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Am J Physiol Gastrointest Liver Physiol 293: G188-G197, 2007. First published March 29, 2007; doi:10.1152/ajpgi.00461.2006
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NEUROREGULATION AND MOTILITY

Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging

Steven J. Coen,1 Lloyd J. Gregory,2 Lidia Yágüez,3 Edson Amaro, Jr.,1 Mick Brammer,1 Steven C. R. Williams,1 and Qasim Aziz4

1Neuroimaging Research Group, Institute of Psychiatry, King's College London; 2Research and Development Directorate, Hope Hospital, Manchester; 3Department of Psychology, Institute of Psychiatry, King's College London, London; and 4Section of GI Sciences, University of Manchester, Manchester, United Kingdom

Submitted 5 October 2006 ; accepted in final form 26 March 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Functional MRI is a popular tool for investigating central processing of visceral pain in healthy and clinical populations. Despite this, the reproducibility of the neural correlates of visceral sensation by use of functional MRI remains unclear. The aim of the present study was to address this issue. Seven healthy right-handed volunteers participated in the study. Blood oxygen level-dependent contrast images were acquired at 1.5 T while subjects received nonpainful and painful phasic balloon distensions ("on-off" block design, 10 stimuli per "on" period, 0.3 Hz) to the distal esophagus. This procedure was repeated on two further occasions to investigate reproducibility. Painful stimulation resulted in highly reproducible activation over three scanning sessions in the anterior insula, primary somatosensory cortex, and anterior cingulate cortex. A significant decrease in strength of activation occurred from session 1 to session 3 in the anterior cingulate cortex, primary somatosensory cortex, and supplementary motor cortex, which may be explained by an analogous decrease in pain ratings. Nonpainful stimulation activated similar brain regions to painful stimulation, but with greater variability in signal strength and regions of activation between scans. Painful stimulation of the esophagus produces robust activation in many brain regions. A decrease in subjective perception of pain and brain activity from the first to the final scan suggests that serial brain imaging studies may be affected by habituation. These findings indicate that for brain imaging studies that require serial scanning, development of experimental paradigms that control for the effect of habituation is necessary.

pain; fMRI; test-retest reliability; brain imaging; habituation

FUNCTIONAL MAGNETIC RESONANCE IMAGING (fMRI) is used extensively to study the cerebral correlates of somatic and visceral sensation (3, 9, 10, 27, 33, 38, 54, 55, 58, 59, 63, 64). Studies involving visceral stimulation have identified the neural correlates of painful and nonpainful sensation arising from different gut organs (2, 3, 9, 27, 33, 37, 38, 42). These studies have identified a network of brain regions involved in the processing of sensory [primary and secondary somatosensory cortex (SI/SII), insula]; cognitive [anterior cingulate cortex (ACC) (BA24; BA represents Brodmann area), dorsolateral prefrontal cortex (DLPFC)]; and emotional aspects [ACC (BA32), anterior insula, amygdala] of pain very similar to those identified in response to somatic pain (12, 13, 19, 53–55, 63, 64). This network is commonly known as the "pain neuro-matrix" (18, 54, 64).

Previous studies employing fMRI to investigate sensory, cognitive/emotional, or treatment effects on pain rely on observing between-scan or between-session differences that are attributed to changes in the experimental paradigm, for example one session under drug modulation and one session placebo (44). However, changes occurring in brain activity between sessions can be attributed to many other factors including nonsystematic variations in the scanner's acquisition characteristics, variations in head orientation, movement, and psychophysiological effects such as the level of arousal that can vary from session to session (26, 31, 39, 41, 50, 60, 67). The latter is a particularly important consideration when investigating pain processing, which can be influenced by cognitive and emotional factors such as level of arousal/attention (25, 64) and state anxiety (54) that can change from session to session. It has also been well documented that responses to sensory stimulation show considerable habituation over time, leading to a reduction in functional brain activity (39, 45). As a result it is currently unclear how generalizable single session results are following visceral stimulation.

A recent review on brain imaging of visceral sensation suggests that interpretation of studies is hindered by the fact that normal variability and reproducibility of brain processing following visceral stimulation has yet to be addressed (28). Such a test-retest study may be valuable in interpreting and generalizing between session observations, as well as providing important information for future studies investigating effects of treatment or disease progression in patients and control subjects.

