BASIC AND TRANSLATIONAL ALIMENTARY TRACT. Neuroticism Influences Brain Activity During the Experience of Visceral Pain

Transcription

1 GASTROENTEROLOGY 2011;141: TRANSLATIONAL ALIMENTARY TRACT Neuroticism Influences Brain Activity During the Experience of Visceral Pain STEVEN J. COEN,* MICHIKO KANO,*, ADAM D. FARMER,* VEENA KUMARI, VINCENT GIAMPIETRO, MICK BRAMMER, STEVEN C. R. WILLIAMS, and QASIM AZIZ* *Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England; Behavioral Medicine, Tohoku University, Sendai, Japan; and Departments of Psychology and Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, King s College London, London, England BACKGROUND & AIMS: One particularly important individual dynamic known to influence the experience of pain is neuroticism, of which little is known about in visceral pain research. Our aim was to study the relationship between neuroticism, psychophysiologic response, and brain processing of visceral pain. METHODS: Thirty-one healthy volunteers (15 male; age range, years) participated in the study. The Eysenck Personality Questionnaire was used to assess neuroticism. Skin conductance level, pain ratings, and functional magnetic resonance imaging data were acquired during anticipation of pain and painful esophageal distention. The effect of neuroticism was assessed using correlation analysis. RESULTS: There was a wide spread of neuroticism scores (range, 0 22) but no influence of neuroticism on skin conductance level and pain tolerance or pain ratings. However, a positive correlation between brain activity and neuroticism during anticipation was found in regions associated with emotional and cognitive pain processing, including the parahippocampus, insula, thalamus, and anterior cingulate cortex. These regions showed a negative correlation with neuroticism during pain (P.001). CONCLUSIONS: This study provides novel data suggesting higher neuroticism is associated with engagement of brain regions responsible for emotional and cognitive appraisal during anticipation of pain but reduced activity in these regions during pain. This may reflect a maladaptive mechanism in those with higher neuroticism that promotes overarousal during anticipation and avoidance coping during pain. Keywords: Pain; fmri; Human Brain; Neuroticism. Knowledge of human brain-gut interactions in health and disease, with particular reference to visceral pain, has progressed substantially since the advent of neuroimaging techniques such as functional magnetic resonance imaging (fmri) and positron emission tomography. Early studies focused on addressing the sensory component of visceral pain by studying viscerotropic representation of painful and nonpainful visceral stimulation as well as investigating the relationship between intensity of pain and brain activity. 1,2 Given the psychological nature of the pain experience, the studies that followed focused on how cognitive and affective factors modulate pain. 3 6 To date, these investigations have used groups of volunteers. However, there is still a paucity of data on how individual differences modulate perceptual and brain responses to visceral pain. This knowledge gap was highlighted in a recent Rome working team report that cited interindividual variability as a key limiting factor in the development of brain imaging as a tool or biomarker for studying visceral pain. 7 One particularly important interindividual factor that is known to affect response to negative emotional stimuli, such as visceral pain, is the personality trait of neuroticism. Neuroticism is defined as a tendency to experience negative emotions, particularly in stressful situations. 8 High neuroticism is associated with increased negative affect and anxiety, as well as with increased autonomic and neural responses to negative stimuli. 9,10 Importantly, neuroticism has consistently been implicated as an important risk factor in the development of chronic somatic and visceral pain following injury 11 or surgery. 12 Neuroticism is higher in patients with irritable bowel syndrome (IBS) 13 and is a risk factor for chronic unexplained pain in IBS. 14 Recent data have also emerged that show higher neuroticism is associated with decreased pain tolerance and a predominately parasympathetic brainstem-mediated activity during painful visceral stimulation. 15 Others have shown that the influence of neuroticism is not simply limited to the painful event but also to the anticipation of pain. 16 Eysenck suggested the neurobiological substrate of neuroticism is localized to the limbic system and hypothalamus, or the the visceral brain system ; several of these regions are involved in pain processing. 17 Despite this, relatively few neuroimaging studies have probed the relationship between neuroticism, pain, and the brain. Using electroencephalography, Pauli et al showed that pain sensitivity is associated with increased right hemisphere activity and with high neuroticism. 18 Vossen et al Abbreviations used in this paper: ACC, anterior cingulate cortex; fmri, functional magnetic resonance imaging; IBS, irritable bowel syndrome; PCC, posterior cingulate cortex; PTT, pain toleration threshold; SCL, skin conductance level; VAS, visual analog scale by the AGA Institute /$36.00 doi: /j.gastro

