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Imaging Biomarkers for Assessment
of the Placebo Response
Ariana E. Anderson, Ph.D.
Assistant Professor
University of California, Los Angeles
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Disclosures In the past 12 months, I’ve received research support and/or consulting income from ZZ
Biotech, NeuroAI, and BlackThorn Therapeutics.
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Overview Placebo response/effect:
Definitions
Differentiation
Placebo response observed in
Pain
Depression
Parkinson’s Disease
New work: Measuring placebo
response using fMRI
Conclusions
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Placebo Controlled Trials
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Placebo Response“An improvement in symptoms caused in part by a set of mind-brain
processes.”
Temporal-Statistical Effects
60
70
80
90
100
0 25 50 75 100
Time
Outc
om
e M
ea
su
re
Group Drug Intervention No Treatment Placebo Intervention
Treatment Response over Time
Placebo Effect
Drug Effect
Placebo Response
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Temporal/Statistical Effects: spontaneous, endogenous improvement
sampling bias, regression to the mean
natural symptom fluctuation (e.g., patients may enroll
in trials when symptoms are at their worst and
subsequently improve)
80
85
90
95
100
0 25 50 75 100
Time
Ou
tco
me M
easure
Group No Treatment
Treatment Response over Time
Temporal-Statistical Effects
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Placebo Effect “The placebo effect is a psychobiological phenomenon that
can be attributable to different mechanisms, including
expectation of clinical improvement and Pavlovian
conditioning.” Benedetti et al., 2005
70
80
90
100
0 25 50 75 100
Time
Ou
tco
me M
easure
Group No Treatment Placebo Intervention
Treatment Response over Time
Temporal-Statistical Effects
Placebo Effect
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Placebo Mechanisms
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Pain and the Placebo
Benedetti, Fabrizio, et al. "Neurobiological mechanisms of the placebo
effect." Journal of Neuroscience 25.45 (2005): 10390-10402.
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Placebo Conditioning
Conditioning Phase Testing Phase
Opioid Group Morphine IV Saline + Naloxone
NSAID Group Ketorolac IV Saline + Naloxone
Amanzio, Martina, and Fabrizio Benedetti. "Neuropharmacological
dissection of placebo analgesia: expectation-activated opioid systems
versus conditioning-activated specific subsystems." Journal of Neuroscience
19.1 (1999): 484-494.
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Placebo Expectations
Wager, Tor D., et al. "Placebo-induced changes in FMRI in the anticipation
and experience of pain." Science 303.5661 (2004): 1162-1167.
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fMRI Predicting Analgesia Placebo
Responders
Tétreault, Pascal, et al. "Brain connectivity predicts placebo response
across chronic pain clinical trials." PLoS biology14.10 (2016): e1002570.
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fMRI Depression: Duloxetine
Default Mode Network
Task Positive Network
van Wingen, Guido A., et al. "Short-term antidepressant administration
reduces default mode and task-positive network connectivity in healthy
individuals during rest." Neuroimage 88 (2014): 47-53.
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fMRI Depression:
Citalopram and Reboxetine
Amygadala seed: (C vs Pl)
Amygdala seed: (R vs Pl)
McCabe, Ciara, and Zevic Mishor. "Antidepressant medications reduce
subcortical–cortical resting-state functional connectivity in healthy
volunteers." Neuroimage57.4 (2011): 1317-1323.
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Parkinsons’ Mechanisms
Benedetti, Fabrizio, et al. "Placebo-responsive Parkinson patients show
decreased activity in single neurons of subthalamic nucleus." Nature
neuroscience 7.6 (2004): 587.
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Parkinsons’ PET Imaging
De la Fuente-Fernández, Raúl, et al. "Expectation and dopamine release:
mechanism of the placebo effect in Parkinson's disease." Science
293.5532 (2001): 1164-1166.
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Endogenous Dopamine in
PD PET Imaging
Lidstone, Sarah C., et al. "Effects of expectation on placebo-induced dopamine
release in Parkinson disease." Archives of general psychiatry 67.8 (2010): 857-865.
