Cerebral cortical representation of external anal sphincter contraction: effect of effort

Mark K. Kern, Ronald C. Arndorfer, James S. Hyde, and Reza Shaker

Medical College of Wisconsin Digestive Disease Center, Division of Gastroenterology and Hepatology, Department of Medicine and Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Submitted 2 May 2003 ; accepted in final form 18 August 2003


    ABSTRACT
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The external anal sphincter (EAS) plays a critical role in maintaining fecal continence; however, cerebral cortical control of voluntary EAS contraction is not completely understood. Our aims were to determine the cortical areas associated with voluntary EAS contraction and to determine the effect of two levels of sphincter contraction effort on brain activity. Seventeen asymptomatic adults (ages 21-48, 9 male) were studied using functional magnetic resonance imaging (fMRI) to detect brain activity. Studies were done in two stages. In stage 1 (10 subjects, 5 male), anal sphincter pressure was monitored from a catheter-affixed bag. Subjects performed maximal and submaximal EAS contractions during two fMRI scanning sessions consisting of alternating 10-s intervals of sustained contraction and rest. In stage 2 studies, seven subjects (4 male) performed only maximum effort sphincter contractions without a catheter. EAS contraction was associated with multifocal fMRI activity in sensory/motor, anterior cingulate, prefrontal, parietal, occipital, and insular regions. Total cortical activity volume was significantly larger (P < 0.05) for maximal (5,175 ± 720 µl) compared with submaximal effort contractions (2,558 ± 306 µl). Similarly, percent fMRI signal change was significantly higher (P < 0.05) for maximal (4.8 ± 0.1%) compared with submaximal effort contractions (2.2 ± 0.1%). Cortical region-of-interest analysis showed the incidence of insular activation to be more common in women compared with men. Other cortical regions showed no such gender differences. fMRI activity detected in stage 2 showed similar regions of cortical activation to those of the stage 1 study. Willful contraction of the EAS is associated with multifocal cerebral cortical activity. The volume and intensity of cerebral cortical activation is commensurate with the level of contractile effort.

fecal continence; functional magnetic resonance imaging


VOLUNTARY CONTROL OF THE EXTERNAL anal sphincter plays an essential role in maintaining fecal continence. This sphincter is comprised of deep, superficial, and subcutaneous striated muscle groups located around the terminus of the gastrointestinal tract (47). Innervation to this sphincter is provided by the somatic fibers of the second, third, and fourth sacral routes through the pudendal nerves (3, 27). Considerable information exists about the peripheral and reflex control of the external anal sphincter (6, 18, 26, 35, 41). Information about the central control of voluntary contraction of this sphincter in humans, however, is scarce and mostly addresses its contraction response to experimental electrical or magnetic stimulation of the motor cortex (1, 12, 15, 19, 29, 44). Although these studies have shown contractile response of the external anal sphincter or pelvic floor to direct stimulation of the motor cortex, the cerebral cortical activity map related to voluntary contraction of this sphincter could be quite different from the cortical topography of its control determined by direct cortical stimulation.

In addition to physiological importance, a better understanding of the cortical control of the continence mechanism has clinical significance because fecal incontinence has been reported in patients following cerebrovascular accident (5, 33) and injuries of the frontal lobe (46).

The aims of the present study were therefore to determine the areas of the human cerebral cortex involved in voluntary contraction of the external anal sphincter and the relationship between cerebral cortical activity and two effort levels of willful contraction of this sphincter.


    METHODS
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Seventeen asymptomatic adult subjects (ages 21-48 yr, 9 males, 8 females) were studied. The study protocol was approved by the Human Research Review Committee of the Medical College of Wisconsin, and subjects gave written informed consent before their studies. All subjects completed a detailed health-related questionnaire before their studies and did not have any present or previous history of gastrointestinal-related diseases.

