Augmented Pain-evoked Brain Responses Account for Greater Pain Sensitivity in Healthy Adolescents

While pain has been identified as a major health issue for adolescents, brain mechanisms of pain processing in this population remain unclear. Previous findings from adult studies may not be applicable given that the adolescent brain, particularly prefrontal cortex (PFC), has not been fully developed. This study was conducted to characterize pain sensitivity, pain-evoked brain responses, and the brain regions mediating the relationship between the stimulus intensity and pain perception in adolescents. Thirty adolescents (ages 13-17) and thirty adults (ages 35-55) underwent functional MRI scans involving acute pain. They received 12 noxious pressure stimuli (2.5 or 4 kg/cm2, each lasting 10 seconds, applied to the left thumbnail) and rated pain intensity and unpleasantness on a 0-100 computerized visual analogue scale. Adolescents reported greater pain intensity (t=2.77, p=0.008) and unpleasantness (t=2.66, p=0.01) in response to stimulations at 2.5 kg/cm2. These differences disappeared at 4 kg/cm2 (pain intensity: t=0.39, p=0.700; pain unpleasantness: t=0.97, p=0.337). A significant group by stimulus intensity interaction effect (F=7.52, p=0.008) was found in pain intensity ratings using a mixed-design ANOVA. Adolescents had greater dorsolateral and dorsomedial PFC as well as supramarginal gyrus activations in response to stimuli at 2.5kg/cm2, and greater rostral anterior cingulate and dorsomedial PFC activations in response to stimuli at 4kg/cm2 (Z>3.1, p<0.05, cluster-corrected). Using whole-brain multilevel mediation analyses we found significantly greater dorsolateral, medial PFC, and superior/middle temporal gyrus responses in adolescents (p<0.05, FDR-corrected) as brain mediators for the observed group difference in the relationship between stimulus intensity and pain intensity ratings. These brain regions are consistent with part of default mode network and frontoparietal network, which are important for modulating pain responses. These findings provide preliminary evidence of augmented brain responses that account for increased pain sensitivity in adolescents. NIH/NIAMS R01 AR074795. Cincinnati Children's Hospital Medical Center Trustee Grant Award.