Not my body, not my pain? Pain perception and placebo analgesia in individuals with body integrity dysphoria.

Acute and chronic states of physical pain are inherently linked to our bodily perception. Bodily illusion paradigms have demonstrated that an experimentally induced sense of body disownership can modulate both acute and chronic pain. Insight into the relationship between enduring clinical alterations in body perception and pain is much more limited. The current study examined both pain perception and placebo analgesia in Body Integrity Dysphoria (BID), a clinical model of long-term alterations of bodily disownership: in its most commonly studied variant, people feel like a part of their body does not belong to them, leading to a desire for amputation of a physically healthy limb. Heat stimulations were applied before and after a placebo intervention (sham analgesic cream) to the desired and the undesired leg of 19 patients with BID with a unilateral leg amputation desire. Pain perception was assessed using pain thresholds, and ratings for pain intensity and pain unpleasantness. Results show that pain perception and placebo efficacy were lower for the undesired than for the desired leg, demonstrating a potential link between a clinical disorder of body ownership, pain perception, and placebo analgesia.

Real Bodies Not Required? Placebo Analgesia and Pain Perception in Immersive Virtual and Augmented Reality.

Pain represents an embodied experience, wherein inferences are not only drawn from external sensory inputs, but also from bodily states. Previous research has demonstrated that a placebo administered to an embodied rubber hand can effectively induce analgesia, providing first evidence that placebos can work even when applied to temporarily embodied, artificial body parts. Using a heat pain paradigm, the present study investigates placebo analgesia and pain perception during virtual embodiment. We examined whether a virtual placebo (a sham heat protective glove) can successfully induce analgesia, even when administered to a virtual body. The analgesic efficacy of the virtual placebo to the real hand (augmented reality setting) or virtual hand (virtual reality setting) was compared to a physical placebo administered to the own, physical body (physical reality setting). Furthermore, pain perception and subjective embodiment were compared between settings. In this mixed design experiment, healthy participants (n = 48) were assigned to either an analgesia-expectation or control-expectation group, where subjective and objective pain was measured at pre- and post-intervention time points. Results demonstrate that pre-intervention pain intensity was lower in the virtual reality setting, and that participants in the analgesia-expectation group, after the intervention, exhibited significantly higher pain thresholds, and lower pain intensity and unpleasantness ratings than control-expectation participants, independent of the setting. Our findings show that a virtual placebo can elicit placebo analgesia comparable to that of a physical placebo, and that administration of a placebo does not necessitate physical bodily interaction to produce analgesic responses. PERSPECTIVE: This study demonstrates that a virtual placebo treatment, even when administered to a virtual body, can produce placebo analgesia. These findings indicate that the efficacy of a virtual placebo is comparable to that of a physical placebo, which could pave the way for effective new non-pharmacological approaches for pain management.

Trust in the health care professional and health outcome: A meta-analysis.

OBJECTIVE: To examine whether patients' trust in the health care professional is associated with health outcomes. STUDY SELECTION: We searched 4 major electronic databases for studies that reported quantitative data on the association between trust in the health care professional and health outcome. We screened the full-texts of 400 publications and included 47 studies in our meta-analysis. DATA EXTRACTION AND DATA SYNTHESIS: We conducted random effects meta-analyses and meta-regressions and calculated correlation coefficients with corresponding 95% confidence intervals. Two interdependent researchers assessed the quality of the included studies using the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. RESULTS: Overall, we found a small to moderate correlation between trust and health outcomes (r = 0.24, 95% CI: 0.19-0.29). Subgroup analyses revealed a moderate correlation between trust and self-rated subjective health outcomes (r = 0.30, 0.24-0.35). Correlations between trust and objective (r = -0.02, -0.08-0.03) as well as observer-rated outcomes (r = 0.10, -0.16-0.36) were non-significant. Exploratory analyses showed a large correlation between trust and patient satisfaction and somewhat smaller correlations with health behaviours, quality of life and symptom severity. Heterogeneity was small to moderate across the analyses. CONCLUSIONS: From a clinical perspective, patients reported more beneficial health behaviours, less symptoms and higher quality of life and to be more satisfied with treatment when they had higher trust in their health care professional. There was evidence for upward bias in the summarized results. Prospective studies are required to deepen our understanding of the complex interplay between trust and health outcomes.

Salivary Alpha-Amylase Correlates with Subjective Heat Pain Perception.

