Abstract text (incl. figure legends and references)

Objectives: Burning mouth syndrome (BMS) is an idiopathic and debilitating burning sensation of the oral mucosa. BMS treatment remains a challenge due to its uncertain aetiopathophysiology, but reports have implied that BMS is a central neuropathic pain disorder. We hypothesised that BMS patients' functional connectivity (FC) was modulated by pain intensity following clonazepam mouthwash (MW) and the difference between treatment responders and non-responders.

Methods: 26 BMS patients underwent two sessions. In session 1, they received clinical and neuropsychological assessments. In session 2, pain scores (NRS, 0-10) and resting-state functional MRI scans were acquired before and after mouthwash. Seed-based FC analysis of the right anterior insula (RAI) cortex was performed (pFWE corrected <0.05), given reports of perturbed functioning in this region in chronic pain. Treatment responders were defined as reporting 50% or greater pain reduction from baseline following clonazepam administration.

Results: After clonazepam, BMS patients experienced a mean NRS reduction of 2.67 (SD ±2.23), and 15 patients responded to treatment. We observed a decrease of post-MW FC across BMS patients, between the RAI and anterior cerebellum and inferior parietal lobe. At baseline, responders showed lower FC than non-responder between RAI, lateral occipital cortex and parietal lobe. After mouthwash responder showed greater FC network changes (∆FC) than the non-responder between RAI and frontal orbital cortex, frontal medial cortex and paracingulate gyrus but a lesser ∆FC between RAI and prefrontal cortex (Figure 1).

Conclusion: This study provides a preliminary insight into the anti-nociceptive mechanism of action of topical clonazepam on brain networks. We demonstrated FC changes between RAI and brain regions involved in pain modulation, which may reflect BMS's ongoing pain symptoms and a valuable marker of treatment response.