The impact of patients' pre-treatment expectations on immunosuppressive treatment outcomes in myasthenia gravis: A pilot correlational study.

INTRODUCTION/AIMS: The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia gravis (MG) the contribution of patients' pre-treatment expectations combined with an immunosuppressant drug on treatment outcomes. METHODS: This pilot correlational study involved 17 patients with generalized MG, scheduled to start immunosuppressant azathioprine. At baseline, a healthcare professional administered: (i) the Stanford Expectations of Treatment Scale; (ii) a structured checklist paper form asking patients which side-effects they expected to develop after starting azathioprine, coupled with a standardized framing of statements. Quantitative Myasthenia Gravis (QMG) score and daily dose of concomitant drugs were assessed by neurologists as clinical outcomes. Clinical outcomes and side-effects were re-assessed at 3 and 6 months, and clinical outcomes were monitored at 18 months. RESULTS: Clinically significant improvement in the QMG scores was achieved at 3 or 6 months. The level of state anxiety appeared to act as moderator of pre-treatment negative expectations (strong, positive, indicative correlation, rs = .733, p = .001). The latter were, in turn, associated with the fulfillment of side-effects that patients expected to develop with the new treatment (moderate, positive, indicative correlation, rs = .699, p = .002). No significant correlation emerged between positive and negative expectations. DISCUSSION: Our findings show a very quick clinical response and also suggest that patients' expectations and anxiety contributed to treatment outcomes, highlighting the importance of promoting safety messages and education strategies around newly introduced treatments. Future goals include evaluating a larger cohort that includes a matched control group.

The Effect of Temporal Information on Placebo Analgesia and Nocebo Hyperalgesia.

OBJECTIVE: Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on the direction and magnitude of the effect, whereas little is known about the influence of temporal information. METHODS: Using an experimental placebo and nocebo design, we investigated whether information about the expected onset of a treatment effect modulates the start and time course of analgesic and hyperalgesic responses. Healthy volunteers (n = 166) in three placebo and three nocebo groups were informed that the application of an (inert) cream would reduce (placebo groups) or amplify pain (nocebo groups) after 5, 15, or 30 minutes. Two control groups were also included (natural history and no expectations). Participants' pain intensity rating of electrical stimuli administered before and 10, 20, and 35 minutes after cream application was obtained. RESULTS: Mixed-method analysis of variance showed a significant interaction between group and time (F(12,262) = 18.172, p < .001, pη2 = 0.454), suggesting that pain variations differed across time points and between groups. Post hoc comparisons revealed that the placebo and nocebo groups began to show a significantly larger change in perceived pain intensity than the no-expectancy control group at the expected time point (p < .05) but not earlier (p > .05). Once triggered, the analgesic effect remained constant over the course of the experiment, whereas the hyperalgesic effect increased over time. CONCLUSIONS: Our results indicate that temporal suggestions can shape expectancy-related treatment effects, which, if used systematically, could open up new ways to optimize treatment outcome.

Effectiveness of a dance-physiotherapy combined intervention in Parkinson's disease: a randomized controlled pilot trial.

BACKGROUND: Physical therapies have been recommended as crucial components in Parkinson's disease (PD) rehabilitation. OBJECTIVE: The study aims to examine the effectiveness of a new dance-physiotherapy combined intervention, called DArT method, in mild PD patients. METHODS: A prospective, randomized, single-blind, controlled pilot trial was conducted on 38 mild PD patients under dopaminergic therapy. The intervention consisted in an add-on protocol: the control group received 1 h of conventional physiotherapy followed by 1 h of conventional physiotherapy each day, 3 times a week, for 5 weeks. The experimental group received 1 h of conventional physiotherapy followed by 1 h of dance class each day, 3 times a week, for 5 weeks. The week before and after the training period, patients were assessed for motor, cognitive, emotional, and sensory components of PD, with MDS-UPDRS-III as primary outcome measure. RESULTS: DArT method was associated with a 2.72-point reduction in the post-treatment MDS-UPDRS-III total score compared to control group (95% CI - 5.28, - 0.16, p = 0.038, d = 0.71), and with a 2.16-point reduction in the post-treatment MDS-UPDRS-III upper body subscore (95% CI - 3.56, - 0.76, p = 0.003, d = 1.02). Conversely, conventional physiotherapy program was associated with a 2.95-point reduction in the post-treatment trait anxiety compared to the experimental group (95% CI 0.19, 5.71, p = 0.037, d = 0.70). Withdrawal and fall rates were equal to 0% in both groups. CONCLUSION: DArT method showed to be safe, well accepted, and more effective than an intensive program of conventional physiotherapy in improving motor impairment in mild PD.

