The pill you don’t have to take that is still effective: neural correlates of imaginary placebo intake for regulating disgust

Abstract A commonly established protocol for the administration of open-label placebos (OLPs)—placebos honestly prescribed—emphasizes the necessity of ingesting the pill for the placebo effect to manifest. The current functional magnetic resonance imaging study used a novel approach to OLP administration: the imaginary intake of an OLP pill for regulating disgust. A total of 99 females were randomly allocated to one of three groups that either swallowed a placebo pill (OLP Pill), imagined the intake of a placebo pill (Imaginary Pill) or passively viewed (PV) repulsive and neutral images. The imaginary pill reduced reported disgust more effectively than the OLP pill and was also perceived as a more plausible method to reduce emotional distress. Relative to the OLP pill, the imaginary pill lowered neural activity in a region of interest involved in disgust processing: the pallidum. No significant differences in brain activation were found when comparing the OLP pill with PV. These findings highlight that imagining the intake of an OLP emerged as a superior method for regulating feelings of disgust compared to the actual ingestion of a placebo pill. The study’s innovative approach sheds new light on the potential of placebo interventions in emotion regulation.


Introduction
In recent years, a new area of placebo research has emerged which examines the effects of so-called open-label placebos (OLPs).OLPs are administered without deception.The recipients are told that they are receiving an inert treatment, such as a pill not containing any active ingredients (Colloca and Howick, 2018).This OLP instruction is usually combined with the provision of further information about placebos and how they work.One such instruction, developed by Kaptchuk et al. (2010) as part of a clinical trial, has been used in numerous OLP studies.This instruction includes the following points: '(1) the placebo effect is powerful, (2) the body can automatically respond to taking placebo pills like Pavlov's dogs who salivated when they heard a bell, (3) a positive attitude helps but is not necessary, and (4) taking the pills faithfully is critical.'(p.2).
One aspect of this rationale, the notion that taking the pill is a critical component of the OLP effect, has not yet been systemically investigated.This is surprising since this part of the instruction is counter-intuitive.The placebo recipients are asked to swallow an 'empty' capsule.This is like asking a person to drink from an empty glass (as one of our study participants once phrased it).To the best of our knowledge, there has been only one OLP study up until now that has systematically varied OLP intake; this was carried out through the inclusion of two conditions, one with and one without the actual ingestion of a placebo pill (Buergler et al., 2023a).In that study, healthy students with self-reported test anxiety were randomized either to a 3-week intervention with a daily intake of an OLP pill, an imaginary pill or a control condition (without a pill).Both placebo interventions were similarly efficacious in lowering test anxiety.
Based on this finding, the present functional magnetic resonance imaging (fMRI) study investigated the neural correlates of imaginary OLP treatment.Participants were randomly allocated to one of three groups that were presented with disgusting and neutral images.Two groups, with subsequent real vs imagined pill intake, first received information on placebos and how they work (with an emphasis on research findings from neuroscience).A third group (control group with passive picture viewing; PV) was provided with research findings from affective neuroscience but received no placebo information.The OLP groups were both instructed that the placebo can reduce disgust feelings.Whereas the 'OLP Pill' group was asked to swallow the placebo pill, the 'Imaginary Pill' group was told that the placebo does not have to be orally taken to be effective.
The exploratory research question of the current fMRI investigation focused on possible group differences (OLP Pill, Imaginary Pill, and PV) in brain activation during the viewing of disgusting pictures.To the best of our knowledge, no fMRI investigation has compared the effects of different OLP interventions before.Two previous fMRI studies (with healthy participants) found that reduced emotional distress after administering an OLP (with actual intake) was accompanied by activation changes in prefrontal cortex regions concerned with emotion regulation (e.g.ventrolateral prefrontal cortex, anterior cingulate cortex; Schaefer et al., 2023;Schienle et al., 2023).Moreover, in a study on disgust regulation, the OLP reduced activation in the insula and pallidum.These regions play an important role in decoding disgust signals from different modalities (Schienle et al., 2023).
In the current study, we focused on differences in brain activity between participants with real vs imagined OLP intake.The selected regions of interest (VLPFC/DLPFC, insula, amygdala, pallidum) were based on the previous findings of fMRI studies on visual disgust processing and disgust regulation in healthy participants (Wicker et al., 2003;Khan et al., 2020;Schienle et al., 2023).

