When pain and hunger collide; psychological influences on differences in brain activity during physiological and non‐physiological gastric distension

Functional neuroimaging has been used extensively in conjunction with gastric balloon distension in an attempt to unravel the relationship between the brain, regulation of hunger, satiety, and food intake tolerance. A number of researchers have also adopted a more physiological approach using intra‐gastric administration of a liquid meal which has revealed different brain responses to gastric balloon distension. These differences are important as they question the utility and relevance of non‐physiological models such as gastric balloon distension, especially when investigating mechanisms of feeding behavior such as satiety. However, an assessment of the relevance of physiological versus non‐physiological gastric distension has been problematic due to differences in distension volumes between studies. In this issue of Neurogastroenterology and Motility, Geeraerts et al. compare brain activity during volume matched nutrient gastric distension and balloon distension in healthy volunteers. Gastric balloon distension activated the ‘visceral pain neuromatrix’. This network of brain regions was deactivated during nutrient infusion, supporting the notion that brain activity during physiological versus non‐physiological distension is indeed different. The authors suggest deactivation of the pain neuromatrix during nutrient infusion serves as a prerequisite for tolerance of normal meal volumes in health.     

Cortical deactivations during gastric fundus distension in health: visceral pain‐specific response or attenuation of ‘default mode’ brain function? A H215O‐PET study

Abstract Gastric distension activates a cerebral network including brainstem, thalamus, insula, perigenual anterior cingulate, cerebellum, ventrolateral prefrontal cortex and potentially somatosensory regions. Cortical deactivations during gastric distension have hardly been reported. To describe brain areas of decreased activity during gastric fundus distension compared to baseline, using data from our previously published study (Gastroenterology, 128, 2005 and 564). H₂¹⁵O‐brain positron emission tomography was performed in 11 healthy volunteers during five conditions (random order): (C₁) no distension (baseline); isobaric distension to individual thresholds for (C₂) first, (C₃) marked, (C₄) unpleasant sensation and (C₅) sham distension. Subtraction analyses were performed (in SPM2) to determine deactivated areas during distension compared to baseline, with a threshold of P_{uncorrected_voxel_level} < 0.001 and P_{corrected_cluster_level} < 0.05. Baseline–maximal distension (C₁–C₄) yielded significant deactivations in: (i) bilateral occipital, lateral parietal and temporal cortex as well as medial parietal lobe (posterior cingulate and precuneus) and medial temporal lobe (hippocampus and amygdala), (ii) right dorsolateral and dorso‐ and ventromedial PFC, (iii) left subgenual ACC and bilateral caudate head. Intragastric pressure and epigastric sensation score correlated negatively with brain activity in similar regions. The right hippocampus/amygdala deactivation was specific to sham. Gastric fundus distension in health is associated with extensive cortical deactivations, besides the activations described before. Whether this represents task‐independent suspension of ‘default mode’ activity (as described in various cognitive tasks) or an visceral pain/interoception‐specific process remains to be elucidated.     

Sensations of gas and pain and their relationship with compliance during distension in human colon

Background Colonic mechanosensory afferents ‘in parallel’ to circular muscle activate prevertebral ganglion reflexes; ‘in series’, afferents convey visceral sensation to the central nervous system; and pain receptors are activated with muscle distension. Our aim was to analyze the relationships of gas and pain sensations during graded distensions, and the association of sensations with colonic compliance in conscious humans. Methods The data were acquired in a prior study performed on 60 healthy volunteers (aged 18–75 years) under baseline conditions... Colonic compliance was measured in response to 4 mmHg stepwise balloon distensions to estimate pressure at half‐maximum volume (Pr_50%). Sensation ratings for gas and pain were averaged over distensions at 16, 24, 30 and 36 mmHg above baseline operating pressure. Associations between mean gas and pain ratings, and colonic compliance were assessed with Pearson correlations. Key Results Gas and pain sensations were significantly correlated at all levels of distension (all P < 0.001). Significant inverse correlations between Pr_50% and sensations of gas and pain were observed, suggesting that lower compliance was associated with lower sensations. Up to 25% of the variance in sensation may be attributed to colonic compliance. Conclusions & Inferences These data are consistent with the hypothesis that, if circumferential colonic receptors are stimulated by distension to mediate gas and pain in humans, they are, at least partly, arranged ‘in parallel’ to the muscle layer.     

