Throughout history, placebo effects have been variously considered as tricks played upon the gullible by medical practitioners and powerful but mysterious healing forces. With the advent of direct measurements of human brain function, modern science has shown that placebo effects are neither of these. Rather, they reflect the principled impact of psychological and brain processes on diseases of the brain and body. Placebo effects represent an opportunity-because they provide a window into internal brain processes that influence health- and a challenge, because dozens of clinical trials have now failed to show the superiority of commonly prescribed drugs to placebo, at great cost to health care providers and consumers. This may not be due to the ineffectiveness of the medications, but rather seems to be related to high placebo response rates. Studies of the brain mechanisms underlying placebo effects can provide valuable insight into how the brain actively anticipates, responds to, and learns about active treatments, and the effects of these processes on pain and other aspects of health. In the previous period of this grant, functional magnetic resonance imaging (fMRI) of placebo and opiate drug effects was instrumental in establishing that placebo treatments impact the neurobiology of pain, including effects on the cortical and subcortical brain regions most closely associated with pain experience. The research also provided some of the first evidence on the interactions in the brain that give rise to placebo effects, and demonstrated the involvement of prefrontal cortical-subcortical-brainstem systems and the endogenous opioid system. The view that emerged is that placebo treatments engage brain systems related to both conceptual thought (explicit beliefs) and learning processes that change the value assigned to treatment cues and pain itself. In this Renewal application, we build on this foundation to address some of the many unanswered questions that need to be addressed before placebo effects are understood, harnessed in therapy, and separated cleanly from drug effects in clinical trials and practice. These include fundamental questions about a) the nature of the "pain-related" processes regulated by placebos (are they specific to pain, or general affective processes?) and b) the critical conditions required to create placebo analgesia. Our working hypothesis is that conceptual and learning processes interact, and that both are critical. Learning systems fundamentally shape the motivational value of pain and modulate nociception in subcortical-brainstem systems, and conceptual processes are needed to attribute perceived benefits to the placebo treatment and engage learning. To better understand these systems, we bring to bear new computational machine-learning tools that can identify and test placebo effects on patterns of brain activity specific to pain. We also test the involvement of several neurochemical systems-opioids, dopamine, and oxytocin-and their relationships with specific brain and psychological aspects of the placebo response-generation process.

Public Health Relevance

Though placebo treatments are pharmacologically inert, placebo responses are active neurobiological processes related to the meaning of the treatment and what has been learned about it. Studying them provides a way of understanding the roles of emotion and learning in clinical treatment effects. This project studies the brain mechanisms that underlie placebo analgesia from a multidisciplinary, neural systems-oriented view. It integrates new advances in functional neuroimaging with manipulations of placebo treatment, pharmacology, and hormones to address several fundamental questions about a) the nature of brain processes influenced by placebo treatment, and b) the critical factors underlying the genesis of robust physiological placebo effects.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
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Meinecke, Douglas L
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Schmidt, Liane; Braun, Erin Kendall; Wager, Tor D et al. (2014) Mind matters: placebo enhances reward learning in Parkinson's disease. Nat Neurosci 17:1793-7
Roy, Mathieu; Shohamy, Daphna; Daw, Nathaniel et al. (2014) Representation of aversive prediction errors in the human periaqueductal gray. Nat Neurosci 17:1607-12
Atlas, Lauren Y; Lindquist, Martin A; Bolger, Niall et al. (2014) Brain mediators of the effects of noxious heat on pain. Pain 155:1632-48
Woo, Choong-Wan; Koban, Leonie; Kross, Ethan et al. (2014) Separate neural representations for physical pain and social rejection. Nat Commun 5:5380
Schambra, H M; Bikson, M; Wager, T D et al. (2014) It's all in your head: reinforcing the placebo response with tDCS. Brain Stimul 7:623-4
Wager, Tor D; Spicer, Julie; Insler, Rachel et al. (2014) The neural bases of distracter-resistant working memory. Cogn Affect Behav Neurosci 14:90-105
Atlas, Lauren Y; Wielgosz, Joseph; Whittington, Robert A et al. (2014) Specifying the non-specific factors underlying opioid analgesia: expectancy, attention, and affect. Psychopharmacology (Berl) 231:813-23
Woo, Choong-Wan; Krishnan, Anjali; Wager, Tor D (2014) Cluster-extent based thresholding in fMRI analyses: pitfalls and recommendations. Neuroimage 91:412-9
Jepma, Marieke; Jones, Matt; Wager, Tor D (2014) The dynamics of pain: evidence for simultaneous site-specific habituation and site-nonspecific sensitization in thermal pain. J Pain 15:734-46
Satpute, Ajay B; Wager, Tor D; Cohen-Adad, Julien et al. (2013) Identification of discrete functional subregions of the human periaqueductal gray. Proc Natl Acad Sci U S A 110:17101-6

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