Identifying the genetic association between the cerebral cortex and fibromyalgia.

Fibromyalgia (FM) is a central sensitization syndrome that is strongly associated with the cerebral cortex. This study used bidirectional two-sample Mendelian randomization (MR) analysis to investigate the bidirectional causality between FM and the cortical surface area and cortical thickness of 34 brain regions. Inverse variance weighted (IVW) was used as the primary method for this study, and sensitivity analyses further supported the results. The forward MR analysis revealed that genetically determined thinner cortical thickness in the parstriangularis (OR = 0.0567 mm, PIVW = 0.0463), caudal middle frontal (OR = 0.0346 mm, PIVW = 0.0433), and rostral middle frontal (OR = 0.0285 mm, PIVW = 0.0463) was associated with FM. Additionally, a reduced genetically determined cortical surface area in the pericalcarine (OR = 0.9988 mm2, PIVW = 0.0085) was associated with an increased risk of FM. Conversely, reverse MR indicated that FM was associated with cortical thickness in the caudal middle frontal region (ß = -0.0035 mm, PIVW = 0.0265), fusiform region (ß = 0.0024 mm, SE = 0.0012, PIVW = 0.0440), the cortical surface area in the supramarginal (ß = -9.3938 mm2, PIVW = 0.0132), and postcentral regions (ß = -6.3137 mm2, PIVW = 0.0360). Reduced cortical thickness in the caudal middle frontal gyrus is shown to have a significant relationship with FM prevalence in a bidirectional causal analysis.

Impaired mitochondrial quality control in fibromyalgia: Mechanisms involved in skeletal muscle alteration.

Fibromyalgia (FMS) is a persistent syndrome marked by widespread musculoskeletal pain and behavioural symptoms. Given the hypothesis linking FMS aetiology to mitochondrial dysfunction and oxidative stress, we examined the biochemical correlation among these factors by studying specific proteins associated with mitochondrial homeostasis in muscle. Additionally, this study investigated the role of Boswellia serrata gum resin extract (BS), known for its various functions, including the potent induction of antioxidant enzymes, in determining protective or reparative mechanisms in the muscle cells. Sprague-Dawley rats were injected with reserpine to induce FMS. These animals exhibited moderate changes in hind limb skeletal muscles, experiencing mobility difficulties. Additionally, there were noteworthy morphological and ultrastructural alterations, along with the expression of myogenin, mitochondrial enzymes and oxidative stress markers in the gastrocnemius muscle. Interestingly, BS demonstrated a reduction in spontaneous motor activity difficulties. Moreover, BS showed a positive impact on musculoskeletal morphostructural aspects, as well as a decrease in oxidative stress and mitochondrial alterations. In particular, BS restored the mRNA expression of citrate synthase and cytochrome-c oxidase subunit II and the activity of electron transfer chain complexes. BS also influenced mitochondrial biogenesis, upregulating PGC-1α expression and the related transcription factors (Nrf1, Tfam, Nrf2, FOXO3a, SIRT3, GCLC, NQO1, SOD2 and GPx4), oxidative stress (lipid peroxidation, GSH levels and GSH-Px activity) and mitochondrial dynamics and function (Mnf2 expression and CoQ10 levels). Overall, this study underlined the key role of the mitochondrial alteration in FMS and that BS had a very high antioxidant effect in these organelles and also in the cells.

Mitochondrial structural alterations in fibromyalgia: a pilot electron microscopy study.

