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