Elsevier

NeuroImage

Volume 41, Issue 3, 1 July 2008, Pages 1032-1043
NeuroImage

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

https://doi.org/10.1016/j.neuroimage.2008.03.009Get rights and content

Abstract

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.

Introduction

Irritable bowel syndrome (IBS) is one of the most common functional pain disorders, characterized by chronic abdominal pain or discomfort (related to visceral hyperalgesia) associated with altered bowel habits (related to autonomic dysregulation). Affected patients show frequent comorbidity with anxiety, (Mayer et al., 2001) as well as symptom-related anxiety (e.g. fears and worry over expected abdominal pain and discomfort (Labus et al., 2007)).Altered brain gut interactions during a visceral stimulus and its expectation have been suggested as an important pathophysiological mechanism for IBS, and functional brain imaging studies have identified brain regions and circuits which may be responsible for these alterations (Mayer et al., 2006).

Like many other syndromes characterized by chronic physical or emotional pain and discomfort, IBS is significantly more common in women (Chang and Heitkemper, 2002) and sex-related differences in the perceptual and emotional responses of IBS patients to aversive visceral stimuli have been reported (Chang et al., 2006b, Heitkemper et al., 2003, Mayer et al., 2004, Tillisch et al., 2005). Greater subjective responses in female IBS patients may be related to sex differences in brain responses to visceral stimuli (Berman et al., 2000, Berman et al., 2006, Naliboff et al., 2003). For example, female patients showed greater activation of limbic and paralimbic regions, including the amygdala and the closely connected anterior cingulate cortex (ACC) while male patients demonstrated greater activation of the insula (INS). Although activation analyses have suggested possible regional differences in central processing between healthy controls and IBS, and between male and female IBS patients (reviewed in Mayer et al., 2006), they are limited in their ability to describe more complete system-level models of the functional neurocircuitry that may be involved.

The current study applied network analyses to test the general hypothesis that at least 3 networks can be identified as operating during an expected and a delivered aversive visceral stimulus including: a) a network central to processing of visceral afferent information (“homeostatic-afferent” network i.e., thalamus, posterior (p) and anterior (a) INS and dorsal (d) ACC, orbital frontal cortex (OFC) (Craig, 2003b, Craig, 2003c, Mayer et al., 2006)), b) a network involved in arousal, and emotion-related pain amplification (“emotional-arousal” network i.e., amygdala, ACC subregions and locus coeruleus complex (LCC) (Pezawas et al., 2005, Stein et al., 2007, Valentino et al., 1999)), and c) a network representing the mediating influence of cortical regions (“cortical-modulatory” network i.e., frontal, parietal) on a) and b) (Mayer et al., 2005, Naliboff et al., 2006). Even though these networks overlap and share some of the same regions, we decided to reduce the complexity of the model and discuss the 3 networks separately.

Based on the proposed role of the amygdala in cognitive and affective modulation of pain (Carrasquillo and Gereau, 2007, Neugebauer et al., 2004) and consistent reports of sex-related differences in amygdala responses in healthy subjects (Cahill, 2006) and IBS patients (Naliboff et al., 2003), we further hypothesized that most of the sex-related differences in brain response are in the effective connectivity of the “emotional-arousal” network, and less in the “cortical-modulatory” and “homoeostatic-afferent” networks. Specifically, we tested the following hypotheses regarding the activity within nodes, and the connectivity between nodes within the 3 networks: 1) Across conditions, male and female IBS patients show similar activity/connectivity in the “homeostatic-afferent” processing network. 2) Across conditions, the activity/connectivity of amygdala-related network(s) shows sex differences. 3) There are sex-related differences in the effective connectivity of the “emotional-arousal” network during both conditions. Specifically, we expected female patients to show greater activity/connectivity or engagement of the amygdala-related networks. Parts of these results have been published in abstract form (Labus et al., 2005, Labus et al., 2006).

Section snippets

Methods

Data from a previously published [15O] water positron emission tomography (PET) neuroimaging study (Naliboff et al., 2003) were analyzed. The sample included 46 men (n = 22) and women (n = 24) with a diagnosis of IBS (Rome I criteria) (Thompson et al., 1994). All patients were free from centrally acting medication for at least 30 days preceding the PET scan. Patients had no history of substance abuse or psychiatric illness. On average, women were 41.5 (10.8) years old and reported a 6 month symptom

Overview

Statistical analyses were performed in steps that will be detailed below. First, a multivariate task partial least squares (PLS) (McIntosh et al., 1996, McIntosh et al., 2004, McIntosh and Lobaugh, 2004) identified spatially distributed patterns of regions activated during INF and EXP relative to BL in males and females. These results, in combination with relevant theoretical and neurobiological information from earlier studies, indicated that bilateral amygdala, and thalamus were involved in

Level 1 analysis: task PLS

Task PLS was employed to identify distributed patterns of regions that relate to the brain's response to aversive visceral stimulus and its expectation. Significant LVs were found for both main effect contrasts, but not the interaction effect contrasts involving sex.

