Human brainstem activation underpinning offset analgesia changes in perceived pain intensity. An ultra-high field functional magnetic resonance imaging investigation

Offset analgesia is a pain modulatory phenomenon whereby a slight decrease in the intensity of a painful stimulus results in a large, disproportionate reduction in perceived pain. While human brain imaging studies have begun to map the brain circuitry underpinning offset analgesia, the brainstem circuits responsible for this phenomenon remain unknown. Furthermore, it is now recognised that previously described analgesic paradigms can evoke pain increases in some individuals, but whether the same brainstem circuitry is responsible for inhibitory and paradoxical facilitatory responses remains to be classified. In this exploratory brain imaging investigation, across 37 pain-free participants we used ultra-high field functional magnetic resonance imaging to define brainstem sites associated with offset pain intensity decreases and paradoxical increases. We found that in response to offset analgesia trials, 12 participants reported significant decreases; 8 reported significant increases; and 17 reported no significant change in perceived pain intensity during noxious heat stimulation of the forearm using a thermode. Brainstem-specific analysis showed offset pain decreases, associated with bilateral signal intensity decreases in the locus coeruleus, part of the rostral ventrolateral medulla, and the nucleus tractus solitarius. Signal increases were found in the parabrachial nucleus and the subcoeruleus region. In striking contrast, pain intensity increases were associated with signal decreases in the rostral ventromedial medulla and signal increases in the pontine reticular nucleus. No significant signal intensity changes were observed in other key brainstem pain modulation regions such as the periaqueductal gray matter and the A5 cell group. These data support the role of and identify specific brainstem nuclei function associated with offset pain intensity decreases and increases.