OBJECTIVES: The pathogenesis of fibromyalgia (FM), characterised by chronic widespread pain and fatigue, remains notoriously elusive, hampering attempts to develop disease modifying treatments. Mitochondria are the headquarters of cellular energy metabolism, and their malfunction has been proposed to contribute to both FM and chronic fatigue. Thus, the aim of the current pilot study, was to detect structural changes in mitochondria of peripheral blood mononuclear cells (PBMCs) of FM patients, using transmission electron microscopy (TEM). METHODS: To detect structural mitochondrial alterations in FM, we analysed PBMCs from seven patients and seven healthy controls, using TEM. Patients were recruited from a specialised Fibromyalgia Clinic at a tertiary medical centre. After providing informed consent, participants completed questionnaires including the widespread pain index (WPI), symptoms severity score (SSS), fibromyalgia impact questionnaire (FIQ), beck depression inventory (BDI), and visual analogue scale (VAS), to verify a diagnosis of FM according to ACR criteria. Subsequently, blood samples were drawn and PBMCs were collected for EM analysis. RESULTS: TEM analysis of PBMCs showed several distinct mitochondrial cristae patterns, including total loss of cristae in FM patients. The number of mitochondria with intact cristae morphology was reduced in FM patients and the percentage of mitochondria that completely lacked cristae was increased. These results correlated with the WPI severity. Moreover, in the FM patient samples we observed a high percentage of cells containing electron dense aggregates, which are possibly ribosome aggregates. Cristae loss and possible ribosome aggregation were intercorrelated, and thus may represent reactions to a shared cellular stress condition. The changes in mitochondrial morphology suggest that mitochondrial dysfunction, resulting in inefficient oxidative phosphorylation and ATP production, metabolic and redox disorders, and increased reactive oxygen species (ROS) levels, may play a pathogenetic role in FM. CONCLUSIONS: We describe novel morphological changes in mitochondria of FM patients, including loss of mitochondrial cristae. While these observations cannot determine whether the changes are pathogenetic or represent an epiphenomenon, they highlight the possibility that mitochondrial malfunction may play a causative role in the cascade of events leading to chronic pain and fatigue in FM. Moreover, the results offer the possibility of utilising changes in mitochondrial morphology as an objective biomarker in FM. Further understanding the connection between FM and dysfunction of mitochondria physiology, may assist in developing both novel diagnostic tools as well as specific treatments for FM, such as approaches to improve/strengthen mitochondria function.

Evaluation of ophthalmic vascular and neuroretinal alterations in fibromyalgia syndrome: a cross-sectional comparative study.

INTRODUCTION: Fibromyalgia syndrome (FMS) is a prevalent rheumatic disorder, and its pathogenesis includes genetic, neuroendocrine, and autonomic abnormalities, which may impact ocular structures. The aim was to conduct a comparative analysis of the ophthalmic vasculature and the retinal nerve fiber layer (RNFL) thickness between FMS and control groups using optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: This cross-sectional comparative study included 43 FMS patients and 40 healthy controls recruited from a tertiary education and research hospital between January 2024 and May 2024. All patients satisfied the 2016 American College of Rheumatology criteria for FMS and consented. OCT and OCTA were used to assess the RNFL thickness and the retinal microvasculature structure. The Fibromyalgia Impact Questionnaire (FIQ) was performed to evaluate disease severity. RESULTS: The study found significantly higher total retinal parafoveal thickness and foveal density in FMS patients (p = 0.017 and p = 0.044, respectively). Nevertheless, there were no significant differences among the groups concerning total retinal foveal thickness, foveal avascular zone characteristics, superficial and deep capillary plexus densities, choriocapillaris flow area, and outer retinal flow area values (p > 0.05). The RNFL thickness in all quadrants did not reveal significant differences between the groups (p > 0.05). Furthermore, there was no significant correlation between FIQ scores and OCTA parameters or RNFL thickness values (p > 0.05). CONCLUSION: The study revealed slight differences in retinal parafoveal thickness and foveal density in FMS patients, but no substantial vascular or neurodegenerative alterations were observed compared to healthy controls. These data indicate that FMS may not substantially affect ocular structures, contrary to earlier hypotheses.

Role of mitochondrial dysfunction and biogenesis in fibromyalgia syndrome: Molecular mechanism in central nervous system.

