The human insula processes both modality-independent and pain-selective learning signals.

Prediction errors (PEs) are generated when there are differences between an expected and an actual event or sensory input. The insula is a key brain region involved in pain processing, and studies have shown that the insula encodes the magnitude of an unexpected outcome (unsigned PEs). In addition to signaling this general magnitude information, PEs can give specific information on the direction of this deviation-i.e., whether an event is better or worse than expected. It is unclear whether the unsigned PE responses in the insula are selective for pain or reflective of a more general processing of aversive events irrespective of modality. It is also unknown whether the insula can process signed PEs at all. Understanding these specific mechanisms has implications for understanding how pain is processed in the brain in both health and in chronic pain conditions. In this study, 47 participants learned associations between 2 conditioned stimuli (CS) with 4 unconditioned stimuli (US; painful heat or loud sound, of one low and one high intensity each) while undergoing functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. We demonstrate that activation in the anterior insula correlated with unsigned intensity PEs, irrespective of modality, indicating an unspecific aversive surprise signal. Conversely, signed intensity PE signals were modality specific, with signed PEs following pain but not sound located in the dorsal posterior insula, an area implicated in pain intensity processing. Previous studies have identified abnormal insula function and abnormal learning as potential causes of pain chronification. Our findings link these results and suggest that a misrepresentation of learning relevant PEs in the insular cortex may serve as an underlying factor in chronic pain.

Food intake and eating behaviour during a real-life Snack Scenario in childhood obesity-An experiment using a hidden camera.

OBJECTIVE: To compare food intake and eating behaviour in children and adolescents with obesity (OBE) undergoing weight loss intervention and normal weight (NW) in a real-life Snack Scenario. METHODS: Sixty OBE were examined before (T0) and after weight loss (T1) and compared to a single measurement comparison group of 27 NW. Participants watched a 20-min film and were encouraged to snack from a variety of foods ad libitum. Food intake was measured and eating behaviour assessed via a hidden camera and a validated questionnaire. RESULTS: The food and energy intake did not differ between NW (155 ± 83 g, 1067 ± 732 kJ) and OBE at T0 (144 ± 106 g, 1088 ± 883 kJ) but increased in OBE at T1 (187 ± 91 g, 1544 ± 845 kJ). Latency of food intake was significantly shorter in NW (0 m:07 s ± 0 m:08 s) compared to OBE (T0: 1 m:11 s ± 2 m:57 s). After weight loss, latency decreased in OBE (0 m:26 s ± 1 m:00 s). NW touched food more often (49 ± 24) than OBE (T0: 29 ± 23), but takes from plate were similar. The questionnaire revealed differences between OBE and NW, not correlating with Snack Scenario observations. CONCLUSION: Eating behaviours differed in NW versus OBE at T0 but food intake was similar. Therefore, behaviour while eating may be an underestimated factor in the considerations for childhood obesity. CLINICAL TRIAL REGISTRATION: German Clinical Trials Register (DRKS) with the trial number DRKS00005122.

The parietal operculum preferentially encodes heat pain and not salience.

Substantial controversy exists as to which part of brain activity is genuinely attributable to pain-related percepts and which activity is due to general aspects of sensory stimulation, such as its salience, or the accompanying arousal. The challenge posed by this question rests largely in the fact that pain per se exhibits highly intense but unspecific characteristics. These therefore should be matched by potential control conditions. Here, we used a unique combination of functional magnetic resonance imaging (fMRI) and behavioral and autonomic measures to address this longstanding debate in pain research. Subjects rated perceived intensity in a sequence alternating between heat and sound stimuli. Neuronal activity was monitored using fMRI. Either modality was presented in 6 different intensities, 3 of which lay above the pain threshold (for heat) or the unpleasantness threshold (for sound). We performed our analysis on 26 volunteers in which psychophysiological responses (as per skin conductance responses [SCRs]) did not differ between the 2 stimulus modalities. Having thus ascertained a comparable amount of stimulation-related but unspecific activation, we analyzed stimulus-response functions (SRFs) after painful stimulation and contrasted them with those of the matched acoustic control condition. Furthermore, analysis of fMRI data was performed on the brain surface to circumvent blurring issues stemming from the close proximity of several regions of interest located in heavily folded cortical areas. We focused our analyses on insular and peri-insular regions that are strongly involved in processing of painful stimuli. We employed an axiomatic approach to determine areas showing higher activation in painful compared to nonpainful heat and, at the same time, showing a steeper SRF for painful heat compared to unpleasant sound. Intriguingly, an area in the posterior parietal operculum emerged, whose response showed a pain preference after satisfying all axiomatic constraints. This result has important implications for the interpretation of functional imaging findings in pain research, because it clearly demonstrates that there are areas where activity following painful stimulation is not due to general attributes or results of sensory stimulation, such as salience or arousal. Conversely, several areas did not conform to the formulated axioms to rule out general factors as explanations.

