1. Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain
Wager, T.D., Rilling, J.K., Smith, E.E., Sokolik, A., Casey, K.L., Davidson, R.J., Kosslyn, S.M., Rose, R.M., Cohen, J.D. (2004)
Kirsten Lee

2. Introduction
Placebo analgesic effect: the belief that one is receiving analgesic treatment reduces pain
Response bias OR influence on sensory, affective, cognitive pain processing?
fMRI -investigate neural mechanism and time course of placebo effect

3. Hypothesis Placebo decreases reported pain – behavioural
decreases activity of pain ROIs during pain stimulation – brain
creates expectation for pain relief (PFC activation) which inhibits pain processing

4. Experimental Task: Study 1
Subjects were scanned by fMRI (BOLD) as they received electric shocks to the right wrist treated with “ineffective/analgesic” (ctrl/placebo) cream

5. Procedure: Study 1 Intense vs mild shock: identified pain ROIs
5 blocks of 15 trials
1 block -- no cream
2 blocks --“analgesic cream” -placebo
2 blocks --“control cream”

6. Experimental Task: Study 2
Subjects were scanned by fMRI as thermal stimuli were applied to patches of skin on the left forearm treated with “ineffective/analgesic” (ctrl/placebo) cream

7. Procedure: Study 2
Calibrate temperatures to reported pain levels of 2, 5, 8 (max 10)
Manipulation phase:
Participants were told all stimuli at level 8
Applied level 8 heat to ctrl patch, level 2 heat to placebo patch

8. Procedure: Study 2 Test phase: Applied level 5 heat to both patches
Identical stimuli-- differences in reported pain (ctrl-placebo) attributed to placebo effects

9. Results Identified pain-responsive regions:
Rostral anterior cingulate cortex (rACC)
Anterior cingulate cortex (ACC)
Secondary somatosensory cortex (SII)
Thalamus (TH)
Insula (INS)
Reported pain: control > placebo (22%)

10. Results
Magnitude of placebo reduction in reported pain correlates with magnitude of placebo reduction in pain ROI activity of
contralateral thalamus
contralateral insula
rACC
during pain stimulation

11. Results
Placebo-induced increase in dorsolateral PFC, orbitofrontal cortex, rACC activity during anticipation correlates with
Behavioural and brain placebo effects
Increased periaqueductal grey (PAG in midbrain) activity during anticipation

12. Results
In insula and thalamus, main placebo effects were found in the late heat period, after stimulus offset
Time (s)

13. Results: Summary Placebo induced:
↓ reported pain (behavioural placebo effect)
↓ TH, INS, rACC activity during pain stimulation (brain placebo effect)
↑ dlPFC, OFC, rACC, PAG activity during anticipation
INS and TH show placebo effects in late heat period

14. Discussion
Correlation between behavioural and brain placebo effects (TH, INS, rACC) during pain stimulation
Placebo
inhibits afferent sensory pain transmission (TH)
has an effect on sensory-discriminative or affective components of pain (INS)
Strongly refutes response bias

15. Discussion
Placebo increases prefrontal (dlPFC/OFC) and midbrain (PAG) activity during anticipation
PFC regions responsible for generating expectation for pain relief contribute to placebo analgesia
Expectancy process may be related to opioid system activation in PAG

16. Discussion
Predominant brain placebo effects occur late in thermal pain response
Placebo effects may:
require a period of pain to develop
involve opioid mechanisms triggered by prolonged pain
involve cognitive reappraisal of pain (positive reinterpretation)
A major portion of the placebo effect is likely controlled centrally by specific pain regions

17. Strengths and Limitations
Comprehensive, well-organized report and discussion of results
Restricted analysis of PFC activation during anticipation to dlPFC and OFC
Repeated stimulation of same area - alter pain sensation?

18. Further Research Activity of other PFC regions during anticipation
Investigate role of rACC in pain processing

19. Thank you!
Wager, T.D., Rilling, J.K., Smith, E.E., Sokolik, A., Casey, K.L., Davidson, R.J., Kosslyn, S.M., Rose, R.M., Cohen, J.D  Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303(5661):