Introduction: Fibromyalgia (FM) is an idiopathic chronic widespread pain syndrome accompanied by a broad range of symptoms encompassing fatigue, sleep disturbances, mood disorders, cognitive dysfunction, irritable bowel, and chronic dizziness, thus deeply worsening the patients’ quality of life. Despite a better understanding of the disease in recent years, which led to recognize FM as a central rather than peripheral disorder of pain processing, the diagnosis, pathogenesis and therapy are still challenging issues (1, 2). Aim: We believe that Systems and Control Theory and Psycho-Neuro-Endocrine-Immunology (PNEI) represent the most suitable framework for the study of such a complex condition (3, 4, 5). We aim at providing a unifying model for FM pathogenesis, based on a loop neural network involving thalamocortical regions, i.e. ventroposterior lateral thalamus (VPL), somatosensory cortex (SC), and thalamic reticular nucleus (TRN). Besides, we aim at finding significant stimuli within the PNEI network able to switch the system from physiological to pathological functioning. Methods: The dynamics of the loop system were described by three differential equations having neuron mean firing rates as variables and containing Hill functions to model mutual interactions among thalamocortical regions. The computational analysis was conducted with MATLAB. As a first assessment of the model, we designed a cross-sectional questionnaire study enrolling FM patients aged 18-65 years. The characterization of the type and intensity of pain was assessed by painDETECT questionnaire. Behavioral problems, psychosocial stress, and self-rated emotional intelligence were explored by Cognitive Behavioral Assessment-Hospital (CBA-H) and Self-Rated Emotional Intelligence Scale (SREIS). Statistical analysis was performed with the software R and included the computation of the correlations between quantitative variables. Results: The thalamocortical loop displayed a transition from monostability to bistability for a weakening of GABAergic transmission between TRN and VPL. This involved the appearance of a high-firing-rate steady state in SC that is assumed to represent pathogenic pain processing giving rise to chronic pain. The questionnaire analysis was based on 173 respondents (88% females), and revealed a prevalence of neuropathic pain (chi-squared test, p<0.05), consistent with a supraspinal origin of pain. FM patients reported a low efficacy of pharmacological medications, whereas complementary mind-body therapies seemed more effective in alleviating pain (Mann-Whitney test, p<0.05). Based on CBA cutoffs, participants revealed a high ability in perceiving emotions but a low capacity to understand and self-manage them, leading to situational anxiety and critical emotional stability. Conclusion: We suggested a thalamocortical feedback loop system and its GABAergic/glutamatergic strength ratio as a crucial hub within the PNEI network underlying FM pathogenesis. The consistency of our model with the clinical features of FM patients suggests that critical targets for FM treatment are to be found among PNEI pathways leading to GABA/glutamate imbalance.