Cortical and subcortical responses to high and low effective placebo treatments

Abstract

The effectiveness of placebo treatments depends on the recipient's expectations, which are at least in part shaped by previous experiences. Thus, positive past experience together with an accordant verbal instruction should enhance outcome expectations and subsequently lead to higher placebo efficacy. This should be reflected in subjective valuation reports and in activation of placebo-related brain structures. We tested this hypothesis in a functional magnetic resonance imaging study, where subjects experienced different levels of pain relief and conforming information about price levels for two placebo treatments during a manipulation phase, thereby establishing a weak and a strong placebo. As expected, both placebos led to a significant pain relief and the strong placebo induced better analgesic efficacy. Individual placebo value estimates reflected treatment efficacy, i.e. subjects were willing to pay more money for the strong placebo even though pain stimulation was completed at this time. On the neural level, placebo effects were associated with activation of the rostral anterior cingulate cortex, the anterior insula, and the ventral striatum and deactivations in the thalamus and secondary somatosensory cortex. However, only placebo-related responses in rostral anterior cingulate cortex were consistent across both the anticipation of painful stimuli and their actual administration. Most importantly, rostral anterior cingulate cortex responses were higher for the strong placebo, thus mirroring the behavioral effects. These results directly link placebo analgesia to anticipatory activity in the ventral striatum, a region involved in reward processing, and highlight the role of the rostral anterior cingulate cortex, as its activity consistently scaled with increasing analgesic efficacy.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1

Experimental design. (a) Illustration of the placebo paradigm. Stimulation sites are indicated by the filled squares on the forearm outline. Placebo creams were introduced as “expensive” and “low priced”, respectively. Subjects underwent two manipulation series on each day, the first one in a medical examination room and the second one inside the MRI scanner without BOLD data acquisition. The temperatures were surreptitiously lowered in the placebo conditions during the manipulation phases. This was done to enhance expectations regarding the placebo treatment efficacy. During test sessions BOLD data were acquired with equal temperatures in placebo and control conditions. Stimulation sites, the order of placebo and control within session and the order of placebos between days were counterbalanced across subjects. (b) Schematic of one trial. Each trial started with a fixed anticipation period of 5 s, followed by 20 s heat pain stimulation, a variable delay, a pain rating and a variable inter trial interval (ITI).

Figure 2

Behavioral placebo effects. (a) Pain ratings averaged over subjects (± SEM). Temperatures were calibrated to equal a VAS score of 60. Reported pain was significantly reduced by placebo treatment (p<0.001) and the reduction was significantly greater in the strong condition (p=0.025). Pain ratings from the control conditions did not differ significantly. (b) Skin conductance responses (SCR) to heat pain stimuli. The interaction term was significant (p=0.004). Follow-up t-tests revealed a significant reduction of SCRs under strong placebo compared to control (p<0.05). (c) Pain ratings were correlated with value estimates (WTP). The slopes were significantly negative (average slope: −5.01, i.e. the more a subject valued a cream, the lower his corresponding pain rating), thereby relating the group level effect shown in a) to inter-individual differences in treatment valuation.

Figure 3

Brain responses during the anticipation period. (a) Activations for placebo > control were observed in the rACC and the ventral striatum. Parameter estimates are plotted for the rACC peak voxel. (b) The rACC showed enhanced placebo induced responses for the strong vs. weak placebo ((strong placebo > control) > (weak placebo > control)). Parameter estimates are plotted for the rACC peak voxel. Error bars indicate 90% confidence interval. Statistical t-maps are overlaid on an average structural image and the significance threshold is set to p < 0.005 (uncorrected) for visualization purposes only.

Figure 4

Placebo-induced BOLD responses during pain stimulation. (a) The pooled placebo > control contrast revealed a bilateral cluster in the pregenual rACC during early pain. Parameter estimates are plotted for the left peak. Error bars indicate 90% confidence interval. (b) Comparison of the placebo effects during early pain. The stronger placebo induced increased activity in the rACC, as indicated by the interaction effect (strong> control) > (weak > control). Parameter estimates are plotted for the rACC peak voxels. Statistical t-maps are overlaid on an average structural image and the significance threshold is set to p < 0.005 (uncorrected) for visualization purposes only.

Figure 5

Reductions in brain responses to placebo. SII (left) and thalamus (right) showed reduced activity under pooled placebo vs. control. Statistical t-maps are overlaid on an average structural image and the significance threshold is set to p < 0.005 (uncorrected) for visualization purposes only.

Figure 6

Correlations between behavioral and cortical placebo responses. During late pain, reductions in pain ratings of the weak placebo correlated with placebo induced reductions in the anterior insula and dACC. Statistical t-maps are overlaid on an average structural image and the significance threshold is set to p