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

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

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

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

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”

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

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

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

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%)

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

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

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

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

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

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

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

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?

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

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. 2004. Placebo-induced changes in fMRI in the anticipation and experience of pain. Science 303(5661):1162-7.