Neurobiology of placebo effects: expectations or learning?

Abstract

Contemporary learning theories suggest that conditioning is heavily dependent on the processing of prediction errors, which signal a discrepancy between expected and observed outcomes. This line of research provides a framework through which classical theories of placebo effects, expectations and conditioning, can be reconciled. Brain regions related to prediction error processing [anterior cingulate cortex (ACC), orbitofrontal cortex or the nucleus accumbens] overlap with those involved in placebo effects. Here we examined the possibility that the magnitude of objective neurochemical responses to placebo administration would depend on individual expectation-effectiveness comparisons. We show that such comparisons and not expectations per se predict behavioral placebo responses and placebo-induced activation of µ-opioid receptor-mediated neurotransmission in regions relevant to error detection (e.g. ACC). Expectations on the other hand were associated with greater µ-opioid system activation in the dorsolateral prefrontal cortex but not with greater behavioral placebo responses. The results presented aid the elucidation of molecular and neural mechanisms underlying the relationship between expectation-effectiveness associations and the formation of placebo responses, shedding light on the individual differences in learning and decision making. Expectation and outcome comparisons emerge as a cognitive mechanism that beyond reward associations appears to facilitate the formation and sustainability of placebo responses.

Keywords: expectations; placebo analgesia; prediction error signal and learning; µ-opioid receptor.

Fig. 1

Effect of expectation classification (Low vs High) on µ-opioid system activation. Left: expectation group effects (High > Low) on Δ in µ-opioid BP_ND after placebo administration (P < 0.001, k > 10 voxels) were found in the DLPFC. Upper Right: regions effect of expectation group on Δ in µ-opioid BP_ND after placebo administration in the DLPFC; lower right: no significant effect of expectations group on Δ VAS ratings after placebo administration was found.

Fig. 2

Effect of expectations-effectiveness classification on placebo-induced Δ in average VAS intensity ratings acquired over 20 min. Greater placebo effects were observed in those with a positive prediction error signal (Low Expectations and High Effectiveness), whereas Lower placebo effects were observed in those with a negative prediction error signal (High Expectations and Low Effectiveness).

Fig. 3

Effect of Expectation − Effectiveness classification on µ-opioid system activation. Left: significant effects of Expectation − Effectiveness comparisons on Δ in µ-opioid BP_ND during placebo administration were found in (P < 0.001, k > 10 voxels) in the left subgenual, rostral and dorsal anterior cingulate cortex (sgACC, rACC, dACC), the OFC bilaterally and the hippocampus/amygdala (AMYG) bilaterally, the posterior hippocampus bilaterally, the left thalamus and the anterior insula bilaterally (INS). Upper right: effect of expectation-effectiveness comparisons on Δ regional in µ-opioid BP_ND during placebo administration in the dACC. Lower right: placebo-induced activation of µ-opioid neurotransmission in the dACC was correlated with reductions in pain ratings after placebo administration as measured by the change in MPQ total scores (MPQ: r = 0.4, P = 0.001).