The Optimal Learning Cocktail for Placebo Analgesia: A Randomized Controlled Trial Comparing Individual and Combined Techniques.

This study investigated for the first time the effects of individual and combined application of 3 learning techniques (verbal suggestions, classical conditioning, and observational learning) on placebo analgesia and extinction. Healthy participants (N = 206) were assigned to 8 different groups in which they were taught through either a verbal suggestion, a conditioning paradigm, a video observing someone, or any combination thereof that a placebo device (inactive transcutaneous electric nerve stimulation [TENS]) was capable of alleviating heat pain, whereas one group did not (control). Placebo analgesia was quantified as the within-group difference in experienced pain when the placebo device was (sham) 'activated' or 'inactivated' during equal pain stimuli, and compared between groups. Placebo analgesia was induced in groups with 2 or 3 learning techniques. Significantly stronger placebo analgesia was induced in the combination of all 3 learning techniques as compared to the individual learning techniques or control condition, underlining the additional contribution of 3 combined techniques. Extinction did not differ between groups. Furthermore, pain expectancies, but not state anxiety or trust, mediated placebo analgesia. Our findings emphasize the added value of combining 3 learning techniques to optimally shape expectancies that lead to placebo analgesia, which can be used in experimental and clinical settings. PERSPECTIVE: This unique experimental study compared the individual versus combined effects of 3 important ways of learning (verbal suggestions, classical conditioning, and observational learning) on expectation-based pain relief. The findings indicate that placebo effects occurring in clinical practice could be optimally strengthened if healthcare providers apply these techniques in combination.

Learned Nocebo Effects on Cutaneous Sensations of Pain and Itch: A Systematic Review and Meta-analysis of Experimental Behavioral Studies on Healthy Humans.

OBJECTIVE: In past decades, the field of nocebo research has focused on studying how sensory perception can be shaped by learning. Nocebo effects refer to aggravated sensory experiences or increased sensitivity to sensations such as pain and itch resulting from treatment-related negative experiences. Behavioral conditioning and verbal suggestions of a negative treatment outcome may aggravate pain and itch perception. Gaining a comprehensive view of the magnitude of nocebo effects and contributing factors will help steer nocebo research toward fruitful directions for understanding complex sensory phenomena. METHODS: We conducted a systematic review and meta-analysis of a total of 37 distinct experimental nocebo studies on healthy participants (all published in English between 2008 and 2021), with four separate meta-analyses for nocebo effects on pain or itch. We conducted subgroup analyses and meta-regression on factors such as type and intensity of sensory stimuli, and length of conditioning paradigms. RESULTS: This meta-analysis showed that, on average, effect sizes of nocebo effects were moderate to large (Hedges g between 0.26 and 0.71 for the four primary outcomes). The combination of conditioning and verbal suggestions yielded stronger nocebo responses on pain in particular. Subgroup analyses, including factors such as the type of sensory stimulation, did not explain the moderate heterogeneity in nocebo magnitudes between different studies. Risk of bias was generally low and was not related to nocebo magnitudes either. CONCLUSIONS: We discuss these results in relation to the role of conditioning and aversive learning, and we recommend more consistency in designing and reporting nocebo experiments.

Placebo effects on cutaneous pain and itch: a systematic review and meta-analysis of experimental results and methodology.

ABSTRACT: Placebo effects, positive treatment outcomes that go beyond treatment processes, can alter sensations through learning mechanisms. Understanding how methodological factors contribute to the magnitude of placebo effects will help define the mechanisms by which these effects occur. We conducted a systematic review and meta-analysis of experimental placebo studies in cutaneous pain and itch in healthy samples, focused on how differences in methodology contribute to the resulting placebo effect magnitude. We conducted meta-analyses by learning mechanism and sensation, namely, for classical conditioning with verbal suggestion, verbal suggestion alone, and observational learning, separately for pain and itch. We conducted subgroup analyses and meta-regression on the type of sensory stimuli, placebo treatment, number of acquisition and evocation trials, differences in calibrated intensities for placebo and control stimuli during acquisition, age, and sex. We replicated findings showing that a combination of classical conditioning with verbal suggestion induced larger placebo effects on pain ( k = 68, g = 0 . 59) than verbal suggestion alone ( k = 39, g = 0.38) and found a smaller effect for itch with verbal suggestion alone ( k = 7, g = 0.14). Using sham electrodes as placebo treatments corresponded with larger placebo effects on pain than when topical gels were used. Other methodological and demographic factors did not significantly affect placebo magnitudes. Placebo effects on pain and itch reliably occur in experimental settings with varied methods, and conditioning with verbal suggestion produced the strongest effects. Although methods may shape the placebo effect to some extent, these effects appear robust overall, and their underlying learning mechanisms may be harnessed for applications outside the laboratory.

