Context-Dependent Placebo Hypoalgesia Through Observational Learning: The Role of Empathy in Virtual and Real-World Settings

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White, Lakota Watson, Yang Wang, Giancarlo Colloca, Jonathan Michael Heagerty, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7139716/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jan, 2026 Read the published version in npj Digital Medicine → Version 1 posted 13 You are reading this latest preprint version Abstract This study examined how empathy and contextual factors influence observationally induced placebo analgesia in virtual and real-world settings. Forty-seven participants observed a human or avatar demonstrator receiving painful stimulation with or without a placebo treatment, then experienced identical stimulations themselves. Observation led to significant placebo hypoalgesia for both pain intensity and unpleasantness. Human demonstrators evoked greater cognitive empathy, while placebo treatments reduced affective and cognitive empathy across contexts. Analgesic effects were stronger in the real world after observing humans, but in VR contexts, avatars induced greater placebo effects. Placebo effects were modulated by individual and experimental factors, including trait empathy and demonstrator type, respectively. These findings highlight how digital context, embodiment, and participant characteristics interact to shape pain outcomes, informing design strategies for immersive digital therapeutics. Health sciences/Health care Health sciences/Medical research Biological sciences/Neuroscience Biological sciences/Psychology Social science/Psychology observation learning empathy virtual reality pain placebo Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction As digital therapeutics rapidly evolve, immersive technologies such as virtual reality (VR) are gaining prominence as tools for non-pharmacologic pain management. VR offers life-like, interactive environments that may enhance embodied perspective-taking, emotional engagement, and ultimately, empathy, a key mechanism known to modulate pain through placebo responses 1–7 . However, the neurocognitive pathways through which VR-based observational learning influences empathy and placebo effects remain underexplored. Placebo effects are influenced by drug marketing features 8–10 , color and number of pills 11,12 , administration route 13,14 , and the context in which a drug is delivered 15 . Conditioning (direct exposure to pain reduction) and verbal suggestions (verbal anticipations of analgesia) have been the best studied manipulations to investigate placebo analgesia in laboratory contexts. Observing others, which begins at birth, is a powerful way to gain information 16 . It influences a variety of behaviors 17 including pain and social threat 18,19 . We and others showed that social learning (changes in behaviors/outcomes related to observation of others) 20 elicits placebo analgesic effects 21,22 comparable in magnitude to those induced by direct experiences 22–26 . A recent meta-analysis further demonstrated a positive association between empathy levels towards the other person and the strength of observationally induced placebo effects 27 . Prior research, including our own, has shown that observational learning can elicit placebo analgesia of similar magnitude to that induced by direct analgesic experience 5–7 . Nonetheless, it remains unclear how and to what extent immersive environments, like VR, compared to real-world contexts in eliciting higher empathy and subsequent stronger placebo hypoalgesia. The type of demonstrator (Human versus Avatar) may further modulate this process, as avatars might be perceived as less emotionally engaging or realistic than human models. Moreover, the type of demonstrator may interact with the environmental context (VR or Real-world) to modulate these effects. Understanding these dynamics is critical for optimizing the design and implementation of digital therapeutics. In this study, we investigated how state empathy defined as an individual’s immediate affective and cognitive response to another’s experience 1 , can be modulated through observation in different environments, and how empathy subsequently impacts observationally induced placebo hypoalgesia 3,6,27–30 either through immersive VR or a traditional real-world display. We defined as immersive VR context a fully immersive 3D environment where participants experienced the scenario within a 360-degree interactive digital space. On the contrary, we considered real-world context a standard 2D display on a tablet where participants observed the same content on a flat screen without immersion. We specifically tested whether the type of demonstrator (Human vs Avatar) and the context (VR vs real-world) influence state empathy and pain perception. This design allowed for the comparison of empathy and placebo responses across immersive and non-immersive contexts. Methods Participants. Healthy adults were recruited for a two-day, within-subjects experimental cross-sectional study conducted at the University of Maryland, Baltimore School of Nursing between December 2, 2021, and September 23, 2023. The final sample was comprised of 47 participants (mean age = 29.2 years; range = 18–61 years, Table 1 ), including 31 females (see also, Suppl Materials). All participants scored within the normal range on standardized measures of anxiety and depression. Table 1. Participants’ characteristics. Abbreviations: Interpersonal Reactivity Index (IRI), Basic Empathy Scale (BES), State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI) The study was approved by the University of Maryland, Baltimore Institutional Review Board (Protocol HP-00085382), and all participants provided written and verbal informed consent. All procedures adhered to the Declaration of Helsinki and applicable ethical guidelines. Participants were fully debriefed upon study completion using a standardized exit form outlining the full purpose of the research 6 . Participants were given the option to withdraw their data from the study after debriefing; however, none chose to do so. Participants were compensated $ 180 for completing all procedures of the study. Participants were screened by telephone and in-person to confirm eligibility as healthy volunteers. Exclusion criteria included: sensory impairments (e.g., impaired hearing, color blindness); allergies or sensitivities to topical creams or food colorings; history of chronic or current pain; neurological conditions (e.g., epilepsy); cardiovascular, pulmonary, renal, or hepatic diseases; psychiatric disorders; use of pain or other prescription medications; and pregnancy or breastfeeding. To ensure compliance with study requirements, participants underwent urine toxicology screening for amphetamines, methamphetamines, cocaine, opioids, and tetrahydrocannabinol prior to beginning experimental procedures on day one, and again on day two if more than 24 hours had elapsed. Individuals with positive results were excluded. Participants were also excluded if they reported VR-induced claustrophobia or symptoms of cybersickness. Experimental procedures The experiment was conducted at the University of Maryland School of Nursing (UMSON) Clinical Suites in Baltimore over two sessions, held no more than 10 days apart. All procedures took place in a controlled laboratory environment. During the first session, participants were informed that the study examined the relationship between brain activity and pain perception. Baseline physiological measures, including blood pressure, heart rate, height, and weight, were collected for monitoring purposes (Table 1 ). Participants then completed a quantitative sensory testing protocol to assess baseline pain sensitivity (see Heat Pain Stimulation). The second session comprised four experimental conditions presented in a counterbalanced order: Virtual Reality–Human (VR-Human), Virtual Reality–Avatar (VR-Avatar), Real-World–Human, and Real-World–Avatar. Each condition consisted of two phases: an observation phase followed by an experiential phase. During the observation phase, participants viewed a demonstrator–either a live human or a digital avatar version of the same individual–receiving painful heat stimulation on the non-dominant forearm. Two visibly distinct creams (colored blue and green) were applied to separate forearm sites prior to stimulation. Participants were informed that the creams contained different ingredients, but no suggestion of analgesic efficacy was made to avoid explicitly inducing treatment expectancy. In the experiential phase, participants received matched heat stimulation on their own non-dominant forearm after the same blue and green creams were applied. Both creams consisted of CeraVe Daily Moisturizing Lotion (L’Oréal, Active Cosmetics Division, New York, USA), a