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ORIGINAL ARTICLES |
From the CURE Digestive Diseases Research Center/Neuroenteric Disease Program (B.D.N., S.W.G.D., J.M., S.B., L.C., E.A.M.), Departments of Medicine (S.W.G.D., L.C., E.A.M.) and Physiology (E.A.M.), University of California School of Medicine, Los Angeles, and the Departments of Psychology (B.D.N.) and Nuclear Medicine (M.M.), VA Greater Los Angeles Healthcare System and University of California (M.M.), Irvine, California.
Address reprint requests to: Bruce D. Naliboff, PhD, UCLA/CURE Neuroenteric Disease Program, CURE Digestive Diseases Research Center, VA Greater Los Angeles Healthcare System, West Los Angeles, Building 115, Room 223, 11301 Wilshire Blvd., Los Angeles, CA 90073. Email: naliboff{at}ucla.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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METHODS: Changes in regional cerebral blood flow were measured using H215O-water positron emission tomography in 12 nonconstipated IBS patients and 12 healthy control subjects. Regional cerebral blood flow responses to moderate rectal distension (45 mm Hg) and anticipated but undelivered distension were assessed before and after a series of repetitive noxious (60-mm Hg) sigmoid distensions.
RESULTS: Brain regions activated by actual and simulated distensions were similar in both groups. Compared with control subjects, patients with IBS showed lateralized activation of right prefrontal cortex; reduced activation of perigenual cortex, temporal lobe, and brain stem; but enhanced activation of rostral anterior cingulate and posterior cingulate cortices.
CONCLUSIONS: IBS patients show altered brain responses to rectal stimuli, regardless of whether these stimuli are actually delivered or simply anticipated. These alterations are consistent with reported alterations in autonomic and perceptual responses and may be related to altered central noradrenergic modulation.
Key Words: irritable bowel syndrome • limbic system • conditioned fear • antinociception.
Abbreviations: ACC = anterior cingulate cortex; BA = Brodmann’s area; CNS = central nervous system; fMRI = functional magnetic resonance imaging; IBS = irritable bowel syndrome; PAG = periaqueductal gray; PET = positron emission tomography; PFC = prefrontal cortex; PHG = parahippocampal gyrus; rCBF = regional cerebral blood flow.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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In addition to these perceptual alterations, IBS patients demonstrate a tendency to rate verbal descriptions of gut sensations in more aversive terms (2) and to show a preference for recall of words with negative affect (9), suggesting the possibility of a generalized affective/cognitive dysfunction (10). Epidemiological surveys have demonstrated considerable overlap of IBS with panic disorder and posttraumatic stress syndrome (11), suggesting overlapping pathophysiological processes. These shared processes may include enhanced responsiveness of central stress circuits, including the locus ceruleus and ascending noradrenergic projections (12).
In an initial study examining CNS responses to rectal distension and simply to anticipation of such distensions using H215O PET, we found differences in rCBF between IBS patients and control subjects in areas of the perigenual cingulate and PFCs (13), providing preliminary evidence to suggest CNS correlates of the altered perceptual and autonomic nervous system responses for the IBS group.
In the current study we assessed regional brain activation during moderate rectal distensions followed by expected but undelivered distensions to address the following specific questions: 1) Do IBS patients differ from healthy control subjects in their activation of brain regions involved in the processing of visceral stimulus intensities within the physiological range? 2) Do IBS patients differ from control subjects in activation of brain regions involved in the anticipation of visceral discomfort based on memory of previous discomfort? On the basis of our preliminary results (13, 14) and the regions identified as part of the integrated brain circuits activated by aversive conditioning (15, 16), we hypothesized that we would see differences in the activation of PFC and subregions of the ACC as well as the PAG, amygdala, and hippocampus. Part of these results were previously published in abstract form (17).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Control subjects.
Twelve healthy control subjects matched to the IBS sample in terms of age and gender (10 men, 2 women; average age = 37 years, range = 22–57 years) were also recruited by advertisement and on the basis of physician screening that excluded those with chronic pain syndromes or a history of other chronic diseases or gastroenterologic disorders.
All subjects were right handed and were evaluated for the presence of depression and anxiety symptoms using the revised Symptom Checklist-90 (19). Means for each scale fell within 2 SDs of the nonpsychiatric patient norm for both groups, and there was no significant difference between the group means for either parameter.
