Absence of increasing cortical fMRI activity volume in response to increasing visceral stimulation in IBS patients
Harjot Sidhu,
Mark Kern, and
Reza Shaker
Division of Gastroenterology and Hepatology and the Digestive Disease Center, The Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Submitted 20 November 2003
; accepted in final form 26 March 2004
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ABSTRACT
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Cerebral cortical activity associated with perceived visceral sensation represents registration of afferent transduction and cognitive processes related to perception. Abnormalities of gut sensory function can involve either or both of these processes. Cortical registration of subliminal viscerosensory signals represents cerebral cortical activity induced by stimulation of intestinal sensory neurocircuitry without the influence of perception-related cortical activity, whereas those associated with perception represent both neural circuitry and cognitive processes. Our aims were to determine and compare quantitatively cerebral cortical functional magnetic resonance imaging (fMRI) activity in response to subliminal, liminal, and nonpainful supraliminal rectal distension between a group of irritable bowel syndrome (IBS) patients and age/gender-matched controls. Eight female IBS patients and eight age-matched healthy female control subjects were studied using brain fMRI techniques. Three barostat-controlled distension levels were tested: 1) 10 mmHg below perception (subliminal), 2) at perception (liminal), and 3) 10 mmHg above perception (supraliminal). In control subjects, there was a direct relationship between stimulus intensity and cortical activity volumes, ie., the volume of fMRI cortical activity in response to subliminal (3,226 ± 335 µl), liminal (5,751 ± 396 µl), and supraliminal nonpainful stimulation (8,246 ± 624 µl) were significantly different (P < 0.05). In contrast, in IBS patients this relationship was absent and fMRI activity volumes for subliminal (2,985 ± 332 µl), liminal (2,457 ± 342 µl), and supraliminal nonpainful stimulation (2,493 ± 351 µl) were similar. Additional recruitment of cortical fMRI activity volume in response to increasing stimulation from subliminal to liminal and supraliminal domains is absent in IBS patients, suggesting a difference in the processing of perceived stimulation compared with controls.
subliminal; perception; functional magnetic resonance imagery; rectal distension; viscerosensation
CEREBRAL CORTICAL ACTIVITY induced by perception of a stimulus represents two intertwined processes: 1) registration of the sensory signal and 2) perception-related cognitive processes. Whereas the former involves the entire sensory neurocircuitry including peripheral and cortical pathways, the latter includes solely the cerebral cortex. Abnormalities of either or both of these processes have been suggested to contribute to gut sensory dysfunction (11, 22, 24, 25, 36, 41, 53).
Objective quantitative evaluation of these two cortical processes in humans, separate from one another, has been impossible until the recent description of the cortical registration of subliminal gut afferent stimulations. Because subliminal stimulations are free from the influence of cognitive processes, it is reasonable to assume that cortical activity induced by them represents the activity of neural circuitry (28, 29). Currently, measuring the cortical activity related to cognitive processes associated with visceral sensation is not directly possible. However, comparison of the cortical activity induced by subliminal stimulation with those induced by liminal/perceived stimulation can provide some measure of the magnitude of additional cortical neuronal recruitment associated with perception-related cognitive processes. This combination of approaches can provide a quantitative measure that may be useful to further define the pathophysiology of gut sensory dysfunction, which is believed to exist in functional bowel disorders.
The aim of the present study, therefore, was to determine and compare quantitatively the patterns of cerebral cortical functional magnetic resonance imaging (fMRI) activity in response to subliminal, liminal, and nonpainful supraliminal rectal distension between the group of irritable bowel syndrome (IBS) patients as defined by Rome II criteria and healthy age- and gender-matched controls.
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METHODS
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A total of eight female IBS patients (aged 1938 yr) and eight age-matched healthy female control subjects was studied. The study protocol was approved by the Human Research Review Committee of the Medical College of Wisconsin, and all participants gave written informed consent before their studies. IBS patients were identified by symptoms and clinical evaluation to conform to the Rome II criteria (21). Healthy control subjects completed a detailed health-related questionnaire before each study. These control subjects did not have any present or previous history of gastrointestinal-related diseases. All participants were studied within 1 wk of menstruation.
To study the brain response to rectal distension, cerebral cortical activity was monitored in all subjects using a blood oxygenation level-dependent (BOLD) fMRI technique.
