Exacerbation of pain by anxiety is associated with activity in a hippocampal network

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.

Fig. 1.

Relevant experimental conditions. Visual signals predicted painful heat stimulation to the back of the left hand. Painful stimulation was delivered either at a lower (LT) or at a discriminably higher (HT) temperature. One visual signal (here:triangle) was consistently followed by LT and came to evoke low anxiety (LA). Another signal (here:square) was followed by LT on most of the trials, but occasionally by HT, and came to evoke higher anxiety (HA). We studied anxiety-induced increases in perceived pain intensity by comparing brain responses to pain in conditions LT/HA and LT/LA. We also assessed temperature-induced increases in perceived pain intensity by comparing brain responses to pain in conditions HT/HA and LT/HA.

Fig. 2.

Behavioral results. A, Ratings of anxiety during presentation of signals HA and LA before the onset of pain LT (bench control group, mean ± one SEM). B, Heart rate changes during presentation of signals HA and LA (scanner group, mean ± one SEM). C, Ratings of perceived pain intensity in conditions LT/LA, LT/HA, and HT/HA (scanner group, mean ± one SEM).

Fig. 3.

Group Z value maps thresholded atp < 0.001 and superimposed on an average anatomical MRI of participating subjects in Talairach space (radiological convention). A, Significant activations associated with temperature-related increases in perceived pain (HT/HA vs LT/HA). The coronal view (left, y= −16) shows activations bilaterally in primary somatosensory cortex (SI), dorsal margin of the posterior insula (pI), thalamus, midcingulate cortex, and in the right hippocampus. The horizontal view (right,z = −14) depicts bilateral hippocampus as well as orbitofrontal cortex. B, Anxiety-related increases in perceived pain (LT/HA vs LT/LA) are associated with significant activation in the left entorhinal cortex. The activation area is shown in coronal (left, y = −16) and horizontal (right, z = −26) view.C, Areas showing activity significantly correlated with the entorhinal FMRI signal during pain modulation by anxiety (LT/HA and LT/LA). The coronal view (left, y = 36) and the horizontal view (right,z = 6) show activation in the perigenual cingulate cortex, and the horizontal view depicts bilateral activity in the mid-insular and parainsular cortices.

Fig. 4.

Significantly different hemodynamic responses in the hippocampus proper and entorhinal cortex (group mean ± one SEM). Regional time courses of FMRI signal represent percentage of change from the rest period preceding each trial, averaged across trials and subjects. The period of painful stimulation is shaded.A, The hippocampus proper was significantly activated bilaterally during HT/HA (●) relative to LT/HA (▴).B, The left entorhinal cortex was significantly activated during LT/HA (▴) relative to LT/LA (▪), as well as relative to baseline. The right entorhinal cortex shows similar, but smaller responses, which is consistent with observations of left-lateralized processing of explicit aversive conditioning in the medial temporal lobes.