Cingulate cortex: a closer look at its gut-related functional topography

Adeyemi Lawal, Mark Kern, Arthi Sanjeevi, Candy Hofmann, and Reza Shaker

Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 14 January 2005 ; accepted in final form 24 May 2005


    ABSTRACT
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Earlier studies have documented activation of the cingulate cortex during gut related sensory-motor function. However, topography of the cingulate cortex in relationship to various levels of visceromotor sensory stimuli and gender is not completely elucidated. The aim was to characterize and compare the activation topography of the cingulate cortex in response to 1) subliminal, 2) perceived rectal distensions, and 3) external anal sphincter contraction (EASC) in males and females. We studied 18 healthy volunteers (ages 18–35 yr; 10 women, 8 men) using functional MRI blood-oxygenation-level-dependent technique. We obtained 11 axial slices (voxel vol. 2.5–6.0 x 2.5 x 2.5 mm3) through the cingulate cortex during barostat-controlled subliminal, liminal, and supraliminal nonpainful rectal distensions as well as EASC. Overall, for viscerosensation, the anterior cingulate cortex exhibited significantly more numbers of activated cortical voxels for all levels of stimulations compared with the posterior cingulate cortex (P < 0.05). In contrast, during EASC, activity in the posterior cingulate was larger than in the anterior cingulate cortex (P < 0.05). Cingulate activation was similar during EASC in males and females (P = 0.58), whereas there was a gender difference in anterior cingulate activation during liminal and supraliminal stimulations (P < 0.05). In females, viscerosensory cortical activity response was stimulus-intensity dependent. Intestinal viscerosensation and EASC induce different patterns of cingulate cortical activation. There may be gender differences in cingulate cortical activation during viscerosensation. In contrast to male subjects, females exhibit increased activity in response to liminal nonpainful stimulation compared with subliminal stimulation suggesting differences in cognition-related recruitment.

functional magnetic resonance imaging; rectal distension; external anal sphincter contraction


HUMAN SOMATOSENSORY RESPONSES are well characterized and localized to the sensory homunculus of the cerebral cortex. A number of studies have addressed cerebral cortical representation of visceral sensation in healthy subjects and patients with functional bowel disorders (2–4, 29, 36). These have generated considerable interest in gaining insight into the brain-gut relationship dysfunction that may be responsible for the clinical aspect of functional gastrointestinal disorders. Functional neuroimaging studies, functional magnetic resonance imaging (fMRI) in particular, has begun to describe the cerebral functional anatomy related to the gastrointestinal tract.

A recent meta-analysis of nonnoxious and noxious visceral stimulations of the upper and lower gut revealed considerable consistency in the activation of the prefrontal, primary, and secondary sensory, supplementary motor areas, mid- and perigenual anterior cingulate (mACC and pACC, respectively), orbitofrontal and insular cortexes (11). Also studies have shown gender differences in cortical activity registration in response to somatic stimulation such as noxious heat (4) and rectal distension in both healthy controls as well as patients with irritable bowel syndrome (IBS) (2, 22).

The anterior cingulate cortex (ACC) is commonly activated by discomfort and painful sensations arising from the gastrointestinal tract (13). This area is believed to be involved in the motivational-affective component of visceral sensation, whereas the posterior cingulate is believed to function in spatial orientation, memory, and the performance of learned tasks (8). The multidimensional experience of noxious stimuli involves activities in a widely distributed set of cerebral regions. The specific contributions of individual brain structures to the perception of visceral sensation are beginning to be dissected.

However, topography of the cingulate cortex in relationship to various levels of gut-related sensory stimuli and gender is not completely elucidated. Previous studies have used fMRI-scanning sequences with large voxel volumes, and because various cortical areas are separated by a few millimeters, volume averaging during fMRI analysis may attenuate the cortical activity in localized regions. The partial volume effect of large-thickness slices causes increase in signal dropout and may explain the lack of activation of some areas reported in previous whole brain studies, e.g., posterior cingulate cortex during external anal sphincter contraction (EASC) (23).

