Functional brain imaging in irritable bowel syndrome with rectal balloon－distention by using fMRI

AIM: Irritable bowel syndrome (IBS) is characterized by abdominal pain and changes in stool habits. Visceral hypersensitivity is a key factor in the pathophysiology of IBS. The aim of this study was to examine the effect of rectal balloon-distention stimulus by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) in visceral pain center and to compare the distribution, extent, and intensity of activated areas between IBS patients and normal controls. METHODS: Twenty-six patients with IBS and eleven normal controls were tested for rectal sensation, and the subjective pain intensity at 90 ml and 120 ml rectal balloon-distention was reported by using Visual Analogue Scale. Then, BOLD-fMRI was performed at 30 ml, 60 ml, 90 ml, and 120 ml rectal balloon-distention in all subjects. RESULTS: Rectal distention stimulation increased the activity of anterior cingulate cortex (35/37), insular cortex (37/37), prefrontal cortex (37/37), and thalamus (35/37) in most cases. At 120 ml of rectal balloon-distention, the activation area and percentage change in MR signal intensity of the regions of interest (ROI) at IC, PFC, and THAL were significantly greater in patients with IBS than that in controls. Score of pain sensation at 90 ml and 120 ml rectal balloon-distention was significantly higher in patients with IBS than that in controls. CONCLUSION: Using fMRI, some patients with IBS can be detected having visceral hypersensitivity in response to painful rectal balloon-distention. fMRI is an objective brain imaging technique to measure the change in regional cerebral activation more precisely. In this study, IC and PFC of the IBS patients were the major loci of the CNS processing of visceral perception.     

Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a disorder of intestinal hypersensitivity and altered motility, exacerbated by stress. Functional magnetic resonance imaging (fMRI) during painful rectal distension in IBS has demonstrated greater activation of the anterior cingulate cortex (ACC), an area relevant to pain and emotions. Tricyclic antidepressants are effective for IBS. The aim of this study was to determine if low dose amitriptyline reduces ACC activation during painful rectal distension in IBS to confer clinical benefits. Secondary aims were to identify other brain regions altered by amitriptyline, and to determine if reductions in cerebral activation are greater during mental stress. METHODS: Nineteen women with painful IBS were randomised to amitriptyline 50 mg or placebo for one month and then crossed over to the alternate treatment after washout. Cerebral activation during rectal distension was compared between placebo and amitriptyline groups by fMRI. Distensions were performed alternately during auditory stress and relaxing music. RESULTS: Rectal pain induced significant activation of the perigenual ACC, right insula, and right prefrontal cortex. Amitriptyline was associated with reduced pain related cerebral activations in the perigenual ACC and the left posterior parietal cortex, but only during stress. CONCLUSIONS: The tricyclic antidepressant amitriptyline reduces brain activation during pain in the perigenual (limbic) anterior cingulated cortex and parietal association cortex. These reductions are only seen during stress. Amitriptyline is likely to work in the central nervous system rather than peripherally to blunt pain and other symptoms exacerbated by stress in IBS.     

Visceral hypersensitivity in irritable bowel syndrome

Altered central processing, abnormal gastrointestinal motility and visceral hypersensitivity may be possible major pathophysiology of irritable bowel syndrome (IBS). These factors affect each other and are probably associated with development of IBS symptoms. It has been confirmed that lower pain threshold to colonic distention was observed in most of patients with IBS than healthy subjects. We have investigated pain perception of the descending colon among different subtypes of IBS. There was no difference in pain threshold to colonic distention between IBS with diarrhea and constipation. Some brain regions such as the anterior cingulate cortex (ACC) may play a major role for generating pain and/or pain-related emotion in humans. IBS patients showed greater activation in the perigenual ACC during painful rectal distention compared with healthy subjects. Inflammation, stress and the combination of both stimuli can induce significant increase in visceral sensitivity in animal models. Serotonin (5-HT) can modulate visceral perception. It has been thought that 5-HT(3) receptors may play an important role for conveying visceral sensation from the gut. Corticotropin-releasing hormone (CRH) may also modulate visceral pain hypersensitivity in IBS. CRH receptor-1 antagonist significantly prevented an increase in gut sensitivity in rats. It has been demonstrated that non-specific CRH receptor antagonist α-helical CRH significantly reduced abdominal pain score during gut stimulus in patients with IBS. In conclusion, visceral hypersensitivity is common in IBS patients and probably plays a major role in development of the symptoms and both central and peripheral factors may enhance the pain sensitivity.     

