Imaging Biomarkers for Assessment

of the Placebo Response

Ariana E. Anderson, Ph.D.

Assistant Professor

University of California, Los Angeles

Disclosures In the past 12 months, I’ve received research support and/or consulting income from ZZ

Biotech, NeuroAI, and BlackThorn Therapeutics.

Overview Placebo response/effect:

Definitions

Differentiation

Placebo response observed in

Pain

Depression

Parkinson’s Disease

New work: Measuring placebo

response using fMRI

Conclusions

Placebo Controlled Trials

Placebo Response“An improvement in symptoms caused in part by a set of mind-brain

processes.”

Temporal-Statistical Effects

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0 25 50 75 100

Time

Outc

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ea

su

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Group Drug Intervention No Treatment Placebo Intervention

Treatment Response over Time

Placebo Effect

Drug Effect

Placebo Response

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)

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90

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100

0 25 50 75 100

Time

Ou

tco

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easure

Group No Treatment

Treatment Response over Time

Temporal-Statistical Effects

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

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0 25 50 75 100

Time

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Group No Treatment Placebo Intervention

Treatment Response over Time

Temporal-Statistical Effects

Placebo Effect

Placebo Mechanisms

Pain and the Placebo

Benedetti, Fabrizio, et al. "Neurobiological mechanisms of the placebo

effect." Journal of Neuroscience 25.45 (2005): 10390-10402.

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.

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.

fMRI Predicting Analgesia Placebo

Responders

Tétreault, Pascal, et al. "Brain connectivity predicts placebo response

across chronic pain clinical trials." PLoS biology14.10 (2016): e1002570.

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.

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.

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.

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.

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

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?

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.

fMRI

INDEPENDENT

COMPONENTS ANALYSIS

(ICA)

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.

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.

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.

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

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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.

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.

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