OBJECTIVE: Self-reports of pain are important for an adequate therapy. This is a problem with patients and infants who are restricted in providing an accurate verbal estimation of their pain. Reliable, real-time, economical, and non-invasive physiological correlates might contribute to a more comprehensive description of pain. Salivary alpha-amylase constitutes one candidate biomarker, which reflects predominantly sympathetic nervous system alterations under stressful conditions and can be measured non-invasively. The current study investigated the effects of acute heat pain on salivary alpha-amylase activity. METHODS: Heat pain tolerance was measured on the non-dominant forearm. Participants completed visual analog scales on pain intensity and unpleasantness. Saliva samples were collected directly after pain induction. SUBJECTS: Twenty-seven healthy volunteers were recruited for this study. RESULTS: While salivary alpha-amylase levels correlated positively with intensity and unpleasantness ratings in response to acute heat pain stimuli, there was no corresponding association with pain tolerance. CONCLUSIONS: Salivary alpha-amylase is suggested to be an indirect physiologic correlate of subjective heat pain perception. Future studies should address the role of salivary alpha-amylase depending on the origin of pain, the concerned tissue, and other pain assessment methods.

Psychosocial Stress-Induced Analgesia: An Examination of Effects on Heat Pain Threshold and Tolerance and of Neuroendocrine Mediation.

Stress-induced analgesia (SIA) is an adaptive response of reduced nociception following demanding acute internal and external stressors. Although a psychobiological understanding of this phenomenon is of importance for stress-related psychiatric and pain conditions, comparably little is known about the psychobiological mechanisms of SIA in humans. The aim of this study was to investigate the effects of acute psychosocial stress on heat pain perception and its possible neuroendocrine mediation by salivary cortisol levels and α-amylase activity in healthy men. Employing an intra-individual assessment of heat pain parameters, acute psychosocial stress did not influence heat pain threshold but significantly, albeit slightly, increased heat pain tolerance. Using linear mixed-model analysis, this effect of psychosocial stress on heat pain tolerance was not mediated by increases of salivary cortisol and state anxiety levels or by the activity of α-amylase. These results show that while psychosocial stress is selectively analgesic for heat pain tolerance, this observed effect is not mediated by stress-induced increases of salivary cortisol and α-amylase activity, as proxies of both the hypothalamus-pituitary-adrenal axis and the autonomic nervous system activation.

Impact of short-term meditation and expectation on executive brain functions.

Meditation improves executive functions such as attention and working memory processes. However, it remains unclear to what extent contextual effects contribute to these improvements, since the role of meditation-associated expectations has not been investigated so far. In a randomized, single-blind, deceptive, between-subject design we compared the impact of short-term meditation (MG) on executive functioning with an expectation (ECG) and a passive control group (CG) as well as the effect of positive and negative outcome expectations. Fifty-nine healthy meditation-naïve volunteers participated on three consecutive days (20 min/session). Five groups were examined: 2 MGs, 2 ECGs and 1 CG. While one MG and one ECG were given positive suggestions concerning the effect of meditation on attention, the other two groups were given negative suggestions. MGs practised a focused attention meditation technique; ECGs were told that they were practising meditation but were given instructions for a sham meditation. CG participants sat in silence with their eyes closed. Interference control (Stroop task), selective sustained attention (d2 task), figural and verbal fluency measures of executive functions were assessed. Results indicate that suggestions have a substantial impact on interference control and verbal fluency, with positive suggestions leading to an increase in performance, whereas negative suggestions impeded improvement. This proof of concept study demonstrates the importance of the implementation of a credible ECG to elucidate context effects in meditation processes. It also indicates that suggestions can modulate the small effect of meditation on verbal fluency.

Moderation of antidepressant and placebo outcomes by baseline severity in late-life depression: A systematic review and meta-analysis.

BACKGROUND: Baseline severity is a crucial moderator of trial outcomes in adult depression, with the advantage of antidepressants over placebo increasing as severity increases. However, this relationship has not been examined in late-life depression. METHODS: PubMed, Embase, Web of Science, PsycINFO, and Cochrane were searched for studies published through September 2014. Randomized, acute phase, and double-blind studies comparing an antidepressant group with a placebo group in depressed elderly patients were included. RESULTS: Nineteen studies met all inclusion criteria. Within-group effect sizes revealed significant improvement in antidepressant groups (g=1.35, p<.000), as well as in placebo groups (g=.96, p<.000). Change in depressive symptoms assessed by Hamilton Depression Rating Scale (HDRS) was moderated by baseline severity in antidepressant groups (Z=2.67, p=.008) and placebo groups (Z=4.46, p<.000). However, this would be expected as a result of regression toward the mean, and mean differences between groups did not increase (r=.19, p=.469) as a function of baseline severity. LIMITATIONS: Limited to published data and information was only analyzed at the level of treatment groups. CONCLUSION: Baseline severity was not associated with an antidepressant-placebo difference and placebo responses are large in the treatment of depressed elderly people. We propose a stepwise approach, i.e., to initially offer elderly depressed patients psychosocial interventions and only consider antidepressants if patients do not respond.