2 910 COEN ET AL GASTROENTEROLOGY Vol. 141, No. 3 showed that higher neuroticism is associated with higher amplitudes of event-related cortical potentials to electrical pain. 19 The influence of neuroticism on brain response to the threat of pain (anticipatory fear) has also been investigated using fmri by Kumari et al, who found neuroticism correlated negatively with brain activity in many regions known to be involved in the processing of visceral pain, including the thalamus, anterior cingulate cortex (ACC), and hippocampus. 20 Importantly, the brain imaging studies listed previously investigated only somatic pain or threat of somatic pain, highlighting the need for a more extensive study on the relationship between neuroticism and visceral pain. In summary, there is a plethora of evidence to suggest neuroticism has a significant influence on the visceral pain experience and that differences in neuroticism may affect, or be driven by, the brain response and processing during anticipation and pain itself. However, as yet there has not been a study to assess the extent to which the brain response to visceral pain and anticipation of visceral pain is influenced by neuroticism. Our aim was to address this knowledge gap. Subjects and Methods Volunteers Thirty-one healthy volunteers (15 male; mean age, 30 years; range, years; all right-handed) participated in the study after providing informed written consent and approval was obtained from the local ethics committee (reference CREC/ 07/08-7). All volunteers were screened for a history of psychiatric or gastrointestinal symptoms and were not taking any medications. Subjects completed the Eysenck Personality Questionnaire-Revised (EPQ-R) 21 to assess neuroticism level (neuroticism range, 0 24; higher scores represent higher neuroticism). Volunteers also completed the Spielberger State and Trait Anxiety (STAI) Questionnaire 22 to assess state (anxiety level on the day of scanning) and trait anxiety (STAI range, 20 80; higher scores represent higher anxiety). The questionnaires used are not screening tools but measures of a spectrum of anxiety and neuroticism traits, and therefore extremely high or low scores are not indicative of pathology. Both questionnaires were administered immediately before intubation and scanning. Esophageal Stimulation During fmri scanning, painful phasic esophageal stimulation (1-second duration) was delivered at pain toleration threshold by mechanical stimulation (balloon distention) of the distal esophagus as previously described. 4 The onset timing of each stimulus was achieved using customized computer software that was synchronized with scanner acquisition. Following intubation (per-nasal), the catheter (commercially available esophageal distention catheter; Sandhill Scientific, Oxford, England) was positioned so that the center of the balloon was in the distal esophagus (35 cm from the nose). Sensory threshold and pain toleration threshold (PTT) was measured in each volunteer. To determine sensory threshold and PTT, the volume of distention was increased in steps of 2-mL increments (from zero) until the volunteers first felt a sensation in the esophagus (sensory threshold) and then until the point at which they could no longer tolerate an increase in stimulus (PTT). The PTT level was measured for each volunteer immediately before positioning in the MRI scanner and used as the level of stimulation throughout the functional brain imaging scan. Experimental Task An event-related design was used. To measure anticipation of pain, we used visual cues (delivered by a program developed in conjunction with Jeff Dalton, Centre for Neuroimaging Sciences, Institute of Psychiatry, King s College London), the details of which were described to volunteers before scanning. The functional imaging scan consisted of 20 trials incorporating 60 events: 20 periods of anticipation, 20 painful esophageal distentions, and 20 null events (rest/baseline). Each trial commenced with the presentation of a visual warning cue (a yellow square) signaling a painful visceral stimulus was imminent (anticipation). The next event was a painful visceral stimulus lasting 1 second (pain), which was immediately followed by a second visual cue (a blue square) signaling a safe condition during which there was no risk of stimulation. Anticipation always preceded pain, but the timing (onset) of each condition (anticipation and pain) was pseudo-randomized and jittered to the repetition time (TR); the anticipation phase signaled the start of a new trial and lasted between 3 and 12 seconds, and the onset of pain therefore was randomized to commence between 3 and 12 seconds after the onset of a new trial while the safe period lasted between 28 and 35 seconds following pain. Because this was an event-related design, we did not model the entire safe period as the rest or control condition. Instead, the middle period of the safe phase included a null event (subjects viewing the rest cue) that served as the baseline or rest condition to which other conditions were compared. The onset of the null event was jittered and modeled as a 1-second event in the same way as the active conditions. The use of colored squares as cues was counterbalanced to avoid any possible confounding effects of color plus condition (pain or anticipation) pairing, such that half the volunteers received the blue square as a warning signal and yellow as safe while the others received the yellow square as a warning and blue as safe. The variable-onset timing of both experimental conditions (anticipation and pain) was pseudorandomized as described previously to increase the unpredictability of stimuli, thereby reducing the effects of habituation and increasing the efficacy of the anticipation period. 23 Subjective Perception of Pain A visual analog scale (VAS; 5-second duration) measuring the subjective perception of the stimulus (0 no sensation, 50 discomfort, 100 extreme pain) was randomized to appear between 9 and 15 seconds after each esophageal stimulation. Skin Conductance Level Skin conductance level (SCL) during anticipation, pain, and rest was measured throughout the experimental task by attaching silver/silver chloride electrodes to the middle phalange of the middle and index fingers of the left hand (SCL measured in microsiemens using a constant voltage method [0.5 V], signal digitized at 25-millisecond intervals [Contact Precision Instruments, Boston, MA]). fmri fmri data (T 2 *-weighted images) were collected on a General Electric (Milwaukee, WI) Signa Excite II 3.0 T scanner based at the Centre for Neuroimaging Sciences, Institute of Psychiatry, King s College London. Head movement was re-