By using an established model of visceral pain involving mechanical stimulation of the esophagus (3) and a standardized method for determining varying intensities of esophageal stimulation (29), the aim of this study was to investigate the between session reproducibility of the neural correlates of four intensities of visceral stimulation across three sessions to delineate the most robust region(s) of activation for future implementation in brain imaging research.


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

Nine healthy volunteers were recruited. However, two volunteers withdrew from the study before the final session, leaving seven healthy volunteers (6 men, mean age 22.7 yr, range 20–25 yr) who participated in the study. All subjects gave informed, written consent before intubation and scanning. Each subject was scanned on three occasions, resulting in 21 separate scanning observations in total. The study was approved by the local ethics committee for research (Institute of Psychiatry Ethical Committee reference 177/01).

Esophageal Stimulation

A standard manometry catheter (3-mm-diameter tube) to which a 2-cm-long silicone balloon was attached, was passed transnasally into the distal esophagus (positioned 35 cm from the nostril). The tube was then connected to a MRI-compatible, purpose-built pump (Medical Physics Department, Hope Hospital, Salford, UK) capable of rapidly distending the balloon to varying intensities (maximum flow rate 200 ml/s, rise time to maximum balloon inflation 165 ms for any given pressure, which ranged from 0 to 35 psi, frequency of stimulus 0.3 Hz). The pressure of the air used to inflate the balloon was varied to produce four quantifiable intensities of esophageal sensation. Each intensity was achieved quantitatively by obtaining a percentage of the difference between sensory threshold (ST) and pain threshold (PT) as described by Hobson and colleagues (29) before each scanning session. In brief, ST was quantified as 0% and PT as 100%. Stimulation was then performed at 25, 50, 75, and 100% of the difference between ST and PT.

Protocol

Volunteers attended three sessions (mean time interval between sessions, 4 ± 1 wk). Session 1 served as the baseline. In each of the three sessions, four separate functional imaging experiments were carried out, each incorporating one of four intensities. The order of presentation of conditions was pseudo-randomized across subjects for each session to avoid any effects of order, resulting in 21 randomized sessions. During each experiment a 30-s epoch of stimulation (10 stimuli; 1 distension every 3 s), was followed by a 30-s epoch control period (no stimulation), this sequence was repeated five times. An electronic visual analog scale (VAS) was presented after each epoch to measure the subjective perception of the stimulus (0 = no sensation, 5 = discomfort, 10 = extreme pain).

Functional Magnetic Resonance Imaging

fMRI was performed using a GE Signa 1.5-T neuro-optimized magnetic resonance system (General Electric, Milwaukee, WI) based at the Eric Buyers Magnetic Resonance Imaging Suite, Maudsley Hospital, London. A quadrature birdcage head coil was used for radio frequency transmission and reception. Head movement was restricted to a minimum by the use of foam padding within the head coil. While inside the scanner, subjects could view a screen on which an electronic version of a VAS was projected. A purpose-built button box was placed in the right hand of each subject to allow the intensity of esophageal stimulus to be rated, using the electronic VAS, after each epoch of stimulation/rest.

Structural acquisition. A gradient echo structural scan for subsequent coregistration (43 x 3 mm slices, 0.3 interslice gap, echo time 40 ms, repetition time 3,000 ms, flip angle 90°, matrix 1282, field of view 240 mm, voxel size 1.875 x 1.875 mm) was acquired in each volunteer before the experiment commenced.

Functional acquisition. A total of 122 T2* weighted images per slice (16 x 7-mm slices, 0.7 interslice gap, echo time 40 ms, repetition time 3,000 ms, flip angle 90°, matrix 642, field of view 240 mm, voxel size 3.75 x 3.75 mm), depicting blood oxygen level-dependent contrast (49) were collected over a 6-min and 6-s period of continuous acquisition, during which subjects received phasic distensions to the esophagus. This procedure was performed on four occasions to collect data for each of the four intensities of esophageal distension.