A critical role for mitochondrial dysfunction has been shown in the pathogenesis of fibromyalgia. It is a chronic pain syndrome characterized by neuroinflammation and impaired oxidative balance in the central nervous system. Boswellia serrata (BS), a natural polyphenol, is a well-known able to influence the mitochondrial metabolism. The objective of this study was to evaluate the mitochondrial dysfunction and biogenesis in fibromyalgia and their modulation by BS. To induce the model reserpine (1 mg/Kg) was subcutaneously administered for three consecutive days and BS (100 mg/Kg) was given orally for twenty-one days. BS reduced pain like behaviors in reserpine-injected rats and the astrocytes activation in the dorsal horn of the spinal cord and prefrontal cortex that are recognized as key regions associated with the neuropathic pain. Vulnerability to neuroinflammation and impaired neuronal plasticity have been described as consequences of mitochondrial dysfunction. BS administration increased PGC-1α expression in the nucleus of spinal cord and brain tissues, promoting the expression of regulatory genes for mitochondrial biogenesis (NRF-1, Tfam and UCP2) and cellular antioxidant defence mechanisms (catalase, SOD2 and Prdx 3). According with these data BS reduced lipid peroxidation and the GSSG/GSH ratio and increased SOD activity in the same tissues. Our results also showed that BS administration mitigates cytochrome-c leakage by promoting mitochondrial function and supported the movement of PGC-1α protein into the nucleus restoring the quality control of mitochondria. Additionally, BS reduced Drp1 and Fis1, preventing both mitochondrial fission and cell death, and increased the expression of Mfn2 protein, facilitating mitochondrial fusion. Overall, our results showed important mitochondrial dysfunction in central nervous system in fibromyalgia syndrome and the role of BS in restoring mitochondrial dynamics.

Reduced sympathetic activity is associated with the development of pain and muscle atrophy in a female rat model of fibromyalgia.

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain accompanied by fatigue and muscle atrophy. Although its etiology is not known, studies have shown that FM patients exhibit altered function of the sympathetic nervous system (SNS), which regulates nociception and muscle plasticity. Nevertheless, the precise SNS-mediated mechanisms governing hyperalgesia and skeletal muscle atrophy in FM remain unclear. Thus, we employed two distinct FM-like pain models, involving intramuscular injections of acidic saline (pH 4.0) or carrageenan in prepubertal female rats, and evaluated the catecholamine content, adrenergic signaling and overall muscle proteolysis. Subsequently, we assessed the contribution of the SNS to the development of hyperalgesia and muscle atrophy in acidic saline-injected rats treated with clenbuterol (a selective ß2-adrenergic receptor agonist) and in animals maintained under baseline conditions and subjected to epinephrine depletion through adrenodemedullation (ADM). Seven days after inducing an FM-like model with acidic saline or carrageenan, we observed widespread mechanical hyperalgesia along with loss of strength and/or muscle mass. These changes were associated with reduced catecholamine content, suggesting a common underlying mechanism. Notably, treatment with a ß2-agonist alleviated hyperalgesia and prevented muscle atrophy in acidic saline-induced FM-like pain, while epinephrine depletion induced mechanical hyperalgesia and increased muscle proteolysis in animals under baseline conditions. Together, the results suggest that reduced sympathetic activity is involved in the development of pain and muscle atrophy in the murine model of FM analyzed.

Adrenalectomy attenuates hyperalgesia but does not regulate muscle wasting in a female rat model of fibromyalgia.

Although it is well established that fibromyalgia (FM) syndrome is characterized by chronic diffuse musculoskeletal hyperalgesia, very little is known about the effect of this pathology on muscle tissue plasticity. Therefore, the present study aimed to characterize the putative alterations in skeletal muscle mass in female rats subjected to a FM model by inducing chronic diffuse hyperalgesia (CDH) through double injections of acidic saline (pH 4.0) into the left gastrocnemius muscle at 5-day intervals. To determine protein turnover, the total proteolysis, proteolytic system activities and protein synthesis were evaluated in oxidative soleus muscles of pH 7.2 (control) and pH 4.0 groups at 7 days after CDH induction. All animals underwent behavioural analyses of mechanical hyperalgesia, strength and motor performance. Our results demonstrated that, in addition to hyperalgesia, rats injected with acidic saline exhibited skeletal muscle loss, as evidenced by a decrease in the soleus fibre cross-sectional area. This muscle loss was associated with increased proteasomal proteolysis and expression of the atrophy-related gene (muscle RING-finger protein-1), as well as reduced protein synthesis and decreased protein kinase B/S6 pathway activity. Although the plasma corticosterone concentration did not differ between the control and pH 4.0 groups, the removal of the adrenal glands attenuated hyperalgesia, but it did not prevent the increase in muscle protein loss in acidic saline-injected animals. The data suggests that the stress-related hypothalamic-pituitary-adrenal axis is involved in the development of hyperalgesia, but is not responsible for muscle atrophy observed in the FM model induced by intramuscular administration of acidic saline. Although the mechanisms involved in the attenuation of hyperalgesia in rats injected with acidic saline and subjected to adrenalectomy still need to be elucidated, the results found in this study suggest that glucocorticoids may not represent an effective therapeutic approach to alleviate FM symptoms.

