Pain-regulation circuitry as a predictor of chronic pain phenotypes
Journal:
bioRxiv
Published Date:
Jan 21, 2026
Abstract
Background: Chronic pain is a multidimensional condition in which emotional distress, negative expectations, and functional impairment signal greater disease severity. Standard diagnostic categories often fail to capture clinically meaningful heterogeneity, highlighting the need for mechanistic phenotyping. Methods: We studied 159 individuals with fibromyalgia or chronic low back pain and 72 healthy controls. Participants completed a cue-based expectation task with calibrated thermal stimuli. Principal component and cluster analyses were used to derive high and low pain, disability, and affective distress (PDA) phenotypes. Groups were compared on expectation-induced pain modulation (EIPM) and resting state connectivity of periaqueductal gray (PAG) subregions. Stepwise machine learning models evaluated whether clinical, behavioral, and neuroimaging features could classify PDA phenotypes. Results: High PDA patients exhibited impaired pain modulation when positive expectations were violated, particularly under low-threat cues (P<0.05), and reported higher catastrophizing, hypervigilance, and medication use than low PDA patients. Resting-state analyses revealed more negative dorsolateral/lateral PAG to dorsomedial prefrontal cortex coupling in the high PDA group. Machine learning models classified PDA subtypes above chance, with maximal accuracy when PAG connectivity was combined with clinical and behavioral measures. Conclusions: Severe chronic pain characterized by high emotional distress, disability, and pain is associated with disrupted expectation driven modulation and altered PAG connectivity. Integrating symptom profiles with neural and behavioral markers provides a biologically informed framework for identifying phenotypes with distinct treatment needs. These results suggest that expectation-related pain regulation and midbrain circuitry represent complementary mechanistic targets for precision interventions in chronic pain.
