Richard J. Traub

Temporomandibular disorder (TMD) and irritable bowel syndrome (IBS) are 2 chronic overlapping pain conditions (COPCs) that present with significant comorbidity. Both conditions are more prevalent in women and are exacerbated by stress. While peripheral mechanisms might contribute to pain hypersensitivity for each individual condition, mechanisms underlying the comorbidity are poorly understood, complicating pain management when multiple conditions are involved. In this study, longitudinal behavioral and functional MRI-based brain changes have been identified in an animal model of TMD-like pain (masseter muscle inflammation followed by stress) that induces de novo IBS-like comorbid visceral pain hypersensitivity in rats. In particular, data indicate that increased activity in the insula and regions of the reward and limbic systems are associated with more pronounced and longer-lasting visceral pain behaviors in female rats, while the faster pain resolution in male rats may be due to increased activity in descending pain inhibitory pathways. These findings suggest the critical role of brain mechanisms in chronic pain conditions and that sex may be a risk factor of developing COPCs.

Mass spectrometry imaging (MSI) is a powerful scientific tool for understanding the spatial distribution of biochemical compounds in tissue structures. MSI data analysis presents problems due to the large file sizes and computational resource requirements and also due to the complexity of interpreting the raw spectral data. Dimensionality reduction techniques that address the first issue do not necessarily result in readily interpretable features. In this paper, we present non-negative matrix factorization (NMF) as a dimensionality reduction algorithm that reduces the size of MSI datasets by three orders of magnitude with limited loss of information, yielding spatial and spectral components with meaningful correlation to tissue structure. This analysis is demonstrated on an MSI dataset from female Sprague-Dawley rats for an animal model of comorbid visceral pain hypersensitivity (CPH). The significant findings are: 1) High-dimensional MSI data ( ∼ 100,000 ions per pixel) was reduced to 20 spectral NMF components with < 20% loss in reconstruction accuracy. 2) Spatial NMF components are reproducible and correlate well with H&E-stained tissue images. 3) Spatial NMF components may be used to provide images with enhanced specificity for different tissue types. 4) Small patches of NMF data (i.e., 20 spatial NMF components over 20 x 20 pixels) provide an accuracy of ∼ 87% in classifying CPH vs näıve control subjects. This paper presents novel methodologies for data augmentation to support classification, ranking of features according to their contribution to classification, and image registration to support tissue-specific imaging.

Background: Stress exacerbates many chronic pain syndromes including irritable bowel syndrome (IBS). Among these patient populations, many suffer from comorbid or chronic overlapping pain conditions and are predominantly female. Nevertheless, basic studies investigating chronic psychological stress‐induced changes in pain sensitivity have been mostly carried out in male rodents. Our laboratory developed a model of comorbid pain hypersensitivity (CPH) (stress in the presence of preexisting orofacial pain inducing chronic visceral pain hypersensitivity that significantly outlasts transient stress‐induced pain hypersensitivity (SIH)) facilitating the study of pain associated with IBS. Since CPH and SIH are phenotypically similar until SIH resolves and CPH persists, it is unclear if underlying mechanisms are similar.Methods: In the present study, the visceromotor response (VMR) to colorectal distention was recorded in the SIH and CPH models in intact females and ovariectomized rats plus estradiol replacement (OVx + E2). Over several months, rats were determined to be susceptible or resilient to stress and the role of peripheral corticotrophin‐releasing factor (CRF) underlying in the pain hypersensitivity was examined.Key Results: Stress alone induced transient (3‐4 weeks) visceral hypersensitivity, though some rats were resilient. Comorbid conditions increased susceptibility to stress prolonging hypersensitivity beyond 13 weeks. Both models had robust peripheral components; hypersensitivity was attenuated by the CRF receptor antagonist astressin and the mast cell stabilizer disodium cromoglycate (DSCG). However, DSCG was less effective in the CPH model compared to the SIH model.Conclusions and Inferences: The data indicate many similarities but some differences in mechanisms contributing to comorbid pain conditions compared to transient stress‐induced pain.