Functional Connectivity and Structural Signatures of the Visual Cortical System in Fibromyalgia: A Magnetic Resonance Imaging Study.

OBJECTIVE: Abnormal functional connectivity (FC) and structure in the brain are found in patients with fibromyalgia (FM). This study investigated FC and structural alterations of the visual cortical system, the emerging contributor to pain processing, in patients with FM. METHODS: Thirty pain-free participants and 26 patients with FM were enrolled. Clinical characteristics were evaluated using standardized scales. Structural and resting-state functional magnetic resonance imaging were conducted. Seed-based FC analyses, voxel-based morphometry, and surface-based morphometry were performed. The FC and cortical structure of the visual system were compared between the 2 groups. The correlation between functional and structural changes in the visual cortical system with clinical presentation in the FM group was analyzed. RESULTS: The patients with FM showed increased FCs within visual networks, of which the FC between the visual medial network and the right lingual gyrus (LG) was positively correlated with the Fibromyalgia Impact Questionnaire (FIQ) score. However, the FM group showed decreased FCs from the visual occipital network (VON) to several regions, of which the FCs from the VON to the bilateral frontal orbital cortices were negatively correlated with the FIQ and Pittsburgh Sleep Quality Index scores. Cortical thickness of the lateral occipital cortex, LG, and pericalcarine in FM tended to increase. CONCLUSION: Altered FCs and structure in the visual cortical system might be involved in the pathomechanisms and clinical presentation in FM. These findings could potentially support further studies that seek to find diagnostic methods and mechanism-based therapies in patients with FM.

AKAP12 and RNF11 as Diagnostic Markers of Fibromyalgia and Their Correlation with Immune Infiltration.

Fibromyalgia (FM) is a chronic nonarticular rheumatic disease mainly characterized by diffuse disseminated skeletal muscle pain, with varied symptoms including anxiety, sleep disturbance, and fatigue. Due to its unknown etiology and pathogenesis, FM is easily ignored in clinical practice, resulting in unclear diagnosis and difficult treatment. This study is aimed at investigating whether AKAP12 and RNF11 can be used as biomarkers for the diagnosis of FM and at determining their correlation with immune infiltration. The FM dataset in Gene Expression Omnibus (GEO) database was downloaded and was randomly divided into the training and test sets. Differentially expressed genes (DEGs) were screened, and functional correlation analysis was performed. Diagnostic markers of FM were screened and validated by random forest (RF). The least absolute shrinkage and selection operator (LASSO) logistic regression algorithm was then used to evaluate immune cell infiltration in the FM patients' peripheral blood. Finally, Spearman's rank correlation analysis was used to identify correlation between the diagnostic indexes and immune cell infiltration. A total of 69 DEGs were selected. Results indicated that AKAP12 and RNF11 can be used as diagnostic markers of FM, and CD8 + T cells might contribute in the pathogenesis of FM. In addition, AKAP12 was positively correlated with CD8 + T cells, while RNF11 was negatively correlated with CD8 + T cells. In conclusion, AKAP12 and RNF11 can be used as diagnostic indicators of FM, and CD8 + T cells may be involved in the occurrence and development of FM.

A behavioral and brain imaging dataset with focus on emotion regulation of women with fibromyalgia.

Fibromyalgia is a chronic condition characterized by widespread pain, as well as numerous symptoms related to central sensitization such as: fatigue, cognitive disturbances, constipation/diarrhea and sensory hypersensitivity. Furthermore, depression and anxiety are prevalent comorbidities, accompanied by emotion processing and regulation difficulties. Although fibromyalgia physiopathology is still not fully understood, neuroimaging research methods have shown brain structural and functional alterations as well as neuroinflammation abnormalities. We believe that open access to data may help fibromyalgia research advance more. Here, we present an open dataset of 33 fibromyalgia female patients and 33 paired healthy controls recruited from a Mexican population. Dataset includes demographic, clinical, behavioural and magnetic resonance imaging (MRI) data. The MRI data consists of: structural (T1- and T2- weighted) and functional (task-based and resting state) sequences. The task was an emotion processing and regulation task based on visual stimuli. The MRI data contained in the repository are unprocessed, presented in Brain Imaging Data Structure (BIDS) format and available on the OpenNeuro platform for future analysis.