Expectancy-induced placebo analgesia in children and the role of magical thinking.

UNLABELLED: Expectations and beliefs shape the experience of pain. This is most evident in context-induced, placebo analgesia, which has recently been shown to interact with the trait of magical thinking (MT) in adults. In children, placebo analgesia and the possible roles that MT and gender might play as modulators of placebo analgesia have remained unexplored. Using a paradigm in which heat pain stimuli were applied to both forearms, we investigated whether MT and gender can influence the magnitude of placebo analgesia in children. Participants were 49 right-handed children (aged 6-9 years) who were randomly assigned-stratified for MT and gender-to either an analgesia-expectation or a control-expectation condition. For both conditions, the placebo was a blue-colored hand disinfectant that was applied to the children's forearms. Independent of MT, the placebo treatment significantly increased both heat pain threshold and tolerance. The threshold placebo effect was more pronounced for girls than boys. In addition, independent of the expectation treatment, low-MT boys showed a lower tolerance increase on the left compared to the right side. Finally, MT specifically modulated tolerance on the right forearm side: Low-MT boys showed an increase, whereas high-MT boys showed a decrease in heat pain tolerance. This study documented a substantial expectation-induced placebo analgesia response in children (girls > boys) and demonstrated MT and gender-dependent laterality effects in pain perception. The findings may help improve individualized pain management for children. PERSPECTIVE: The study documents the first experimental evidence for a substantial expectancy-induced placebo analgesia response in healthy children aged 6 to 9 years (girls > boys). Moreover, the effect was substantially higher than the placebo response typically found in adults. The findings may help improve individualized pain management for children.

Pain and placebo in pediatrics: a comprehensive review of laboratory and clinical findings.

Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. After highlighting crucial aspects that need to be considered in studying pain modulation in children, this comprehensive review examines studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. We critically discuss psychological mechanisms underlying placebo effects, including (1) verbally induced expectations, (2) conditioning and learning mechanisms, and (3) child-parent-physician interactions. Taken together, research suggests that placebo mechanisms can affect therapeutic outcomes and potentially be exploited clinically to improve clinical outcomes in pediatric population. Recommendations for further investigating the mechanistic bases and harnessing placebo effects for supportive therapeutic applications are given.

Help-seeking in people with exceptional experiences: results from a general population sample.

BACKGROUND: Exceptional experiences (EE) are experiences that deviate from ordinary experiences, for example precognition, supernatural appearances, or déjà vues. In spite of the high frequency of EE in the general population, little is known about their effect on mental health and about the way people cope with EE. This study aimed to assess the quality and quantity of EE in persons from the Swiss general population, to identify the predictors of their help-seeking, and to determine how many of them approach the mental health system. METHODS: An on-line survey was used to evaluate a quota sample of 1580 persons representing the Swiss general population with respect to gender, age, and level of education. Multinomial logistic regression was applied to integrate help-seeking, self-reported mental disorder, and other variables in a statistical model designed to identify predictors of help-seeking in persons with EE. RESULTS: Almost all participants (91%) experienced at least one EE. Generally, help-seeking was more frequent when the EE were of negative valence. Help-seeking because of EE was less frequent in persons without a self-reported mental disorder (8.6%) than in persons with a disorder (35.1%) (OR = 5.7). Even when frequency and attributes of EE were controlled for, people without a disorder sought four times less often help because of EE than expected. Persons with a self-reported diagnosis of mental disorder preferred seeing a mental health professional. Multinomial regression revealed a preference for healers in women with less education, who described themselves as believing and also having had more impressive EE. CONCLUSION: Persons with EE who do not indicate a mental disorder less often sought help because of EE than persons who indicated a mental disorder. We attribute this imbalance to a high inhibition threshold to seek professional help. Moreover, especially less educated women did not approach the mental health care system as often as other persons with EE, but preferred seeing a healer.