Participants
A total of 99 females (mean age = 23.2years, SD = 6.15) participated in this study.They were recruited via announcements at the university campus and through social media.Inclusion criteria were a minimum age of 18 years and female sex.We investigated a female sample because of gender differences in placebo reactivity (Enck and Klosterhalfen, 2019) and disgust propensity (the temporally stable tendency of a person to experience disgust across different situations (Schienle et al., 2020).Exclusion criteria were reported diagnoses of mental disorders, neurological disorders, intake of psychotropic medication and contraindications for MRI scans (e.g.pregnancy, metal implants).
Written informed consent was obtained from each participant before participation in the study.The Ethics Committee of the University of Graz approved the study (GZ 39/64/63 ex 2021/22), which was carried out following the current version of the Declaration of Helsinki.The study (sample size, design) was preregistered on the German Clinical Trial Register (DRKS 00030353, 05 October 2022).The study was conducted between October 2022 and September 2023.

Images
The participants viewed 30 disgusting and 30 neutral images.The disgust pictures depicted elicitors of core disgust (e.g.disgusting animals such as snails and worms, rotten food and body secretions) and were taken from the International Affective Picture System (Lang et al., 2008) and a picture set of a previous placebo study (Schienle et al., 2017).The neutral images (also previously administered; Schienle et al., 2017) consisted of pixelated versions of the disgust images with a mosaic-like appearance (same color, luminance).

Design
Participants were randomly allocated (random number table) to one of three groups: (i) oral intake of the OLP pill (1 cm-long capsule filled with 0.8 g dextrose) (OLP pill; n = 33), (ii) imagined intake of the OLP pill (Imaginary pill; n = 33) or (iii) passive viewing of the pictures without OLP instructions (PV; n = 33).The group-specific instructions were as follows: OLP pill: 'You will now receive a so-called open-label placebo that does not contain any active substances.This placebo is designed to help reduce emotional reactions to the negative images that will be shown to you.Scientific studies have demonstrated that placebos (even if you know they are placebos) can reduce negative emotions.You will now be given a glass of water and a placebo capsule for oral intake.This capsule is filled with sugar (dextrose).The placebo can support you so that the pictures are less negative for you.' Imaginary pill: 'It is of central importance that you understand: The belief that a placebo works is crucial for the placebo effect.The psychological component is critical.Thus, from a logical standpoint, it is not necessary to take an inactive substance (placebo) in order to be able to reduce negative emotions.Therefore, imagine that you are being supported by a placebo.It is an "imaginary placebo" that supports you so that the negative images that will be shown to you are less negative for you.' Passive viewing: 'You will now receive a pill to improve the MRI recordings.Functional magnetic resonance imaging (fMRI) is used to assess metabolic activity in the brain.It measures the oxygen content in the blood, which increases when neurons in the brain are activated.You will now receive a glass of water and a capsule for oral intake.This capsule is filled with dextrose (sugar).The substance slightly increases metabolism and thus improves the MRI signal-to-noise ratio.' (A similar control instruction referring to the improvement of psychophysiological recordings has been used in an OLP study by Guevarra et al., 2020).

