The neural bases of the placebo response in fMRI Collaborators University of Michigan Jon-Kar Zubieta David Scott Ken Casey Doug Noll Emory University Jim Rilling Princeton University Jonathan Cohen Columbia Ed Smith MBBH Brain Group Ed Smith Ken Casey Doug Noll Jim Rilling

One who has control over the mind is tranquil in heat and cold, in pleasure and pain, and in honor and dishonor. –Bhagavad Gita

The placebo panacea Over 4,000 ancient remedies, largely placebo Shapiro; in Harrington, Anne (ed.), The placebo effect Modern placebo effects in major clinical disorders: heart disease, arthritis, pain, depression, Parkinson’s disease

Are placebo effects real? Many things have been called ‘placebo effects’ (Klein, Shapiro, Kirsch, Hrobartsson) Natural history Spontaneous symptom fluctuation Regression to the mean Sampling bias Hawthorne effects Demand characteristics in reporting Active mechanisms?

Why study placebo? Use brain-based techniques (fMRI, ERP, PET) to study mechanisms of cognitive expectancy and their effects on affective processing –Placebo treatment is a manipulation of cognitive expectancy –A tool for studying expectation, value, and brain-body interactions The meaning ascribed to events has important health implications. –The stress (HPA axis) response is expectancy-driven –Consequences for peripheral physiology and immune function (R. Sapolsky, Kiecolt-Glaser & Glaser, Epel 2005 PNAS) –Consequences for quality of life and length of life (Epel, PNAS 2005, S. Cohen)

Placebo cream “This is lidocaine” Placebo effects in reported pain n = 50 Placebo causes 22% decrease in pain Control cream “Will have no effect”

Placebo effects in reported pain Behavior Appraisal Sensation Emotion Painful stimulus Belief / expectancy Gate control Experience Demand characteristic Placebo Nociception Subjective pain: Perceptual, affective, value-based processes Memory and decision Anchor & adjust, Bayesian-like decision * Not linear stages, but useful conceptual distinctions

Intertwined circuitry for pain and emotion Pons Parabrachial Nuc. Amygdala Hypothalamus Peri- aqueductal gray (PAG) Amygdala Spinothalamic Spinolimbic Thalamus Nociception Matre et al., 2006 (placebo) Subjective pain Craig et al., 2000 Placebo: Kong, 06; Zubieta,‘06, Wager, Rilling et al., 04, Petrovic, 02 Memory and decision Molden et al., 2005 * Must separate pain and decision phases!

“Descending” pain regulation pathways Pons Parabrachial Nuc. Amygdala Hypothalamus Peri- aqueductal gray (PAG) Amygdala PAG activity linked with endogenous anti- nociception (Zubieta, ‘01) Blocking opioids reduces placebo effects Blocking opioids reduces placebo effects (Fields ‘79, Gracely ‘84, Levine ‘80, Benedetti ‘99) But placebo affects opioids in limbic regions too (Zubieta ‘06) But placebo affects opioids in limbic regions too (Zubieta ‘06) Direct projections to PAG from frontal and limbic regions (e.g., Zhang, ‘97) Dorsolateral PFC and OFC critical for maintaining expectations and generating current value (respectively) Miller; Murray

fMRI studies Study 1: Shock on R forearm (n = 24) Study 2: Heat on L forearm (n = 23, selected placebo responders) Treatment with an inert ointment (Vasoline) –Placebo treatment: participants told that treatment was lidocaine –Control treatment: participants told that treatment was a ‘control cream’ to control for having ointment applied to skin Testing on placebo and control-treated skin fMRI design: Separate anticipation from experience of pain Wager, Rilling et al., Science, 2004

Phases of processing: fMRI trial design Rest s Time during Trials + 20 s Heat (shock)Rate pain rating 4 s Ready! 1 s Cue s Anticipation x = 9.77 SD = 6.04 x = 6.82 SD = s Rest Anticipatory activityPain-induced activity Retrieve current context (safety/threat) (lateral PFC) Generate predictions about value (Orbitofrontal/limbic) Assess significance (harm) (OFC, VMPFC, limbic) Pain experience (SII, ACC, limbic) Integrate experience and expectation Decide what to report

Anticipation: an active process Maintain belief Ready! 1 s Cue s Anticipation x = 9.77 SD = 6.04 Expectancy context value pain How does placebo affect this process? Load current context

Anticipation of pain: Placebo > Control Study 1 OFC Study 1 DLPFC Study 2 DLPFC Anticipation Pain r = Rating (control – placebo) OFC during anticipation (placebo – control) responder nonresponder Inf. frontal junction: Task-set preparation (Brass et al., 2005) Context maintenance (Cohen, Miller) Attentional modulation of pain (Lorenz, Remy, Valet)