Both written and verbal informed consent were obtained from all subjects. The protocol was approved by the Human Subject Protection Committee at the VA Greater Los Angeles Healthcare System.
Visceral Distension Protocol
Distension of the sigmoid colon and rectum was accomplished using a computer-driven pump (barostat), which allowed for controlled inflations of the two separate balloons. Methods for balloon insertion and inflation were previously described (5). Briefly, the double-balloon catheter consisted of two identical latex balloons (external diameter, 5 cm; length of each balloon, 9 cm) attached to a silastic elastomer tube (external diameter, 18F) at both the proximal and distal ends (MAK-LA, Los Angeles, CA). The distance between the balloons was 9 cm. Before insertion and after removal, each balloon was inflated repeatedly to rule out any leak and to measure intrinsic compliance. To guide the balloons into the sigmoid colon and rectum, endoscopy (without premedication) was performed on each subject. Using an endoscope the proximal tip of a Teflon guidewire was inserted 40 cm from the anal verge. The lubricated double-balloon catheter was then passed over the guide wire so that the distal balloon was 4 cm from the anal orifice. Air from the rectosigmoid colon was evacuated during withdrawal of the endoscope. The catheter was secured with tape, and the wire was withdrawn. During inflation trials the rectal or sigmoid balloon was inflated at a rapid volume rate (870 ml/min) and held at a constant pressure plateau by the barostat.
After balloon insertion each subject rested in a supine position for at least 30 minutes. Eyes were closed during all scans, and headphones were worn to exclude extraneous auditory stimuli. Standardized recorded messages provided a general explanation of the distension protocol and specific information about each set of distensions. As shown in Figure 1, the procedure involved a total of six PET scans. During the first scan subjects were informed they would not feel any rectal inflation, and neither balloon was inflated (0 mm Hg, baseline). During the second scan subjects were told the rectal balloon would be inflated and would probably feel like pressure or discomfort. During this scan the rectal balloon was inflated to 45 mm Hg for 60 seconds. The next message indicated that during the upcoming scan the inflation would "feel more intense than the previous one," but in fact the inflation was again 0 mm Hg (anticipation). After these three scans, subjects received 15 30-second inflations of the sigmoid balloon at 60 mm Hg (with 30 seconds at 5 mm Hg between inflations). No PET scans were taken during the sigmoid inflations. About 5 minutes after the sigmoid inflations a second series of three PET scans was begun under identical conditions and instructions as the first three scans (baseline, 45 mm Hg, and anticipation). Data from the second baseline scan were not used in the analysis. During each scan the technician performed the same procedure by approaching the subject and injecting the tracer. Each scan lasted 90 seconds, and 10 minutes separated the end of each scan and the beginning of the next scan to allow for sufficient decay of the isotope. After sufficient tracer decay for operator safety (about 8 minutes), subjects were asked to rate the subjective perception of the visceral stimulus during the scan on verbal descriptor–anchored visual analog scales of intensity and unpleasantness as previously described (2).
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Image Data Analysis
PET data were subjected to statistical parametric mapping analysis by the method of Friston et al. (20, 21). Briefly, images were coregistered and reoriented into the standardized coordinate system of the coplanar stereotactic brain atlas (22). To account for variation in radioactive counts due to differences in radiotracer doses between scans and the proportion of administered radiotracer reaching the brain in each subject, each image matrix was corrected for global changes in blood flow between scans using analysis of covariance. To adjust for differences in subjects’ individual neuroanatomy, a 12-mm, full-width/half-maximal-height, three-dimensional Gaussian smoothing filter was applied. Differences between experimental conditions and the initial baseline scan were then assessed with the t statistic on a voxel-by-voxel basis to identify the profile of voxels that significantly differed in each condition relative to baseline for the control and IBS groups separately (within-group analysis). Additionally, each condition compared with baseline was examined with subject group as an interaction term. In this analysis significant voxels were those in which the increase during a condition over baseline was greater for one group compared with the other. The statistics used for analysis of these condition effects examine differences between and within groups using error variances calculated from the within-subject variability. This variability is applicable only to the study sample, and results cannot be extrapolated to infer population differences. To formally assess absolute group differences, the first baseline scan from each subject was entered into a direct group comparison. This analysis incorporates the between-subjects variability, allowing inference of baseline population differences between the IBS and control groups. For display purposes in all analyses, any cluster more than 23 voxels in extent with a signal intensity corresponding to an uncorrected threshold of p < .01 is shown as significant. This follows other work with functional imaging and noxious stimuli (13, 23, 24) and reduces the possibility of reporting false-negative results (25). To reduce the risk of overinterpreting false-positive findings, interpretative weight is given a particular cluster based on the statistical significance of that region, the confirmation of within-group differences in the direct between-group comparisons, the presence of an a priori hypothesis for the area, and the consistency of activation across like conditions.
