The Subjective Experience of Feelings Past

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Placebo effects in pain A window into the
cognitive regulation of affect Tor D.
Wager Columbia University
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• 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

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Causal effects of mere belief?

• Study the effects of sham (placebo) treatments
• Placebo effect
• Beneficial effects attributable to the treatment
  context rather than the physical effects of the
  treatment itself
• Meaning of treatment (D. Moerman)
• Conditioned responses (R. Ader)
• In pain, analgesia caused by a sham treatment
  (e.g., an injection of saline, an inert ointment)

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The placebo panacea

• Over 4,000 ancient remedies
• Shapiro in Harrington, Anne (ed.), The placebo
  effect
• Almost all effects now attributed to placebo
• Some deadly

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Use of placebos throughout history

• the patient, though conscious that his
  condition is perilous, may recover his health
  simply through his contentment with the goodness
  of the physician
• Hippocrates
• Volume II on decorum and the physician.
  LondonWilliam Heinemann, 1923.

c. 460 BC
c. 1800
c. 2007
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• One of the most successful physicians I have
  ever known has assured me that he used more bread
  pills, drops of colored water and powders of
  hickory ashes than of all other medicines put
  together
• Thomas Jefferson

c. 460 BC
c. 1800
c. 2007
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• Placebo use survey of 466 physicians in Chicago
  area (50 response rate) Sherman Hickner, 2007
• 45 reported placebo use in clinical practice
• 96 believed placebos can have therapeutic
  benefit

c. 460 BC
c. 1800
c. 2007
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Indirect evidence for placebo effects

• Lower mortality following myocardial infarction
  is predicted by medication adherenceeven if
  medication was placebo. (Canner et al., NEJM,
  1980 Drug Research Project Group, NEJM, 1980,
  Irving, 1999)
• Improvements after sham surgery
• Coronary angina (Cobb et al., NEJM, 1959)
• Arthroscopic knee surgery (Moseley et al., 1996,
  2002)
• Some patients satisfied with sham surgery results
  even after two years

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Problems for early research on placebo and
related context effects

• Does improvement in placebo groups in sham
  surgery studies mean that placebos cause any
  actual improvement?
• Not necessarily!
• (Keine Kienle, 1998 Shapiro, Kirsch,
  Hrobartsson Gottsche, 2001, 2004, NEJM)
• Natural history Natural course of disease
• Spontaneous symptom fluctuation
• Regression to the mean Extreme cases tend to
  become less extreme
• Sampling bias Participants who stay in study are
  those who are improving anyway
• Hawthorne effects The act of being studied
  changes behavior
• Demand characteristics People report what they
  feel like they should (sometimes unconsciously)
• Hrobartsson Gottsche Found placebo effects
  only in graded, not binary outcomes, and
  significant only for pain argued that all
  placebo effects may be artifacts.

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Human experimental evidence for placebo

• Pain (Benedetti, 2007 Benedetti Amanzio, 1997
  De Pascalis, Chiaradia, Carotenuto, 2002
  Liberman, 1964 Montgomery Kirsch, 1997 Price
  et al., 1999 Vase, Robinson, Verne, Price,
  2005 Voudouris, Peck, Coleman, 1985 Wager,
  Matre, Casey, 2006 Wager, Scott, Zubieta,
  2007)
• Asthma (Kemeny et al., 2007)
• Depression (Mayberg et al., 2002)
• Parkinsons Disease (Benedetti et al., 2004
  Colloca, Lopiano, Lanotte, Benedetti, 2004 de
  la Fuente-Fernandez et al., 2001 Pollo et al.,
  2002)
• Conditioned immunosuppression (Goebel et al.,
  2002 Goebel, Meykadeh, Kou, Schedlowski,
  Hengge, In press.)
• Insomnia(Storms Nisbett, 1970)
• Respiratory rate (Benedetti et al., 1998
  Benedetti, Amanzio, Baldi, Casadio, Maggi,
  1999)
• Heart rate/HR variability (Lanotte et al., 2005
  Pollo, Vighetti, Rainero, Benedetti, 2003)
• Cortisol release (Benedetti, Amanzio, Vighetti,
  Asteggiano, 2006 Benedetti et al., 2003
  Johansen, Brox, Flaten, 2003)

• Little research on brain mechanisms
• Few principles for understanding
• Which kinds of outcomes are affected?
• In what kinds of people?
• Under what circumstances?

