Imaging Biomarkers for Assessment of the Placebo Response Ariana E. - - PowerPoint PPT Presentation
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, Ive received research support and/or consulting income from
Ariana E. Anderson, Ph.D. Assistant Professor University of California, Los Angeles
In the past 12 months, I’ve received research support and/or consulting income from ZZ
Biotech, NeuroAI, and BlackThorn Therapeutics.
Placebo response/effect:
Definitions Differentiation
Placebo response observed in
Pain Depression Parkinson’s Disease
New work: Measuring placebo
response using fMRI
Conclusions
“An improvement in symptoms caused in part by a set of mind-brain processes.”
Temporal-Statistical Effects
60 70 80 90 100 25 50 75 100 Time Outcome Measure Group Drug Intervention No Treatment Placebo InterventionTreatment Response over Time
Placebo Effect Drug Effect Placebo Response
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 25 50 75 100 Time Outcome Measure Group No TreatmentTreatment Response over Time
Temporal-Statistical Effects
“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 25 50 75 100 Time Outcome Measure Group No Treatment Placebo InterventionTreatment Response over Time
Temporal-Statistical Effects Placebo Effect
Benedetti, Fabrizio, et al. "Neurobiological mechanisms of the placebo effect." Journal of Neuroscience 25.45 (2005): 10390-10402.
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.
Wager, Tor D., et al. "Placebo-induced changes in FMRI in the anticipation and experience of pain." Science 303.5661 (2004): 1162-1167.
Tétreault, Pascal, et al. "Brain connectivity predicts placebo response across chronic pain clinical trials." PLoS biology14.10 (2016): e1002570.
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.
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.
Benedetti, Fabrizio, et al. "Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus." Nature neuroscience 7.6 (2004): 587.
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.
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
Treatment Responses
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?
Blinded placebo pill Blinded drug pill (buproprion) CBT
N = 19 N = 14 N = 18 fMRI Scan 1
4
Smoking Levels Post-treatment 8 weeks treatment Post-treatment fMRI Pre-treatment fMRI Treatment Group
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.
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.
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.
Auditory
Network Changes with CBT
Default Mode Attentional Visual
Anderson et al., (2018) fMRI Measurement of the Neural Placebo Response within Subjects Receiving Active Medications and Cognitive Behavioral Therapy. Under review.
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.
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.
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