Reduction of motion sickness with an enhanced placebo instruction: an experimental study with healthy participants.

OBJECTIVE: Expectancy and conditioning are underlying mechanisms of placebo and nocebo responses. In previous studies with motion sickness, we could induce nocebo responses by both methods, but no placebo responses. METHODS: In Experiment 1, 64 volunteers (50% women, mean age = 23.5 years) were evaluated to determine the degree they realized speed changes in nauseogenic rotation. For Experiment 2, 32 volunteers (50% women, mean age = 26.0 years) were exposed to fast rotation (15 rounds per minute, or rpm) on Day 1. On Day 2, they either received a drink with a presumed effective antiemetic (actually placebo) or were told they belonged to the control group. Rotation was surreptitiously reduced (to 10 rpm). On Day 3, they were tested with the initial rotation speed. Outcome variables in both experiments were symptom ratings; additionally in Experiment 2, the number of nauseogenic head movements, tolerated rotation time, and electrogastrogram were analyzed for changes between Days 1 and 2 (expectancy plus speed reduction) and Days 1 and 3 (expectancy plus conditioning). RESULTS: In Experiment 1, a dose-response function was established for different rotation speeds, with the smallest perceived difference between 10 and 15 rpm. In Experiment 2, placebo application induced better maximal symptom rating, head movement, and rotation time at Day 2 (F = 3.097, p = .043) and Day 3 (F = 3.401, p = .031). Electrogastrogram was unaffected. CONCLUSIONS: Verbal suggestions combined with a conditioning procedure are effective in reducing symptoms of motion sickness.

Temporal Summation of the Thermal Grill Illusion is Comparable to That Observed Following Noxious Heat.

The thermal grill illusion (TGI) describes a peculiar or even painful percept caused by non-noxious, interlaced warm and cold stimuli. It involves the glutamatergic system and is affected in putatively nociplastic syndromes such as fibromyalgia. The glutamatergic system is also involved in wind-up, that is, the increased activation of spinal neurons following repeated noxious stimulation leading to a temporal summation of perceived stimulus intensity. Here we combined both stimulation methods to further investigate whether non-noxious stimuli as employed in the TGI can lead to a similar summation of perceived stimulus intensity. In an experiment using a full crossover within-subjects design, 35 healthy volunteers received repeated stimuli, either in a thermal grill configuration or simply noxious heat. Both modalities were presented as sequences of 1 lead-in contact, followed by 11 consecutive contacts (each between 1.5 and 3 seconds), with either fast repetition ("wind-up" condition), or 2 slow-repeating control conditions. The main analyses concerned the relative pre-to-post sequence changes to quantify putatively wind-up-related effects. Pain ratings and skin conductance level (SCL) increased more strongly in "wind-up" than in control conditions. Interestingly, wind-up-related effects were of the same magnitude in TGI as compared to the pain control modality. Further, contact-by-contact SCL tracked how the effect emerged over time. These results indicate that although TGI does not involve noxious stimuli it is amenable to temporal summation and wind-up-like processes. Since both phenomena involve the glutamatergic system, the combination of wind-up with the TGI could yield a promising tool for the investigation of chronic pain conditions. PERSPECTIVE: Using thermal stimuli in an experimental protocol to combine 1) the TGI (painful or peculiar percept from simultaneous cold/warm stimulation) and 2) wind-up (increase in stimulus intensity after repeated exposure) holds promise to investigate pain and thermoceptive mechanisms, and chronic pain conditions.