Neuronal correlates of gastric pain induced by fundus distension: a 3T-fMRI study

Visceral hypersensitivity in gastric fundus is a possible pathogenesis for functional dyspepsia. The cortical representation of gastric fundus is still unclear. Growing evidence shows that the insula, but not the primary or secondary somatosensory region (SI or SII), may be the cortical target for visceral pain. Animal studies have also demonstrated that amygdala plays an important role in processing visceral pain. We used fMRI to study central projection of stomach pain from fundus balloon distension. We also tested the hypothesis that there will be neither S1 nor S2 activation, but amygdala activation with the fundus distension. A 3T-fMRI was performed on 10 healthy subjects during baseline, fullness (12.7 +/- 0.6 mmHg) and moderate gastric pain (17.0 +/- 0.8 mmHg). fMRI signal was modelled by convolving the predetermined psychophysical response. Statistical comparisons were performed between conditions on a group level. Gastric pain activated a wide range of cortical and subcortical structures, including thalamus and insula, anterior and posterior cingulate cortices, basal ganglia, caudate nuclei, amygdala, brain stem, cerebellum and prefrontal cortex (P < 0.001). A subset of these neuronal substrates was engaged in the central processing of fullness sensation. SI and SII were not activated during the fundus stimulation. In conclusion, the constellation of neuronal structures activated by fundus distension overlaps the pain matrices induced musculocutaneous pain, with the exception of the absence of SI or SII activation. This may account for the vague nature of visceral sensation/pain. Our data also confirms that the insula and amygdala may act as the central role in visceral sensation/pain, as well as in the proposed sensory-limbic model of learning and memory of pain.     

Proximal colon distension induces Fos expression in the brain and inhibits gastric emptying through capsaicin-sensitive pathways in conscious rats

We assessed brain nuclei activated during noxious mechanical distension of the proximal colon in conscious rats, using Fos as a marker of neuronal activation, and functional reflex changes in gastric emptying associated to colon distension. The role of capsaicin-sensitive afferents in Fos and gastric responses to distension was also investigated. Compared with sham distension, isovolumetric phasic distension of the proximal colon (10 ml, 30 s on/off for 10 min) increased significantly Fos expression 1 h after distension in selective brain areas, most prominently, the paraventricular and supraoptic nuclei of the hypothalamus (13-fold and 80-fold, respectively), the locus coeruleus-Barrington's nucleus complex (2-fold), area postrema (7-fold) and the nucleus tractus solitarius (4-fold). Increased Fos expression was also observed in the cingulate cortex, posterior paraventricular nucleus of the thalamus, periaqueductal gray and ventrolateral medulla. Distension of the proximal colon significantly inhibited gastric emptying by 82% and 34%, as measured 30 and 60 min after the distension respectively, compared with control. Pretreatment with systemic capsaicin prevented both the brain increase in Fos expression and the inhibition of gastric emptying induced by the colon distension. These results show that visceral pain arising from the proximal colon activates a complex neuronal network that includes specific brain nuclei involved in the integration of autonomic, neuroendocrine and behavioral responses to pain and an inhibitory motor reflex in other gut areas (delayed gastric emptying). Capsaicin-sensitive afferent pathways are involved in mediating brain neuronal activation and functional changes associated with noxious visceral stimulation.     

Influence of the 5‐HT3 receptor antagonist ondansetron on gastric sensorimotor function and nutrient tolerance in healthy volunteers

Background Serotonin is believed to be involved in the regulation of the gastric accommodation reflex in man however which receptor subtype(s) are involved remains to be elucidated. Methods Eleven healthy subjects (nine men, age 19–30) underwent a gastric barostat and a drinking test after treatment with either placebo or ondansetron (8 mg intravenously). During the barostat protocol an intragastric flaccid bag was stepwise distended (2 mmHg increments 2 min) to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra‐abdominal pressure +2 mmHg while volume was followed before and after administration of a liquid meal (200 mL; 300 kcal). During the drink test volunteers drank at a rate of 15 mL min^?1 until maximal satiation. Results (mean ± SEM) were compared using t‐tests and mixed model analysis. Key Results Gastric compliance was not significantly altered by ondansetron (51.5 ± 5.6 vs 49.2 ± 5.2 mL mmHg^?1), neither were the pressure thresholds for first perception or discomfort. Ondansetron treatment did not affect basal gastric tone (173 ± 14 vs 156 ± 12 mL), neither did it affect the amplitude of the meal‐induced relaxation (160 ± 52 vs 131 ± 43 mL) or the maximum volume increase after the meal (264 ± 54 mL vs 234 ± 51 mL). During the drinking test the amount of liquid meal ingested at maximum satiation was significantly increased by ondansetron (784 ± 74 vs 907 ± 64 mL, P < 0.05). Conclusions & Inferences These data suggest that 5‐HT acting at 5‐HT₃ receptors is not involved in the control of gastric sensorimotor function, but contributes to the regulation of hunger and satiation in man.     