Nocebo and the contribution of psychosocial factors to the generation of pain.

The biopsychosocial model claims that illness is generated by biological, psychological, and social factors. The nocebo response, particularly nocebo hyperalgesia, is an excellent model and approach to understand these effects and their psychophysiological underpinnings, as nocebos are made of negative psychological and social factors, such as negative expectations and social interactions. There is today experimental evidence that nocebos can create symptoms and illness from nothing, in particular pain, whereby a combination of biological, psychological and social factors interact with each other in the generation of the global painful experience. Several biochemical pathways have been identified, e.g. cholecystokinin and cyclooxygenase, and the activation of these mechanisms has been specifically investigated in the field of pain, analgesia and hyperalgesia. The study of placebo and nocebo oxygen at high-altitude has been crucial to unravel these mechanisms, as reduction of oxygen pressure (hypoxia) leads to headache pain. Indeed, the investigation of oxygen-related conditions, such as hypoxia, represents today an excellent approach to understand how nocebos can contribute to generate illness and pain. In this review we discuss old and new findings that help us better understand the interplay between biology and psychology.

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain.

Background: The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain. Methods: Fifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups. Results: Tolerance change at Test 10 (Δ10) was greater in N5 (MED = -36.8; IQR = 20.9) compared to NE (MED = -5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = -36.3; IQR = 35.3; p = 0.002) and in N30 (MED = -33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR. Conclusions: Our study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain.

Unraveling Negative Expectations and Nocebo-Related Effects in Musculoskeletal Pain.

This Perspective adapts the ViolEx Model, a framework validated in several clinical conditions, to better understand the role of expectations in the recovery and/or maintenance of musculoskeletal (MSK) pain. Here, particular attention is given to the condition in which dysfunctional expectations are maintained despite no longer being supported by confirmatory evidence (i.e., belief-lifting the arm leads to permanent tendon damage; evidence-after the patient lifts the arm no tendon damage occurs). While the ViolEx Model suggests that cognitive immunization strategies are responsible for the maintenance of dysfunctional expectations, we suggest that such phenomenon can also be understood from a Bayesian Brain perspective, according to which the level of precision of the priors (i.e., expectations) is the determinant factor accounting for the extent of priors' updating (i.e., we merge the two frameworks, suggesting that highly precise prior can lead to cognitive immunization responses). Importantly, this Perspective translates the theory behind these two frameworks into clinical suggestions. Precisely, it is argued that different strategies should be implemented when treating MSK pain patients, depending on the nature of their expectations (i.e., positive or negative and the level of their precision).

A new visual feedback-based system for the assessment of pinch force, endurance, accuracy and precision. A test-retest reliability study.

Introduction: Given that pinch is a precision grip involved in sustained submaximal activities, a Sustained Contraction (SC) task could be associated to Maximal Voluntary Contraction (MVC). To better evaluate the thumb-index system, the test-retest reliability of pinch MVC and SC, measured by a visual feedback-based pinch gauge was assessed. Methods: 26 healthy participants performed MVC and SC in two separate sessions. SC required to maintain 40%MVC as long as possible and it was evaluated in terms of time, accuracy (Mean Distance between force trace and target force, MD), precision (Coefficient of Variability of force trace, CV). MD and CV analyses were conducted dividing the SC task into three equivalent time stages (beginning, middle, exhaustion). Relative Reliability (RR) was measured by Intraclass Correlation Coefficient, and Absolute Reliability (AR) was measured by Standard Error of Measurement and by Bland-Altman plot. Results: MVC and Time showed high RR and AR in both hands. RR of MD and CV in right hand was excellent in the beginning and middle stages, and fair in the exhaustion one, showing decreasing reliability as fatigue increases. In the left hand RR of MD and CV was generally lower. MD showed excellent reliability in the beginning stage and good reliability in the other stages. CV showed fair relative reliability at both beginning and middle stages, excellent in the last one. Conversely, it was observed high AR of MD and CV in all stages in both hands. Conclusions: All indices are reliable to assess motor control of thumb-index pinch in both hands.

