Autonomic changes as reaction to experimental social stress in an inpatient psychosomatic cohort.

Objectives: Patients with psychosomatic disorders suffer from social isolation that might further lead to destabilization and exacerbation of bodily symptoms via autonomic pathways. We aimed to investigate the influence of controlled social stress (model of social ostracism) on the autonomic nerve system (ANS) in an inpatient cohort with psychosomatic disorders. Methods: We examined heart rate variability (HRV), skin conductance (SC) and skin temperature (ST) as well as ECG-derived respiration rate (EDR) and subjective reports on stress during exposure to experimental social stress (cyberball game). Data were collected from 123 participants (f:m = 88:35, 42.01 ± 13.54 years) on admission and upon discharge from the university psychosomatic clinic. All data were recorded during baseline, inclusion and exclusion phases of the cyberball game as well as during the recovery phase. Results: We found significant changes between admission and discharge with a decline in parasympathetic-related HRV parameters (SDRR -3.20 ± 1.30 ms, p = 0.026; RMSSD: -3.77 ± 1.28 ms, p = 0.007) as well as a decrease in SC (-0.04 ± 0.17 µS, p = 0.019) and EDR (-0.01 ± 0.01 Hz, p = 0.007), suggesting a drop in sympathetic tonus, with no changes in ST (p = 0.089) and subjective stress levels (p = 0.322). HRV parameters decreased during the cyberball game (SDRR p = 0.026; RMSSD p = 0.002; lnHF p < 0.001). In contrast, both SC (p < 0.001) and EDR (p < 0.001) increased during the game with SC being slightly lower during the exclusion phase. This can point toward a stimulation of sympathetic nervous system during game participation, which was concordant with the rise in subjective stress values (p < 0.001). ST showed a continuous, unspecific rise over time (p < 0.001). Conclusion: Our data demonstrate the decrease of ANS parameters during experimental social stress when data upon discharge were compared to those upon admission. These results are partially contradictory to previous studies that showed a rise in HRV in a psychiatric cohort over the course of (outpatient) treatment. Further research is required to help attributing these differences to effects of treatment or acute states relating to admission to or discharge from a psychosomatic department.

A virtual experimenter does not increase placebo hypoalgesia when delivering an interactive expectancy manipulation.

Lack of standardization and unblinding threaten the research of mechanisms involved in expectancy effects on pain. We evaluated a computer-controlled virtual experimenter (VEx) to avoid these issues. Fifty-four subjects underwent a baseline-retest heat pain protocol. Between sessions, they received an expectancy manipulation (placebo or no-treatment) delivered by VEx or text-only control condition. The VEx provided standardized "social" interaction with the subjects. Pain ratings and psychological state/trait measures were recorded. We found an interaction of expectancy and delivery on pain improvement following the intervention. In the text conditions, placebo was followed by lower pain, whereas in the VEx conditions, placebo and no-treatment were followed by a comparable pain decrease. Secondary analyses indicated that this interaction was mirrored by decreases of negative mood and anxiety. Furthermore, changes in continuous pain were moderated by expectation of pain relief. However, retrospective pain ratings show an effect of expectancy but not of delivery. We conclude that we successfully applied an automated protocol for inducing expectancy effects on pain. The effect of the VEx regardless of treatment may be due to interactions of attention allocation and locus of control. This points to the diversity of expectancy mechanisms, and has implications for research and computer-based treatment applications.

Knowledge Gaps in Placebo Research: With Special Reference to Neurobiology.

This article addresses different ways to identify knowledge gaps in placebo research. Following a short description of the history of placebo research and our contributions, we describe the creation of the Journal of Interdisciplinary Placebo Studies (JIPS) literature database and compare its content (on a meta-level) with two other approaches to survey the current state of the art of placebo research: a bibliometric analysis of a (limited) selection of placebo papers, and the analysis of the content of all abstracts submitted to a 2017 placebo conference. We summarize this discussion with a critical assessment of these approaches and a perspective of future approaches in such placebo "meta"-analyses.