MRI echo planar images were acquired in the sagittal plane for 11 contiguous slices, 12 mm in thickness, spanning the whole brain volume. MRI scanning was performed on a 3-Tesla Bruker Scanner (Brucker Medical, Karlsruhe, Germany). The scanner was equipped with a custom three-axes head coil designed for rapid gradient field switching and a shielded, transmit/receive "birdcage" radio-frequency coil to acquire a time course of echo planar images across the entire brain volume with the desired slice specifications. Echo planar images resolved to 64 x 64 pixels/slice at a repetition time (TR) of 1 s and an echo time of 40 ms were obtained during six scanning sequences with a 1-min interval between scans. High-resolution spoiled gradient-recalled acquisition at steady state anatomical images was also acquired for subsequent superposition of colored maps indicating regions of stimulus-related cortical activity.
Data analysis.
To compensate for subtle changes in head position over the course of the MRI scanning sessions, an algorithm for 3-dimensional (3-D) volume registration was used. This algorithm is designed to be efficient at fixing motions of a few millimeters and rotations of a few degrees. With the use of this limitation, the basic technique is to align each volume in a time series to a fiducial volume (usually an early volume from the first imaging run in the scanning session). The fiducial volume is expanded in a first-order Taylor series at each point in the six motion parameters (3 shifts, 3 angles). This expansion is used to compute an approximation to a weighted linear least-squares fit of the target to the fiducial volume. The target volume is then moved according to the fit, and the new target volume is refit to the fiducial. This iteration proceeds until the movement is small. Effectively, this is gradient descent in the nonlinear least-squares estimation of the movement parameters that best make the target volume fit the fiducial volume. This iteration is rapid (usually only 24 iterations are needed), because the motion parameters are small. It is efficient, based on a new method using a four-way 3-D shear matrix factorization of the rotation matrix. It is also accurate, because Fourier interpolation is used in the resampling process. On the Intel workstation used for this project, a 64 x 64-pixel x 11-slice volume can be aligned to a fiducial in <1 s.
All fMRI signal analysis was carried out using the Analysis of Functional NeuroImaging (AFNI) software package developed by Robert Cox of the National Institute of Mental Health. This software allows the user to visualize a 3-D representation of two-dimensional MRI data in an interactive Unix-based X11 Windows format. In addition to providing a straightforward method for image visualization, the AFNI package also provides the statistical tools for testing the correlation of fMRI-signal waveforms to applied stimulation protocols. A nonbiased method of detecting cortical regions that exhibit BOLD changes is achieved by applying a deconvolution and 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 (2832), a threshold correlation coefficient of 0.7 was used as a limiting criterion for accepting an fMRI time course as being correlated to the stimulus paradigm. The probability of making a type I error is one minus the complimentary error function assuming Gaussian variance about the fMRI time series response waveforms. In the present study, a correlation threshold of 0.7 with 120 images per scanning session and a 64 x 64-pixel image resolution yield a probability of 1.09 x 1017, which we considered to be a conservative standard for minimizing the chance of claiming a significant correlation when one did not actually exist. Furthermore, we applied the additional clustering requirement that a displayed region of correlated activity must be represented by a cluster of three or more contiguous correlated voxels. In the present study, we used a 64 x 64-pixel matrix for each sagittal image covering a 240 x 240-mm field of view and a slice thickness of 12 mm to be able to include the whole cerebral cortex. Thus one echo planar image voxel was 3.75 x 3.75 x 12
169 mm3. With the use of this criterion, an activated cluster must be >506 mm3 to be included in the analysis. This cluster criterion was applied to avoid including single-voxel activities that may represent artifact (7, 27). The percent change in fMRI signal intensity was calculated by determining the difference between the maximum and minimum magnetic field intensity in a correlated fMRI time series and dividing this difference by the minimum intensity in that time series. Calculation of the maximum percent fMRI-signal increase has been previously described (2832) and is illustrated in the following example. An example of an fMRI-signal response in a single voxel from a control subject during perceived distension that was statistically correlated to the stimulus paradigm is shown in Fig. 1. As seen, the units of measurement on the y-axis are magnetic signal intensity. The minimum prestimulus reading for magnetic signal intensity in this example was 1,067 U. The maximum signal increase during the first distension response was 1,119; therefore, the percent increase from the minimum signal was (1,1191,067)/1,067 or 4.87% signal increase. The maximum signal for the second stimulation interval was 1,128, yielding a percent increase of (1,1281,067)/1,067 or 5.72%. Percent signal increases for all fMRI waveforms that were significantly correlated with the stimulus paradigm were evaluated in the above-described fashion. The volume of cortical activity was calculated by counting the number of activated voxels and multiplying by the voxel volume. As stated, the volume of a single echo planar image voxel was 169 mm3. The cortical mantle was divided into four regions designated by Brodmann Area (BA) numbers and standard anatomical structures. The sensory/motor region was designated by BA 1, 2, 3, 4, 5, and 6; the anterior cingulate/prefrontal region by BA 8, 10, 24, and 32; the parietal/occipital region by BA 7, 18, 19, and 30. The insular cortex was designated as the portion of the cerebral cortex deep within the lateral fissure consisting of several long gyri paralleling the lateral fissure and five short gyri located more rostrally. Cortical activity volumes were calculated for each of these cortical regions and compared using analysis of variance with multiple t-testing employing Tukey's correction. All data are expressed as means ± SE unless otherwise stated.

