Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network

TLDR

Anxiety about pain commonly exacerbates the pain sensation, and the hippocampal formation is thought to amplify aversive events during anxiety to prime adaptive responses. The study aimed to compare brain activation responses to noxious thermal stimulation while manipulating perceived pain intensity through physical intensity changes or induced anxiety. Event‑related fMRI was used to measure activation responses during these manipulations. Visual cues predicting moderate pain induced low anxiety, while cues predicting higher pain induced higher anxiety, and the entorhinal cortex responded differentially to identical noxious stimuli depending on anxiety‑enhanced pain, with its activity predicting engagement of perigenual cingulate and mid‑insula, suggesting that accurate preparatory information can alleviate pain by disengaging the hippocampus.

Abstract

It is common clinical experience that anxiety about pain can exacerbate the pain sensation. Using event-related functional magnetic resonance imaging (FMRI), we compared activation responses to noxious thermal stimulation while perceived pain intensity was manipulated by changes in either physical intensity or induced anxiety. One visual signal, which reliably predicted noxious stimulation of moderate intensity, came to evoke low anxiety about the impending pain. Another visual signal was followed by the same, moderate-intensity stimulation on most of the trials, but occasionally by discriminably stronger noxious stimuli, and came to evoke higher anxiety. We found that the entorhinal cortex of the hippocampal formation responded differentially to identical noxious stimuli, dependent on whether the perceived pain intensity was enhanced by pain-relevant anxiety. During this emotional pain modulation, entorhinal responses predicted activity in closely connected, affective (perigenual cingulate), and intensity coding (mid-insula) areas. Our finding suggests that accurate preparatory information during medical and dental procedures alleviates pain by disengaging the hippocampus. It supports the proposal that during anxiety, the hippocampal formation amplifies aversive events to prime behavioral responses that are adaptive to the worst possible outcome.