1. Summary and Conclusions
Differences in Brain Structure and Connectivity in Female Adolescents with IBS Relate to Altered Pain Perception
Ravi R. Bhatt, BS1, Arpana Gupta, PhD2, Jen S. Labus, PhD2, Lonnie K. Zeltzer, MD1, Jennie T. Tsao, PhD1, Kirsten Tillisch, MD2
1UCLA Pediatric Pain and Palliative Care Program, David Geffen School of Medicine at UCLA, Los Angeles, CA
2G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine at UCLA, Los Angeles, CA
Background
Results
Patients with IBS had greater trait anxiety (t(22.25) = 2.054, p = .045, d = 0.85) and higher pain thresholds (t(20.42) = 1.854, p = 0.078, d = .721). No group differences were observed in CPM.
Patients with IBS have decreased GM in the thalamus, caudate nucleus, nucleus accumbens, ACC, PCC and frontal, inhibitory control regions in comparison to controls (Figure 1).
Decreased GM in the caudate nucleus and nucleus accumbens is associated with lower pain thresholds in patients with IBS (r = 0.71, p = .02; r = 0.83, p = .003) but not controls.
Decreased GM in the thalamus is associated with decreased pain thresholds in HCs (r = -0.72, p = .004) but not patients with IBS.
IBS patients exhibited decreased connectivity between the caudate nucleus and somatosensory regions (Figure 2).
Lower connectivity between the caudate nucleus and somatosensory cortex was associated with decreased amount of time in the CPT in HC (r = .66, p = .03) but not patients with IBS.
Lower connectivity between the caudate nucleus and supramarginal gyrus is associated with increased CPM pain threshold marginally in patients with IBS (r = -.487, p .12) = and controls (r = -.61 p = .06).
Figure 1: IBS patients exhibit lower GM in the striatum, cingulate and frontal regions
Figure 2: IBS patients exhibit decreased connectivity between the caudate nucleus somatosensory regions.
Irritable Bowel Syndrome (IBS) is a functional disorder of the brain-gut axis characterized by recurrent abdominal pain and altered bowel habits not explained by structural or biochemical abnormalities (Chogel et al., 2014).
Conditioned pain modulation (CPM), a measure of endogenous pain modulation involves measuring the extent of pain inhibition in the presence of a noxious heterotopic counter pain stimulus (Le Bars, 1988). It has been shown that children with IBS have impaired CPM – on the contrary, facilitation of pain – compared to healthy controls (Williams et al., 2013).
Decreases in gray matter (GM) in adult IBS patients have been shown in the cingulate, somatosensory cortex, insula, putamen, hippocampus, amygdala and frontal executive control regions (Labus et al., 2014). Only one analogous study in children has been conducted (Hubbard et al., 2016).
Aims
The primary aim of this study was to examine differences in gray matter (GM) and seed-based resting state functional connectivity analysis in female adolescents with IBS and age/gender matched healthy controls (HC).
A secondary aim was to assess if these changes in brain structure and connectivity were associated with differences in state anxiety, trait anxiety, daily pain levels, anxiety to pain, pain threshold, and extent of CPM.
Methods
32 total female children aged between 7 – 17 years and diagnosed with IBS using Rome III criteria (mean age = 11.40, SD = 3.01) and 26 matched healthy controls (mean age = 10.72, SD = 2.79).
Psychophysiological measurements included the numerical rating scale (NRS) to assess perceived levels of pain and anxiety, pain threshold during the conditioning stimulus (˚C), pain threshold during the conditioning stimulus (˚C) and CPM (Cold Pressor Task (CPT) = unconditioned stimulus, Heat Probe = conditioned stimulus).
Whole brain analyses were conducted as the literature in cortical differences adolescents is still scarce.
Voxel-Based Morphometry analyses were conducted in FSL-VBM to determine whole brain differences in GM density while controlling for age and total GM volume.
Significant clusters were determined Threshold Free Cluster Enhancement (TFCE) method and corrected at a threshold of p(FWE) < 0.05.
VBM Workflow
Based on regional differences in GM, those regions were used as seeds in a resting state, seed-to- voxel, functional connectivity analyses using the CONN toolbox in SPM8.
Whole brain voxel-wise analyses were completed with an initial height threshold of p < and cluster-based multiple comparisons correction at p(FDR) < 0.05.
CONN Workflow
Summary and Conclusions
Female adolescents with IBS have decreased GM in the basal ganglia, associated with decreased pain sensitivity. Additionally they exhibited decreased connectivity from the basal ganglia to somatosensory regions, associated with altered pain sensitivity. This suggests that anomalies in the pain circuitry may be present in adolescents with IBS, warranting further investigation on the mechanisms underlying these pathologies.
Supported by: NIH/NCATS, UCLA CTSI Grant Number UL1TR000124, (J Tsao, K Tillisch), and the Pediatric Cancer Research Foundation, Arthur Wallace Pediatric Cancer Research Fund and the UCLA Division of Pediatric Hematology Oncology (L Zeltzer).