Bruce D. Naliboff

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.

Evidence for two distinct perceptual alterations in irritable bowel syndrome

Background and aims—Visceral hyperalgesia has been implicated as a factor contributing to symptom generation in irritable bowel syndrome (IBS). However, previous studies using intestinal balloon distension have used psychophysical procedures which do not provide adequate and unbiased measures of visceral sensitivity. Methods—Three psychophysical tasks were examined in 45 patients with IBS (positive Rome criteria) and 14 controls using rectal balloon distension with a computerised distension device. Discomfort threshold and tolerance were assessed during an ascending series of phasic pressure stimuli and during an interactive threshold tracking procedure. In addition, stimulus response functions were generated from intensity and unpleasantness ratings of the rectal distensions. Results—Discomfort threshold and tolerance for the ascending stimuli were significantly lower for the patients with IBS compared with the controls. In contrast, discomfort thresholds during the tracking procedure and stimulus response curves for the ascending series were not different between the groups. A factor analysis of the psychophysical data was consistent with the presence of two distinct and unrelated perceptual alterations related to rectal distension: hypervigilance for visceral stimuli, manifested as lowered response criteria for using the descriptor “discomfort”; and rectal hypersensitivity, manifested as a lower discomfort threshold and left shift of the stimulus response curves. Conclusions—Patients with IBS as a group have a greater propensity to label visceral sensations negatively and show a lower tolerance for rectal balloon distension. A subgroup of patients also have baseline rectal hypersensitivity, assessed by unbiased measures of discomfort threshold and stimulus intensity judgements.

Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome.

BACKGROUND & AIMS Only a fraction of patients with irritable bowel syndrome (IBS) show hypersensitivity to rectal distention. The current study sought to determine if repetitive high-pressure stimulation of sigmoid mechanoreceptors modulates perception of rectal pain and discomfort. METHODS In 14 patients with IBS and 11 healthy controls, perception thresholds for discomfort and pain during rectal sensory tracking and verbal descriptor ratings of the perceived intensity of a rectal tonic stimulus were obtained before and after repetitive high-pressure mechanical sigmoid stimulation. Gastrointestinal and psychological symptoms were assessed by questionnaires. RESULTS Despite heterogeneity in baseline rectal sensitivity in patients with IBS, after sigmoid stimulation, 100% of patients, regardless of baseline sensitivity, developed rectal hyperalgesia manifested by at least two of the following three criteria: lowered thresholds for pain and discomfort and increased viscerosomatic referral and lower abdominal discomfort outlasting the experimental stimulation. This pattern of responses was not observed in any of the healthy controls. CONCLUSIONS In patients with IBS, repetitive stimulation of sigmoid splanchnic afferents results in the development of central sensitization manifested as hyperalgesia and increased viscerosomatic referral during rectal distention and as spontaneous rectosigmoid hyperalgesia in the absence of applied stimuli. Repetitive sigmoid contractions may induce rectosigmoid hyperalgesia in patients with IBS.

Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation.

Objective Patients with irritable bowel syndrome (IBS) show evidence of altered perceptual responses to visceral stimuli, consistent with altered processing of visceral afferent information by the brain. In the current study, brain responses to anticipated and delivered rectal balloon distension were assessed. Methods Changes in regional cerebral blood flow were measured using H215O-water positron emission tomography in 12 nonconstipated IBS patients and 12 healthy control subjects. Regional cerebral blood flow responses to moderate rectal distension (45 mm Hg) and anticipated but undelivered distension were assessed before and after a series of repetitive noxious (60-mm Hg) sigmoid distensions. Results Brain regions activated by actual and simulated distensions were similar in both groups. Compared with control subjects, patients with IBS showed lateralized activation of right prefrontal cortex; reduced activation of perigenual cortex, temporal lobe, and brain stem; but enhanced activation of rostral anterior cingulate and posterior cingulate cortices. Conclusions IBS patients show altered brain responses to rectal stimuli, regardless of whether these stimuli are actually delivered or simply anticipated. These alterations are consistent with reported alterations in autonomic and perceptual responses and may be related to altered central noradrenergic modulation.

Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans☆☆☆

BACKGROUND & AIMS Chronic tissue injury in the esophagus associated with gastroesophageal reflux disease may result in sensitization of afferent pathways mediating mechanosensitivity and chemosensitivity. The aim of this study was to evaluate the sensitivity to intraluminal acid and to distention of the esophagus in patients with mild-to-moderate gastroesophageal reflux disease. METHODS Perceptual responses to intraluminal acid perfusion and to esophageal distention and pressure volume relationships were evaluated in 10 healthy volunteers and in 11 patients. Mechanosensitivity was evaluated with a barostat using unbiased distention protocols and verbal descriptor ratings of sensations. Chemosensitivity to acid was determined at baseline and after a 1-month treatment of acid suppression. RESULTS Patients showed enhanced perception of acid perfusion but not of esophageal distension. Chemosensitivity but not mechanosensitivity was correlated with reflux symptoms and with the degree of endoscopically shown tissue injury at baseline. Tissue injury was not associated with altered compliance. CONCLUSIONS Mild-to-moderate chronic tissue injury in gastroesophageal reflux disease differentially affects mechanosensitive and chemosensitive afferent pathways. Chronic acid reflux by itself is not likely to play a role in reported esophageal hypersensitivity to distention in patients with noncardiac chest pain.