A randomized pharmacological fMRI trial investigating D-cycloserine and brain plasticity mechanisms in learned pain responses.

Learning and negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. Here, we examined how a targeted pharmacological manipulation of learning would impact nocebo responses and their brain correlates. Participants received either a placebo (n = 27) or a single 80 mg dose of D-cycloserine (a partial NMDA receptor agonist; n = 23) and underwent fMRI. Behavioral conditioning and negative suggestions were used to induce nocebo responses. Participants underwent pre-conditioning outside the scanner. During scanning, we first delivered baseline pain stimulations, followed by nocebo acquisition and extinction phases. During acquisition, high intensity thermal pain was paired with supposed activation of sham electrical stimuli (nocebo trials), whereas moderate pain was administered with inactive electrical stimulation (control trials). Nocebo hyperalgesia was induced in both groups (p < 0.001). Nocebo magnitudes and brain activations did not show significant differences between D-cycloserine and placebo. In acquisition and extinction, there were significantly increased activations bilaterally in the amygdala, ACC, and insula, during nocebo compared to control trials. Nocebo acquisition trials also showed increased vlPFC activation. Increased opercular activation differentiated nocebo-augmented pain aggravation from baseline pain. These results support the involvement of integrative cognitive-emotional processes in nocebo hyperalgesia.

A jury of scientists: Formal education in biobehavioral sciences reduces the odds of punitive criminal sentencing.

This study examines how formal education in biological and behavioral sciences may impact punishment intuitions (views on criminal sentencing, free will, responsibility, and dangerousness) in cases involving neurobiological evidence. In a survey experiment, we compared intuitions between biobehavioral science and non-science university graduates by presenting them with a baseline case without a neurobiological explanation for offending followed by one of two cases with a neurobiological explanation (described as either innate or acquired biological influences to offending). An ordinal logistic regression indicated that both science and non-science graduates selected significantly more severe punishments for the baseline case as compared to when an innate neurobiological explanation for offending was provided. However, across all cases, science graduates selected significantly less severe sentences than non-science graduates, and only science graduates' decisions were mediated by free will and responsibility attributions. Findings are discussed in relation to scientific understandings of behavior, the impact of science education on attitudes towards punishment, and potential criminal-legal implications.

Temporal structure of brain oscillations predicts learned nocebo responses to pain.

This study aimed to identify electrophysiological correlates of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) has been found to impact how healthy and patient populations experience pain and is a phenomenon that could be better understood in terms of its neurophysiological underpinnings. In this study, nocebo hyperalgesia was induced in 36 healthy participants through classical conditioning and negative suggestions. Electroencephalography was recorded during rest (pre- and post-acquisition) and during pain stimulation (baseline, acquisition, evocation) First, participants received baseline high thermal pain stimulations. During nocebo acquisition, participants learned to associate an inert gel applied to their forearm with administered high pain stimuli, relative to moderate intensity control stimuli administered without gel. During evocation, all stimuli were accompanied by moderate pain, to measure nocebo responses to the inert gel. Pre- to post-acquisition beta-band alterations in long-range temporal correlations (LRTC) were negatively associated with nocebo magnitudes. Individuals with strong resting LRTC showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. These findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing.

How Negative Experience Influences the Brain: A Comprehensive Review of the Neurobiological Underpinnings of Nocebo Hyperalgesia.

