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

Abstract

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 [¹⁵O] 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.

Introduction

Multiple peripheral and central mechanisms (Mayer and Gebhart, 1994, Munakata et al., 1997, Verne et al., 2001) including central pain amplification have been implicated in the enhanced perceptual responsiveness of patients with irritable bowel syndrome (IBS) to experimental visceral stimuli [“visceral hypersensitivity”] (Kellow et al., 1991, Naliboff et al., 1997a, Whitehead and Palsson, 1998). Hypervigilance and selective attention to experimental visceral and somatic stimuli is a key feature of IBS (Naliboff et al., 2000), related functional pain disorders (Crombez et al., 2004, Eccleston et al., 1997, Roelofs et al., 2003) and anxiety disorders (Bishop, 2007, Paulus and Stein, 2006) and these factors may play an important role in this central pain amplification.

Studying IBS patients with ¹⁵O PET, we have previously reported that following repeated exposure to experimental rectal stimuli over a 12-month period, visceral hypersensitivity as indexed by patient ratings of stimulus intensity normalized and activity in cortical regions functionally associated with attention (parietal cortex (PC), Mid-cingulate cortex (MCC)) and arousal [dorsal brainstem including locus coeruleus complex (LCC) and amygdala (AMYG)] decreased (Naliboff et al., 2006a). Although the involvement of the parietal cortex was a post hoc finding in these analyses, our findings were consistent with the well established concept that repeated exposure to anxiety-provoking stimuli in the absence of aversive consequences leads to reduced vigilance and associated arousal (decreased salience of threat) (Lorenz and Tracey, 2009). Consistent with this interpretation, other reports have demonstrated that in healthy controls, reducing attention to an aversive visceral stimulus via distraction reduces the perceptual ratings of the stimulus (Coen et al., 2008).

Several distinct networks of attention have been extensively characterized in healthy control populations. The alerting network of attention (Posner, 2008, Posner and Dehaene, 1994) supports achieving and maintaining a high state of sensitivity to all incoming stimuli and includes prefrontal and parietal cortex regions (PFC, PC). The engagement of this alerting network is in part related to emotional arousal and the ascending noradrenergic influences from the LCC (Posner, 2008, Posner and Rothbart, 1980, Posner et al., 2007, Posner et al., 2006). Enhanced activity of the LCC and the closely connected AMYG has been well characterized in animal models of IBS (Valentino et al., 1999, Valentino and Van Bockstaele, 2008, Van Bockstaele et al., 1998). Supporting evidence has been reported in human patient populations (Berman et al., 2008a, Naliboff et al., 2006a) and suggests that the reported reduction in amygdala and dorsal pontine activity following repeated rectal stimulation may in part reflect reduced activation of ascending noradrenergic arousal mechanisms (Naliboff et al., 2006b).

An alternate mechanism of this reduction in arousal can be explained via the interaction of the alerting and executive control network of attention. The executive control network comprises top-down control mechanisms involved in allocation of attentional resources as well as resolving conflict among thoughts, feelings, and behavioral responses. It is supported by the lateral (l) PFC and rostral ACC/medial PFC (rACC/mPFC) (Botvinick, 2007, Bunge et al., 2001, Fan et al., 2003, Fan et al., 2005, Hopfinger et al., 2000, Posner et al., 2007). More specifically, research suggests that the rACC/mPFC, which has close connections to the anterior insula (aINS), detects conflicts in information processing (e.g., ‘something doesn't feel right’) and triggers reactive adjustments of cognitive control. The lPFC is believed to govern allocation of attention resources by governing selection of stimuli to optimize further processing in the posterior attention system (PC) (Botvinick, 2007, Sarter et al., 2003). This view is consistent with Corbetta et al's (2008) model of attention where afferents from a ventral network, including the aINS to the dorsal network (PC, PFC) can switch the focus of attention (Corbetta et al., 2008).

Extending Posner's work on attention networks and ‘biased competition models of attention’ (Matthews and Mackintosh, 1998) to address selective attention to threat, Bishop (Bishop, 2008, Bishop et al., 2004, Bishop et al., 2007, Matthews and Mackintosh, 1998) has provided evidence to support a model in which selective attention to threat circuitry comprises the relative signal strength from a pre-attentive threat evaluation mechanism (AMYG) versus that from a top-down control mechanisms of information flow (lPFC, rACC/mPFC). In this model, inputs from pre-attentive threat detection/evaluation mechanisms and top-down information control mechanisms influence the outcome of this competition for attention resources. This model of selective attention to threat can easily be applied to IBS patients, a patient population with increased general (Mayer et al., 2001) as well as disease-related anxiety (Labus et al., 2007). Experimentally-induced visceral hypersensitivity in these patients is greatest when they are asked to focus their attention exclusively on the rating of an experimental visceral stimulus (as in all visceral sensitivity testing paradigms), and during ascending method of limit testing (Naliboff et al., 1997b), but is greatly reduced or normalized when patients' attentional resources are engaged in another experimental task (Accarino et al., 1997) or by a specific context demanding attention, e.g. scanner environment.

Given the role of attention in the modulation of experimental pain (Bantick et al., 2002, Coen et al., 2008), and recent ERP findings indicating that attentional mechanisms as measured by the P300 component differ between IBS patients and healthy controls (Vianna et al., 2009), there is a need to evaluate the involvement of attentional networks in the modulation of the perception of experimentally induced pain. Although previous statistical parametric mapping of this data set via the general linear model provided evidence supporting the involvement of general attention mechanisms (Naliboff et al., 2006a), some of the results were based on posthoc analyses (parietal cortex), and multivariate techniques that apply system-level algorithms are better-suited to test hypotheses regarding networks of brain regions and the effective connectivity of underlying brain circuits. In the current paper, a behavioral partial least squares analysis (bPLS) was applied to determine the brain regions associated with reduced perceptual ratings of experimental induced pain after repeated exposure to the visceral distension paradigm over a 12-month period. Next, focusing on attentional mechanisms, path analysis within a structural equation modeling framework was applied to assess changes in the effective connectivity of attentional circuitry over time. This network approach complements previous work by evaluating possible changes in the engagement of a selective attention network (Naliboff et al., 2006a). Specifically, we test the hypothesis that perceptual habituation to the repeated visceral stimuli resulted in part from the reduced connectivity within a network involved in selective attention to threat over time.