Elevated insular glutamate in fibromyalgia is associated with experimental pain

Abstract

Objective: Central pain augmentation resulting from enhanced excitatory and/or decreased inhibitory neurotransmission is a proposed mechanism underlying the pathophysiology of functional pain syndromes such as fibromyalgia (FM). Multiple functional magnetic resonance imaging studies implicate the insula as a region of heightened neuronal activity in this condition. Since glutamate (Glu) is a major cortical excitatory neurotransmitter that functions in pain neurotransmission, we undertook this study to test our hypothesis that increased levels of insular Glu would be present in FM patients and that the concentration of this molecule would be correlated with pain report.

Methods: Nineteen FM patients and 14 age- and sex-matched pain-free controls underwent pressure pain testing and a proton magnetic resonance spectroscopy session in which the right anterior insula and right posterior insula were examined at rest.

Results: Compared with healthy controls, FM patients had significantly higher levels of Glu (mean +/- SD 8.09 +/- 0.72 arbitrary institutional units versus 6.86 +/- 1.29 arbitrary institutional units; P = 0.009) and combined glutamine and Glu (i.e., Glx) (mean +/- SD 12.38 +/- 0.94 arbitrary institutional units versus 10.59 +/- 1.48 arbitrary institutional units; P = 0.001) within the right posterior insula. No significant differences between groups were detected in any of the other major metabolites within this region (P > 0.05 for all comparisons), and no group differences were detected for any metabolite within the right anterior insula (P > 0.11 for all comparisons). Within the right posterior insula, higher levels of Glu and Glx were associated with lower pressure pain thresholds across both groups for medium pain (for Glu, r = -0.43, P = 0.012; for Glx, r = -0.50, P = 0.003).

Conclusion: Enhanced glutamatergic neurotransmission resulting from higher concentrations of Glu within the posterior insula may play a role in the pathophysiology of FM and other central pain augmentation syndromes.

Figures

Figure 1. Insula Voxel Placement and Resulting Spectrum

A. Axial and sagittal T1-weighted images showing single voxel placements for right anterior (ant Ins) and right posterior (post Ins) insula. B. Representative H-MRS spectrum from the posterior insula fit with LCModel (red trace; * = resonance from two Glu γ proton resonances at 2.35ppm). LCModel uses a linear combination of individual spectra obtained from pure molecular species to fit the experimental spectra. Absolute concentrations of Glu were calculated in arbitrary institutional units (AIU) using water as an internal scaling factor.

Figure 2. Elevated Levels of Glu and Glx within the Posterior Insula of FM Patients

A. Individual plots of FM (filled circles) and HC (open circles) participants for corrected Glx (left) and Glu (right) levels in the posterior insula. FM patients have elevated concentrations of Glu and Glx. B. Individual plots of FM (filled circles) and HC (open circles) for corrected Glx (left) and Glu (right) levels in the anterior insula. There is no difference in Glu and Glx within the anterior insula between FM and HC participants.

Figure 3. Glx Levels within the Posterior Insula are Negatively Correlated with Pressure Pain Thresholds

Scatter plot of Glx concentrations versus medium pain pressure thresholds for FM (filled circles) and HC (open circles). Regression line across groups (r=−0.50; p=0.003).