Functional imaging of pain in patients with primary fibromyalgia

OBJECTIVE: To examine the function of the nociceptive system in patients with fibromyalgia (FM) using functional magnetic resonance imaging (fMRI). METHODS: Two groups of women, 9 with FM and 9 pain-free, volunteered to participate. In Experiment 1, we assessed psychophysical responses to painful stimuli and prepared participants for fMRI testing. For Experiment 2, subjects underwent fMRI scanning while receiving painful and nonpainful heat stimuli. Conventional and functional MR images were acquired using a 1.5 T MR scanner. Scanning occurred over 5 conditions. Condition 1 served as a practice session (no stimuli). Conditions 2 and 5 consisted of nonpainful warm stimuli. Conditions 3 and 4 consisted of an absolute thermal pain stimulus (47 degrees C) and a perceptually equivalent pain stimulus delivered in counterbalanced order. RESULTS: Experiment 1 indicated that subjects with FM were significantly more sensitive to experimental heat pain than controls (p < 0.001). In Experiment 2, fMRI data indicated that the FM group exhibited greater activity than controls over multiple brain regions in response to both nonpainful and painful stimuli (p < 0.01). Specifically, in response to nonpainful warm stimuli, FM subjects had significantly greater activity than controls in prefrontal, supplemental motor, insular, and anterior cingulate cortices (p < 0.01). In response to painful stimuli, FM subjects had greater activity in the contralateral insular cortex (p < 0.01). Data from the practice session indicated brain activity in pain-relevant areas for the FM group but not for controls. CONCLUSION: Our results provide further evidence for a physiological explanation for FM pain.     

Longitudinal change in perceptual and brain activation response to visceral stimuli in irritable bowel syndrome patients

BACKGROUND & AIMS: Symptom-related fears and associated hypervigilance toward visceral stimuli may play a role in central pain amplification and irritable bowel syndrome (IBS) pathophysiology. Repeated stimulus exposure leads to decreased salience of threat and reduction of hypervigilance. We sought to evaluate hypervigilance in IBS visceral hypersensitivity and associated brain activity. METHODS: Twenty IBS patients (14 female; moderate to severe symptoms) and 14 healthy controls participated in symptom and rectal distention assessments 6 times over 12 months. In a subset of 12 IBS patients, H2 15O-positron emission tomography images were obtained during baseline, rectal distentions, and anticipation of an aversive distention during the first and last session. Statistical parametric mapping (SPM99) was used to identify areas and networks activated during each session as well as those with differential activation across the 2 sessions. RESULTS: Perceptual ratings of the rectal inflations normalized over 12 months, whereas IBS symptom severity did not. There were no sex-related differences in these response patterns. Stable activation of the central pain matrix was observed over 12 months, and activity in limbic, paralimbic, and pontine regions decreased. During the anticipation condition, there were significant decreases in amygdala, dorsal anterior cingulate cortex, and dorsal brainstem activation at 12 months. Covariance analysis supported the hypothesis of changes in an arousal network including limbic, pontine, and cortical areas underlying the decreased perception seen over the multiple stimulations. CONCLUSIONS: In IBS patients, repeated exposure to experimental aversive visceral stimuli results in the habituation of visceral perception and central arousal, despite stable activation of networks processing visceral pain and its anticipation.     

Brain responses to visceral and somatic stimuli in patients with irritable bowel syndrome with and without fibromyalgia