Although thinner fMRI slices afford a more accurate spatial resolution for assigning activity to a specific brain region, there is a fine line between achieving this goal and maintaining an acceptable signal-to-noise ratio (16, 20, 21). It is suggested that for most fMRI studies, a 5- to 8-mm slice thickness optimizes signal sensitivity and spatial resolution (16, 20). However, Hyde et al. (21) found that a 1.5-mm3 cubic voxel yielded robust fMRI data. Furthermore, thinner slices reduce the magnitude of susceptibility artifacts including those induced by motion correlated with the stimulus (20).

In this study, we aimed to characterize and compare regional cingulate cortex activation in response to subliminal and liminal rectal distensions and EASC in males and females.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Subjects

We studied 18 right-handed healthy controls (8 men and 10 women, 18–35 yr). The Human Research Review Committee of the Medical College of Wisconsin approved the study, and all volunteers gave written informed consent before the study. Healthy controls were recruited by advertisement and did not have any gastrointestinal symptoms or diagnosis of IBS by interview as well as following a detailed health questionnaire.

Magnetic Resonance Imaging Scanning

Gradient echo planar magnetic resonance (MR) images were acquired using a 3.0-tesla GE Signa System (General Electric Medical Systems, Waukesha, WI) equipped with a custom three-axes head coil designed for rapid gradient field switching and a shielded transmit/receive birdcage radiofrequency coil. The MR scanner and head coil were used to acquire a time course of echo planar images over the entire cingulate cortex from its superior to the inferior margins. In each of eleven contiguous 2.5- to 6.0-mm-thick axial slices depending on whether the cingulate gyrus has a single sulcus or double parallel sulci on sagittal localization (32); 120 images were captured with an echo time (TE) of 41.6 ms and a repetition time (TR) of 1,200 ms. Echo planar images were 96 x 96 pixels over a 240-mm field of view (in-plane resolution of 2.5 mm; Fig. 1). High-resolution spoiled gradient recalled acquisition at steady-state images were also obtained consisting of whole brain 1.2-mm-thick slices. These high-resolution anatomical images were used for subsequent superposition of cortical activity regions derived from the lower-resolution echo planar blood oxygenation level-dependent (BOLD) contrast image data. All MRI data were stereotaxically transformed to the Talairach-Tournoux coordinate system for comparison and display purposes (39).



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Fig. 1. Eleven contiguous axial slices through the cingulate cortex with a 240-mm field of view (FOV). D, distension; S, squeeze. R, relaxation.

 
Study Protocol

Eighteen subjects participated in the following paradigm-driven rectal distention 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 5 cm. Maximum bag volume was 300 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 outer diameter, 1.8-mm inner diameter). 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 in 5-mmHg steps and sustained for 10 s by means of the computer-controlled barostat. After each pressure step, the subject was asked whether he or 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 subjects 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 MRI scan, air was infused into the rectal bag until a minimal static pressure of 3–5 mmHg was observed. 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. Three barostat-controlled distension levels were tested: 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 106-s scan sessions of 15-s intervals of sustained distension alternated with 15 s of no distension (Fig. 2). Two scans were performed at each distension level.



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Fig. 2. Computerized barostat connected to an infinitely complaint polyethylene rectal bag by a 30-ft-long single-lumen catheter. Graded distension of the rectum was performed using on/off distension paradigm during 1 epoch scanning time. A 10-s on/off paradigm was employed during the external anal sphincter contraction (EASC) activity.

 
EASC

All subjects participated in a similar paradigm-driven external anal sphincter contraction protocol. All contraction scans were performed in a block trial format alternating 10 s of sustained maximum effort EASC with 10 s of rest. Before each fMRI scanning sequence, subjects were told that they would be cued to contract their anal sphincter to the desired level by a light tap on the right lower leg and to then stop the contraction when cued by another light tap on the left leg. This cuing procedure has been used previously and shows no confounding fMRI signal activity (23).