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Fig. 1. A graphical representation of a single functional magnetic resonance imaging (fMRI) time series that was significantly correlated to the stimulus paradigm from a control subject illustrating the critical points for calculation of the percent maximum fMRI signal change. The gray shaded areas represent intervals of perceived rectal distension. %Maximum signal increase was calculated as the %increase in signal from the predistension minimum (1,067 in this example) to the postdistension maximum signal (1,119 for the first distension response), i.e., (1,1191,067)/1,067 = 4.87% signal increase.
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AFNI analyses and statistical comparisons were performed on a Pentium III-based PC (Southwest Computers, Houston, TX) with dual-boot capabilities for running both the AFNI software out of a Linux operating system and SigmaStat statistics software (SPSS, Chicago, IL) out of the Microsoft (Redmond, WA) Windows 98 operating system.
Evaluation of cortical activity during subliminal, liminal, and nonpainful supraliminal rectal distension.
IBS patients and control subjects participated in the following paradigm-driven rectal distension protocol, using a commercially available computer-controlled 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 roughly cylindrical shaped with a length of 10 cm and a fully inflated diameter of 8 cm. 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-ft polyethylene tube (3-mm OD, 1.8-mm ID). After the catheter-affixed bag was inserted into the rectum, the perception threshold for each individual subject was determined. Air was incrementally pumped into the rectal bag to induce an increase in intrabag pressure in 5-mmHg steps and was sustained for 10 s by means of the computer-controlled barostat. After each pressure step, the subject was asked whether she "felt anything." This stepwise procedure was continued until the subject reported feeling the inflated bag. The air in the bag was then evacuated, and the stepwise perception threshold procedure was repeated two more times to ascertain the threshold. The barostat pressure recorded at this level was deemed to reflect the perception awareness threshold for rectal distension of that particular subject. All tested participants reliably reproduced the same perception threshold pressure during the stepwise determination procedure. During the experimental scans, air was infused and evacuated from the rectal bag at the maximum possible flow rate of 60 ml/s to maintain the desired constant distension pressure or nondistension (zero) pressure. Before every magnetic resonance scan, air was infused into the rectal bag until a minimal static pressure of 35 mmHg was seen. A small quantity of air was then evacuated from the bag so that the pressure in the bag was zero relative to atmospheric pressure. Thus the rectal bag before each scan was preloaded with air up to the volume at which a nominal pressure was measured. An example of typically registered volumes and pressures follows: for a perception level pressure reading of 30 mmHg, a bag air volume of 250 ml was registered. The subliminal distending pressure would then be 20 mmHg, requiring a bag volume 220 ml of air, and the supraliminal pressure would be 40 mmHg, which requires 275 ml air. A zero-pressure reading was established in the bag at a maximum volume of 175 ml air. By starting each magnetic resonance scan with a preloaded volume of 175 ml air in the rectal bag, the subliminal distending pressure could be achieved in <1 s, the perception level pressure in 1.3 s, and the supraliminal pressure in 1.7 s. Three barostat-controlled distension levels were tested in each subject: 1) 10 mmHg below perception threshold (subliminal); 2) at the perception threshold (liminal); and 3) 10 mmHg above the perception threshold (supraliminal). There was a 1-min interval between each distension-scanning session. Subjects were asked whether or not they had any sensation after each distension scan. MRI data were acquired during six 120-s scan sessions of 20-s intervals of sustained distension alternated with 20 s of no distension. The order of distension level sessions was randomized in each subject. Two scans were performed at each distension level. In this schema, whereas some trials started with subliminal distension, others were initiated with liminal or supraliminal distension. Because the distension paradigm included periods of stimulation and rest, we did not believe that anticipation during the studies that started with liminal distension could induce activity during subliminal/unperceived sequences that match the stimulation/rest paradigm.
