Expectations, Beliefs and the origins of the Placebo effect. The Brain and Reality. The Brain and Reality. Input Signals

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1 Expectations, Beliefs and the origins of the Placebo effect René Descartes Input Signals Knowledge Goals Expectation Salvador Dalí Prof. Richard Gregory, University of Bristol 1

2 Placebo effect Placebo effect Same underlying mechanism? Expectations The opioidsystem and placebo analgesia Opioid analgesia Placebo analgesia - - Naloxon (opioid-receptorblocker) Frida Kahlo Levine et al The Lancet 2 ( )

3 Treatment Expectation and Placebo Analgesia Pain control Pain Placebo Pain Difference Pain presentation Expectation manipulation and learning Placebo manipulation Placebo cream Placebo cream Rating: 75 Rating: 25 Rating: 50 Verbally induced expectations AND implicit expectations induced by conditioning Voundouris et al J Per Soc Psychol 48 (47-53) 1985 Voundouris et al pain 38 ( ) 1989 Voundouris et al pain 43 ( ) 1990 Montgomery and Kirsch Pain 72 ( ) 1997 Price et al Pain 127 (63-72) 2007 Anterior cingulate cortex - Opioid and Placebo effect Orbitofrontal cortex - Placebo effect (POP+WOP)-(P+W) (PPL P) (PPL P) Petrovic et al Science 295 ( ) 2002 Petrovic et al Science 295 ( ) 2003 Vincent van Gogh 3

4 Study of Emotional Placebo Day 1 Day 2 Study of Emotional Placebo Day 1 expectation modulation Bezodiazepin i.v. Lanexat i.v. IAPS IAPS IAPS International Affective Picture System (IAPS) Petrovic et al Neuron 46, ( ) 2005 Anxiety reducing drug (benzdiazepine) Placebo (saline) 51 Petrovic et al Neuron 46, ( ) Unpleasantness rating 61 Study of Emotional Placebo Day 2 The brain and the placebo effect Information: Lanexat (No anxiety reduction) IAPS Information: Bezodiazepins (Anxiety reduction) IAPS x3 Study of Emotional Placebo Decreased emotional processing in placbo condition Unpleasantness processing Placebo decrease in unpleasantness Placebo dependent inceased activity Petrovic et al Neuron 46, ( ) 2005 Unpleasantness rating Petrovic et al Neuron 46, ( ) 2005 Opioid- and Placebo analgesia Rostral anterior cingulate cortex (POP+WOP)-(P+W) (PPL P) Petrovic et al Science 295 ( )

5 Cortical opioid system Anterior cingulate cortex Petrovic et al Science 295 ( ) 2003 Willoch et al 1999 Opioid receptor imaging of Placebo Analgesia POP PPL P Naloxone Zubieta et al Journal of Neuroscience, 25 ( ) 2005 Regression analysis Filelds et al Nature Reviews Neuroscience 2004 Petrovic et al Science 295 ( ) 2002 Eippert et al Neuron 63 (533) 2009 Anterior Cingulate and Attention Emotional Stroop Task Congruent Incongruent racc in placebo analgesia: Interaction between attentional processes and opioid system Bush et al Journal of Neuroscience, 4 ( ) 2000 Etkin et al Neuron 21 ( )

6 Orbitofrontal cortex Orbitofrontal cortex (PPL P) Petrovic et al Science 295 ( ) 2003 Placebo analgesia vs. opioid analgesia Motivational and homeostatic goals in Obfc Petrovic et al Pain 150 (59-65) 2010 Schoenbaum Neuron 47 ( ) 2005 Expected reward and Obfc Aversive error-signal Reward expectation Reward Tremblay and Schultz Progress in brain research 126 ( ) 2000 Seymour et al Nature Neuroscience 8 ( )

7 Orbitofrontal cortex in placebo analgesia: Cognitive processes including emotional goals, expectations, emotional tracking and aversive error signals. racc-roi used in the PPI correlation Why do we have the placebo effect? Placebo analgesia (PET-study) Emotional placebo (fmri-study) Hypothesis: The placebo effect is just a concequence of a system trying to understand and predict the world. Petrovic et al Pain 150 (59-65) 2010 To understand the world - through expectation and error-signals To understand the world - through expectation and error-signals Treatment expectation Errorsignal Nociceptive signal - - Treatment expectation Errorsignal Nociceptive signal - Orbitofrontal cortex - Minimizing error + Top-down regulation Minimizing error + Top-down regulation Anterior cingulate cortex 7

8 Placebo and Expectations High hierarchy (concious manifestation) Augmentation (eg nocebo hyperalgesia) Internal signals (eg pain, emotion, depression) External signals (eg visual and auditory stimuli) Internal signals Supression (eg placebo analgesia) Low hierarchy (non-conscious manifestations) Nocebo Hyperalgesia and the CCK-system Placebo analgesia and the opioid system Nocebo Hyperalgesia Placebo (habituation) Nocebo (habituation) Nocebo Benedetti et al Journal of Neuroscience 26 ( ) 2006 Colloca et In progress Konge et al Journal of Neuroscience 28 ( ) 2010 Placebo and Expectations High hierarchy (concious manifestation) Augmentation (eg nocebo hyperalgesia) Internal signals (eg pain, emotion, depression) External signals (eg visual and auditory stimuli) Internal signals External signals Supression (eg placebo analgesia) Low hierarchy (non-conscious manifestations) 8

9 Magic glasses Sterzer, Frith and Petrovic Current Biology 18 (697-8) 2008 Complex associative learning - Expectations and error-signals Turner et al Cerebral Cortex 14( ) 2004 Schizophrenia and expectations / error signals Placebo and Expectations High hierarchy (concious manifestation) Augmentation (eg nocebo hyperalgesia) Internal signals (eg pain, emotion, depression) External signals (eg visual and auditory stimuli) Corlett et al Brain 130 ( ) 2007 Supression (eg placebo analgesia) Low hierarchy (non-conscious manifestations) 9

10 Placebo and Conditioning effects Amanzio et al Journal of Neuroscience 19 ( ) 1999 Placebo and Conditioning effects Placebo and Conditioning effects Benedetti et al Journal of Neuroscience 23 ( ) 2003 Benedetti et al Journal of Neuroscience 23 ( ) 2003 Consciousness vs. Non-consciousness Dehaenne et al TICS 10 ( ) 2006 Friston Nature Reviews Neuroscience 11 ( )

11 De La Fuente-Fenandez and Stessel TINS 25 ( ) 2002 Pollo and Benedetti Progress in Brain Research 175 ( ) 2009 Midbrain dopamine system Placebo och Amphetamine Amphetamine Placebo Reward processing, expectations and errrosignaling. Boileau al Journal of Neuroscience 27 ( ) 2007 Opiod and Dopamine involement in placebo analgeisa Placebo and Expectations High hierarchy (concious manifestation) Augmentation (eg nocebo hyperalgesia) Internal signals (eg pain, emotion, depression) External signals (eg visual and auditory stimuli) Scott al Arch Gen Psychiatry 65 ( ) 2008 Supression (eg placebo analgesia) Low hierarchy (non-conscious manifestations) 11

12 Placebo analgesia Opioid system Emotional placebo Serotonin system? Expectation of stability in the external world Expectations Dopaminesystem Expectation Errorsignal External signal - - Minimizing error + Top-down regulation PD placebo Hjärnan och Verkligheten Inattentional blindness Johansson et al Science 310 ( ) 2005 Simons et al Psychonomic Bulletin and Review 5 ( ) 1998 Simons et al Psychonomic Bulletin and Review 5 ( )