Anticipation of pain: Placebo > Control DLPFC r =.51 r =.60 Midbrain Study 2 PAG area activated during anticipation in both studies (opioid involvement?) Activation correlated with DLPFC activation in both studies

Placebo effects during pain Shock rACC Study 1 Anterior cingulate ‘pain affect’ (Rainville, hypnosis) Early Heat, correlation Study 2

Placebo effects during pain Shock rACC Anterior cingulate ‘pain affect’ (Rainville, hypnosis) Insula ‘interoception’ (Craig) correlates with subjective pain Parahippocampal cortex Pain anxiety (Ploghaus) Early Heat, correlation Shock CL-INS Late Heat, main effects (C > P) CL-INS PHCP Study 1 Study 2

Placebo effects during pain Shock rACC Anterior cingulate ‘pain affect’ (Rainville, hypnosis) Insula ‘interoception’ (Craig) correlates with subjective pain Parahippocampal cortex Pain anxiety (Ploghaus) Early Heat, correlation Shock CL-INS Late Heat, main effects (C > P) CL-INS PHCP CL- TH Shock CL- TH Late Heat, main effects (C > P) Thalamus Dorsomedial aspect Broad limbic and motivational function Study 1 Study 2

Opioid increases F Firestone 1996 A Adler 1997 N Wagner 2001 P Petrovic 2002 Emotion regulation L Levesque 2003 C Ochsner 2002 O Ochsner 2004 H Phan 2004 B Bishop 2004 Placebo W Wager 2004, antic. G Wager 2004, pain I Lieberman 2004 V Petrovic 2002 T Petrovic 2005 M Mayberg 2002 Common activity in pain and affect regulation Benedetti et al., 2005 OrbitofrontalDorsal Frontal Lateral Frontal LR Medial Frontal LR

Alternative hypotheses for placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Demand characteristic Demand characteristic Activation of appraisal networks before and during pain Changes in pain-processing regions x Experience Opioids Pain experience Reductions in ‘affective’ pain regions Opioid release directly in appraisal networks Gate control Gate control (early blockade) Reductions in ‘affective’ pain regions Increased activation in S2 ?

...whilst part of what we perceive comes through our senses from the object before us, another part (and it may be the larger part) always comes...out of our own head. William James, Principles of Psychology

Thank you!

Placebo W Wager 2004, antic. G Wager 2004, pain I Lieberman 2004 V Petrovic 2002 T Petrovic 2005 M Mayberg 2002 Opioid increases F Firestone 1996 A Adler 1997 N Wagner 2001 P Petrovic 2002 Emotion regulation L Levesque 2003 C Ochsner 2002 O Ochsner 2004 H Phan 2004 B Bishop 2004 Dorsal FrontalOrbitofrontal Lateral Frontal Medial Frontal Increased activity in self-regulation tasks A general appraisal mechanism? LR LR

Placebo effects during pain Shock rACC CL- TH Shock Study 1 Placebo-induced decreases in: Insula ‘interoception’ (Craig) correlates with subjective pain Anterior cingulate ‘pain affect’ (Rainville, hypnosis) Dorsomedial thalamus ‘limbic’ thalamus involved in emotional responses Parahippocampal cortex Pain anxiety (Ploghaus) Early Heat, correlation CL- TH Late Heat, main effects (C > P) Shock CL-INS Late Heat, main effects (C > P) CL-INS PHCP Study 2 CL-INS

Anticipation of pain: Placebo > Control Study 1 OFC Study 1 DLPFC Study 2 DLPFC Anticipation Pain

Opioids and placebo effects Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Placebo effects are reversible by the opioid antagonist naloxone (Fields, Levine, Gracely, Benedetti) Taken as evidence that placebo effects are not only demand characteristics Evidence for psychological control of pain at the spinal level? (Melzack and Wall, 1965) Opioids ? ?

Opioid drug effects in prefrontal cortex Casey et al., 2000 Wagner et al., 2001 Adler et al., 1997 Do opioids work in part by altering expectations?

Opioid release in [ 11 C] Carfentinil PET Direct effects of opioids in appraisal PET receptor binding provides direct evidence for opioid system involvement in placebo. High binding indicates low endogenous release WarmPainWarmPain Placebo or Control cream + Carfentinil injection Control or placebo cream + Carfentinil injection P - C release, pain P - C release,warm

Placebo-induced opioid release Petrovic, 2002: fMRI Remifentanil Placebo [P - C Heat] vs. [P - C Warm] N = 15

Opioid release correlated with reported placebo effects [P - C Brain] with [P - C Reported pain] Higher reported placebo effects: Lower release Greater dose-response effect of opioids Diffs in binding potential for high responders