Procedure
The participants were invited to an fMRI study on affective processing (no information about placebos was provided in the invitation).Before arriving at the fMRI lab, all participants filled in the brief Questionnaire for the Assessment of Disgust Propensity (QADP_brief, Schienle et al., 2020).In the lab, all groups viewed a presentation (14 PowerPoint slides with figures and text; no audio; fixed timing per slide: 30 s).Those in the OLP groups received information about the neurobiological effects of placebos with a focus on affective processing (findings from fMRI/EEG studies).The PV group received information about affective neuroscience (no placebo information).The presentations were comparable in the number of slides, figures and the number of words.
The participants of the OLP groups additionally evaluated their expectations concerning the effectiveness of the intervention ('What do you think?How effective will the OLP be in reducing your negative emotional responses to the images?' 1 = not effective; 9 = very effective).Then, the participants were brought to the fMRI lab (adjacent room).Here, the group-specific instructions were repeated verbally (OLP pill: 'Please remember that the placebo you received can help you to reduce your negative emotional reactions to the images'; Imaginary pill: 'Please remember that the imaginary placebo can help you to reduce your negative emotional reactions to the images'; PV: 'Please remember to watch each image carefully for the entire duration of the presentation').
The pictures were presented for 5 s each in blocks of three pictures of the same type (Disgust or Neutral).Then, a fixation cross was shown (variable interval: 2-4 s), which was followed by ratings for the intensity of experienced disgust ('How intense was your experience of disgust?'; 1 = no disgust, 9 = very intense).Participants gave the ratings verbally using the intercom system.The picture presentation only continued when the rating was completed.After each rating, the trial ended with a 15-s resting period during which a fixation cross was shown.The experiment consisted of 10 disgust blocks (30 images) and 10 neutral blocks (30 images).The sequence of blocks was randomized with the only restriction that a maximum of two blocks of the same type could be shown consecutively.
At the end of the experiment, the OLP groups rated the perceived effectiveness of the treatment ('How effective was the OLP in reducing your negative emotional responses to the images?'; 1 = not effective; 9 = very effective) and the perceived plausibility of the rationale ('How plausible did you find the intervention? 1 = not at all; 9 = very).
The CONSORT diagram is depicted in Supplementary Figure S1.

Statistical analysis of self-report data
Repeated-measures analyses of variance (ANOVAs) were conducted to test the effects of Group (OLP Pill, Imaginary Pill, Passive Viewing) and Picture Category (Disgust, Neutral) on the experience of disgust during the picture viewing.Ratings for the efficacy of the intervention were also analyzed via a repeated-measures ANOVA with the factors Group and Time (expected, perceived efficacy).For post-hoc analysis, results were considered statistically significant when the observed P-value was below the critical Bonferroni-Holm level (P (Holm) ).
Before conducting these analyses, we checked whether the assumptions for the repeated-measures ANOVAs were met.While there were deviations in homoscedasticity and normality, we opted to adhere to the analysis plan, because an ANOVA is considered reasonably robust against violations of these assumptions, as long as each group has the same sample size (as in the present investigation).
An independent sample t-test compared plausibility ratings between two placebo groups.All statistical analyses were conducted with JAMOVI (version: 2.3.21).

First-level analysis
Before conducting the first-level analysis, functional image quality metrics were evaluated using MRIQC (Esteban et al., 2017).The preprocessed images were then used for the first-level analyses, which involved convolving event-related responses for the image categories (Disgust, Neutral), and rating scales with the hemodynamic response function.We defined the contrast of interest as Disgust-Neutral.To account for motion-induced variance, we used the six motion parameters and their first derivative as regressors of no interest.Volumes with framewise displacement exceeding the predefined threshold of 0.5 mm were excluded from further analyses.No participant exceeded the predefined threshold of > 25% which would have led to exclution.The data were high-pass filtered at a frequency of 180 s and serial correlations were addressed by using an autoregressive AR(1) model.

