Functional connectivity associated with attention networks differs among subgroups of fibromyalgia patients: an observational case-control study

Abstract

Fibromyalgia is a heterogenous chronic pain disorder diagnosed by symptom-based criteria. The aim of this study was to clarify different pathophysiological characteristics between subgroups of patients with fibromyalgia. We identified subgroups with distinct pain thresholds: those with a low pressure pain threshold (PL; 16 patients) and those with a normal pressure pain threshold (PN; 15 patients). Both groups experienced severe pain. We performed resting-state functional MRI analysis and detected 11 functional connectivity pairs among all 164 ROIs with distinct difference between the two groups (p < 0.001). The most distinctive one was that the PN group had significantly higher functional connectivity between the secondary somatosensory area and the dorsal attention network (p < 0.0001). Then, we investigated the transmission pathway of pain stimuli. Functional connectivity of the thalamus to the insular cortex was significantly higher in the PL group (p < 0.01 - 0.05). These results suggest that endogenous pain driven by top-down signals via the dorsal attention network may contribute to pain sensation in a subgroup of fibromyalgia patients with a normal pain threshold. Besides, external pain driven by bottom-up signals via the spinothalamic tract may contribute to pain sensations in another group of patients with a low pain threshold. Trial registration: UMIN000037712.

Figure 1

A significant difference between the two groups for pain threshold. There were no significant differences between the two groups in terms of the degree of pain (numeric rating scale score, NRS; PL; 7.6 (± 1.3) vs. PN; 6.9 (± 1.6), p = 0.158). However, there was a significant difference in pressure pain threshold, PPT, (PL; 0.13 (± 0.11) vs. PN; 2.57 (± 0.65), p = 3.80 × 10⁻¹⁵) between the PL and PN groups. The pain threshold in the PN group was equivalent to that in subjects with no pain, as previously determined in a previous study (25 females, age; 42.6 (± 7.3), pressure pain threshold; 2.44 (± 0.75), Student’s t test; p = 0.572 vs. PN, J. Clin. Med. 2022, 11(19), 5587). Graphs represent mean and 95% CI values for each group and each dot represents a different patient.

Figure 2

Connected pairs with significantly different functional connectivity between the two patient groups. (a–c) The functional connectivity in the PL group were significantly larger than those of the PN group (p < 0.001). (d–f) The functional connectivity in the PN group were significantly larger than those of the PL group (p < 0.001). Graphs represent mean and 95% CI values for each group. FC functional connectivity, sLOCr superior division of lateral occipital cortex right, MidFGr middle frontal gyrus right, PT left planum temporale left, PC posterior division of cingulate gyrus, Cereb2 left cerebellum crus2 left, FO left frontal operculum cortex left, IFG oper left pars opercularis of inferior frontal gyrus left, PO left parietal operculum cortex left, DA IPS left intraparietal sulcus in dorsal attention network left, CO left central opercular cortex left, aSMG left anterior supramarginal gyrus left.

Figure 3

Significant differences in FC between the two groups were observed in several regions related to pain perception. (a) Functional connectivity of the parietal operculum cortex to the intraparietal sulcus in the dorsal attention network was significantly higher on both the same side and the contralateral side in the PN group than that in the PL group. (b) Functional connectivity of the middle frontal gyrus right in the ventral attention network to the right intraparietal sulcus in the dorsal attention network was significantly higher in the PL group. (c) Functional connectivity of the right and left insular cortex to the anterior cingular cortex was high in both patient groups, whereas there was no significant difference between them (right; p = 0.350, left; p = 0.756). (d) Functional connectivity between the thalamus and the insular cortex on both hemispheres was significantly higher in the PL group. Graphs represent mean and 95% CI values for each group. FC functional connectivity, DA IPS intraparietal sulcus in dorsal attention network, PO parietal operculum cortex, MidFGr middle frontal gyrus right, IC insular cortex, ACC anterior cingular cortex.

Figure 4

Functional connectivity of the insular cortex left to the periaqueductal gray region. (a) Functional connectivity to the insular cortex left in the brainstem regions (x, y, −10). Higher connectivity was observed around the periaqueductal gray region in the PN group. PAG; periaqueductal gray (white arrow; −2, −30, −10), IC; insular cortex. (b) Functional connectivity of the insular cortex left to the periaqueductal gray region (−2, −30, −10) in the PN group was significantly higher than that in the PL group. Graphs represent mean and 95% CI values for each group. FC functional connectivity, PAG periaqueductal gray.