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RESULTS
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Cortical activity was detected with all perceived and unperceived distension intensities in all subjects. The distension pressure measured from the barostat bag assembly at the level of perception was significantly lower in the IBS patients (24 ± 1.0 mmHg) compared with control subjects (31 ± 3 mmHg; P < 0.05). Neither the distension induced by liminal pressure nor the distension induced by the supraliminal pressure of 10 mmHg higher than the liminal pressure was reported to be painful by any of the study participants.
Comparison of the pattern of cerebral cortical fMRI activity in response to graded stimulation ranging from subliminal to nonpainful supraliminal rectal distension pressures.
Representative examples of total fMRI cortical activity volume induced by subliminal, liminal, and supraliminal distension in IBS patients and control subjects are shown in Fig. 2. Comparison of the total volume of cortical activity associated with the three levels of rectal distension in the tested healthy control subjects showed a direct relationship between stimulus strength spanning subliminal, liminal, and supraliminal, nonpainful domains and cortical activity volume (3,226 ± 335, 5,751 ± 396, and 8,246 ± 624 µl, respectively). In contrast, such a relationship was absent in the IBS patients (Fig. 3) in that the volume of cortical activity did not increase when the stimulus intensity reached the liminal and nonpainful supraliminal levels (2,985 ± 332, 2,457 ± 342, and 2,493 ± 351 µl, respectively).

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Fig. 2. Representative examples of three dimensional brain volumes rendered with regions of cortical activity shown in color [irritable bowel syndrome (IBS) patient 1 and control subject 1 in Tables 13]. Cortical activity in deep cortical structures shows through the anatomical brain image.
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Fig. 3. Cortical activity volume in response to 3 levels of rectal distension in healthy controls and IBS patients. The volume of cortical activity for each subject at each distension level is depicted. A horizontal line shows the mean of fMRI cortical activity volume for each pressure level. The mean pressure (means ± SD) for each distension level is shown beneath the x-axis of the graph. As seen, although in the control group, there was a progressive significant increase in cortical activity volume from subliminal to supraliminal pressure levels, in IBS patients the cortical activity volume remained flat despite the increase in distension pressures.
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Regional cerebral cortical activity associated with three levels of rectal distension was distributed among four regions in both the IBS and control groups. At liminal and supraliminal levels, there was little change in the regional cortical activity in the IBS patients, whereas incrementally increasing activated cortical volumes were present in the control subjects in response to stronger stimuli (Fig. 4).

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Fig. 4. Average regional cortical activity volume in response to subliminal, liminal, and supraliminal rectal distension in controls and IBS patients. As seen, although cortical activity volumes increase with increasing stimulus level in all 4 cortical regions for the control subjects, there is no significant increase in cortical activity volume with increasing stimulus intensity in any of the 4 cortical regions in IBS patients. This finding clearly indicates that the lack of response to increasing stimulus intensity in IBS patients is consistent throughout the brain volume and is not the result of activity increases in 1 region of the brain and concurrent decreases in activity in some other cortical region. I, insula.
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The average maximum percent fMRI signal change showed incrementally increasing levels of activity with increasing stimulus intensity (Fig. 5). Analysis of variance showed the percent signal change associated with supraliminal rectal distension was significantly different from that associated with liminal and subliminal stimuli in the IBS patients. Similar analysis of the control subject data showed significant differences among all three levels of stimulation. Between-group comparison showed significant differences only at the supraliminal stimulus level in that the maximum fMRI signal change in IBS patients was significantly lower than that of the controls.

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Fig. 5. Maximum %fMRI signal increase at 3 levels of rectal distension in IBS patients and control subjects. The values presented are the average of the mean %signal increases across all subjects for all activated cortical regions regardless of brain location. As seen in both groups, the fMRI signal intensity progressively increases in response to increasing stimulus intensity. In both groups, higher distension pressures induced significantly higher fMRI signal change except between subliminal and liminal distension levels in IBS patients.
