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

Abstract

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.

Keywords

Adolescents adults nocebo effect placebo effect conditioning thermal perception

Introduction

Several studies in adults have shown that learning processes, such as conditioning, can be used to modulate the perception of pain.^1–6 In these studies, individuals learn to associate a specific cue (e.g., visual, tactile) with pain (e.g. thermal) and another cue with pain relief. In a subsequent testing phase, it is investigated if those conditioned cues can alter the pain or discomfort of intermediate stimulation intensities. The cue-heat association can be either established implicitly (i.e., participants are not informed about the meaning of the cues) or explicitly (i.e., the cue-heat contingency is explained and marked with red/green cues, or labeled as “treatment” when applying a cream). Importantly, during explicit conditioning, the effects of conditioning are intertwined with effects of verbal suggestions. Studies investigating explicit conditioning (cue-heat association was verbalized) in adolescence show conflicting results.^7,8 While previous studies using implicit conditioning suggest smaller effects in youth,^43,44 these effects of youth and adults have not been yet compared within the same study design, which will be done in the current study.

During adolescence, the brain is undergoing crucial changes in structural and functional brain networks,^9–11 possibly affecting conditioned placebo and nocebo effects. For example, the ability to distinguish between threat and safety cues is still maturing in youth, which has been linked to age differences in the maturation of prefrontal and subcortical brain regions.¹² Neuropsychological models emphasize a temporal imbalance of maturation between emotional, social and reward-related brain systems (limbic regions) and brain systems associated with regulation and control of thought and action during adolescence (prefrontal regions).^13,14 An imbalance in the maturation of these systems is associated with increased reactivity toward motivational rewarding stimuli, without appropriate cognitive regulation and serves as a theoretical foundation of difficulties in self-regulation and increased risk behavior during adolescence.^13–17 It remains unclear whether these developmental changes are responsible for weaker or non-significant conditioned placebo-like and nocebo-like effects in youth. Studies in adults point to the importance of prefrontal brain system for pain regulation, as higher activity in prefrontal brain regions, is associated with lower pain ratings,¹⁸ higher magnitude of the placebo-like effect,¹⁹ and decreased activity in other pain processing brain regions.²⁰ Furthermore, inhibition of prefrontal brain regions with transcranial direct current stimulation (tDCS), was able to diminish placebo and nocebo effects.^21,22 This study therefore adds to the current literature, by investigating whether there are differences between placebo-like and nocebo-like effects induced by an implicit conditioning paradigm in youth and adults.

We hypothesize that implicit neutral cues can be used in a conditioning paradigm to modulate thermal discomfort (low heat cues decrease discomfort, whereas high heat cues increase discomfort) and that these effects would be smaller in adolescents compared to adults.

We furthermore investigated whether hope, anxiety and interoceptive awareness would predict the magnitude of placebo-like and nocebo-like effects. In previous studies it has been shown that high hope is associated with less pain,^23,24 and lower nocebo-like effects.⁴⁴ To the best of our knowledge, interoceptive awareness has not yet been investigated in relation to placebo and nocebo effects. Higher interoceptive awareness, however, has been associated with lower pain thresholds and pain tolerance in response to pressure pain.²⁵ That is, if participants are more aware of/are more able to detect their inner sensations, they were found to be more sensitive to pain.

Methods

Participants

In total, N = 44 participants were included in the analysis of this study (N = 52 participants finished the trial but n = 5 participants had to be excluded due to technical issues, n = 3 had to be excluded due to showing outliers greater than 3 standard deviations above and below the mean). The sample included adolescents (n = 20; age: mean = 15.6 years, SD = 1.09; 18 female) recruited in local high schools, and adults (n = 24, age: mean = 25.5 years, SD = 5.44; 17 female) recruited through the University of British Columbia Paid Studies List. Individuals with any chronic illness or medication use that would potentially interfere with the study, such as psychiatric disorders and or medication that can influence cognition or emotional processing (i.e., sleep medication, antidepressants, anti-convulsants or opioids), were excluded. An a priori power-analysis for a one-way repeated measures ANOVA, within-between interaction was conducted with G*Power²⁶ in order to determine the needed sample size. A necessary sample size of n = 50 was estimated, assuming a medium effect size of Cohen´s f = 0.30 (estimated based on previous studies in adults Jensen et al.¹ and youth^43,44) and a correlation of 0.16 between the measurements as found by Jensen et al.,¹ α = 0.05 and a 95% chance of detecting an effect. Due to the COVID-19 pandemic data collection was stopped before reaching the recruitment goal of 50 participants (when accounted for outliers).

