3D magnetic resonance spectroscopic imaging reveals links between brain metabolites and multidimensional pain features in fibromyalgia

Abstract

Background: Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood.

Methods: We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87).

Results: Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus.

Conclusions: These findings support single voxel placement targeting nociceptive processing areas in prior ¹ H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia.

Significance: This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians.

Figure 1.

Magnetic Resonance Spectral Imaging (MRSI) data collection. (A) Volume of interest (VOI) was placed manually to cover the bilateral insular and cingulate cortices, and thalami. The overlay shows spatial distribution for overlapped collected voxels across participants (FM and HC), and data analysis was performed only for voxels with contribution from 100% of participants. (B) Sample spectra (thin black line, fit in the range of 4.2 to 1.8 ppm) from a right mid-insular cortex voxel is presented (SNR = 15 and FWHM = 0.040 ppm for this example), with LCModel fit (thick red line). The average values and percentage of ‘low’- and ‘adquate’-quality data voxels for SNR and FWHM were reported for quality measurement in the same region (SNR: ‘low’-quality data voxels = 4.56 ± 1.29, 29.17%, ‘adequate’-quality data voxels = 7.28 ± 1.85, 70.83%; FWHM: ‘low’-quality data voxels = 0.11 ± 0.02 ppm, 23.33%, ‘adequate’-quality data voxels = 0.07 ± 0.01 ppm, 76.67%). L = left hemisphere, NAA = N-acetylaspartate, NAAG = N-acetylaspartylglutamate, Glu = glutamate, Gln = glutamine, mIno = myo-inositol, Cr = creatine, PCr = phosphocreatine, GPC = glycerophosphocholine, pCho = phosphocholine).

Figure 2.

Study flowchart. Glx = combined glutamate and glutamine concentration, mIno = myo-inositol concentration, tNAA = combined N-acetylaspartate and N-acetylaspartylglutamate concentration, tCr = combined creatine and phosphocreatine concentration.

Figure 3.

Spatial distribution of ‘low’-quality data voxels (SNR < 5, FWHM ≥ 0.1 ppm, or CRLB ≥ 20%) for Glx/tCr with N = 86 (A), mIno/tCr with N = 85 (B), and tNAA/tCr with N = 87 (C) in FM. The majority of ‘low’-quality data voxels were found in the ventromedial part of the VOI and ventricles. L = left hemisphere, Glx = combined glutamate and glutamine concentration, mIno = myo-inositol concentration, tNAA = combined N-acetylaspartate and N-acetylaspartylglutamate concentration, tCr = combined creatine and phosphocreatine concentration.

Figure 4.

Brain Glx/tCr correlates of PCS scores (A) and BPI severity scores (B). Significant positive correlations between PCS scores and Glx/tCr levels in the anterior and middle insular cortices (A), and BPI severity and Glx/tCr levels in the middle/posterior insular and posterior cingulate cortices (B) were found. N.b. Correlation plots were shown for black border voxel. L = left hemisphere, PCS = pain catastrophizing scale, BPI = Brief Pain Inventory, Glx = combined glutamate and glutamine concentration, tCr = combined creatine and phosphocreatine concentration. Age, gabapentin/pregabalin usage, and average tCr level were controlled.

Figure 5.

Brain mIno/tCr correlates of PCS scores (A) and BPI severity scores (B). Significant negative correlations between PCS scores and mIno/tCr levels in the posterior cingulate cortex (A), and BPI severity scores and mIno/tCr levels in the anterior midcingulate cortex and thalamus (B) were found. N.b. Correlation plots were shown for black border voxels. Significant voxels from the cluster-correction for multiple comparisons (Z > 2.3, P < 0.05) were highlighted with a red border. L = left hemisphere, PCS = pain catastrophizing scale, BPI = brief pain inventory, mIno = myo-inositol concentration, tCr = combined creatine and phosphocreatine concentration. Age, gabapentin/pregabalin usage, and average tCr level were controlled.

Figure 6.

Brain tNAA/tCr correlates of clinical pain measures. Metabolite concentrations of tNAA/tCr were positively correlated with (A) PCS scores in the middle and anterior insular cortices and negatively correlated with (B) BPI severity scores in the anterior midcingulate cortex. (C) Positive correlations between tNAA/tCr levels and Cuff P40 pressure were found in the posterior insular cortex, anterior/posterior middle and posterior cingulate cortices, and thalamus. N.b. Correlation plots were shown for black border voxels. Significant voxels from the cluster-correction for multiple comparisons (Z > 2.3, P < 0.05) were highlighted with a red border. L = left hemisphere, R = right hemisphere, PCS = pain catastrophizing scale, BPI = brief pain inventory, tNAA = combined N-acetylaspartate and N-acetylaspartylglutamate concentration, tCr = combined creatine and phosphocreatine concentration. Age, gabapentin/pregabalin usage, and average tCr level were controlled.