hypoallergenic product free from dyes, fragrances, parabens, lanolin, and formaldehyde. Creams were colored with FDA-approved food dyes and counterbalanced across participants to avoid associating a specific color with treatment efficacy. The location of each cream application (upper vs lower ventral forearm) was also counterbalanced to control for site-specific effects. Since experimenter sex and race may influence pain-related outcomes, one experimenter collected all behavioral data, keeping constant the experimenter sex and race. Study design A within-subjects cross-sectional design was employed, with each participant completing four experimental conditions that varied by setting (virtual reality vs real-world) and demonstrator type (Human vs Avatar). Each condition included a placebo (treatment cue) and control (non-treatment cue) manipulation. Observation Phase Each observation phase comprised two blocks (treatment and control), each consisting of 10 trials. Block order was counterbalanced across participants. In each trial, a colored visual cue (blue or green; 2 seconds) indicated which cream the demonstrator would receive heat stimulation on. This was followed by a video of the demonstrator (2.5 seconds) reacting to the stimulus. After a brief delay, participants viewed the demonstrator’s pain intensity and unpleasantness ratings using visual analogue scales (VAS; 5 seconds). During the treatment block, the demonstrator rated their pain between 10–30 on the VAS; during the control block, ratings ranged from 70–90, thus reinforcing a modeled hypoalgesic effect. Each block concluded with an inter-trial interval of 4–7 seconds. At the end of each observation block, participants completed a state empathy assessment consisting of four questions (see Fig. 1 for details). Experiential Phase Each experiential phase also included two blocks (treatment and control), with 20 trials per block. Each trial began with a colored anticipatory cue (2 seconds), followed by a heat stimulus (2 seconds, plus 0.5 seconds for thermode ramp-up). After a brief delay (2 seconds), participants rated their own pain intensity and unpleasantness using a VAS ranging from 0 (no pain) to 100 (maximum tolerable pain). Heat pain temperature was held constant across treatment and control trials and was individualized based on prior calibration to produce moderate pain (VAS 50–60). Each trial concluded with a 4–7 second inter-trial interval. Heat Pain Stimulation Painful heat stimuli were delivered using a CHEPS thermode (PATHWAY System, Medoc, Ramat Yishai, Israel). To assess individual pain sensitivity, participants first completed a quantitative sensory test using the limits paradigm. During this pain calibration phase, each participant received a series of 12 brief thermal pulses. For instance, at a destination temperature of 46°C, the total pulse duration was approximately 890 ms, with the plateau at maximum temperature lasting around 20 ms. After each stimulus, participants rated their pain intensity on a visual analogue scale (VAS; see Measurements) ranging from 0 = no pain to 100 = maximum tolerable pain. These ratings were used to determine a personalized stimulus intensity corresponding to moderate pain (VAS ratings between 50–60), which was then used in the experiential phase of the experiment. Stimuli ramped from a 32°C baseline at a rate of 70°C/s, plateaued for less than one second, and returned to baseline at a rate of 40°C/s. Several pain outcomes were recorded, including the pain sensitivity threshold, defined as the temperature required to elicit the first sensation of pain (rated 1–10 out of 100) and the moderate pain threshold used for the experiential phase, defined as the temperature required to elicit a moderate pain intensity (rated 40–60 out of 100). Ramp-up and ramp-down durations were adjusted for each participant to achieve a VAS pain rating of approximately 5 out of 10. For reference, a 46°C stimulus had a mean ramp-up time of 291 ms and a ramp-down time of 612 ms 31 . On average, the individualized pain sensitivity threshold was 35.4°C (SEM = 1.2°C; range: 34.4°C–49.4°C). The mean temperature used during the experiential phase was 47.1°C (SEM = 0.3°C; range: 43°C–50°C). Virtual reality vs real-world context An HTC Vive Pro Eye high-resolution virtual reality headset (HTC Inc., San Francisco, California), running on the SteamVR platform, was used to deliver immersive content. Immersive VR and 2D real-world content were developed collaboratively by engineers at the University of Maryland, College Park (UMD) and the University of Maryland School of Nursing (UMSON), using the Unity game engine (Unity Technologies, San Francisco, California). In this project, we developed a 3D digital avatar that closely replicates the physical appearance and posture of the human demonstrator we used for this study. Using 3D applications such as Autodesk Maya, we rigged the model to match the position and orientation of the human participant seated in the chair. To further enhance realism, we matched the avatar’s clothing color, texture, and skin tone to those of this participant. We also adjusted the lighting within the virtual environment to reflect the physical setup, ensuring visual consistency between the real and virtual assets. Additionally, we created a 3D model of the pain-stimulation device, positioned on the avatar’s left hand to accurately reflect the setup in the human scenario. To integrate the avatar into the virtual environment, we used a 3D rendering pipeline in combination with a virtual reality head-mounted display, allowing for precise spatial alignment within the scene. The avatar’s size, proportions, and placement were carefully adjusted relative to the environment and surrounding elements, such as the chair, desk, and computer monitor. This setup provided a more immersive, realistic, and familiar experience for the viewer. The 3D 360-degree videos captured the Human demonstrator receiving both painful and non-painful thermal stimulation on two different cream-treated sites. To enable synchronized stimulus presentation, the UMD team also developed a custom network socket module that interfaced with E-Prime software. From this footage, matched 2D real-world content was extracted using the same visual angles and depth of field. In parallel, the demonstrator was digitally recreated as a computer-generated (CG) avatar using Autodesk Maya, maintaining consistent posture, clothing, and environmental context. In the VR conditions, participants observed either the Human or Avatar demonstrator in immersive 3D through the headset. Trials were separated by simple visual cues (e.g., blue or green crosshairs), and participants rated pain intensity and unpleasantness using an electronic VAS interface, presented within the headset and controlled via a wireless, motion-tracked HTC controller. We created eight base scenarios for the Human demonstrator, each with five variations, and eight corresponding avatar scenarios with matched content. The 2D real-world conditions, used as a control for immersion effects 32 , involved viewing the same human or avatar demonstrator videos on a standard computer monitor. The 2D content replicated the scenario structure, visual cues, and VAS interface used in the VR conditions, ensuring visual and procedural consistency across settings. Measurements Pain intensity, referring to physical sensation, and pain unpleasantness, referring to the emotionally uncomfortable experience associated with the heat stimulations, were measured using a VAS anchored from 0 = no pain to 100 = maximum tolerable pain. Data were acquired using E-Prime v3 (Psychology Software Tools, Sharpsburg, PA, USA). Socially induced placebo hypoalgesia was quantified by subtracting trial-by-trial VAS ratings in the placebo treatment condition from those in the control condition (VAS_control – VAS_placebo), separately for pain intensity and unpleasantness. Two types of state empathy – affective empathy and cognitive empathy, were assessed using four questions. Questions 1 and 2 assessed affective empathy: 1) How intense was your experience of pain while watching the demonstrator receive the stimulation? (sensory, self-referred) 2) How unpleasant was your experience of pain while watching the demonstrator receive the stimulation? (emotional, self-referred) and questions 3 and 4 assessed cognitive empathy: 3) How intense do you think was the sensation the demonstrator experienced while receiving the stimulation? (sensory, other-referred) and 4) How unpleasant do you think was the sensation the demonstrator experienced while receiving the stimulation? (emotional, other-referred) on a VAS anchored from 0 to 100 (infinite until response). Finally, we assessed individual empathy using the Interpersonal Reactivity Index (IRI) 33 and the Basic Empathy Scale (BES) 34,35 . We controlled for