Procedure

The study was approved by the University of British Columbia Research Ethics Board and the BC Women´s Hospital Research Review Committee. All participants (or parents if participants were <19 years of age) gave written informed consent before starting the study. Participants then completed the thermal conditioning paradigm, in which participants were asked to rate thermal stimuli applied to their forearm. The paradigm consisted of a calibration phase, a conditioning phase and a testing phase. Afterwards, they were asked to fill out the personality questionnaires and a post study questionnaire. Adult participants were debriefed after study participation. Adolescent participants were debriefed in groups in their high schools. All participants received a 20 dollar gift card for their participation.

Thermal conditioning paradigm

The thermal conditioning paradigm was similar to previous studies^1,43,44 and consisted of a calibration phase, a conditioning phase and a testing phase. Thermal stimuli were presented for 4 s with a ramp up and ramp down period of 8 degrees per second using the Thermal Sensory Analyzer (Medoc Advanced Medical Systems, Rimat Yishai, Israel; Biomedical Engineering Device), with a 3 cm × 3 cm probe, on participants left volar forearm.

During the calibration phase a high and low thermal stimulus was determined. Calibration started at 36°C. Each temperature was presented three times and then increased in steps of 1°C. On each trial, participants were asked to rate their discomfort on a visual numeric scale between 0 (“no discomfort”) and 100 (“worst imaginable discomfort”). The thermal stimulus, which was rated as a subjective discomfort rating of 60 on the visual scale, was used as high heat stimulus. The low heat stimulus was determined by subtracting 3°C from the high heat stimulus. As adolescents are considered a vulnerable population, all participants were instructed that the sensation would be “warm” but should not be painful. We therefore asked them to verbalize if the stimulus was getting painful. The average temperature for the high heat stimulus was 44.9°C (SD = 2.06°C; adults M = 44.60°C (SD = 15.02) and adolescents: M = 45.09°C (SD = 13.31)). Three distinct blue Fribbles were used as visual cues for the conditioning design. Fribbles are novel artificial 3D-shaped objects composed of shapes in different colors and textures, which are well established and evaluated for research.²⁷ During the conditioning phase, the low and high heat stimulus was repeatedly paired with two different Fribbles, that is, the conditioned cues. Discomfort was rated on a computerized visual numeric scale.

The conditioning phase consisted of 2 blocks with a total of 44 cue stimulus-heat parings, with 20 high and 20 low temperatures each paired with the high and low temperature conditioned Fribbles, respectively. Four trials were catch trials, in these trials the low and high temperature was paired with a blue hexagon shaped visual cue. Participants were asked to press a button in response to the catch trial to focus participants’ attention to the cues on the screen. Catch trials and first trials were excluded from the analyses. Cues were visible for the entire duration of the thermal stimulus (4 s). During the testing phase, moderate temperatures were presented with the same two Fribbles, plus a novel unconditioned Fribble.

The testing phase consisted of a total of 66 trials presented in 3 blocks, 48 were cue-moderate heat pairing trials (14 high cue/moderate heat, 14 low cue/moderate heat, 20 neutral cue/moderate heat), 12 booster trials (6 low cue/low heat, 6 high cue/high heat) and 6 catch trials (2 low cue/moderate heat, 2 high cue/moderate heat, 2 neutral/moderate heat). The booster trails were used to prevent extinction. The first trial of each block (3 neutral cues), the booster trials, and the catch trials were excluded from the analyses. For both the conditioning and testing phase, the intertrial interval varied randomly from 3 to 5 s. Between runs, participants were able to take a short break if needed. Study design is visualized in Figure 1.