Generic Brain Activation Mapping

Data were processed to remove low-frequency signal changes (<1/4 of the alternation frequency between the two experimental conditions in order not to remove experimental responses) by use of a wavelet-based band-pass filter and then realigned to an average image computed across the whole time series to minimize the effect of motion-related artifacts (16). The data were then smoothed by using a 7.2-mm full width half maximum Gaussian filter to improve local signal-to-noise ratio. The responses at each voxel were analyzed by regressing the corrected time-series data on a linear model produced by convolving each contrast vector with two Poisson functions parameterizing hemodynamic delays of 4 and 8 s (15). Following least squares fitting of this model, a goodness of fit statistic composed of the ratio of model to residual sum of squares quotient (SSQ) ratio was calculated for each contrast (24). The distribution of the same statistics under the null hypothesis of no experimental effect was then calculated by wavelet-based resampling of the time-series at each voxel and refitting the models to the resampled data (15). An experimentally derived null distribution of the goodness of fit statistic was then derived by following this procedure 10 times at each intracerebral voxel and combining the resulting data. This method has been shown to give excellent control of nominal type I error rates in fMRI data from a variety of scanners (15). Activations for any contrast at any required P value can then be determined by obtaining the appropriate critical values from the null distribution (14). Generic group activation maps were constructed by mapping the observed and randomized test statistics for each individual into the standard stereotactic space of Talairach and Tournoux (61) and computing and testing median activation maps as previously described (11).

ANOVA

To compare responses in different sessions, an ANOVA model was fitted to the SSQ data, where SSQ ratio at each intracerebral voxel as beta0 + beta1Gi + ei, where beta0 is the intercept, beta1 the size of the intersession difference in response, Gi the element of the contrast matrix G for individual i (e.g., –1 or 1), and ei is the residual error after model fitting for individual i.

The null hypothesis was tested by comparing coefficient beta1 to critical values of its nonparametrically obtained null distribution (16). Critical values for a two-tailed test of size {alpha} (alpha can be any desired type I error rate for the test) are the 100*({alpha}/2)th and 100*(1–{alpha}/2)th percentile values of this distribution. This ANOVA model delineates the between-group differences in brain activation maps with the significance level of P = 0.01 or better. In addition, ANOVA was used to investigate differences in the data further by linear and quadratic trend analysis. Maps of the ratios of the model to residual sum of squares (SSQ ratio) were calculated for each of the four stimulation levels for each individual over three sessions and transformed into standard space. These standard space maps were then analyzed by fitting orthogonal linear and quadratic trends at each voxel (orthogonal polynomial trend analysis). Linear trends and quadratic trends of cortical activation were investigated. Null distributions of each trend were constructed by systematic permutation of the data at each voxel and the voxelwise probability of each trend was calculated with reference to these distributions (24).

To find the direction of the trend, a standardized power of response (SSQ) for each subject was extracted from each cluster showing a trend. To determine the effect of experimental condition (i.e., intensity of stimulation or scan session) on the intensity of activation within each of the chosen brain regions, statistical comparisons of SSQs in each region for all subjects were made using repeated-measures ANOVAs and post hoc matched-pairs t-tests. All tests were corrected for multiple comparisons.

Conjunction Analysis

To highlight robust regions of activation across three sessions, conjunction analysis was carried out. By using each volunteer's activation maps, conjunction analysis localizes regions where all subjects demonstrated brain activation at a minimum chosen level over several conditions. In this case the analysis was used to highlight regions that were reproducibly activated in scanning sessions 1, 2, and 3.

Behavioral Data

Data were tested for differences, effect of intensity of stimulation, and effect of scan session on VAS ratings by a Friedman test and post hoc Dunn's multiple-comparison test.

Definition of Terms

Sensory threshold is the point at which the subject first perceived a sensation in the esophagus, obtained by increasing the air pressure in the balloon at increments of 1 psi until the subject reported a sensation in the esophagus. Pain threshold is the point when the stimulus was first reported as painful, obtained by increasing the air pressure in the balloon at increments of 1 psi until the subject reported pain.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Behavioral Data from Session 1

All subjects tolerated the study well. Mean VAS scores increased progressively with increasing stimulation intensities [{chi}2 = 10.9, degrees of freedom (df) 3, P = 0.001, mean ± SE VAS; 25% = 3 ± 0.8, 50% = 3.68 ± 0.9, 75% = 5.6 ± 0.7, 100% = 7.3 ± 0.4].