OBJECTIVE: Symptoms of irritable bowel syndrome (IBS) and fibromyalgia (FM) commonly coexist. We hypothesized that one of the mechanisms underlying this comorbidity is increased activation of brain regions concerned with the processing and modulation of visceral and somatic afferent information, in particular subregions of the anterior cingulate cortex (ACC). METHODS: Regional cerebral blood flow (rCBF) was assessed in age-matched female IBS (n = 10) and IBS + FM (n = 10) subjects using H(2)(15)O positron emission tomography during noxious visceral (rectal) and somatic pressure stimuli. RESULTS: GI symptom severity was significantly higher in the IBS patients compared with the IBS + FM patients (p < 0.05). In addition, IBS + FM patients rated somatic pain as more intense than their abdominal pain (p < 0.05). Whereas the somatic stimulus was less unpleasant than the visceral stimulus for IBS patients without FM, the somatic and visceral stimuli were equally unpleasant in the IBS + FM group. Group differences in regional brain activation were entirely within the middle subregion of the ACC. There was a greater rCBF increase in response to noxious visceral stimuli in IBS patients and to somatic stimuli in IBS + FM patients. CONCLUSION: Chronic stimulus-specific enhancement of ACC responses to sensory stimuli in both syndromes may be associated with cognitive enhancement of either visceral (IBS) or somatic (IBS + FM) sensory input and may play a key pathophysiologic role in these chronic pain syndromes.     

Cortical mapping of visceral pain in patients with GI disorders using functional magnetic resonance imaging

OBJECTIVE: We sought to identify central loci that activate in response to visceral stimuli (stool and pain). We had a particular interest in observing the anterior cingulate gyrus and frontal cortex in normals and in patients with intestinal disease, including inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). METHODS: Subjects underwent rectal balloon distention to a sensation of stool and to a sensation of pain while undergoing blood oxygenation level-dependent functional magnetic resonance imaging. Experiments were conducted in a Magnex 3.0-T whole body magnet with a Bruker Biospec console and a quadrature head coil. Four contiguous 5.0-mm oblique axial slices designed to optimize coverage of areas believed to be responsive to noxious stimulation were acquired. Activations were detected by using cross-correlation maps (p < 0.001) for individual subjects. The experimental groups were compared using both an analysis of variance and profile analysis. RESULTS: A significantly higher percentage of pixels activated in the anterior cingulate gyrus over both pain and stool conditions for the control group than for the IBS group and for the IBS group than for the IBD group (p < 0.035). Deactivation of left somatosensory cortex was greater for the IBS group than for the IBD group and greater for the IBD group than for the controls (p < 0.0065) in the boxcar condition. Frontal deactivation in controls compared with disease groups bordered on statistical significance. Profile analysis of the three groups across six regions of interest revealed that the control and IBD groups were distinguished by different profiles of response (p < 0.005). Nonparametric evaluation of the data suggests that, among the pixels in the anterior cingulate activating to pain, there are two patterns of response to pain-on/off and graded. This was true for both controls and disease groups. CONCLUSIONS: Normal controls and subjects with IBD and IBS share similar loci of activations to visceral sensations of stool and pain. Both activation and deactivation of particular regions of interest differentiate the three groups, as do profiles of patterned response across six of the regions of interest for the control and IBD groups.     

Repetitive rectal painful distention induces rectal hypersensitivity in patients with irritable bowel syndrome

Background A reduced rectal perceptual threshold has been reported in patients with irritable bowel syndrome (IBS), but this phenomenon may be induced by a comorbid psychological state. We evaluated the rectal pain threshold at baseline and after conditioning (repetitive rectal painful distention: RRD) in patients with IBS or functional abdominal pain syndrome (FAPS), which is an abdominal pain disorder, and in healthy controls, and determined whether rectal hypersensitivity is a reliable marker for IBS. Methods The rectal sensory threshold was assessed by a barostat. First, a ramp distention of 40 ml/min was induced, and the threshold of pain and the maximum tolerable pressure (mmHg) were measured. Next, RRD (phasic distentions of 60-s duration separated by 30-s intervals) was given with a tracking method until the subjects had complained of pain six times. Finally, ramp distention was induced again, and the same parameters were measured. The normal value was defined by calculating the 95% confidence intervals of controls. Results Five or six of the seven IBS patients showed a reduced rectal pain threshold or maximum tolerable pressure, respectively, at baseline. In all patients with IBS, both thresholds were reduced after RRD load, but they were reduced in none of the patients with FAPS. RRD significantly reduced both thresholds in the IBS group (P < 0.05), but it had no effect in the control or FAPS groups. Conclusions Rectal hypersensitivity induced by RRD may be a reliable marker for IBS. Conditioning-induced visceral hypersensitivity may play a pathophysiologic role in IBS.     