Questionnaires

State and trait anxiety was measured with the State Trait Anxiety Questionnaire (STAI).²⁸ Hope was measured with the Hope Scale.²⁹ The Multidimensional Assessment of Interoceptive Awareness (MAIA, youth and adult version) was applied to assess different aspects of interoceptive awareness.³⁰ For the analysis, we focused on the subscales “Body Listening” and “Not Distracting,” as they were considered relevant for learning and placebo-like and nocebo effects. The “Body Listening” subscale is measuring the ability to listen to bodily symptoms. The “Not Distracting” subscale is measuring the tendency to distract oneself from uncomfortable sensations.

Post study questionnaire

After completing the study, the investigator completed a brief interview with participants about the nature of the study. Participants were asked what they thought the study tested, and to indicate how many different levels of temperatures they thought we used during the thermal conditioning paradigm.

Outcomes

Subjective discomfort, as rated on the visual numeric scale, was used as main outcome. Mean discomfort was calculated for low and high heat stimuli in the conditioning phase. Sensory discrimination was calculated by the difference of mean discomfort of high and low heat in the conditioning (i.e. learning) phase. For the main analysis, mean discomfort of moderate temperatures paired with the high heat cue, low heat cue, and neutral cue, presented during the testing phase was calculated. The placebo-like effect was defined as the difference in mean discomfort between moderate temperatures paired with neutral and low heat cues, and the nocebo-like effect was defined as the difference in mean discomfort between moderate temperatures paired with high heat cues and neutral cues. The overall magnitude of the conditioning effect was estimated as difference in discomfort between a moderate temperature paired with high versus low heat cues.

Statistical approach

The influence of conditioning on thermal ratings was analyzed using mixed repeated measures analyses of variance (rmANOVA) with Cue Type (high cue, low cue, or neutral cue) as a within-subjects factor, age group (adult, adolescents) as between-subjects factor and Cue Type*age as interaction term. Hochberg corrected post hoc paired t-tests were conducted for significant rmANOVA effects. A multiple regression analysis was conducted in order to identify unique contributions of individual differences in personality traits (hope, anxiety, interoceptive awareness) to the magnitude of conditioned placebo-like and nocebo-like effects. A significance level of p < .05 was used, and if applicable, Bonferroni-corrected for multiple comparisons. Statistical analyses were performed using the statistical software R, Version 3.6.1.³¹ RmANOVAs were calculated with the package ezANOVA,³² and graphics were compiled with ggplot2.³³ If sphericity assumption was violated, p-value was corrected (Greenhouse-Geisser for ε < 0.75 and Huynd-Feldt for ε > 0.75).

Results

Differences between youth and adults in temperature and discomfort

Adults (M = 44.54°C) and youth (M = 45.10°C) did not differ in the individually calibrated high temperature (t(42) = −0.89, p = .375). They also did not differ in how much discomfort they experienced during the high (adult: M = 47.36, youth: M = 45.29, t(42) = 0.488, p = .628) and the low temperature (adult: M = 13.13, youth: M = 13.18, t(42) = −0.01, p = .988). Additional analyses regarding differences in sensory discrimination (defined as rated discomfort of high heat minus rated discomfort of low heat stimuli during the conditioning phase), as well as standard deviations calculated (based on trial differences in discomfort ratings for each phase and temperature level or cue separately) on trial-by-trial basis between adults and youth did not reach significance (see Table 1).

Table 1.

Differences in discomfort ratings between youth and adults.

