cortical activity volume ( , , and L for distention pressures of 10, 15, and 20 mm Hg, respectively) (P.001). In IBS patients, there was no stimulus intensity dependent increase in fmri activity volume ( , , and L for distention pressures of 10, 15, and 20 mm Hg distention pressures, respectively) (Figure 2). The percent maximum signal intensity change was similar between IBS patients and controls for all 3 levels of subliminal distention pressures. However, in both groups there was a progressive increase in maximum fmri signal intensity change that was related directly to stimulus intensity: IBS, , , and (P.001); controls: , , and (P.001) for 10, 15, and 20 mm Hg, respectively (Figure 3). fmri activity in response to subliminal rectal distentions was represented bilaterally in 5 broad cortical regions for all 3 levels of distention pressures. These regions include sensory/motor, the parietal/occipital, the cingulate gyrus, the prefrontal cortex, and the insular cortex. Composite data showing regional cerebral fmri cortical activity associated with all 3 levels of subliminal rectal distention pressures in IBS patients is shown in Figure 4. A Posteriori Studies Effect of length of barostat connecting tube on perception threshold. As seen in Figure 5, there was no significant difference in the perception threshold pressure when comparing the ascending method of limits with

4 January 2006 EVIDENCE FOR HYPERSENSITIVITY IN IBS 29 Figure 1. The presence or absence of cortical fmri activity to all tested rectal pressures. Presence of fmri activity is shown by a symbol and its absence is shown by a symbol. In addition to the perceived distention (shown in red), several unperceived distentions also induced cortical activity. Three levels of subliminal rectal distention pressure, 10, 15, and 20 mm Hg, were represented in the subliminal domain of the healthy controls and IBS patients tested in the present study. that of the forced choice method for either the long tube (25 2 mm Hg compared with 24 3 mm Hg) or the short tube (17 1 mm Hg compared with 16 1mm Hg) configurations. However, there were significant differences when the perception threshold pressures measured using the long tube were compared with those Figure 2. Total fmri cortical activity volume response to 3 levels of subliminal rectal distention pressures in IBS patients and controls. In all 3 subliminal distention pressures the fmri activity volumes in IBS patients were significantly larger than those of controls. Furthermore, fmri cortical activity volumes showed a stimulus intensity dependent relationship in controls (P.001), but not in IBS patients for the 3 analyzed pressure levels. measured using the short tube in that the use of a 30-foot tube resulted in a significantly higher perception pressure compared with that obtained using a 3-foot connecting tube (ascending method of limits, 25 2 and 17 1; forced choice, 24 3 and 16 1, respectively) (P.05 for both methods). Discussion In this study, we compared quantitatively the cerebral cortical fmri response with similar subliminal rectal distentions between diarrhea-predominant IBS patients as defined by Rome II criteria 18 and age-matched healthy controls. The findings of the present study indicate that IBS patients show a significantly larger cortical fmri activity volume in response to equal subliminal distention pressures compared with age-matched controls, indicating hypersensitivity of the afferent neural circuitry without the influence of cognitive processes inherent to perception of the stimulus. Multiple aberrations along the brain-gut axis 1 6 can contribute to gut hypersensitivity in IBS patients. Previous studies of visceral hypersensitivity in IBS patients have relied on the effects of perceived painful and nonpainful stimulations 9,23 and as such could not have sep-

5 30 LAWAL ET AL GASTROENTEROLOGY Vol. 130, No. 1 Figure 3. fmri impulse response waveforms (signal intensity) induced by the 3 levels of subliminal distention pressures in IBS patients and controls. There was a progressive increase in maximum fmri signal strength that was related directly to stimulus intensity in both groups. However, the stimulus intensity related fmri signal changes were similar between the 2 groups. arated the contribution of neural sensitization from that of changes in the central cognitive mechanism related to the stimulus. The finding of the present study showing significantly more recruitment of fmri activity volume in response to unperceived rectal distention in IBS patients compared with controls shows in human beings the long-suspected hypersensitivity of the neural sensory circuitry without the influence of stimulus-related cognitive activity. The study finding, however, does not specify the exact cause or site of the sensitization within the neural sensory circuit, but shows the hypersensitivity of the sensory neural circuitry as a whole. Whether alterations of perception-related cognitive processes exist in addition to neural hypersensitivity was not investigated in this study. The information obtained in this study can potentially be utilized to separately evaluate the neural and neurocognitive effects of therapeutic agents in IBS patients. Another potential use of these findings is for objective stratification of IBS patients with regard to neural or neurocognitive abnormalities. The findings of this study also objectively show the existence of long-suspected neural hypersensitivity in IBS patients and as such help better dissect and define different pathophysiologic components that may exist in this patient group. Previous studies have shown that the anticipation of a perceived stimulus may induce cortical activity This possibility, from the findings of the present study of unperceived stimuli, seems highly unlikely for the following reasons. Because fmri activity in this study was induced by periodic stimulation and detection of these Figure 4. The anatomic location of composite fmri activity associated with subliminal rectal distention in 10 diarrhea-predominant female IBS patients. FMRI activity can be characterized to exist in 5 broad cortical regions: the sensory/motor, the parietal/occipital, the cingulate gyrus, the prefrontal cortex, and the insula cortex.