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Effects of mere belief?
Cognitive context
Emotional appraisal
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Are placebo responses relevant to health,
medicine, quality of lifeor not?

• 1) Do placebo treatments cause placebo outcomes?
• Correlated cause problem Irving, 1999 Adherence
  to placebo predicts mortality, but age and social
  isolation predict adherence.
• Solution Experimental manipulation of placebo
  treatment with randomization
• 2) Which brain systems and which outcomes
  (clinical, physiological, emotional) are
  affected?
• In pain, nociceptive systems, affective systems,
  cognitive systems

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Brain mediators of subjective pain
Temperature calibrated for each participant
Warm (Level 1)
Low Pain (Level 3)
Med Pain (Level 5)
High Pain (Level 7)
10s
14s
8s
6s
4s





Ready
Heat
Rate Pain
Anticipatory delay
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Pain ratings are reliable, but depend on more
than the temperature
Individual participants
Brain mediators
Which regions?
Pain
Anterior insula (Craig, 2003) Anterior cingulate
Temperature
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Figure 6. Pain path analysis
Key brain mediators fMRI evidence
Mediators (Brain)
NSF pain-pathway mapping project
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Figure 6. Pain path analysis
Key brain mediators fMRI evidence
Mediators (Brain)
NSF pain-pathway mapping project
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Placebo fMRI Study Procedures

• Study 1 Electric Shock, Right arm
• N 24 in fMRI
• Look mainly for brain placebo -- reported
  placebo correlations

• Study 2 Thermal Pain, Left arm
• N 22 in fMRI
• High responders selected from preliminary
  placebo session
• Expectancy manipulation
• Hospital setting
• Look mainly for main effects of brain placebo

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Placebo effects in reported pain
Thermal stimulation on both Placebo- and
control-treated sites (within subjects design)
Many replications (see Benedetti, Price, others)
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fMRI Study Procedures
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fMRI trial design
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Placebo effects in reported pain
Many replications (see Benedetti, Price, others)
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Does placebo reduce brain responses to painful
stimuli?
Key mediators Rostral dorsal cingulate, ant.
insula, SII, thalamus
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Placebo expectancy Effects on pain
Rostral dorsal anterior cingulate
Mid- and anterior insula
Parahippocampal, Subthalamic region, thalamus
Wager et al., 2004, Science. P lt .005, all
results replicated in 2 expts
Anticipation and response-related activity
controlled for in regression
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Price et al., 2007Replication and extension in
irritable bowel syndrome patients
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Mechanisms of placebo pain modulation
Cognitive context
Lateral prefrontal cortex
Emotional appraisal
Medial and orbital prefrontal cortex
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Anticipation of pain Placebo gt Control
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Anticipatory activity predicting the magnitude of
placebo responses Combined sample
Anticipation
Placebo analgesia
Blue areas Placebo-induced increases predict the
magnitude of analgesia Fronto-parietal
regions Yellow/red areas Placebo-induced
decreases predict the magnitude of analgesia SII
and limbic regions
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How predictive of analgesia is anticipatory
activity?

• Network analysis based on Wager et al., 2007 in
  press
• 4 separable networks, 3 independently predictive
  of placebo analgesia R2 0.77

In preparation
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How does frontal activity cause pain relief?

• If placebo effects are demand characteristics,
  frontal activity should be unrelated to
  subcortical systems
• If they affect pain processing, they should
  impact brainstem opioids and related systems
  (Melzack Wall, 1963)

• Opioids and PAG are major target for analgesia
  in humans and animals Adams (1976), Hosobuchi et
  al. (1979), Behbehani et al. (1995)
• Blocking opioids with naloxone reverses
  behavioral placebo effects Benedetti (1999)
  Fields Levine (1981) cf. Gracely et al. (1984)

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PAG is under prefrontal control
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Anticipation of pain Placebo gt Control

• PAG area activated during anticipation in both
  studies (suggests opioid involvement.)
• Activation correlated with DLPFC activation in
  both studies

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Placebo effects in endogenous opioid activity

• Evidence for opioid mechanisms?