3 September 2011 NEUROTICISM AND VISCERAL PAIN 911 stricted to a minimum by the use of foam padding within the head coil. While inside the scanner, participants could view a screen on which an electronic version of a VAS and the cuerelated colored squares were projected. To record subjective ratings of visceral sensation via VAS, an MRI-compatible button box was placed in the right hand of each participant so they could respond when the VAS was presented. Before the start of the fmri experiment, a high-resolution gradient echo structural scan (43 3 mm slices, 0.3 interslice gap, echo time (TE) 30 milliseconds, TR 3000 milliseconds, flip angle 90, matrix 128 2, in-plane voxel dimensions ) was acquired to be used for Talairach normalization. During fmri, a total of 480 T 2 *-weighted images per slice (40 3 mm slices, 0.3 interslice gap, TE 30 milliseconds, TR 2500 milliseconds, flip angle 80, matrix 64 2, total number of images per scan 19,200) depicting blood oxygen level dependent contrast were collected while participants underwent the experimental task. Statistical Analysis of fmri Data All MRI data were analyzed using XBAM ( an fmri analysis software package developed at the Institute of Psychiatry, King s College London, which implements permutation-based methods to minimize the number of assumptions used in making statistical inference. fmri data preprocessing, smoothing, and individual brain activation mapping were performed according to the method previously described. 4 Correlation Analysis In the first instance, correlation analysis was performed between the blood oxygen level dependent effect data for each individual and their neuroticism score. This proceeds by first choosing the statistical map (fmri response) corresponding to the particular experimental contrast of interest. The Pearson product moment correlation coefficient is then computed between the neuroticism score for each subject and the fmri responses at each voxel for each subject, yielding one correlation coefficient (r) per intracerebral voxel. To determine the significance of these correlation coefficients, the appropriate null distribution of r is computed robustly using data permutation. The order of the behavioral data is randomly permuted without replacement (ie, each data value occurs once, but the order is changed), breaking the association between individual behavioral data and their corresponding fmri responses. The correlation coefficient is then recomputed many times at each voxel and the resulting values of r combined over all voxels to produce a whole brain null distribution of r. The critical value of r for significance at any particular P value can then be obtained from this distribution after simply sorting it by value of r and selecting the appropriate point from the sorted distribution; for example, the critical value of r for a one-tailed test at a P value of.05 would be the value of r in the null distribution chosen such that 95% of all the null values of r lay below that point. Testing can then be extended to cluster level as described previously. The cluster probability under the null hypothesis can be chosen to set the level of expected type I error clusters at an acceptable level (eg, 1 per whole brain). Analysis of Psychophysical Data SCL amplitude to each stimulus event was analyzed using a custom-made software program, SC-ANALYZE (Neuroimaging Research, Institute of Psychiatry, London, England). SCL (in microsiemens) was defined as the maximum increase 1 to 4 seconds after onset of condition and therefore represents the maximum arousal to each stimulus. This time window is variable due to the uncertain characteristics of SCL response and has been previously validated. 24,25 Mean SCL level for each condition was calculated per individual and then averaged across the group to produce mean SCL for anticipation, pain, and rest. Repeated-measures analysis of variance with Bonferroni correction was used to examine differences in mean SCL during rest, anticipation, and pain. All correlation analysis, such as examining the relationship between neuroticism and PTT, was performed using Pearson s correlation coefficient test and partial correlation where necessary (ie, to correct for the effect of anxiety on brain responses). All behavioral data were processed using SPSS ( and GraphPad Prism (www. graphpad.com). Results Group Psychometric Data All 31 volunteers tolerated the study well. There was a wide range of neuroticism scores (mean, ; range, 0 22) with no significant difference between male and female subjects (mean neuroticism SEM; male, [range, 0 20]; female, [range, 1 20]; P.49, t 0.68, df 29). There was also a scope of state/trait anxiety scores across the group (mean state anxiety, [range, 20 41]; mean trait anxiety, [range, 20 58]). Group Physiologic Data All volunteers rated the esophageal stimulus as painful (mean VAS SEM, ). The mean balloon volume (in milliliters) to reach sensory threshold was and pain toleration threshold was Mean group SCL increased progressively from baseline to pain (mean SCL SEM at baseline , anticipation , and pain ; P.0001, F 70.7, R ). Post hoc tests showed that mean SCL during anticipation was significantly higher than baseline (P.001) and SCL during pain was significantly higher than anticipation (P.001). Group Brain Activity Brain activation during anticipation and painful stimulation. The neural correlates of painful visceral stimulation and anticipation have previously been well described in the literature 26 ; as such, the results of the present study will focus on the influence of neuroticism on brain responses during these conditions. A summary of brain regions showing a significant increase in activity during pain and anticipation can be found in Supplementary Table 1. Effect of Neuroticism Relationship between neuroticism and psychophysiologic response. There was no significant correlation between neuroticism and pain ratings (r 0.18, P.32), pain tolerance volume (r 0.18, P.31), or SCL response during pain (r 0.003, P.98) and anticipation of pain (r 0.01, P.93). However, there was a positive correlation between neuroticism and state

4 912 COEN ET AL GASTROENTEROLOGY Vol. 141, No. 3 Table 1. Summary of Brain Regions Showing a Correlation Between Neuroticism and Brain Activity During Anticipation of Visceral Pain Size P value R value X Y Z Side Brain region Clusters showing a positive correlation between brain activity during anticipation and neuroticism scores Right Putamen Right ACC (BA32) Left Secondary association area (SII) Right Thalamus Right Anterior insula Left Claustrum Right Parahippocampal gyrus Left Medial frontal gyrus (BA9) Right Medial frontal gyrus (BA8) Right Cerebellum (posterior) Left Thalamus Clusters showing a negative correlation between brain activity during anticipation and neuroticism scores Left Middle temporal gyrus (BA21) Left Superior temporal gyrus (BA22) Right Superior temporal gyrus (BA22) Left Cingulate cortex (BA31) Right Fusiform gyrus (BA37) Right Precuneus Right PCC (BA30) Left Angular gyrus Left Middle frontal gyrus (BA8) NOTE. Talairach and Tournoux coordinates are expressed in millimeters (x, y, z); size indicates number of voxels. The coordinates for each cluster represent points of maximum activation at the group level (highest median response in the cluster). Clusters are defined using cluster mass statistics and therefore do not have cluster size limitations. BA, Brodmann area. (r , P.01) and trait (r , P.001) anxiety. Relationship between neuroticism and brain activity during anticipation of pain. A significant positive correlation between brain activity during anticipation and neuroticism score was found in several brain regions, including the right parahippocampal gyrus, right insula, bilateral thalamus, and ACC (BA32). In contrast, a negative correlation between neuroticism and brain activity was evident in regions including bilateral superior temporal gyrus, precuneus, and posterior cingulate cortex (PCC). See Table 1 for a summary of all brain regions showing correlations and Figure 1 for representative plots. Relationship between neuroticism and brain activity during pain. During pain, there was a positive association between level of brain activity and neuroticism score in the right hemisphere in the insula, amygdala, primary somatosensory cortex (SI), and left hemisphere in the culmen and middle temporal gyrus. There was a negative correlation in several areas, including bilateral thalamus, parahippocampal gyrus and insula, right ACC (BA24), left putamen, and ventral ACC (BA32). See Table 2 for a summary of all brain regions showing correlations and Figure 1 for representative plots. Effect of anxiety. Because there was a relationship between anxiety and neuroticism, a partial correlation analysis was conducted to determine the relationship between neuroticism and brain activity when corrected for anxiety. This analysis showed that the correlation between neuroticism and brain activity is indeed mediated by neuroticism (ie, the correlations remained significant when anxiety was accounted for) with the exception of the positive correlation between neuroticism and brain activity in the cerebellum during anticipation (r 0.26, P.15), the SI (r 0.34, P.06) and middle temporal gyrus (r 0.29, P.12) during pain, and the negative correlation with neuroticism during pain in the superior frontal gyrus (r 0.26, P.16). Discussion To our knowledge, this is the first study to report a significant effect of neuroticism on brain processing during visceral pain stimulation and anticipation. The level of brain activity during anticipation and pain varied depending on neuroticism score in several brain regions previously shown to be involved in pain processing, including the mid-acc (BA24), perigenual ACC (BA32), insula, thalamus, inferior frontal gyrus, PCC, and supplementary motor area (SMA). Behavioral Findings There was an increase in SCL during anticipation compared with baseline. This reflects an increase in sympathetic activity during anticipation compared with baseline (safe period) and provides evidence that the study design was effective in eliciting an anticipatory response because volunteers showed increased autonomic arousal during this period. When the influence of neuroticism was examined, no significant correlation between SCL and neuroticism was

5 September 2011 NEUROTICISM AND VISCERAL PAIN 913 Figure 1. Representative graphical examples of correlations (positive, red; negative, blue) found between neuroticism and level of brain activity (SSQ) during (A) anticipation and (B) pain. This figure shows several brain regions, including the thalamus, parahippocampal gyrus, and ACC, where brain activity increases with higher neuroticism during anticipation but decreases during pain processing.