Alterations of brain activity associated with resolution of emotional distress and pain in a case of severe irritable bowel syndrome

BACKGROUND & AIMS: The association of psychosocial disturbances with more severe irritable bowel syndrome (IBS) is well recognized. However, there is no evidence as to how these associations might be mediated. Functional magnetic resonance imaging (fMRI) offers an opportunity to study whether activation of the cingulate cortex, an area involved with the affective and pain intensity coding might be linked to poorer clinical status with IBS. In this case report, we found an association between the severity of a patient's clinical symptoms and psychosocial state, with activation of the cingulate cortex. We also found that clinical and psychosocial improvement was associated with reduced cingulate activation. METHODS: Observational case report of a young woman observed for 16 years with a history of sexual abuse, psychosocial distress, and functional GI complaints. Psychosocial, clinical, and fMRI assessment was performed when the patient experienced severe symptoms and again 8 months later when clinically improved. RESULTS: During severe illness, the patient had major psychosocial impairment, high life stress, a low visceral pain threshold, and activation of the midcingulate cortex (MCC), prefrontal area 6/44, and the somatosensory cortex, areas associated with pain intensity encoding. When clinically improved, there was resolution in activation of these 3 areas, and this was associated with psychosocial improvement and an increased threshold to rectal distention. CONCLUSIONS: Activation of the MCC and related areas involved with visceral pain encoding are associated with poor clinical status in patients with severe IBS and psychosocial distress and appear to be responsive to clinical improvement.     

Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls

BACKGROUND AND AIMS: Many patients with irritable bowel syndrome (IBS) show intestinal hypersensitivity to distension and sensitisation after repeated intestinal distensions. Abnormalities in endogenous pain inhibitory mechanisms, such as diffuse noxious inhibitory controls (DNIC), may be implicated and were investigated during brain functional magnetic resonance imaging (fMRI). PATIENTS AND METHODS: fMRI was performed in 10 female patients with IBS (five constipated (IBS-C) and five with diarrhoea (IBS-D)) and 10 female healthy controls during rectal balloon distension alone or during activation of DNIC by painful heterotopic stimulation of the foot with ice water. Rectal pain was scored with and without heterotopic stimulation (0 = none, 10 = maximal). RESULTS: Heterotopic stimulation decreased median rectal pain scores significantly in healthy controls (-1.5 (interquartile range -2 to -1); p = 0.001) but not in IBS-C (-0.7 (-1 to 0.5)), IBS-D (-0.5 (-1.5 to 0.5)), or in all IBS patients (0 (-1.5 to 1.3)). Brain activation changes during heterotopic stimulation differed highly significantly between IBS-C, IBS-D, and controls. The main centres affected were the amygdala, anterior cingulate cortex, hippocampus, insula, periaqueductal gray, and prefrontal cortex, which form part of the matrix controlling emotional, autonomic, and descending modulatory responses to pain. CONCLUSIONS: IBS-C and IBS-D appear to have differing abnormal endogenous pain inhibitory mechanisms, involving DNIC and other supraspinal modulatory pathways.     

Novel techniques to study visceral hypersensitivity in irritable bowel syndrome

Visceral hypersensitivity has emerged as a key hypothesis in explaining the painful symptoms of irritable bowel syndrome (IBS), and it has been proposed as a “biologic marker” for the condition. Visceral hypersensitivity can be influenced by peripheral and central mechanisms affecting pain perception. The optimal method for its assessment in humans has not been determined. Current techniques include stimulation via the computerized barostat and electrical stimulation, response measures including the lower limb reflex, and brain imaging modalities such as functional MRI and positron emission tomography. It has been shown that IBS patients have decreased sensory thresholds to colonic and rectal balloon distention by barostat. Studies using electrical stimulation and the RIII lower limb reflex have further confirmed enhanced visceral perception in IBS. Evidence from more recent neuroimaging studies suggests that IBS patients have abnormal activation of brain circuits involved in emotional and cognitive modulation of sensory information, resulting in ineffective pain modulation; these circuits may have a pathophysiologic role in enhancing visceral perception. There are few effective pharmacologic treatments that relieve IBS symptoms, and improved understanding of brain-gut interactions and factors relating to enhanced visceral perception may guide us in developing more efficacious treatments.     

The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: a double blind, randomized, placebo-controlled study.