Brain activity fMRI
Neurochemistry PET
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Modulation of pain by the opioid system (see
Fields, 2004, Nat. Rev. Neurosci)
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Positron Emission TomographyOpioid binding

• 11-C Carfentinil binding in PET
• Sub-pharmacological dose of Carfentinil competes
  with endogenous opioids
• Decreases in Carfentinil binding indicate
  endogenous opioid system activation

Wager, Scott, Zubieta, 2007, PNAS
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Placebo increases endogenous opioid activity
Opioids released (PET)
Small volume correction (SVC) within each
ROI Omnibus nonparametric test on whether
significant number of ROIs activated
Wager, Scott, Zubieta, 2007, PNAS
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Placebo increases opioid activity
Heatplacebo - Heatcontrol - Warmplacebo -
Warmcontrol
Right
Right
Left
Left
rACC
Amy
mOFC
LOS
Right
Ant.
DLPFC
PAG
LOS
aINS
Amy
lOFC
mOFC
Post.
rACC
Thal
pgACC
aINS
Inset Midbrain detail
aINS
DLPFC
lOFC
Z -11
Left
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Placebo modulation of connectivity
Hypothesis based on Bingel et al., 2006
rACC
PAG
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Does placebo elicit centralized opioid release?

• Opioid binding values are different in different
  areas of the brain.
• Centralized opioid release should increase
  correlations in opioid binding values across many
  regions.

• Test
• Take set of placebo-responsive regions
• Count the of increased correlations with vs.
  without placebo
• Permutation test for inference

PAG
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Placebo increases functional integration

• 36 Pairs with significant increases in
  connectivity with placebo
• 5 pairs with significant decreases
• Permutation test p lt .0001

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Conclusions Effects of placebo

• Reductions in regions that mediate pain
  experience
• Anticipatory increases in frontal cortex and PAG
• Opioid release

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Putting the pieces togetherPlacebo and
affective appraisal systems

• Placebo and meaning-based regulation of emotion
  Common activity in orbital and medial frontal
  cortices, limbic system
• Amygdala specific to emotion regulation
• PAG specific to placebo in pain

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Summary of key brain placebo effects
appraisal
pain affect
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Placebo and appraisal Systems for survival
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Placebo effects on Systems for survival
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PAG is part of a more general system for
regulating emotional behavior
e.g., Bandler Shipley, 1994
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Abler ASL baseline CBF Pos correl with ERQ
suppression
Johnstone 2007
Grimm, correl with valence
Activation of these regions is common to many
affective tasks
Threat-related
Regulation and extinction-related
Urry, correl with cort rel.
Preussner, stress, Responders decrease more in
Stress-Control
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Comparison with normal human emotionsMeta-anal
ysis of emotional experience
163 studies
Question How are medial PFC/OFC, insula and
cingulate regions related to other negative
emotional experiences?
Wager et al., 2008 Kober et al. 2008
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Emotional experience effects in meta-analysis
MPFC/OFC-limbic-PAG appraisal system
Experience gt Perception
Wager et al., 2008, Handbook of Emotion Kober et.
al., 2008, Neuroimage
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Placebo effects on Systems for survival
Threat/Negative
Safety/Positive
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If brain responses to placebo tap into a more
general process of emotional appraisal

• Other kinds of manipulations may affect the same
  systems, with implications for different outcomes

Attention
Perceived control
Conditioning
Emotional priming
Cognitive reappraisal
Drug therapy
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Expectancy Effects of sham treatments
Sham knee surgery Sham Parkinsons

• Sham subthalamic nucleus (STN) stimulation
• STN is current treatment for Parkinsons
• Decreased STN firing, muscle rigidity (Benedetti
  et al., 2004)
• Belief that stimulator was on better predictor of
  clinical relief than whether stimulator was
  actually on (Pollo et al., 2002).