The three-dimensional Talairach coordinates (x, y, z) of the peak voxel for some of the small areas of activity are given in the text (when first cited) to facilitate anatomical location. Because of space limitations, full tables of the peak voxels for all significant areas and analyses are not included (these can be obtained from the first author on request). Analyses were carried out with the SPM99b software package (Wellcome Department of Cognitive Neurology, Functional Imaging Laboratory, London, UK).
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RESULTS |
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These differences were formally assessed by direct group contrast; the results are shown in Figure 2,right, row 2. Similar to the differences seen during the actual 45-mm Hg distension, significantly greater responses in the control subjects can be observed in the left medial orbitofrontal cortex and PFC (BA 10, 11), in the right perigenual cingulate (BA 24), lentiform nucleus, temporal cortex (BA 22), thalamus, and PAG region. Significantly greater responses in the IBS patients can be observed in the ACC (BA 24), left posterior cingulate cortex (BA 31), and right occipital cortex (BA 19).
rCBF Responses to the 45-mm Hg Rectal Stimulus After Sigmoid Stimulation
After sigmoid stimulation, the 45-mm Hg distension led in the control subjects to extensive bilateral activation of the orbitofrontal (BA 11), PFC (BA 10), and perigenual cingulate cortex (BA 24) as well as bilateral activation of the thalamus and lentiform nucleus and extensive activation of the left temporal cortex (BA 21/22) and PAG region. In the IBS group, activation was observed in the right medial orbitofrontal cortex (BA 11) (see Figure 2,left, row 3).
Formal analysis of these group differences (Figure 2,right, row 3) indicated greater control responses in the left medial orbitofrontal cortex (BA 11), PFC (BA 10), temporal cortex (BA 21/22 spreading into BA 40), left PHG (x, 16; y, -36; z, -2), bilateral thalamus, and the PAG region. The IBS patients show greater activation in the right inferior parietal cortex (BA 40 spreading into BA 22) and left posterior cingulate cortex (BA 31).
rCBF Responses to Stimulus Anticipation After Sigmoid Stimulation
Similar to the 45-mm Hg stimulus, during anticipation the control subjects showed extensive bilateral activation of the medial orbitofrontal cortex (BA 11) and PFC (BA 10) spreading into the perigenual cingulate and medial frontal region (BA 24/32). There was also extensive activation of the left temporal cortex (BA 21/22) and the PHG and activation of the PAG region. The IBS patients show exclusive activation of right orbitofrontal cortex and PFC and activation of the rostral ACC (BA 24') extending from the midline into the left side (see Figure 2,left, row 4).
The formal group contrasts for this condition (Figure 2,right, row 4) indicate greater activation in control subjects in the PFC (BA 10 and BA 44/9 on the right), the left lentiform nucleus in the region of the putamen and right caudate, left temporal cortices (BA 21/38 and BA 21/22), PHG, hippocampus (x, 20; y, -36; z, -6), and PAG. Greater IBS activity can be observed in the rostral ACC (BA 24') and the left posterior cingulate cortex (BA 31).
Summary of Group Differences in rCBF
Figure 3 shows, in sagittal view along the medial surface, a summary of the responses from the comparisons of the two 45-mm Hg stimulations and the two anticipation conditions with baseline (described above). Extensive activation of the brain stem, including the PAG region, thalamus, perigenual and infragenual cingulate cortex (BA 24), medial PFC (BA 32, 10), and supraorbital cortex (BA 11) can be clearly observed in the control subjects. In contrast, the IBS patients show only minimal responses in thalamus and brain stem and do not activate the other regions. Rather IBS patients activate the rostral ACC (more superior and posterior to that observed in the control subjects) and posterior cingulate/retrosplenial cortex.