6 914 COEN ET AL GASTROENTEROLOGY Vol. 141, No. 3 Table 2. Summary of Brain Regions Showing a Correlation Between Neuroticism and Brain Activity During Visceral Pain Size P value R value X Y Z Side Brain region Clusters showing a positive correlation between brain activity during pain and neuroticism scores Left Culmen Right Posterior insula Right Amygdala Right Postcentral gyrus Left Middle temporal gyrus Clusters showing a negative correlation between brain activity during pain and neuroticism scores Right ACC (BA24) Right Thalamus Left Mid insula Right Parahippocampal gyrus Left Parahippocampal gyrus Left Thalamus Right Superior frontal gyrus (BA6) Right Anterior insula Left ACC (BA32) Left Putamen NOTE. Talairach and Tournoux coordinates are expressed in millimeters (x, y, z); size indicates number of voxels. The coordinates for each cluster represent points of maximum activation at the group level (highest median response in the cluster). Clusters are defined using cluster mass statistics and therefore do not have cluster size limitations. BA, Brodmann area. found. The fact that a significant effect of neuroticism on sympathetic nervous system response during pain and anticipation was not found is not entirely surprising because several studies have shown mixed results, with some showing increased SCLs in individuals with high neuroticism and others showing the opposite finding. 15,27,28 Analysis of the psychophysical data provided no evidence of an effect of neuroticism on threshold balloon volumes or pain ratings. This finding is consistent with previous studies suggesting that sensory mechanisms of nociceptive processing such as pain scores or thresholds are not related to neuroticism. Rather, it is the cognitive and emotional aspects of pain processing such as suffering/unpleasantness, affective disturbance related to pain, 29 and pain-related fear during vigilance to pain that are affected by neuroticism. 30 In particular, Harkins et al 29 showed that higher neuroticism was associated with significantly higher unpleasantness ratings. We did not acquire unpleasantness ratings in the present study because we did not want to compromise the brain response by having too many tasks while the volunteers were scanned. Pain intensity ratings were chosen in preference because it was important to confirm the stimuli were indeed painful for each volunteer throughout the scanning session. Although in our study neuroticism did not affect pain responses, it is important to acknowledge that the volunteer sample used, although more than adequate for an fmri study, may not be large enough to detect subtle changes in subjective behavioral responses such as pain ratings. Indeed, previous work involving a larger sample of healthy volunteers has shown lower pain toleration thresholds to visceral pain in those with higher neuroticism. 31 Investigation of the psychometric data revealed a positive correlation between neuroticism and anxiety, which was not an unexpected finding. It is difficult to disentangle the effect of anxiety from neuroticism because increased negative affect such as high anxiety is one of the factors that contribute to neuroticism as a personality dimension. 8,32 Furthermore, evidence suggests that neuroticism and anxiety are correlated and refer to approximately the same emotional condition. 33 Indeed, Cattell and Scheier, who devised their own anxiety measure, concluded that Eysenck s neuroticism dimension (as measured in the present study) is identical to their concept of anxiety. 34 Nevertheless, a question can be raised about whether it is neuroticism or anxiety mediating the brain response during anticipation and pain in the current study. However, it is well known that high anxiety increases SCL, reduces pain tolerance and sensory thresholds, and exacerbates pain perception. In the present study, there was no relationship between anxiety and pain scores or stimulation thresholds. This suggests that the level of anxiety, although greater in volunteers with high neuroticism, was not significant enough to influence the behavioral and cerebral response during pain and anticipation of pain. This is supported by the fact that all brain regions remained significantly correlated with neuroticism even when the effect of anxiety was controlled for, with the exception of the cerebellum during anticipation and postcentral gyrus, middle temporal gyrus, and superior frontal gyrus during pain. This suggests that although anxiety is an important factor, the relationship between brain activity and neuroticism during pain and anticipation found in the present study is independent of anxiety. Brain Activity During Anticipation Anticipation of pain resulted in increased brain activity in several regions, including the anterior insula, ACC (BA24 and 32), frontal cortex (BA9 and 10), and

7 September 2011 NEUROTICISM AND VISCERAL PAIN 915 secondary somatosensory cortex, which is consistent with previous studies assessing anticipation of visceral pain. 6,35 Neuroticism and Brain Activity During Anticipation During anticipation, there was a negative correlation between brain activity and neuroticism in the middle and superior temporal gyrus, precuneus, and PCC, consistent with the findings of Kumari et al, who found negative correlations in the same brain regions during anticipatory fear induced by the threat of pain. 20 The PCC has been implicated in encoding stimulus intensity 36 during pain. However, the present study showed no significant effect of neuroticism on the sensory discriminative nature of the stimulus (pain scores, thresholds), and therefore neuroticism-associated differences in brain activity in the PCC in the present study are unlikely to be related to encoding stimulus intensity. In the present study, we found a positive relationship between brain activity and neuroticism during anticipation in several regions. These regions include the ACC (BA32), parahippocampal gyrus, anterior insula, frontal cortex, putamen, and bilateral thalamus, all of which are primarily believed to be involved in the cognitive and emotional modulation of pain. The positive relationship between brain activity and neuroticism in the thalamus was localized to the medial dorsal nucleus, which has been implicated in attention, preparation/planning, and memory during fear anticipation. 