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Conditioning Expectancy-based pain modulation
without placebo treatment
Atlas Wager, in prep
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Figure 6. Pain path analysis
Key brain mediators Medium-temperature
Does expectancy affect the brains response to
pain?
Mediators (Brain)
Which brain regions predict pain ratings?
Atlas Wager
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Conclusions Effects of placebo

• Reductions in regions that mediate pain
  experience
• Anticipatory increases in frontal cortex and PAG
• Opioid release
• Similar to survival systems for emotional
  appraisal
• Links to related expectancy effects in other
  areas
• Pain modulation without placebo administration
• Non-pain (Parkinsons, depression)

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Conclusions Effects of placebo

• Placebo treatments are not inert
• When giving a drug or treatment, not acting on an
  inert system

• New areas of study How do expectations influence
  how, and how well, medical treatments work?

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Thoughts are things
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Thank you!
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Acknowledgements
Ed Smith
Martin Lindquist
Joy Hirsch
Kevin Ochsner
Niall Bolger
Lisa Feldman Barrett
Tom Nichols
Students Lauren Kaplan Lauren Atlas Jason
Buhle Hedy Kober Jared Van Snellenberg
Robin Goldman Crawford Clark
Jon-Kar Zubieta
Dave Scott
Christian Waugh
Barb Fredrickson
Dagfinn Matre
Jim Rilling
Steve Taylor
Funding agencies National Science
Foundation NIMH MBBH
Ken Casey
Doug Noll
Richie Davidson Jonathan Cohen Luis
Hernandez Stephen Kosslyn
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What distinguishes physical pain from emotion,
threat, etc.?

• Differences may be not in which regions are
  involved, but in how they are connected into
  functional network
• Same brain, different network
• Case study Pain empathy
• Physical pain vs. other pain
• Singer, Science, 2004 Both activate anterior
  cingulate and anterior insula
• Lamm Decety, Botvinick, Eisenberger Lieberman

Zaki et al, 2007, Soc. Neuroscience
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Direct comparison of physical pain vs. pain
empathy
Distinct functional connectivity

• Known Anatomical Connections
• (based on prior work)

ACC anterior cingulate AI, anterior insula MI,
mid-insula STS, sup. temporal sulcus
Zaki et al, 2007, Soc. Neuroscience
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Placebo effects on Systems for survival
Endocrine system
Innervation of Organs Cholinergic system (Ach),
Vagus Adrenergic system (NE), sympathetic
Blood, saliva
Biochemical cortisol
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Placebos dont simply dampen noxious inputs

• 1. Placebos selectively reduce pain-related brain
  activity (some areas are increased!)
• 2. Effects on early nociceptive processes exist,
  but are relatively small (Wager et al., 2006
  Colloca et al., 2007)
• 3. Brain activity patterns in placebo studies are
  similar to patterns related to other kinds of
  affective appraisal
• 4. Placebo responses are highly dependent on
  anticipatory brain activity and mediated by
  changes in affective systems

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Brain systems that predict individual differences
in placebo responses

• Multiple brain contributions to placebo analgesia
  during expectancy (anticipation) and experience?
• Re-analysis of fMRI studies (Wager et al., 2004)
• Combined subjects from both studies
  nonparametric analyses on rank orders of brain
  activity and reported placebo analgesia
• 1. Locate multiple networks underlying
  anticipatory brain activity that predict placebo
  analgesia
• 2. Locate activity during peak pain experience
  that mediates placebo analgesic responses

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Anticipatory activity predicting the magnitude of
placebo responses
Anticipation
Placebo analgesia
Pain processing
Blue areas Placebo-induced increases predict the
magnitude of analgesia Fronto-parietal
regions Yellow/red areas Placebo-induced
decreases predict the magnitude of analgesia SII
and limbic regions
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Anticipatory activity predicting the magnitude of
placebo responses Combined sample
Anticipation
Placebo analgesia
Blue areas Placebo-induced increases predict the
magnitude of analgesia Fronto-parietal
regions Yellow/red areas Placebo-induced
decreases predict the magnitude of analgesia SII
and limbic regions
70
How predictive of analgesia is anticipatory
activity?