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In six of eight IBS patients and six of eight control subjects, increases in stimulus intensity to the liminal and supraliminal levels resulted in recruitment of additional BAs; however, none of the additional recruitments resulted in representation in BA not seen in other subjects (Tables 1, 2, and 3). In the remaining two subjects in each group, additional volumes of cortical activity remained confined within the BA observed during subliminal stimulation. RxC analysis showed there was no significant difference in the distribution of BA representation for the three levels of rectal distension within each group. Furthermore, there was no significant difference found between the two groups with regard to BA representation.
Cerebral cortical fMRI activity during subliminal rectal distension: examination of sensory neurocircuitry devoid of perception-related cognitive processes.
In all studied participants, subliminal rectal distension was associated with a detectable and similar increase in maximum cerebral cortical fMRI activity of 3.0 ± 0.3% in IBS patients and 3.3 ± 0.3% in control subjects. As seen in Table 1, cortical activity designated by BA was generally bilateral and included the sensory/motor, parieto/occipital, and cingulate/prefrontal regions as well as the insula. RxC analysis of the frequency of representation in each BA showed no significant difference between IBS patients and control subjects. The Talairach-Tournoux coordinates of the voxels with the greatest fMRI signal change in each BA are presented in Table 4. The volume of cortical activity due to subliminal rectal distension in IBS patients (2,985 ± 332 µl) was similar to that of controls (3,226 ± 335 µl). Considering the fact that the threshold distension pressure for perception, i.e., liminal pressure in IBS, was significantly lower compared with controls, the applied calculated subliminal pressure, namely, a pressure 10 mmHg below the perception threshold in IBS patients, was significantly lower than that of controls (Fig. 6). This significantly lower distension pressure, however, induced similar volumes of cortical fMRI activity (Fig. 7A), supporting the concept of hypersensitivity of the sensory neurocircuitry in the absence of perception-related cortical processes.
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Table 4. Talairach-Tournoux coordinates of the voxel with the greatest fMRI signal change within five cortical regions during subliminal rectal distension
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Fig. 6. Threshold for perception of rectal distension (liminal) pressure in IBS patients and controls. The threshold (liminal) pressure as well as subliminal (10 mmHg below the perception threshold) and supraliminal (10 mmHg above the perception threshold) for each individual is depicted. The solid, horizontal lines represent the mean at each pressure level. The perception threshold in IBS patients was significantly lower than that of controls.
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Fig. 7. fMRI cortical activity in response to subliminal (A), liminal (B), and supraliminal (C) rectal distension. The cortical activity volume in response to rectal distension pressure is depicted for each individual. As seen, in the subliminal domain, a given rectal distension pressure in IBS patients induced a larger cortical activity volume compared with control subjects, suggesting hypersensitivity. However, contrary to controls, IBS patients did not exhibit additional cerebral cortical activity volumes at liminal and supraliminal distension levels, suggesting differences in the cortical processing related to perception of the stimuli.
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Cerebral cortical activity during liminal rectal distension: examination of combined neurocircuitry and perception-related cognitive processes.
Similar to subliminal stimulation, liminal distension of the rectum was associated with detectable fMRI cortical activity in all subjects. The average maximum percent fMRI activity change in IBS patients in response to liminal distension (3.5 ± 0.6%) was similar to that of controls (5.2 ± 0.7%). Volume of cerebral cortical fMRI activity in response to liminal distension in IBS patients (2,457 ± 342 µl), however, was significantly smaller than that of controls (5,751 ± 396 µl; P < 0.05; Figs. 3 and 7B), whereas cortical activity subregions were similar in the two groups. In both groups, the activated regions due to liminal rectal distension were similar to those of subliminal rectal distension (Table 2). The Talairach-Tournoux coordinates of the voxels with the greatest fMRI signal change in each BA are presented in Table 5.
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Table 5. Talairach-Tournoux coordinates of the voxel with the greatest fMRI signal change within five cortical regions during liminal rectal distension
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Cerebral cortical activity during supraliminal, nonpainful rectal distension.
The average maximum fMRI signal change in IBS patients observed during supraliminal, nonpainful rectal distension (6.4 ± 0.9%) was significantly different from that of controls (9.8 ± 0.8%; P < 0.05). The volume of fMRI cortical activity in IBS patients (2,493 ± 351 µl) was significantly smaller than that for the controls (8,246 ± 624 µl; P < 0.05; Figs. 3 and 7C). Subregions of activity remained similar in the two groups and, as earlier stated, similar to subliminal and liminal rectal distension (Table 3). The Talairach-Tournoux coordinates of the voxels with the greatest fMRI signal change in each BA are presented in Table 6.
