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, 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.” Treatment Response over Time 100 Temporal-Statistical Effects 90 Placebo Response Outcome Measure 80 Placebo Effect 70 Drug Effect 60 0 25 50 75 100 Time Group Drug Intervention No Treatment Placebo Intervention

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) Treatment Response over Time 100 95 Outcome Measure Temporal-Statistical Effects 90 85 80 0 25 50 75 100 Time Group No Treatment

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 Treatment Response over Time 100 Temporal-Statistical Effects 90 Outcome Measure 80 Placebo Effect 70 0 25 50 75 100 Time Group No Treatment Placebo Intervention

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 biology 14.10 (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 Putamen Ventral Striatum 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.

Measuring the Placebo using fMRI  Smoking cession study: Treatment Responses 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 Pre-treatment� fMRI Post-treatment� fMRI Smoking� Levels� Post-treatment Treatment� Group 8� weeks� treatment fMRI� Scan� 1� � � � � � � � � � � 2� � � � � � � � � � � 3 4� � � � � � � � � � � 5� � � � � � � � � � 6 Blinded placebo pill N� =� 19 Blinded drug pill (buproprion) N� =� 14 CBT N� =� 18 Step 1: Step 2: Train model to measure post- Validate by treatment fMRI network changes 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

I NDEPENDENT C OMPONENTS A NALYSIS (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 Network Changes with Placebo Generalized / Pill Generalized / Pill Pill Placebo Effect Placebo Effect Placebo Effect Ventral Sensorimotor Dorsal Attention Attention 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? Network Changes with CBT Auditory Attentional Default Mode 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 Treatment Effects fMRI measured changes significantly increased ability to predict treatment response. Generalized Placebo Response by Intervention Pill Placebo Effect by Intervention fMRI-measured changes from receiving a blinded pill (either active or inert) fMRI-measured changes from receiving any intervention (CBT or a pill) 0.4 0.5 0.2 0.0 0.0 -0.5 -0.2 Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group CBT Effect by Intervention Drug Effect by Intervention 2 fMRI-measured changes from receiving bupropion in a blinded manner 1 1 fMRI measured changes from receiving CBT 0 0 -1 -2 -1 -3 Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group Cognitive Behavioral Therapy Active Pill Group Placebo Pill Group Group 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