BL versus INF

Common INF-related network. The first significant LV (LV1) from the task PLS represented a pattern of brain regions that maximally distinguished between the BL and INF scans for both females and males. This LV explained

Discussion

The primary goal of the current study was to identify brain networks activated by expected and delivered aversive pelvic visceral stimuli in male and female patients with chronic abdominal pain, and to test for sex differences in the hypothesized circuitry within these networks. Multivariate network analyses using partial least squares and structural equation modeling provided support for the involvement of regions comprising “homeostatic-afferent”, “emotional-arousal” and “cortical-modulatory”

Conclusions

In summary, the results of formal network analyses suggest the activation of distinct yet overlapping networks concerned with the processing of ascending visceral information, emotional-arousal (induced by expectation or actual experience of the stimulus) and modulatory cortical influences. While there was common activation of these networks in both sexes, network functioning during expectation was uniquely characterized by sex differences in the cortico-limbic circuits involved in

References (75)

  • McIntoshA.R. et al.

    Spatial pattern analysis of functional brain images using partial least squares

    Neuroimage

    (1996)
  • McIntoshA.R. et al.

    Spatiotemporal analysis of event-related fMRI data using partial least squares

    NeuroImage

    (2004)
  • MertzH. et al.

    Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention

    Gastroenterology

    (2000)
  • NaliboffB.D. et al.

    Sex-related differences in IBS patients: central processing of visceral stimuli

    Gastroenterology

    (2003)
  • NaliboffB.D. et al.

    Longitudinal change in perceptual and brain activation response to visceral stimuli in irritable bowel syndrome patients

    Gastroenterology

    (2006)
  • PetrovicP. et al.

    Imaging cognitive modulation of pain processing

    Pain

    (2002)
  • PloghausA. et al.

    Neural circuitry underlying pain modulation: expectation, hypnosis, placebo

    Trends Cogn. Sci.

    (2003)
  • PorroC.A. et al.

    Functional activity mapping of the mesial hemispheric wall during anticipation of pain

    NeuroImage

    (2003)
  • PosserudI. et al.

    Altered rectal perception in irritable bowel syndrome is associated with symptom severity

    Gastroenterology

    (2007)
  • SarinopoulosI. et al.

    Brain mechanisms of expectation associated with insula and amygdala response to aversive taste: implications for placebo

    Brain Behav. Immun.

    (2006)
  • SilvermanD.H. et al.

    Regional cerebral activity in normal and pathological perception of visceral pain

    Gastroenterology

    (1997)
  • SteinJ.L. et al.

    A validated network of effective amygdala connectivity

    Neuroimage

    (2007)
  • StrotherS.C. et al.

    The quantitative evaluation of functional neuroimaging experiments: the NPAIRS data analysis framework

    NeuroImage

    (2002)
  • ValentinoR.J. et al.

    Pontine regulation of pelvic viscera: Pharmacological target for pelvic visceral dysfunction

    Trends Pharmacol. Sci.

    (1999)
  • Van HoesenG.W.

    Anatomy of the medial temporal lobe

    Magn. Reson. Imaging

    (1995)
  • VerneG.N. et al.

    Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome

    Pain

    (2003)
  • AmodioD.M. et al.

    Meeting of minds: the medial frontal cortex and social cognition

    Nat. Rev., Neurosci.

    (2006)
  • ArbuckleJ.L.

    AmosTM 6.0 User's Guide

    (2005)
  • BaciuM.V. et al.

    Central processing of rectal pain: a functional MR imaging study

    AJNR Am. J. Neuroradiol.

    (1999)
  • BermanS.M. et al.

    Sex differences in regional brain response to aversive pelvic visceral stimuli

    Am. J. Physiol., Regul. Integr. Comp. Physiol.

    (2006)
  • BermanS.M. et al.

    Reduced brainstem inhibition during anticipated pelvic visceral pain correlates with enhanced brain response to the visceral stimulus in women with irritable bowel syndrome

    J. Neurosci.

    (2008)
  • BerryW.D.

    Nonrecursive Causal Models

    (1984)
  • CahillL.

    Why sex matters for neuroscience

    Nat. Rev., Neurosci.

    (2006)
  • CarrasquilloY. et al.

    Activation of the extracellular signal-regulated kinase in the amygdala modulates pain perception

    J. Neurosci.

    (2007)
  • CavadaC. et al.

    The anatomical connections of the macaque monkey orbitofrontal cortex. A review

    Cereb. Cortex

    (2000)
  • ChangL. et al.

    Effect of sex on perception of rectosigmoid stimuli in irritable bowel syndrome

    Am. J. Physiol., Regul. Integr. Comp. Physiol.

    (2006)
  • CraigA.D.

    How do you feel? Interoception: the sense of the physiological condition of the body

    Nat. Rev., Neurosci.

    (2002)
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    Supported in part by grants from the National Institutes of Health (K08 DK071626 (JSL), P50 DK064539 (EAM), RO1 DK 48351(EAM)), the Office of Research in Women's Health (ORWH) (P50 DK064539 (EAM)) and the National Center for Complementary and Alternative Medicine (NCCAM) (R24 AT002681).

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