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Table 6. Talairach-Tournoux coordinates of the voxel with the greatest fMRI signal change within five cortical regions during supraliminal rectal distension
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As stated earlier, the volumes of cortical activity in the healthy control group, at the liminal and supraliminal levels of rectal distension, were significantly larger compared with those of IBS patients. Considering the fact that the liminal pressure in IBS patients was significantly lower than that of the controls, this raises the possibility that the observed smaller cortical fMRI activity volume could have been due to lower stimulus pressure. To address this issue, we also compared the cortical activity volume of IBS patients in response to supraliminal distension pressures (33 ± 3 mmHg) to that of the cortical volume in response to liminal distension pressure (30 ± 7) of the control subjects. The unpaired Student's t-test showed no statistical difference between these two distension pressure groups. As seen in Fig. 3, IBS patients generate a significantly smaller total cortical activity volume compared with that of the controls in response to equivalent distension pressures.
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DISCUSSION
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In this study, we determined and compared quantitatively the pattern of the cerebral cortical fMRI response to subliminal, liminal, and nonpainful supraliminal rectal distension between a group of IBS patients as defined by Rome II criteria and age- and gender-matched control subjects.
The findings of the present study indicate that among healthy individuals, there is a direct relationship between the magnitude of the rectal distending pressure and the volume of corresponding cerebral cortical activity. This relationship was observed for stimulating pressures extending from the subliminal domain to the nonpainful liminal domain. On the basis of the above assumption, it can be suggested that the additionally recruited fMRI activity volumes at liminal levels, compared with subliminal levels, may represent the cortical neuronal mass engaged in the cognitive process associated with the perceived sensory information. Study findings also indicate that this additional recruitment of cortical neuronal mass is absent in IBS patients, indirectly suggesting fundamental differences in the processing of the registered sensory signals at the nonpainful perceived level in this group. On the surface, this finding seems contrary to the common notion that IBS patients have an exaggerated response to gut stimulation. However, lack of exaggerated cortical activity volume does not necessarily translate into absence of exaggerated perception, ie., it is conceivable that the absence of additional neuronal recruitment may influence the normal processing of the perceived signal in this patient group resulting in exaggerated perception or reaction to registered sensation. This potentially can occur by inhibition of the cortical centers vital to normal management of sensory information. The fact that in IBS patients, additional recruitment does not occur in response to increasing stimulation suggests that cognitive processes engaged in a healthy individual during perception are absent or underutilized in the IBS patients, and therefore, the perceived information may not be processed in the same manner as in healthy controls. Absence of increasing cortical activity volume in response to increasing stimulus intensity, if confirmed, may have important ramifications concerning the pathophysiology of functional bowel disorders and can provide an objective approach to the diagnosis of IBS. However, further studies are needed to ascertain the reproducibility of this finding.
Our study finding of cortical activity in response to subliminal stimuli devoid of perception-related cognitive processes indicates hypersensitivity of the sensory neurocircuitry in IBS patients. This concept has been proposed previously, and indeed many earlier studies (40, 41, 45, 47, 55) have documented a significantly lower threshold of perception for lower gut stimulation in IBS patients. However, given the fact that these studies only evaluated the perceived stimulations, their findings represent both neural and cognitive functions and, as such, have not been able to distinguish between influences of neural hypersensitivity and those of changes in cognitive processes. Our finding in the subliminal domain of lower degrees of rectal distension in IBS patients compared with controls inducing cortical activity volumes similar to control subjects' supports the notion of the existence of neural hypersensitivity in IBS patients.
The distending pressure that was associated with awareness in the current study is higher than some of the previously reported studies (33, 39, 51, 52). This discrepancy is possibly due to differences in the length of the connecting tube (in our case,
30 feet) that was necessitated by the need to keep the barostat device outside of the scanner suite. Therefore, the pressure registered at the perception level reported in the current study may not accurately reflect the actual distension pressure for perception, but it provides a quantifiable measure for inducing uniform subliminal and supraliminal distensions in all study subjects. Because of these technical limitations, accurate determination of the subliminal and perceived distension pressures that cause cortical activity awaits improvements in barostatic recording systems and catheter assemblies.
