Distinct aberrations in cerebral pain processing differentiating patients with fibromyalgia from patients with rheumatoid arthritis

Angelica Sandström, Isabel Ellerbrock, Monika Löfgren, Reem Altawil, Indre Bileviciute-Ljungar, Jon Lampa, Eva Kosek, Angelica Sandström, Isabel Ellerbrock, Monika Löfgren, Reem Altawil, Indre Bileviciute-Ljungar, Jon Lampa, Eva Kosek

Abstract

The current study used functional magnetic resonance imaging to directly compare disease-relevant cerebral pain processing in well-characterized patient cohorts of fibromyalgia (FM, nociplastic pain) and rheumatoid arthritis (RA, nociceptive pain). Secondary aims were to identify pain-related cerebral alterations related to the severity of clinical symptoms such as pain intensity, depression, and anxiety. Twenty-six patients with FM (without RA-comorbidity) and 31 patients with RA (without FM-comorbidity) underwent functional magnetic resonance imaging while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100-mm visual analogue scale. Stimulation sites were at the most inflamed proximal interphalangeal joint in the left hand in patients with RA and the left thumbnail in patients with FM, 2 sites that have previously been shown to yield the same brain activation in healthy controls. The current results revealed disease-distinct differences during pain modulation in RA and FM. Specifically, in response to painful stimulation, patients with FM compared to patients with RA exhibited increased brain activation in bilateral inferior parietal lobe (IPL), left inferior frontal gyrus (IFG)/ventrolateral prefrontal cortex (vlPFC) encapsulating left dorsolateral prefrontal cortex, and right IFG/vlPFC. However, patients with RA compared to patients with FM exhibited increased functional connectivity (during painful stimulation) between right and left IPL and sensorimotor network and between left IPL and frontoparietal network. Within the FM group only, anxiety scores positively correlated with pain-related brain activation in left dorsolateral prefrontal cortex and right IFG/vlPFC, which further highlights the complex interaction between affective (ie, anxiety scores) and sensory (ie, cerebral pain processing) dimensions in this patient group.

Trial registration: ClinicalTrials.gov NCT01197144 NCT01226784.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

Figures

Figure 1.
Figure 1.
(A) Boxplots illustrate average pressure (kPa) corresponding to subjective pain ratings of 50 mm on a visual analogue scale (VAS) when stimulated with painful pressure. Patients with rheumatoid arthritis (RA) were stimulated at the most inflamed proximal phalangeal joint, left hand, and patients with fibromyalgia (FM) at the left thumbnail (We have previously demonstrated that patients with RA had increased pain sensitivity at the inflamed joint, but normal pain sensitivity at the nonaffected thumbnail compared to HC). Horizontal lines within boxes represent median values. Diamond-shaped dots represent mean values. Box top and bottom frames represent 25th and 75th percentiles, respectively. Whiskers represent minimum and maximum values. Black dots represent individual painful pressure values. (B) All patients' (collapsed groups) brain activation in response to painful minus sensory (50 kPa) pressure stimulation. Significantly activated clusters across all patients encapsulated several pain-related brain regions such as right S1, right M1, bilateral S2, MCC, bilateral thalamus, and insula. (C) Brain regions where FM compared to RA exhibited increased brain activation in response to painful minus sensory stimulation. Significantly activated clusters were located in bilateral IPL, left dlPFC, and right IFG. The depicted brain activation was derived from a whole-brain statistical map corrected for multiple comparisons using FWE correction PFWE <0.05 at an initial threshold of P < 0.001 uncorrected with 20 contiguously activated voxels. dlPFC, dorsolateral prefrontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; FWE, family-wise error; HC, healthy control; kPa, kilopascal; M1, primary motor cortex; MCC, midcingulate cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex.
Figure 2.
Figure 2.
Differences in task-based connectivity between patients with rheumatoid arthritis (RA) and FM during [Pain-Sensory] stimulation. Specifically, (A) patients with RA compared to FM exhibited increased task-based connectivity between left inferior parietal lobe (IPL) (red dot) and brain regions involved in FPN (purple dots) and SMN (blue dots). (B) Patients with RA compared to FM exhibited increased task-based connectivity between right IPL (red dot) and SMN (blue dots). The depicted brain activation (including PPI) was derived from a whole-brain statistical map corrected for multiple comparisons using FWE correction PFWE <0.05 at an initial threshold of P < 0.001 uncorrected with 20 contiguously activated voxels. dlPFC, dorsolateral prefrontal cortex; FM, fibromyalgia (patients); FWE, family-wise error; IPL, inferior parietal lobe; IFG, inferior frontal gyrus; aIns, anterior insula; M1, primary motor cortex; PPC, posterior parietal cortex; PPI, psychophysiological interaction; RA, rheumatoid arthritis (patients); S1, primary somatosensory cortex; S2, secondary somatosensory cortex; SMN, sensorimotor network.
Figure 3.
Figure 3.
(A) Significant whole-brain activation during [Pain-Sensory] stimulation within the FM group that positively correlated with summarized anxiety scores of the hospital anxiety and depression scale (HADS-anxiety). Specifically, patients with FM with higher HADS-anxiety scores exhibited higher pain-related brain activation in (A) right IFG/vlPFC and (B) left dlPFC. Significant clusters showing a positive correlation between BOLD response and HADS-anxiety are displayed in yellow, marked with a white circle and displayed in the top left corner within the respective correlational plot. Correlational plots were plotted in R exclusively for visual purposes. The x-axis indicates HADS-anxiety scores and the y-axis indicates raw (unscaled) beta weights extracted from each significant cluster. Black dots within correlational plots indicate individual FM subjects. The depicted brain activation was derived from a whole-brain statistical map corrected for multiple comparisons using FWE correction PFWE < 0.05 at an initial threshold of P < 0.001 uncorrected with 20 contiguously activated voxels. dlPFC, dorsolateral prefrontal cortex; FWE, family-wise error correction; IFG, inferior frontal gyrus; vlPFC, ventrolateral prefrontal cortex.

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