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Below is a cache of http://www.aapspharmaceutica.com/inside/focus_groups/ModelSim/imagespdfs/Wager05.pdf. It's a snapshot of the page taken as our search engine crawled the Web.
The web site itself may have changed. You can check the current page or check for previous versions at the Internet Archive. Yahoo! is not affiliated with the authors of this page or responsible for its content. The neural bases of the placebo response in fMRI The neural bases of the placebo response in fMRI Collaborators QuickTime and a decompressor are needed to see this picture. Columbia Ed Smith
Kevin Ochsner
Martin Lindquist University of Michigan Ken Casey
Doug Noll
Tom Nichols Boston College Lisa Feldman Barrett MBBH Brain Group Jim Rilling
Jonathan Cohen
Bob Rose
Ed Smith
Steve Kosslyn
Richie Davidson
Margaret Kemmeny Why study placebo? Placebo treatment is a manipulation of expectancy and appraisal of meaning. A tool for studying meaning generation, mechanisms of belief, and brain-body interactions Appraisals are fundamental determinants of emotional well- being and health The difference between a condition that can be lived with and one that is debilitating Appraisals drive stress (HPA axis) response, with consequences for endocrine and immune function and genetic markers of aging (Sapolsky, Kiecolt-Glaser & Glaser, Epel 2005 PNAS) Appraisals drive behaviors, maladaptive and adaptive
Appraisals modify pain processing in the brain 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 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, Parkinsons 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? Placebo effects in reported pain n = 50 Appraisal Sensation Emotion Painful stimulus Belief / expectancy Gate
control Experience Demand
characteristic Placebo Behavior Placebo causes 22% decrease in pain The demand characteristic hypothesis fMRI predictions:
No changes in pain regions
during pain Demand
characteristic Behavior Emotion Belief / expectancy Appraisal Painful stimulus Sensation The gate control hypothesis (Melzack & Wall, 1965) Behavior Emotion Belief / expectancy fMRI predictions:
Placebo reduces activity
throughout sensory and
affective pain processing
regions Opioid system activity
correlated with pain relief Appraisal Sensation Painful stimulus Gate
control Opioids Active mechanisms of placebo Behavior fMRI predictions:
Placebo reduces activity in
affective pain networks Opioid release in frontal and
limbic regions Experience Emotion Belief / expectancy Appraisal Painful stimulus Sensation Opioids and placebo effects Opioids Opioids ? ? Appraisal Sensation Emotion Behavior 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) Belief / expectancy Opioids Painful stimulus 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) 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 fMRI trial design Rest + 40 - 50 s Time during Trials + 20 s Heat Rate pain rating 4 s Ready! 1 s Cue + 1-16 s Anticipation x = 9.77
SD = 6.04 x = 6.82
SD = 4.18 + 1-12 s Rest Anticipatory activity Pain-induced activity Anticipation of pain: Placebo > Control Study 1 OFC Study 1 DLPFC Study 2 DLPFC Pain Anticipation 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 Study 1 Placebo effects during pain CL-INS Shock Early Heat, correlation Shock Late Heat, main effects (C > P) A B C rACC CL-INS CL-INS CL-
TH CL-
TH CL-INS D E F Shock Late Heat, main effects (C > P) PHCP 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) Study 2 General mechanisms of placebo? Appraisal as a general mechanism In pain, leads to altered significance of stimulation
In emotions, leads to altered thoughts, feelings and action tendencies In Parkinsons disease, leads to increased self-efficacy Ochsner et al.
Regulation of emotion Mayberg et al. Placebo in depression Opioid drug effects in prefrontal cortex Casey et al., 2000 Wagner et al., 2001 Adler et al., 1997 Increases in activity with placebo Study 1 - Anticipation
Study 2 - Anticipation
Study 2 - Pain Increased activity in self-regulation tasks Dorsal Frontal Orbitofrontal 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 L R L R Lateral
Frontal Medial
Frontal Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate
control Experience Demand
characteristic Demand characteristic
Activation of appraisal
networks before and during
pain
Changes in pain-processing
regions Opioids x Pain experience
Reductions in affective
pain regions
Opioid release directly in
appraisal networks
Gate control (early blockade)
Reductions in affective ? pain regions
Increased activation in S2 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)?