37 This area has connections with the frontal cortex, which also showed a positive correlation and has been widely implicated in cognitive functioning, including that during visceral pain. 3 There was a positive correlation with neuroticism in the ACC (BA32) and brain activity during anticipation. Several neuroimaging studies have associated the ACC (BA32) with the neural basis for mood disorders, 38 negative emotional states, 39 and negative affect in pain 4,5,40 ; therefore, higher ACC activity may reflect the tendency for those with higher neuroticism to experience negative emotions during stressful situations. 8 It should be noted that this finding is not consistent with that of Kumari et al, who found a negative correlation in this region. However, Kumari et al actually found a negative correlation in the left hemisphere whereas the positive correlation in the present study was in the right hemisphere; this may reflect specificity of brain response between somatic and visceral pain threat but is more likely due to several differences in methodology between the studies. When considering the results of the current study with that of Kumari et al, 20 it is important to note that the present study also showed positive correlations in several brain regions, whereas no positive correlations were detected in the study by Kumari et al. The reason for this difference is probably that the current study used double the number of volunteers, which could quite easily account for the increased statistical power of the present study to detect significant positive correlations. The study by Kumari et al also did not involve pain, so it is conceivable that the anticipation period was not as threatening as it could have been had volunteers received pain intermittently to reinforce the anticipation response. Brain Activity During Pain Brain activity during pain increased in a number of brain regions previously implicated in visceral pain processing and commonly referred to as the visceral pain matrix. 26 This included activity of the primary and secondary somatosensory cortex, thalamus, ACC, amygdala, and anterior insula. Neuroticism and Brain Activity During Pain There was a negative correlation between neuroticism and brain activity during pain in several brain regions, including the ACC (BA32), bilateral thalamus, parahippocampal gyrus, anterior and mid insula, and putamen. It is striking to note that the majority of these regions are the same as those showing a positive correlation during anticipation. The negative relationship between neuroticism and brain activity in the thalamus was specifically localized to the pulvinar nucleus, a region that is directly connected to the ACC and amygdala and previously implicated in relaying information related to the emotional component of a stimulus to the limbic system. 41 This suggests that differences in brain activity linked to neuroticism in the thalamus during pain may be related to the emotional response to the stimulus. The pattern of amygdala activity, which was greater in those with higher neuroticism, is in contrast to several other regions of the limbic system showing a decrease in activity in those with higher neuroticism during the pain period. Activation of the amygdala with simultaneous suppression of other cognitive-emotional brain regions could be explained by previous studies suggesting that increased amygdala activity is associated with passive coping strategies such as learned helplessness, 42 particularly when humans are presented with an unsolvable cognitive problem. 43 In the present study, it is possible the amygdala response is involved in suppression of other brain regions because the unavoidable painful stimulus evokes a greater state of learned helplessness in the volunteers with higher neuroticism. Higher neuroticism was also associated with reduced bilateral parahippocampal gyrus activity during pain. This is particularly interesting because this region has been widely implicated in processes related to memory, and therefore this relationship may reflect poorer memory processing during pain in those with higher neuroticism. This suggestion is supported by several studies showing reduced memory performance during stress in those who score highly on neuroticism. 44 Given the fact that neuroticism is considered a risk factor for IBS, it is pertinent to note that a recent metaanalysis of brain activity in patients with IBS compared with controls suggests that regions involved in emotional arousal (eg, amygdala) and homeostasis are more active in patients. 45 Many of these regions were also more active in

8 916 COEN ET AL GASTROENTEROLOGY Vol. 141, No. 3 volunteers with higher neuroticism during anticipation and the amygdala during pain. In contrast, decreased activity in several of these regions during pain seems to be contradictory to that seen in patients with IBS. However, relating the present findings to neuroimaging studies of brain response to pain in patients with IBS is somewhat problematic because the majority of studies have not explicitly examined the role of anticipation and pain separately. The role of anticipation should not be underestimated because previous studies have shown that anticipation significantly contributes to the brain response seen during pain 6 and this may be the case in brain imaging studies of IBS, as also suggested in the meta-analysis by Tillisch et al. 45 Taken together, the data provide considerable evidence to suggest an overall trend toward greater activity in brain regions associated with cognitive-emotional processing in those with higher neuroticism during anticipation of pain, which may reflect increased cognitive and emotional processing during threat of an aversive stimulus in these volunteers. In contrast, higher neuroticism is associated with a suppression of this response during pain. This is an important finding and may reflect a tendency for those with higher neuroticism toward anticipatory anxiety and a lack of coping when the source of anxiety (such as pain) becomes a reality. This type of behavior has been noted in previous studies that have suggested neuroticism increases vigilance for distressing/threatening stimuli but promotes emotional blunting when escape is not an option 46 and avoidance/passive coping strategies. 