Elicitation of transient lower oesophageal sphincter relaxations in response to gastric distension and meal ingestion

The aim of this study was to compare the effect of graded gastric barostat distension and meal-induced fundic relaxation on the elicitation of transient lower oesophageal sphincter relaxation (TLOSR). In 15 healthy subjects, stepwise fundic distension and oesophageal manometry were performed simultaneously. Next, the effect of meal ingestion on proximal stomach volume and lower oesophageal sphincter function was studied. During stepwise barostat distension of the proximal stomach, a significant linear correlation between intragastric pressure (r = 0.91; P < 0.01) and the TLOSR rate during inflation and subsequent deflation (r = 0.96; P < 0.01) was found. A similar relationship was found for volume. In addition, after meal ingestion, the TLOSR rate increased significantly from 1.40 +/- 3 to 5.4 +/- 1.5 h-1 (P < 0.01) and 5.2 +/- 1.7 h-1 (P < 0.01), respectively, during the first and second 30-min postprandially. However, at similar calculated intragastric volumes, barostat distension led to a significantly higher TLOSR rate than the meal. Similarly, distension-induced increase in gastric wall tension, estimated from the measured bag pressure and volume using Laplace's law, was associated with significantly higher TLOSR rates (P < 0.01). In conclusion, the rate of TLOSRs in healthy volunteers is directly related to the degree of proximal gastric distension and pressure-controlled barostat distension is a more potent trigger of TLOSRs than a meal. The latter finding suggests that tension receptor activation is an important stimulus for TLOSRs.     

Responses and afferent pathways of C(1)-C(2) spinal neurons to gastric distension in rats

Some evidence shows that the upper cervical spinal cord might play an important role in propriospinal processing as a sensory filter and modulator for visceral afferents. The aims of this study were to determine (1). the responses of C(1)-C(2) spinal neurons to gastric distension and (2). the relative contribution of vagal and spinal visceral afferent pathways for transmission of gastric input to the upper cervical spinal cord. Extracellular potentials of single C(1)-C(2) spinal neurons were recorded in pentobarbital anesthetized male rats. Graded gastric distension (20-80 mm Hg) was produced by air inflation of a latex balloon surgically placed in the stomach. Sixteen percent of the neurons (32/198) responded to gastric distension; 17 neurons were excited and 15 neurons were inhibited by gastric distension. Spontaneous activity of neurons with inhibitory responses was higher than those neurons with excitatory responses (18.1+/-2.7 vs. 3.8+/-1.7 impulses s(-1), p<0.001). Twenty-eight of thirty-two (87.5%) neurons responded to mechanical stimulation of somatic fields on head, neck, ears or shoulder. Most lesion sites of neurons with excitatory responses were found in laminae V, VII; however, neurons with inhibitory responses were in laminae III, IV. Bilateral cervical vagotomy abolished responses of 4/8 neurons tested. Spinal transection at C(6)-C(7) abolished responses of the other four neurons that still responded to gastric distension after bilateral vagotomy. Results of these data supported the concept that a group of C(1)-C(2) spinal neurons might play a role in processing sensory information from the stomach that travels in vagal and spinal visceral afferent fibers.     

