Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging

Abstract

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABA_A receptor concentration, an indirect marker of neuronal integrity measured with [¹⁸F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABA_A receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABA_A receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABA_A receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain.

Significance statement: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABA_A receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABA_A receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.

Keywords: chronic pain; flumazenil PET; grey matter; neurodegeneration; voxel-based morphometry.

Figure 1.

Proton MR spectroscopy voxel. Localization of the 20 × 40 × 15 mm voxel in the ACC for MR spectroscopy in a single subject.

Figure 2.

Processing pipelines. Middle, VBM analysis of GMVs. Other panels, Voxel-based analysis pipelines that we developed specifically for analysis of BP_ND maps for flumazenil PET (left), and voxel-based relaxometry (VBR) analysis of T1 maps, a surrogate marker of water content (right). Blue box represents data in standard space (MNI space).

Figure 3.

GMV decreases in patients with fibromyalgia and their relationship with tissue water content. Whole-brain map of GMV decreases in patients compared with controls. Results are presented at a voxelwise threshold of z > 2.3 and a cluster-extent threshold of k > 200, overlaid on the mean anatomical image of the whole sample (N = 51). Scatter plots represent GMV (in mm³) and T1 time in seconds (a surrogate for water content) in each significant cluster. Axial images are displayed in neurological convention. Right, Right hemisphere.

Figure 4.

GMV increases in patients with fibromyalgia and their relationship with GABA_A receptor concentration. Whole-brain map of gray matter increases in patients compared with controls. Results are presented at a voxelwise threshold of z > 2.3 and a cluster-extent threshold of k > 200, overlaid on the mean anatomical image of the whole sample (N = 51). Scatter plots display GMV (in mm³) against flumazenil BP_ND in each cluster. The axial image is displayed in neurological convention. Right, Right hemisphere.