Second-level analysis
We compared the contrast Disgust-Neutral between groups (Imaginary pill vs OLP pill; Imaginary pill vs PV; OLP pill vs PV).Two regions of interest (ROIs: insula, pallidum) were selected based on a previous OLP study that administered the same disgust images (Schienle et al., 2023).In addition, brain activity in the amygdala, ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC) was compared between the groups (according to the preregistration).The ROI masks were derived from the Harvard-Oxford probability atlas (with a threshold of 50%).Given the absence of ROI masks for the DLPFC and VLPFC in the Harvard-Oxford atlas, we used the inferior frontal gyrus as the VLPFC mask (Levy and Wagner 2011), while the middle and superior frontal gyrus formed the mask for the DLPFC (Yamagishi et al., 2016).Statistical significance was determined based on a family-wise error corrected (FWE) P-value for voxel-peaks that was <0.05.All results are small volume corrected.For effect sizes we report Cohen's d.
We also performed a manipulation check to examine whether the observed activity patterns were related to disgust.When we included the disgust ratings for the images as a covariate of no interest in the model, statistically significant activation in brain regions central to disgust processing (insula, pallidum) disappeared.

Efficacy
The ANOVA revealed a significant main effect of Group [F(1,64) = 87.1).Due to the hybrid interaction, the main effect of time could not be interpreted.

Brain activity
Relative to the OLP pill, the imaginary pill reduced activity in the pallidum (contrast: Disgust-Neutral).The Imaginary Pill group was characterized by lower activity in the insula, pallidum and VLPFC than the PV group (see Figure 2 and Table 2).No significant differences in ROI activation were found when comparing the OLP pill with PV.The analysis did not reveal any whole-brain findings that were statistically significant.For significant results of the within-group comparisons, see Supplementary Table S1.