Cortical registration of both subliminal somatic (16, 23, 35, 38) and visceral (30, 32) sensory signals has been previously reported. Accumulating evidence suggests that, similar to peripheral afferents that are amenable to sensitization and desensitization (37, 43, 48, 49) by repeated stimuli, cerebral cortical processes are likewise influenced by subliminal stimulation. Inhibition as well as stimulation of cortical processes by somatic subliminal signals have been reported. For example, the detection rate of near-threshold stimulation of the upper extremity has been reported to be reduced with subliminal electrical stimulation and the somatic sensory threshold was found to be increased during additional subliminal stimulation (8). Studies of intracerebral event-related potentials recorded from noninvolved areas of the cerebrum in patients with intractable seizure disorders using supraliminal and subliminal visual stimuli have suggested a shorter latency period for processing subliminal compared with that of supraliminal visual stimulation. Subliminal stimulation also induced a significantly smaller evoked potential amplitude (9). With regard to viscerosensation, subliminal visceral esophageal acid stimulation in healthy individuals has been shown to increase the cortical activity volume associated with swallowing (28). Repeated subliminal rectal distension in earlier studies has found a significant reduction in the perception threshold for rectal distension and increase in its associated cortical activity (29). In the present study, the stimulation design did not allow evaluation of the effect of subliminal stimulation on subsequent responses in IBS patients; however, this topic merits further consideration.
Although the stimuli used in this study were not painful, they did activate regions generally believed to constitute the cortical pain pathway. These cortical regions are believed to be involved in the three commonly accepted aspects of pain, namely, sensory-discriminative, affective-motivational, and cognitive-evaluative aspects (5, 26, 44). These areas include the primary and secondary somatosensory cortexes, the insula, anterior cingulate, prefrontal, and parietooccipital areas. The findings of the present study support the notion that the tested nonpainful/perceived as well as subliminal stimulations share the central processing pathways of somatic (4, 12, 14, 54) and visceral (3, 7, 39) pain.
Primary and secondary somatosensory cortexes receive noxious as well as innocuous somatic (10) and visceral (2, 3, 7) sensory information relayed from the thalamus (46, 50). Previous studies indicate the discriminative function of this region regarding the spacial, temporal, and intensity aspect of the pain in determining the possibility of injury due to painful, or potentially painful, stimuli (10). However, activation of the primary somatosensory cortex has been inconsistently observed in somatic pain studies (44). This is believed to be due to the differences in the size of the stimulated area as well as temporal summation rather than the intensity of the stimulus (44). Previous studies (18) have shown that contrary to moderately painful stimuli, stimulus just above the pain threshold failed to activate the primary somatosensory cortex. In the present study, except for one individual in each group, the somatosensory cortex was activated by subliminal, liminal, as well as supraliminal nonpainful mechanical stimulation. This finding in the healthy group is in contrast to infrequent activation of sensory cortex in response to subliminal chemical stimulation by intraesophageal acid perfusion (31, 32).
Anterior cingulate cortex receives projections from nociceptive neurons contained in the medial thalamic nuclei. (1, 13) In humans, evoked potentials have been recorded in the anterior cingulate in response to painful stimuli (34). It is generally believed that the anterior cingulate is involved in pain processing (26) in addition to its role in cognitive processes such as attention (15, 19). Previous studies (17, 20) have also documented direct thalamocortical nociceptive input to the insular cortex. The insula is believed to be involved in the affective aspect of pain in addition to its role in autonomic control (26). Insular lesions are reported to result in atypical behavioral and physiological responses to painful stimuli, despite the fact that the pain sensation appears to remain normal (6, 42), suggesting abnormal processing of the affective component of the stimulus (26). The lack of an increase in activity volume for any of these areas in IBS patients with increasing stimulus intensity, as seen in healthy controls, could suggest that neural modulating processes that normally occur with sensory perception and that are represented by recruitment of additional cortical neurons, as seen in healthy controls, may be inadequately activated in IBS patients.
In summary, compared with controls, in IBS patients, 1) cortical processing of nonpainful, perceived rectal distension involves significantly smaller fMRI activity volumes, and 2) additional recruitment of cortical fMRI activity volume in response to increasing stimulation from subliminal to liminal and supraliminal domains is absent, suggesting differences in the processing of perceived stimulation.
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GRANTS
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This work was supported, in part, by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK-25731.
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FOOTNOTES
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Address for reprint requests and other correspondence: R. Shaker, Division of Gastroenterology and Hepatology, Froedtert Memorial Lutheran Hospital, 9200 W. Wisconsin Ave., Milwaukee, WI 53226 (E-mail: rshaker{at}mcw.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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