Stress‐induced modulation of vagal afferents

Vagally dependent gastric functions, including motility, tone, compliance, and emptying rate, play an important role in the regulation of food intake and satiation. Vagal afferent fibers relay sensory information from the stomach, including meal‐related information, centrally and initiate co‐ordinated autonomic efferent responses that regulate upper gastrointestinal responses. The purpose of this mini‐review is to highlight several recent studies which have uncovered the remarkable degree of neuroplasticity within gastric mechanosensitive vagal afferents and the recent study by Li et al, in this issue of Neurogastroenterology and Motility, who show that the mechanosensitivity of gastric vagal afferents is dysregulated in a murine model of chronic stress. The authors demonstrate that both gastric mucosal and tension afferents are hypersensitive following chronic stress, and responses to mucosal stroking and muscle stretch are enhanced significantly. As gastric distension and volumetric signaling is important in satiety signaling and meal termination, this may provide a mechanistic basis for the gastric hypersensitivity associated with stress‐associated clinical problems such as functional dyspepsia.     

Cardiovascular effects of gastric intubation and distension in healthy humans

Abstract  Few data exist on the effect of upper gut stimuli on the cardiovascular system. Aim of our study was to evaluate the cardiovascular effects of gastric intubation and distension. Eleven healthy subjects (eight men, aged 21–30 years) were studied and a non-invasive beat-to-beat cardiovascular monitoring system was used. After 15-min basal recording, a bag catheter was positioned in the proximal stomach and connected to a barostat. Recordings were first performed for 15 min with the bag deflated, then during inflation of air using a 100 mL per 2 min stepwise protocol until epigastric discomfort was reported, and finally for 15 min with the bag inflated at 75% of discomfort volume separed from the preceding period by 10 min with the bag deflated. Presence of the deflated bag catheter significantly increased mean arterial pressure. Stepwise distension progressively increased heart rate and cardiac index, while mean arterial pressure was affected only at discomfort volume. Peripheral resistances and systemic plasma catecholamines were unaffected. During prolonged distension, the effect on heart rate and cardiac index was transient. In conclusion, both gastric intubation and distension alter cardiovascular parameters, but the effect of distension undergoes rapid adaptation. Experimentally induced gastric distension is a valuable stimulus to study viscero-cardiovascular reflexes and their mechanisms using beat-to-beat measurements.     

Intolerance to visceral distension in functional dyspepsia or irritable bowel syndrome: an organ specific defect or a pan intestinal dysregulation?

Functional gastrointestinal disorders (FGID) are characterized by visceral hypersensitivity that could be specific to a region of the gut or reflect a diffuse pan-intestinal disorder. Sensory thresholds to distension at two visceral sites in patients with different FGIDs were determined. According to Rome II criteria, 30 patients from three groups were studied: patients with (i) functional dyspepsia (FD) or (ii) irritable bowel syndrome (IBS), and (iii) patients with concomitant symptoms of FD and IBS. Pain thresholds to balloon distension were determined in stomach and rectum. In FD patients, gastric intolerance to balloon distension was found in 91% patients; rectal hypersensitivity was documented in 18% patients. In IBS patients, rectal hypersensitivity was seen in 75% patients; while gastric hypersensitivity was never found. In patients with concomitant symptoms of FD + IBS, gastric and rectal intolerance to distension were present respectively in 82 and 91% patients. In the whole group, visceral intolerance to distension was documented at one site in 90% patients and at both sites, i.e. stomach and rectum, in 33% patients. Visceral intolerance to distension can be pan-intestinal in patients with multiple sites of symptoms, but appears organ-specific in patients exhibiting a specific site of symptoms.     

Somatic afferent modulation of thoracic (T9‐T10) spinal neurons receiving gastric mechanical input in rats

Objectives: The aim was to determine whether somatic afferent fiber stimulation influences thoracic spinal neuronal activity responding to gastric distensions. Materials and Methods: Extracellular potentials of single T9‐T10 spinal neurons were recorded in anesthetized male rats. Ipsilateral median and peroneal nerve afferent stimulation (MNAS, PNAS) was delivered by electrodes. Inflation of a latex balloon was used to produce gastric distension. Results: MNAS and PNAS (1.5 mA, 50 Hz, 10 sec) altered activity of 63% and 66% of the spinal neurons excited or inhibited by gastric distension, respectively. MNAS more frequently reduced spinal neuronal activity with excitatory responses to gastric distension than did PNAS (p < 0.05). PNAS more likely increased neuronal activity with low‐threshold excitatory responses to gastric distension than MNAS (p < 0.05). Conclusions: Peripheral somatic afferent information utilizes central pathways to modulate gastric afferent processing in T9‐T10 spinal neurons. Thus, somatic afferent stimulation might be used to treat gastric pain and/or hypersensitivity.     