individual anxiety and depression using the State-Trait Anxiety Inventory (STAI) 36 , Beck Anxiety Inventory (BAI) 37 and the Beck’s Depression Inventory (BDI) 38 at baseline. A privacy-compliant link was sent via Research Electronic Data Capture (REDCap) for completion of the measurements 39,40 . Statistical Analysis Based on our previous studies 41 , 47 participants were required to achieve 0.8 statistical power to detect an effect size of Cohen’s f = 0.35 at an alpha level of 0.001 on behavioral pain changes (G*Power). A flow-chart showed the initial accrual and final sample (See Suppl Materials). The main dependent measures were observationally induced pain intensity and unpleasantness (see Measurement section), and affective and cognitive state empathy. We conducted a cross-sectional analysis using data collected from participants randomly assigned to one of four experimental conditions in a 2 (Demonstrator: Human vs Avatar) × 2 (Context: VR vs Real-world) between-subjects design. Participants were recruited using stratified sampling to ensure balanced representation across key demographic variables (e.g., sex) that could influence empathy and pain perception. We tested for moderation effects and controlled for relevant covariates (see also Suppl Materials). The experimental design included the within-subjects factors of Context (VR vs. real world), Demonstrator (Human vs. Avatar), and Placebo condition (control, placebo). All subjects were exposed to all 8 conditions (repeated measures design). Accordingly, we used a 3x2 factorial Linear Mixed Model (LMM) to analyze the data and follow up on significant main effects and interactions with planned post-hoc comparisons using Bonferroni corrections. Furthermore, we used additional linear mixed models (LMMs) to evaluate the effects of context (VR vs. real-world) and demonstrator type (Human vs. Avatar) on participants’ state empathy ratings differences (delta scores of control - placebo empathy ratings), and on placebo hypoalgesia (delta scores of control - placebo pain ratings) for both pain intensity and unpleasantness during the experiential phase. Cue color (blue vs. green); Block order (placebo-first vs. control-first); and Cream site (placebo cream on upper vs. lower forearm) were randomized and included as covariates. In addition, participants’ sex and race were included as covariates. Participant ID was treated as a random effect to account for within-subject variability. To assess the potential mediating role of state empathy in placebo effects, we used Rockwood’s Multilevel Mediation Model (MLmed, Beta 2) 42,43 , which accommodates the hierarchical structure of repeated-measures data. Given that we only observed a significant main effect of demonstrator type (Human vs. Avatar) on cognitive empathy of pain intensity and pain unpleasantness, mediation analyses were performed treating the demonstrator type (Human vs. Avatar) as the independent variable (X), the differences in cognitive empathy between the control and placebo conditions were treated as the mediator (M), and the magnitude of placebo effects across VR and real-world settings were treated as the dependent variable (Y). Outliers were identified using Tukey’s method with a 2.2 interquartile range (IQR) multiplier, where the upper limit calculated was defined as Q3 + 2.2 * IQR, and the lower limit defined as Q1–2.2 * IQR. Q1 and Q3 represent the 25th and 75th percentiles, respectively. All statistical analyses were conducted using IBM® SPSS Statistics, version 29.0. Statistical significance was set at p = 0.05 and Bonferroni corrected for multiple comparisons. Results Empathy and observational phase During the observation phase, we manipulated affective and cognitive state empathy by showing either a human or an avatar demonstrator experiencing pain in both the no-treatment (control) and pain relief (placebo) treatments. Characteristics of the participants are shown in Table 1 . Cognitive Empathy The same three-way LMM analysis was applied to cognitive empathy ratings. A robust main effect of treatment emerged, with higher cognitive empathy scores in the control condition compared to the placebo condition for both pain intensity (F 1,173.73 = 618.41, p < 0.001) and pain unpleasantness (F 1,170.24 = 617.83, p < 0.001). We observed a significant main effect of demonstrator type, with higher cognitive empathy scores when participants viewed a human demonstrator compared to an avatar. This effect was present for both pain intensity (F 1,173.73 = 30.01, p < 0.001) and pain unpleasantness (F 1,170.25 = 37.68, p < 0.001). There was no main effect of context (VR vs. real world) on cognitive empathy (pain intensity: F 1,173.73 = 0.13, p = 0.724; pain unpleasantness: F 1,170.25 = 0.30, p = 0.587). For pain intensity, a significant two-way interaction was observed between demonstrator type and treatment (F 1,173.73 = 12.16, p < 0.001), indicating that the effect of treatment differed based on whether participants observed a human or avatar. However, the interaction between setting and treatment (p = 0.409), setting and demonstrator (p = 0.520), and the three-way interaction (p = 0.774) were all non-significant ( Suppl Fig. 2A ). A similar pattern emerged for pain unpleasantness, where we found a significant demonstrator × treatment interaction (F 1,170.24 = 17.02, p 0.05) ( Suppl Fig. 2B ). Additional LMMs on cognitive empathy delta scores indicated a significant main effect of demonstrator type on cognitive empathy differences for pain intensity (F 1,147.67 = 14.43, p < 0.001). The Human demonstrator induced greater cognitive empathetic differences between the control and placebo conditions (pain intensity: mean = 61.62, SEM = 2.17) than the Avatar demonstrator did (pain intensity: mean = 46.49, SEM = 3.34, p < 0.001) (Fig. 2 A). Similar findings were found for cognitive empathy for pain unpleasantness (F 1,142.45 = 20.70, p < 0.001), with the Human demonstrator inducing greater differences in cognitive empathy (mean = 61.73, SEM = 2.02) compared with the Avatar demonstrator (mean = 44.20, SEM = 3.28, p < 0.001) (Fig. 2 B). Finally, neither the order of demonstrator presentation (Human first vs. Avatar first) nor the order of context exposure (VR first vs. real world first) significantly influenced cognitive empathy ratings (all ps > 0.05). However, white participants exhibited smaller differences in cognitive empathy for pain unpleasantness between the control and placebo conditions (mean = 48.21, SEM = 2.82) as compared with the non-white participants (mean = 56.31, SEM = 2.41, F 1,109.55 = 5.30. p = 0.023). Sex did not appear to influence the magnitude of cognitive empathy differences (p > 0.05). Affective Empathy To examine affective empathy, we conducted a three-way Linear Mixed Model (LMM) with Context (VR vs. real world), Demonstrator (Human vs. Avatar), and Treatment (control vs. placebo) as within-subject factors. The analysis revealed a significant main effect of treatment, with participants reporting significantly higher affective empathy in the control condition compared to the placebo condition, for both pain intensity (F 1,185.71 = 20.42, p < 0.001) and pain unpleasantness (F 1,185.01 = 31.52, p < 0.001). There was no significant main effect of demonstrator type (Human vs. Avatar) on affective empathy ratings (pain intensity: F 1,185.71 = 0.09, p = 0.769; pain unpleasantness: F 1,185.01 = 3.05, p = 0.082), and no effect of context (VR vs. real world; pain intensity: F 1,185.71 = 0.24, p = 0.627; pain unpleasantness: F 1,185.01 = 0.46, p = 0.499). Furthermore, no significant two-way or three-way interactions were observed among the factors, suggesting that the treatment effect on affective empathy was consistent across demonstrator types and contexts (all ps > 0.05). We further conducted LMMs on the delta scores of affective empathy between the control and placebo conditions, with the setting (VR vs. Real-world) and demonstrator type (Human vs. Avatar) as the two fixed factors. No significant main effects or interactions were observed for affective empathy differences for pain intensity (all ps > 0.05) or pain unpleasantness (all ps > 0.05). Observationally Induced Placebo Effects on Self-Experienced Pain After observing a demonstrator receive painful stimulation with or without an analgesic treatment, participants underwent trial-by-trial painful stimulations of identical intensity to assess observationally induced placebo effects. After each trial, they rated their self-experienced pain intensity and pain unpleasantness. Pain Intensity A Linear Mixed Model revealed a significant main effect of treatment, with lower pain ratings in the placebo condition (mean = 13.34, SEM = 0.33) compared to the control condition (mean = 17.89, SEM = 0.38, F 1,6096.98 = 81.88, p < 0.001), confirming the presence of observationally induced placebo hypoalgesia. A main