Group Brain Activation From Session 1 (Baseline Scan)

25% Intensity of esophageal stimulation. A group analysis of data following 25% intensity of stimulation during session 1 (as can be seen in Table 1 showed significant (P = 0.001) bilateral activation of the superior temporal gyrus (STG), postcentral gyrus (SI), and insula cortex. Activation was also observed in the ACC (BA24), posterior cingulate (BA23, BA31), precentral gyrus (motor cortex), inferior frontal gyrus (BA47, BA44), middle frontal gyrus on the border of BA46/9 (dorsolateral prefrontal cortex), and medial frontal gyrus (premotor cortex and SMA, BA6).


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  		Table 1. Summary of group brain activation following nonpainful esophageal stimulation (25% intensity) during session 1

 
50% Intensity of esophageal stimulation. Group data following stimulation at this intensity during session 1 (Table 2) resulted in activation comparable to regions seen at 25% intensity, with the exception of the ACC and additional activation in the superior frontal gyrus (BA8), which was not apparent during 25% (P = 0.001).


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  		Table 2. Summary of group brain activation following nonpainful esophageal stimulation (50% intensity) during session 1

 
75% Intensity of esophageal stimulation. Stimulation at this intensity during session 1 resulted in a very similar pattern to that seen during 25 and 50% intensity, with additional activation (P = 0.001, see Table 3) found bilaterally in the SII, which was not seen following 25 or 50% intensities.


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  		Table 3. Summary of group brain activation following nonpainful esophageal stimulation (75% intensity) during session 1

 
100% Intensity of esophageal stimulation. Stimulation at the pain threshold level (session 1) resulted in a similar pattern to that seen during 75% intensity of stimulation (see Table 4, P = 0.001). In addition, activation was also seen in the thalamus, which was not present during any other condition. See Fig. 1 for a summary of brain activations throughout all conditions.


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  		Table 4. Summary of group brain activation following painful esophageal stimulation (100% intensity) during session 1

 

Figure 1
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  		Fig. 1. Summary of group brain activity during session 1 for each stimulation level (25, 50, 75, and 100%). Representative axial slices show the effects of stimulation intensity (100%, painful to 25%, nonpainful) on extent of brain activation in the insula (8 mm), primary and second somatic sensory cortexes (SI/SII; 16 mm), and anterior cingulate cortex (ACC; 42 mm).

 
Trend Analysis

As can be seen in Fig. 2, the magnitude of bilateral activation in the ACC (BA24) and SI, increased significantly (P < 0.05) with increasing stimulation intensities during session 1. A subanalysis of this interaction revealed no significant differences in strength of activity between right and left SI (P > 0.05). However, a significant difference was identified between the right and left ACC whereby right ACC activity was significantly greater than left ACC activity during painful stimulation (P < 0.05, t = 2.76).


Figure 2
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  		Fig. 2. Trend analysis of group brain activity for each stimulation level (25, 50, 75, and 100%) during session 1. A: summary of mean sum of squares (SSQ) scores for each intensity of esophageal stimulation in the left ACC [Talaraich and Tournoux (61) coordinates (tal) X = –5.4, Y = 5.5, Z = 31.3), and the right ACC (tal X = 3.3], Y = 2.27, Z = 42.3). A significant linear trend was found at P < 0.006 (left ACC 25% = –0.07, 50% = 0.014, 75% = 0.045, 100% = 0.061) and P ≤ 0.035 (right ACC 25% = 0.027, 50% = 0.027, 75% = 0.096, 100% = 0.144), both Bonferroni corrected. B: summary of mean SSQ scores for each intensity of esophageal stimulation in the left SI (tal X = –55.1, Y = –21.1, Z = 14.8) and the right SI (tal X = 59.5, Y = –18.5, Z = 20.3). A significant linear trend was found at P < 0.015 (left SI 25% = –0.019, 50% = 0. 007, 75% = 0.078, 100% = 0.110) and P ≤ 0.023 (right SI 25% = 0.023, 50% = 0.026, 75% = 0.079, 100% = 0.125), both Bonferroni corrected.