BACKGROUND & AIMS: Although widely prescribed, the evidence for the use of antidepressants for the treatment of irritable bowel syndrome (IBS) is limited. In this study, we hypothesized that fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has visceral analgesic properties, leading to increased sensory thresholds during rectal distention and improvement of symptoms, in particular in IBS patients with visceral hypersensitivity. METHODS: Forty non-depressed IBS patients underwent a rectal barostat study to assess the sensitivity to rectal distention before and after 6 weeks of treatment with fluoxetine 20 mg or placebo. Abdominal pain scores, individual gastrointestinal symptoms, global symptom relief, and psychologic symptoms were assessed before and after the intervention. RESULTS: At baseline, 21 of 40 patients showed hypersensitivity to rectal distention. Fluoxetine did not significantly alter the threshold for discomfort/pain relative to placebo, either in hypersensitive (19 +/- 3 vs. 22 +/- 2 mm Hg above MDP) or in normosensitive (34 +/- 2 vs. 39 +/- 4 mm Hg above MDP) IBS patients. Overall, 53% of fluoxetine-treated patients and 76% of placebo-treated patients reported significant abdominal pain scores after 6 weeks (not significant). In contrast, in hypersensitive patients only, fluoxetine significantly reduced the number of patients reporting significant abdominal pain. Gastrointestinal symptoms, global symptom relief, and psychologic symptoms were not altered. CONCLUSIONS: Fluoxetine does not change rectal sensitivity in IBS patients. Possible beneficial effects on pain perception need to be confirmed in larger trials.     

Gene, environment, and brain-gut interactions in irritable bowel syndrome

The genetic predisposition and influence of environment may underlie in the pathogenesis and/or pathophysiology of irritable bowel syndrome (IBS). This phenomenon, gene x environment interaction together with brain-gut interactions is emerging area to be clarified in IBS research. Earlier studies focused on candidate genes of neurotransmitters, cytokines, and growth factors. Among them, some studies but not all studies revealed association between phenotypes of IBS and 5-hydroxytryptamine (5-HT)-related genes, noradrenaline-related genes, and cytokine genes. Recent prospective cohort study showed that genes encoding immune and adhesion molecules were associated with post-infectious etiology of IBS. Psychosocial stressors and intraluminal factors especially microbiota are keys to develop IBS. IBS patients may have abnormal gut microbiota as well as increased organic acids. IBS is disorder that relates to brain-gut interactions, emotional dysregulation, and illness behaviors. Brain imaging with or without combination of visceral stimulation enables us to depict the detailed information of brain-gut interactions. In IBS patients, thalamus, insula, anterior cingulate cortex, amygdala, and brainstem were more activated in response to visceral stimulation than controls. Corticotropin-releasing hormone and 5-HT are the candidate substances which regulate exaggerated brain-gut response. In conclusion, gene x environment interaction together with brain-gut interactions may play crucial roles in IBS development. Further fundamental research on this issue is warranted.     

Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

BACKGROUND AND AIMS: Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients. METHODS: Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied. The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline. Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of alphahCRH (10 micro g/kg). RESULTS: ES induced significantly higher motility indices of the colon in IBS patients compared with controls. This response was significantly suppressed in IBS patients but not in controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by alphahCRH. CONCLUSION: Peripheral administration of alphahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.     

Uneven acute non-alcoholic fatty change of the liver after percutaneous transhepatic portal vein embolization in a patient with hilar cholangiocarcinoma – a case report

Irritable bowel syndrome (IBS) is a common functional disease of the gastrointestinal tract. The current study aimed to examine the association between visceral hypersensitivity in IBS and cortical activation using functional magnetic resonance imaging (fMRI), and to elucidate the role of psychological factors in the pathogenesis of IBS. The present study included 31 patients with IBS and 20 healthy controls. Cerebral function was assessed using fMRI. During imaging, a Sengstaken-Blakemore tube was placed within the rectum approximately 10 cm from the anus, following which gas was rapidly injected into the airbag using a 150-ml syringe. Images were obtained at 40 ml, 80 ml, and 120 ml of expansion. Psychological status was evaluated using the Hospital Anxiety and Depression Scale (HADS). Anxiety and depression scores were higher among patients with IBSthan among controls (both P < 0.05), although scores in both groups were below the level of clinical diagnosis. Brain activation in regions of interest (parietal areas, prefrontal cortex, cerebellum, anterior cingulate cortex, insular cortex, and thalamus) increased along with increases in rectal balloon dilation, except in women with IBS and patients with disease duration less than 5 years. Furthermore, region of interest (ROI) activation (such as the parietal region, prefrontal cortex, cerebellum, anterior cingulate cortex, insular cortex, and thalamus) differed significantly between the 40-ml and 120-ml conditions, and between the 80-ml and 120-ml conditions (P < 0.05), among patients with IBS with anxiety or depression scores less than 9 points. Overall, our findings indicate that changes in brain activation due to changes in rectal balloon distension can be objectively and accurately measured using fMRI. Although our results indicated that visceral hypersensitivity during IBS is associated with changes in cortical activation, further studies utilizing larger sample sizes are required to more fully elucidate the association between psychological factors and visceral hypersensitivity in IBS.     

