Papers of the Week

Approximately 1.7 million youth suffer from debilitating chronic pain in the US alone, conferring risk for continued pain in adulthood. Abberations in threat-safety (T-S) discrimination are proposed to contribute to pain chronicity in adults and youth by interacting with pain-related distress. Yet, few studies have examined the neural circuitry underlying T-S discrimination in patients with chronic pain or how T-S discrimination relates to pain-related distress. In this study, 91 adolescents (10-24 years; 78 females) including 30 chronic pain patients with high pain-related distress, 29 chronic pain patients with low pain-related distress, and 32 healthy peers without chronic pain completed a developmentally-appropriate T-S learning paradigm. We measured self-reported fear, psychophysiology (skin conductance response), and functional MRI responses (N = 72 after fMRI exclusions). After controlling for age and anxiety symptoms, patients with high pain-related distress showed altered self-reported fear and fronto-limbic activity in response to learned threat and safety cues compared to both patients with low pain-related distress and healthy controls. Specifically, adolescent patients with high pain-related distress reported elevated fear and showed elevated limbic (hippocampus, amygdala) activation in response to a learned threat cue (CS+). In addition, they showed decreased frontal (vmPFC) activation and aberrant fronto-limbic connectivity in response to a learned safety cue (CS-). Patients with low pain-related distress and healthy controls appeared strikingly similar across brain and behavior. These findings indicate that altered T-S discrimination, mediated by fronto-limbic activation and connectivity, may be one mechanism maintaining pain chronicity in adolescents with high levels of pain-related distress.