Vestibular stimulation attenuates unrealistic optimism.

INTRODUCTION: Unrealistic optimism refers to the pervasive tendency of healthy individuals to underestimate their likelihood of future misfortune, including illness. The phenomenon shares a qualitative resemblance with anosognosia, a neurological disorder characterized by a deficient appreciation of manifest current illness or impairment. Unrealistic optimism and anosognosia have been independently associated with a region of right inferior frontal gyrus, the pars opercularis. Moreover, anosognosia is temporarily abolished by vestibular stimulation, particularly by irrigation of the left (but not right) ear with cold water, a procedure known to activate the right inferior frontal region. We therefore hypothesized that left caloric stimulation would attenuate unrealistic optimism in healthy participants. METHODS: Thirty-one healthy right-handed adults underwent cold-water caloric vestibular stimulation of both ears in succession. During each stimulation episode, and at baseline, participants estimated their own relative risk of contracting a series of illnesses in the future. RESULTS: Compared to baseline, average risk estimates were significantly higher during left-ear stimulation, whereas they remained unchanged during right-ear stimulation. Unrealistic optimism was thus reduced selectively during cold caloric stimulation of the left ear. CONCLUSIONS: Our results point to a unitary mechanism underlying both anosognosia and unrealistic optimism, and suggest that unrealistic optimism is a form of subclinical anosognosia for prospective symptoms.

Naloxone modulates visual judgments of similarity but not dissimilarity.

Endogenous opioids have been implicated in mediating (placebo) analgesia, in reward processes, and in the regulation of socially relevant emotions. To explore their potential contributions to higher cognitive functions, we used a novel task with tachistoscopically presented (for 150 ms) pairs of meaningless figures. Healthy right-handed men judged the similarities and dissimilarities between the two figures on a visual analogue scale (VAS) in two separate runs. In a double-blind, between-subjects design, subjects were administered intravenously either 0.2-mg/kg naloxone or placebo 10 min prior to the task, and VAS judgments and response latencies were measured. We found a significant interaction between substance group and type of judgment: The magnitude of the similarity judgments was lower in the naloxone than in the placebo group, while dissimilarity judgments remained uninfluenced by the treatment. Reaction latencies and mood scores, assessed before and after substance administration, did not differ between the two groups, indicating that the findings did not rely on altered motor performance or motivation. We suggest that naloxone decreased the "similarity criterion" in comparative judgments, indicating its potentially modulatory effect on visual cognition. The task introduced here could be used for the implicit study and quantification of subtle affective-cognitive processes beyond the level of mere questionnaire data.

Placebo-mediated, Naloxone-sensitive suggestibility of short-term memory performance.

Physiological studies of placebo-mediated suggestion have been recently performed beyond their traditional clinical context of pain and analgesia. Various neurotransmitter systems and immunological modulators have been used in successful placebo suggestions, including Dopamine, Cholecystokinin and, most extensively, opioids. We adhered to an established conceptual framework of placebo research and used the µ-opioid-antagonist Naloxone to test the applicability of this framework within a cognitive domain (e.g. memory) in healthy volunteers. Healthy men (n=62, age 29, SD=9) were required to perform a task-battery, including standardized and custom-designed memory tasks, to test short-term recall and delayed recognition. Tasks were performed twice, before and after intravenous injection of either NaCl (0.9%) or Naloxone (both 0.15 mg/kg), in a double-blind setting. While one group was given neutral information (S-), the other was told that it might receive a drug with suspected memory-boosting properties (S+). Objective and subjective indexes of memory performance and salivary cortisol (as a stress marker) were recorded during both runs and differences between groups were assessed. Short-term memory recall, but not delayed recognition, was objectively increased after placebo-mediated suggestion in the NaCl-group. Naloxone specifically blocked the suggestion effect without interfering with memory performance. These results were not affected when changes in salivary cortisol levels were considered. No reaction time changes, recorded to uncover unspecific attentional impairment, were seen. Placebo-mediated suggestion produced a training-independent, objective and Naloxone-sensitive increase in memory performance. These results indicate an opioid-mediated placebo effect within a circumscribed cognitive domain in healthy volunteers.

Prefrontal cortex modulates placebo analgesia.