Agency affects pain inference through prior shift as opposed to likelihood precision modulation in a Bayesian pain model.

Agency and expectations play a crucial role in pain perception and treatment. In the Bayesian pain model, somatosensation (likelihood) and expectations (prior) are weighted by their precision and integrated to form a pain percept (posterior). Combining pain treatment with stimulus-related expectations allows the mechanistic assessment of whether agency enters this model as a shift of the prior or a relaxation of the likelihood precision. In two experiments, heat pain was sham treated either externally or by the subject, while a predictive cue was utilized to create high or low treatment expectations. Both experiments revealed additive effects and greater pain relief under self-treatment and high treatment expectations. Formal model comparisons favored a prior shift rather than a modulation of likelihood precision. Electroencephalography revealed a theta-to-alpha effect, temporally associated with expectations, which was correlated with trial-by-trial pain ratings, further supporting a prior shift through which agency exerts its influence in the Bayesian pain model.

Bibliometric Properties of Placebo Literature From the JIPS Database: A Descriptive Study.

Objectives: First dedicated articles about placebo effects have been published in the 1940s, and more than 5,000 articles have been published in scientific organs since. However, the evolution of this research field has rarely been examined. By means of bibliometric analyses we aim to generate research metrics such as the number and types of publications as well as topics, authorship networks, impacts, and future directions. Methods: Bibliometric methods were applied to the Journal of Interdisciplinary Placebo Studies (JIPS) database. It comprises around 5,000 scientific articles dedicated to researching placebo effects and mechanisms and is expanded continually through individual curation, making it a prime candidate for investigation. Web scraping was used to obtain complete article information from PubMed and Web of Science. The same information was obtained for addiction research as reference field. Analyses include a general characterization of the database as well as focus points concerning publication types (data vs. non-data articles), high-impact publications and more. Results: Analyses show that the JIPS database is a comprehensive collection of placebo publications. The development of the field is comparable to that of the comparator field and scientific publication in general. The most frequently used keywords describe populations or study design topics; the most frequent symptoms were pain, depression and anxiety. Data and non-data (e.g., review) papers are related in proportion of about 6:4 in recent decades, indicating a stable degree of productivity. A network of 26 interconnected researchers was identified who published 25 or more articles. Placebo research contributes comparable numbers of publications to high-impact journals as the comparator field. Several additional analyses are performed, with a focus on visualization of various database parameters. Conclusions: Bibliometric analyses of the JIPS database can be used to answer questions to the field, for example, to get an impression of blind spots and future directions. However, keywords used in indexing and publications themselves are often general and suggest that placebo research may still be considered a subspecialty of superordinate fields, particularly since there are no journals dedicated to placebo research itself. We invite interested colleagues to use this database for further analyses.

Association of nocebo hyperalgesia and basic somatosensory characteristics in a large cohort.

Medical outcomes are strongly affected by placebo and nocebo effects. Prediction of who responds to such expectation effects has proven to be challenging. Most recent approaches to prediction have focused on placebo effects in the context of previous treatment experiences and expectancies, or personality traits. However, a recent model has suggested that basic somatosensory characteristics play an important role in expectation responses. Consequently, this study investigated not only the role of psychological variables, but also of basic somatosensory characteristics. In this study, 624 participants underwent a placebo and nocebo heat pain paradigm. Additionally, individual psychological and somatosensory characteristics were assessed. While no associations were identified for placebo responses, nocebo responses were associated with personality traits (e.g. neuroticism) and somatosensory characteristics (e.g. thermal pain threshold). Importantly, the associations between somatosensory characteristics and nocebo responses were among the strongest. This study shows that apart from personality traits, basic somatosensory characteristics play an important role in individual nocebo responses, in agreement with the novel idea that nocebo responses result from the integration of top-down expectation and bottom-up sensory information.