42,47 In addition, the results show little support for neuroticism modulation of brain regions believed to be involved in sensory-discriminative responses to pain and therefore support those theories that suggest it is the cognitive and emotional aspects of pain processing that are affected by neuroticism 29,30 and not the sensory aspects per se. Limitations A whole brain analysis approach to examine the modulation of brain response to pain and anticipation by neuroticism was used. This exploratory approach was used because the effect of neuroticism, although examined to somatic pain, has not previously been assessed using visceral pain. As such, using an a priori hypothesis based on somatic pain risks excluding associations that are specific to visceral pain. Nevertheless, the limitation of the whole brain analysis approach is reflected in the results because although positive correlations during anticipation and negative correlations during pain were seen in the same brain regions, they were not exactly the same coordinates or voxels. There were, for example, various subregions of ACC and thalamus that were different between anticipation and pain. This should not weaken the importance of the present findings, which do show regions positively correlated during anticipation to be negatively correlated during pain. However, future research could adopt a region of interest approach to determine in more detail the proximity of regions positively correlated with neuroticism during anticipation that are negatively correlated during pain. Summary and Conclusion This study provides novel data suggesting that higher neuroticism is associated with greater activity in limbic areas of the brain during anticipation of visceral pain but with lower activity in the same brain regions during painful visceral stimulation. In the context of neuroticism and pain, this is important because it may reflect a maladaptive mechanism in those with higher neuroticism that promotes overarousal during anticipation, which may in turn promote a lack of coping during pain. This behavior may help explain the greater incidence of those with higher neuroticism attending outpatient pain clinics and being at greater risk for developing chronic pain conditions. Furthermore, this theory finds support in several studies investigating functional gastrointestinal disorders associated with visceral pain (such as IBS) that have shown differences between patients and healthy controls in several of the brain regions identified as being linked with neuroticism in our study. 45 Finally, this investigation has shown that individual differences in neuroticism affect brain response during the experience of visceral pain and provides knowledge on one of the factors responsible for interindividual variability in brain responses during visceral pain. In doing so, the results of this study also provide rationale for more detailed volunteer selection criteria with the aim of increasing homogeneity in groups used in experimental research. This approach may also help finesse the development of novel behavioral and pharmacologic interventions and improve the utility of fmri to identify biomarkers of pain. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at doi: /j.gastro References 1. Aziz Q, Andersson JL, Valind S, et al. Identification of human brain loci processing esophageal sensation using positron emission tomography. Gastroenterology 1997;113: Aziz Q, Thompson DG, Ng VW, et al. Cortical processing of human somatic and visceral sensation. J Neurosci 2000;20: Coen SJ, Aziz Q, Yaguez L, et al. Effects of attention on visceral stimulus intensity encoding in the male human brain. Gastroenterology 2008;135: Coen SJ, Yaguez L, Aziz Q, et al. Negative mood affects brain processing of visceral sensation. Gastroenterology 2009;137: Phillips ML, Gregory LJ, Cullen S, et al. The effect of negative emotional context on neural and behavioural responses to oesophageal stimulation. Brain 2003;126: Yaguez L, Coen S, Gregory LJ, et al. Brain response to visceral aversive conditioning: a functional magnetic resonance imaging study. Gastroenterology 2005;128: Mayer EA, Aziz Q, Coen S, et al. Brain imaging approaches to the study of functional GI disorders: a Rome working team report. Neurogastroenterol Motil 2009;21:

9 September 2011 NEUROTICISM AND VISCERAL PAIN Costa PT, McCrae RR. Influence of extraversion and neuroticism on subjective well-being: Happy and unhappy people. J Pers Soc Psychol 1980;38: Norris CJ, Larsen JT, Cacioppo JT. Neuroticism is associated with larger and more prolonged electrodermal responses to emotionally evocative pictures. Psychophysiology 2007;44: Canli T. Functional brain mapping of extraversion and neuroticism: learning from individual differences in emotion processing. J Pers 2004;72: Taylor KS, Anastakis DJ, Davis KD. Chronic pain and sensorimotor deficits following peripheral nerve injury. Pain 2010;151: Bisgaard T, Klarskov B, Rosenberg J, et al. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 2001;90: Hazlett-Stevens H, Craske MG, Mayer EA, et al. Prevalence of irritable bowel syndrome among university students: the roles of worry, neuroticism, anxiety sensitivity and visceral anxiety. J Psychosom Res 2003;55: Gwee KA, Leong YL, Graham C, et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 1999;44: Paine P, Worthen SF, Gregory LJ, et al. Personality differences affect brainstem autonomic responses to visceral pain. Neurogastroenterol Motil 2009;21:1155 e Naliboff BD, Waters AM, Labus JS, et al. Increased acoustic startle responses in IBS patients during abdominal and nonabdominal threat. Psychosom Med 2008;70: Eysenck HJ. The biological basis of personality. Springfield, IL: Charles C Thomas, Pauli P, Wiedemann G, Nickola M. Pain sensitivity, cerebral laterality, and negative affect. Pain 1999;80: Vossen HG, van Os J, Hermens H, et al. Evidence that trait-anxiety and trait-depression differentially moderate cortical processing of pain. Clin J Pain 2006;22: Kumari V, ffytche DH, Das M, et al. Neuroticism and brain responses to anticipatory fear. Behav Neurosci 2007;121: Eysenck HJ, Eysenck SBG. Manual of the Eysenck Personality