Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain?

Abstract

Fibromyalgia is an intractable widespread pain disorder that is most frequently diagnosed in women. It has traditionally been classified as either a musculoskeletal disease or a psychological disorder. Accumulating evidence now suggests that fibromyalgia may be associated with CNS dysfunction. In this study, we investigate anatomical changes in the brain associated with fibromyalgia. Using voxel-based morphometric analysis of magnetic resonance brain images, we examined the brains of 10 female fibromyalgia patients and 10 healthy controls. We found that fibromyalgia patients had significantly less total gray matter volume and showed a 3.3 times greater age-associated decrease in gray matter than healthy controls. The longer the individuals had had fibromyalgia, the greater the gray matter loss, with each year of fibromyalgia being equivalent to 9.5 times the loss in normal aging. In addition, fibromyalgia patients demonstrated significantly less gray matter density than healthy controls in several brain regions, including the cingulate, insular and medial frontal cortices, and parahippocampal gyri. The neuroanatomical changes that we see in fibromyalgia patients contribute additional evidence of CNS involvement in fibromyalgia. In particular, fibromyalgia appears to be associated with an acceleration of age-related changes in the very substance of the brain. Moreover, the regions in which we demonstrate objective changes may be functionally linked to core features of the disorder including affective disturbances and chronic widespread pain.

Figure 1.

a, Brain gray matter, white matter, CSF, and total volume in 10 fibromyalgia patients and 10 healthy control subjects. Values are expressed in millimeters cubed ± SEM. Including age as a covariate of no interest, fibromyalgia patients had significantly less gray matter and total brain volume than controls. b, Brain gray matter tissue volume plotted against age. Gray matter volume correlated significantly with age in fibromyalgia patients (r = −0.90; p < 0.001), with a similar trend in healthy controls (r = −0.57; p = 0.086). Fibromyalgia patients showed a significantly steeper age-related decline than controls (F_(1,18) = 281.57; p < 0.001). c, Gray matter volume versus time since the patient had been diagnosed with fibromyalgia. Gray matter volume was significantly correlated with time since diagnosis (r = −0.79; p = 0.007), with a loss of 10.5 cm³ in gray matter with each year of diagnosed fibromyalgia. The slope was significantly greater than age-associated loss in healthy controls (F_(1,18) = 310.78; p < 0.001) with a magnitude of decrease equivalent to ∼9.5 years of normal aging seen in healthy controls. Gray matter volume for healthy controls is depicted on the figure, but was not used in the regression analysis. yrs, Years. *p < 0.05.

Figure 2.

Voxel-wise comparison of gray matter density between fibromyalgia patients and healthy control subjects. In the top panel, an example of the tissue classification procedure on one subject is shown. a, The first step of tissue classification into gray matter (green) white matter (white) and CSF (blue). b, The same image after applying a mask, which removes the skull, dura, cerebellum, and brainstem. c, Statistical t maps are depicted, with the t threshold set at 2.0 for visualization and superimposed on the MNI/ICBM 152 template. A cluster analysis was used to determine significance levels (for details, see Table 1 and Materials and Methods). Left side of brain is displayed on left. Regions showing significantly less gray matter density for fibromyalgia patients than healthy controls included left parahippocampal gyrus (PHG), left and right mid/posterior cingulate gyrus (CG), left insular cortex (IC), and medial frontal cortex (MFC) (for coordinates, see Table 1).