Fibromyalgia syndrome (FMS) is a chronic pain disorder with hypersensitivity to painful stimuli. A subgroup of patients shows damage to small peripheral nerve fibers. Previous studies support the hypothesis that increased activation of the pain-processing insular cortex is mediated by an imbalance of insular glutamate and γ-aminobutyric acid (GABA) concentrations. Here, we aimed to test this hypothesis in a large cohort of FMS patients comparing data of patients and healthy controls. In addition, we tested the hypothesis whether a reduction in small peripheral nerve fibers relates to glutamate concentrations in the insular cortex. We recruited 102 subjects (all female, 44 FMS patients, 40 healthy age-matched controls, and 19 patients with rheumatoid arthritis (RA) as disease controls. Study participants underwent single-voxel magnetic resonance spectroscopy of the right and left insular cortex. All patients completed questionnaires on symptom severity (pain intensity, impairment due to symptoms, depression). FMS patients were further stratified into subgroups with and without reduced intraepidermal nerve fiber density (IENFD) assessed on skin punch biopsies. We found no intergroup difference of the glutamate/GABA metabolite concentrations between FMS and RA patients and healthy controls. Glutamate/GABA levels did not correlate with symptom severity. Cerebral glutamate concentrations were independent of skin innervation. We found similar insular glutamate/GABA concentrations in FMS patients and disease and healthy controls. Therefore, our data cannot support the hypothesis that a glutamate/GABA mismatch leads to a sensitization of the insular cortex of fibromyalgia patients and thereby induces the symptoms.

The authors have declared no competing interest.

This research was funded by the Interdisciplinary Center for Clinical Research (IZKF) Wuerzburg (project F-376 to MP and CS). HCA is a "Clinician Scientist" fellow of the IZKF. The Else Kroener-Fresenius-Stiftung in part funded the study (EKFS, N.UE.: 2014_A129).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committee of the University of Wuerzburg University provided approval of the study (105/19).

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All data produced in the present study are available upon reasonable request to the authors.