Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study

Abstract

We use a novel balanced experimental design to specifically investigate brain mechanisms underlying the modulating effect of expected pain intensity on afferent nociceptive processing and pain perception. We used two visual cues, each conditioned to one of two noxious thermal stimuli [ approximately 48 degrees C (high) or 47 degrees C (low)]. The visual cues were presented just before and during application of the noxious thermal stimulus. Subjects reported significantly higher pain when the noxious stimulus was preceded by the high-intensity visual cue. To control for expectancy effects, for one-half of the runs, the noxious thermal stimuli were accompanied by the cue conditioned to the other stimulus. Comparing functional magnetic resonance imaging blood oxygenation level-dependent activations produced by the high and low thermal stimulus intensities presented with the high-intensity visual cue showed significant activations in nociceptive regions of the thalamus, second somatosensory cortex, and insular cortex. To isolate the effect of expectancy, we compared activations produced by the two visual cues presented with the high-intensity noxious thermal stimulus; this showed significant differences in the ipsilateral caudal anterior cingulate cortex, the head of the caudate, cerebellum, and the contralateral nucleus cuneiformis (nCF). We propose that pain intensity expectancy modulates activations produced by noxious stimuli through a distinct modulatory network that converges with afferent nociceptive input in the nCF.

Figure 1.

Maximum BOLD activation is observed when high-temperature noxious stimulation (Noxious Stim) occurs in the presence of high expectation. fMRI BOLD activation in a variety of regions was modulated by changes in both expectation (“HIGH EXPECTATION” and “LOW EXPECTATION”) and the intensity of the noxious thermal stimulus (“HIGH TEMPERATURE” and “LOW TEMPERATURE”). The high-temperature and high-expectation BOLD data were collected using the high-temperature stimulus preceded by a red (high-temperature) cue. The high-temperature and low-expectation BOLD data were collected using the high-temperature stimulus preceded by a blue (low-temperature) cue. The low-temperature and high-expectation BOLD data were collected using the low-temperature stimulus preceded by a red (high-temperature) cue. The maximum BOLD signal compared with baseline occurred with concomitant high-temperature stimulus and high stimulus-intensity expectancy. Markedly lower BOLD activation compared with baseline was observed when the conditioned cue was changed from red to blue (i.e., to the lower intensity predictive cue) or when the noxious thermal stimulation was changed from 48 to 47°C.

Figure 2.

Expectation-associated BOLD activation. To identify brain regions participating in expectation, the expectancy effect was isolated. Using the high-temperature stimulus (∼48°C) condition, we compared high-intensity expectancy (red cue) and low-intensity expectancy (blue cue). The cACC, cerebellum, and the dorsolateral pontomesencephalic region including the nCF have increased BOLD activation when expectancies are for higher pain intensity.

Figure 3.

Thermal stimulus intensity-associated BOLD activation. To identify brain regions participating in the discrimination of noxious thermal stimuli, a small increase in noxious thermal stimulus intensity (1°C) was applied while the level of expectancy (predictive cue) was maintained. When the visual cue predicted the high-intensity stimulus (red cue), the BOLD contrast between high and low thermal stimulus intensity revealed activations in the nociceptive regions of the thalamus, second somatosensory cortex, and the contralateral insula.