Different Disclosed Probabilities to Receive an Antiemetic Equally Decrease Subjective Symptoms in an Experimental Placebo Study: To Be or Not to Be Sure.

PURPOSE: The purpose of this study was to examine whether the disclosed probability of receiving an antiemetic affects nausea. METHODS: Forty-eight healthy participants (mean [SD] age, 26.8 [5.4] years; 50% female) were exposed to 5 × 2 minutes of nauseogenic body rotations on 2 days. On day 2, participants were randomized to 3 experimental groups that were given different instructions concerning the probability of receiving an antiemetic remedy (100%, 50%, or 0% probability), whereas all received an inert substance. Subjective symptoms, behavioral (rotation tolerance) measures, and physiologic (electrogastrogram) measures of nausea were assessed and mediator and moderator analyses performed for effects of expectations and psychological characteristics on outcomes. FINDINGS: Disclosed probabilities of both 100% and 50% significantly reduced subjective symptoms of nausea in an equal manner compared with the 0% probability group from day 1 to day 2. This effect was found for neither rotation tolerance nor myoelectric gastric activity. Expectations and psychological characteristics did not affect the results found. Post hoc analyses revealed that women only seem to be susceptible to this placebo effect. IMPLICATIONS: Nausea is susceptible to placebo effects independent of the disclosed probability of receiving a drug and of explicit expectations. In line with placebo research, this effect is probably attributable to central mechanisms, and it is speculated that it could be related to the reward circuitry and social interactions.

Effect of a weight reduction program on baseline and stress-induced heart rate variability in children with obesity.

OBJECTIVE: Autonomic dysregulation is a well-established feature in adults with obesity but not in children. Since this dysregulation could contribute to weight dynamics, this study aimed to compare autonomic regulation in children with obesity and normal-weight peers and to track autonomic status during weight reduction. METHODS: Sixty children with obesity and 27 age- and sex-matched normal-weight healthy participants were included. Heart rate variability (HRV) was assessed at baseline and during a mental stress test and a subsequent recovery period. Children with obesity were investigated both upon admission and discharge. RESULTS: Upon admission, no significant differences in HRV parameters were found for normal-weight participants and those with obesity. Inpatient treatment led to significant changes in HRV with increase in general variability (standard deviation of the normal-to-normal interval (SDNN), P < 0.001) as well as of parasympathetic regulation (root mean square successive difference (RMSSD) and high frequency power (logHF), P < 0.01). Children with obesity had sympathetic activation similar to normal-weight controls during mental stress with subsequent return to baseline values, and weight loss did not affect this profile. CONCLUSIONS: A weight reduction program induced a change in autonomic activity in children with obesity toward parasympathetic dominance but had no influence on autonomic nervous system reactivity during stress conditions.

How to study placebo responses in motion sickness with a rotation chair paradigm in healthy participants.

Placebo responses occur in every medical intervention when patients or participants expect to receive an effective treatment to relieve symptoms. However, underlying mechanisms of placebo responses are not fully understood. It has repeatedly been shown that placebo responses are associated with changes in neural activity but for many conditions it is unclear whether they also affect the target organ, such as the stomach in motion sickness. Therefore, we present a methodology for the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm. The physiological correlate of motion sickness is a shift in gastric myoelectrical activity towards tachygastria that can be recorded with electrogastrography. The presented study applied the so-called balanced placebo design (BPD) to investigate the effects of ginger compared to placebo and the effects of expectations by verbal information. However, the study revealed no significant main or interactional effects of ginger (as a drug) or information on outcome measures but showed interactions when sex of participants and experimenters are taken into considerations. We discuss limitations of the presented study and report modifications that were used in subsequent studies demonstrating placebo responses when rotation speed was lowered. In general, future placebo studies have to identify the appropriate target organ for the studied placebo responses and to apply the specific methods to assess the physiological correlates.

PreDictor Research in Obesity during Medical care - weight Loss in children and adolescents during an INpatient rehabilitation: rationale and design of the DROMLIN study.