Putamen
Ventral Striatum
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Measuring the Placebo
using fMRITreatment Responses
Effect CBTGroup ActivePillGroup PlaceboPillGroup
DrugEffect
CBTEffectGeneralizedPlaceboResponse:Regressiontothemean,
SpontaneousImprovement,PositiveExpectations
PillPlaceboEffect:Uncertainty
Smoking cession study: bupropion, placebo, CBT
Use fMRI to measure treatment effects:
Generalized Placebo Response: temporal/statistical effects
Pill Placebo Effect: Effects from receiving a blinded pill
CBT Effect
Drug Effect
Can fMRI measure placebo within drug and CBT group?
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Experimental Design
Blinded
placebo pill
Blinded drug
pill (buproprion)
CBT
N=19
N=14
N=18
fMRIScan123 456
SmokingLevelsPost-treatment8weekstreatment
Post-treatmentfMRIPre-treatmentfMRITreatmentGroup
Step 1:
Train model to measure post-
treatment fMRI network changes
Step 2:
Validate by
predicting
addiction
Anderson et al., (2018) fMRI Measurement of the Neural Placebo Response within Subjects Receiving Active Medications and Cognitive Behavioral Therapy. Under review.
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fMRI
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INDEPENDENT
COMPONENTS ANALYSIS
(ICA)
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Independent Component Analysis
(ICA) ICA: Y=DX, D=time series weights
Estimation in fMRI usually by maximizing negentropy (FAST-ICA) or
minimizing mutual information (INFOMAX)
Independence is assumed on the voxel level- p(x1,x2,..xk) =
p(x1)p(x2)…p(xk)
This necessarily assumes that the ability of a voxel to contribute to
any network is not affected by its contribution to any other networks.
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Placebo Brain Changes
Dorsal
Attention
Network Changes with Placebo
Ventral
Attention
Sensorimotor
Generalized / Pill
Placebo Effect
Pill
Placebo Effect
Generalized / Pill
Placebo Effect
Anderson et al., (2018) fMRI Measurement of the Neural Placebo Response within Subjects Receiving Active Medications and Cognitive Behavioral Therapy. Under review.
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Is CBT a Placebo?
Auditory
Network Changes with CBT
Default Mode AttentionalVisual
Anderson et al., (2018) fMRI Measurement of the Neural Placebo Response within Subjects Receiving Active Medications and Cognitive Behavioral Therapy. Under review.
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fMRI-measured
Treatment Effects
-0.5
0.0
0.5
Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group
fMR
I-mea
sure
d ch
ange
s fro
m re
ceiv
ing
a bl
inde
d pi
ll (e
ither
act
ive
or in
ert)
Pill Placebo Effect by Intervention
-3
-2
-1
0
1
2
Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group
fMR
I mea
sure
d ch
ange
s fro
m re
ceiv
ing
CB
T
CBT Effect by Intervention
-1
0
1
Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group
Group
fMR
I-mea
sure
d ch
ange
s fro
m re
ceiv
ing
bupr
opio
n in
a b
linde
d m
anne
r
Drug Effect by Intervention
Forconventionally-cleaned20-networkdata
-0.2
0.0
0.2
0.4
Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group
fMR
I-mea
sure
d ch
ange
s fro
m re
ceiv
ing
any
inte
rven
tion
(CB
T or
a p
ill)
Generalized Placebo Response by Intervention
Effect CBTIntervention ActivePillIntervention PlaceboPillIntervention
DrugEffect
CBT
GeneralizedPlaceboResponse:Regressiontothemean,SpontaneousImprovement,PositiveExpectations
PillPlaceboResponse:Uncertainty
fMRI measured changes significantly increased ability to predict treatment response.
Anderson et al., (2018) fMRI Measurement of the Neural Placebo Response within Subjects Receiving Active Medications and Cognitive Behavioral Therapy. Under review.
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Conclusions: Brain imaging can
Predict placebo responders
Identify placebo group response patterns
Measure placebo response within subjects receiving medications
Phase 1 (n of 1 studies, rare diseases): brain imaging can separate drug effects from placebo responses.
Placebo response may mimic effective treatments.
Brain imaging can localize, predict, and measure placebo response.
fMRI placebo changes are sensitive to conditioning, disorder, and stimulus.
Most studies using fMRI may not translate well clinically.
EEG would be ideal for such biophysical measurements given its cost and availability.
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Acknowledgements Co-authors: Pamela K. Douglas, Arthur Brody, Tor Wager
Sponsors: NIH and Burroughs Wellcome Fund
ISCTM Program Committee
UCLA colleagues: Robert Bilder, Steven Marder, Mirella Diaz-Santos,
Catherine Hagerty