Image Registration, Data Analysis, and Movement Correction

To compensate for subtle changes in head position over the course of the MRI scanning sessions, an algorithm for three-dimensional (3-D) volume registration was used (9). 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-square fit of the target volume 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-square estimation of the movement parameters that best make the target volume fit the fiducial volume. This iteration is rapid (usually only 2–4 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 SGI and Intel workstations used for this project, a 96 x 96 pixel x 11 slice volume can be aligned to a fiducial in <1 s.

All fMRI signal analysis was performed using the Analysis of Functional Neuro-Imaging (AFNI) software package (10). 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 (24, 31). 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. Furthermore, we applied an additional clustering requirement that the displayed region of cortical activity must be represented by a cluster of three or more contiguous correlated voxels (25–26).

Statistical comparisons were performed using SigmaStat 2.03 statistical package (SPSS, Chicago, IL). Average data are shown as means ± SE unless otherwise stated. Reproducibility of fMRI signal time series and cortical topography was tested using ANOVA and regression analysis as indicated. Differences in total number of activated voxels were determined for the levels of distension and gender by unpaired t-test. Regional differences in the same individual at each level of stimulation were determined by the paired t-test. Repeated measure ANOVA with Tukey's correction was used to determine differences in the number of activated voxels among the three levels of distension.


    RESULTS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The mean distension pressure measured from the barostat bag assembly at the level of perception was 29 (25–35) and 26 mmHg (15–30) in males and females, respectively. The mean age for female and male subjects was 26.1 ± 1.6 (22–35) and 26.3 ± 2.0 yr (20–35), respectively; P = 0.95.

In six of nine female subjects, we observed fMRI activity in the cingulate cortex in response to subliminal, liminal, and supraliminal nonpainful rectal distension. fMRI cortical activity was observed in two subjects only to liminal and supraliminal distensions. In one subject (subject 4 in Table 1), cingulate cortical activity was observed in response to subliminal and supraliminal, but not liminal rectal distensions. In all nine female volunteers, we observed fMRI cingulate activity during EASC. The data were unanalyzable during all levels of rectal distension for one subject (subject 1 in Table 1) during liminal rectal distension for subject 4 (Table 1) and during EASC in subject 2 (Table 1) due to significant artifact. These data points were not included in the analysis.


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Table 1. Total Cingulate fMRI activity

 
Among male volunteers, we observed fMRI cingulate activity only in three of eight in response to all levels of rectal distension. In three subjects, we did not observe cingulate activity in response to any level of rectal distension. Of the remaining two, we observed cingulate activity in one subject only to supraliminal distension and the other to subliminal and supraliminal, but not liminal distension. Cingulate fMRI activity during EASC was observed in seven of eight male volunteers (Table 1). Regional cingulate activity in all subjects and the Talairach-Tournoux coordinates of the fMRI voxels with the highest percent signal change are shown in Tables 2 and 3. An example of cingulate cortical activity response to rectal distension and EASC is shown in Fig. 3.


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Table 2. Total and regional cingulate fMRI activity

 

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Table 3. Talairach-Tournoux coordinates of the fMRI voxels with the highest percent signal change

 


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Fig. 3. Representative cingulate cortical activity in a female subject. As seen, the functional magnetic resonance imaging (fMRI) cortical activity voxels are more concentrated in the anterior cingulate cortex during rectal distension and in the posterior cingulate cortex during EASC in a female subject.

 
Cingulate Loci Activated by Rectal Distension and Maximum EASC

Comparison of anterior and posterior cingulate cortical activation. Evaluation of the regions of activation stereotaxically mapped on the anatomic images in the Talairach-Tournoux coordinate system revealed that the ACC exhibited a significantly greater number of fMRI cortical activity voxels for all distending stimulations (P < 0.05) compared with the posterior cingulate cortex (Fig. 4). In contrast, during maximum EASC, the number of activated voxels in the posterior cingulate was more than in the ACC (P < 0.05).