Scales. London, UK: Hodder and Stoughton, Spielberger CD, Gorsuch RL, Lushene RE. Manual for the State- Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press, Carlsson K, Andersson J, Petrovic P, et al. Predictability modulates the affective and sensory-discriminative neural processing of pain. Neuroimage 2006;32: Williams AE, Rhudy JL. The influence of conditioned fear on human pain thresholds: does preparedness play a role? J Pain 2007;8: Kotses H, Glaus KD. Latency of multiple skin conductance responses in differential classical conditioning. Biol Psychol 1977;5: Van Oudenhove L, Coen SJ, Aziz Q. Functional brain imaging of gastrointestinal sensation in health and disease. World J Gastroenterol 2007;13: Matthews G. Neuroticism from the top down: psychophysiology and negative emotionality. In: Stelmack RM, ed. On the psychobiology of personality. Oxford, England: Elsevier, 2004: Hagemann D, Naumann E, Lürken A, et al. EEG asymmetry, dispositional mood and personality. Pers Individual Differences 1999;27: Harkins SW, Price DD, Braith J. Effects of extraversion and neuroticism on experimental pain, clinical pain, and illness behavior. Pain 1989;36: Goubert L, Crombez G, Van Damme S. The role of neuroticism, pain catastrophizing and pain-related fear in vigilance to pain: a structural equations approach. Pain 2004;107: Farmer AD, Coen SJ, Kano M, et al. Human psychophysiological responses to visceral and somatic pain: towards an integrated reproducible pain endophenotype? Gut 2009;59:A Gray JA, McNaughton N. The neuropsychology of anxiety. Oxford, UK: Oxford University Press, Luteijn F, Bouman TK. The concepts of depression, anxiety, and neuroticism in questionnaires. Eur J Pers 1988;2: Cattell RB, Scheier IH. The meaning and measurement of neuroticism and anxiety. New York, NY: Ronald Press, Berman SM, Naliboff BD, Suyenobu B, et al. Reduced brainstem inhibition during anticipated pelvic visceral pain correlates with enhanced brain response to the visceral stimulus in women with irritable bowel syndrome. J Neurosci 2008;28: Tolle TR, Kaufmann T, Siessmeier T, et al. Region-specific encoding of sensory and affective components of pain in the human brain: a positron emission tomography correlation analysis. Ann Neurol 1999;45: Li XB, Inoue T, Nakagawa S, et al. Effect of mediodorsal thalamic nucleus lesion on contextual fear conditioning in rats. Brain Res 2004;1008: Drevets WC, Price JL, Simpson JR Jr, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997;386: Bishop S, Duncan J, Brett M, et al. Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat Neurosci 2004;7: Ochsner KN, Ludlow DH, Knierim K, et al. Neural correlates of individual differences in pain-related fear and anxiety. Pain 2006; 120: Ohman A. The role of the amygdala in human fear: automatic detection of threat. Psychoneuroendocrinology 2005;30: Amorapanth P, LeDoux JE, Nader K. Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus. Nat Neurosci 2000;3: Schneider F, Gur RE, Alavi A, et al. Cerebral blood flow changes in limbic regions induced by unsolvable anagram tasks. Am J Psychiatry 1996;153: Neupert SD, Mroczek DK, Spiro A. Neuroticism moderates the daily relation between stressors and memory failures. Psychol Aging 2008;23: Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology 2011;140: Wilson GD, Kumari V, Gray JA, et al. The role of neuroticism in startle reactions to fearful and disgusting stimuli. Pers Individual Differences 2000;29: Endler NS, Parker JD. Multidimensional assessment of coping: a critical evaluation. J Pers Soc Psychol 1990;58: Received January 24, Accepted June 3, Reprint requests Address requests for reprints to: Steven J. Coen, PhD, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, 26 Ashfield Street, London, E1 2AJ, England. s.j.coen@qmul.ac.uk; fax: (44) Conflicts of interest The authors disclose the following: Q.A. has received educational grants from GlaxoSmithKline, Pfizer, and Novartis, none of which are relevant to the work described in this report. S.J.C., M.K. A.D.F., V.K., V.G., M.B., and S.C.R.W. disclose no conflicts. Funding Supported jointly by a Medical Research Council grant (to Q.A.) and a British Academy grant (to S.J.C.).

10 917.e1 COEN ET AL GASTROENTEROLOGY Vol. 141, No. 3 Supplementary Table 1. Summary of Brain Regions Showing an Increase in Activity During Anticipation and Visceral Pain Size X Y Z Side Cerebral region Brain activity during anticpation of painful visceral stimulation Right Anterior insula Right Cerebellum (posterior) Left Precentral gyrus (motor cortex) Right Caudate Right Precuneus Left Precuneus Right Fusiform gyrus Right Lingual gyrus (occipital lobe) Right Inferior frontal gyrus (BA45) Left Cerebellum (culmen) Left Lingual gyrus (occipital lobe) Left Thalamus Left PCC (BA30) Left ACC (BA24) Right ACC (BA32) Right ACC (BA24) Left Anterior insula Right Thalamus Right Secondary somatosensory cortex (SII) Right Middle frontal gyrus (BA9) Left ACC (BA32) Right Superior temporal gyrus (BA22) Left Middle frontal gyrus (BA10) Right Middle frontal gyrus (BA10) Left Superior temporal gyrus (BA22) Brain activity during painful visceral stimulation Left Middle frontal gyrus (BA6) Right Primary somatosensory cortex (SI) Right Precentral gyrus (motor cortex [BA6]) Right Putamen Left Primary somatosensory cortex (SI) Left Mid insula Right Parrahippocampal gyrus Right Mid insula Left Cerebellum (culmen) Right Thalamus Left Putamen Left Secondary somatosensory cortex (SII) Right Secondary somatosensory cortex (SII) Right ACC (BA24) Left ACC (BA24) Right Cerebellum Left Precentral gyrus (motor cortex [BA6]) Right Superior frontal gyrus (BA6) Left Inferior frontal gyrus (BA47) Left Amygdala Right Superior frontal gyrus (BA9) Right Precuneus Right Middle frontal gyrus (BA46) Left Precuneus Left Superior frontal gyrus (BA10) NOTE. Talairach and Tournoux coordinates in millimeters (x, y, z); size indicates number of voxels. The coordinates for each cluster represent points of maximum activation at the group level (highest median response in the cluster). Clusters defined using cluster mass statistics and therefore do not have cluster size limitations. All clusters corrected to P.003, ensuring a rate of less than one false-positive cluster per brain. BA, Brodmann area.