 
Test-retest reliability. Following observations made from the baseline scan (session 1), 100% (painful) and 50% intensity (nonpainful) were chosen as two representative stimulation intensities to investigate the reproducibility of nonpainful and painful stimulation over the three scanning sessions. The 50% intensity was chosen over 25% because previous data suggests this level should be used in studies involving nonpainful stimuli as it produces more robust, reproducible activation of the afferent pathway that is less susceptible to the effects of habituation (29).

Nonpainful stimulation. There were no significant changes in balloon pressure required to induce nonpainful stimulation across the three scanning sessions [mean ± SE balloon pressure for 50% intensity (psi); scan 1 = 8 ± 0.4, scan 2 = 7 ± 1, scan 3 = 9 ± 1, F statistic 0.034, df 2, P > 0.05].

There was no significant effect of scan session on VAS ratings for a nonpainful stimulus ({chi}2 = 3.4, df 2, P = 0.1). No significant differences in VAS responses between the three sessions were found (df 6, P > 0.05, mean ± SE VAS; scan 1 = 3.6 ± 0.8, scan 2 = 4.5 ± 0.7, scan 3 = 3.4 ± 0.6).

Conjunction analysis revealed reproducible brain activation across three scanning sessions, in the insula cortex (bilateral), SI (left), SII, SMA (BA6), STG (bilateral), precentral gyrus (motor cortex), and right DLPFC. Other regions including the posterior cingulate gyrus and right SI were not significantly activated during each scanning session. For a summary of brain activity following nonpainful stimulation over three scanning sessions, shown using conjunction analysis, please see Table 5.


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  		Table 5. Results of conjunction analysis showing reproducibility of brain regions over 3 scanning sessions (nonpainful)

 
Although the majority of brain regions identified in session 1 were shown to be robust by conjunction analysis, an ANOVA revealed variability in the strength of activation bilaterally in the STG, SI, precentral gyrus, insula, and left inferior frontal gyrus (BA44). Further analysis demonstrated a significant (P < 0.05) positive quadratic trend, whereby intensity of brain activity increased significantly during scan 2, in the SI, inferior frontal gyrus, and STG.

Painful stimulation. There were no significant changes in balloon pressure required to induce pain across the three scanning sessions [mean balloon pressure for PT (psi) ± SE; scan 1 = 23 ± 1.9, scan 2 = 24 ± 2.5, scan 3 = 26 ± 1.8, F statistic 1.57, df 2, P > 0.05]. Despite this, analysis of pain ratings for 100% intensity of stimulation revealed a significant effect ({chi}2 = 6, df 2, P < 0.05) of scan order on mean pain ratings (mean ± SE VAS; scan 1 = 7.3 ± 0.3, scan 2 = 6.1 ± 0.9, scan 3 = 4.9 ± 0.8). There was a significant decrease in pain ratings from the first scanning occasion to the third scanning occasion (df 6, P < 0.05).

Conjunction analysis of brain activity following painful stimulation revealed reproducible bilateral brain activation across the three scanning sessions in the insula cortex, thalamus, SI, SII, ACC, SMA (BA6), STG, bilateral precentral gyrus (motor cortex), and the DLPFC; see Table 6 for a summary of findings.


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  		Table 6. Results of conjunction analysis showing reproducibility of brain regions over 3 scanning sessions (painful)

 
Although brain regions identified were shown to be consistently activated over three sessions, an ANOVA revealed variability in the strength of activation in the SMA (BA6), SI, and ACC (BA24). Further analysis of regions of variation showed a significant (P = 0.05) decrease in strength of activation across the three scans: SMA (BA6), ACC (BA24), and SI; see Fig. 3.