effect of demonstrator also emerged, with higher pain ratings after observing the Human compared to the Avatar demonstrator ( F 1,6096.98 = 18.20, p < 0.001). In contrast, no significant main effect was found for VR settings (VR vs. real world; p = 0.980). Analyses of interactions revealed a significant two-way interaction between the VR setting and demonstrator type ( F 1,6096.98 = 8.08, p = 0.004), as well as between the VR setting and treatment ( F 1,6096.98 = 5.10, p = 0.024). However, the interaction between demonstrator type and treatment was not significant ( p = 0.505). Crucially, a three-way interaction among VR setting, demonstrator type, and treatment was observed ( F 1,6096.98 = 11.04, p < 0.001), indicating that the magnitude of the placebo effect was modulated by the specific combination of context and demonstrator ( Suppl Fig. 3A ). Post hoc Bonferroni-corrected comparisons indicated that the placebo effect was stronger in the real-world (mean = 4.35, SEM = 0.50) than in the VR setting (mean = 2.36, SEM = 0.52, p = 0.006). Furthermore, the effect of demonstrator type varied by setting: in the real-world setting, Human demonstrator induced greater placebo effects (mean = 6.13, SEM = 0.75) than the Avatar (mean = 2.56, SEM = 0.67, p < 0.001), whereas in the VR condition, stronger placebo hypoalgesia was observed following observation of the Avatar (mean = 3.61, SEM = 0.63) compared to the Human demonstrator (mean = 1.11, SEM = 0.83, p = 0.017) (Fig. 3 A). Pain Unpleasantness A similar pattern emerged for pain unpleasantness. The Linear Mixed Model revealed a significant main effect of treatment, with participants reporting significantly less unpleasantness in the placebo condition compared to the control ( F 1,5943.25 = 79.06, p < 0.001). There was also a significant main effect of the demonstrator, with higher unpleasantness ratings in the Human vs the Avatar demonstrator conditions ( F 1,5943.25 = 36.43, p < 0.001). No significant main effect was found for VR settings ( p = 0.709). Significant two-way interactions were observed between VR setting and treatment ( F 1,5943.25 = 11.35, p < 0.001), and between VR setting and demonstrator type ( F 1,5943.25 = 17.41, p < 0.001). The interaction between treatment and demonstrator type was not significant ( p = 0.104). However, a significant three-way interaction between VR setting, demonstrator type, and treatment was found ( F 1,5943.25 = 8.52, p = 0.004), consistent with the pattern observed for pain intensity ( Suppl Fig. 3B ). Post-hoc analyses indicated that placebo effects were greater in the real-world setting (mean = 4.69, SEM = 0.50) than the VR setting (mean = 2.02, SEM = 0.52, p < 0.001). Again, the type of demonstrator interacted with the setting: in the real-world context, stronger placebo hypoalgesia was observed after viewing the Human (mean = 6.51, SEM = 0.76) compared to the Avatar demonstrator (mean = 2.88, SEM = 0.66, p < 0.001), while in the VR setting, no significant differences in placebo effects were found between observing the Human demonstrator and the Avatar ( p = 0.060) (Fig. 3 B ) . Finally, no extinction effects were observed across repeated trials for either pain intensity or pain unpleasantness ratings ( ps > 0.05). We did not observe a significant sex effect on placebo hypoalgesia (pain intensity: F 1,2891.34 = 3.66, p = 0.056; pain unpleasantness: F 1,2853.85 = 2.67, p = 0.102). However, race significantly influenced the magnitude of placebo effects (pain intensity: F 1,2891.34 = 115.49, p < 0.001; pain unpleasantness: F 1,2853.85 = 80.56, p < 0.001), with white participants exhibiting greater placebo effects than non-white participants for both pain intensity and pain unpleasantness. Empathy and placebo effects We examined the relationship between the level of trait empathy and the magnitude of placebo effects using bivariate correlations. We found that higher BES cognitive subscale scores (Pearson r = 0.37, p = 0.014), and higher IRI personal distress (Pearson r = 0.33, p = 0.030) were associated with greater placebo hypoalgesia induced by the Human demonstrator in the VR setting. However, placebo effects induced by the real-world setting or by the Avatar demonstrator in the VR setting were not dependent on the trait empathy levels (all ps > 0.05). Similar findings were found regarding placebo effects for pain unpleasantness, where greater BES cognitive subscale (Pearson r = 0.35, p = 0.021) and IRI personal distress (Pearson r = 0.34, p = 0.028) were associated with higher placebo effects for pain unpleasantness ( Suppl Fig. 4 ). In terms of state empathy ratings, we found that affective state empathy (Pearson r = 0.39, p = 0.008), but not cognitive state empathy (Pearson r = 0.03, p = 0.824) was associated with placebo effects. Again, this association was only observed when placebo hypoalgesia was induced by the Human demonstrator in the VR setting, while no significant correlations between state empathy and placebo effects were induced by real-world settings or by the Avatar demonstrator in the VR setting (all ps > 0.05). Similar patterns were observed in terms of placebo effects for pain unpleasantness and affective state empathy (Pearson r = 0.44, p = 0.002). However, after removing the outliers identified using Tukey’s method, the correlations between affective state empathy and placebo hypoalgesia were not significant (pain intensity: Pearson r = 0.22, p = 0.165; pain unpleasantness: Pearson r = 0.22, p = 0.162). Multi-level mediation models indicated that neither affective state empathy (a*b = 0.03, 95%BCI = [-0.73, 0.81]), nor cognitive state empathy (a*b = 0.28, 95%BCI = [-2.33, 2.93]) mediated the influence of demonstrator type (Human vs. Avatar) on placebo hypoalgesia for pain intensity. Similarly, neither affective state empathy (a*b = -0.33, 95%BCI = [-2.14, 1.13]), nor cognitive state empathy (a*b = 1.54, 95%BCI = [-1.66, 5.07]) mediated the influence of demonstrator type on placebo hypoalgesia for pain unpleasantness (Fig. 4 A and B ). Discussion We investigated how empathy, modulated through observation of a human or avatar demonstrator, influences placebo analgesia in both VR and real-world settings. Observing an effective treatment reduced both affective and cognitive state empathy for pain, with cognitive empathy being more sensitive to demonstrator type. We found robust observationally induced placebo effects on self-experienced pain, shaped by demonstrator type, treatment condition, and setting: avatars were more effective in VR, while human demonstrators produced stronger effects in real-world contexts. Trait empathy, particularly for the VR-Human condition, was associated with placebo responsiveness, although mediation was not supported. Importantly, individual differences including race, trait empathy, treatment order, and even cream color, significantly modulated placebo effects. White participants exhibited greater analgesia than non-White participants, and trait empathy predicted responses only in the VR-Human context. These findings highlight the critical role of socio-contextual and perceptual factors in shaping digital placebo responses and offer actionable insights for designing effective, personalized virtual interventions for pain management. The ability to learn from observing others is a fundamental mechanism shared across species 44,45 . Extensive research has shown that witnessing fear in others can shape direct behavioral responses 46,47 . Social learning—defined as behavioral or outcome changes resulting from the observation of others 20 —has been shown to elicit placebo analgesia of similar magnitude to that produced by direct experience 22–26 . The current study aimed to build on this body of work by examining how manipulation of state empathy, using well-established experimental procedures and VR 48–54 , modulates observationally induced placebo effects. In our previous work, a strong correlation between analgesic responses and trait empathy (e.g., empathic concern) was observed when participants watched a live demonstrator (r = 0.67, p < 0.005) 3 . However, when observers watched video recordings, robust placebo effects on sensory pain intensity emerged, but were not linked to dispositional empathy traits 24,25 . Earlier studies had not directly manipulated state empathy, which comprises cognitive (perspective-taking) and affective (emotional resonance) components 1 . Here, we directly assessed both aspects of state empathy by asking participants to evaluate the perceived pain intensity (sensory, other-referred) and unpleasantness (emotional, other-referred) experienced by a demonstrator undergoing identical painful thermal stimulations under placebo and control (no treatment) conditions—though in reality, both creams were inert. Empathy is known to be influenced by both contextual (e.g., sex 55–58 ) and individual (e.g., reduced