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Fig. 4. Topographic representation of response within the cingulate cortex to rectal distension and EASC. In all subjects, males and females combined, visceromotor stimulation induced different patterns of fMRI cortical activated voxels, with distension inducing more anterior cingulate cortical activity and vice versa for EASC (*P < 0.05). Anterior cingulate cortex activity volume (no. of activated voxels) increased precipitously from subliminal to liminal and supraliminal nonpainful distensions. ANOVA showed a significant difference among these activity levels. {Delta}P (ANOVA) = 0.002. Sublim, subliminal rectal distension; supra, supraliminal rectal distension.

 
The total number of activated fMRI voxels associated with various levels of rectal distension for all subjects with observed cortical activity demonstrated a stimulus-intensity-dependent pattern of cingulate fMRI activity voxels in the ACC (subliminal, 10.47 ± 4.0; liminal, 18.31 ± 5.45; and supraliminal, 25.06 ± 8.3; P = 0.002) compared with the posterior cingulate cortex (subliminal, 4.24 ± 2.3; liminal, 4.56 ± 2.7; and supraliminal, 8.8 ± 2.3; P = 0.08) (Fig. 4).

Gender differences in cingulate loci activation. The total number of activated voxels in response to liminal and supraliminal levels of distension in women was significantly more than in men (P < 0.05; Fig. 5). Comparison of the anterior as well as posterior cingulate activity between male and female subjects exhibited significant activity differences between genders in the anterior cingulate for all levels of stimulation. There were no appreciable gender differences in posterior cingulate activity (Table 2). In contrast, cingulate cortical activation was similar during maximum EASC in males and females (P = 0.58). Overall, there was a stimulus-dependent increase in cingulate cortical recruitment in females from subliminal to supraliminal distensions (22.8 ± 10.1, 39.75 ± 12.2, and 54.5 ± 13.9; P < 0.001)] compared with males, in which there seemed to be no significant additional cortical recruitment with increasing stimulus intensity (5.6 ± 2.7, 5.9 ± 2.7, and 7.6 ± 4.2; P = 0.13; Table 1). This pattern was also true for regional cingulate cortical activation (Fig. 6).



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Fig. 5. Gender differences in cingulate cortical activity. Comparison of the total number of fMRI-activity voxels between male and female healthy volunteers during rectal distension and EASC. As shown, when combined anterior and posterior segmental activity of the cingulate cortex was considered, significant differences between genders were only seen during perceived nonpainful liminal and supraliminal rectal distensions. Despite the presence of a trend, the difference for subliminal distensions did not reach statistical significance. In addition, total cingulate cortex activity during EASC was similar between males and female subjects. *P < 0.05 (posterior vs. anterior cingulate activity) {Delta}P (ANOVA) = 0.002 (ANOVA of anterior cingulate cortical activity from subliminal to liminal and supraliminal distensions.)

 


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Fig. 6. Comparison of regional cingulate cortical fMRI activity during rectal distension and EASC in males and females. Although the anterior cingulate cortex in female subjects exhibited a significant increase in the number of fMRI-activity voxels, from subliminal to liminal and supraliminal distension pressures [{Delta}P (ANOVA) = 0.002], the posterior cingulate cortex did not exhibit a similar progressive activation in response to increased stimuli. In contrast, among male subjects, there were no regional differences within the cingulate cortex in response to increasing rectal distension pressures. EASC induced a similar pattern of fMRI voxel activity in both genders, i.e., significantly more volume of activity in the posterior compared with anterior cingulate gyrus. *P < 0.001.

 
Maximum Percent fMRI Signal-Intensity Change

There were no regional differences in percent fMRI signal-intensity change within the cingulate cortex for all levels of distension and external anal squeeze contraction in both genders (Table 4). However, the average maximum percent fMRI signal-activity change in both genders showed incremental increase with increasing stimulus intensity from subliminal to liminal and supraliminal stimulations (P < 0.05; Table 5).