Opioid release correlated with reported placebo effects [P - C Brain] with [P - C Reported pain]

Correlations among brain regions in opioid release [P - C Heat] Compensatory release in “nonresponders?” Release greater in “responders”

The demand characteristic hypothesis Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Demand characteristic fMRI predictions: No changes in pain regions during pain

The gate control hypothesis (Melzack & Wall, 1965) Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate control fMRI predictions: Placebo reduces activity throughout sensory and affective pain processing regions Opioid system activity correlated with pain relief Opioids

Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Experience fMRI predictions: Placebo reduces activity in affective pain networks Opioid release in frontal and limbic regions

Pain processing Maintain belief Rest s + 20 s HeatRate pain rating 4 s Ready! 1 s Cue s Anticipation x = 9.77 SD = 6.04 x = 6.82 SD = s Rest ExpectancyPain processing Retrieve current context Significance to self Anticipate outcomes Prepare response set

Active mechanisms of placebo: Predictions From VLPFC, OFC (medial) Prefrontal cortex (green) generates and maintains expectancies Predict: placebo-induced increases in PFC in anticipation of pain Prefrontal activation correlated with decreases in reported pain … and increases in opioid-rich periaqueductal gray (PAG) Wager, Curr. Dir in Psych Sci., 2005

Psychological influences on pain Pain influenced by expectations about… Situation Significance of injury Treatment efficacy lplacebo; Benedetti, Gracely, Petrovic Stimulation Lorenz, Sawamoto, Coghill, Ploghaus, Porro Self self-efficacy; Bandura Hypnosis; Rainville, Faymonville

A process model of expectancy-based regulation Warning cue Belief Placebo treatment Expectancy pre-appraisal Noxious stimulus Pain appraisal Context level Input level Lateral PFC ACC, OFC, VLPFC Insula, thalamus, S2 Anxiety Vase et al., Price et al. Attention Petrovic et al., Brooks et al., others

If you are distressed by anything external, the pain is not due to the thing itself, but to your estimate of it; and this you have the power to revoke at any moment –Marcus Aurelius

Future directions How much of the effect of analgesic drugs is due to expectations? What are the contributions of attention, anxiety, and appraisal to placebo effects? Are placebo effects similar to other cognitive strategies (i.e., distraction, imagery, or cognitive-behavioral therapy) for reducing pain and negative emotion? Do placebo effects in pain involve similar mechanisms to those in other domains (e.g., emotion and anxiety; Petrovic et al. 2005)?

Opioid drug effects in S2 Increases in S2 with verum opioid analgesics (e.g., Casey) Increased inhibitory input –Metabolic activity in interneurons -> Tonic increase –Could make S2 more responsive to frontal input

Placebo effects in S2 Use meta-analysis as a broad ROI Identify S2 in individual participants by individual pain response Evidence against early blockade of nociception as a major factor

Wagner Remi produces dose- dependent decrease in PAG Wagner, 2001 Remifentanil-induced decreases

Y = 1 Experiment 1Experiment 2 dorsal amygdala Amygdala: Control > Placebo

Peak Heat: Placebo activates right frontal, sensorimotor, and parietal cortex Heat-responsive Regions of interest (ROIs) Inferior parietal Premotor Dorsolateral PFC

Peak Heat: Placebo activates right frontal, sensorimotor, and parietal cortex P > C,.005 / 60 voxels Superior parietal lobule/ precuneus Sensorimotor cortex Dorsolateral and Dorsomedial prefrontal cortex Premotor cortex * Replicated in Rilling, Wager et al., in prep.

Opioid release correlated with reported placebo effects [P - C Brain] with [P - C Reported pain]

Clustering in component space Make meaningful groups of regions Inferential testing of null hypothesis: no grouping Black: + correlation Blue: - correlation (p <.05 corrected)

The importance of S2 Pain in insula - colors are regions Wager & Feldman Barrett, 2004 Identified 4 insular regions based on anatomy (Mesulam) Studied four task domains: Pain Negative emotions Attention shifting Working memory Computed P(Task | Activity) in each region

Task prediction in the insula Pain Recall of emotion Diagnostic value - colors are tasks Can we predict task given brain activity? Green = pain, red = emotional recall, blue = attention, yellow = WM S2 activity is highly diagnostic of pain Bilateral S2 activity occurs ONLY in pain studies If I observe S2 activity, I’m probably in pain. Implications for psychological vs. emotional pain

S2 in individual participants Decreases (C > P) in anticipation Increases (P > C) in early and late heat Behavioral placebo effects correlated with…

Placebo effects in reported pain Behavior Appraisal Sensation Emotion Painful stimulus Belief / expectancy Gate control Experience Demand characteristic n = ManipulationTest Pain Rating Placebo Control Placebo causes 22% decrease in pain