Figure 3
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  		Fig. 3. ANOVA on brain activity following painful stimulation during sessions 1, 2, and 3 shows the effect of serial scanning sessions on brain activation (SSQ, y-axis). Activation decreases in the supplementary motor cortex (SMA), ACC, and SI from session 1 to session 3, despite the fact that stimulation volumes remain constant.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Effect of Stimulus Intensity

The results of this study demonstrate that visceral stimulation results in a complex pattern of brain activation which is similar across varying levels of stimulation. The intensity of mid-ACC (BA24) activation increases linearly with an increase in perceived intensity of stimulation. This observation has also been reported in a previous fMRI study (55) in which intensity of somatic heat stimulation was found to correlate with intensity of activation in the ACC. Porro et al. (55) suggest that this provides evidence for the importance of the anterior cingulate in the encoding of stimulation intensity. Other studies have produced similar findings (8, 9, 12). The linear relationship seen in the present study could therefore be explained by the encoding of stimulus intensity, as Porro et al. suggest. However, the increase of activation could also be due to an increase in attention devoted toward the stimulus as intensity is increased, supporting the proposed role of this region of the anterior cingulate in attention (23, 66).

In addition to the ACC's proposed role in attention and sensory encoding, the midcingulate gyrus (BA24) has connections with the motor cortex and has been shown to be involved in response decisions and preparatory motor functions (66). It is therefore equally plausible to suggest that the linear relationship between perceived intensity of stimulus and ACC activity may be explained by an increase in preparatory motor functions, because an increase in stimulation intensity could cause an increase in avoidance motor response. Finally, a recent study (63) has shown that activation in the ACC (BA24) was associated with an increase in unpleasantness of the stimulus, suggesting the ACC may be involved in perception of the affective component of a stimulus.

The fact the right ACC was significantly more active than the left ACC during painful esophageal stimulation possibly reflects previous suggestions that the right hemisphere is more involved in mediating cognitive and attentional aspects of stimuli than the left hemisphere (6, 20). Furthermore, it has also been suggested that sympathetic nervous system activity is represented in the right hemisphere of the brain (21). In the present study, it is likely that cognitive, emotional, and sympathetic activity would be influenced at the most threatening level of stimulation, which could explain why activity of the right ACC is significantly different at the most painful level and not those levels below pain threshold.

Activation of the SI is commonly associated with processing sensory-discriminative aspects, such intensity and location, of somatic (5, 32) and visceral sensations (3). More recently, some studies and reviews have suggested the SI may be also important in processing affective (30, 56, 57) and cognitive dimensions of pain (17). Although the exact role of SI in the processing of visceral sensations remains unclear, our results suggest that the SI region may be involved in the encoding of stimulus intensity, as the intensity of cerebral activity increased linearly with perceived intensity of stimulation. Similar observations relating to intensity coding in the SI have been reported following somatic stimulation (17, 55, 62, 65).

Activation of the anterior insula cortex bilaterally across all intensities is a finding that has been consistently reported in fMRI studies on visceral stimulation (3, 4, 9, 10). The insula cortex is recognized as an important visceral sensory and motor area (1). Interestingly, it has recently been suggested that the insula encodes intensity of thermal sensation (19, 52). However, data from the present study show that insula activity is consistent, regardless of stimulation level, suggesting that this region does not encode the intensity of visceral sensation. It may be more likely that the role of the anterior insula is in processing emotional responses to visceral sensation, as some previous studies suggest (51, 53).

Reproducibility of Brain Activity

The main objective of this study was to assess whether fMRI can generate a robust and reliable measure of the cerebral correlates associated with painful and nonpainful esophageal stimulation. Our results show that painful visceral stimulation results in a network of brain activation commonly associated with processing pain that is reproducible across three scanning occasions. Following nonpainful stimulation, activation occurs in regions similar to those seen in response to painful stimulation but with less consistency.

During painful stimulation the behavioral data suggest that volunteers habituated to the stimulus over three scanning sessions despite the level of esophageal distension remaining constant. During the first session the mean rating for 100% stimulation was within the painful range; by the last scan, however, the mean VAS rating for this intensity was in the range of discomfort. This is an interesting point worthy of some discussion and clarification. Stimulation levels were titrated identically before each scanning session by using thresholds (ST and PT) rather than a set level or score on a VAS. It may be that differences seen in the pain ratings can be explained by a disparity between methods (thresholding) used to establish stimulation levels and measures used to assess subjective perception of pain (VAS). In this case, although the balloon pressure required to induce pain remained constant over time, the subjective perception of the same level of stimulation changed. This observation could be explained by subjects learning more about the rating scale and the pain experience. Such learning may alter interpretation of the spectrum of visceral sensation (from no sensation to extreme pain), resulting in a change in subjective perception of pain and therefore a change in visual analog scores. In essence this is an example of volunteers habituating to the stimulus and the experimental situation.

