White matter abnormalities in irritable bowel syndrome and relation to individual factors

doi:10.1016/j.brainres.2011.03.069

Brain Research

Volume 1392, 25 May 2011, Pages 121-131

https://doi.org/10.1016/j.brainres.2011.03.069 Get rights and content

Abstract

Patients with irritable bowel syndrome (IBS) have abnormal cortical responses to rectal distension and grey matter thinning in brain areas associated with nociception. These abnormalities may be driven by white matter changes and individual factors. Therefore, we tested the hypothesis that WM subserving the pain system is compromised in IBS, and that disease characteristics and personality contribute to these abnormalities. MRI diffusion tensor imaging (DTI) images were obtained from 10 female IBS patients (20–54 years old, mean ± SD 32.8 ± 10.4), and 16 female healthy controls (20–44 years old, mean ± SD 29.1 ± 7.9). Mean fractional anisotropy (FA) was extracted from WM regions associated with nociception. The IBS group had higher FA in the fornix and external capsule adjacent to the right posterior insula. IBS chronic pain severity correlated with FA of the bilateral anterior insula and lateral thalamus and left anterior insula FA correlated with pain unpleasantness. IBS duration correlated with FA in the external capsule adjacent to the left posterior insula. Neuroticism correlated with FA in the left medial thalamus in IBS patients only. Pain catastrophizing correlated negatively to cingulum FA in IBS, whereas controls showed correlation between pain catastrophizing and FA of the external capsule adjacent to the left anterior and posterior insula. Thus, fornix and insular white matter is related to IBS symptoms. These data suggest that dysregulation of brain–gut communication via the neuroendocrine pathway or via abnormal visceral sensory and homeostatic input has a role in the pathology of IBS chronic pain.

Research highlights

► IBS patients have elevated FA in the fornix and right insula white matter. ► IBS pain and duration correlated with insula white matter FA. ► Neuroticism correlated with medial thalamus FA in IBS patients but not controls. ► Pain catastrophizing correlated negatively to cingulum FA in IBS patients. ► Disease symptoms and personality are related to white matter abnormalities in IBS.

Introduction

Irritable bowel syndrome (IBS) has been attributed to altered gastrointestinal motility, visceral hypersensitivity, and psychosocial factors, but recent studies suggest that there is a dysregulation of the brain–gut axis in IBS (Ohman and Simren, 2007). In particular, functional MRI (fMRI) studies (Kwan et al., 2005, Rapps et al., 2008) and recent studies of cortical grey matter (Blankstein et al., 2010, Davis et al., 2008) point to dysfunction of emotional and attentional processing of pain in IBS. Furthermore, the subjective nature of pain perception underlines the importance of individual differences such as personality and coping strategy. In particular, neuroticism is associated with increased sensitivity to negative cues (Costa and McCrae, 1992) and catastrophic thinking increases maladaptive thoughts about pain (Sullivan et al., 1995). These traits contribute greatly to individual variation in pain perception and may represent key vulnerabilities to developing chronic pain.

It is also important to recognise that regions of the brain do not act in isolation but rather as an intricate network, where the experience of pain is an integrative phenomenon of network activity. The six most commonly reported cortical areas that display pain-evoked activity during acute stimulation in humans are the anterior/mid cingulate cortex (ACC/MCC), primary and secondary somatosensory cortex (S1, S2), insular cortex (IC), thalamus (Th), and prefrontal cortex (PFC) (Apkarian et al., 2005, Treede et al., 1999). These same regions have been found to respond differently in patients compared to healthy controls, in studies of chronic pain conditions including migraine, cardiac pain, fibromyalgia (FM), chronic back pain, temporomandibular disorder and IBS (Weissman-Fogel et al., 2011). Several studies have also reported grey matter abnormalities within these brain regions in chronic pain conditions such as chronic back pain (Apkarian et al., 2004, Buckalew et al., 2008, Schmidt-Wilcke et al., 2006), FM (Kuchinad et al., 2007, Schmidt-Wilcke et al., 2007), chronic tension-type headache (Schmidt-Wilcke et al., 2005), temporomandibular disorder (Moayedi et al., 2011) and IBS. Therefore, it appears that functional abnormalities in chronic pain are accompanied by structural grey matter abnormalities, and thus the emergence of new techniques that examine white matter (WM) integrity is spurring a new line of study in chronic pain.