Magnetic resonance imagery scanning. Gradient echo planar magnetic resonance (MR) images were acquired using a 1.5 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 brain volume. In each of 13 contiguous 10-mm thick sagittal slices, 120 images were captured with an echo time (TE) of 40 ms and a repetition time (TR) of 1,000 ms. Echo planar images were 64 x 64 pixels over a 240-mm field of view (in-plane resolution of 3.75 mm). High resolution spoiled gradient recalled acquisition at steady-state images were also obtained consisting of 124 1.2-mm-thick slices (TE of 76 ms, TR of 16,000 ms). These high-resolution anatomic 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 MR imagery (MRI) data were stereotaxically transformed to the Talairach-Tournoux coordinate (42) system for comparison and display purposes.

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-squares 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-squares 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 Intel workstation used for this project, a 64-pixel x 64-pixel x 13-slice volume can be aligned to a fiducial in <1 s.

All functional MRI (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 (8). 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 cross-correlation technique that compares an idealized waveform with an actual MRI-generated magnetic signal time course. This technique has been used in many fMRI investigations including studies of cortical response to esophageal stimulation. 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.

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.

Data are represented as means ± SE unless stated otherwise. Gender comparisons of cortical activity volume and temporal signal characteristics were performed using unpaired Student's t-testing with Bonferroni correction for multiple comparisons. Intragroup comparison of cortical activity volume and temporal characteristics of fMRI signals were done using analysis of variance with paired Student's t-test and Tukey's correction.

External anal sphincter contraction effort. 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 external anal sphincter contraction with 10 s of rest.

Studies were carried out in two stages. Stage 1 was monitored contraction, in which we studied 10 healthy volunteers (5 males, 5 females). Sphincter contraction was monitored by recording pressure using a catheter-affixed, air-filled bag positioned within the anal sphincter segment. The latency of sphincter contraction to recorded pressure signal upstroke was tested before each scanning session by having the subject verbally report the instant of a practice sphincter contraction while we monitored the pressure recording 30 ft from the magnet. We observed the upstroke in recorded pressure to be concurrent with the subject's reported instant of sphincter contraction. Subjects participating in the stage 1 studies performed maximal and submaximal effort external anal sphincter contractions during two different fMRI scanning sequences. These subjects were instructed before the submaximal effort scans as to what level of effort produced a bag pressure that was approximately one-half the recorded maximum effort pressure. Subjects performed 10 s of sustained contraction followed by 10 s of rest for a total of five pairs per scanning period. 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 right leg. This cuing procedure has been used previously and shows no confounding fMRI signal activity. (24)

At the conclusion of stage 1 studies, four subjects performed three additional scans in which maximum contraction followed by rest were alternated with submaximum contractions followed by rest in the same scanning period.

Stage 2 was self-reported contraction without catheter-affixed balloon. To ascertain the effect of the presence of a measuring device on topography of cortical representation of external anal sphincter contraction, we studied an additional four male and three female healthy subjects. They performed six scans of alternating 10-s intervals of self-determined maximum external anal sphincter contraction and rest in the absence of the pressure-measuring device.


    RESULTS
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All 17 subjects were able to complete their studies. A representative example of cortical activity during maximum effort contraction from one male and one female subject is shown in Fig. 1. The regions of cortical activity are shown as red and yellow areas superimposed on the sagittal and axial anatomic slices. An example of a magnetic signal intensity recording with its concurrent pressure recording from the air-filled bag positioned within the external anal sphincter is shown in Fig. 2. As seen, the cortical fMRI signal changes are well correlated with the sphincter muscle contractions; however, the cortical BOLD responses lag the times of contraction and relaxation by 5-9 s. Figure 3 shows an example of the effect of alternating maximum and submaximum contraction effort on the fMRI activity signal. As seen, the magnitude of fMRI signal increase is directly related to the effort applied for external anal sphincter contraction. The average external anal sphincter plateau pressure increase in all subjects during maximum contraction was 8 ± 1 mmHg compared with 4 ± 1 mmHg during submaximum contractions (P < 0.05). It must be noted that these pressures only represent the effort of external anal sphincter contraction and not the actual sphincter pressure, because pressure within the inserted air-filled bag was connected to a recorder 30 ft from the bore of the MRI scanner. The catheter was also air-filled; therefore, the contraction pressure amplitude recorded from the bag was dampened by the compliance inherent in the use of long catheters filled with a compressible substance such as air.