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DISCUSSION |
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Effects of Nonnoxious Rectal Distension in Healthy Control Subjects
In the control subjects, the moderate rectal stimulus used in this study led to reliable, bilateral increases in rCBF in several areas of frontal cortex, including the lateral PFC (BA 10), the orbital frontal cortex (BA 11) extending up into the medial PFC, and perigenual cingulate. The lateral portion of the PFC (including BA 10) may play a significant role in the planning for and vigilance to incoming stimuli, and activity in this area increases with increasing subjective intensity of somatic painful stimuli (23) and visceral stimuli (26). In addition, activity in this region plays an important role in keeping information in short-term memory (working memory) (27). The orbitofrontal cortex ("orbital network") (28) is thought to function as a general sensory association cortex receiving somatosensory, viscerosensory, gustatory, olfactory, and visual input. The more medial portions of the PFC, including BA 32, and the perigenual/infragenual cingulate have been associated with visceromotor responses (14, 29–31). Activity in this region may reflect activity in the "medial network" based on input from the sensory association cortex and ascending aminergic pathways (32, 33) in anticipation of an unpleasant visceral experience. Specific projections of the medial network to subregions of PAG, hypothalamus, and amygdala presumably mediate the integrated autonomic and antinociceptive response to acute aversive stimuli (34) or to the fear associated with their anticipation (15). Also, consistent activation during the 45-mm Hg distension was seen in the left anterior insula, a region associated with autonomic responses and with the processing of emotionally relevant contexts, such as disgust (35) and somatic pain (36). This functional characterization fits with insular projections to ACC, perirhinal and periamygdaloid cortices, and amygdala (37). Finally, consistent activation of thalamus and hypothalamus was observed during the stimulus. Taken together these areas of increased rCBF to a nonnoxious but presumably aversive visceral stimulus correspond well with those involved in the medial pain system and networks associated with affective, attentional, and autonomic responses to noxious somatic (25, 31, 38) and visceral stimuli (39). In control subjects no significant activation was observed in other subregions of the cingulate cortex (mid cingulate, posterior cingulate) and somatosensory regions.
Effects of Expected but Undelivered Rectal Distension in Control Subjects
Brain regions activated during mere anticipation of a more intense visceral stimulus (following the experience of the actual distension) were generally similar to those seen during the actual visceral stimulus, with the exception of activation of the insula. It is of interest that activation of the thalamic region was also seen during the anticipation condition. This finding is consistent with the concept that thalamic activation observed during actual stimulus delivery is not simply a reflection of ascending, spinothalamic input but may be related to central modulation of thalamic activity. Considerable evidence supports the concept that similar networks are activated during actual stimulus processing as during retrieval of sensory information stored in long-term memory (27). Memory formation is likely to occur in the form of aversive conditioning, related to the preceding 45-mm Hg rectal distension and possibly the previous aversive experience of endoscopic placement of the rectosigmoid balloon catheter. In particular, the context of the tracer injection by the technologist would become the conditioned stimulus, with the actual rectal distension being the unconditioned stimulus. Evidence for rapid aversive contextual conditioning in humans even after a single trial has been reported (40). Although in the current study the similarities in activations seen during actual and anticipated distensions may be due to carryover (because anticipation always followed actual stimuli) or an unconditioned fear response (to the "more intense" instruction), similar results have recently been reported for anticipation of cutaneous thermal pain in the PFC and ACC in a well-controlled fMRI study (41). In the latter study, activation during anticipated pain was seen in slightly more rostral subregions of ACC and insula, compared with more caudal activation of these brain regions during actual stimulation.
Differences in Brain Responses Between IBS Patients and Healthy Control Subjects
IBS patients differed in their brain responses to the aversive rectal distension and to its anticipation. These differences are discussed in terms of 1) laterality of activation and emotional stimulus processing, 2) difference in subregions of cingulate activation, and 3) decreased activation of "fear and defense circuits."
Laterality of activation and emotional stimulus processing.
Although control subjects showed bilateral activation of the PFC and orbitofrontal cortex, IBS patients showed a preferential activation of right-sided frontal structures. Lateralization was equally observed during the anticipation conditions, making laterality related to the sensory innervation of the rectosigmoid unlikely. Preferential right-sided frontal activity has been associated in a series of human and some animal studies (42) with greater behavioral inhibition (43), higher cortisol levels and autonomic responses (44), and greater negative emotional processing of stimuli (10). For example, negative affect (disgust, fear) has been found to increase right-sided prefrontal electrophysiological activation, whereas positive affect increases left-sided activation (42). Left-activated subjects report greater positive and less negative affect than their right-activated counterparts (45). Finally, individuals who habitually use a coping strategy that minimizes negative affect are characterized by left-sided prefrontal electrophysiological activation (46). Increased laterality in response to a psychological stress has been reported in patients with coronary artery disease (47).