spontaneous empathy in psychopathy 59 ) factors. VR has previously been used to elicit vicarious pain and pleasure 60,61 and can also be manipulated to reduce self-experienced pain 62 . Based on this, we hypothesized that VR might enhance state empathy. Contrary to our expectations, VR did not increase either cognitive or affective state empathy compared to the real-world setting. This is consistent with meta-analytic findings showing that VR does not reliably enhance cognitive empathy 63 . Independently of the VR context, our manipulation of state empathy showed higher cognitive empathy when participants observed a human demonstrator compared to an avatar, in line with studies exploring the impact of robots on empathy 64 . Recent work also demonstrates that even between two avatars, a human-like avatar elicits more empathy than a robot-like avatar 65 . These findings, together with our results, suggest that facial expressions, biological motion, or the perceived realism of a demonstrator may be critical for eliciting cognitive empathy 66–70 . It is known that observational learning influences neural and cognition systems 4 throughout mentalizing (the ability to cognitively understand the mental states of others) 71–73 , empathy (the ability to share an emotional experience) 74–76 , and other factors (sociodemographics) 77 . After a pioneering study 21 , other studies showed that observationally induced placebo effects are comparable in size to the effect of directly experienced conditioning 22–26 . Recent studies have demonstrated the demonstrator’s sex 28 , social status 78 and self-confidence 79 can influence observationally induced placebo effects. Observational learning and prosocial choices are shaped by empathic discomfort and endogenous opioid activity 80 . It has been shown that observing a video or a live demonstrator generates the same magnitude of pain reductions that are significantly different from a control group (e.g., watching colored light stimulations) 22 . To our knowledge, we are the first to investigate the role of observation of a human or avatar demonstrator, in influencing placebo analgesia within both VR and real-world settings. We observed a significant interaction between setting (VR vs. real-world) and demonstrator type (Human vs. Avatar). In VR, observing the Avatar induced stronger placebo hypoalgesia than the Human demonstrator, while in the real-world setting, the opposite was true: placebo hypoalgesia was stronger after observing a human demonstrator. Overall, socially induced hypoalgesia was greater in the real-world than in VR, suggesting that learning through observation may be more effective in naturalistic contexts. This effect was associated with trait empathy but did not state empathy, but only in the VR setting with the Human demonstrator showing a key role of empathy in shaping observationally learned placebo effects. Contextual factors such as race and demonstrator identity shape observationally induced placebo effects. Using a white male demonstrator and his avatar, we found no sex differences in empathy or placebo responses. Prior studies report stronger nocebo effects after observing male models 25 . White participants in our study showed greater placebo responses than non-white participants, aligning with existing literature on race and placebo effects 81 . However, it should be noted that these differences were also associated with race-concordance between experimenter and participant, which was not directly manipulated in this study. Limitations This study has some limitations. We did not track attention during VR observation (using eye-tracking technology 82,83 ), which may affect our ability to study empathy and learning. Furthermore, affective empathy ratings showed little variability, possibly due to the passive nature of the task. Additionally, while we did find significant influences of race on placebo hypoalgesia, this study was not designed to directly measure or manipulate placebo effects as a direct effect of race or racial concordance. For this reason, any conclusions based on racial influences should be evaluated with caution. Finally, we used avatars with no facial expressions, limiting their ecological validity. Conclusions Together, these results expand our understanding of how VR and demonstrator type affect both empathy and observationally induced placebo effects within digital and real-world contexts. While trait empathy influenced responses in specific conditions, notably the VR-Human context, state empathy did not significantly modulate placebo effects. The interaction between demonstrator type and observation context remains critical: avatars were more effective in VR settings, whereas human demonstrators elicited stronger effects in real-world environments. These findings underscore the importance of contextual and social factors beyond momentary empathic engagement in the design of digital interventions. These findings could offer actionable insights for developing personalized, socially informed, and scalable non-pharmacological strategies for symptom management across diverse care settings. Abbreviations BAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory; BES: Basic Empathy Scale; IRI: Interpersonal Reactivity Index STAI: State-Trait Anxiety Inventory Declarations Acknowledgements The authors would like to thank Nandini Raghuraman for helping with the procedure setup and Yavin Shaham for thoughtful comments to the manuscript. The authors acknowledge the support of the National Institute of Dental and Craniofacial Research Helping to End Addiction Long-term (NIDCR HEAL) Initiative (1R21 DE032532-01, Dorsey/Colloca; J. White) and the National Center for Complementary and Integrative Health (R01- 5R01AT010333, L. Colloca). The funding source was not involved in this work. Author Contributions J.N.W., and L.C., conceived and designed the study. L.W., R.S., J.M.H., S.L., and B.B. contributed to data collection and preprocessing. J.N.W., L.W. performed initial data analysis. A.V. provided expertise and oversight on virtual reality design and implementation. 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White","email":"","orcid":"","institution":"University of Maryland School of Nursing, University of Maryland School of Nursing","correspondingAuthor":false,"prefix":"","firstName":"Jewel","middleName":"N.","lastName":"White","suffix":""},{"id":487765199,"identity":"18bd0da8-dd24-4c52-96f3-bbe9bcdf1bfe","order_by":1,"name":"Lakota Watson","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lakota","middleName":"","lastName":"Watson","suffix":""},{"id":487765200,"identity":"1fb28b67-8b23-4337-9f31-1b4503ab6f0c","order_by":2,"name":"Yang Wang","email":"","orcid":"","institution":"University of Maryland School of Nursing, University of Maryland School of Nursing","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Wang","suffix":""},{"id":487765201,"identity":"368ad97e-1946-4e43-b491-bcda4ace1d84","order_by":3,"name":"Giancarlo Colloca","email":"","orcid":"","institution":"Towson University","correspondingAuthor":false,"prefix":"","firstName":"Giancarlo","middleName":"","lastName":"Colloca","suffix":""},{"id":487765202,"identity":"e8d23b63-6828-4462-8e30-95f02d715cee","order_by":4,"name":"Jonathan Michael Heagerty","email":"","orcid":"","institution":"University of Maryland College Park","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"Michael","lastName":"Heagerty","suffix":""},{"id":487765203,"identity":"70745f12-5fc3-4fcc-9a9e-dc58a9baa5c8","order_by":5,"name":"Sida Li","email":"","orcid":"","institution":"University of Maryland College Park","correspondingAuthor":false,"prefix":"","firstName":"Sida","middleName":"","lastName":"Li","suffix":""},{"id":487765204,"identity":"6ea12a87-5594-4497-a58c-f1e860ab836c","order_by":6,"name":"Barbara Brawn","email":"","orcid":"","institution":"University of Maryland College Park","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Brawn","suffix":""},{"id":487765205,"identity":"25339584-de70-419a-b62f-e6f04c980acc","order_by":7,"name":"Amitabh Varshney","email":"","orcid":"","institution":"University of Maryland College Park","correspondingAuthor":false,"prefix":"","firstName":"Amitabh","middleName":"","lastName":"Varshney","suffix":""},{"id":487765206,"identity":"9c97e6f9-8595-4528-8f8b-66247f9ff2ea","order_by":8,"name":"Roni Shafir","email":"","orcid":"","institution":"University of Maryland School of Nursing, University of Maryland School of Nursing","correspondingAuthor":false,"prefix":"","firstName":"Roni","middleName":"","lastName":"Shafir","suffix":""},{"id":487765207,"identity":"070a47e1-b8f8-4d89-bd29-7f1e5efcb781","order_by":9,"name":"Carmen-Édith Belleï-Rodriguez","email":"","orcid":"","institution":"University of Maryland School of Nursing, University of Maryland School of