Impaired Gastric Myoelectrical Reactivity in Children and Adolescents with Obesity Compared to Normal-Weight Controls.

Obesity often has its onset in childhood and can be accompanied by various comorbidities such as functional gastrointestinal disorders and altered gastric myoelectrical activity (GMA). This study investigates whether obesity in childhood and adolescence is already associated with altered GMA, and whether an inpatient weight loss program affects GMA. Sixty children with obesity (OBE) and 27 normal-weight children (NW) (12.9 ± 1.7 years; 51% female) were compared for their GMA at rest, after a stress test, and after a drink-to-full water load test. A continuous electrogastrogram (EGG) was recorded and analyzed with respect to gastric slow waves and tachygastric activity. OBE were examined upon admission (T1) and before discharge (T2) following an inpatient weight loss program; NW served as control group. Compared to NW, children with obesity showed flattened GMA as indicated by lower tachygastric reactivity after stress and water load test at T1. Data of OBE did not differ between T1 and T2. EGG parameters were associated neither with sex, age, and BMI nor with subjective stress and food intake. Children with obesity show impaired gastric myoelectrical reactivity in response to a stress and water load test compared to normal-weight controls, which does not change during an inpatient weight loss program.

A virtual experimenter to increase standardization for the investigation of placebo effects.

BACKGROUND: Placebo effects are mediated by expectancy, which is highly influenced by psychosocial factors of a treatment context. These factors are difficult to standardize. Furthermore, dedicated placebo research often necessitates single-blind deceptive designs where biases are easily introduced. We propose a study protocol employing a virtual experimenter - a computer program designed to deliver treatment and instructions - for the purpose of standardization and reduction of biases when investigating placebo effects. METHODS: To evaluate the virtual experimenter's efficacy in inducing placebo effects via expectancy manipulation, we suggest a partially blinded, deceptive design with a baseline/retest pain protocol (hand immersions in hot water bath). Between immersions, participants will receive an (actually inert) medication. Instructions pertaining to the medication will be delivered by one of three metaphors: The virtual experimenter, a human experimenter, and an audio/text presentation (predictor "Metaphor"). The second predictor includes falsely informing participants that the medication is an effective pain killer, or correctly informing them that it is, in fact, inert (predictor "Instruction"). Analysis will be performed with hierarchical linear modelling, with a sample size of N = 50. Results from two pilot studies are presented that indicate the viability of the pain protocol (N = 33), and of the virtual experimenter software and placebo manipulation (N = 48). DISCUSSION: It will be challenging to establish full comparability between all metaphors used for instruction delivery, and to account for participant differences in acceptance of their virtual interaction partner. Once established, the presence of placebo effects would suggest that the virtual experimenter exhibits sufficient cues to be perceived as a social agent. He could consequently provide a convenient platform to investigate effects of experimenter behavior, or other experimenter characteristics, e.g., sex, age, race/ethnicity or professional status. More general applications are possible, for example in psychological research such as bias research, or virtual reality research. Potential applications also exist for standardizing clinical research by documenting and communicating instructions used in clinical trials.

Resting blood pressure differentially predicts time course in a tonic pain experiment.