Diffusion tensor imaging (DTI) has become a popular method to assess WM integrity and connectivity in the brain, and a DTI-derived value called fractional anisotropy (FA) is often examined as a measure of microstructural WM integrity. A recent study combined DTI with fMRI during rectal distention in healthy volunteers to delineate WM connectivity between the aforementioned brain regions and found direct connections between IC, Th, S1, S2, ACC, and PFC (Moisset et al., 2010). However, little is known concerning WM abnormalities in patients with IBS.

Therefore, in this study we used DTI to determine if the connections subserving sensory, emotional, and attentional components of the pain network are compromised in IBS patients, and to then test the impact of individual factors pertaining to disease characteristics and personality. We identified regions of interest (ROIs) based on fMRI studies that have shown IBS patients to have increased activity in brain areas associated with sensory processing, attention and affect, and arousal and autonomic responses, in addition to abnormal responses in descending pain modulation areas. Thus, we expected that WM integrity would be higher in patients compared to controls in regions that feed into and out of visceral pain processing areas such as thalamus, insula, primary somatosensory cortex, and the fornix. On the other hand, we expected WM integrity to be lower in regions associated with descending modulation of pain, such as the cingulum (feeding the ACC/MCC). In addition, we expected that symptom measures such as duration since IBS symptom onset, and severity of pain and unpleasantness would correlate positively with the direction of FA differences observed. Finally, since neuroticism and catastrophizing are thought to be predisposing factors for developing chronic pain, we expected both measures to correlate positively with the direction of FA differences observed, but only in patients.

Section snippets

Group characteristics

A total of 21 healthy controls and 14 patients entered the study. Five healthy controls and four patients were excluded from the final analysis due to technical and medical reasons. Thus, the final control group consisted of 16 healthy women (20–54 years old, mean ± SD age 32.8 ± 10.4), and the patient group included 10 women (20–44 years old, mean ± SD age 29.1 ± 7.9). PCS scores ranged from 6 to 38 in controls (mean ± SD PCS 18.8 ± 8.1) and from 1 to 41 in patients (mean ± SD PCS 19.5 ± 12.6). Neuroticism

Discussion

Our novel findings that patients with IBS have WM abnormalities in the insula, ACC and other brain areas associated with pain, interoception and homeostasis indicate that functional and grey matter abnormalities in IBS patients are indeed accompanied by WM abnormalities. Abnormalities of the fornix, insula, and mid anterior cingulum raise the possibility that there could be WM deficiencies of the descending modulation of pain and dysfunction of the medial pain system responsible for the

Subjects and study design

IBS patients were identified according to the Rome III criteria by local gastroenterologists. Inclusion criteria were: right-handed, English-speaking, female, and 21–55 years old. Exclusion criteria included other gastrointestinal, pain (such as fibromyalgia and temporomandibular disorder), psychiatric, neurological, metabolic, rheumatoid, or vascular disorders, current use or history of taking medications known to affect brain function or vascular flow, and any contraindication to undergo MRI

Acknowledgments

The authors thank Geoff Pope and Dr. Adrian Crawley for technical assistance and advice regarding statistical analyses, and Massih Moayedi and Irit Weissman-Fogel for providing some control data. This study was funded by the Canadian Institutes of Health Research (CIHR MOP 53304). Karen D. Davis is a Canada Research Chair in Brain and Behaviour. Mr. Chen was funded by a CIHR scholarship and Strategic Training Program: Pain Molecules to Community Fellowship, and an OGS scholarship. Mr Blankstein

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Research ReportWhite matter abnormalities in irritable bowel syndrome and relation to individual factors

Abstract

Research highlights

Introduction

Section snippets

Group characteristics

Discussion

Subjects and study design

Acknowledgments

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Research Report
White matter abnormalities in irritable bowel syndrome and relation to individual factors