The neural correlates of placebo effects: a disruption account.

The neurocognitive pathways by which placebo effects operate are poorly understood. Positron emission tomography (PET) imaging was used to assess the brain response of patients with chronic abdominal pain (irritable bowel syndrome; IBS) to induced intestinal discomfort both before and after a 3-week placebo regimen. A daily symptom diary was used to measure symptom improvement. Increases in right ventrolateral prefrontal cortex (RVLPFC) activity from pre- to post-placebo predicted self-reported symptom improvement, and this relationship was mediated by changes in dorsal anterior cingulate (dACC), typically associated with pain unpleasantness. These results are consistent with disruption theory [Lieberman, M.D., 2003. Reflective and reflexive judgment processes: a social cognitive neuroscience approach. In: Forgas, J.P., Williams, K.R., von Hippel, W. (Eds.), Social Judgments: Explicit and Implicit Processes. Cambridge Univ. Press, New York, pp. 44-67], which proposes that activation of prefrontal regions associated with thinking about negative affect can diminish dACC and amygdala reactivity to negative affect stimuli. This is the first study to identify a neural pathway from a region of the brain associated with placebos and affective thought to a region closely linked to the placebo-related outcome of diminished pain unpleasantness.

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.

IMMUNOLOGICAL CHANGES IN YOUNG AND OLD ADULTS DURING BRIEF LABORATORY STRESS

&NA; Few data are available on the response of the human immune system to acute psychological stressors under controlled laboratory conditions. Young female subjects (21–41 years) showed increases in natural killer (NK) cell activity, and in the numbers of circulating CD8 suppressor/cytotoxic T cells, and natural killer lymphocytes following a brief (12 minute) stressful mental arithmetic examination. Older female subjects (65–85 years) failed to show the stress‐related increase in NK activity. The psychological stress did lead to increases in the numbers of circulating CD8 suppressor/cytotoxic T cells and NK lymphocytes in old subjects to a similar degree as that seen in the young group. No changes in the numbers of helper/inducer T cells (CD4), total T cells (CD3), or B cells (CD20) were found following the stressor for either group. Cardiovascular, catecholamine, and subjective stress responses were similar for the two age groups. These results demonstrate that brief psychological stress is associated with some rapid immune cell changes, including release of CD8 suppressor/cytotoxic T cells and NK cells into circulation, and in young subjects, increases in NK activity. The absence of an NK activity increase in the older subjects indicates that NK cell mobilization and cell lysis induced by NK cells may be differentially affected by stress. The results also suggest the possibility of an age‐related deficit in the up‐regulation of NK activity under some environmental demands.

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.

Symptoms and visceral perception in severe functional and organic dyspepsia

Background—Hypersensitivity of gastric afferent pathways may play an aetiological role in symptoms of functional dyspepsia. Aims—To determine whether patients with severe organic dyspepsia (associated with tissue irritation/injury) and those with functional dyspepsia (no detectable tissue irritation) differ in their perception of gastric distension and whether this difference is reflected in differences in their gastrointestinal and psychological symptoms. Methods—Perceptual thresholds, referral patterns, and gastrointestinal and psychological symptoms were compared in 23 patients with functional dyspepsia, 10 organic dyspeptics, and 15 healthy controls. Results—Fifteen (65%) functional dyspeptics and no organic dyspeptics had reduced perceptual thresholds for fullness, discomfort, or pain (odds ratio (OR) 19.56, 95% confidence interval (CI) 1.95 to 476.09, p=0.0017). Either reduced perceptual thresholds or altered referral was found in 20 (87%) functional dyspeptics and four (20%) organic dyspeptics (OR 10.0, 95% CI 1.34 to 89.54, p=0.014). During sham distension fullness, discomfort and pain were reported by healthy controls, organic dyspeptics, and functional dyspeptics. A sham response of pain but no other sensation was more frequent among functional dyspeptics (43%) than healthy controls (7%) (OR 10.77, 95% CI 1.10 to 257.35, p=0.026). Gastrointestinal and psychological symptoms and gastric compliance were similar in the functional and organic groups. Conclusions—Alterations in the perception of gastric distension distinguishes between functional and organic dyspepsia, while symptoms do not. A total of 87% of functional dyspeptics studied had evidence of altered visceral afferent function. In this study population, psychological abnormalities or changes in compliance did not explain the findings.