In a smaller study comparing brain responses to rectal balloon distension between IBS patients and healthy control subjects (13), we observed a predominant left-sided activation of dorsolateral PFC in IBS patients and no significant activation of lateral PFC in control subjects. The smaller sample size and several methodological differences, including the less invasive nature of the rectal balloon placement in the earlier study, may be responsible for the observed differences in prefrontal activation between the two studies, and further study is needed to substantiate laterality differences between the groups.
Another finding consistent with differences in the emotional processing of the visceral stimulus was the greater activation of posterior cingulate/retrosplenial cortex in IBS patients. Although traditionally this cingulate subregion has been implicated in visuospatial orientation, and a role in affect has not been accepted (31), it was recently suggested that these brain regions are frequently activated by emotionally salient stimuli and that they play an important role in episodic memory formation (48). Patients with neuropathic pain have been found to have increased blood flow in posterior cingulate areas 23 and 31 (24), whereas studies of acute nociceptive responses showed reduced blood flow in these same areas (49, 50). Retrosplenial activation is seen more often in experiments that involve unpleasant stimuli (fearful, disgusting, or sad words and images) than in those involving pleasant (happy) stimuli (48). Increased activation of this brain region has also been reported in major depression (51), and activity correlates with anxiety symptoms in affective disorders (52–55).
Taken together these findings are consistent with the hypothesis that the brain response in IBS patients reflects a difference in the emotional processing of visceral sensory information arising from the rectosigmoid. This pattern of more negative emotional processing of information may not be limited to processing of viscerosensory information but may be a more generalized negative bias in IBS patients (2, 56).
Difference in subregions of cingulate activation.
ACC activation has been found in nearly all reported acute pain studies (25, 31, 38). Based on functional and neuroanatomical evidence, distinct subregions of human cingulate cortex have been identified: infralimbic or infragenual (BA 25), perigenual areas 24 and 32, mid cingulate areas 24' and 32', posterior areas 23 and 31, and retrosplenial areas 29 and 30 (31, 57). An additional subregion between mid cingulate and perigenual cingulate has been found to be activated in some pain studies (58, 59) and may correspond to an additional, functionally distinct rostral ACC region (BA 24, 32). Consistent with our previous report (13), IBS patients showed decreased activation of perigenual cingulate compared with control subjects, both during delivered and expected rectal stimuli. Based on neuroanatomical, stimulation, and functional brain imaging studies, perigenual areas are associated with affective responses. For example, electrical stimulation of this area in humans and subhuman primates produces strong emotional responses of fear or pleasure (60, 61), and decreased baseline blood flow in this region has been associated with the anhedonia of certain subtypes of depression (62). Bremner et al. (63) reported a decrease in blood flow in this area in patients with posttraumatic stress syndrome during exposure to traumatic pictures and sound. In addition, because of the prominent projections from areas 24 and 25 to the PAG, the dorsal vagal complex, and the intermediolateral cell column, perigenual cingulate is likely to play an important role in endogenous pain modulation and autonomic responses. The anterior portions of the cingulate cortex have a high density of mu opioid receptors, as shown in PET radioligand-binding studies (64). The finding of decreased activation of both perigenual cortex and PAG in IBS patients is consistent with a reduced activation of these integrative defense circuits (65), which in turn may be responsible for altered autonomic regulation of the gut and inadequate activation of descending pain modulation systems (see below).
In contrast, IBS patients consistently showed apparent greater activation in the rostral portion of the anterior cingulate bordering on the mid cingulate, a region previously found to correlate with unpleasant-ness ratings of a somatic pain stimulus (58) and with intensity and unpleasantness of visceral stimuli (26). Many different cognitive and behavioral paradigms produce elevated blood flow in mid cingulate cortex. Mid cingulate activation has primarily been associated with motivation, goal orientation, and premotor planning. It remains to be determined if the rostral mid cingulate region observed in this and in the Rainville et al. (58) study is identical in function with the slightly more caudal subregion, which is adjacent to premotor cortex. A recent fMRI study by Ploghaus et al. (41) using a somatic pain stimulus suggests that the more rostral subregions of the ACC are activated during anticipated pain and that the more caudal subregions are activated during actually delivered painful stimuli. Because control subjects had higher baseline activity in this area of the rostral ACC, the observed differences after stimulus delivery or anticipation may not reflect a true difference in activation by the stimulus.