Nursing","correspondingAuthor":false,"prefix":"","firstName":"Carmen-Édith","middleName":"","lastName":"Belleï-Rodriguez","suffix":""},{"id":487765208,"identity":"706fd44c-df9e-4f8c-b12b-c61a77bcf6ed","order_by":10,"name":"Luana Colloca","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYFAC5sYDQFIOwikAYiBXAr8WxgaQFmMIx4AELYkNRGvhb29sOPChxi59w7XDzz7zGNjl8R1gPnibB48WiTMHGw7OOJacu+F2mvFsHoPkYskDbMnW+LQYSCQ2HOZtYAZqSTBm5jFgTtxwgMdMmggt9ekGt9M/A7XUA7XwfyNGy+EEg9s5IFsOg2xhw6sF6pfjhjNv5xQzzjE4njjzMJux5Rw8Wvjbmw8++FBTLc93O30zw5uK6sS+480Pb7zBowUFMIHdw0yschBg/EGK6lEwCkbBKBgxAACxfVJ2J9fQLgAAAABJRU5ErkJggg==","orcid":"","institution":"University of Maryland School of Nursing, University of Maryland School of Nursing","correspondingAuthor":true,"prefix":"","firstName":"Luana","middleName":"","lastName":"Colloca","suffix":""}],"badges":[],"createdAt":"2025-07-16 11:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7139716/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7139716/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41746-026-02373-3","type":"published","date":"2026-01-27T15:58:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87378216,"identity":"276978d4-b9a8-4f43-adce-24fc2c274139","added_by":"auto","created_at":"2025-07-23 08:22:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":185574,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy Design: State Empathy Manipulation and Socially Induced Placebo Hypoalgesia\u003c/strong\u003e. The experiment consisted of two phases: an observation phase and a self-experience phase. Observation phase: Participants observed a series of 20 video trials in which a blue or green cue was followed by a demonstrator (human or avatar) reacting to a thermal pain stimulus and reporting pain intensity and unpleasantness using visual analogue scales (VAS; 0 = no pain, 100 = maximum tolerable pain). Each cue appeared 10 times in a randomized order. After completing the observation phase, participants rated their cognitive and affective empathy (VAS) toward both the demonstrator and them in the observed scenario. Self-Experiential Phase (Placebo Testing): Participants then underwent 40 thermal pain trials on their forearm, preceded by either a blue or green cue (20 trials per cue, randomized). After each stimulus, they rated their own pain intensity and unpleasantness on VAS. This phase tested whether observing reduced pain responses in others influenced participants’ own pain experience.\u003c/p\u003e\n\u003cp\u003eIn the observation phase, each trial began with the 2 cues (2 seconds), a variable delay (4–8 seconds) indicated by a fixation cross, followed by a 2.5-second video of a demonstrator—either a human or their 3D avatar—receiving the painful stimulation and the treatment (Placebo vs Control). After a brief delay of 2 seconds, the demonstrator rated the pain intensity/unpleasantness on a visual analogue scale (VAS) from 0 (no pain) to 100 (maximum tolerable pain), with 5 seconds allotted for the rating.\u003c/p\u003e\n\u003cp\u003eA final delay (4–7 seconds) concluded each trial. This observation sequence was repeated for 20 trials (10 per cue type). At the end of the observation phase, participants completed state empathy ratings, assessing both affective and cognitive empathy toward the demonstrator and toward themselves in the observed situation. This empathy rating period was untimed. A final 2-second delay preceded the next phase. In the self-experience phase, participants first saw the cue (blue or green) for 2 seconds, followed by a variable fixation delay (4–8 seconds). They then received a thermal pain stimulus on the forearm for 2.5 seconds along with the treatment (Placebo or Control cream). After a 2-second delay, participants rated their own pain intensity on a VAS, followed by 2 second delay preceding the pain unpleasantness rating, each with a 5-second response window. A final inter-trial delay (4–7 seconds) closed the trial before the next loop began. This self-experience sequence was repeated for 40 trials (20 per cue type).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7139716/v1/aa384c2acf6a4eec02751408.png"},{"id":87378217,"identity":"8b795aac-63d7-4fcb-b7bd-a9fb8c8024aa","added_by":"auto","created_at":"2025-07-23 08:22:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":424289,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCognitive state empathy ratings (control – placebo) for human and avatar demonstrators in VR and real-world settings.\u003c/strong\u003e\u003cbr\u003e\nParticipants rated their cognitive empathy for the demonstrator's pain intensity (left panel) and pain unpleasantness (right panel) on a visual analogue scale (VAS; 0 = no pain, 100 = maximum tolerable pain) following the observation phase. Delta empathy scores reflect the difference between control and placebo cue conditions. Greater cognitive empathy was reported for the human demonstrator compared to the avatar in both dimensions of pain and independently of the VR vs real-world settings. Error bars represent ± SEM. ***p \u0026lt; .001.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7139716/v1/570625fb93193778d74ede48.png"},{"id":87381978,"identity":"d82afe32-8b9e-4481-b2ed-f268b2870bf1","added_by":"auto","created_at":"2025-07-23 08:38:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":387286,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDelta scores for observationally induced placebo effects across conditions.\u003c/strong\u003e\u003cbr\u003e\nDelta values represent the difference in self-reported pain ratings between the control and placebo conditions (Control – Placebo) for pain intensity and unpleasantness. Higher delta scores indicate stronger placebo hypoalgesia. Data are shown for each condition (Human vs. Avatar demonstrators) presented in Virtual Reality (VR) and Real-world settings. Bar graphs display mean delta values ± SEM.\u003cbr\u003e\nAcross both VR and Real-world settings, observationally induced placebo effects were present for both demonstrator types, with no significant interaction between setting and demonstrator type.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7139716/v1/b49221af5c5b3cddc480f065.png"},{"id":87379588,"identity":"f250bdec-c8e5-4d21-a728-0251cd83a0d7","added_by":"auto","created_at":"2025-07-23 08:30:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":298106,"visible":true,"origin":"","legend":"\u003cp\u003eTrait empathy, state empathy and placebo effects induced by the human demonstrator in VR setting and real-world settings. (A) greater levels of basic empathy scale (BES) cognitive empathy subscale were associated with greater placebo hypoalgesia (r=0.37, p = 0.014). (B) greater levels of interpersonal reactivity index (IRI) personal distress subscale were associated with greater placebo hypoalgesia (r = 0.33, p = 0.030).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-7139716/v1/97fba87fd12b8bb1ae0295f2.png"},{"id":101690520,"identity":"1a82a575-5e9f-40b1-8f4e-1b4a5c1be444","added_by":"auto","created_at":"2026-02-02 16:04:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2235178,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7139716/v1/05bd46ac-99f8-4bfd-865f-d9f91dae9c5a.pdf"},{"id":87378234,"identity":"e29577fd-aeb1-4863-a588-2b82b2905247","added_by":"auto","created_at":"2025-07-23 08:22:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2615651,"visible":true,"origin":"","legend":"","description":"","filename":"WhiteSupplMaterials07142025.docx","url":"https://assets-eu.researchsquare.com/files/rs-7139716/v1/b4cd8b4bdfe668a2f49f2256.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Context-Dependent Placebo Hypoalgesia Through Observational Learning: The Role of Empathy in Virtual and Real-World Settings","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAs digital therapeutics rapidly evolve, immersive technologies such as virtual reality (VR) are gaining prominence as tools for non-pharmacologic pain management. VR offers life-like, interactive environments that may enhance embodied perspective-taking, emotional engagement, and ultimately, empathy, a key mechanism known to modulate pain through placebo responses \u003csup\u003e1–7\u003c/sup\u003e. However, the neurocognitive pathways through which VR-based observational learning influences empathy and placebo effects remain underexplored.