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Fig. 1. Examples of cerebral cortical functional magnetic resonance imagery (fMRI) activity during maximum effort external anal sphincter contraction in representative female (A; subject 8 in Tables 1, 2, 3) and male (B; subject 2 in Tables 1, 2, 3) subjects. Regions of activity are shown as colored areas superimposed on anatomic MRI slices in the sagittal and axial planes. Activated cortical regions include the sensory/motor, cingulate gyrus, prefrontal and parietooccipital regions, as well as the insular cortex. The Talairach-Tournoux (x, y, z) coordinates in millimeters of the voxels that show the maximum increase in fMRI signal intensity within these regions in the female example are (1, 26, 53) in the sensory/motor region, (1, -34, 17) in the cingulate gyrus, (0, -49, 4) in the prefrontal region, (-2, 48, 57) in the parietooccipital region, and (41,-16, 1) in the insular cortex. In the male example, the Talairach-Tournoux coordinates for these voxels are (49, 20, 43) for the sensory/motor and (-5, 46, 57) for the parietooccipital regions. In the Talairach-Tournoux coordinate system, the x direction is right-left, the y direction is front-back, and the z direction is top-bottom relative to the level of a line drawn through the anterior and posterior commissures.

 


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Fig. 2. Cortical regions of activity in a male subject are shown superimposed on 25 sagittal anatomic slices (A) along with a graph of fMRI signal changes within an activated voxel (B) and a concurrent manometric recording of pressure from within the catheter-affixed, air-filled bag (C) during a maximal effort external anal sphincter contraction sequence. As seen, the fMRI signal response is well correlated with the manometric recording; however, the fMRI signal changes lag the changes in the manometric recording by several seconds.

 


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Fig. 3. Cortical regions of activity in a male subject are shown superimposed on 25 anatomic slices (A) along with a graph of fMRI signal changes within an activated voxel (B) and a concurrent manometric recording of pressure from within the catheter-affixed, airfilled bag (C) during alternating intervals of maximal and submaximal effort external anal sphincter contraction. As seen, the increase in fMRI signal intensity is commensurate with the relative increases in contraction pressures shown in the manometric recording.

 


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Table 1. Volume of regional cortical activity and maximum percent change in signal associated with voluntary external anal sphincter contraction

 

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Table 2. Cerebral cortical activity during submaximal external anal sphincter contraction

 

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Table 3. Volume of cortical activity and maximum percent change in signal during submaximal external anal sphincter contraction

 

Stage 1: comparison of objectively monitored maximal and submaximal external anal sphincter contractions. During maximal anal sphincter contraction, cerebral cortical fMRI signal changes were detected in the sensory motor cortex in 10 of 10 subjects, cingulate gyrus and prefrontal cortex in 7 of 10, parietooccipital activity in 9 of 10, and insular cortex in 6 of 10 subjects. The volumes of regional cortical activity associated with voluntary maximum external anal sphincter contraction and its accompanied maximum percent change in signal intensity are shown in Table 1. Cerebral cortical activity during submaximal external anal sphincter contraction was detected in the majority but not all individuals who exhibited activity with maximum anal sphincter contraction (Table 2). The volume of cortical activity and its related maximum percent fMRI signal changes for submaximal external anal sphincter contraction are shown in Table 3.

Comparison of the volume of cerebral cortical activity during maximal and submaximal anal sphincter contraction showed significant differences in the total cortical activity volume between the two tested effort levels (Fig. 4; P < 0.05). Comparison of regional cortical activity volumes between maximal and submaximal contraction, however, showed significant differences between effort levels only for the sensory motor cortex (P < 0.05). The differences for parietooccipital, cingulate gyrus, and prefrontal cortices did not reach statistical significance. The fMRI activity volume for the insular cortex was virtually identical between the two effort levels (Fig. 4). Similar to the findings for total activity volume, the maximum fMRI percent signal changes associated with maximal external anal sphincter contraction (4.8 ± 0.1) were significantly higher (P < 0.05) than those of submaximal contraction (2.2 ± 0.1).



