Jennifer S. Labus

Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity

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.

Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis

&NA; Patients with mild chronic inflammation of the rectum or ileum have reduced perceptual responses to rectosigmoid distension compared to patients with irritable bowel syndrome (IBS). The current study sought to identify differences in regional cerebral blood flow (rCBF) during rectal distension, which might correspond to these perceptual differences. In 8 male ulcerative colitis (UC) patients with quiescent disease, 7 male IBS patients and 7 healthy male controls, rCBF was assessed using 15O‐water positron emission tomography at baseline and during actual and anticipated but undelivered rectal distensions. No group differences were seen in anterior insula and dorsal anterior cingulate cortex (dACC), two regions consistently activated by painful intestinal stimuli. However, IBS patients showed greater activation of the amygdala, rostroventral ACC, and dorsomedial frontal cortical regions. In contrast, no significant differences were observed between UC and controls. When these two non‐IBS groups were combined, functional connectivity analyses showed that right lateral frontal cortex (RLFC) activation positively correlated with activation of the dorsal pons/periaqueductal gray, a key region involved in endogenous pain inhibition. According to the connectivity analysis, this effect was mediated by inhibition of medial frontal cortex by the RLFC. Chronic colonic inflammation is not necessarily associated with increased visceral afferent input to the brain during rectal distension. In the sample studied, the primary difference between functional and quiescent inflammatory disease of the colon was in terms of greater activation of limbic/paralimbic circuits in IBS, and inhibition of these circuits in UC and controls by the RLFC.

Quantitative Meta-analysis Identifies Brain Regions Activated During Rectal Distension in Irritable Bowel Syndrome

BACKGROUND AND AIMS The responsiveness of the central nervous system is altered in patients with irritable bowel syndrome (IBS). However, because of variations in experimental paradigms, analytic techniques, and reporting practices, little consensus exists on brain responses to visceral stimulation. We aimed to identify brain regions consistently activated by supraliminal rectal stimulation in IBS patients and healthy subjects (controls) by performing a quantitative meta-analysis of published studies. METHODS Significant foci from within-group statistical parametric maps were extracted from published neuroimaging studies that employed rectal distension. Voxel-based activation likelihood estimation was applied, pooling the results and comparing them across groups. RESULTS Across studies, there was consistent activation in regions associated with visceral afferent processing (ie, thalamus, insula, anterior midcingulate) among IBS patients and controls, but considerable differences in the extent and specific location of foci. IBS patients differed from controls in that there were more consistent activations in regions associated with emotional arousal (pregenual anterior cingulate cortex, amygdala) and activation of a midbrain cluster, a region playing a role in endogenous pain modulation. Controls showed more consistent activation of the medial and lateral prefrontal cortex. CONCLUSIONS Patients with IBS have greater engagement of regions associated with emotional arousal and endogenous pain modulation, but similar activation of regions involved in processing of visceral afferent information. Controls have greater engagement of cognitive modulatory regions. These results support a role for central nervous system dysregulation in IBS. These findings provide specific targets for guiding development of future neuroimaging protocols to more clearly define altered brain-gut interactions in IBS.

Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome

Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention. The brain functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to anticipated and delivered mild and moderate rectal distention was recorded from 14 female IBS patients and 12 healthy controls. During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls. IBS patients showed less anticipatory inactivation. Group differences were significant in the right posterior insula and bilateral DBS. Self-rated measures of negative affect during scanning were higher in patients than controls (p < 0.001), and the anticipatory BOLD decreases in DBS were inversely correlated with these ratings. During subsequent distention, both groups showed activity increases in insula, dorsal ACC, and DBS and decreases in the infragenual ACC. The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS. The amplitude of the anticipatory decrease in the pontine portion of DBS was associated with greater activation during distention in right orbitofrontal cortex and bilateral sACC. Both regions have been associated previously with corticolimbic inhibition and cognitive coping. Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS.

The Visceral Sensitivity Index: development and validation of a gastrointestinal symptom-specific anxiety scale.

Background : Anxiety related to gastrointestinal sensations, symptoms or the contexts in which these may occur is thought to play a significant role in the pathophysiology as well as in the health outcomes of patients with irritable bowel syndrome.

Regional Gray Matter Density Changes in Brains of Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS Several studies have examined structural brain changes associated with chronic pain syndromes, including irritable bowel syndrome (IBS), but study sample sizes have been small and heterogeneous. METHODS We used magnetic resonance imaging-based techniques, voxel-based morphometry, and cortical thickness analysis to examine brain anatomical differences in a relatively large, tightly screened sample of IBS patients (n = 55); we compared data with that from healthy persons (controls; n = 48). RESULTS IBS was associated with decreased gray matter density (GMD) in widespread areas of the brain, including medial prefrontal and ventrolateral prefrontal cortex, posterior parietal cortex, ventral striatum, and thalamus. Compared with controls, we observed increased GMD in patients with IBS in the pregenual anterior cingulate cortex and the orbitofrontal cortex, as well as trends in the posterior insula/secondary somatosensory cortex, (para)hippocampus, and left dorsolateral prefrontal cortex. In accounting for anxiety and depression, we found that several of the regions involved in affective processing no longer differed between patients with IBS and controls, whereas the differences in prefrontal and posterior parietal cortices remained. The areas of decreased GMD associated with IBS were largely consistent across clinical subgroups, based on predominant bowel habit and pain predominance of symptoms. No overall or regional differences were observed in cortical thickness between patients with IBS and controls. CONCLUSIONS Changes in density of gray matter among regions involved in cognitive/evaluative functions are specifically observed in patients with IBS, whereas changes in other areas of the brain can be explained by levels of anxiety and depression.