• Network analysis based on Wager et al., 2007 in
  press
• 4 separable networks, 3 independently predictive
  of placebo analgesia R2 0.77

In preparation
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Are anticipatory changes mediated by changes in
pain processing?
Anticipation
Placebo analgesia
Pain processing
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Are anticipatory changes mediated by changes in
pain processing?
Anticipation
Placebo analgesia
Pain processing
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Are anticipatory changes mediated by changes in
pain processing?
Anticipation
Placebo analgesia
Pain processing
Mediators
Decreases in striatum, posterior cingulate,
insula limbic, rather than pain matrix
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Valence effects anxiety disorders
meta-analysisEtkin Wager, AJP, 2007
Evoked emotion (163 studies)
Placebo
MPFC, OFC
Anterior insula
Amygdala
Anticipation only
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Study 2 Placebo effects in laser-evoked
potentials

• Evidence for placebo modulation of early
  nociceptive processes?

Early sensory effects ERP
Brain activity fMRI
Neurochemistry PET
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Study 2 Laser-Evoked Potentials (LEPs)

• Test for early decreases in pain processing
• Fast, early responses not susceptible to
  retrospective reporting biases (Posner Keele,
  1971)

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P2 is sensitive to laser intensity and pain
Preliminary study, n 10
N2
P2
Extract individual P2 peak amplitudes and
latencies analyze for Placebo effects,
controlling for order of administration
Perceived Pain
Laser intensity (mJ)
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Placebo reduces P2 evoked potentials (n 24)
Cz
P2
FCz
FCz
Run 1 t(21) 2.37, p .013 Placebo x Run
t(21) 1.75 (F 3.06), p .047

• Significant reduction
• Could reflect early spinal inhibition, or
  reduced anxiety / attentional capture under
  placebo similar to P3a (Garcia-Larrea et al.,
  2003 Dowman, 2001)

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LEP reduction not sufficient to account for
reported placebo effects

• P2 LEP placebo habituates, but reported pain
  does not
• (LEP habituation is common feature in pain
  experiments)
• Suggests that early inhibition cannot explain
  all observed effects on reported pain

Reported Pain
FCz
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Testing the input blockade (gate control)
hypothesis
Spinothalamic
Spinolimbic

• P2 reductions are significant
• But also significantly smaller than expected if
  early nociceptive blockade were the only
  mechanism
• Conclusion Smaller spinal and larger central
  evaluative components

SI
DLPFC
SII
APFC
Thal
AINS
PAG
PBN
Pons
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Why study pain?

• Pain is highly relevant for human happiness and
  productivity clinically relevant
• Probe for fundamental affective responses Old
  system connected to homeostatic regulatory
  systems
• Relatively precise control over stimulus
• Long history of modulation by placebo and other
  context effects (Benedetti, Bushnell, Lorenz,
  Fields, Gracely, Marchand, Price, Voudouris,
  Zubieta, others)
• Specific hypotheses about brain pathways from
  history of pain research

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• Disease is an experience of a so-called mortal
  mind. It is fear made manifest on the body.
• Health is not a condition of matter, but of Mind
• Mary Baker Eddy, 1821 - 1910
• Founder, Christian Science

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Thoughts are things
voodoo death may be real, and that it may be
explained as due to shocking emotional stress
Cannon, W., B. (1957). 'Voodoo' Death.
Psychosomatic Medicine, 19(3), 182-190
Sternberg, E.M. Walter B. Cannon and "voodoo
death" A perspective from 60 years on. American
Journal of Public Health. Vol 92(10) Oct 2002,
1564-1566
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20 April 2004 - SYDNEY (Reuters) - Aborigines
have invoked an ancient curse on Australian Prime
Minister John Howard by "pointing the bone" at
the conservative politician Aborigine Geoff
Clark told reporters, "Mr Howard can refuse to
ignore the message at his own peril and be put
under a curse up until the next federal election."
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Placebos dont simply dampen noxious inputs

• 1. Placebos selectively reduce pain-related brain
  activity (some areas are increased!)
• 2. Effects on early nociceptive processes exist,
  but are relatively small (Wager et al., 2006
  Colloca et al., 2007)
• 3. Brain activity patterns in placebo studies are
  similar to patterns related to other kinds of
  affective appraisal
• 4. Placebo responses are highly dependent on
  anticipatory brain activity and mediated by
  changes in affective systems