Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required

Coping Skills Are Associated With Gastrointestinal Symptom Severity and Somatization in Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS: Coping resources and processes are altered in patients with irritable bowel syndrome (IBS). We investigated the relationship between coping resources and gastrointestinal (GI) and extraintestinal symptom severity in patients with IBS and potential mediators of this relationship. METHODS: We performed a cross-sectional study of 216 patients with IBS attending a secondary/tertiary care specialized outpatient center in Sweden from 2003 through 2007. We collected data on coping resources, levels of anxiety (general and GI specific), depressive symptoms, levels of GI symptoms, and extraintestinal somatic symptoms (somatization) by administering validated self-report questionnaires. General Linear Models were used to assess associations and mediation. RESULTS: GI symptoms: low levels of physical coping resources (practice of activities that are beneficial for health; P = .0016), high levels of general anxiety symptoms (P = .033), and GI-specific anxiety symptoms (P < .0001), but not depressive symptoms (P = .89), were independently associated with GI symptom levels (R2 = 0.31). Anxiety and GI-specific anxiety partially mediated the effect of physical coping. Somatization: low levels of physical coping resources (P = .003), high levels of anxiety (P = .0147), depressive (P = .0005), and GI-specific anxiety symptoms (P = .06) were associated with somatization levels (R2 = 0.35). Levels of general and GI-specific anxiety and depressive symptoms partially mediated this physical coping effect. The effect of psychological coping resources (including optimism, social support, and accepting/expressing emotions) on somatization levels was not significant (P = .98), but was fully mediated by levels of anxiety and depressive symptoms, and partially by levels of GI-specific anxiety symptoms. CONCLUSIONS: In a cross-sectional study of patients with IBS in Sweden, we found associations of levels of coping resources with GI and extraintestinal symptom severity; these associations were mediated by levels of anxiety and depressive symptoms. Although confirmation in longitudinal studies is needed, this identifies coping as a potential psychological treatment target in IBS

The three R’s of scientific integrity:Replicability, reproducibility, and robustness

It has been proposed that memory retrieval can destabilize consolidated memories, after which they need to be reconsolidated in order to be retained. The presentation of relevant information during memory reconsolidation could then result in the modification of a destabilized memory trace, by allowing the memory trace to be updated before being reconsolidated. In line with this idea, Schiller et al. (2010) have demonstrated that memory retrieval shortly before extinction training can prevent the later recovery of conditioned fear responding that is observed after regular extinction training. Those findings have been the subject of considerable controversy, due in part to theoretical reasons but also due to a number of failures to obtain similar results in conceptual replication attempts. Here, we report the results of a highly powered, direct, independent replication of the critical conditions of Schiller et al. (2010, Experiment 1). Due to misrepresentation of the exclusion criteria in the original Schiller et al. (2010) report, data collection was considerably delayed. When we eventually managed to attain our pre-registered sample size, we found that we could not observe any benefit of reactivation-extinction over regular extinction training in preventing recovery of conditioned fear. The results of the present study, along with the mixed findings in the literature and the misreporting in Schiller et al. (2010), give cause to question whether there is robust evidence that reactivation-extinction prevents the return of fear in humans.status: publishe

Poor subjective sleep quality predicts symptoms in Irritable Bowel Syndrome using the Experience Sampling Method