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Fig. 4. Total and regional volumes of cerebral cortical activity during maximal and submaximal external anal sphincter contraction effort. The average values and errors were calculated using activity volume data only from those subjects who exhibited cortical activity for both effort levels of external anal sphincter contraction. The number of subjects represented in each cortical region designation is shown below the region names on the x axis. As seen, there was a significant difference in the total volume of cortical activity between maximal and submaximal effort contractions. Similarly, there was a significant difference in the cortical activity volumes in the sensory/motor (SM) region between effort levels. The differences between effort levels in cortical activity volumes in the parietaloccipital (PO) and cingulate gyrus (CG)-prefrontal (PF) regions did not reach statistical significance. Activity volumes in the insula (I) were practically identical between the two contraction effort levels.

 

Comparison of the incidence of cortical activity in various regions associated with maximal and submaximal anal sphincter contraction between male and female subjects (5 males, 5 females) using a Fischer exact test revealed that insular activation was significantly more prevalent among female subjects compared with male subjects (P < 0.05). Insular activity was observed in 100 vs. 20% for maximal and 80 vs. 20% for submaximal anal sphincter contraction among female and male subjects, respectively. There were no gender differences for activation incidence in other studied brain regions.

Stage 2. Self-reported maximum external anal sphincter contraction without the presence of a measurement device resulted in changes in cerebral cortical blood oxygenation level in four distinctive areas of the brain, similar to studies conducted with the presence of the manometric device. The cortical activity was detected in the sensory motor cortex in seven of seven subjects, the cingulate gyrus and prefrontal regions in four of seven, the parietooccipital area in five of seven, as well as the insular cortex in three of seven subjects (Table 4). Because the studied groups were different, no comparison could be done on magnitude of volume of cortical activation or its maximum percent fMRI signal change in activity between monitored maximum contraction and self-reported maximum contraction.


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Table 4. Volume of cerebral cortical activity and maximum percent change in signal associated with self-reported maximum external anal sphincter contraction

 


    DISCUSSION
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this study, we determined the cerebral cortical regions activated during voluntary contraction of the external anal sphincter. Study findings indicate that voluntary motor control of the external anal sphincter involves multiple cortical regions. These regions include the sensory/motor, cingulate gyrus, prefrontal, insular, and parietooccipital regions of the cerebral cortex. Furthermore, we have shown that the volume of cerebral cortical activity was directly related to the level of effort applied in generating two levels of contraction, in that generation of higher levels of contraction is accompanied by recruitment of larger volumes of the cerebral cortex exhibiting higher levels of fMRI activity.

We asked the volunteers to induce two levels of anal sphincter contraction; the maximum level of contraction that they could generate and a second level of contraction approximately one-half the maximum. Applying these two levels of effort was easily learned by the subjects before they were placed in the scanner. Applying any predetermined level of effort in contracting the external anal sphincter requires planning, control, and execution. Regional cortical activity observed in this study in areas other than the primary motor cortex, which previously has been shown to be involved in external anal sphincter contraction (44), may reflect these requirements. For example, activity detected in Brodmann area six corresponds to the supplementary motor areas that have been thought to be involved in the execution of simple tasks (37). Whereas the anterior cingulate gyrus activity detected in this study is in agreement with previous reports implicating this region of the brain in many motor behaviors, especially those that concern novel or difficult tasks (20), it is also believed that the anterior cingulate gyrus is involved in attention to body parts (36). Both of these areas have been reported to participate in control of the pelvic floor musculature (4). Representation of the pelvic floor muscles in the primary motor cortex has been previously demonstrated using direct stimulation of this region in humans as well as various animal species.

Stimulation of the upper area of the precentral gyrus is reported to cause protrusion of the anal canal and closure of the anal sphincter in monkeys (13, 45) and chimpanzees. Transcranial electrical stimulation of the primary motor cortex stimulated the external anal sphincter (12, 28). Transcranial magnetic stimulation in humans has shown that the anorectal muscles are represented bilaterally in the motor cortex (44). The finding of the present study of voluntary contraction of the external anal sphincter corroborates the involvement of the primary and secondary motor cortices in motor control of the external anal sphincter. However, study findings indicate that motor control of the external anal sphincter involves several other regions in addition to the motor cortex.

