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BackgroundIncreased attention to gastrointestinal (GI) symptoms and disease-specific contexts may play an important role in the enhanced perception of visceral stimuli frequently reported in patients with irritable bowel syndrome (IBS). In this study, we test the hypothesis that altered attentional mechanisms underlie central pain amplification in IBS.MethodsTo evaluate brain networks that support alerting, orienting, and executive attention, we employed the attention network test (ANT), a modified flanker task which measures the efficiency of functioning of core attentional networks, during functional magnetic resonance imaging in 15 IBS patients (mean age=31 [11.96]) and 14 healthy controls (HCs; mean age=31 [10.91]).Key resultsPatients with IBS, compared to HCs, showed shorter reaction times during the alerting and orienting conditions which were associated with greater activation of anterior midcingulate and insular cortices, and decreased activity in the right inferior frontal junction and supplementary motor cortex. Patients also showed activation in the dorsal medial prefrontal cortex and concurrent thalamic deactivation during the executive control portion of the ANT relative to HCs, but no group difference in reaction times were found. The activity in brain regions showing group differences during the ANT were associated with measures of GI-specific anxiety, pain catastrophizing, and fear of uncertainty. In IBS, activity in the anterior midcingulate during alerting correlated with duration of GI-symptoms and overall symptom severity.Conclusions & inferencesTogether, these results suggest that IBS patients have specific abnormalities in attentional network functioning and these deficits may underlie symptom-related anxiety, hypervigilance, and visceral hypersensitivity.

Alterations in gray matter (GM) density/volume and cortical thickness (CT) have been demonstrated in small and heterogeneous samples of subjects with differing chronic pain syndromes, including irritable bowel syndrome (IBS). Aggregating across 7 structural neuroimaging studies conducted at University of California, Los Angeles, Los Angeles, CA, USA, between August 2006 and April 2011, we examined group differences in regional GM volume in 201 predominantly premenopausal female subjects (82 IBS, mean age: 32 ± 10 SD, 119 healthy controls [HCs], 30 ± 10 SD). Applying graph theoretical methods and controlling for total brain volume, global and regional properties of large-scale structural brain networks were compared between the group with IBS and the HC group. Relative to HCs, the IBS group had lower volumes in the bilateral superior frontal gyrus, bilateral insula, bilateral amygdala, bilateral hippocampus, bilateral middle orbital frontal gyrus, left cingulate, left gyrus rectus, brainstem, and left putamen. Higher volume was found in the left postcentral gyrus. Group differences were no longer significant for most regions when controlling for the Early Trauma Inventory global score, with the exception of the right amygdala and the left postcentral gyrus. No group differences were found for measures of global and local network organization. Compared to HCs, in patients with IBS, the right cingulate gyrus and right thalamus were identified as being significantly more critical for information flow. Regions involved in endogenous pain modulation and central sensory amplification were identified as network hubs in IBS. Overall, evidence for central alterations in patients with IBS was found in the form of regional GM volume differences and altered global and regional properties of brain volumetric networks.

Abnormal responses of the brain to delivered and expected aversive gut stimuli have been implicated in the pathophysiology of irritable bowel syndrome (IBS), a visceral pain syndrome occurring more commonly in women. Task-free resting-state functional magnetic resonance imaging (fMRI) can provide information about the dynamics of brain activity that may be involved in altered processing and/or modulation of visceral afferent signals. Fractional amplitude of low-frequency fluctuation is a measure of the power spectrum intensity of spontaneous brain oscillations. This approach was used here to identify differences in the resting-state activity of the human brain in IBS subjects compared with healthy controls (HCs) and to identify the role of sex-related differences. We found that both the female HCs and female IBS subjects had a frequency power distribution skewed toward high frequency to a greater extent in the amygdala and hippocampus compared with male subjects. In addition, female IBS subjects had a frequency power distribution skewed toward high frequency in the insula and toward low frequency in the sensorimotor cortex to a greater extent than male IBS subjects. Correlations were observed between resting-state blood oxygen level-dependent signal dynamics and some clinical symptom measures (e.g., abdominal discomfort). These findings provide the first insight into sex-related differences in IBS subjects compared with HCs using resting-state fMRI.

Background & Aims The study of intrinsic fluctuations in the blood oxygen level-dependent signal of functional magnetic resonance imaging can provide insight into the effect of physiologic states on brain processes. In an effort to better understand the brain−gut communication induced by the absorption and metabolism of nutrients in healthy lean and obese individuals, we investigated whether ingestion of nutritive and non-nutritive sweetened beverages differentially engages the hypothalamus and brainstem vagal pathways in lean and obese women. Methods In a 2-day, double-blind crossover study, 11 lean and 11 obese healthy women underwent functional magnetic resonance imaging scans after ingestion of 2 beverages of different sucrose content, but identical sweetness. During scans, subjects rested with eyes closed. Results Blood oxygen level-dependent fluctuations demonstrated significantly greater power in the highest frequency band (slow-3: 0.073−0.198 Hz) after ingestion of high-sucrose compared with low-sucrose beverages in the nucleus tractus solitarius for both groups. Obese women had greater connectivity between the right lateral hypothalamus and a reward-related brain region and weaker connectivity with homeostasis and gustatory-related brain regions than lean women. Conclusions In a functional magnetic resonance imaging study, we observed sucrose-related changes in oscillatory dynamics of blood oxygen level-dependent fluctuations in brainstem and hypothalamus in lean and obese women. The observed frequency changes are consistent with a rapid vagally mediated mechanism due to nutrient absorption, rather than sweet taste receptor activation. These findings provide support for altered interaction between homeostatic and reward networks in obese individuals.

