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Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kunkel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Positive and negative treatment expectations are powerful modulators of health and treatment outcomes. A substantial part of treatment success is due to contextual factors modulating patient's expectations towards a treatment. Consequently, treatment expectations should be a target of therapeutic interventions themselves., Objectives: This article highlights the neurobiological underpinnings of treatment expectations as well as strategies to modulate contextual factors to optimize treatment outcomes in daily clinical settings., Methods: This clinical update aligns with the 2022 IASP Global Year Translating Pain Knowledge into Practice and selectively reviews the best available evidence and practice., Results: The effects of treatment expectations, also known as placebo and nocebo effects, are observed in various clinical conditions and physiological systems. However, most of our knowledge comes from the field of pain, where expectation effects substantially contribute to overall analgesic treatment outcomes. Experimental placebo analgesia paradigms provide the best illustration of how analgesic effects can be attributed not only to a pharmacological or specific treatment, but instead are the result of the expectation towards the treatment. The impact of expectations on treatment outcome is highly variable between individuals, and the identification of factors predicting an individual's response has proven to be challenging. Further research is required to provide personalized treatment strategies for the daily clinical practice., Conclusion: Patient's previous experiences and expectations are powerful modulators of treatment efficacy, tolerability, and adherence. By providing a comprehensive overview of recent advances in this field, this review offers valuable insights for clinicians and researchers seeking to improve patient-clinician interaction., Competing Interests: The authors have no conflict of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: Patients' expectations toward any given treatment are highly important for the effectiveness of such treatment, as has been demonstrated for several disorders. In particular, in major depressive disorder (MDD), one of the most frequent and most serious mental disorders with severe consequences for the affected, the augmentation of available treatment options could mean a ground-breaking success. Repetitive transcranial magnetic stimulation (rTMS), a new, non-invasive, and well-tolerated intervention with proven effects in the treatment of MDD, appears particularly suitable in this context as it is assumed to exert its effect via structures implicated in networks relevant for both expectation and depression., Methods: All patients will receive rTMS according to its approval. Half of the patients will be randomized to a psychological intervention, which is a comprehensive medical consultation aiming to improve positive treatment expectations; the control group will receive a conventional informed consent discussion (in the sense of a treatment-as-usual condition). As outcome parameters, instruments for both self-assessment and external assessment of depression symptoms will be applied. Furthermore, psycho-immunological parameters such as inflammation markers and the cortisol awakening response in saliva will be investigated. Resting-state functional magnetic resonance imaging (rs fMRI) will be performed to analyze functional connectivity, including the cerebellum, and to identify neuronal predictors of expectation effects. In addition, possible cerebellar involvement will be assessed based on a cerebellar-dependent motor learning paradigm (i.e., eyeblink conditioning)., Discussion: In this study, the effects of treatment expectations towards rTMS are investigated in patients with MDD. The aim of this study is to identify the mechanisms underlying the expectation effects and, beyond that, to expand the potential of non-invasive and well-tolerated treatments of MDD., Trial Registration: German Registry of Clinical Studies (DRKS DRKS00028017. Registered on 2022/03/07. URL: https://www.drks.de/drks_web/ ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Expectations of patients influence the perception and neuronal processing of acute and chronic pain and modulate the effectiveness of analgesic treatment. The expectation of treatment is not only the most important determinant of placebo analgesia. Expectations of treatment also influence the efficacy and tolerability of "active" pharmacological and non-pharmacological treatment of pain. Recent insights into the psychological and neurobiological mechanisms underlying the clinically relevant effects of treatment expectations enable and call for the systematic integration and modulation of treatment expectations into analgesic treatment concepts. Such a strategy promises to optimize analgesic treatment and to prevent or reduce the burden of unwanted side effects and the misuse of analgesics, particularly of opioids. This review highlights the current concepts, recent achievements and also challenges and key open research questions., (© 2023. The Author(s).)

Background: The efficacy of pain therapies can be substantially modulated by treatment expectations, which is reflected by the substantial placebo effects observed in pain (so called placebo analgesia)., Question: What is currently known about the neurobiological and neurochemical mechanisms underlying placebo analgesia?, Materials and Methods: A focused presentation of key publications in the field embedded in a structured overview of the mechanistic concepts and current theories according to recent evidence., Results: Experimental studies with functional neuroimaging showed that the effect of placebo analgesia is reflected by changes in brain activity related to pain processing and cognitive control. The important neurotransmitters involved include opioids and dopamine., Conclusion: Placebo analgesia is associated with complex neurobiological and -physiological mechanisms. An advanced comprehension of these processes should be applied to optimize existing and future therapeutic approaches in pain therapy., (© 2022. The Author(s).)

Recently, we showed that when participants passively read about moral transgressions (e.g., adultery), they implicitly engage in the evaluative (good-bad) categorization of incoming information, as indicated by a larger event-related brain potential (ERP) positivity to immoral than to moral scenarios (Leuthold, Kunkel, Mackenzie, & Filik in Social, Cognitive, and Affective Neuroscience, 10, 1021-1029, 2015). Behavioral and neuroimaging studies indicated that explicit moral tasks prioritize the semantic-cognitive analysis of incoming information but that implicit tasks, as used in Leuthold et al. (Social, Cognitive, and Affective Neuroscience, 10, 1021-1029, 2015), favor their affective processing. Therefore, it is unclear whether an affective categorization process is also involved when participants perform explicit moral judgments. Thus, in two experiments, we used similarly constructed morality and emotion materials for which their moral and emotional content had to be inferred from the context. Target sentences from negative vs. neutral emotional scenarios and from moral vs. immoral scenarios were presented using rapid serial visual presentation. In Experiment 1, participants made moral judgments for moral materials and emotional judgments for emotion materials. Negative compared to neutral emotional scenarios elicited a larger posterior ERP positivity (LPP) about 200 ms after critical word onset, whereas immoral compared to moral scenarios elicited a larger anterior negativity (500-700 ms). In Experiment 2, where the same emotional judgment to both types of materials was required, a larger LPP was triggered for both types of materials. These results accord with the view that morality scenarios trigger a semantic-cognitive analysis when participants explicitly judge the moral content of incoming linguistic information but an affective evaluation when judging their emotional content.

Experimental studies using fictional moral dilemmas indicate that both automatic emotional processes and controlled cognitive processes contribute to moral judgments. However, not much is known about how people process socio-normative violations that are more common to their everyday life nor the time-course of these processes. Thus, we recorded participants' electrical brain activity while they were reading vignettes that either contained morally acceptable vs unacceptable information or text materials that contained information which was either consistent or inconsistent with their general world knowledge. A first event-related brain potential (ERP) positivity peaking at ∼200 ms after critical word onset (P200) was larger when this word involved a socio-normative or knowledge-based violation. Subsequently, knowledge-inconsistent words triggered a larger centroparietal ERP negativity at ∼320 ms (N400), indicating an influence on meaning construction. In contrast, a larger ERP positivity (larger late positivity), which also started at ∼320 ms after critical word onset, was elicited by morally unacceptable compared with acceptable words. We take this ERP positivity to reflect an implicit evaluative (good-bad) categorization process that is engaged during the online processing of moral transgressions., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)