Abstract text (incl. figure legends and references)

Objectives: Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain with poorly understood aetiopathogenesis, making treatment challenging. Studies have highlighted central and autonomic nervous system (ANS) dysregulations in BMS, yet studies investigating the interaction between ANS and brain are lacking. The periaqueductal grey area (PAG) has a crucial role in mediating the relationship between ANS and pain, and changes in PAG have been described in other chronic pain conditions. We combined Heart Rate Variability (HRV) as a measure reflective of ANS function, resting-state functional MRI and voxel-based morphometric analysis of brain structure to explore the interaction between ANS and brain mechanisms underpinning BMS pain experiences, focusing on the role of PAG.

Methods: 26 BMS patients were assessed in two sessions. In session 1, resting heart rate (HR) was measured for 5 minutes. In session 2, structural and functional MRI scans were acquired. The root mean square of successive differences (a measure of vagal-mediated HRV; RMSSD) was extracted from HR inter-beat. Associations between seed-based PAG functional connectivity (FC) and the interaction between RMSSD and pain scores were investigated (pFWE corrected <0.05). Patients were divided into low and high RMSSD groups for further analysis.

Results: The mean pain score (NRS 0-10) was 5.5 (SD ±1.42). Patients with lower RMSSD had higher pain scores in session 1 (p=0.009). RMSSD was positively associated with FC between the PAG and insula and negatively associated with insula grey matter volume. The association between RMSSD and pain was positively mediated by the strength of FC between PAG and thalamus. (Figure 1).

Conclusion: BMS brain structure and function changes are associated with parasympathetic tone and perceived pain intensity. These complex relationships provide indications of linkages between the brain and ANS, which may be insightful for developing future therapeutic interventions.