PET脑成像观察电针天枢穴治疗腹泻型肠易激综合征：脑内脏感觉中心的变化

题目：电针天枢穴治疗腹泻型肠易激综合征的PET脑成像研究 目的：运用脑功能成像正电子发射扫描技术（PET）,观察D-IBS患者在直肠扩张刺激下脑内脏感觉中心的功能变化,以及电针天枢穴对内脏感觉中心的影响,并初步探讨天枢穴治疗肠易激综合征的神经生物学机制。 方法：6例D-IBS患者（4例男性,2例女性）,其中4例行静息状态、直肠气囊扩张、直肠气囊扩张加电针天枢穴三状态下18F-FDG PET脑显像,2例行直肠气囊扩张、直肠气囊扩张加电针天枢穴两状态下18F-FDG PET脑显像,应用统计参数图（SPM）软件对患者静息状态和正常人静息状态、自身直肠气囊扩张前后、电针天枢穴前后脑PET图像进行配对t检验,分析比较脑局部葡萄糖代谢的差异,P值设为0.001。 结果：① 与正常人对照,D-IBS患者存在双侧颞上回、右枕中回、右额上回、双侧额中回等脑区的葡萄糖代谢增强,但内脏感觉中心并没有增强的表现;② 直肠气囊扩张前后对照,直肠疼痛刺激能使额前皮质、左侧扣带回、中央前后回、颞回等脑区的葡萄糖代谢增强,出现了内脏感觉中心如扣带前回等的激活;③ 电针天枢穴前后对照,电针天枢穴能使左侧扣带回、右侧脑岛、右侧海马旁回、楔前叶、右侧尾状核等脑区葡萄糖代谢降低,内脏感觉中心区域葡萄糖代谢明显降低。 结论：① IBS患者存在内脏敏感性异常,尤其是中枢内脏感觉网络的扣带前回、额前皮质等敏感性有升高的趋势。这可能是临床IBS腹痛、腹胀或腹部不适、腹泻等症状发生的重要的病理生理基础;② 电针天枢穴可以降低扣带回等内脏感觉中心的葡萄糖代谢率,该作用可能是电针天枢穴有效缓解IBS腹痛、腹泻等症状的神经生物学机制。电针天枢穴能削弱内脏高敏感性的原理,可能存在两条途径：一、在脊髓层面抑制内脏疼痛信息的上传;二、在丘脑层面通过整合内脏疼痛信息,抑制内脏感觉信息的上传。     

Relationship between symptom pattern, assessed by the PAGI-SYM© questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia

Abstract The patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) questionnaire was recently developed and validated for the evaluation of therapeutic responsiveness in functional dyspepsia (FD). Functional dyspepsia is a heterogeneous disorder, with different pathophysiological mechanisms underlying the symptom pattern. The relationship between PAGI‐SYM scores and putative pathophysiological mechanisms has not been studied. The aim of this study was to evaluate the relationship between PAGI‐SYM subscales and gastric emptying, gastric sensitivity and gastric accommodation in FD. A total of 161 consecutive FD patients underwent Helicobacter pylori (HP), gastric barostat and standardized gastric emptying testing (n = 126), and completed the PAGI‐SYM questionnaire. Relationships between scores for the six subscales (heartburn/regurgitation, nausea/vomiting, fullness/satiety, bloating, upper abdominal pain, lower abdominal pain) and gastric function were analysed using Pearson’s linear correlation, multiple regression analysis, chi‐square and Student’s t‐tests. Gastric emptying was significantly correlated with scores for heartburn/regurgitation (r = 0.26), nausea/vomiting (r = 0.19), fullness/satiety (r = 0.20), bloating (r = 0.21) and lower abdominal pain (r = 0.22; all P < 0.05). Patients with delayed emptying had significantly higher scores for each of these subscales (all P < 0.05). Discomfort volume during gastric distension was significantly correlated with scores for fullness/satiety (r = ?0.27), bloating (r = ?0.23), heartburn/regurgitation (r = ?0.21), and upper abdominal pain (r = ?0.20). Patients with hypersensitivity to distension had significantly higher scores for fullness/satiety (P < 0.05). At different cut‐off levels of symptom severities, consistent associations were found between fullness/satiety and gastric discomfort volume, between preprandial volumes and upper abdominal pain, compliance and upper abdominal pain, and between bloating and gastric discomfort volume. Multiple regression analysis revealed that gastric emptying rate contributed significantly to models for the severity of these subscales. The importance of discomfort volume disappeared in favour of gender when sex was included in the model. No significant correlations were found with HP status or with gastric accommodation. PAGI‐SYM scores are mainly correlated with gastric emptying rate and with gastric hypersensitivity. Multivariate analysis suggests that the questionnaire may be useful in the evaluation of gastroprokinetics. Its role in the evaluation of drugs that alter gastric sensitivity is less clear.     

