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Abstract. Introduction:. Small fiber pathology may be involved in the pathophysiology of pain in women with fibromyalgia syndrome (FMS). Objectives:. This prospective single-center case-control study provides detailed pain phenotyping and small fiber pathology data in a cohort of men with FMS on a morphological and functional level. Methods:. Forty-two men with FMS underwent a comprehensive pain-related interview and neurological examination, a questionnaire and neurophysiological assessment, and specialized small fiber tests: skin punch biopsy, quantitative sensory testing including C-tactile afferents, and corneal confocal microscopy. Data were compared with those of healthy male controls. Results:. Men with FMS reported generalized and permanent pain with additional pain attacks and a mostly pressing pain character. Intraepidermal nerve fiber density was reduced at ≥1 biopsy site in 35 of 42 (83%) men with FMS (controls: 32/65, 49%). Compared with male controls, men with FMS had elevated cold (P < 0.05) and warm detection thresholds (P < 0.001) and an increased mechanical pain threshold (P < 0.05) as well as an impairment of C-tactile afferents (P < 0.05). Corneal nerve fiber density was lower in male patients with FMS vs healthy men (P < 0.01). Male FMS patients with pathological skin innervation at ≥1 biopsy site compared with those with normal skin innervation had a higher clinical Widespread Pain Index (P < 0.05) indicating an association between the severity of cutaneous denervation and symptom load. Conclusion:. We show a distinct pain phenotype and small nerve fiber dysfunction and pathology in male patients with FMS. These findings may have implications for the diagnosis and management of men with FMS.

Abstract. Introduction:. Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. Objective:. To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. Methods:. We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. Results:. FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 %) FMS patients and 39/53 (73.6 %) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p

Abstract We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case–control study included 43 women diagnosed with fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.

ObjectivesThe pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS.MethodsSixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis.ResultsQuantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (pConclusionWe found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression.

Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson’s disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.

INTRODUCTION:We characterized dermal innervation in patients with fibromyalgia syndrome (FMS) as potential contribution to small fiber pathology. METHODS:Skin biopsies of the calf were collected (86 FMS patients, 35 healthy controls). Skin was immunoreacted with antibodies against protein gene product 9.5, calcitonine gene-related peptide, substance P, CD31, and neurofilament 200 for small fiber subtypes. We assessed two skin sections per patient; on each skin section, two dermal areas (150 x 700 μm each) were investigated for dermal nerve fiber length (DNFL). RESULTS:In FMS patients we found reduced DNFL of fibers with vessel contact compared to healthy controls (p

BackgroundMicroRNA (miRNA) mainly inhibit post-transcriptional gene expression of specific targets and may modulate disease severity.ObjectiveWe aimed to identify miRNA signatures distinguishing patient clusters with fibromyalgia syndrome (FMS).Subjects and methodsWe previously determined four FMS patient clusters labelled "maladaptive", "adaptive", "vulnerable", and "resilient". Here, we cluster-wise assessed relative gene expression of miR103a-3p, miR107, miR130a-3p, and miR125a-5p in white blood cell (WBC) RNA of 31 FMS patients and 16 healthy controls. Sum scores of pain-, stress-, and resilience-related questionnaires were correlated with miRNA relative gene expression. A cluster-specific speculative model of a miRNA-mediated regulatory cycle was proposed, and its potential targets verified by the online tool "target scan human".ResultsOne-way ANOVA revealed lower gene expression of miR103a-3p, miR107, and miR130a-3p in FMS patients compared to controls (p < 0.05). Follow-up post-hoc tests indicated the highest peak of gene expression of miR103a-3p for the adaptive cluster (p < 0.05), i.e. in patients with low disability in all symptom categories. Gene expression of miR103a-3p correlated with FMS related disability and miR107 with the score "physical abuse" of the trauma questionnaire (p < 0.05). Target scan identified sucrose non-fermentable serine/threonine protein kinase, nuclear factor kappa-b, cyclin dependent kinase, and toll-like receptor 4 as genetic targets of the miR103a/107 miRNA family.ConclusionWe show an association between upregulated gene expression of miR103a, tendentially of miR107, and adaptive coping in FMS patients. Validation of this pair of miRNA may enable to identify a somatic resilience factor in FMS.

BackgroundCoping strategies and their efficacy vary greatly in patients suffering from fibromyalgia syndrome (FMS).ObjectiveWe aimed to identify somatic and psychosocial factors that might contribute to different coping strategies and resilience levels in FMS.Subjects and methodsStandardized questionnaires were used to assess coping, pain, and psychological variables in a cohort of 156 FMS patients. Quantitative real-time polymerase chain reaction (qRT-PCR) determined gene expression of selected cytokines in white blood cells of 136 FMS patients and 25 healthy controls. Data of skin innervation, functional and structural sensory profiles of peripheral nociceptive nerve fibers of a previous study were included into the statistics. An exploratory factor analysis was used to define variance explaining factors, which were then included into cluster analysis.Results54.9% of the variance was explained by four factors which we termed (1) affective load, (2) coping, (3) pain, and (4) pro-inflammatory cytokines (p < 0.05). Considering differences in the emerged factors, coping strategies, cytokine profiles, and disability levels, 118 FMS patients could be categorized into four clusters which we named "maladaptive", "adaptive", "vulnerable", and "resilient" (p < 0.05). The adaptive cluster had low scores in disability and in all symptom categories in contrast to the vulnerable cluster, which was characterized by high scores in catastrophizing and disability (p < 0.05). The resilient vs. the maladaptive cluster was characterized by better coping and a less pro-inflammatory cytokine pattern (p < 0.05).ConclusionOur data suggest that problem- and emotion-focused coping strategies and an anti-inflammatory cytokine pattern are associated with reduced disability and might promote resilience. Additional personal factors such as low anxiety scores, ability of acceptance, and persistence further favor a resilient phenotype. Individualized therapy should take these factors into account.

Background MicroRNA (miRNA) mainly inhibit post-transcriptional gene expression of specific targets and may modulate disease severity. Objective We aimed to identify miRNA signatures distinguishing patient clusters with fibromyalgia syndrome (FMS). Subjects and methods We previously determined four FMS patient clusters labelled “maladaptive”, “adaptive”, “vulnerable”, and “resilient”. Here, we cluster-wise assessed relative gene expression of miR103a-3p, miR107, miR130a-3p, and miR125a-5p in white blood cell (WBC) RNA of 31 FMS patients and 16 healthy controls. Sum scores of pain-, stress-, and resilience-related questionnaires were correlated with miRNA relative gene expression. A cluster-specific speculative model of a miRNA-mediated regulatory cycle was proposed, and its potential targets verified by the online tool “target scan human”. Results One-way ANOVA revealed lower gene expression of miR103a-3p, miR107, and miR130a-3p in FMS patients compared to controls (p < 0.05). Follow-up post-hoc tests indicated the highest peak of gene expression of miR103a-3p for the adaptive cluster (p < 0.05), i.e. in patients with low disability in all symptom categories. Gene expression of miR103a-3p correlated with FMS related disability and miR107 with the score “physical abuse” of the trauma questionnaire (p < 0.05). Target scan identified sucrose non-fermentable serine/threonine protein kinase, nuclear factor kappa-b, cyclin dependent kinase, and toll-like receptor 4 as genetic targets of the miR103a/107 miRNA family. Conclusion We show an association between upregulated gene expression of miR103a, tendentially of miR107, and adaptive coping in FMS patients. Validation of this pair of miRNA may enable to identify a somatic resilience factor in FMS.