Before the study commenced, the main source of variability was expected to stem from the methodological aspects of fMRI. However, our results suggest that the perceptual response to repetitive phasic esophageal stimulation may be a major source of variability in brain activation across the three scanning occasions.

Despite the decrease in the perception of the painful stimulus across the three scans, the majority of cerebral regions activated during the first scan proved to be robustly activated across all scanning sessions. For instance, bilateral insula, thalamus, SI, SII, ACC (BA24/32), SMA, STG, motor cortex, and right dorsolateral prefrontal cortex were all consistently activated. Although activation of the mid/anterior cingulate (BA24), SMA, and SI was extremely robust over the three scans, there was a significant linear decrease in activity from the first scan to the last in these areas. This observation is consistent with the notion that the perception of the stimulus decreased over the three sessions, most probably owing to habituation to the stimulus (40, 48).

In comparison to painful stimulation, many of the cerebral regions activated during nonpainful stimulation were more variable over the three scanning sessions. For instance, variations in activation (such as the increase in SI, STG, and inferior frontal gyrus activity during scan 2) cannot be explained by changes in the perception of stimulus intensity, because there were no significant changes in perception over the three sessions. The strength of activation in the insula was significantly variable without demonstrating any trend, whereas the right SI, posterior cingulate (BA31, BA30), and superior frontal gyrus were not consistently activated over the three scanning sessions.

It is possible that the variation in brain activity following nonpainful esophageal stimulation may be due to weaknesses in the method of fMRI, such as differences in magnetic field homogeneity, head orientation, and subject movement between scanning sessions. However, the high reproducibility of fMRI activation over three sessions during painful sensation suggests that such differences cannot be explained by such systematic errors.

Our results are in agreement with Hobson and colleagues (29), who demonstrated that reproducible cortical evoked potentials in response to esophageal stimulation could only be recorded at painful levels, nonpainful intensities produced less consistent cortical evoked potentials.

The mechanisms that make fMRI activation to nonpainful sensation less reproducible than painful sensation are not clear. However, it is likely that variation over the three scanning sessions is linked to levels of arousal and attention. Pain is considered threatening by subjects and therefore would be accompanied by more persistent level of higher arousal and vigilance toward the noxious stimulus. This high level of arousal and attentiveness would result in an increase in neural activity, particularly in limbic regions such as the anterior cingulate (BA24), and also sensory regions such as SI (43). Although the perception of stimulus intensity does decrease throughout the three scanning sessions, the perception is always within the range of discomfort and would therefore remain threatening across all scanning occasions. Thus attention and arousal levels are less likely to influence brain activation during pain than nonpainful stimulation, because this level is permanently uncomfortable and threatening, resulting in a permanent state of arousal and attentiveness toward the stimulus.

The findings of the present experiment are similar to those recently published in a positron emission tomography study examining longitudinal changes in perceptual and brain activation response to visceral stimuli in 12 irritable bowel syndrome patients (47).

Over two positron emission tomography sessions, Naliboff and colleagues (47) found that ratings of pain intensity decreased significantly during the second session, as did brain activity in the ACC and dorsal brain stem, suggesting that patients habituate in a similar way to the healthy volunteers in the present study. Interestingly, Naliboff et al. point out that patients showed decreases only in brain regions thought to be involved in arousal and vigilance but not in those regions processing visceral afferent input or the sensory aspects of visceral sensation. In the present study, however, it is clear that healthy volunteers show a habituation across three sessions in the SI, a region primarily believed to be involved in sensory discrimination. Therefore, by assessing the data from both this and the study by Naliboff et al., it could be suggested that whereas visceral afferents in the healthy population desensitize to repetitive stimulation (a normal response), visceral afferents in an irritable bowel syndrome patient population do not, a phenomenon that may contribute to the etiology of the condition.

