Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia

Abstract

Objective: While patients with fibromyalgia (FM) are known to exhibit hyperalgesia, the central mechanisms contributing to this altered pain processing are not fully understood. This study was undertaken to investigate potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain, such as anticipation of pain and anticipation of pain relief.

Methods: Thirty-one FM patients and 14 controls underwent functional magnetic resonance imaging, while receiving cuff pressure pain stimuli on the leg calibrated to elicit a pain rating of ~50 on a 100-point scale. During the scan, subjects also received visual cues informing them of the impending onset of pain (pain anticipation) and the impending offset of pain (relief anticipation).

Results: Patients exhibited less robust activation during both anticipation of pain and anticipation of relief within regions of the brain commonly thought to be involved in sensory, affective, cognitive, and pain-modulatory processes. In healthy controls, direct searches and region-of-interest analyses of the ventral tegmental area revealed a pattern of activity compatible with the encoding of punishment signals: activation during anticipation of pain and pain stimulation, but deactivation during anticipation of pain relief. In FM patients, however, activity in the ventral tegmental area during periods of pain and periods of anticipation (of both pain and relief) was dramatically reduced or abolished.

Conclusion: FM patients exhibit disrupted brain responses to reward/punishment. The ventral tegmental area is a source of reward-linked dopaminergic/γ-aminobutyric acid-releasing (GABAergic) neurotransmission in the brain, and our observations are compatible with reports of altered dopaminergic/GABAergic neurotransmission in FM. Reduced reward/punishment signaling in FM may be related to the augmented central processing of pain and reduced efficacy of opioid treatments in these patients.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Copyright © 2014 by the American College of Rheumatology.

Figures

Figure 1. Experimental design (A) and psychophysical results (B)

Bars represent median and 25-75% interquartile range.

Figure 2. Brain responses to pain anticipation (whole brain analyses)

FM patients exhibited lower brain responses in several brain regions. S1/M1 = primary somatosensory / motor cortices; SMA = supplementary motor area; MCC = middle cingulate area; sgACC = subgenual anterior cingulate cortex; VTA = ventral tegmental area; PAG = periaqueductal gray; DLPFC = dorsolateral prefrontal cortex

Figure 3. Brain responses to pain (whole brain analyses)

In whole-brain searches, the responses to cuff pain were not statistically different across groups. S2 = secondary somatosensory cortex; VLPFC = ventrolateral prefrontal cortex; MPFC = medial prefrontal cortex.

Figure 4. Brain responses to relief anticipation (whole brain analyses)

FM patients exhibited lower brain responses in several brain regions. S1/M1 = primary somatosensory / motor cortices; DLPFC = dorsolateral prefrontal cortex; SPL = superior parietal lobule; VLPFC = ventrolateral prefrontal cortex.

Figure 5. Direct searches in the ventral tegmental area

The VTA mask for the ROI analyses (left) was drawn in the midbrain, medial to the substantia nigra and ventral to the red nucleus (right; adapted from the Duvernoy's atlas (24)) (A). In FM, VTA responses to anticipation of pain, pain and anticipation of relief were statistically reduced, compared to controls. Bars represent mean ± SEM (B). VTA responses to pain anticipation and relief anticipation were negatively correlated in healthy controls, but not in FM patients (C).