OBJECTIVES: Sleep quality may impact symptom experience in Irritable Bowel Syndrome (IBS). Our aim was to investigate the relationship between sleep quality and gastrointestinal (GI) symptoms using actigraphy and the Experience Sampling Method (ESM). METHODS: IBS patients were recruited from a tertiary Neurogastroenterology clinic and the community. GI symptoms and mood were recorded on a smartphone application, ten times per day, over seven consecutive days. Subjective sleep quality was recorded every morning to reflect the night before. Objective measures of sleep quality were estimated from wrist-worn actigraphy. Cross-lagged structural equation models were built to assess the directionality of sleep-symptom relationships over time. RESULTS: Eighty IBS patients completed the study (mean age: 37 (range 20 - 68), 89% female, 78% community). Sixty-six % had a Pittsburgh Sleep Quality Index (PSQI) score ≥ 8 indicating a clinically significant sleep disturbance. Eighty-two % (95% CI: 72-90) screened positive for a sleep disorder, most commonly insomnia. In cross-lagged analysis, poor subjective sleep quality predicted next day abdominal pain (0.036 < p < 0.040) and lower GI symptoms (0.030 < p < 0.032), but not vice versa. No significant relationship with GI symptoms was found for any objective sleep measure using actigraphy. CONCLUSIONS: Poor subjective sleep quality was associated with higher next day lower GI symptom levels, but not vice versa. Objective sleep measures did not predict next day abdominal symptoms, potentially supporting the conclusion that it is the perception of sleep quality which is most influential. This study may be used to guide future research into the effect of sleep interventions on GI symptoms

Erythritol and xylitol differentially impact brain networks involved in appetite regulation in healthy volunteers

Background: There is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown. Aim: The study’s objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release. Methods: The study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose. Results: We found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin. Conclusion: Xylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose

Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts

The functional gastrointestinal disorders (FGIDs), are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances. Methods: A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs. Results: Five criteria are proposed: 1) presence of the abnormality in a subset of patients; 2) temporal association between proposed mechanism and symptom(s); 3) correlation between the level of impairment of the mechanism and symptom(s); 4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and 5) treatment response by a therapy specifically correcting the underlying disorder, or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these 5 criteria, a plausibility score is proposed. Conclusion: Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these 5 plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies

Global prevalence and burden of meal-related abdominal pain

BACKGROUND: Patients with disorders of gut-brain interaction (DGBI) report meal intake to be associated with symptoms. DGBI patients with meal-related symptoms may have more severe symptoms overall and worse health outcomes, but this subgroup has not been well characterized. We aimed to describe the global prevalence of meal-related abdominal pain and characterize this subgroup. METHODS: The data analyzed originated from the Internet survey component of the population-based Rome Foundation Global Epidemiology Study, completed in 26 countries (n = 54,127). Adult subjects were asked whether they had abdominal pain and how often this was meal-related. Respondents were categorized into no, occasional, and frequent meal-related abdominal pain groups based on 0%, 10-40%, and ≥50% of the pain episodes being meal-related, respectively. DGBI diagnoses, frequency of other GI symptoms, psychological distress, non-GI somatic symptoms, quality of life, and healthcare utilization were compared between groups. Mixed linear and ordinal regression was used to assess independent associations between psychological distress, non-GI somatic symptoms, quality of life, other GI symptoms, and meal-related abdominal pain. RESULTS: Overall, 51.9% of the respondents reported abdominal pain in the last 3 months, and 11.0% belonged to the group with frequent meal-related abdominal pain, which included more females and younger subjects. DGBI diagnoses were more common in subjects with frequent meal-related abdominal pain, and the frequency of several GI symptoms was associated with having more frequent meal-related abdominal pain. Having meal-related abdominal pain more frequently was also associated with more severe psychological distress, non-GI somatic symptoms, and a poorer quality of life. The group with frequent meal-related abdominal pain also more often consulted a doctor for bowel problems compared to the other groups of meal-related abdominal pain. CONCLUSION: Reporting frequent meal-related abdominal pain is common across the globe and associated with other GI and non-GI somatic symptoms, psychological distress, healthcare utilization, and a poorer quality of life. Individuals who frequently experience meal-related abdominal pain also more frequently fulfill the diagnostic criteria for DGBI. Assessing meal-related symptoms in all DGBI patients could be of major importance to improve and individualize symptom management

Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers

Background: Denatonium benzoate (DB) has been shown to influence ongoing ingestive behavior and gut peptide secretion.Objective: We studied how the intragastric administration of DB affects interdigestive motility, motilin and ghrelin plasma concentrations, hunger and satiety ratings, and food intake in healthy volunteers.Design: Lingual bitter taste sensitivity was tested with the use of 6 concentrations of DB in 65 subjects. A placebo or 1 μmol DB/kg was given intragastrically to assess its effect on fasting gastrointestinal motility and hunger ratings, motilin and ghrelin plasma concentrations, satiety, and caloric intake.Results: Women (n = 39) were more sensitive toward a lingual bitter stimulus (P = 0.005) than men (n = 26). In women (n = 10), intragastric DB switched the origin of phase III contractions from the stomach to the duodenum (P = 0.001) and decreased hunger ratings (P = 0.04). These effects were not observed in men (n = 10). In women (n = 12), motilin (P = 0.04) plasma concentrations decreased after intragastric DB administration, whereas total and octanoylated ghrelin were not affected. The intragastric administration of DB decreased hunger (P = 0.008) and increased satiety ratings (P = 0.01) after a meal (500 kcal) in 13 women without affecting gastric emptying in 6 women. Caloric intake tended to decrease after DB administration compared with the placebo (mean ± SEM: 720 ± 58 compared with 796 ± 45 kcal; P = 0.08) in 20 women.Conclusions: Intragastric DB administration decreases both antral motility and hunger ratings during the fasting state, possibly because of a decrease in motilin release. Moreover, DB decreases hunger and increases satiety ratings after a meal and shows potential for decreasing caloric intak

Startle responding in the context of visceral pain

This study aimed to investigate affective modulation of eye blink startle by aversive visceral stimulation. Startle blink EMG responses were measured in 31 healthy participants receiving painful, intermittent balloon distentions in the distal esophagus during 4 blocks (positive, negative, neutral or no pictures), and compared with startles during 3 ‘safe’ blocks without esophageal stimulations (positive, negative or neutral emotional pictures). Women showed enhanced startle during blocks with distentions (as compared with ‘safe’ blocks), both when the balloon was in inflated and deflated states, suggesting that fear and/or expectations may have played a role. Men's startle did not differ between distention and non-distention blocks. In this particular study context affective picture viewing did not further impose any effect on startle eye blink responses. The current results may contribute to a better understanding of emotional reactions to aversive interoceptive stimulation

Learned Fear of Gastrointestinal Sensations in Healthy Adults

Background & Aims Gastrointestinal symptom-specific fear and anxiety are important determinants of gastrointestinal symptom perception. We studied learning of fear toward innocuous gastrointestinal sensations as a putative mechanism in the development of gastrointestinal symptom-specific fear and anxiety. Methods Fifty-two healthy subjects (26 women) received 2 types of esophageal balloon distention at a perceptible but nonpainful intensity (conditioned stimulus [CS], the innocuous sensation) and at a painful intensity (unconditioned stimulus [US]). Subjects were assigned randomly to 1 of 2 groups. During the learning phase, the innocuous CS preceded the painful US in the experimental group (n = 26). In the control group (n = 26), on the contrary, the US never followed the CS directly. During a subsequent extinction phase, both groups received only CS distention—the painful US was no longer administered. Indexes of fear learning toward the innocuous CS distention included the skin conductance response, fear-potentiated startle (measured by the eye-blink electromyogram), and self-reported expectancy of the US. Results During the learning phase, only the experimental group learned to fear the innocuous gastrointestinal CS, based on the increase in US expectancy (compared with the control group, P = .04), increased skin conductance response (compared with the control group, P = .03), and potentiated startle reflex (compared with the control group, P = .001) in response to the CS. The differences between the experimental and control groups in US expectancy and skin conductance, but not fear-potentiated startle, disappeared during the extinction phase. Conclusions Fear toward innocuous gastrointestinal sensations can be established through associative learning in healthy human beings. This may be an important mechanism in the development of fear of gastrointestinal symptoms, implicated in the pathophysiology of functional gastrointestinal disorders