Regional Brain Activation in Response to Rectal Distension in Patients with Irritable Bowel Syndrome and the Effect of a History of Abuse

Previous studies have demonstrated alterations in brain response to rectal distension in patients with irritable bowel syndrome (IBS) compared to controls. Our aim was to compare regional brain activity in response to rectal balloon distension in patients with IBS and healthy controls. We studied six patients with IBS and six healthy controls. Positron emission tomography scans were obtained during rectal balloon distensions. Statistical parametric mapping and region of interest analysis were performed to identify and compare differences in regional cerebral blood flow (CBF) for each distension pressure within and between the groups of interest. In post-hoc analyses, patients with a history of sexual or physical abuse were compared to patients without abuse. In response to rectal distension, controls exhibit a greater increase in anterior cingulate cortex (ACC) activity compared to the IBS group (Z = 3.2, P = 0.001). Thalamic activity was higher in the IBS patients relative to the control group (Z = 3.3, P < 0.001). Increased ACC activity was observed in IBS patients with no history of abuse (Z = 5.2, P < 0.001) similar to controls, whereas no such increased activity was noticed in the abused group. In conclusion, this study replicates previous findings showing alterations in brain response to rectal distension in patients with IBS. The observations on the effect of abuse suggest a possible modulating role of abuse history on this brain response.     

Novel evidence for hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome patients

BACKGROUND & AIMS: Visceral hypersensitivity in irritable bowel syndrome (IBS) patients has been documented by evaluation of perceived stimulations that can reflect abnormalities of both sensory neurocircuitry and cognitive processes. The presence of actual neurohypersensitivity in human beings has not been documented separately. Because subliminal stimulations are free from the influence of stimulus-related cognitive processes, functional magnetic resonance imaging (fMRI) cortical response to these stimuli can be considered a measure of activity of the neural circuitry alone. The aim of this study was to compare quantitatively the cerebral cortical fMRI activity response to equal subliminal stimulations between IBS patients and age-matched controls. METHODS: We studied 10 IBS patients and 10 healthy controls using a computerized barostat-controlled rectal distention device. fMRI activity volume and percent maximum signal intensity change for equal subliminal distention pressures were compared between controls and patients. RESULTS: Three levels of subliminal distention pressures (eg, 10, 15, and 20 mm Hg), were represented in both controls and patients and were analyzed for fMRI response. In all 3 distention levels the fMRI activity volume in IBS patients was significantly larger than age- and sex-matched controls (P < .05). The percent maximum signal intensity change was similar between IBS patients and controls. CONCLUSIONS: The volume of cerebral cortical activity response to equal subliminal distention pressures in IBS patients is significantly larger than in controls, documenting the existence of hypersensitivity of the neural circuitry in this patient group irrespective of stimulus-related cognitive processes.     

Alterations in cerebral potentials evoked by rectal distention and drinking ice water in patients with irritable bowel syndrome

AIM: Visceral hypersensitivity has been found to be present in irritable bowel syndrome (IBS). The current study sought to study visceral afferent hypersensitivity in IBS patients and obtain further objective evidence of alterations in intestinal afferent pathways in IBS patients by cerebral evoked potentials (CEP). METHOD: We studied 30 female IBS patients and 12 female healthy subjects. Rectal perception thresholds to balloon distention were measured and CEP was recorded in response to rhythmic rectal distention (two distention series, each of 100 repetitions at a frequency of 1 Hz) at the volume of perception thresholds. All subjects were then asked to drink 220 mL 4 degrees C ice water and the above steps were repeated 20 min later. RESULTS: Rectal distention led to recognizable and reproducible CEP. Compared to healthy subjects, IBS patients demonstrated significantly shorter N1, P1 and N2 latencies (P < 0.05). After drinking ice water, IBS patients exhibited further shortened N1, P1 and N2 latencies (P < 0.05), but drinking did not alter the latencies of healthy controls and the amplitudes of both IBS patients and healthy controls. CONCLUSION: The shorter latency of cerebral potentials evoked by rectal distention and ice water stimulation in IBS patients provided further objective evidence for defective visceral afferent transmission in IBS patients.     