Background & Aims Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). Methods We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. Results Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls - an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. Conclusions Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain. © 2013 by the AGA Institute.

Central sensitization and dysregulation of peripheral substance P and neurokinin-1 receptor (NK-1R) signaling are associated with chronic abdominal pain in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although positron emission tomography (PET) has demonstrated that patients with injury-related chronic pain have diminished NK-1R availability in the brain, it is unknown whether these deficits are present in IBD and IBS patients, who have etiologically distinct forms of non-injury-related chronic pain. This study's aim was to determine if patients with IBD or IBS exhibit deficits in brain expression of NK-1Rs relative to healthy controls (HCs), the extent to which expression patterns differ across patient populations, and if these patterns differentially relate to clinical parameters. PET with [(18)F]SPA-RQ was used to measure NK-1R availability by quantifying binding potential (BP) in the 3 groups. Exploratory correlation analyses were performed to detect associations between NK-1R BP and physical symptoms. Compared to HCs, IBD patients had NK-1R BP deficits across a widespread network of cortical and subcortical regions. IBS patients had similar, but less pronounced deficits. BP in a subset of these regions was robustly related to discrete clinical parameters in each patient population. Widespread deficits in NK-1R BP occur in IBD and, to a lesser extent, IBS; however, discrete clinical parameters relate to NK-1R BP in each patient population. This suggests that potential pharmacological interventions that target NK-1R signaling may be most effective for treating distinct symptoms in IBD and IBS.

Background & Aims Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. Methods Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis , Streptococcus thermophiles , Lactobacillus bulgaricus , and Lactococcus lactis subsp Lactis . Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. Results FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. Conclusions Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.

We hypothesized that alterations of this network can accompany the cognitive abnormalities observed in cirrhotic patients. The aim of the present study, therefore, was to determine and compare the resting functional connectivity of the DMN between healthy controls and cirrhotic patients with and without MHE. Methods: 30 cirrhotics (17 with MHE and 13 without MHE) [Table 1] and 16 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI). Standard pre-processing was completed using Analysis of Functional NeuroImages (AFNI). Seed-based large-scale network was employed in the DMN and significant changes in connectivity were investigated. Correlation between activity in 14 apriori selected regions of interest (ROIs) of the DMN based on coordinates published in the literature were assessed. Unpaired t-test was used to differentiate the z-scored correlation coefficients between the ROI pairs and was corrected for multiple comparisons using false discovery rate (FDR). Results: Large-scale network analysis of the DMN showed significant differences in connectivity among controls and cirrhotics with MHE. Significant differences in connectivity were seen between the right posterior cingulate and the left posterior cingulate as well as between the right anterior cingulate and the right precuneus (p=0.004) [Figure 1]. Analysis also showed significant differences between cirrhotics with and without MHE. The significant differences included the right inferior parietal and the left anterior cingulate (p=0.006) [Figure 2]. There were no significant differences seen between controls and cirrhotics without MHE. Conclusion: Cirrhotic patients withminimal hepatic encephalopathy (MHE) exhibit significant alteration of the brain default-mode network when compared to cirrhotics without MHE and healthy controls Demographics

Background: Ingestion of sweet food is driven by central reward circuits and restrained by interoceptive satiety signals. Obesity is in part related to an upregulation of these reward mechanisms in association with a downregulation of vagally mediated satiety mechanisms. The specific influence of sucrose intake on central affective and reward circuitry, and differences in these influences in the obese population is incompletely understood.Hypotheses: 1) Similar brain regions are engaged by the stimulation of sweet taste receptors by sucrose and by non-nutrient sweeteners. 2) During visual food related cues, obese subjects show greater brain responses specifically to sucrose compared to lean controls.Methods: In a two-day, double blind, crossover design, 10 obese and 10 lean healthy females received either a sucrose or a non-nutrient sweetened beverage prior to viewing agreeable food or neutral images. BOLD signal was measured using a 1.5Tesla MRI scanner. Results: Viewing food images after ingestion of either the sucrose or the non-nutrient drink was associated with engagement of similar brain regions, including the amygdala, hippocampus, thalamus and dorsolateral prefrontal cortex, Obese differed from lean subjects in both behavioral and brain responses: While obese subjects rated both beverages as less tasteful and satisfying, they showed greater brain responses. Obese subjects also showed engagement of an additional brain network (including anterior insular and anterior cingulate cortices, hippocampus, amygdala), and this was only seen after sucrose ingestion.Conclusion: Obese subjects had a reduced behavioral hedonic response yet a greater engagement of affective brain networks in response to food images, particularly after sucrose ingestion. These findings suggests that in obese subjects lingual and gut derived signaling generate less central hedonic effects than recalling memories of food experiences in response to visual cues, analogous to response patterns implicated in food addiction.