Expectations and beliefs modulate the experience of pain, which is particularly evident in placebo analgesia. The dorsolateral prefrontal cortex (DLPFC) has been associated with pain regulation and with the generation, maintenance and manipulation of cognitive representations, consistent with its role in expectation. In a heat-pain paradigm, we employed non-invasive low-frequency repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt left and right DLPFC function or used the TMS device itself as a placebo, before applying an expectation-induced placebo analgesia. The results demonstrated that placebo significantly increased pain threshold and pain tolerance. While rTMS did not affect pain experience, it completely blocked placebo analgesia. These findings suggest that expectation-induced placebo analgesia is mediated by symmetric prefrontal cortex function.

Dopamine, paranormal belief, and the detection of meaningful stimuli.

Dopamine (DA) is suggested to improve perceptual and cognitive decisions by increasing the signal-to-noise ratio. Somewhat paradoxically, a hyperdopaminergia (arguably more accentuated in the right hemisphere) has also been implied in the genesis of unusual experiences such as hallucinations and paranormal thought. To test these opposing assumptions, we used two lateralized decision tasks, one with lexical (tapping left-hemisphere functions), the other with facial stimuli (tapping right-hemisphere functions). Participants were 40 healthy right-handed men, of whom 20 reported unusual, "paranormal" experiences and beliefs ("believers"), whereas the remaining participants were unexperienced and critical ("skeptics"). In a between-subject design, levodopa (200 mg) or placebo administration was balanced between belief groups (double-blind procedure). For each task and visual field, we calculated sensitivity (d') and response tendency (criterion) derived from signal detection theory. Results showed the typical right visual field advantage for the lexical decision task and a higher d' for verbal than facial stimuli. For the skeptics, d' was lower in the levodopa than in the placebo group. Criterion analyses revealed that believers favored false alarms over misses, whereas skeptics displayed the opposite preference. Unexpectedly, under levodopa, these decision preferences were lower in both groups. We thus infer that levodopa (1) decreases sensitivity in perceptual-cognitive decisions, but only in skeptics, and (2) makes skeptics less and believers slightly more conservative. These results stand at odd to the common view that DA generally improves signal-to-noise ratios. Paranormal ideation seems an important personality dimension and should be assessed in investigations on the detection of signals in noise.

Implicit learning of sequential bias in a guessing task: failure to demonstrate effects of dopamine administration and paranormal belief.

Previous research suggests that implicit sequence learning (ISL) is superior for believers in the paranormal and individuals with increased cerebral dopamine. Thirty-five healthy participants performed feedback-guided anticipations of four arrow directions. A 100-trial random sequence preceded two 100-trial biased sequences in which visual targets (arrows) on trial t tended to be displaced 90 degrees clockwise (CW) or counter-clockwise (CCW) from those on t - 1. ISL was defined as a positive change during the course of the biased run in the difference between pro-bias and counter-bias responses. It was hypothesized that this difference would be greater for believers in the paranormal than for skeptics, for those who received dopamine than for those who received placebo, and for believers who received dopamine than for the other groups. None of the hypotheses were supported by the data. It is suggested that a simple binary guessing task with a focus on prediction accuracy during early trials should be considered for future explorations.

Psychometric schizotypy modulates levodopa effects on lateralized lexical decision performance.

Emergence of psychotic thought has been related to a breakdown in left-hemisphere language dominance. Dopamine (DA) is implicated in both psychotic pathology and modulation of the semantic system. The present study explored whether controlled DA administration modulates basic language functions: (1) in general and/or (2) as a function of schizophrenia-associated thought. Forty healthy men performed a tachistoscopic lexical decision task. Participants' performance was also analyzed as a function of their positive (magical ideation, MI) and negative (physical anhedonia, PHYSAN) schizotypal features. Half of the subjects received 200 mg levodopa, the other half a placebo. Our findings showed that pharmacological treatment per se did not influence task performance, but influenced laterality patterns as a function of participants' schizotypal features. In the placebo, but not in the levodopa group, right hemisphere language contribution increased as a function of increasing MI scores. In the levodopa, but not in the placebo group, superior left hemisphere lexical decision performance was related to increasing PHYSAN scores. The findings from both substance groups suggest that in the healthy brain, a DA agonist restores left-hemispheric dominance for language by reducing right-hemispheric contribution with respect to a positive schizotypal trait and by increasing left-hemispheric specialization with respect to a negative schizotypal trait. We conjecture that the healthy brain compensates through intact neurochemical mechanisms an increased DA concentration, in particular for persons with elevated positive psychotic-like features.