\u003c/p\u003e\u003cp\u003ePlacebo effects are influenced by drug marketing features\u003csup\u003e8–10\u003c/sup\u003e, color and number of pills\u003csup\u003e11,12\u003c/sup\u003e, administration route\u003csup\u003e13,14\u003c/sup\u003e, and the context in which a drug is delivered \u003csup\u003e15\u003c/sup\u003e. Conditioning (direct exposure to pain reduction) and verbal suggestions (verbal anticipations of analgesia) have been the best studied manipulations to investigate placebo analgesia in laboratory contexts. Observing others, which begins at birth, is a powerful way to gain information\u003csup\u003e16\u003c/sup\u003e. It influences a variety of behaviors\u003csup\u003e17\u003c/sup\u003e including pain and social threat \u003csup\u003e18,19\u003c/sup\u003e. We and others showed that social learning (changes in behaviors/outcomes related to observation of others)\u003csup\u003e20\u003c/sup\u003e elicits placebo analgesic effects\u003csup\u003e21,22\u003c/sup\u003e comparable in magnitude to those induced by direct experiences \u003csup\u003e22–26\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eA recent meta-analysis further demonstrated a positive association between empathy levels towards the other person and the strength of observationally induced placebo effects\u003csup\u003e27\u003c/sup\u003e. Prior research, including our own, has shown that observational learning can elicit placebo analgesia of similar magnitude to that induced by direct analgesic experience\u003csup\u003e5–7\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNonetheless, it remains unclear how and to what extent immersive environments, like VR, compared to real-world contexts in eliciting higher empathy and subsequent stronger placebo hypoalgesia. The type of demonstrator (Human versus Avatar) may further modulate this process, as avatars might be perceived as less emotionally engaging or realistic than human models. Moreover, the type of demonstrator may interact with the environmental context (VR or Real-world) to modulate these effects. Understanding these dynamics is critical for optimizing the design and implementation of digital therapeutics.\u003c/p\u003e\u003cp\u003eIn this study, we investigated how state empathy defined as an individual’s immediate affective and cognitive response to another’s experience\u003csup\u003e1\u003c/sup\u003e, can be modulated through observation in different environments, and how empathy subsequently impacts observationally induced placebo hypoalgesia \u003csup\u003e3,6,27–30\u003c/sup\u003e either through immersive VR or a traditional real-world display. We defined as \u003cem\u003eimmersive VR\u003c/em\u003e context a fully immersive 3D environment where participants experienced the scenario within a 360-degree interactive digital space. On the contrary, we considered \u003cem\u003ereal-world context\u003c/em\u003e a standard 2D display on a tablet where participants observed the same content on a flat screen without immersion. We specifically tested whether the type of demonstrator (Human vs Avatar) and the context (VR vs real-world) influence state empathy and pain perception. This design allowed for the comparison of empathy and placebo responses across immersive and non-immersive contexts.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eParticipants.\u003c/strong\u003e Healthy adults were recruited for a two-day, within-subjects experimental cross-sectional study conducted at the University of Maryland, Baltimore School of Nursing between December 2, 2021, and September 23, 2023. The final sample was comprised of 47 participants (mean age\u0026thinsp;=\u0026thinsp;29.2 years; range\u0026thinsp;=\u0026thinsp;18\u0026ndash;61 years, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), including 31 females (see also, Suppl Materials). All participants scored within the normal range on standardized measures of anxiety and depression.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Participants\u0026rsquo; characteristics.\u003cbr\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1753108868.png\"\u003e\u003c/div\u003e\n \u003cp\u003eAbbreviations: Interpersonal Reactivity Index (IRI), Basic Empathy Scale (BES), State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Beck Depression Inventory (BDI)\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThe study was approved by the University of Maryland, Baltimore Institutional Review Board (Protocol HP-00085382), and all participants provided written and verbal informed consent. All procedures adhered to the Declaration of Helsinki and applicable ethical guidelines. Participants were fully debriefed upon study completion using a standardized exit form outlining the full purpose of the research\u003csup\u003e6\u003c/sup\u003e. Participants were given the option to withdraw their data from the study after debriefing; however, none chose to do so. Participants were compensated \u003cspan\u003e$\u003c/span\u003e180 for completing all procedures of the study.\u003c/p\u003e\n\u003cp\u003eParticipants were screened by telephone and in-person to confirm eligibility as healthy volunteers. Exclusion criteria included: sensory impairments (e.g., impaired hearing, color blindness); allergies or sensitivities to topical creams or food colorings; history of chronic or current pain; neurological conditions (e.g., epilepsy); cardiovascular, pulmonary, renal, or hepatic diseases; psychiatric disorders; use of pain or other prescription medications; and pregnancy or breastfeeding.\u003c/p\u003e\n\u003cp\u003eTo ensure compliance with study requirements, participants underwent urine toxicology screening for amphetamines, methamphetamines, cocaine, opioids, and tetrahydrocannabinol prior to beginning experimental procedures on day one, and again on day two if more than 24 hours had elapsed. Individuals with positive results were excluded. Participants were also excluded if they reported VR-induced claustrophobia or symptoms of cybersickness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperimental procedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe experiment was conducted at the University of Maryland School of Nursing (UMSON) Clinical Suites in Baltimore over two sessions, held no more than 10 days apart. All procedures took place in a controlled laboratory environment.\u003c/p\u003e\n\u003cp\u003eDuring the first session, participants were informed that the study examined the relationship between brain activity and pain perception. Baseline physiological measures, including blood pressure, heart rate, height, and weight, were collected for monitoring purposes (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Participants then completed a quantitative sensory testing protocol to assess baseline pain sensitivity (see Heat Pain Stimulation).\u003c/p\u003e\n\u003cp\u003eThe second session comprised four experimental conditions presented in a counterbalanced order: Virtual Reality\u0026ndash;Human (VR-Human), Virtual Reality\u0026ndash;Avatar (VR-Avatar), Real-World\u0026ndash;Human, and Real-World\u0026ndash;Avatar. Each condition consisted of two phases: an observation phase followed by an experiential phase.\u003c/p\u003e\n\u003cp\u003eDuring the observation phase, participants viewed a demonstrator\u0026ndash;either a live human or a digital avatar version of the same individual\u0026ndash;receiving painful heat stimulation on the non-dominant forearm. Two visibly distinct creams (colored blue and green) were applied to separate forearm sites prior to stimulation. Participants were informed that the creams contained different ingredients, but no suggestion of analgesic efficacy was made to avoid explicitly inducing treatment expectancy.\u003c/p\u003e\n\u003cp\u003eIn the experiential phase, participants received matched heat stimulation on their own non-dominant forearm after the same blue and green creams were applied. Both creams consisted of CeraVe Daily Moisturizing Lotion (L\u0026rsquo;Or\u0026eacute;al, Active Cosmetics Division, New York, USA), a hypoallergenic product free from dyes, fragrances, parabens, lanolin, and formaldehyde. Creams were colored with FDA-approved food dyes and counterbalanced across participants to avoid associating a specific color with treatment efficacy. The location of each cream application (upper vs lower ventral forearm) was also counterbalanced to control for site-specific effects.\u003c/p\u003e\n\u003cp\u003eSince experimenter sex and race may influence pain-related outcomes, one experimenter collected all behavioral data, keeping constant the experimenter sex and race.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA within-subjects cross-sectional design was employed, with each participant completing four experimental conditions that varied by setting (virtual reality vs real-world) and demonstrator type (Human vs Avatar). Each condition included a placebo (treatment cue) and control (non-treatment cue) manipulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObservation Phase\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach observation phase comprised two blocks (treatment and control), each consisting of 10 trials. Block order was counterbalanced across participants. In each trial, a colored visual cue (blue or green; 2 seconds) indicated which cream the demonstrator would receive heat stimulation on. This was followed by a video of the demonstrator (2.5 seconds) reacting to the stimulus. After a brief delay, participants viewed the demonstrator\u0026rsquo;s pain intensity and unpleasantness ratings using visual analogue scales (VAS; 5 seconds). During the treatment block, the demonstrator rated their pain between 10\u0026ndash;30 on the VAS; during the control block, ratings ranged from 70\u0026ndash;90, thus reinforcing a modeled hypoalgesic effect. Each block concluded with an inter-trial interval of 4\u0026ndash;7 seconds. At the end of each observation block, participants completed a state empathy assessment consisting of four questions (see Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e for details).