'External timing' of placebo analgesia in an experimental model of sustained pain.

BACKGROUND: Research on placebo analgesia commonly focuses on the impact of information about direction (i.e., increase or decrease of pain) and magnitude of the expected analgesic effect, whereas temporal aspects of expectations have received little attention so far. In a recent study, using short-lasting, low-intensity stimuli, we demonstrated that placebo analgesia onset is influenced by temporal information. Here, we investigate whether the same effect of temporal suggestions can be found in longer lasting, high-intensity pain in a Cold Pressor Test (CPT). METHODS: Fifty-three healthy volunteers were allocated to one of three groups. Participants were informed that the application of an (inert-)cream would reduce pain after 5 min (P5) or 30 min (P30). The third group was informed that the cream only had hydrating properties (NE). All participants completed the CPT at baseline and 10 (Test 10) and 35 min (Test 35) following cream application. Percentage change in exposure time (pain tolerance) from baseline to Test 10 (Δ10) and to Test 35 (Δ35) and changes in heart rate (HR) during CPT were compared between the three groups. RESULTS: Δ10 was greater in P5 than in NE and P30, indicating that analgesia was only present in the group that was expecting an early onset of analgesia. Δ35 was greater in P5 and P30 compared to NE, reflecting a delayed onset of analgesia in P30 and maintained analgesia in P5. HR differences between groups were not significant. CONCLUSIONS: Our data suggest that 'externally timing' of placebo analgesia may be possible for prolonged types of pain. SIGNIFICANCE: Research on placebo effects mainly focuses on the influence of information about direction (i.e., increase or decrease of pain) and magnitude (i.e., strong or weak) of the expected effect but ignores temporal aspects of expectations. In our study in healthy volunteers, the reported onset of placebo analgesia followed the temporal information provided. Such 'external timing' effects could not only aid the clinical use of placebo treatment (e.g., in open-label placebos) but also support the efficacy of active drugs.

Context matters: the psychoneurobiological determinants of placebo, nocebo and context-related effects in physiotherapy.

BACKGROUND: Placebo and nocebo effects embody psychoneurobiological phenomena where behavioural, neurophysiological, perceptive and cognitive changes occur during the therapeutic encounter in the healthcare context. Placebo effects are produced by a positive healthcare context; while nocebo effects are consequences of negative healthcare context. Historically, placebo, nocebo and context-related effects were considered as confounding elements for clinicians and researchers. In the last two decades this attitude started to change, and the understanding of the value of these effects has increased. Despite the growing interest, the knowledge and the awareness of using the healthcare context to trigger placebo and nocebo effects is currently limited and heterogeneous among physiotherapists, reducing their translational value in the physiotherapy field. OBJECTIVES: To introduce the placebo, nocebo and context-related effects by: (1) presenting their psychological models; (2) describing their neurophysiological mechanisms; (3) underlining their impact for the physiotherapy profession; and (4) tracing lines for future researches. CONCLUSION: Several psychological mechanisms are involved in placebo, nocebo and context-related effects; including expectation, learning processes (classical conditioning and observational learning), reinforced expectations, mindset and personality traits. The neurophysiological mechanisms mainly include the endogenous opioid, the endocannabinoid and the dopaminergic systems. Neuroimaging studies have identified different brain regions involved such as the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the periaqueductal gray and the dorsal horn of spine. From a clinical perspective, the manipulation of the healthcare context with the best evidence-based therapy represents an opportunity to trigger placebo effects and to avoid nocebo effects respecting the ethical code of conduct. From a managerial perspective, stakeholders, organizations and governments should encourage the assessment of the healthcare context aimed to improve the quality of physiotherapy services. From an educational perspective, placebo and nocebo effects are professional topics that should be integrated in the university program of health and medical professions. From a research perspective, the control of placebo, nocebo and context-related effects offers to the scientific community the chance to better measure the impact of physiotherapy on different outcomes and in different conditions through primary studies.

Explicit and Implicit Own's Body and Space Perception in Painful Musculoskeletal Disorders and Rheumatic Diseases: A Systematic Scoping Review.