The central role of gastrointestinal-specific anxiety in irritable bowel syndrome: further validation of the visceral sensitivity index.

Objectives: The Visceral Sensitivity Index (VSI) was developed as the first instrument to assess gastrointestinal-specific anxiety, the cognitive, affective, and behavioral response to fear of gastrointestinal sensations, symptoms, and the context in which these visceral sensations and symptoms occur. The purpose of the current study was to a) replicate the previously reported psychometric properties of the VSI, b) assess the known-groups and concurrent validity of the instrument, and c) test conceptual hypotheses regarding gastrointestinal-specific anxiety in comparison to other general measures of psychological distress as a crucial mechanism (mediator/moderator) underlying irritable bowel syndrome diagnosis and its symptoms. Methods: Two undergraduate student samples (n > 500) were administered the VSI along with measures assessing presence of lower gastrointestinal symptoms, nongastrointestinal pain, health-service utilization, anxiety, depression, vitality, neuroticism, and anxiety sensitivity. Path analyses tested the hypothesis that gastrointestinal-specific anxiety mediates the relationship between affective variables and irritable bowel syndrome diagnosis and symptoms. A ‘known-groups’ validity approach elucidated the relevance of gastrointestinal-specific anxiety across a spectrum of irritable bowel syndrome patients. Results: Good concurrent, divergent and discriminant validity was demonstrated. Logistic regression revealed that gastrointestinal-specific anxiety is the key explanatory variable of irritable bowel syndrome diagnostic status. Path analysis demonstrated that gastrointestinal-specific anxiety mediates the relationship between general psychological distress measures and gastrointestinal symptom severity. The VSI was related to gastrointestinal, but not nongastrointestinal, symptom severity. Conclusions: Overall, the VSI demonstrated excellent psychometric properties providing further support for its use in mechanistic studies of the role of anxiety in irritable bowel syndrome presentation. ANX = anxiety; ASI = Anxiety Sensitivity Index; BSQ-SF = Bowel Symptom Questionnaire-Short Form; DEP = depression; EPQN = Eysenck Personality Questionnaire-Short Form; GI = gastrointestinal; HAD = Hospital Anxiety and Depression Scale; IBS = irritable bowel syndrome; VIT = Medical Outcomes Study-SF-36 energy/fatigue subscale; VSI = Visceral Sensitivity Index.

Brain imaging approaches to the study of functional GI disorders: A Rome Working Team Report

Abstract  Progresses in the understanding of human brain‐gut interactions in health and disease have been limited by the lack of non‐invasive techniques to study brain activity. The advent of neuroimaging techniques has made it possible not only to study the structure and function of the brain, but also to characterize signaling system underlying brain function. This article gives a brief overview of relevant functional neuroanatomy, and of the most commonly used brain imaging techniques. It summarizes published functional brain imaging studies using acute visceral stimulation of the oesophagus, stomach and colon in healthy control subjects and patients with functional GI disorders, and briefly discusses pertinent findings from these studies. The article concludes with a critical assessment of published studies, and with recommendations for improved study paradigms and analysis strategies.

Sex specific alterations in autonomic function among patients with irritable bowel syndrome

Background: Irritable bowel syndrome (IBS) is associated with increased psychological symptoms, early life stressors, and alterations in visceral perception and brain responses to noxious visceral stimuli. The autonomic nervous system (ANS) is a likely mediator for these brain-gut interactions. The few studies directly examining ANS measures have been suggestive of alterations in some IBS patients, but no studies to date have examined the potentially critical variables of sex differences or response to visceral stimulation. Aims: (1) To test differences in ANS function during rest and during a visceral stressor (rectosigmoid balloon distension) between IBS patients and healthy control subjects. (2) To examine the role of sex on the autonomic responses of IBS patients. Methods: Baseline autonomic measures were evaluated from 130 Rome I positive IBS patients and 55 healthy control subjects. Data were also collected from a subset of 46 IBS patients and 16 healthy control subjects during a sigmoid balloon distension study. Heart rate variability measures of peak power ratio (PPR) and peak power high frequency (PPHF) were analysed to assess sympathetic balance and parasympathetic response, respectively. Peripheral sympathetic response was measured by skin conductance. Results: IBS patients showed a greater skin conductance response to visceral distension than controls. IBS patients had higher PPR and lower PPHF across conditions. Male IBS patients had higher skin conductance and PPR than females and lower PPHF. Conclusions: IBS patients have altered autonomic responsiveness to a visceral stressor, with increased sympathetic and decreased parasympathetic activity. These differences are predominantly seen in males.

Self-reports of pain intensity and direct observations of pain behavior: when are they correlated?

&NA; Meta‐analytic techniques were utilized to investigate the relationship between self‐reports of pain intensity and direct observations of pain behavior. Estimation of the overall effect size from 29 studies and 85 effect sizes yielded a moderately positive association, z=0.26. High variability across studies permitted a random‐effects moderator analysis that determined chronicity of pain, the timing of the pain assessment, the use of global measures of pain behavior, and pain site significantly moderate the relationship between self‐reports of pain intensity and direct observations of pain behavior. These findings indicate that self‐reports of pain intensity and direct observations of pain behavior are more likely to be significantly related to each other when the individual being studied has acute pain (z=0.35), when the self‐report of pain intensity data are collected soon after the observation of pain behavior (z=0.40), when global composite measures are used to quantify pain behavior (z=0.37), and when the person being observed suffers from chronic low back pain (z=0.30). Other factors not found to be significant moderators include: extent of observer training, relevance of the pain‐inducing task, and pain behavior observation measure used. The implications of the findings for the assessment of pain are discussed.