The web site itself may have changed. You can check the current page or check for previous versions at the Internet Archive. Yahoo! is not affiliated with the authors of this page or responsible for its content. The neural bases of the placebo response in fMRI The neural bases of the placebo response in fMRI Collaborators QuickTime and a decompressor are needed to see this picture. Columbia Ed Smith
Kevin Ochsner
Martin Lindquist University of Michigan Ken Casey
Doug Noll
Tom Nichols Boston College Lisa Feldman Barrett MBBH Brain Group Jim Rilling
Jonathan Cohen
Bob Rose
Ed Smith
Steve Kosslyn
Richie Davidson
Margaret Kemmeny Why study placebo? Placebo treatment is a manipulation of expectancy and appraisal of meaning. A tool for studying meaning generation, mechanisms of belief, and brain-body interactions Appraisals are fundamental determinants of emotional well- being and health The difference between a condition that can be lived with and one that is debilitating Appraisals drive stress (HPA axis) response, with consequences for endocrine and immune function and genetic markers of aging (Sapolsky, Kiecolt-Glaser & Glaser, Epel 2005 PNAS) Appraisals drive behaviors, maladaptive and adaptive
Appraisals modify pain processing in the brain 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 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, Parkinsons 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? Placebo effects in reported pain n = 50 Appraisal Sensation Emotion Painful stimulus Belief / expectancy Gate
control Experience Demand
characteristic Placebo Behavior Placebo causes 22% decrease in pain The demand characteristic hypothesis fMRI predictions:
No changes in pain regions
during pain Demand
characteristic Behavior Emotion Belief / expectancy Appraisal Painful stimulus Sensation The gate control hypothesis (Melzack & Wall, 1965) Behavior Emotion Belief / expectancy fMRI predictions:
Placebo reduces activity
throughout sensory and
affective pain processing
regions Opioid system activity
correlated with pain relief Appraisal Sensation Painful stimulus Gate
control Opioids Active mechanisms of placebo Behavior fMRI predictions:
Placebo reduces activity in
affective pain networks Opioid release in frontal and
limbic regions Experience Emotion Belief / expectancy Appraisal Painful stimulus Sensation Opioids and placebo effects Opioids Opioids ? ? Appraisal Sensation Emotion Behavior 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) Belief / expectancy Opioids Painful stimulus 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) 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 fMRI trial design Rest + 40 - 50 s Time during Trials + 20 s Heat Rate pain rating 4 s Ready! 1 s Cue + 1-16 s Anticipation x = 9.77
SD = 6.04 x = 6.82
SD = 4.18 + 1-12 s Rest Anticipatory activity Pain-induced activity Anticipation of pain: Placebo > Control Study 1 OFC Study 1 DLPFC Study 2 DLPFC Pain Anticipation 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 Study 1 Placebo effects during pain CL-INS Shock Early Heat, correlation Shock Late Heat, main effects (C > P) A B C rACC CL-INS CL-INS CL-
TH CL-
TH CL-INS D E F Shock Late Heat, main effects (C > P) PHCP 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) Study 2 General mechanisms of placebo? Appraisal as a general mechanism In pain, leads to altered significance of stimulation
In emotions, leads to altered thoughts, feelings and action tendencies In Parkinsons disease, leads to increased self-efficacy Ochsner et al.
Regulation of emotion Mayberg et al. Placebo in depression Opioid drug effects in prefrontal cortex Casey et al., 2000 Wagner et al., 2001 Adler et al., 1997 Increases in activity with placebo Study 1 - Anticipation
Study 2 - Anticipation
Study 2 - Pain Increased activity in self-regulation tasks Dorsal Frontal Orbitofrontal 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 L R L R Lateral
Frontal Medial
Frontal Active mechanisms of placebo Belief / expectancy Appraisal Sensation Emotion Behavior Painful stimulus Gate
control Experience Demand
characteristic Demand characteristic
Activation of appraisal
networks before and during
pain
Changes in pain-processing
regions Opioids x Pain experience
Reductions in affective
pain regions
Opioid release directly in
appraisal networks
Gate control (early blockade)
Reductions in affective ? pain regions
Increased activation in S2 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)?