Background: Pain and body perception are essentially two subjective mutually influencing experiences. However, in the field of musculoskeletal disorders and rheumatic diseases we lack of a comprehensive knowledge about the relationship between body perception dysfunctions and pain or disability. We systematically mapped the literature published about the topics of: (a) somatoperception; (b) body ownership; and (c) perception of space, analysing the relationship with pain and disability. The results were organized around the two main topics of the assessment and treatment of perceptual dysfunctions. Methods: This scoping review followed the six-stage methodology suggested by Arksey and O'Malley. Ten electronic databases and grey literature were systematically searched. The PRISMA Extension for Scoping Reviews was used for reporting results. Two reviewers with different background, independently performed study screening and selection, and one author performed data extraction, that was checked by a second reviewer. Results: Thirty-seven studies fulfilled the eligibility criteria. The majority of studies (68%) concerned the assessment methodology, and the remaining 32% investigated the effects of therapeutic interventions. Research designs, methodologies adopted, and settings varied considerably across studies. Evidence of distorted body experience were found mainly for explicit somatoperception, especially in studies adopting self-administered questionnaire and subjective measures, highlighting in some cases the presence of sub-groups with different perceptual features. Almost half of the intervention studies (42%) provided therapeutic approaches combining more than one perceptual task, or sensory-motor tasks together with perceptual strategies, thus it was difficult to estimate the relative effectiveness of each single therapeutic component. Conclusions: To our knowledge, this is the first attempt to systematically map and summarize this research area in the field of musculoskeletal disorders and rheumatic diseases. Although methodological limitations limit the validity of the evidence obtained, some strategies of assessment tested and therapeutic strategies proposed represent useful starting points for future research. This review highlights preliminary evidence, strengths, and limitations of the literature published about the research questions, identifying key points that remain opened to be addressed, and make suggestions for future research studies. Body representation, as well as pain perception and treatment, can be better understood if an enlarged perspective including body and space perception is considered.

What is the relative contribution of biological and psychosocial factors to the generation of hypoxia headache?

BACKGROUND: The biopsychosocial model claims that illness is generated by both biological and psychosocial factors. Accordingly, several studies have shown that both factors contribute to the generation of pain. AIMS: The aim of the present study is to manipulate biological, psychological, and social factors in hypobaric hypoxia headache in order to understand their relative contribution to the generation of headache pain. METHODS: Healthy subjects were subdivided into three groups and brought to our high-altitude labs for the assessment of hypoxia-induced headache, blood oxygen saturation (SO2), prostaglandins, and cortisol during the first 24 h after arrival. The first group did not undergo any manipulation. The second group (negative expectation) was told that severe headache would occur if SO2 dropped to less than 80% and their oximeters were set to display a saturation of 75%, even though real SO2 was much higher. The third group (negative expectation and social interaction) underwent the same manipulation as the second group, but these subjects spent the night together with people experiencing headache and insomnia. RESULTS: Although none of the three groups differed significantly for SO2, the second group, compared to the first, experienced more severe headache and showed an increase in prostaglandins and cortisol. The third group, compared to the second group, showed a further increase of headache as well as of prostaglandin (PG) E2 and cortisol. CONCLUSIONS: These findings indicate that biological, psychological, and social factors are additive not only in the generation of headache but also for the biochemical changes related to hypoxia.

Contexte : Le modèle biopsychosocial affirme que la maladie est engendrée à la fois par des facteurs biologiques et psychosociaux. Plusieurs études ont donc démontré que ces deux types de facteurs contribuent à engendrer de la douleur.But : Le but de la présente étude est de manipuler les facteurs biologiques, psychologiques et sociaux dans les cas de céphalées associées à l'hypoxie hypobarique afin de comprendre leur contribution relative dans l'apparition de la douleur occasionnée par les céphalées.Méthodes : Des sujets en bonne santé ont été répartis en trois groupes et ont été conduits dans des laboratoires à haute altitude afin d'évaluer les céphalées induites par hypoxie, la saturation de l'oxygène dans le sang (SO2), les prostaglandines et le cortisol au cours des premières 24 heures suivant leur arrivée. Le premier groupe n'a été soumis à aucune manipulation. Le second groupe (attente négative) a été informé qu'une céphalée sévère surviendrait si le SO2 diminuait à moins de 80 % et les oxymètres des sujets de ce groupe ont été réglés de manière à indiquer une saturation de 75 %, même si le SO2 réel était beaucoup plus élevé. Le troisième groupe (attente négative et interaction sociale) a été soumis à la même manipulation que le second groupe, mais ces sujets ont passé la nuit avec des personnes souffrant de céphalées et d'insomnie.Résultats : Bien qu'aucun de ces trois groupes ne différait de manière sinificative en ce qui a trait au SO2, le deuxième groupe, comparativement au premier, a souffert de céphalées plus sévères, en plus de démontrer une augmentation des prostaglandins et du cortisol. Le troisième groupe, comparativement au deuxième, a démontré une augmentation des céphalées, des prostaglandines (PG) E2 et du cortisol encore plus marquée.Conclusions : Ces résultats indiquent que les facteurs biologiques, psychologiques et sociaux sont cumulatifs non seulement dans l'apparition de la céphalée, mais aussi dans les changements biochimiques liés à l'hypoxie.