CNS imaging characteristics in fibromyalgia patients with and without peripheral nerve involvement.

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.

Scoping review and interpretation of myofascial pain/fibromyalgia syndrome: An attempt to assemble a medical puzzle.

BACKGROUND: Myofascial Pain Syndrome (MPS) is a common, overlooked, and underdiagnosed condition and has significant burden. MPS is often dismissed by clinicians while patients remain in pain for years. MPS can evolve into fibromyalgia, however, effective treatments for both are lacking due to absence of a clear mechanism. Many studies focus on central sensitization. Therefore, the purpose of this scoping review is to systematically search cross-disciplinary empirical studies of MPS, focusing on mechanical aspects, and suggest an organic mechanism explaining how it might evolve into fibromyalgia. Hopefully, it will advance our understanding of this disease. METHODS: Systematically searched multiple phrases in MEDLINE, EMBASE, COCHRANE, PEDro, and medRxiv, majority with no time limit. Inclusion/exclusion based on title and abstract, then full text inspection. Additional literature added on relevant side topics. Review follows PRISMA-ScR guidelines. PROSPERO yet to adapt registration for scoping reviews. FINDINGS: 799 records included. Fascia can adapt to various states by reversibly changing biomechanical and physical properties. Trigger points, tension, and pain are a hallmark of MPS. Myofibroblasts play a role in sustained myofascial tension. Tension can propagate in fascia, possibly supporting a tensegrity framework. Movement and mechanical interventions treat and prevent MPS, while living sedentarily predisposes to MPS and recurrence. CONCLUSIONS: MPS can be seen as a pathological state of imbalance in a natural process; manifesting from the inherent properties of the fascia, triggered by a disrupted biomechanical interplay. MPS might evolve into fibromyalgia through deranged myofibroblasts in connective tissue ("fascial armoring"). Movement is an underemployed requisite in modern lifestyle. Lifestyle is linked to pain and suffering. The mechanism of needling is suggested to be more mechanical than currently thought. A "global percutaneous needle fasciotomy" that respects tensegrity principles may treat MPS/fibromyalgia more effectively. "Functional-somatic syndromes" can be seen as one entity (myofibroblast-generated-tensegrity-tension), sharing a common rheuma-psycho-neurological mechanism.

Right anterior insula is associated with pain generalization in patients with fibromyalgia.

ABSTRACT: Despite diffuse tenderness, patients with fibromyalgia (FM) have reported a wide range of areas with musculoskeletal pain. This study investigated the neural structures and neuroanatomical networks associated with self-reported widespread pain in FM using magnetic resonance imaging. We collected clinical profiles and brain magnetic resonance imaging data of newly diagnosed patients with FM. A total of 138 patients with FM were divided into 3 subgroups based on the number of pain areas, with 3 to 8, 9 to 12, and 13 to 19 areas, respectively. Using voxel-based morphometry analysis, we first identified the neural structure that showed a trend of volumetric change across the 3 subgroups. We then used it as a candidate seed of interest with a seed-to-voxel analytical approach to explore the structural covariance (SC) networks of the whole brain. Finally, we studied the trend of changes in the distribution and strength of SC networks across subgroups of patients. We found a decreasing trend in the volumes of the right anterior insular cortex (rAIC) across the 3 subgroups that had an increased number of pain areas. An increasing trend in the number of neural substrates over the subcortical regions, especially the basal ganglion, showed SC to the rAIC, and a decreasing trend of SC strength was shown between the rAIC and the precuneus, frontal cortex, anterior and posterior cingulate, and lingual gyri, across the patient subgroups with increased pain areas. The rAIC and its altered connection with specific brain regions indicates widespread pain in patients with FM.

Prognostic factors of trochanteric bursitis in surgical-staged patients: a prospective study.