The external anal sphincter is part of the pelvic floor musculature that also includes the levator ani, puborectalis, and the external sphincter of the urinary bladder. Although each one of these muscles has a primary function, all are closely related and show concurrent activity during other functions. For example, during pelvic straining and during voluntary external anal sphincter contraction, other muscles including the levator ani and puborectalis unintentionally contract along with the external anal sphincter. Therefore, areas of the cerebral cortex activated during the present experiments may also represent function of muscles other than the external anal sphincter. This issue also exists with experiments using direct cortical stimulation. Because the above mentioned muscles of the pelvic floor were not recorded during these cortical stimulations, the specificity of cortical areas reported in these studies including the present report to the external anal sphincter is not conclusive. However, from a functional point of view, these short-comings are of less importance, because the external anal sphincter usually contracts voluntarily in concert with other muscles involved in continence. From this perspective, areas of the brain identified in this study practically may represent the voluntary continence mechanism of the anorectum and not only the external anal sphincter.

Previous studies (7, 39, 40) of simple motor tasks such as finger tapping have documented activation of multiple cortical regions. Animal studies have shown correlated neuronal discharge between the sematosensory and motor cortex (31) as well as between the thalamus and sensory cortex (21) and within and between hemispheres (34). These correlated or synchronous activities of different regions of the brain for performing a motor task are believed to be important for sensory motor integration and memory (25). Our findings also support the fact that generating external anal sphincter contraction requires correlated activities of various cortical regions, including primary and secondary sensory motor cortex as well as association areas of the brain, such as the cingulate gyrus and parietooccipital lobe. Of interest is the activity of the insular cortex, predominately found in female subjects, during external anal sphincter contraction.

The role of the insular cortex in voluntary motor activity is inconclusive. Studies of cortical activity during finger flexion have reported no activity in the insula (14) using combined fMRI and electromyography. Similarly, positron emission tomographic (PET) studies during arm flexion have not reported changes in blood flow in the insular cortex (38). Illusionary arm flexion/extension has been reported to be associated with insular activity (32). Additionally, studies of coordinated hand movement and simultaneous hand and foot movement have reported insular activity using PET (11). Activation of the insula is not confined to motor activity of the extremities. Volitional swallowing and swallow-related motor tasks such as lip pursing, tongue rolling, and jaw clenching have also been associated with activity in the insula (22, 24, 30, 43).

Although not a part of the original aims of this study, results indicate that there are significant differences in recruitment of the insular cortex during external anal sphincter contraction between male and female subjects. Gender differences in cortical processing of intestinal visceral sensations have been reported previously (2, 23). The findings of the present study support the notion of gender differences with regard to voluntary contraction of the external anal sphincter and indicate a broader spectrum of differences than previously thought regarding cortical control of intestinal function between males and females.

Previous studies (16, 17) of the primary motor cortex in monkeys have reported a direct relationship between exerted force and discharge rate of the single neurons. A direct relationship between flexion force of the index finger and the increase in cerebral blood flow in the motor cortex detected by PET has also been reported (10). In this study, activity was observed in four regions of the brain including contralateral sensory motor cortex, supplementary motor area, cingulate cortex, and cerebellum. Similarly a recent study (14) of cerebral cortical activity related to handgrip clearly demonstrated that the degree of striated muscle activity measured either as force or electromyographic signals is directly proportional to the amplitude of the brain signals determined by fMRI.

Findings of the present study documenting a significantly larger area of brain activity with significantly higher signal intensity during maximum compared with submaximum contraction of the external anal sphincter corroborate these previous findings and indicate that the cerebral cortical activity measured by fMRI signals is directly related to external anal sphincter contractile output.

In summary, voluntary contraction of the external anal sphincter is associated with correlated, multifocal cerebral cortical activity. These regions of activity include the primary and secondary sensory/motor cortices, the insula, as well as the association areas of the brain such as the cingulate gyrus, prefrontal cortex, and the parietooccipital region. The volume and intensity of activation of recruited cortical regions during external anal sphincter contraction is commensurate with the level of contractile effort.


    FOOTNOTES
 

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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