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Table 4. Regional cortical maximum %fMRI signal increases

 

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Table 5. Maximum %fMRI signal increases with increasing stimulus intensity

 

    DISCUSSION
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this study, we elucidated in healthy volunteers the regional activation within the cingulate cortex in response to sensory and motor stimuli originated from the lower gastrointestinal tract. The most salient features of activation within the cingulate cortex in the current study are 1) visceral stimulation and EASC (motor task) induce different patterns of cingulate cortical activation, with more activated voxels in the ACC than the posterior during rectal distension and vice versa during EASC; 2) gender differences exist in cingulate cortical activity in response to lower gut sensory, but not motor stimulation. These differences were localized in the anterior cingulate; 3) perception of a sensory signal from the rectum results in activation of significantly more numbers of voxels in the anterior cingulate in females compared with males.

Previous studies (38) have demonstrated differential representation of visceral and cutaneous sensation within the cingulate cortex in response to noxious and nonnoxious stimuli. Balloon distension of the rectum and anal canal resulted in greater activation of the ACC during rectal stimulation and posterior midcingulate during anal canal stimulation, respectively (19, 28). The data of the present study demonstrate regional differences in cortical activation in response to nonnoxious visceral stimuli and motor tasks, with visceral stimuli activating areas involved in affect and emotion, whereas motor (somatosensory) tasks activated areas involved with motor preparation and learned tasks.

In females, during subliminal, liminal, and supraliminal levels of rectal distension, the number of activated voxels in the anterior cingulate was significantly higher compared with the posterior cingulate. This difference was not observed in male subjects. However, when anterior and posterior cingulate activity was combined, gender differences were only seen for liminal and supraliminal nonpainful stimuli and not for subliminal stimulations. Cingulate cortical response was also stimulus intensity dependent in females but not in males.

Previously, studies have shown gender difference in cortical registration in response to rectal distension in healthy adults (22) and in patients with IBS (2), with little or no cingulatecortical activation during whole brain study in males during perceived rectal distensions (22). Findings of the present study corroborate this prior report. The findings of the current study suggest greater anterior cingulate cortical activation and thus greater activation of "motivational affective area" to visceral sensation in females compared with males. Despite this evidence and those in the literature on gender differences in cortical activation, this finding should be viewed with caution, because it is possible that the gender difference seen during nonnoxious rectal distension may be due to additional stimulation that can potentially arise from contiguous structures such as the posterior vaginal wall.

Another possible explanation for the observed gender differences could include the effect of anxiety, which might have existed at different levels among the genders, influencing differently the fMRI response to visceral sensation. Anticipation and anxiety of stimuli have been reported to induce or modify cortical activity (7, 35) and potentially could have contributed to the gender differences observed in this study. However, because the subliminal stimulation was always given before the perceived stimulus, it is unlikely that it could have been influenced by anticipation of a stimulus not experienced previously.

Earlier studies have shown that EASC is associated with multifocal fMRI activity in sensory/motor, cingulate cortex, prefrontal, parietal, occipital, and insular regions (23). The posterior cingulate cortex (PCC) is known to function in spatial orientation, spatial memory, visual imagery, and the performance of learned tasks (8). In the present study, EASC induced more PCC activation compared with ACC. Cortical activation in the PCC in response to EASC was similar in both genders. It is not surprising that there were no gender differences in cortical activation in the PCC in response to EASC, because this is a learned motor task. The involvement of the PCC in visceral sensation described here is in contrast to the majority of findings of other functional neuroimaging studies. However, the finding of the present study is in concordance with previous reports that have shown an increase in the severity of gastric erosions in rats following PCC lesions (17), suggesting the involvement of PCC in visceral sensation.