6 January 2006 EVIDENCE FOR HYPERSENSITIVITY IN IBS 31 Figure 5. Comparison of the perception thresholds determined by the ascending method of limits and forced choice technique using 3-foot and 30-foot long barostat connecting catheters in 5 healthy volunteers. For both techniques the use of a longer connecting tube resulted in a significantly higher distention pressure for perception threshold (P.05). The perception threshold using the ascending method of limits and forced choice technique were similar irrespective of the length of the connecting tube. *P.05. activities depends on the temporal correlation of the stimulus paradigm and fmri activity, it is difficult to imagine how a stimulation that is never perceived can be anticipated at certain intervals, especially when there is no overt cue that can lead the participants to respond in a manner similar to the distention paradigm. Furthermore, there is no memory of distention in the scanning period because both patients and controls received the lowest tested pressure first with subsequent paradigms incorporating higher pressures until a perception level was reached. For the subliminal pressures, therefore, there was no point of reference for start and stop of distention to be anticipated. The possibility of remembering the perception threshold from the hour or so before when their threshold was tested outside of the scanner seems to be equally remote. Considering the fact that the ascending method of limits used to ascertain the perception threshold before fmri scanning is different from our experimental distention paradigm, it is unlikely that a dissimilar memory could create anticipation of cortical activity that matches the on/off configuration of the fmri activity recorded in our participants. Further evidence against the role of anticipation in the generation of observed cortical response stems from the fact that in the control group there was a dose response to the intensity of subliminal stimulations. One would think that if these responses were from anticipation of a given prior stimulation, they would have been similar to each other and not produce more activity with higher subliminal pressures. In addition, previous studies 17 have shown that randomly timed intervals of subliminal rectal distention were never anticipated (ie, did not develop fmri signal increase before or after the actual randomly timed rectal distention and only matched the randomly timed stimulation paradigm). Similarly, it seems unlikely that participants could modulate their fear, anxiety, or expectation in such close synchrony to a stimulus they did not perceive. Whether the differences in the emotional and psychologic status of the IBS patients and controls could have influenced the cortical response to the unperceived rectal stimulation at the subperception level and resulted in recruitment of larger fmri activity volumes compared with healthy controls merits further investigation and by itself could constitute one of the elements contributing to the hyperresponsiveness of sensory neurocircuitry in IBS patients. The phenomenon if proven, however, would be different from the alteration in the cortical response to a perceived stimuli induced by psychologic or emotional status of those reported previously. 27 This latter phenomenon represents the neurocognitive effect, whereas the former would represent a neural effect. Whether the psychologic state and emotions can influence neural activity in the absence of stimulus-related cognition is speculative at this stage and its differentiation from neural sensitization of organic causes is difficult with the techniques used in this study. The threshold pressure for perception in the present study was higher than some previous reports 9,28 30 and as such some of the subliminal pressures inducing cortical activity seem to overlap those observed as sensation threshold in clinical studies. The reason for this discrepancy, we believe as reported before, 7,17 is caused by differences in the length of the barostat connecting tube of 30 feet used in the present study, which artificially resulted in higher pressures. The 30-foot connecting tube was necessitated by the need to keep the barostat device outside of the scanner suite. As such the pressures registered at the perception of the rectal distention in the current study do not reflect accurately the actual perception threshold, but merely provides a quantifiable measure for inducing uniform subliminal distentions in all of our study participants. As reported in the a posteriori experiment, although the perception pressure using a short tube was within the range of clinically reported values, those of the long tube were higher by 7 8 mm Hg, reaching the range reported in the current article using the long tube, confirming the artificial nature of these pressures as stated previously.

7 32 LAWAL ET AL GASTROENTEROLOGY Vol. 130, No. 1 These findings corroborate previous reports concerning the higher perception threshold pressures reported using the long connecting tube configuration. 7,17,21 Considering the fact that in this study our goal was not to establish the absolute values for perception among IBS and controls but to deliver reliable perceived and unperceived distending stimulation to interrogate the cortex, the pressure values have less relevance than the perception or lack thereof experienced by our study participants. Among healthy individuals, there was a stimulus intensity dependent pattern of fmri cortical response suggesting recruitment of additional cortical neuronal mass represented by additional fmri activity volume. This relationship was not observed in IBS patients. Similar findings have been reported in earlier studies for liminal and supraliminal rectal distentions in IBS patients. 7 Subliminal rectal stimulation activated similar regions in both IBS and healthy controls in this study and corroborates previous reports. 7,31 33 These areas include the primary and secondary somatosensory cortices, insula, cingulate gyrus, prefrontal, and parietooccipital areas, which are believed to be involved in sensorydiscriminative, affective-motivational, and cognitiveevaluative aspects, and are activated commonly by both somatic and visceral pain sensation. 34,35 A detailed discussion of the structure function relationship of these regions has been reported previously and is beyond the scope of this study, which was not designed to address the differences in the functions of the activated regions between studied groups but to provide objective data for the existence of neural hypersensitivity even in the absence of cognition related to tested stimulus. 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