Background. Converging evidence suggests that increased attention to afferent signals from the gut plays an important role in the increased perceptual response to visceral stimuli reported in irritable bowel syndrome (IBS). We hypothesize that prefrontal circuitry controlling attention to threat-related stimuli is less efficient in IBS patients compared to healthy controls (HCs). Aims. To quantify and compare the efficiency of cognitive control regions underlying selective attention to threat-related stimuli between IBS patients and HCs, using a GI symptom unrelated paradigm. Methods. We measured brain response (Siemens 3 Tesla Trio MRI scanner) in 32 females (16 IBS patients, 16 HCs) during administration of the house face matching task, a cognitive task developed and validated to test selective attention to threatening stimuli as well as index processing of task-irrelevant threat stimuli. Subjects were presented with pictures of pairs of houses and faces (fearful or neutral) arranged in a vertical or horizontal orientation around a central fixation cross. During the task subjects were asked to match either houses or faces.. SPM8 was employed to preprocess and analyze the imaging data using the general linear model and a region of interest analysis examining cognitive control and emotional arousal regions. Results were considered significant at p

Background. Converging evidence suggests that increased attention to afferent signals from the gut plays an important role in the increased perceptual response to visceral stimuli reported in irritable bowel syndrome (IBS). We hypothesize that prefrontal circuitry controlling attention to threat-related stimuli is less efficient in IBS patients compared to healthy controls (HCs). Aims. To quantify and compare the efficiency of cognitive control regions underlying selective attention to threat-related stimuli between IBS patients and HCs, using a GI symptom unrelated paradigm. Methods. We measured brain response (Siemens 3 Tesla Trio MRI scanner) in 32 females (16 IBS patients, 16 HCs) during administration of the house face matching task, a cognitive task developed and validated to test selective attention to threatening stimuli as well as index processing of task-irrelevant threat stimuli. Subjects were presented with pictures of pairs of houses and faces (fearful or neutral) arranged in a vertical or horizontal orientation around a central fixation cross. During the task subjects were asked to match either houses or faces.. SPM8 was employed to preprocess and analyze the imaging data using the general linear model and a region of interest analysis examining cognitive control and emotional arousal regions. Results were considered significant at p

Background: IBS patients are known to attribute high relevance to interoceptive signals from the gut and show selective attention to perceived threat from such signals. Based on these clinical observations, one would expect that IBS patients show stronger interference of mild rectal distention with attention tasks. It is unclear, however, if such interference is independent of the difficulty (load) of the attention task, with high, but not low attentional loads overriding the visceral perception. In this case focusing away from the symptoms might be sufficient to control them, otherwise a direct and relevant impact of the symptoms on every day life would supported without the option just to focus away. We therefore studied the influence of visceral stimuli on a letter search task. Methods: 19 IBS patients and 20 healthy controls (HCs) completed a validated high and low load attention letter search task during randomly ordered 20s blocks of mild rectal distention (20mmHg) or baseline (5mmHg). Subjects were instructed to focus exclusively on the attention task and to ignore the balloon, while functional brain images were acquired on a 3T MRI scanner. Image preprocessing included realignment, normalization to MNI space using a high-dimensional DARTEL-warp, and smoothing. Effects of interest were attention processing irrespective of distracting balloon inflations, as well as the interaction between attention processing and those distensions. All results were thresholded at p≤0.05 (FWE cluster level corrected). Results: Performing the high-load attention task itself was associated with stronger activations in HCs versus IBS in dorsal and ventral visual stream as well as parietal and frontal regions. These differences were much less pronounced during low load. Rectal distention during low load tasks was associated with significantly less activation of ventral and dorsal visual stream activity as well as sensorimotor areas, without group differences. However, during high attentional load, rectal distention had no significant effect in HC, while IBS showed significantly reduced activation in the dorsal and ventral visual stream, and right sensorimotor areas. Conclusions: Differences between IBS and HC were observed particularly during high attention load tasks, providing evidence for a direct impact of mild visceral stimuli on attentional processes in IBS. This may be interpreted as a deficit in suppressing distracting information from the viscera, preventing the full utilization of attention switching resources to efficiently solve the demanding attention task. This interpretation is further supported by the observation that brain areas associated with the localization and recognition of target letters (including ventral and dorsal visual stream) were affected. Supported by NIH grants DK048351, DK064539, AT002681 (EAM); DK071626, DK084169 (JSL)