The cingulate cortex forms a cingulum around the corpus callosum. It is divided into anterior and posterior regions that have unique functions, cytoarchitectures, and connections (44). The ACC is comprised of the perigenual-pACC [Brodmann areas (BA 25, 24, and 32)] and midcingulate (MCC) regions (BA 24' and 32'). The PCC includes posterior gyri (BA 23 and 31) and retrosplenial gyri (BA 29 and 30). The MCC is further divided into an anterior nociceptive (aMCC) and posterior skeletomotor (pMCC) division. The MCC contains the cingulate motor areas (44).

The pACC is believed to be reciprocally connected to the visceral sensory cortex of the insular area. It has been shown to receive large input from the amygdala and has efferent fibers that project to the visceromotor centers, including those of periaqueductal gray, solitary nucleus, motor nucleus of the vagus, reticular formation nuclei, and thoracic sympathetic lateral horn (8). Functionally, the ACC is divided into an affect and a cognitive region (8). Autonomic and visceromotor responses such as respiratory and cardiac responses, mydriasis, piloerection, and facial flushing (12,14, 3334, 40), and gastrointestinal symptoms such as nausea, vomiting, epigastric sensation, salivation, and bowel or bladder evacuation (27, 30, 33) have been reported following electrical stimulation of perigenual ACC. Also different types of emotions have been invoked by electrical stimulation of different parts of the ACC (1). Thus the affect division (pACC) of the cingulate cortex is believed to regulate autonomic and endocrine functions as well as assess emotional and motivational responses to a variety of stimuli.

The MCC is believed to be the cognitive division of the ACC (8). The aMCC is reported to coordinate fear and avoidance of noxious stimuli with skeletomotor responses. Although poorly localized, several studies have shown activation of aMCC to noxious somatic and visceral stimuli. In addition, it has been shown that the skeletomotor region (pMCC) has extensive cortical connections to the supplementary and primary motor areas, red nucleus, striatum, and spinal cord (8). Earlier studies suggest that this region of the cingulate cortex coordinates skeletomotor reflex responses (44).

The PCC is reported to be a key component in the caudal limbic system receiving projections from the hippocampal formation, anterior thalamic nuclei complex, and the medial pulvinar nuclei (8). It is believed to be involved in visuospatial orientation and performance of learned complex motor tasks (8, 41). Studies in human volunteers have shown that activation of the PCC could reflect the presence of a "nonexecutive" cognitive control system with a less effortful passive attention (37, 4143) and little strategic decision making capability (15). In addition, changes in the metabolism of glucose in PCC have been implicated in disorientation to time and place in Alzheimer's disease as well as phasic pain processing in PCC (5, 18). Thus the available data suggest that the PCC may be involved in multiple tasks.

In the present study, with the use of thinner slices [2.5–6.0 mm (providing voxel volumes of 15.63–37.5 mm3)] relative to previous whole brain acquisition slices (10 mm providing voxel volumes of 141 mm3) (23), subregions of activation within the cingulate cortex in response to rectal distension and EASC were better defined. This approach affords a closer look at functional activation within a particular region of interest and helps to further elucidate the functional complexity of the cingulate cortex in relationship to intestinal sensory motor function and extends further the current knowledge of the "visceral brain" in regulating gut sensory/motor functions.

In conclusion, intestinal viscerosensation and EASC induce different patterns of cingulate cortical activation. Whereas the viscerosensation involves the anterior cingulate more than the posterior, EASC induces the opposite, suggesting the existence of a task-specific regional cingulate cortex activity. In contrast to male subjects, females exhibit increased activity in the ACC in response to subliminal, liminal, and supraliminal nonpainful rectal stimulation, suggesting possible gender differences in cognition-related recruitment of this region in response to intestinal viscerosensation.


    ACKNOWLEDGMENTS
 
This work was supported in part by National Institutes of Health Grants R01-DK-Z57311 and T32-DK-61923 and The Medical College of Wisconsin General Clinical Research Center (M01 RR00058).


    FOOTNOTES
 

Address for reprint requests and other correspondence: R. Shaker, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 West 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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 DISCUSSION
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