The Role of Insular Cortex and Prefrontal Cortex in the Pathogenesis of Fibromyalgia: Biochemical and Electrophysiological Rodent Study

Neuroimaging implicates the medial prefrontal cortex (mPFC) and insula in fibromyalgia (FM), but synaptic and network mechanisms are unclear. To verify mPFC hypersynapticity in a reserpine-induced FM model and test whether anterior insular deep brain stimulation (DBS) restores mPFC oscillations and pain behavior. Thirty-six male Sprague–Dawley rats received reserpine (1 mg·kg⁻¹ i.p., days 1–3) or vehicle. For Objective 1, mPFC tissue was analyzed by ELISA for glutamate, γ-aminobutyric acid (GABA), C-FOS, nerve growth factor (NGF), synaptophysin, and postsynaptic density protein-95 (PSD-95). For Objective 2, rats were assigned to control-sham, control-DBS, FM-sham, or FM-DBS. Monopolar DBS (130 Hz, 60 µs, 100 µA; 15 min·day⁻¹ for 3 days) targeted the anterior insula; local field potentials were recorded from mPFC, and thermal nociception was assessed by tail immersion and hot-plate tests. Reserpine increased glutamate, C-FOS, NGF, synaptophysin, and PSD-95 and reduced GABA (all p < 0.001), confirming hypersynapticity. Insular DBS increased delta-band normalized ratios (NR) in FM and controls ( p < 0.0001), normalized FM-associated theta reductions, decreased alpha/beta NR in controls, and suppressed elevated gamma NR in FM ( p < 0.0001). DBS increased withdrawal latencies in FM, indicating improved pain thresholds ( p < 0.001). Reserpine induces biochemical hypersynapticity in mPFC, and brief anterior insular DBS rebalances mPFC oscillations and alleviates hyperalgesia. Insular DBS may correct cortical network dysfunction in FM.