BACKGROUND: Obesity in adults and children is increasing worldwide at alarming rates. Obese children and adolescents are likely to become obese adults with increased risk of a number of comorbidities. In addition to preventing the development of obesity at young age, it is necessary to individualize the therapy of already obese children and adolescents in order to increase the likelihood of weight loss and maintenance. Therefore, the aim of this study is to identify predictors which play a significant role in successful weight loss and weight loss maintenance in children and adolescents. METHODS/DESIGN: Over a one year period, 60 obese children and adolescents between 9 to 17 years of age shall be recruited at an inpatient children rehabilitation facility in Germany. They will be investigated twice within a few days following admission and prior to discharge. The study will be an integrated component of an established inpatient weight-loss and in part psychosomatic therapy. The collected data can be grouped into four clusters: 1) demographic, sociometric and psychometric data, 2) objective and subjective parameters of body condition, 3) autonomic nervous system regulated functions and 4) objective and subjective parameters for eating behavior. Primary outcome is the change of the body mass index standard deviation score (BMI-SDS). In order to evaluate the data appropriately, all examinations will be also conducted in a normal-weight reference group, matched for age and gender. DISCUSSION: For some of the collected parameters the time span between measures may be too short. Therefore, a 6 months, 1 year and 2 year follow-up will be performed for evaluating the different predictors and their influence in regard to a successful intervention. Further middle- and long-term follow-up studies are planned. TRIAL REGISTRATION: The study protocol was approved by the Ethics Committee of the University Hospital Tübingen, Germany. This study is registered at the German Clinical Trials Register (DRKS) with the clinical trial number DRKS00005122.

Nicotine stimulus expectancy differentially affects reaction time in healthy nonsmokers and smokers depending on sex: a pilot study.

Effects of nicotine on neurocognitive performance have been shown but are influenced by nonpharmacological expectancies in smokers, whereas there is little knowledge about expectancy effects in nonsmokers. A half balanced placebo design provides no drug but only placebo and tests the effects of expectations elicited by the information that nicotine was given. Sixty-four healthy participants balanced for smoking status and sex were told that a chewing gum may contain either nicotine or is a placebo in a double-blinded and randomized fashion. One hour later and immediately before neurocognitive function testing (Parametric Go/No-Go task) they were informed--balanced for smoking status and sex--that they belong to the nicotine or to the placebo group. Reaction times of Go responses (RT) and the number of false No-Go responses were analyzed. A significant interaction of all three factors (information, smoking status, sex) was found, indicating that the information to have received nicotine compared with placebo shortened RTs in female smokers but increased it in female nonsmokers, whereas results in men are in part reversed. No effects on No-Go errors were found, and beliefs about nicotine effects had no influence on results. Therefore, the known effects of nicotine on RTs could be influenced by stimulus expectancy not only in smokers but also in nonsmokers. Furthermore, previous results on sex-specific responsiveness to nicotine instructions are supported.

Effects of ginger and expectations on symptoms of nausea in a balanced placebo design.

OBJECTIVE: Ginger effects on (experimental) nausea have been described, but also strong placebo effects and sex differences when nausea is involved. The "balanced placebo design" has been proposed to allow better separation of drug and placebo effects. METHODS: Sixty-four healthy participants (32 women) were randomly assigned to receive an antiemetic ginger preparation or placebo, and half of each group was told to have received drug or placebo. They were exposed to 5×2 min body rotations to induce nausea. Subjective symptoms and behavioral (rotation tolerance, head movements) and physiological measures (electrogastrogram, cortisol) were recorded. Groups were balanced for sex of participants and experimenters. RESULTS: Ginger and the information given did not affect any outcome measure, and previous sex differences could not be confirmed. Adding the experimenters revealed a significant four-factorial interaction on behavioral but not on subjective or physiological measures Men who received placebo responded to placebo information when provided by the male experimenter, and to ginger information when provided by the female experimenter. This effect was not significant in women. CONCLUSION: The effects of an antiemetic drug and provided information interact with psychosocial variables of participants and experimenters in reports of nausea.

The placebo response in clinical trials: more questions than answers.

Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This 'additive model' is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in 'comparator' studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.