Fibromyalgia pathogenesis explained by a neuroendocrine multistable model.

Fibromyalgia (FM) is a central disorder characterized by chronic pain, fatigue, insomnia, depression, and other minor symptoms. Knowledge about pathogenesis is lacking, diagnosis difficult, clinical approach puzzling, and patient management disappointing. We conducted a theoretical study based on literature data and computational analysis, aimed at developing a comprehensive model of FM pathogenesis and addressing suitable therapeutic targets. We started from the evidence that FM must involve a dysregulation of central pain processing, is female prevalent, suggesting a role for the hypothalamus-pituitary-gonadal (HPG) axis, and is stress-related, suggesting a role for the HP-adrenocortical (HPA) axis. Central pathogenesis was supposed to involve a pain processing loop system including the thalamic ventroposterolateral nucleus (VPL), the primary somatosensory cortex (SSC), and the thalamic reticular nucleus (TRN). For decreasing GABAergic and/or increasing glutamatergic transmission, the loop system crosses a bifurcation point, switching from monostable to bistable, and converging on a high-firing-rate steady state supposed to be the pathogenic condition. Thereafter, we showed that GABAergic transmission is positively correlated with gonadal-hormone-derived neurosteroids, notably allopregnanolone, whereas glutamatergic transmission is positively correlated with stress-induced glucocorticoids, notably cortisol. Finally, we built a dynamic model describing a multistable, double-inhibitory loop between HPG and HPA axes. This system has a high-HPA/low-HPG steady state, allegedly reached in females under combined premenstrual/postpartum brain allopregnanolone withdrawal and stress condition, driving the thalamocortical loop to the high-firing-rate steady state, and explaining the connection between endocrine and neural mechanisms in FM pathogenesis. Our model accounts for FM female prevalence and stress correlation, suggesting the use of neurosteroid drugs as a possible solution to currently unsolved problems in the clinical treatment of the disease.

Efficacy of non-invasive brain stimulation and neuronavigation for major depressive disorder: a systematic review and meta-analysis.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are increasingly used for major depressive disorder (MDD). Most tDCS and rTMS studies target the left dorsolateral prefrontal cortex, either with or without neuronavigation. We examined the effect of rTMS and tDCS, and the added value of neuronavigation in the treatment of MDD. METHODS: A search on PubMed, Embase, and Cochrane databases for rTMS or tDCS randomized controlled trials of MDD up to 1 February 2023, yielded 89 studies. We then performed meta-analyses comparing tDCS efficacy to non-neuronavigated rTMS, tDCS to neuronavigated rTMS, and neuronavigated rTMS to non-neuronavigated rTMS. We assessed the significance of the effect in subgroups and in the whole meta-analysis with a z-test and subgroup differences with a chi-square test. RESULTS: We found small-to-medium effects of both tDCS and rTMS on MDD, with a slightly greater effect from rTMS. No significant difference was found between neuronavigation and non-neuronavigation. CONCLUSION: Although both tDCS and rTMS are effective in treating MDD, many patients do not respond. Additionally, current neuronavigation methods are not significantly improving MDD treatment. It is therefore imperative to seek personalized methods for these interventions.

Online Questionnaire with Fibromyalgia Patients Shows Negative Correlations between Disease Severity and Adherence to Mediterranean Diet.

Fibromyalgia (FM) is a multidimensional disorder in which intense chronic pain is accompanied by a variety of psychophysical symptoms that impose a burden on the patients' quality of life. Despite the efforts and the recent advancement in research, FM pathogenesis and effective treatment remain unknown. Recently, the possible role of dietary patterns and/or components has been gaining attention. The current study aimed to investigate a potential correlation between adherence to the Mediterranean diet (MedDiet) and FM severity in a sample of Italian FM patients. An online survey was designed, composed of customized questions and validated questionnaires with the aim of investigating the intensity and type of pain, the presence of other psychophysical symptoms, the overall impact of FM, general food and lifestyle habits, and adherence to the MedDiet. The collected responses were analyzed for descriptive statistics, linear regression, and propensity score analyses. The results show that, despite considerable use of pharmaceuticals and supplements, FM participants suffered from a high-severity grade disease. However, those with good adherence to the MedDiet experienced a lower pain intensity and overall FM impact. A propensity score analysis indicates a positive influence of the MedDiet against FM severity, thus unveiling the need for well-designed intervention studies to evaluate the therapeutic potential of different dietary patterns.