Conditioning induced placebo-like and nocebo-like effects of thermal discomfort in adults but not in youth.

Introduction: Conditioning can be used to modulate the perception of pain, in the form of placebo and nocebo effects. Previous studies show inconsistent results as to whether adolescents show similar, weaker, or non-significant conditioned placebo and nocebo effects compared to effects found in adults. There are suggestions that such differences (if any) may dependent on the cues used in the thermal conditioning paradigms. Therefore, in this current study, we utilized novel, neutral 3D-shaped visual cues to implicitly induce conditioned placebo-like and nocebo-like effects in adolescents and adults. Methods: During the conditioning paradigm, distinct cues (Fribbles) were paired with low and high temperatures in 24 adults and 20 adolescents (mean age = 25.5 years). In the testing phase, these conditioned cues as well as a neutral (unconditioned) cue were presented with moderate temperatures. Results: Thermal discomfort of moderate temperatures was lower when presented with the conditioned low heat cue (placebo-like effect) and higher when thermal stimuli were presented with the high heat cue (nocebo-like effect) compared to the neutral cue. The effects were driven by adults, as neither the placebo-like nor the nocebo-like effect was significant in adolescents. The difference between adolescents and adults was not explained by differences in temperature or discomfort levels, as adults and adolescents had comparable calibrated temperatures and levels of discomfort during heat stimuli. Conclusion: Our findings suggest that thermal perception in adolescents is less influenced by conditioning to an engaging novel visual cue, compared to adults. Our work may have implications for better understanding the scope and limitations of conditioning as a key mechanism of placebo and nocebo effects in youth.

A matter of perspective: Distinct brain mechanisms for evaluating positive and negative social feedback about oneself and another person.

Social rejection is a common experience in the life of young adults. Electroencephalographic (EEG) such as N1, P1 and P3 amplitude has been linked to experiencing social rejection; it remains unclear, whether these components are also influenced by the perspective, e.g., feedback directed to oneself or another person. We used EEG to investigate brain mechanisms associated with social feedback, directed either to oneself or another person. Female students (N = 57) engaged in a Chatroom Interact Task (CIT) during EEG. In this task participants received feedback as to whether themselves or someone else was accepted or rejected as a video chat partner. Mood was measured with the Positive Affect Negative Affect Schedule (PANAS). Participants showed more negative mood after rejection compared to acceptance. Spatiotemporal EEG cluster analysis revealed significant differences in P1, N1 and P3 ERP components associated with Acceptance vs. Rejection. The late positive potential (LPP) component was larger when processing self vs. other-related social feedback. Higher empathy, neuroticism, and lower age were associated with smaller LPP amplitude differences between Self and Other conditions. In this study we identified distinct brain dynamics associated with encoding social feedback and whether the feedback was targeted toward the self or to others.

Placebo and nocebo effects in youth: subjective thermal discomfort can be modulated by a conditioning paradigm utilizing mental states of low and high self-efficacy.

INTRODUCTION: Conditioning is a key mechanism of placebo and nocebo effects in adults, but little is known about these effects in youth. This study investigated whether personalized verbal cues evoking a sense of high or low self-efficacy can induce conditioned placebo and nocebo effects on subjective discomfort of noxious heat in youth. METHODS: In a structured interview, 26 adolescents (13-18 years) described personal situations in which they experienced a sense of high, low or neutral self-efficacy. Participants were then asked to recall these memories during a conditioning paradigm, in which a high thermal stimulus applied to the forearm was repeatedly paired with a low self-efficacy cue and a low thermal stimulus with a high self-efficacy cue. In a testing phase, high, low and neutral self-efficacy cues were paired with the same moderate temperature. We hypothesized that conditioned high and low self-efficacy cues would induce conditioned placebo and nocebo responses to moderate temperatures. RESULTS: Moderate temperatures were rated as more uncomfortable when paired with the conditioned low compared with the neutral self-efficacy cue (nocebo effect). While in the whole-group analysis, there was no significant difference between ratings of moderate thermal stimuli paired with high compared with neutral self-efficacy cues (placebo effect), a sub-group of participants with a greater range of emotional valence between high and neutral self-efficacy cues revealed a significant placebo effect. The strength of the nocebo effect was associated with higher anxiety and lower hope. CONCLUSION: Conditioned associations using internal self-efficacy states can change subjective discomfort of thermal sensations.

Prenatal antidepressant exposure and sex differences in neonatal corpus callosum microstructure.

Prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants may influence white matter (WM) development, as previous studies report widespread microstructural alterations and reduced interhemispheric connectivity in SSRI-exposed infants. In rodents, perinatal SSRIs had sex-specific disruptions in corpus callosum (CC) axon architecture and connectivity; yet it is unknown whether SSRI-related brain outcomes in humans are sex specific. In this study, the neonate CC was selected as a region-of-interest to investigate whether prenatal SSRI exposure has sex-specific effects on early WM microstructure. On postnatal day 7, diffusion tensor imaging was used to assess WM microstructure in SSRI-exposed (n = 24; 12 male) and nonexposed (n = 48; 28 male) term-born neonates. Fractional anisotropy was extracted from CC voxels and a multivariate discriminant analysis was used to identify latent patterns differing between neonates grouped by SSRI-exposure and sex. Analysis revealed localized variations in CC fractional anisotropy that significantly discriminated neonate groups and correctly predicted group membership with an 82% accuracy. Such effects were identified across three dimensions, representing sex differences in SSRI-exposed neonates (genu, splenium), SSRI-related effects independent of sex (genu-to-rostral body), and sex differences in nonexposed neonates (isthmus-splenium, posterior midbody). Our findings suggest that CC microstructure may have a sex-specific, localized, developmental sensitivity to prenatal SSRI exposure.

Informing About the Nocebo Effect Affects Patients' Need for Information About Antidepressants-An Experimental Online Study.

Relevance: Understanding patients' informational needs and adapting drug-related information are the prerequisites for a contextualized informed consent. Current information practices might rather harm by inducing nocebo effects. Objective: To investigate whether informing about the nocebo effect using a short information sheet affects patients' need for information about antidepressants. Methods: A total of 97 patients taking recently prescribed antidepressants (≤4 months intake) were recruited over the internet and randomized to receiving either a one-page written information about the nocebo effect or a control text about the history of antidepressants. After experimental manipulation, informational needs about the side effects and mechanisms of antidepressants were assessed with 3 and 7 items on categorical and 5-point Likert scales. Group differences in informational needs were calculated with Chi-square tests and ANOVAs. Results: Patients received antidepressants for depression (84.5%) and/or anxiety disorders (42.3%). Three participants (6.0%) of the nocebo group reported previous knowledge of the nocebo effect. After the experimental manipulation, participants in the nocebo group reported a reduced desire for receiving full side effect information [ X ( 4 , 97 ) 2 = 12.714, Cramer's V = 0.362, p = 0.013] and agreed more frequently to the usefulness of withholding information about possible side effects [ X ( 4 , 97 ) 2 = 14.878, Cramer's V = 0.392, p = 0.005]. Furthermore, they desired more information about the mechanisms of antidepressants (F = 6.373, p = 0.013, partial η2 = 0.063) and, specifically, non-pharmacological mechanisms, such as the role of positive expectations (F = 16.857, p < 0.001, partial η2 = 0.151). Conclusions: Learning about the nocebo effect can alter patients' informational needs toward desiring less information about the potential side effects of antidepressants and more information about general mechanisms, such as expectations. The beneficial effects of including nocebo information into contextualized informed consent should be studied clinically concerning more functional information-seeking behavior, which may ultimately lead to improved treatment outcomes, such as better adherence and reduced side effect burden.

Conditioned Placebo- and Nocebo-Like Effects in Adolescents: The Role of Conscious Awareness, Sensory Discrimination, and Executive Function.

Background: Conditioning is a key mechanism of placebo and nocebo effects in adults. Little is known about the underlying mechanisms of placebo and nocebo effects in youth and how they might be influenced by conscious awareness and cognitive abilities. In this study, the role of conditioning on thermal perception in youth was investigated. Methods: Differences in thermal ratings were assessed in response to consciously and non-consciously perceived cues that were conditioned to either low or high heat. Furthermore, we tested whether executive function mediates the effect of conditioning on thermal perception. Thirty-five high-school students (14-17 years) completed an executive function task and underwent a sensory perception paradigm. In a conditioning phase, two distinct neutral faces (conditioned cues) were coupled to either a low or a high temperature stimulus delivered to participants' forearms. In a testing phase, the conditioned cues, and novel faces (non-conditioned control cues), were paired with identical moderate thermal stimuli. In this testing phase, for half of the participants cues were presented consciously (supraliminally) and for the other half non-consciously (subliminally). Results: We found a significant main effect of cue type on thermal ratings (p = 0.003) in spite of identical heat being administered following all cues. Post-hoc analyses indicated that the nocebo-like effect (conditioned high cue compared to control) was significant (p = 0.027); the placebo-like effect (conditioned low cue compared to control) was non-significant. No difference between cues presented supra- vs. subliminally and no significant interaction effects were found. The association between sensory discrimination and the magnitude of the nocebo-like effect was mediated by executive function. Conclusions: To our best knowledge, this is the first study establishing a relationship between thermal perception, nocebo effects, and executive function in youth. Our results may have important implications for understanding cognitive/ learning processes involved in nocebo effects.