Peter Krummenacher

Prefrontal cortex modulates placebo analgesia.

&NA; 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.

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.

Impaired Spatial-Temporal Integration of Touch in Xenomelia (Body Integrity Identity Disorder)

Abstract Body integrity identity disorder (BIID), or xenomelia, is a failure to integrate a fully functional limb into a coherent body schema. It manifests as the desire for amputation of the particular limb below an individually stable ‘demarcation line.’ Here we show, in five individuals with xenomelia, defective temporal order judgments to two tactile stimuli, one proximal, the other distal of the demarcation line. Spatio-temporal integration, known to be mediated by the parietal lobes, was biased towards the undesired body part, apparently capturing the individuals attention in a pathologically exaggerated way. This finding supports the view of xenomelia as a parietal lobe syndrome.

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.

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

&NA; Are developing children more prone than older children and adults to form placebo analgesic effects? We address this issue providing a comprehensive analysis of both nociception and pain modulation in pediatrics. &NA; 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.

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.

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.

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.