Orbitofrontal cortex mediates pain inhibition by monetary reward

Abstract

Pleasurable stimuli, including reward, inhibit pain, but the level of the neuraxis at which they do so and the cerebral processes involved are unknown. Here, we characterized a brain circuitry mediating pain inhibition by reward. Twenty-four healthy participants underwent functional magnetic resonance imaging while playing a wheel of fortune game with simultaneous thermal pain stimuli and monetary wins or losses. As expected, winning decreased pain perception compared to losing. Inter-individual differences in pain modulation by monetary wins relative to losses correlated with activation in the medial orbitofrontal cortex (mOFC). When pain and reward occured simultaneously, mOFCs functional connectivity changed: the signal time course in the mOFC condition-dependent correlated negatively with the signal time courses in the rostral anterior insula, anterior-dorsal cingulate cortex and primary somatosensory cortex, which might signify moment-to-moment down-regulation of these regions by the mOFC. Monetary wins and losses did not change the magnitude of pain-related activation, including in regions that code perceived pain intensity when nociceptive input varies and/or receive direct nociceptive input. Pain inhibition by reward appears to involve brain regions not typically involved in nociceptive intensity coding but likely mediate changes in the significance and/or value of pain.

Keywords: cognitive-emotional pain modulation; functional magnetic resonance imaging; pain biomarker; psychological pain modulation.

Fig. 1.

Time line of one trial of the wheel of fortune game with simultaneous thermal stimulation. VAS: visual analogue scale. Depicted in the figure is an example of the wining condition. In the losing condition, participants saw the message in the outcome phase of the game that they lost a certain amount of money. In the neutral trials, no pointer was displayed on the wheel.

Fig. 2.

Perceived pain intensity and pain modulation by monetary wins as a function of perceived intensity of nociceptive stimuli. (A) Means and standard errors of intensity ratings for the thermal stimuli in the winning, losing and neutral condition in the mildly painful stimulation category; (B) Correlation of pain modulation displayed as the difference between ratings in the winning and neutral condition in the mildly painful stimulation category (y-axis) as a function of perceived intensity of the stimuli in the neutral condition (x-axis). Successful modulation (i.e. inhibited perception by monetary wins) is displayed as positive values. Post hoc comparisons * P < 0.05, ^tP < 0.10.

Fig. 3.

Neurological pain signature response and brain correlates of moderate compared to mild pain. (A) An univariate analysis showed that moderate pain was associated with higher brain activations compared to mild pain (contrast: [win_mod + neut_mod + lose_mod] > [win_mild + neut_mild + lose_mild]): anterior insula (aINS), posterior insula (pINS), primary somatosensory cortex (SI), secondary somatosensory cortex (SII), posterior-dorsal anterior cingulate cortex (pdACC) and supplementary motor area (SMA). Images are displayed in neurological convention, i.e. right side of the brain is on the right. Coordinates are given in MNI space. Statistical inference was based on a voxel-based threshold of z = 2.3, cluster corrected at p <.05 on a whole brain level. For details see Table 1; (B) A priori defined pattern of the Neurological Pain Signature (NPS). The inset show examples of the pattern distribution of voxel weights within certain brain areas; (C) NPS responses in the winning, losing, and neutral condition with mildly painful, moderately painful, or no stimulation of the wheel of fortune game; mean scalar values expressing the NPS across subjects; error bars: standard error of the mean. Post hoc comparisons ** P < 0.01. Scaling of the NPS values depends on many factors such as voxel size, contrast weight, field strength, etc. Because only a within-study comparison was of interest here, we did not attempt to equate scaling of the NPS values with previous studies.

Fig. 4.

Brain correlates of pain inhibition by reward. Behavioral pain modulation correlated with brain activation in the medial orbitofrontal cortex (mOFC) in the condition with monetary wins and mild pain. Images are displayed in neurological convention, i.e. right side of the brain is on the right. Statistical inference was based on a voxel-based threshold of z = 2.3, cluster corrected at P <.05 across the mask comprising typical pain and reward processing regions (see section ‘Statistical analysis’). Coordinates are given in MNI space.

Fig. 5.

PPI analysis of connectivity of the medial orbitofrontal cortex (mOFC). The mOFC as the seed shows increased negative connectivity with the right primary somatosensory cortex (SI) in the hand area contralateral to the stimulation site, the right rostral anterior insula (raINS), and the anterior-dorsal anterior cingulate cortex (adACC). Subdivision of the ACC according to Etkin et al. (2011); pd, posterior-anterior; pg perigenual; sg, subgenual. Images are displayed in neurological convention, i.e. right side of the brain is on the right. Statistical inference was based on a voxel-based threshold of z = 1.6 and cluster threshold of P  < 0.05 within the regions of interest anterior insula, ACC, and SI (postcentral gyrus). Coordinates are given in MNI space.