Resting blood pressure (BP) shows a negative relationship with pain sensitivity (BP-related hypoalgesia). In chronic pain conditions, this relationship is inverted. The precise mechanisms responsible for the inversion are unknown. Using a tonic pain protocol, we report findings closely resembling this inversion in healthy participants. Resting BP and state measures of anxiety and mood were assessed from 33 participants (21 female). Participants then immersed their dominant hand in painfully hot water (47 °C) for five trials of 1-min duration, with 30-s intertrial intervals. Throughout the trials, participants continually registered their pain. After a 35-min intermission, the trial sequence was repeated. A disassociation of the negative relationship of resting systolic BP (as per Trial 1) was found using hierarchical linear modeling (p < .001, R(2) = .07). The disassociation unfolds over each consecutive trial, with an increasingly positive relationship. In Sequence 2, the initially negative relationship is almost completely absent. Furthermore, the association of BP and pain was found to be moderated by anxiety, such that only persons with low anxiety exhibited BP hypoalgesia. Our findings expand the existing literature by incorporating anxiety as a moderator of BP hypoalgesia. Furthermore, the protocol emulates the changing relationship between BP and pain observed in chronic pain patients. The protocol has potential as a model for chronic pain; however, future research should determine if similar physiological systems are involved. The finding holds potential diagnostic or prognostic relevance for certain clinical pain conditions, especially those involving dysfunction of the descending modulation of pain.

Prediction of Symptom Change in Placebo Versus No-Treatment Group in Experimentally Induced Motion Sickness.

The long-standing question of who responds to placebo and who does not is of great theoretical and clinical relevance and has received increasing attention in recent years. We therefore performed a post hoc analysis of one of our previously published studies on placebo responses (PRs). In the analysis, fourteen potential predictors for the PR on experimentally induced motion sickness in 32 healthy volunteers were explored using moderated multiple regression. Generalized self-efficacy, generalized self, internal locus of control and cognitive flexibility were significantly associated with symptom improvement in the placebo group, as compared to the untreated control group. Notably, the directions of the associations were such that the "unfavorable" side of the constructs (e.g. low self-efficacy) predicted a higher PR. Instead, the "favorable" side predicted symptom improvement in the control group. Results fit well with prior research into psychological influences on motion sickness. Although PRs in motion sickness are not well established, it is suggested to include the identified constructs in future research involving motion sickness-related symptoms such as nausea and vertigo. Concerning PRs in general, the results may have implications for clinical as well as experimental research on other symptoms and disorders, such as pain or depression.

Prediction of placebo responses: a systematic review of the literature.

OBJECTIVE: Predicting who responds to placebo treatment-and under which circumstances-has been a question of interest and investigation for generations. However, the literature is disparate and inconclusive. This review aims to identify publications that provide high quality data on the topic of placebo response (PR) prediction. METHODS: To identify studies concerned with PR prediction, independent searches were performed in an expert database (for all symptom modalities) and in PubMed (for pain only). Articles were selected when (a) they assessed putative predictors prior to placebo treatment and (b) an adequate control group was included when the associations of predictors and PRs were analyzed. RESULTS: Twenty studies were identified, most with pain as dependent variable. Most predictors of PRs were psychological constructs related to actions, expected outcomes and the emotional valence attached to these events (goal-seeking, self-efficacy/-esteem, locus of control, optimism). Other predictors involved behavioral control (desire for control, eating restraint), personality variables (fun seeking, sensation seeking, neuroticism), or biological markers (sex, a single nucleotide polymorphism related to dopamine metabolism). Finally, suggestibility and beliefs in expectation biases, body consciousness, and baseline symptom severity were found to be predictive. CONCLUSIONS: While results are heterogeneous, some congruence of predictors can be identified. PRs mainly appear to be moderated by expectations of how the symptom might change after treatment, or expectations of how symptom repetition can be coped with. It is suggested to include the listed constructs in future research. Furthermore, a closer look at variables moderating symptom change in control groups seems warranted.

Placebo responses and placebo effects in functional bowel disorders.

The nature and determinants of the placebo response are widely unknown, as are the underlying psychological and biological mechanisms. Placebo response rates in functional bowel disorders (functional dyspepsia, irritable bowel syndrome) trials are similar to those in nonintestinal pain conditions and are comparable with other organic gastrointestinal diseases (duodenal ulcer, inflammatory bowel diseases). In this narrative review, different methodologies (meta-analyses, reanalyses, and experimental setups) are discussed that have been applied to the study of the placebo response in functional dyspepsia and the irritable bowel syndrome.