	Mean	Statistics
Sensory Discrimination	Adults: M = 35.26	t(42) = 41.86, p = .591
Sensory Discrimination	Youth: M = 32.84	t(42) = 41.86, p = .591
Standard deviation of discomfort in
Conditioning phase low heat	Adults: M_SD = 5.96	t(42) = 41.98, p = .291
Conditioning phase low heat	Youth: M_SD = 5.08	t(42) = 41.98, p = .291
Conditioning phase high heat	Adult: M_SD = 6.89	t(42) = −0.70, p = .490
Conditioning phase high heat	Youth: M_SD = 7.50	t(42) = −0.70, p = .490
Testing phase moderate heat with low cue	Adults: M_SD = 6.53	t(42) = 36.00, p = .858
Testing phase moderate heat with low cue	Youth: M_SD = 6.70	t(42) = 36.00, p = .858
Testing phase moderate heat with moderate cue	Adults: M_SD= 6.77	t(42) = 35.86, p = .703
Testing phase moderate heat with moderate cue	Youth: M_SD = 6.42	t(42) = 35.86, p = .703
Testing phase moderate heat with moderate cue	Adults: M_SD = 7.10	t(42) = 40.17, p = .542
Testing phase moderate heat with moderate cue	Youth: M_SD = 6.55	t(42) = 40.17, p = .542

Thermal sensory discrimination

During the conditioning phase, rmANOVA revealed a significant main effect of temperature on self-reported discomfort, F(1,42) = 278.15, p < .001, indicating that participants rated the high temperature higher (M = 46.42, SD = 14.07) than the lower temperature (M = 13.15, SD = 10.14). The main effect for the age group did not reach significance, F(1,42) = 0. 10, p =.750, neither did the interaction between temperature and age group, F(1,42) = 0.28, p = .599. This indicates that adults and adolescents did not differ in their discomfort ratings associated with the individually calibrated low and high temperatures.

Thermal conditioning

During the testing phase, rmANOVA revealed a significant main effect for the factor Cue Type, F(284) = 13.59, p <.001, indicating that participants perceived moderate temperatures differently depending on which cue was paired with the stimulus, a non-significant main effect for the factor Age group (F(1,42) = 0.27, p = .608), and a significant Cue Type*Age group interaction (F(2,84) = 4.56, p = .013), indicating that the effects differed between youth and adults. Hochberg corrected post hoc paired t-test revealed a moderate to large significant conditioning effect (M_Diff = 6.53 p = .002, d = .55 [.25 .84]), indicating that adults perceived the moderate temperature paired with the high cue as more uncomfortable than when the same moderate temperature was paired with the low cue. The difference in mean discomfort between the same moderate temperature paired with neutral and low cues was significant (M_Diff = 3.82, p = .006, d = .32 [.11 .53]), reflecting the presence of a moderate significant placebo-like effect. Similarly, the difference in mean discomfort ratings between a moderate temperature condition paired with high and neutral cues was significant, reflecting a small significant nocebo-like effect (M_Diff = 2.71, p = .006, d = .22 [.07 .38]). None of the effects, however, reached significance in the youth group alone (conditioning effect M_Diff = 1.58 p = .520, d = .10 [.05 .26]; placebo-like effect M_Diff = 0.75 p = 1.00 d = .06 [.10 .21]; nocebo-like effect M_Diff = .83 p = .980, d =.05 [.05 .16]. Results are visualized in Figure 2.

Association between sensory discrimination and conditioned effects

There was a moderate significant positive correlation between sensory discrimination and the conditioned effects (r = .34 p = .025), meaning the better the discrimination between heat stimuli during the conditioning phase, the greater the differences in discomfort ratings for low or high cues in the testing phase. Interestingly, adults and youth differed in the correlation between sensory discrimination and the conditioned effect. While there was a significant large positive correlation in adults (r = .48, p = .015), adolescents showed a moderate positive, but non-significant correlation (r = .23, p = .333).

Post study questionnaire

During the post study interview participants were asked to indicate how many different levels temperatures they perceived during the thermal sensation paradigm. Two participants did not mention a specific number, and were therefore excluded from the analysis. Most participants reported having experienced five different temperature levels, with an average of 6.09 different temperature levels. Only two participants (one adult, one adolescent) stated correctly that we used three different levels of temperatures. Four participants reported more than 10 different levels. Adolescents and adults did not differ in the amount of reported temperature levels (M_youth = 6.84, M_adults = 5.50, t(21) = −0.97, p = .344).