This comprehensive review summarizes and interprets the neurobiological correlates of nocebo hyperalgesia in healthy humans. Nocebo hyperalgesia refers to increased pain sensitivity resulting from negative experiences and is thought to be an important variable influencing the experience of pain in healthy and patient populations. The young nocebo field has employed various methods to unravel the complex neurobiology of this phenomenon and has yielded diverse results. To comprehend and utilize current knowledge, an up-to-date, complete review of this literature is necessary. PubMed and PsychInfo databases were searched to identify studies examining nocebo hyperalgesia while utilizing neurobiological measures. The final selection included 22 articles. Electrophysiological findings pointed toward the involvement of cognitive-affective processes, e.g., modulation of alpha and gamma oscillatory activity and P2 component. Findings were not consistent on whether anxiety-related biochemicals such as cortisol plays a role in nocebo hyperalgesia but showed an involvement of the cyclooxygenase-prostaglandin pathway, endogenous opioids, and dopamine. Structural and functional neuroimaging findings demonstrated that nocebo hyperalgesia amplified pain signals in the spinal cord and brain regions involved in sensory and cognitive-affective processing including the prefrontal cortex, insula, amygdala, and hippocampus. These findings are an important step toward identifying the neurobiological mechanisms through which nocebo effects may exacerbate pain. Results from the studies reviewed are discussed in relation to cognitive-affective and physiological processes involved in nocebo and pain. One major limitation arising from this review is the inconsistency in methods and results in the nocebo field. Yet, while current findings are diverse and lack replication, methodological differences are able to inform our understanding of the results. We provide insights into the complexities and involvement of neurobiological processes in nocebo hyperalgesia and call for more consistency and replication studies. By summarizing and interpreting the challenging and complex neurobiological nocebo studies this review contributes, not only to our understanding of the mechanisms through which nocebo effects exacerbate pain, but also to our understanding of current shortcomings in this field of neurobiological research.

Nocebo Effects on Cowhage-evoked Itch: A Randomized Controlled Trial of Classical Conditioning and Observational Learning.

To investigate learning processes underlying nocebo effects on itch, this study measured the efficacy of classical conditioning and observational learning for inducing nocebo effects on cowhage-evoked itch and scratching behaviour. A total of 58 healthy female participants were assigned to classical conditioning, observational learning, or sham conditioning groups. In the classical conditioning group, experimenters associated the application of an inert gel with increased itch intensity themselves. In the observational learning group, a video of the conditioning paradigm was shown. Nocebo effects were measured as the difference in itch or scratching between control and nocebo test phase trials, compared between learning and control groups. Compared with sham conditioning, classical conditioning induced a significant nocebo effect on itch, while observational learning did not. No nocebo effect on scratching was detected. These results highlight the role that learning through direct experiences plays in pruritic symptoms. Future research should investigate how a patient's history of unsuccessful treatments shapes treatment outcomes.

A single administration of 'microbial' D-alanine to healthy volunteers augments reaction to negative emotions: A comparison with D-serine.

BACKGROUND: Activation of the glutamate N-methyl-D-aspartate receptor with its co-agonist D-serine has been shown to improve subjective mood in healthy volunteers. D-alanine is another potent N-methyl-D-aspartate receptor co-agonist which arises from the natural breakdown of host gut microbes, and is predominantly sequestered in the pituitary. This may suggest that D-alanine influences the neuroendocrine stress response which may then impact on emotion. AIMS: The current study explored the effects of D-serine and D-alanine on emotional processing, cognition and the levels of the stress hormone cortisol in healthy volunteers. METHODS: In a double-blind, placebo-controlled randomised study, participants (n=63) received a single oral dose of either D-serine, D-alanine (60 mg/kg) or placebo and then performed the Emotional Test Battery and N-back task (two hours post-administration) and provided saliva samples at fixed intervals. RESULTS: Subjects administered with D-alanine were faster at identifying facial expressions of fear, surprise and anger, and at categorising negative self-referential words. Participants on D-alanine also showed a trend to recall more words than placebo in a memory task. D-serine did not have any meaningful effects in any of the tasks. Neither amino acid had a significant effect on salivary cortisol or working memory. CONCLUSION: This study is the first to suggest that D-alanine can modulate emotional cognitive processing after a single dose. The lack of findings for D-serine nevertheless contrasts a previous study, emphasising a need for further investigation to clarify discrepancies. A better understanding of the physiological actions of D-amino acids would be beneficial in evaluating their therapeutic potential.