Final Report Summary - EXPECT HEAL-TH (Empowering expectations for health and disease: training the immune and endocrine system)
Expectations about health and disease, including chronic inflammatory itch and pain conditions, are known to induce immune and endocrine responses and to directly affect health and treatment outcomes. What has been unknown up to now is which are the central mechanisms of how peoples’ expectations affect immune and endocrine responses and related health outcomes. In the project “Empowering expectations for health and disease: training of the immune and endocrine system”, the impact of our expectations on health and disease and the mechanisms through which this impact works has been examined by means of innovative multidisciplinary methods in experimental studies, varying from fundamental to clinical in both healthy participants and patients with chronic somatic conditions. Three main projects have been conducted, including a number of smaller studies that test specific parts of, or connections between, the projects.
In the first project, we have systematically reviewed the state-of-the-art with regard to the impact of expectancy learning processes on endocrine and immune responses, gaining a clear view on current knowledge gaps, methodological challenges, and suggestions for clinical applications (Meeuwis et al., in preparation; Skvortsova et al., 2019a; Wolters et al., 2019). We subsequently trained endocrine (oxytocin, cortisol) and immune (antihistamine) responses by means of different expectancy learning approaches (e.g. pharmacological conditioning, verbal suggestions), assessing both basal outcomes and responsiveness to health challenges (e.g. allergic histamine reactions, heat pain stimulation), including neurobiological mechanisms (e.g. fMRI). In several randomized controlled studies, new evidence was found for the potential to condition endocrine and immune responses in healthy participants and the related brain activity (oxytocin, Skvortsova et al., in press, in preparation; cortisol, Tekampe et al., in preparation; antipruritic, Meeuwis et al., in press). Subquestions addressed whether open-label verbal suggestions (i.e. informing patients about receiving an inert treatment) could also impact outcomes (e.g. symptom reporting), illustrating a potential role of (open- and closed-label) placebo for optimizing expectations and especially self-reported treatment effects for itch in clinical practice (Meeuwis et al., 2018, 2019, in preparation). Also, it has been examined whether placebo effects could be enhanced by means of specific endocrine or immunological agents (e.g. oxytocin), which was not the case, suggesting that we need to look into other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects (Skvortsova et al., 2018, 2019b).
In the second project, we have examined the short-term effectiveness of psychological interventions, including expectancy learning processes, on immune-related challenges. A systematic review and meta-analysis has shown support for the effectiveness of stress-reducing psychological interventions in improving immunity in response to a variety of in vivo, in vitro, and psychophysiological challenges (Schakel et al., 2019a). We developed an innovative guided eHealth training combined with health-related serious gaming elements directed at optimizing immune functioning, incorporating immunological and psychophysiological challenges (Schakel et al., 2017), showing some support for the optimization of health outcomes (e.g. sleep, well-being, antibody responses) by means of this training (Schakel et al., under review). Within substudies, the effectiveness of specific training elements, such as serious gaming, has been shown in optimizing specific health behaviors (e.g. Schakel et al., 2018, under review), with limited evidence for the add-on effectiveness of verbal suggestions (Schakel et al., 2019b) or conditioning (Manaï et al., in preparation).
In the third project, the long-term effects of a constant versus intermittent treatment regimen in recent-onset rheumatoid arthritis has been examined by means of an innovative research design (Manaï et al., in press). The pilot proof-of-principle study provided first indications of a lower self-reported disease activity and pain, and better physical health in the intermittent treatment group (Manaï et al., in preparation). As part of this project, also a clinical review on how to prevent, minimize, or extinguish nocebo effects has been written (Manaï et al., 2019).
With these series of studies, we add significant evidence to unravel the mechanisms of how people’s expectations affect immune and endocrine responses and related health outcomes. This interdisciplinary project has progressed key theoretical knowledge of the central expectation mechanisms for immune and endocrine responses. Findings are of crucial importance for various health problems and treatments, opening new horizons for innovative health prevention strategies and therapeutic interventions for a broad range of inflammatory conditions and physical symptoms.
In the first project, we have systematically reviewed the state-of-the-art with regard to the impact of expectancy learning processes on endocrine and immune responses, gaining a clear view on current knowledge gaps, methodological challenges, and suggestions for clinical applications (Meeuwis et al., in preparation; Skvortsova et al., 2019a; Wolters et al., 2019). We subsequently trained endocrine (oxytocin, cortisol) and immune (antihistamine) responses by means of different expectancy learning approaches (e.g. pharmacological conditioning, verbal suggestions), assessing both basal outcomes and responsiveness to health challenges (e.g. allergic histamine reactions, heat pain stimulation), including neurobiological mechanisms (e.g. fMRI). In several randomized controlled studies, new evidence was found for the potential to condition endocrine and immune responses in healthy participants and the related brain activity (oxytocin, Skvortsova et al., in press, in preparation; cortisol, Tekampe et al., in preparation; antipruritic, Meeuwis et al., in press). Subquestions addressed whether open-label verbal suggestions (i.e. informing patients about receiving an inert treatment) could also impact outcomes (e.g. symptom reporting), illustrating a potential role of (open- and closed-label) placebo for optimizing expectations and especially self-reported treatment effects for itch in clinical practice (Meeuwis et al., 2018, 2019, in preparation). Also, it has been examined whether placebo effects could be enhanced by means of specific endocrine or immunological agents (e.g. oxytocin), which was not the case, suggesting that we need to look into other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects (Skvortsova et al., 2018, 2019b).
In the second project, we have examined the short-term effectiveness of psychological interventions, including expectancy learning processes, on immune-related challenges. A systematic review and meta-analysis has shown support for the effectiveness of stress-reducing psychological interventions in improving immunity in response to a variety of in vivo, in vitro, and psychophysiological challenges (Schakel et al., 2019a). We developed an innovative guided eHealth training combined with health-related serious gaming elements directed at optimizing immune functioning, incorporating immunological and psychophysiological challenges (Schakel et al., 2017), showing some support for the optimization of health outcomes (e.g. sleep, well-being, antibody responses) by means of this training (Schakel et al., under review). Within substudies, the effectiveness of specific training elements, such as serious gaming, has been shown in optimizing specific health behaviors (e.g. Schakel et al., 2018, under review), with limited evidence for the add-on effectiveness of verbal suggestions (Schakel et al., 2019b) or conditioning (Manaï et al., in preparation).
In the third project, the long-term effects of a constant versus intermittent treatment regimen in recent-onset rheumatoid arthritis has been examined by means of an innovative research design (Manaï et al., in press). The pilot proof-of-principle study provided first indications of a lower self-reported disease activity and pain, and better physical health in the intermittent treatment group (Manaï et al., in preparation). As part of this project, also a clinical review on how to prevent, minimize, or extinguish nocebo effects has been written (Manaï et al., 2019).
With these series of studies, we add significant evidence to unravel the mechanisms of how people’s expectations affect immune and endocrine responses and related health outcomes. This interdisciplinary project has progressed key theoretical knowledge of the central expectation mechanisms for immune and endocrine responses. Findings are of crucial importance for various health problems and treatments, opening new horizons for innovative health prevention strategies and therapeutic interventions for a broad range of inflammatory conditions and physical symptoms.