Personality traits: anxiety, hope, and interoceptive awareness

We furthermore tested whether different personality traits (anxiety, hope, and interoceptive awareness) were associated with the strength of placebo- and nocebo-like effects. As the placebo- and nocebo-like effect was only significant in the adult group, only adults were included. We ran a stepwise regression model, which automatically selected the best fitted predictors for placebo- and nocebo-like effects, by bidirectional elimination of the predictors. We included hope, trait anxiety, as well as “Body Listening” and “Not Distracting” in the model. For the placebo-like effect the model with “Not Distracting” and “Body Listening” was the best fitting model (F(2,21) = 4.69, p = .031 adj. R² = 0.21), with “Not Distracting” (standardized β = −.459, p = .024) as a significant factor. The factor “Body Listening” was not significant (standardized β = −.369, p = .064). This means that adults with a lower ability to distract themselves from pain showed higher placebo-like effects. Results are displayed in Figure 3. For the nocebo-like effect none of the models reached significance.

Discussion

Implicit conditioning to a novel visual cue induced significant placebo- and nocebo-like effects in adults but not in youth. There was a moderate to large correlation between sensory discrimination of different heat stimuli and the magnitude of conditioned effects in adults, whereas this correlation did not reach significance in youth. Further, in adults a high magnitude of the conditioned placebo-like effect was predicted by a low tendency to distract oneself from uncomfortable sensations.

In adults, it has been shown that pain amplification and pain relief cues, established during a conditioning paradigm, can be used to modulate the perception of pain.^1–6 Successful conditioning requires the establishment of a predictive mental model to create a strong expected contingency between a cue and a response. During adolescence, the brain is undergoing crucial changes in structural and functional brain networks,^9–11 possibly affecting conditioned placebo- and nocebo-like effects to occur (or magnitude), as suggested by previous studies.^8,43,44 Results revealed a significant placebo- as well as nocebo-like effect in adults, as shown in previous studies.¹ In youth, neither the overall conditioning effect, nor the specific placebo and nocebo-like reached significance, while calibrated temperatures and reported levels of discomfort during calibration where similar in youth and adults. In two previous studies by our lab, we found significant nocebo-like but no significant (overall) placebo-like effects in youth,^43,44 suggesting that differences between youth and adults in conditioning paradigms might vary with the cues used in the conditioning paradigm. It is possible that the ability to establish a predictive mental model of the cue-heat association during the conditioning phase is reduced in youth, especially during implicit learning when there are no explicit suggestions or intuitive association between cue and discomfort. It seems that engaging and more distinct cues (i.e., neutral facial cues and self-efficacy memories vs. Fribbles), enhances conditioning effects in youth as suggested by comparing the effect size from our study with our previous studies.^43,44 In line with this idea, a study from Lau and colleagues¹² showed that the ability to distinguish between threat and safety cues is still maturing in youth. Furthermore, the more different participants experienced the thermal sensations to be during the conditioning phase, the stronger the conditioned effect.^1,43 The ability to discriminate sensory stimuli (e.g. odors, visual cues, pitch, touch) is also associated with higher executive functioning,^34–36 and executive functioning mediated the association between sensory discrimination and the nocebo-like effect in youth in our previous study.⁴³

When explicitly informing participants about cue-heat association (e.g. this cream is effective) Wrobel et al.⁷ found a placebo effect, and the magnitude of the placebo effect did not differ between children/youth (10–15 years) and adults. Interestingly, using a similar design Gniß and colleagues⁸ found a significant placebo effect in children (6–9 years and 10–13 years) in response to conditioning, but no effect in youth (14–17 years).

