Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation

TLDR

Frontal lobe activity during pain is generally linked to attentional processing. The study investigates whether bottom‑up and top‑down modulation of nociceptive information dissociate anatomically within the frontal lobe, and proposes that the DLPFC actively controls pain perception by modulating corticosubcortical and corticocortical pathways. The authors used PET scanning during painful thermal stimulation and applied PCA and multiple regression to analyze the covariance of VOI activated during heat allodynia in 14 male subjects, relating them to pain intensity and affect ratings. Heat allodynia activates extensive bilateral DLPFC, VOFC, and perigenual ACC, with a primary principal component positively correlating with pain intensity and unpleasantness, while right and left DLPFC activity load on separate components that negatively correlate with pain and modulate connectivity between midbrain‑medial thalamic and anterior insula pathways.

Abstract

Frontal lobe activity during pain is generally linked to attentional processing. We addressed the question of whether 'bottom-up' processing and 'top-down' modulation of nociceptive information dissociate anatomically within the frontal lobe by using PET scanning during painful thermal stimulation of normal and capsaicin-treated skin. We showed recently that pain following normally non-painful heat stimuli on chemically irritated skin (heat allodynia) uniquely engages extensive areas of the bilateral dorsolateral prefrontal (DLPFC), ventral/orbitofrontal (VOFC) and perigenual anterior cingulate (ACC) cortices. Here, we applied principal component analysis (PCA) and multiple regression analysis to study the covariance structure of the volumes of interest (VOI) activated specifically during heat allodynia in 14 male healthy subjects and evaluated the relationship of these VOI to ratings of pain intensity and affect. Results yielded a primary principal component (PC) that correlated positively with intensity and unpleasantness and accounted for activity in the medial thalamus, bilateral anterior insula, ventral striatum, perigenual ACC and bilateral VOFC. Activities in the right and left DLPFC loaded on separate PC and correlated negatively with perceived intensity and unpleasantness. The inter-regional correlation of midbrain and medial thalamic activity was significantly reduced during high left DLPFC activity, suggesting that its negative correlation with pain affect may result from dampening of the effective connectivity of the midbrain-medial thalamic pathway. In contrast, right DLPFC activity was associated with a weakened relationship of the anterior insula with both pain intensity and affect. We propose that the DLPFC exerts active control on pain perception by modulating corticosubcortical and corticocortical pathways.