Critical Life Functions: Can Placebo Replace Oxygen?

A crucial question in placebo research is related to which conditions and physiological functions are affected by placebos. Here we present evidence that critical life functions, like ventilation, oxygenation, circulation, and perfusion, can be sensitive to placebo treatments in some circumstances. Indeed, we have investigated the role of placebo effects at an altitude of 3500m, where oxygen pressure is 64% compared to the sea level. In these extreme conditions, hypoxia triggers several compensatory responses, such as hyperventilation, increased cardiac output, and increased brain perfusion. A conditioned placebo procedure was found to mimic the effects of oxygen on these compensatory responses, and these effects are still present at altitudes as high as 4500 and 5500m, where oxygen pressure is only 57% and 50%, respectively, compared to the sea level. Thus, placebo effects also take place for those functions that are critical for life and whereby oxygen is the key element.

Explicit and implicit experience of own's body in painful musculoskeletal disorders and rheumatic diseases: A scoping review protocol of available quantitative and qualitative evidence.

INTRODUCTION: Our body experience is organized at twofold levels: perceptual and cognitive-emotional. These higher-order processes are clearly different from the primary sensory processing of somatic stimuli (somatosensation). However, most of the available studies have mainly investigated the mechanisms of somatosensation. Moreover, disturbances of our body experience have been documented in some pathological conditions of interest for rehabilitative interventions, but their clinical role and relevance is yet to be clarified. Because in this field we have limited knowledge on perceptual and cognitive body experience, there emerges a need to better clarify this matter. The aim of the present scoping review is to systematically map this topic and to examine the magnitude and the nature of the available evidences. MATERIALS AND METHODS: The scoping review will be performed following the six-stage methodology suggested by Arksey and O'Malley. Ten electronic databases will be investigated since their inception. The search strategy will be peer reviewed by PRESS 2015 Evidence-Based Checklist as a quality assurance step. All records retrieved will be screened by two independent reviewers. The Population, Concept, and Context method will be adopted for eligibility criteria and Preferred Reporting Items for Systematic Reviews and Meta-Analyses will be used for results reporting. Two reviewers with different background will perform the search process independently. One author will extract data, checked by a second reviewer checking the matching with the research questions and goals. Any disagreements will be solved by a third reviewer. ETHICS AND DISSEMINATION: Ethical approval is not required for scoping reviews. Dissemination will include submission to peer-reviewed journal and presentations in conferences in the area of rehabilitation.

Enhancing Primary School Children's Knowledge of Online Safety and Risks with the CATZ Cooperative Cross-Age Teaching Intervention: Results from a Pilot Study.

Children are heavy users of the Internet and prior studies have shown that many of them lack a good understanding of the risks of doing so and how to avoid them. This study examined if the cross-age teaching zone (CATZ) intervention could help children acquire important knowledge of online risks and safety. It allowed older students to act as CATZ tutors to design and deliver a lesson to younger schoolmates (tutees), using content material about online risks and safety provided by adults. Students in Year 6 (mean age = 11.5 years) were randomly assigned to act as either CATZ tutors (n = 100) or age-matched controls (n = 46) and students in Year 4 (mean age = 9.5 years) acted as either CATZ tutees (n = 117) or age-matched controls (n = 28) (total N = 291). CATZ tutors, but not matched controls scored significantly higher on objective measures of knowledge of both online risks and safety, and CATZ tutees, but not matched controls did so for online safety. Effect sizes were moderate or large. CATZ was highly acceptable to participants. The results suggest that CATZ is a viable way to help school students learn about online dangers and how to avoid them.