Baseline Resting-State Functional Connectivity Determines Subsequent Pain Ratings to a Tonic Ecologically Valid Experimental Model of Orofacial Pain

Abstract

Pain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure--the insertion of an elastomeric separator between teeth--which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity (rsFC) of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional (rs-fMRI) scanning prior to the placement of a separator between the first and second molars, which was kept in place for five days. Participants recorded pain ratings three times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve, or grey matter volume of any brain region. Peak pain did, however, positively correlate with baseline rsFC between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, pre-interventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.