title: Neurobiology of placebo effects: expectations or learning?
abstract: Contemporary learning theories suggest that conditioning is heavily dependent on the processing of prediction errors, which signal a discrepancy between expected and observed outcomes. This line of research provides a framework through which classical theories of placebo effects, expectations and conditioning, can be reconciled. Brain regions related to prediction error processing [anterior cingulate cortex (ACC), orbitofrontal cortex or the nucleus accumbens] overlap with those involved in placebo effects. Here we examined the possibility that the magnitude of objective neurochemical responses to placebo administration would depend on individual expectation-effectiveness comparisons. We show that such comparisons and not expectations per se predict behavioral placebo responses and placebo-induced activation of µ-opioid receptor-mediated neurotransmission in regions relevant to error detection (e.g. ACC). Expectations on the other hand were associated with greater µ-opioid system activation in the dorsolateral prefrontal cortex but not with greater behavioral placebo responses. The results presented aid the elucidation of molecular and neural mechanisms underlying the relationship between expectation-effectiveness associations and the formation of placebo responses, shedding light on the individual differences in learning and decision making. Expectation and outcome comparisons emerge as a cognitive mechanism that beyond reward associations appears to facilitate the formation and sustainability of placebo responses.
authors.affiliation: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute and Department of Radiology, Medical School, University of Michigan, Ann Arbor, MI, USA, and School of Dentistry, University of Maryland, Baltimore, MD, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Peciña
authors.affiliation: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute and Department of Radiology, Medical School, University of Michigan, Ann Arbor, MI, USA, and School of Dentistry, University of Maryland, Baltimore, MD, USA.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Stohler
authors.affiliation: Department of Psychiatry, Molecular and Behavioral Neuroscience Institute and Department of Radiology, Medical School, University of Michigan, Ann Arbor, MI, USA, and School of Dentistry, University of Maryland, Baltimore, MD, USADepartment of Psychiatry, Molecular and Behavioral Neuroscience Institute and Department of Radiology, Medical School, University of Michigan, Ann Arbor, MI, USA, and School of Dentistry, University of Maryland, Baltimore, MD, USADepartment of Psychiatry, Molecular and Behavioral Neuroscience Institute and Department of Radiology, Medical School, University of Michigan, Ann Arbor, MI, USA, and School of Dentistry, University of Maryland, Baltimore, MD, USA zubieta@umich.edu.
authors.forename: Jon-Kar
authors.initials: JK
authors.lastname: Zubieta
mesh_terms: D000328:Adult; D059031:Anticipation, Psychological / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007858:Learning / Q000502:physiology*; D008297:Male; D010146:Pain / Q000503:physiopathology*; D010812:Physical Stimulation; D015990:Placebo Effect; D049268:Positron-Emission Tomography; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012462:Saline Solution, Hypertonic; D055815:Young Adult
chemical_list: D017450:Receptors, Opioid, mu; D012462:Saline Solution, Hypertonic
keywords: expectations; placebo analgesia; prediction error signal and learning; µ-opioid receptor