BACKGROUND: Trochanteric bursitis or greater trochanteric pain syndrome is a common disorder and frequent cause of lateral hip pain. It can lead to severe functional impairment with increase morbidity and poor quality of life.The purpose of the current study was to identify and evaluate relationship between health-related factors, as prognostic indicators, and clinical outcomes. METHODS: A single-centre, prospective study was conducted and 60 patients (62 hips) were included with a minimum 12 months of follow-up. Clinical outcomes were evaluated using Hip Outcome Scale, Single Assessment Numeric Evaluation and Visual Analogue Scale. Radiological assessments and health-related factors were documented in an attempt to understand their validity as predictors of clinical outcomes. Complications and recurrence rates were also analyzed. RESULTS: Univariate model revealed that an increased BMI (p = 0.001; OR = 1.05; 95% CI, 1.02-1.07); number of previous corticosteroid infiltrations (p = 0.001; OR = 1.28, 95% CI, 1.11-1.48); longer time from symptom onset to surgery (p = 0.001; OR = 1.19; 95% CI, 1.12-1.28); smoker status (p = 0.001; OR 11.2; 95% CI, 3.30-44.2); and the presence of prior lumbosacral fusion (LSF) (p = 0.001; OR 13.8; 95% CI, 2.96-101); were prognostic factors predisposing for poor clinical outcomes.Among prognostic health-related factors were medical comorbidities such as emotional distress (p < 0.001; OR 26.1; 95% CI, 5.71-192); fibromyalgia (p = 0.026; OR 3.56; 95% CI, 1.16-11.7); and hyporthyroidism (p = 0.005, OR = 6.55, 95% CI, 1.73-28.7). CONCLUSIONS: Better overall physical function was predicted by lower number of corticosteroid infiltrations, shorter time span from symptom onset to surgery, non-smoker status and the absence of prior lumbosacral fusion. Obesity, smoking, the presence of emotional distress, fibromyalgia and hypothyroidism seem to increase the risk of poor clinical outcomes. A proper selection and/or correction of modifiable prognostic factors could reduce the incidence of endoscopic treatment failure and, as a consequence, improve patient outcomes and quality of life. However, future efforts should focus on experimental and randomised studies to fully determine these associations.

Elevation of hilar mossy cell activity suppresses hippocampal excitability and avoidance behavior.

Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders.

Comment on Siracusa et al. Fibromyalgia: Pathogenesis, Mechanisms, Diagnosis and Treatment Options Update. Int. J. Mol. Sci. 2021, 22, 3891.

We have read the study by Siracusa et al. [...].

The mapping of cortical activation by near-infrared spectroscopy might be a biomarker related to the severity of fibromyalgia symptoms.

The delta value of oxyhemoglobin (Δ-HbO) determined by functional near-infrared spectroscopy at prefrontal cortex (PFC) and motor cortex (MC) based on primary (25 °C) and secondary (5 °C) thermal stimuli presented a larger peak latency at left MC in fibromyalgia than in controls. The difference between HbO concentration 15 s after the thermal stimuli ending and HbO concentration before the thermal stimuli onset (Δ-HbO*) at left PFC increased 47.82% in fibromyalgia and 76.66% in controls. This value had satisfactory discriminatory properties to differentiate cortical activation in fibromyalgia versus controls. A receiver operator characteristics (ROC) analysis showed the Δ-HbO* cutoffs of - 0.175 at left PFC and - 0.205 at right PFC offer sensitivity and specificity of at least 80% in screening fibromyalgia from controls. In fibromyalgia, a ROC analysis showed that these cutoffs could discriminate those with higher disability due to pain and more severe central sensitization symptoms (CSS). The ROC with the best discriminatory profile was the CSS score with the Δ-HbO* at left PFC (area under the curve = 0.82, 95% confidence interval = 0.61-100). These results indicate that cortical activation based on Δ-HbO* at left PFC might be a sensitive marker to identify fibromyalgia subjects with more severe clinical symptoms.

Could ferritin, vitamin B12, and vitamin D play a role in the etiopathogenesis of fibromyalgia syndrome?