Although the present study had similarities with the Naliboff experiment (47), it also had some fundamental methodological differences. The study by Naliboff et al. involved two imaging sessions (12 months apart) instead of three, and the visceral stimulus employed was a tonic rectal rather than a phasic esophageal distension as used in our study. Furthermore, the two studies employed different brain imaging techniques that may produce different findings relevant to each imaging modality. Despite these methodological differences, perhaps the most fundamental issue is that in the 12 months between each imaging point patients attended several more visits without brain scanning during which they were subjected to further experimental visceral pain. In contrast, our study combined serial scanning with exposure to experimental pain on each occasion.

Limitations

Following the withdrawal of two volunteers, one limitation of this study is the relatively small number of subjects who completed the study. The decision to continue with analysis and interpretation on seven subjects was based on several reasons: 1) Brain activity reported in the present experiment is analogous to previous studies that demonstrated that between six to eight volunteers provide adequate statistical power to produce a network of brain activity consistent with that of pain processing (3, 25, 53, 68). 2) It is also important to note the consistency in activation across four intensities of stimulation and three scanning sessions. 3) In addition to this, the behavioral data demonstrated that seven subjects are sufficient to detect significant differences even when using stringent nonparametric, repeated-measures multiple-comparison tests.

Because the sample consisted of both men and women it is not clear to what extent gender differences may have contributed to the results. However, it is important to note that although gender differences in cortical activation following visceral stimulation have been shown (35, 46) the evidence is not conclusive and an agreement on this subject has yet to be achieved (7, 22, 34). Further research is required to clarify this issue.

It may be that the effects of cognitive and emotional influences on reproducibility such as those suggested in the present study could be reduced by including a placebo or sham stimulus during the rest condition. This may help control for the possible confounding effects of the pain experience such as attention and anticipation. It is possible this could be achieved by the use of subliminal stimulation, which has been shown to contribute to the neuro-pain matrix (36). However, it should be noted that reproducibility of brain activation to subliminal stimulation requires further investigation.

It is of course important to note that any observations drawn from this study are influenced by the acquisition parameters employed. That is to say that the slice thickness, orientation, image repetition, and echo times, among other parameters, can all influence the data. For example, data acquired by using a more limited region of interest approach (selecting slices only in a specific region of the brain) with a small voxel size may provide more detailed information at higher temporal resolution for a given region. Nevertheless, the data and observations drawn from the present study are relatively standard for whole brain studies and do show widespread significance while also providing important information on the central response to visceral pain over time.

In conclusion, robust activation patterns in response to esophageal stimulation can be obtained at both painful and nonpainful intensities. However, brain activation to nonpainful stimulation is more variable between scans, suggesting that a nonpainful stimulation level is less salient and therefore more susceptible to changes in levels of attention, arousal, and anxiety. This phenomenon may influence neural activity and therefore have an effect on reproducibility, as well as having considerable implications for future functional imaging studies requiring serial assessment. Such implications could include altering the protocol of a study to include procedures that may help reduce anxiety and arousal during the first session. For example, the confounding effects of anxiety and arousal during the first scanning session might be reduced by including a screening session (several days before the first scanning session) involving a "mock" MRI scan, esophageal intubation and stimulation, and a practice run of the experimental protocol. This approach has could be achieved by the use of a mock MRI scanner, which would reduce the financial and logistical impact of including an extra screening and training session in a fully functional MRI environment. This will help increase familiarity of the experimental surroundings and procedures and may help to reduce high anxiety levels during the first scan that may affect reproducibility. In a similar way, a mock scanner could also specifically be used to habituate volunteers before a multisession study begins; this would eliminate the confounding effects of habituation. In addition to this attention to the stimulus could be monitored or controlled by a distraction or attention task.

Both painful and nonpainful stimulation levels are susceptible to changes in perception of stimulus and alterations in signal strength between scans. This is an important consideration when interpreting changes in strength of activation between scan sessions. Such changes may be an effect of a change in the experimental variable between sessions but could equally be a consequence of scanning individuals over a number of sessions.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. Coen, Neuroimaging Research Group, PO89, Institute of Psychiatry, Kings College London, De Crespigny Park, London, SE5 8AF, UK (e-mail: s.coen{at}iop.kcl.ac.uk)

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.


   REFERENCES
TOP
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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