Steve Berman

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.

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.

Brain responses to visceral and somatic stimuli in patients with irritable bowel syndrome with and without fibromyalgia

OBJECTIVE:Symptoms of irritable bowel syndrome (IBS) and fibromyalgia (FM) commonly coexist. We hypothesized that one of the mechanisms underlying this comorbidity is increased activation of brain regions concerned with the processing and modulation of visceral and somatic afferent information, in particular subregions of the anterior cingulate cortex (ACC).METHODS:Regional cerebral blood flow (rCBF) was assessed in age-matched female IBS (n = 10) and IBS + FM (n = 10) subjects using H215O positron emission tomography during noxious visceral (rectal) and somatic pressure stimuli.RESULTS:GI symptom severity was significantly higher in the IBS patients compared with the IBS + FM patients (p < 0.05). In addition, IBS + FM patients rated somatic pain as more intense than their abdominal pain (p < 0.05). Whereas the somatic stimulus was less unpleasant than the visceral stimulus for IBS patients without FM, the somatic and visceral stimuli were equally unpleasant in the IBS + FM group. Group differences in regional brain activation were entirely within the middle subregion of the ACC. There was a greater rCBF increase in response to noxious visceral stimuli in IBS patients and to somatic stimuli in IBS + FM patients.CONCLUSION:Chronic stimulus-specific enhancement of ACC responses to sensory stimuli in both syndromes may be associated with cognitive enhancement of either visceral (IBS) or somatic (IBS + FM) sensory input and may play a key pathophysiologic role in these chronic pain syndromes.

Sex differences in brain activity during aversive visceral stimulation and its expectation in patients with chronic abdominal pain: A network analysis

Differences in brain responses to aversive visceral stimuli may underlie previously reported sex differences in symptoms as well as perceptual and emotional responses to such stimuli in patients with irritable bowel syndrome (IBS). The goal of the current study was to identify brain networks activated by expected and delivered aversive visceral stimuli in male and female patients with chronic abdominal pain, and to test for sex differences in the effective connectivity of the circuitry comprising these networks. Network analysis was applied to assess the brain response of 46 IBS patients (22 men and 24 women) recorded using [15O] water positron emission tomography during rest/baseline and expected and delivered aversive rectal distension. Functional connectivity results from partial least squares analyses provided support for the hypothesized involvement of 3 networks corresponding to: 1) visceral afferent information processing (thalamus, insula and dorsal anterior cingulate cortex, orbital frontal cortex), 2) emotional-arousal (amygdala, rostral and subgenual cingulate regions, and locus coeruleus complex) and 3) cortical modulation (frontal and parietal cortices). Effective connectivity results obtained via structural equation modeling indicated that sex-related differences in brain response are largely due to alterations in the effective connectivity of emotional-arousal circuitry rather than visceral afferent processing circuits. Sex differences in the cortico-limbic circuitry involved in emotional-arousal, pain facilitation and autonomic responses may underlie the observed differences in symptoms, and in perceptual and emotional responses to aversive visceral stimuli.

Sex-based differences in gastrointestinal pain

Recent interest has focused on sex‐related differences in irritable bowel syndrome (IBS) physiology and treatment responsiveness to novel pharmacologic therapies. Similar to a variety of other chronic pain conditions and certain affective disorders, IBS is more prevalent amongst women, both in population‐based studies as well as in clinic‐based surveys. Non‐painful gastrointestinal symptoms, constipation and somatic discomfort are more commonly reported by female IBS patients. While perceptual differences to rectosigmoid stimulation are only observed following repeated noxious stimulation of the gut, sex‐related differences in certain sympathetic nervous system (SNS) responses to rectosigmoid stimulation are consistently seen. Consistent with experimental findings in animals, current evidence is consistent with a pathophysiological model which emphasizes sex‐related differences in autonomic and antinociceptive responses to certain visceral stimuli.

Brain networks underlying perceptual habituation to repeated aversive visceral stimuli in patients with irritable bowel syndrome

Patients with irritable bowel syndrome (IBS) show decreased discomfort and pain thresholds to visceral stimuli, as well hypervigilance to gastrointestinal sensations, symptoms, and the context in which these visceral sensations and symptoms occur. Previous research demonstrated normalization of visceral hypersensitivity following repeated exposure to experimental rectal stimuli over a 12-month period that was associated with reduction in cortical regions functionally associated with attention and arousal. Building upon these functional analyses, multivariate functional and effective connectivity analyses were applied to [(15)O] water positron emission tomography (PET) data from 12 IBS patients (male=4) participating in a PET study before and after 4 visceral sensory testing sessions involving rectal balloon distensions over a 1-year period. First, behavioral partial least squares was applied to test for networks related to reduced subjective ratings observed following repeated application of an aversive rectal stimulus. Next, path analysis within a structural equation modeling framework tested the hypothesis that perceptual habituation to the repeated visceral stimuli resulted in part from the reduced connectivity within a selective attention to threat network over time. Two independent, perception-related networks comprised of interoceptive, attentional and arousal regions were engaged differentially during expectation and distension. In addition, changes in the effective connectivity of an attentional network as well as modulatory amygdala influence suggested that perceptual habituation associated with repeated stimulus delivery results both in an increase in top-down modulation of attentional circuits, as well as in a reduction of amygdala-related interference with attentional mechanisms.

D2 dopamine receptor gene polymorphism discriminates two kinds of novelty seeking

Cloningers psychobiological model of personality as applied to substance misuse has received mixed support. Contrary to the model, recent data suggest that a combination of high novelty seeking (NS) and high harm avoidance (HA) represents a significant risk for the development of severe substance misuse. A genetic polymorphism previously implicated in severe substance dependence, the A1 allele of the D2 dopamine receptor (DRD2) gene, was examined in relation to NS and HA amongst 203 adolescent boys. Specifically, we hypothesized that subjects with the A1 + allele (A1/A1 and A1/A2 genotypes) would report stronger NS and would exhibit a more positive relationship between NS and HA than those with the A1-allele (A2/A2 genotypes). These predictions were supported. The correlation between NS and HA in 81 A1 + allelic boys (r = 0.27, P = 0.02), and that in the 122 A1- allelic boys (r = -0.15, P = 0.09), indicated that this relationship differed according to allelic status (F = 8.52, P < 0:004). Among those with the A1-allele, the present results are consistent with the traditional view that novelty seeking provides positive reinforcement, or the fulfillment of appetitive drives. In contrast, novelty seeking in those with the A1 + allele appears to include a negative reinforcement or self-medicating function

Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study

Aliment Pharmacol Ther 28, 344–352