Distinct neural representations of placebo and nocebo effects

Neuroimage. 2015 May 15;112:197-207. doi: 10.1016/j.neuroimage.2015.03.015. Epub 2015 Mar 14.


Expectations shape the way we experience the world. In this study, we used fMRI to investigate how positive and negative expectation can change pain experiences in the same cohort of subjects. We first manipulated subjects' treatment expectation of the effectiveness of three inert creams, with one cream labeled "Lidocaine" (positive expectancy), one labeled "Capsaicin" (negative expectancy) and one labeled "Neutral" by surreptitiously decreasing, increasing, or not changing respectively, the intensity of the noxious stimuli administered following cream application. We then used fMRI to investigate the signal changes associated with administration of identical pain stimuli before and after the treatment and control creams. Twenty-four healthy adults completed the study. Results showed that expectancy significantly modulated subjective pain ratings. After controlling for changes in the neutral condition, the subjective pain rating changes evoked by positive and negative expectancies were significantly associated. fMRI results showed that the expectation of an increase in pain induced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray, whereas the expectation of pain relief evoked significant fMRI signal changes in the striatum. No brain regions were identified as common to both "Capsaicin" and "Lidocaine" conditioning. There was also no significant association between the brain response to identical noxious stimuli in the pain matrix evoked by positive and negative expectancies. Our findings suggest that positive and negative expectancies engage different brain networks to modulate our pain experiences, but, overall, these distinct patterns of neural activation result in a correlated placebo and nocebo behavioral response.

Keywords: Expectancy; Negative expectancy; Nocebo; Pain; Placebo; Positive expectancy; fMRI.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Anesthetics, Local / pharmacology
  • Capsaicin / pharmacology
  • Cerebral Cortex / physiology
  • Female
  • Hot Temperature
  • Humans
  • Lidocaine / pharmacology
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Nervous System / drug effects*
  • Nocebo Effect*
  • Pain / psychology
  • Pain Perception / drug effects
  • Periaqueductal Gray / physiology
  • Placebo Effect*
  • Reward
  • Set, Psychology
  • Young Adult


  • Anesthetics, Local
  • Lidocaine
  • Capsaicin