Facilitation of gastric compliance and cardiovascular reaction by repeated isobaric distension of the rat stomach

Gastric distension causes cardiovascular reactions and enhances gastric compliance. Here, we investigated how these responses are related to each other, whether they change upon repeated distension and which neural mechanisms are involved. Mean arterial blood pressure (MAP) in phenobarbital-anaesthetized rats was recorded from a carotid artery and gastric compliance determined with an electronic barostat. Runs of intermittent gastric distension were generated by stepwise increments (5 mmHg) of intragastric (IG) pressure. While gastric compliance peaked at IG pressures of 20 mmHg, the change in MAP (predominantly hypotension) was largest at IG pressures beyond 30 mmHg. Repeated distension enhanced the MAP response to IG pressures beyond 35 mmHg, whereas gastric compliance was facilitated primarily at IG pressures below 20 mmHg. This facilitation of gastric compliance depended on the magnitude of the preceding distension. The MAP response to distension was enhanced by nitric oxide synthase inhibition, inhibited by subdiaphragmatic vagotomy but hardly affected by coeliac ganglionectomy. The facilitation of gastric compliance was changed by vagotomy in a complex manner but left unaltered by the other interventions. These findings show that isobaric gastric distension elicits both MAP and gastric compliance responses whose characteristics, mechanisms and sensitization properties differ profoundly.     

Diurnal variation of abdominal motor responses to colorectal distension and plasma cortisol levels in rats

Most patients with functional bowel disorders complain of daytime symptoms while they remain asymptomatic at night. As symptoms are associated with heightened visceral sensitivity, we hypothesized that circadian fluctuations of the visceral sensory function occur. At four different timepoints (06.00, 12.00, 18.00 and 24.00 h), colorectal distensions (CRD) were performed in fasting conscious male Lewis rats using a balloon catheter and a barostat device. The abdominal wall contractions (behavioural pain response) were assessed during colorectal distension by abdominal wall electromyography (EMG). Plasma levels for endogenous cortisol were determined simultaneously at these timepoints. EMG responses to CRD were significantly (P < 0.05) higher at midnight and in the early morning. Plasma cortisol levels peaked in the evening. In night-active Lewis rats, the behavioural pain response to noxious visceral stimulation is augmented at night and fluctuations of visceral sensitivity are accompanied by circadian changes of plasma concentrations of endogenous cortisol. We conclude that there are marked circadian fluctuations in visceral sensory functions. Thresholds are low during time periods of normal behavioural activity. These findings suggest that fluctuation of the sensory functions may be linked to the circadian variability of symptoms in patients with functional GI disorders.     

Novel pharmacology: asimadoline, a κ-opioid agonist, and visceral sensation

Abstract Asimadoline is a potent κ‐opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the κ receptor, with IC₅₀ of 5.6 nmol L^?1 (guinea pig) and 1.2 nmol L^?1 (human recombinant), and high selectively with κ : μ : δ binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post‐on‐demand treatment with asimadoline was not significantly reduced. Post hoc analyses suggest that asimadoline was effective in mixed IBS. In a 12‐week study in 596 patients, chronic treatment with 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain‐free days in patients with IBS‐D. The 1.0 mg dose was also efficacious in IBS‐alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date.     