Introduction. Fibromyalgia syndrome (FS) comprises general body pain, sleep disturbances, and fatigue. Vitamin B12 (VB), vitamin D (VD), and iron deficiencies lead to similar complaints. First, this study aimed to evaluate the VB, VD, and ferritin levels of patients with FS. Second, it aimed to investigate whether there was a relationship between these parameters and FS severity. Material and methods. The study included 58 female patients with FS and 58 healthy females as a control group. The patients completed the Fibromyalgia Impact Questionnaire (FIQ), Visual Analog Scale (VAS), fatigue questionnaire, Pittsburgh sleep quality scale, and the Short Form-36 (SF-36). This study examined the VD, VB, and ferritin levels of the patient and control groups. Results. The VB (240.0 [110.0-394.0] vs 291.0 [210.0-609.0] pg/ml, p<0.001), VD (12.5 [3.0-45.0] vs 20.0 [5.0-54.0] ng/ml, p=0.013), and ferritin levels (21.2 [4.0-86.0] vs 32.0 [7.1-120.0], ng/ml, p=0.009) of the FS patients were determined to be significantly lower than those of the control group. A negative correlation was determined between the number of tender points and VB, VD, and ferritin levels. In the regression analysis, we found low ferritin levels (odds ratio [OR] 1.036, 95% confidence interval [CI] 1.015-1.058, p<0.001) and VB (OR 1.010, CI 1.002-1.018, p=0.010) to be an independent risk factor for FS. Conclusions. There may be a relationship between VB, VD, and ferritin levels and the number of tender points in patients with FS. Levels of iron and VB may play a vital role in FS etiopathogenesis. However, VD levels may not be a risk factor for FS etiopathogenesis.

Serotonergic Neurotransmission System Modulator, Vortioxetine, and Dopaminergic D2/D3 Receptor Agonist, Ropinirole, Attenuate Fibromyalgia-Like Symptoms in Mice.

Fibromyalgia is a disease characterized by lowered pain threshold, mood disorders, and decreased muscular strength. It results from a complex dysfunction of the nervous system and due to unknown etiology, its diagnosis, treatment, and prevention are a serious challenge for contemporary medicine. Impaired serotonergic and dopaminergic neurotransmission are regarded as key factors contributing to fibromyalgia. The present research assessed the effect of serotonergic and dopaminergic system modulators (vortioxetine and ropinirole, respectively) on the pain threshold, depressive-like behavior, anxiety, and motor functions of mice with fibromyalgia-like symptoms induced by subcutaneous reserpine (0.25 mg/kg). By depleting serotonin and dopamine in the mouse brain, reserpine induced symptoms of human fibromyalgia. Intraperitoneal administration of vortioxetine and ropinirole at the dose of 10 mg/kg alleviated tactile allodynia. At 5 and 10 mg/kg ropinirole showed antidepressant-like properties, while vortioxetine had anxiolytic-like properties. None of these drugs influenced muscle strength but reserpine reduced locomotor activity of mice. Concluding, in the mouse model of fibromyalgia vortioxetine and ropinirole markedly reduced pain. These drugs affected emotional processes of mice in a distinct manner. Hence, these two repurposed drugs should be considered as potential drug candidates for fibromyalgia. The selection of a specific drug should depend on patient's key symptoms.

Cationic liposome-encapsulated carotenoids as a potential treatment for fibromyalgia in an animal model.

The present study investigated the efficacy of cationic liposome-encapsulated carotenoids (lutein or beta-carotene) as a treatment in an animal model of fibromyalgia (FM). Preparation and characterization of the nano-sized cationic liposomal carotenoids have been carried out. FM has been induced in the experimental animals via successive subcutaneous reserpine injection (1 mg/kg). Animals were divided into four groups; control, reserpinized (Res), reserpinized and cationic liposomal lutein-treated (Res + CL-Lut), and reserpinized and liposomal beta-carotene-treated (Res + CL-Bc). Levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT), and oxidative stress markers (MDA, H2O2, NO, and GSH) were determined in the brain's cortical tissue of the different groups of animals. Furthermore, the spectral analysis of the electrocorticogram (ECoG) was carried out. Animal behavior was tested for different animal groups. Results showed a significant reduction in monoamines, an elevation of oxidative stress markers, a shift in the ECoG frequency band power, and a change in pain threshold of the reserpinized animals. A return to a non-significant difference from the control values of all the measured parameters has been obtained after two weeks of cationic liposomal carotenoid preparations treatment. The present findings shed more light on the validity of the reserpine model of FM and provide evidence for the antidepressant, antioxidant, and anti-nociceptive potential of the cationic liposomal carotenoids. The present results proofed that the natural product preparations on a nano-sized scale could be a good alternative to the pharmacological interventions for FM treatment.