It could also be that youth need more trials to establish a predictive model. In adults, it has been shown that more trials resulted in more robust placebo and nocebo effects during explicit conditioning.³⁷ Enhancing the number of trials might make it easier to establish a mental prediction model. Another possibility is that the establishment of a predictive mental model is comparable between adults and youth, but that the extinction of the learned cue-heat association is faster in adolescence, leading to a more precise experience of the heat stimuli compared to adults. Adolescence is an important developmental window¹⁵ and it might be adaptive to re-evaluate predictive cues quickly. However, Waters and colleagues³⁸ found that youth compared to adults had more difficulties to re-evaluate cues when their meaning was changed from threat to safety during fear conditioning. It is therefore more likely that sensory discrimination and/or number of trials needed to for prediction explains differences between youth and adults in the present study.

Last, we investigated whether hope, trait anxiety, as well as the interoceptive awareness dimensions “Body Listening” and “Not Distracting” were predictive of the magnitude of placebo- and nocebo-like effects. The placebo-like effect was predicted by “Not Distracting,” showing that adults with a poorer ability to distract themselves from pain showed higher placebo-like effects. This may seem counterintuitive at first glance; however, our data may suggest that conditioned placebo-like effects are more easily established in participants who attend to the uncomfortable sensations during the learning phase. This supports the assumption that participants have to sustain attention toward the heat-cue association in order to establish a predictive model, and to evoke a motivational drive. None of the other factors in the placebo-like model, and no factor in the nocebo-like model, reached significance, in spite of previous studies suggesting that, for example, anxiety and hope are associated with placebo- and nocebo-like effects.^23,24,39,44

Limitations and future studies

The present study is small and thus the effect sizes and correlations need to be interpreted in light of low statistical power. Effect sizes may also get inflated in small samples.^40–42 For example, Schönbrodt and Perugini⁴⁰ showed that a sample size of n = 250 is needed for a stable estimate of correlation coefficients. Thus, the present study should be interpreted with caution. In particular, the sample used for the regression analysis was small, and the nocebo effect showed a smaller effect size. It might therefore be possible that there was not enough power and not enough variance to show effects for the nocebo-like effect.

In order to unpack the differences between youth and adults in conditioned placebo and nocebo effects, it would be helpful to utilize various brain imaging methods, such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG) or diffusion tensor imaging (DTI). Such data would be able to elucidate the role of brain development on conditioning and the magnitude of placebo and nocebo effects. It would also be helpful to further investigate the data on a trial-by-trial basis, to get a better idea of whether the differences in youth and adults are expressed during different phases of the experiment (e.g. acquisition or extinction).

Conclusions and significance

Conditioning with implicit cues induced placebo-like and nocebo-like effects in adults but not in youth. Our findings may have implications for better understanding the scope and limitations of conditioning as a key mechanism of placebo and nocebo effects in youth.

Footnotes

Acknowledgements

We would like to thank all youth and adults for their participation. We also thank the teachers and principals for their support during data collection.

Author contributions

All authors have discussed the results and commented on the manuscript. Thus, our authorship is based on (1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; (3) final approval of the version to be published.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Support for this research was provided by a Brain, Behavior & Development Theme Catalyst Grant from BC Children’s Hospital Research Institute to CT and TFO and an Investigator Establishment Award to CT.

Ethical approval

The study was approved by the University of British Columbia Behavioral Research Ethics Board and the BC Women’s Hospital Research Review Committee, certificate number H16-01192.

Informed consent

Written informed consent was obtained from the parents or legal participants, as well as written informed assent from participants themselves for their anonymized information to be published in this article.

Guarantor

TFO

Contributorship

EW was responsible for the research question, designing the study, data collection and analysis, and wrote the manuscript. BE was responsible for the data collection and manuscript preparation. RN, KJ, CT and TFO contributed to the design of the study. TFO and CT were responsible for overseeing the development of research design and research question, data analysis and manuscript preparation. All authors contributed to manuscript revision, read, and approved the submitted version.

ORCID iDs

Ella Weik

Tim F Oberlander

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