Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients

Abstract

Objective: Fibromyalgia (FM) is a disorder characterized by chronic pain and enhanced responses to acute noxious events. However, the sensory systems affected in FM may extend beyond pain itself, as FM patients show reduced tolerance to non-nociceptive sensory stimulation. Characterizing the neural substrates of multisensory hypersensitivity in FM may thus provide important clues about the underlying pathophysiology of the disorder. The aim of this study was to characterize brain responses to non-nociceptive sensory stimulation in FM patients and their relationship to subjective sensory sensitivity and clinical pain severity.

Methods: Functional magnetic resonance imaging (MRI) was used to assess brain response to auditory, visual, and tactile motor stimulation in 35 women with FM and 25 matched controls. Correlation and mediation analyses were performed to establish the relationship between brain responses and 3 types of outcomes: subjective hypersensitivity to daily sensory stimulation, spontaneous pain, and functional disability.

Results: Patients reported increased subjective sensitivity (increased unpleasantness) in response to multisensory stimulation in daily life. Functional MRI revealed that patients showed reduced task-evoked activation in primary/secondary visual and auditory areas and augmented responses in the insula and anterior lingual gyrus. Reduced responses in visual and auditory areas were correlated with subjective sensory hypersensitivity and clinical severity measures.

Conclusion: FM patients showed strong attenuation of brain responses to nonpainful events in early sensory cortices, accompanied by an amplified response at later stages of sensory integration in the insula. These abnormalities are associated with core FM symptoms, suggesting that they may be part of the pathophysiology of the disease.

Figure 1

Regions showing significant task-evoked activation in healthy controls (A) and fibromyalgia (FM) patients (B) and between-group differences in task-evoked activation (C and D). Results are displayed at a corrected threshold P_{family-wise error} < 0.05 estimated using Monte Carlo simulations. t = t-test.

Figure 2

Regions for which task-evoked activation was significantly correlated with symptom severity in fibromyalgia patients. A, Correlation between brain activation and Fibromyalgia Impact Questionnaire (FIQ) total score. B, Correlation between brain activation and FIQ functional score (item 1 of the FIQ assessing functional impairment in a variety of daily life activities). C, Correlation between brain activation and spontaneous pain. The plots illustrate the correlation at the peak voxel (further information is available at http://wagerlab.colorado.edu/files/papers/Lopez-Sola-fMRI-responses-to-Nonpainful-stimulation-in-fibromyalgia-patients-supplement.pdf) for each analysis. Lines above and below the regression line represent the 95% confidence interval of the correlation. Brain map results are displayed at a corrected threshold P_{family-wise error} < 0.05 estimated using Monte Carlo simulations within the mask of regions showing significant between-group effects. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.38781/abstract.

Figure 3

Regions for which task-evoked activation was significantly correlated with measures of hypersensitivity to sound (A) and touch (B). The plots illustrate the correlation at the peak voxel (further information is available at http://wagerlab.colorado.edu/files/papers/Lopez-Sola-fMRI-responses-to-Nonpainful-stimulation-in-fibromyalgia-patients-supplement.pdf) for each analysis. Lines above and below the regression line represent the 95% confidence interval of the correlation. Brain map results are displayed at a corrected threshold P_{family-wise error} < 0.05 estimated using Monte Carlo simulations within the mask of regions showing significant between-group effects. AASP = Adolescent/Adult Sensory Profile. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.38781/abstract.

Figure 4

Significant brain regions mediating the relationship between multisensory hypersensitivity and clinical category (fibromyalgia [FM] diagnosis present versus absent). The mediation analysis tests whether the covariance between 2 variables (the predictor X and the predicted outcome Y) can be explained by a third variable (the mediator, M). In this case, path a (−) indicates that subjective sensory sensitivity (X) negatively predicts (stimulation – baseline) brain activity in occipital, temporal, and cerebellar regions (M). Path b (−) shows that (stimulation – baseline) brain activity in such regions (M) negatively predicts FM status (Y) in a logistic regression, controlling for subjective sensory sensitivity. Path a*b corresponds to the product of path a and path b coefficients and shows that response in the brain areas illustrated (top) explains a significant proportion of the covariation between sensory sensitivity and FM status. Path c’ indicates the relationship between X and Y controlling for M. All voxels show 2-tailed P < 0.05 for paths a, b, and a*b (10,000 bootstrapped tests). Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.38781/abstract.