The role of somatosensory cortical regions in the processing of painful gastric fundic distension: an update of brain imaging findings

Abstract  Painful gastric distension is processed in a network consisting of brainstem, thalamus, insula, anterior cingulate cortex, (lateral) orbitofrontal and prefrontal cortex, superior temporal cortex and cerebellum. However, the role of primary and secondary somatosensory cortical regions (SI/SII) in the processing of visceral sensation or pain in general and gastric sensation in particular remains unclear. The aim of this study was to localize activations in the SI/SII area from our previously published functional brain imaging studies on gastric distension more precisely, using newly available cytoarchitectonic probability maps of SI/SII, implemented in the SPM Anatomy toolbox. In healthy volunteers, we found two clusters to be overlapping with SII (mainly the OP4 subregion) and, to a lesser extent, SI, although this overlap was small in size. In functional dyspepsia patients, we found two clusters to be overlapping with SII (mainly OP4), of which the cluster in the right hemisphere also overlapped with SI. These findings were confirmed in a conjunction analysis of both groups. Activation in right SI/SII was significantly higher in healthy volunteers when formally compared to patients. These results provide more detailed information on the brain processing of gastric sensation, supporting the hypothesis that SI/SII are involved. This is in line with some previously published studies on visceral sensation, but at variance with some other studies. Methodological differences between the brain imaging studies on gastric distension may account for these somewhat discrepant findings.     

Altered brain activation to colorectal distention in visceral hypersensitive maternal-separated rats

Background Early life trauma can predispose to increased visceral pain perception. Human neuroimaging studies emphasize that altered brain processing may contribute to increased visceral sensitivity. The aim of our study was to evaluate brain responses to painful visceral stimuli in maternal‐separated rats before and after acute stress exposure in vivo. Methods H₂¹⁵O microPET scanning was performed during colorectal distention in maternal‐separated rats before and after water avoidance stress. Brain images were anatomically normalized to Paxinos space and analyzed by voxel‐based statistical parametric mapping (SPM2). Colorectal induced visceral pain was assessed by recording of the visceromotor response using abdominal muscle electromyography. Key Results Colorectal distention (1.0–2.0 mL) evoked a volume‐dependent increase in visceromotor response in maternal‐separated rats. Stress [water avoidance (WA)] induced an increased visceromotor response to colorectal distention in awake and anesthetized rats. In pre‐WA rats, colorectal distention evoked significant increases in regional blood flow in the cerebellum and periaquaductal gray (PAG). Colorectal distention post‐WA revealed activation clusters covering the PAG as well as somatosensory cortex and hippocampus. At maximal colorectal distention, the frontal cortex was significantly deactivated. Conclusions & Inferences WA stress induced increased pain perception as well as activation of the somatosensory cortex, PAG, and hippocampus in maternal‐separated rats. These findings are in line with human studies and provide indirect evidence that the maternal separation model mimics the cerebral response to visceral hypersensitivity in humans.     

Do we have an alternative for the Rome III gastroduodenal symptom‐based subgroups in functional gastroduodenal disorders? A cluster analysis approach

Background Functional dyspepsia (FD) is a heterogeneous biopsychosocial disorder. The Rome III consensus proposed a subdivision into epigastric pain syndrome and postprandial distress syndrome, based on gastroduodenal symptom pattern only; nausea/vomiting‐ and belching disorders were classified as separate functional gastroduodenal disorders (FGD). We aimed to investigate an alternative subdivision of FGD, taking into account gastric sensorimotor function, anxiety & depression and ‘somatization’, besides gastroduodenal symptoms. Methods Gastroduodenal symptom data were available for 857 consecutive FGD patients (Rome II criteria). In a subsample (n = 259), additional data were obtained on gastric sensitivity, anxiety, depression and ‘somatization’. Two separate cluster analyses were performed. In analysis 1, clustering was based on individual gastroduodenal symptom scores. In analysis 2, gastric sensitivity, anxiety & depression and ‘somatization’, besides total gastroduodenal symptoms score, were used for clustering. Key Results Analysis 1 identified four clusters, largely supporting the Rome III classification, with early satiation, pain and nausea/vomiting clusters, besides a limited severity cluster (R² = 0.32). Analysis 2 suggested a five‐cluster solution (R² = 0.48). Anxiety, depression and ‘somatization’ were the most important variables separating the clusters. ‘Primary somatization’ (with low psychiatric symptom levels) as well as ‘secondary somatization’ (with high anxiety & depression scores) subgroups were identified, besides three other subgroups characterized by psychiatric/gastroduodenal symptoms, mild anxiety symptoms and limited overall severity, respectively. Conclusions & Inferences We propose an alternative to the current subgrouping in FGD that is exclusively based on gastroduodenal symptoms. This may have consequences for future classification of FGD, as well as broader relevance towards the debate on subgrouping ‘functional somatic syndromes’.