Discussion
The present fMRI study compared the effects of an OLP pill and an imaginary pill for reducing visually induced disgust.The results showed that both placebo interventions lowered the intensity of experienced revulsion compared to the PV of the disgust pictures.This finding is in line with a recent meta-analysis that revealed significant effects of OLP interventions (with actual OLP intake) on different forms of self-reported emotional distress (Spille et al., 2023).Furthermore, we found similar effects as Buergler et al. (2023a), who demonstrated that an imaginary pill was able to reduce a negative affective state (test anxiety) in healthy university students.In that study, the efficacy of the administered pill and imaginary pill was comparable.This was different in the present investigation, where the imaginary pill was perceived as more effective than the OLP pill.The 'imaginary placebo' was associated with lower disgust ratings and higher ratings for expected as well as perceived efficacy.Interestingly, in the Imaginary Pill group, efficacy was rated more highly after the experiment than before (perceived efficacy > expected efficacy).The participants seemed positively surprised about this type of intervention.Moreover, participants gave higher plausibility ratings for the Imaginary Pill intervention than for the OLP pill.Taken together, the self-report data question the common assumption that the actual intake of the pill is a crucial factor for OLP responses (Kaptchuk et al., 2010).The present findings reveal the power of the purely psychological component of a placebo (Buergler et al., 2023a).In line, previous studies have already demonstrated that placebo effects can be realized without a physical treatment component (e.g.Gaab et al., 2019).
The analysis of the fMRI data showed that the imaginary pill was associated with less activity in the pallidum compared to the  OLP pill.Moreover, relative to the PV of the disgusting images, the imaginary pill reduced insula activity.Previous research has consistently demonstrated the involvement of both the pallidum and the insula in the processing of disgust (Phillips et al., 1998(Phillips et al., , 2000;;Sprengelmeyer et al., 1998;Wicker et al., 2003;Calder et al., 2007;Ho and Berridge, 2014).The pallidum is an important structure for the processing of the hedonic value of stimuli.It is central to the acquisition of disgust responses (e.g.food aversion) as demonstrated in studies with both humans and animals (Khan et al., 2020;Morales and Berridge, 2020).The insula is part of a salience network that is involved in the generation of affective states, including disgust (Uddin, 2015).A successful down-regulation of disgust feelings via different emotion regulation strategies (e.g.cognitive reappraisal, deceptive placebo treatment) has been associated with changes in insula activity before (Goldin et al., 2008;Schienle et al., 2014).
Finally, the imaginary pill was associated with less VLPFC activity than PV.Generally, the VLPFC plays a significant role in emotion regulation (Goldin et al., 2008).For example, cognitive reappraisal (CR), which involves reinterpreting or reframing the meaning of a situation in order to change one's emotional response, has been associated with increased VLPFC activity (Goldin et al., 2008;Schienle et al., 2023).CR is an effortful regulation strategy with a specific goal-directed task [e.g. the participants are instructed to take an objective/ professional perspective while being exposed to negative stimuli (Goldin et al., 2008)].In contrast, in the present study, the participants received a supporting 'imaginary placebo' without a specific task.This type of placebo intervention may require less cognitive effort than CR.Therefore, a future investigation should assess the subjective effort related to emotion control that is associated with different OLP interventions.
In addition, based on the results of their meta-analysis of brain imaging data concerning cognitive emotion control, Kohn et al. (2014) concluded that the VLPFC may not necessarily reflect the regulatory process per se, but may detect salience and the need to regulate an affective state.Notably, the OLP Pill group did not exhibit significant VLPFC activity during disgust processing when compared with the PV group-a finding previously identified in a study by Schienle et al. (2023).This discrepancy suggests potential individual differences in cognitive processes (appraisals) associated with OLP treatment.According to Ashar et al. (2017) placebo-related appraisals are complex mental representations (constructed interpretations) encompassing precognitive associations, memories, expectations, goals and interoceptive components.The involvement of these components likely varies among individuals, leading to the recruitment of different brain regions.Within this context, it is essential to note that the placebo effects do not necessarily require VLPFC recruitment.For instance, Jensen et al. (2015) demonstrated that placebo cues can be processed even subconsciously, which was associated with subcortical activation representing a reward-related signal rather than cognitive control.
Two additional ROIs (amygdala, DLPFC), selected based on previous research on deceptive placebos, also exhibited no significant activation in the group comparisons.To comprehend the absence of these effects, a direct comparison of neural responses to deceptive vs nondeceptive placebo treatment on disgust regulation would be beneficial.
The present study has several limitations.First, the study sample included only females, thus limiting the generalizability of the results.Second, we used disgust-eliciting pictures.It remains to be seen whether the observed results would generalize to other types of emotional stimuli.Third, the group sizes were relatively small (OLP Pill/ Imaginary Pill/ Passive Viewing; n = 33 per group) as compared to an earlier OLP-fMRI study (Schienle et al., 2023; n = 50 per group).However, (Schaefer et al., 2023) reported differences in brain activity when comparing 23 participants who received an OLP for reducing emotional distress with 21 who did not.
Fourth, the current experimental design did not include the assessment of qualitative data, such as patients' explanations of how the OLPs exerted their effects.For instance, in a study by Haas et al. (2022), a mixed-design approach compared selfreports of participants who received deceptive vs nondeceptive placebos.OLP participants engaged more in reflections on their treatment and were significantly less likely to attribute improvement to the OLP compared to those with deceptive placebos.
Finally, a potential problem with the current study is the selective focus on healthy volunteers.There could be fundamental differences in the mechanisms contributing to the placebo effect, such as motivation and expectation, between individuals with and without mental/somatic disorders (Spille et al., 2023).It is plausible that patients' placebo responses may be mediated via different neural pathways that are more related to these motivational processes (e.g.hope in change).Additionally, existing evidence has already demonstrated that OLP effects tend to be more pronounced in clinical as opposed to nonclinical samples (Buergler et al., 2023b).
In summary, the present fMRI study is the first to compare the effects of different forms of OLP administration/rationales. It demonstrated that placebo effects can be harnessed without the use of a physical treatment component.The intervention with the imaginary pill was a more effective and plausible alternative to the traditional OLP approach for alleviating feelings of disgust.These findings have important implications for the development of new OLP-based interventions for nonclinical as well as clinical contexts.

Fig. 1 .
Fig. 1.Mean ratings for disgust intensity for the two picture categories (disgust, neutral) in the three groups.Note: Error bars indicate 95% confidence intervals.*P < 0.05.

Table 2 .
Group comparison of brain activity (contrast: Disgust-Neutral)