These findings point towards a potential role of insular Glu in the pathophysiology of fibromyalgia. The levels of glutamate in the posterior insula were higher for individuals with FM as compared to controls, and the levels of glutamate were negatively correlated with pressure pain thresholds. This suggests that the “left-ward shift” in the stimulus response function seen in both experimental pain testing and functional imaging in FM (i.e. hyperalgesia) is associated with higher levels of glutamate in certain brain regions involved in pain processing, such as the posterior insula (9
). The posterior insula is known to play a prominent role in pain and interoceptive sensory processing (22
), whereas the anterior insula is involved in the affective processing of pain and other subjective feelings (22
). Since the levels of Glu in the anterior insula were no different in the FM group, this could suggest that a component of this disorder involves an amplification in sensory but not affective processing.
Our findings are entirely consistent with the broader literature and knowledge regarding FM and related syndromes, which suggests that individuals with these conditions are at the far right end of the bell shaped curve of pain and sensory processing in the population (25
). Our data suggest that glutamate is playing a role in this augmented pain processing, in those individuals who have elevated glutamate. Since greater Glu was associated with lower pain thresholds, this suggests that Glu in the posterior insula is related to pain processing. The elevated levels of Glu in the FM group could raise the set point of baseline neural activity in this region which could result in augmented responses to painful stimuli. In a related line of inquiry, cold pain has been shown to increase Glu within the cingulate of pain free controls (26
FM patients may have more glutamate within their synaptic vesicles, higher numbers or densities of glutamatergic synapses, or even less uptake of glutamate from the synaptic cleft. Any of these changes would be consistent with the hypothesis that there is augmentation of pain and sensory processing in FM. If true, this aspect of the pathophysiology of FM may be more similar to conditions such as epilepsy or neurodegenerative diseases than to the rheumatic syndromes which it has historically been associated with. For example, in epilepsy cortical and sub-cortical neurons appear to be hyper-excitable as a result of elevated concentrations of glutamate (27
). These clusters of excited neurons are thought to form a locus of heightened activity which can then initiate a spreading wave of action potentials which propagate to other connected brain regions. FM may simply represent a condition wherein glutamatergic “hyperactivity” occurs within brain regions devoted to processing and modulating pain. This could arise from local increases in Glu or enhanced ascending activity to this area. This hypothesis is consistent with the fact that one of the FDA approved medications for FM is pregabalin, a drug whose action is thought to involve inhibition of presynaptic glutamate release (28
). Interestingly this drug is also used in the treatment of epilepsy (29
As with any trial, our study has limitations. The voxels used during H-MRS include multiple cell types. Our metabolite estimates of Glu and Glx reflect an ensemble average of all cell types (i.e. neurons, astrocytes, and glia) within the tissue samples. As such our findings must be interpreted with the knowledge that the cellular and sub-cellular location of the elevated glutamate is unknown. That said our methods have been empirically validated by other reported single voxel spectroscopy studies (30
) indicating that this approach is “state of the art” for non-invasive assessment of molecular concentrations within the brain. We also recognize that our findings pertain only to the insula. Future studies that detect Glu levels in other pain processing structures such as the secondary somatosensory cortex, amygdala, cingulate etc. are needed to determine the spatial extent of elevated Glu levels. Of note a recent H-MRS study has shown decreased NAA within the hippocampus of individuals with FM (32
) whereas we observed increased NAA in the posterior insula albeit at the trend level. In addition, our patient population excluded individuals with current major depression. It is possible that Glu levels within the anterior insula of depressed FM patients might be elevated, since it is known that the anterior insula is more involved in emotional processing of sensory information. Thus, our lack of group differences in anterior insula Glu may be due to the absence of depression in our sample. Finally although our results are significant, they originate from a relatively small number of participants. Validation of these findings from other studies could be made with larger study populations.
Overall we find that glutamate within the posterior insula is a potential pathologic factor in FM. The previously observed allodynia and hyperalgesia seen in these patients may be due to elevated excitatory glutamatergic neurotransmission within the posterior insula. Future studies are needed to confirm whether these findings are observed in other functional pain syndromes.