Decreased activation of fear and defense circuits.
Decreased activation of fear and defense circuits was found in IBS subjects. In contrast to the control subjects, the IBS subjects overall had much smaller and less widespread responses to the actual and anticipated rectal stimuli before and after the noxious sigmoid distension. Similar findings were recently reported from a study comparing brain responses between IBS patients and control subjects using fMRI (66). A generally decreased rCBF response to acute somatic pain stimuli has also been reported for patients with tonic postsurgical tooth pain and with rheumatoid arthritis pain (67, 68). In the latter case, the reduced responses in the medial and lateral PFC as well as areas of the insula, lentiform nucleus, and thalamus have been interpreted as reflecting an altered cognitive and evaluative processing of acute pain based on experience of coping with chronic pain or adaptation-level effects (69, 70). Other possible explanations for the observed reduced regional activation in the current study include more rapid adaptation to the stimulus, a priming-like phenomenon by which more rapid behavioral responses are associated with reduced blood flow in associated brain regions (71), or alterations in the activity of ascending monoaminergic pathways projecting to these brain regions (72, 73). Determination of which explanation for decreased rCBF in different patient populations is correct awaits further study.
Subjective Ratings of Rectosigmoid Stimuli
The group differences found for rCBF and similarities across conditions of anticipation and actual distension were not paralleled by the subjective reports. These discrepancies may result from the rating process itself. To avoid radiation exposure of the technologist, stimuli were rated 10 minutes after delivery and in the case of the anticipation condition, long after subjects had stopped "anticipating" an intense distension. Because rCBF was assessed during stimulus delivery or the period of uncertainty in which a stimulus could be delivered, the ratings may be an inadequate representation of the experience at the time of the scan. In addition, we previously showed that hypersensitivity in IBS patients predominantly alters perception of short phasic (30-second) distensions but not longer (3-minute) tonic stimuli (5). The current study used intermediate-length (1-minute) stimuli.
Limitations of the current design include a lack of replication of conditions and a fixed order of presentation. In addition, we did not attempt to directly separate the relative contributions of anticipation and actual stimulus delivery to the brain activation seen during the delivered stimulus (41). It is also possible that the gender mix of the subjects (male predominance in both groups) may have influenced the results. This is less likely because the groups were matched for gender, but an interaction between gender and group response cannot be ruled out. IBS impacts both men and women, although prevalence rates for women are generally higher. To date there is no clear evidence for differential responses between men and women to visceral stimuli, and brain imaging studies using noxious stimuli have also reported small differences or inconsistent results with regard to gender-specific activations (74, 75). Further study of possible gender differences in IBS are warranted.
In summary, our findings demonstrate that in both healthy control subjects and in IBS patients, rCBF responses to anticipated and delivered visceral stimuli are similar. In addition, IBS patients differ in their processing of the delivered and expected stimulus in two fundamental ways: 1) They show reduced activation of circuits involved in the integrated affective, autonomic, and antinociceptive response to an aversive stimulus; and 2) they preferentially activate brain regions involved in processing of negatively charged emotional information. Studies are needed to test the specific hypotheses arising from these findings.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication April 20, 2000.
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 M. Heitkemper, M. Jarrett, E. F. Bond, and L. Chang Impact of Sex and Gender on Irritable Bowel Syndrome Biol Res Nurs, July 1, 2003; 5(1): 56 - 65. [Abstract] [PDF]
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P. Henningsen, T. Zimmermann, and H. Sattel Medically Unexplained Physical Symptoms, Anxiety, and Depression: A Meta-Analytic Review Psychosom Med, July 1, 2003; 65(4): 528 - 533. [Abstract] [Full Text] [PDF]
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A. Ploghaus, C. Narain, C. F. Beckmann, S. Clare, S. Bantick, R. Wise, P. M. Matthews, J. N. P. Rawlins, and I. Tracey Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network J. Neurosci., December 15, 2001; 21(24): 9896 - 9903. [Abstract] [Full Text] [PDF]
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