Aberrant Brain Signal Variability and COMT Genotype in Chronic TMD Patients

The analysis of brain signal variability is a promising approach to understand pathological brain function related to chronic pain. This study investigates whether blood-oxygen-level-dependent signal variability (BOLD_SV) in specific frequency bands is altered in temporomandibular disorder (TMD) and correlated to its clinical features. Twelve patients with chronic myofascial TMD and 24 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. The BOLD_SV was measured as the standard deviation of the BOLD time series at each voxel and compared between groups. We also examined the potential relationship between the BOLD_SV and the catechol-O-methyltransferase (COMT) Val¹⁵⁸Met polymorphism. We assessed sensory-discriminative pain in the craniofacial region, pain sensitivity to sustained masseteric pain challenge, and TMD pain frequency for clinical correlation. Patients displayed reduced BOLD_SV in the dorsolateral prefrontal cortex (dlPFC) as compared with HC in all frequency bands. In the slow-3 band, patients also showed reduced BOLD_SV in the medial dorsal thalamus, primary motor cortex (M1), and primary somatosensory cortex (S1) and heightened BOLD_SV in the temporal pole. Notably, we found a significant correlation between lower BOLD_SV (slow-3) in the orofacial M1/S1 regions and higher clinical pain (intensity/area) and higher sensitivity of the masseter muscle pain. Moreover, lower BOLD_SV (slow-3) in the dlPFC and ventrolateral PFC was associated with a higher TMD pain frequency. Participants who had the COMT¹⁵⁸Met substitution exhibited lower BOLD_SV in the dlPFC and higher BOLD_SV in the temporal pole as compared with participants without the COMT¹⁵⁸Met substitution. An increasing number of Met alleles was associated with lower dlPFC and greater temporal pole BOLD_SV in both HC and TMD groups. Together, we demonstrated that chronic TMD patients exhibit aberrant BOLD_SV in the top-down pain modulatory and sensorimotor circuits associated with their pain frequency and severity. COMT Val¹⁵⁸Met polymorphism might affect clinical symptoms in association with regional brain signal variability, specifically involved in cognitive and emotional regulation of pain.