Tegaserod inhibits noxious rectal distention induced responses and limbic system c-Fos expression in rats with visceral hypersensitivity

AIM: To examine the effects of tegaserod, a serotonin (5-HT) 4 receptor partial agonist, on abdominal withdrawal reflex (AWR) to rectal distention (RD) and c-Fos expression in limbic system. METHODS: Neonatal Sprague-Dawley rats randomly received colonic irritation by acetic acid from postnatal day 8 to d 21 as a visceral hypersensitive model (group H) or by intrarectal saline as a control group (group C). When they became adults, rectal distention (RD) was performed by a balloon (6F; Fogarty arterial embolectomy catheter; length, 20 mm; diameter, 2 mm) which was rapidly inflated with increasing volumes of saline (0.4, 0.8 and 1.2 mL) for 20 s at five-minute intervals. Five subgroups of group H (H-saline, H-vehicle, H-Teg0.1, H-Teg0.3 and H-Teg1.0) were injected randomly with saline, vehicle (1-methyl-2-thpyrrolidone) or tegaserod at doses of 0.1, 0.3 and 1.0 mg/kg ip, respectively. Two subgroups of group C (C-Saline and C-Teg1.0) were injected with saline or tegaserod (1.0 mg/kg) ip. RD was performed 10 min after injection, AWR was recorded and c-Fos expression in limbic system was analyzed quantitatively by immunohistochemistry. RESULTS: Compared to saline, tegaserod significantly inhibited AWR in group H (0.4 mL: from 2.0 to 0.5; 0.8 mL: from 3.5 to 1.5; 1.2 mL: from 4.0 to 3.0, P<0.01), but had no significant effect on group C. Tegaserod dose-dependently attenuated the number of c-Fos positive neurons in limbic structures, anterior cingulate cortex (ACC) showed the greatest attenuation. In group H, tegaserod (1.0 mg/kg) resulted in a significant overall decrease to 57% of H-saline (283+/-41 vs 162+/-16, P<0.01), in ACC to 42% of H-saline (72+/-10 vs 31+/-8, P<0.01). In group C, tegaserod (1.0 mg/kg) resulted in an overall decrease to 77% of C-saline (214+/-13 vs 164+/-22, P<0.01), in ACC to 65% of C-saline (48+/-8 vs 31+/-7, P<0.01). CONCLUSION: Tegaserod inhibits the response to rectal distention in rats with visceral hypersensitivity and dose-dependently attenuates c-Fos expression in limbic system, especially in anterior cingulate cortex.     

Sex-related differences in IBS patients: central processing of visceral stimuli

BACKGROUND & AIMS: Women have a higher prevalence of irritable bowel syndrome (IBS) and possible differences in response to treatment, suggesting sex-related differences in underlying pathophysiology. The aim of this study was to determine possible sex-related differences in brain responses to a visceral and a psychological stressor in IBS. METHODS: Regional cerebral blood flow measurements using H(2)(15)O positron emission tomography were compared across 23 female and 19 male nonconstipated patients with IBS during a visceral stimulus (moderate rectal inflation) and a psychological stimulus (anticipation of a visceral stimulus). RESULTS: In response to the visceral stimulus, women showed greater activation in the ventromedial prefrontal cortex, right anterior cingulate cortex, and left amygdala, whereas men showed greater activation of the right dorsolateral prefrontal cortex, insula, and dorsal pons/periaqueductal gray. Similar differences were observed during the anticipation condition. Men also reported higher arousal and lower fatigue. CONCLUSIONS: Male and female patients with IBS differ in activation of brain networks concerned with cognitive, autonomic, and antinociceptive responses to delivered and anticipated aversive visceral stimuli.