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperiential Phase\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach experiential phase also included two blocks (treatment and control), with 20 trials per block. Each trial began with a colored anticipatory cue (2 seconds), followed by a heat stimulus (2 seconds, plus 0.5 seconds for thermode ramp-up). After a brief delay (2 seconds), participants rated their own pain intensity and unpleasantness using a VAS ranging from 0 (no pain) to 100 (maximum tolerable pain).\u003c/p\u003e\n\u003cp\u003eHeat pain temperature was held constant across treatment and control trials and was individualized based on prior calibration to produce moderate pain (VAS 50\u0026ndash;60). Each trial concluded with a 4\u0026ndash;7 second inter-trial interval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHeat Pain Stimulation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePainful heat stimuli were delivered using a CHEPS thermode (PATHWAY System, Medoc, Ramat Yishai, Israel). To assess individual pain sensitivity, participants first completed a quantitative sensory test using the limits paradigm. During this pain calibration phase, each participant received a series of 12 brief thermal pulses. For instance, at a destination temperature of 46\u0026deg;C, the total pulse duration was approximately 890 ms, with the plateau at maximum temperature lasting around 20 ms.\u003c/p\u003e\n\u003cp\u003eAfter each stimulus, participants rated their pain intensity on a visual analogue scale (VAS; see Measurements) ranging from 0\u0026thinsp;=\u0026thinsp;no pain to 100\u0026thinsp;=\u0026thinsp;maximum tolerable pain. These ratings were used to determine a personalized stimulus intensity corresponding to moderate pain (VAS ratings between 50\u0026ndash;60), which was then used in the experiential phase of the experiment.\u003c/p\u003e\n\u003cp\u003eStimuli ramped from a 32\u0026deg;C baseline at a rate of 70\u0026deg;C/s, plateaued for less than one second, and returned to baseline at a rate of 40\u0026deg;C/s. Several pain outcomes were recorded, including the pain sensitivity threshold, defined as the temperature required to elicit the first sensation of pain (rated 1\u0026ndash;10 out of 100) and the moderate pain threshold used for the experiential phase, defined as the temperature required to elicit a moderate pain intensity (rated 40\u0026ndash;60 out of 100). Ramp-up and ramp-down durations were adjusted for each participant to achieve a VAS pain rating of approximately 5 out of 10. For reference, a 46\u0026deg;C stimulus had a mean ramp-up time of 291 ms and a ramp-down time of 612 ms \u003csup\u003e31\u003c/sup\u003e. On average, the individualized pain sensitivity threshold was 35.4\u0026deg;C (SEM\u0026thinsp;=\u0026thinsp;1.2\u0026deg;C; range: 34.4\u0026deg;C\u0026ndash;49.4\u0026deg;C). The mean temperature used during the experiential phase was 47.1\u0026deg;C (SEM\u0026thinsp;=\u0026thinsp;0.3\u0026deg;C; range: 43\u0026deg;C\u0026ndash;50\u0026deg;C).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVirtual reality vs real-world context\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn HTC Vive Pro Eye high-resolution virtual reality headset (HTC Inc., San Francisco, California), running on the SteamVR platform, was used to deliver immersive content.\u003c/p\u003e\n\u003cp\u003eImmersive VR and 2D real-world content were developed collaboratively by engineers at the University of Maryland, College Park (UMD) and the University of Maryland School of Nursing (UMSON), using the Unity game engine (Unity Technologies, San Francisco, California).\u003c/p\u003e\n\u003cp\u003eIn this project, we developed a 3D digital avatar that closely replicates the physical appearance and posture of the human demonstrator we used for this study. Using 3D applications such as Autodesk Maya, we rigged the model to match the position and orientation of the human participant seated in the chair. To further enhance realism, we matched the avatar\u0026rsquo;s clothing color, texture, and skin tone to those of this participant. We also adjusted the lighting within the virtual environment to reflect the physical setup, ensuring visual consistency between the real and virtual assets. Additionally, we created a 3D model of the pain-stimulation device, positioned on the avatar\u0026rsquo;s left hand to accurately reflect the setup in the human scenario. To integrate the avatar into the virtual environment, we used a 3D rendering pipeline in combination with a virtual reality head-mounted display, allowing for precise spatial alignment within the scene. The avatar\u0026rsquo;s size, proportions, and placement were carefully adjusted relative to the environment and surrounding elements, such as the chair, desk, and computer monitor. This setup provided a more immersive, realistic, and familiar experience for the viewer.\u003c/p\u003e\n\u003cp\u003eThe 3D 360-degree videos captured the Human demonstrator receiving both painful and non-painful thermal stimulation on two different cream-treated sites. To enable synchronized stimulus presentation, the UMD team also developed a custom network socket module that interfaced with E-Prime software. From this footage, matched 2D real-world content was extracted using the same visual angles and depth of field. In parallel, the demonstrator was digitally recreated as a computer-generated (CG) avatar using Autodesk Maya, maintaining consistent posture, clothing, and environmental context.\u003c/p\u003e\n\u003cp\u003eIn the VR conditions, participants observed either the Human or Avatar demonstrator in immersive 3D through the headset. Trials were separated by simple visual cues (e.g., blue or green crosshairs), and participants rated pain intensity and unpleasantness using an electronic VAS interface, presented within the headset and controlled via a wireless, motion-tracked HTC controller. We created eight base scenarios for the Human demonstrator, each with five variations, and eight corresponding avatar scenarios with matched content.\u003c/p\u003e\n\u003cp\u003eThe 2D real-world conditions, used as a control for immersion effects \u003csup\u003e32\u003c/sup\u003e, involved viewing the same human or avatar demonstrator videos on a standard computer monitor. The 2D content replicated the scenario structure, visual cues, and VAS interface used in the VR conditions, ensuring visual and procedural consistency across settings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMeasurements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePain intensity, referring to physical sensation, and pain unpleasantness, referring to the emotionally uncomfortable experience associated with the heat stimulations, were measured using a VAS anchored from 0\u0026thinsp;=\u0026thinsp;no pain to 100\u0026thinsp;=\u0026thinsp;maximum tolerable pain. Data were acquired using E-Prime v3 (Psychology Software Tools, Sharpsburg, PA, USA).\u003c/p\u003e\n\u003cp\u003eSocially induced placebo hypoalgesia was quantified by subtracting trial-by-trial VAS ratings in the placebo treatment condition from those in the control condition (VAS_control \u0026ndash; VAS_placebo), separately for pain intensity and unpleasantness.\u003c/p\u003e\n\u003cp\u003eTwo types of state empathy \u0026ndash; affective empathy and cognitive empathy, were assessed using four questions. Questions 1 and 2 assessed affective empathy: 1) How intense was your experience of pain while watching the demonstrator receive the stimulation? (sensory, self-referred) 2) How unpleasant was your experience of pain while watching the demonstrator receive the stimulation? (emotional, self-referred) and questions 3 and 4 assessed cognitive empathy: 3) How intense do you think was the sensation the demonstrator experienced while receiving the stimulation? (sensory, other-referred) and 4) How unpleasant do you think was the sensation the demonstrator experienced while receiving the stimulation? (emotional, other-referred) on a VAS anchored from 0 to 100 (infinite until response).\u003c/p\u003e\n\u003cp\u003eFinally, we assessed individual empathy using the Interpersonal Reactivity Index (IRI) \u003csup\u003e33\u003c/sup\u003e and the Basic Empathy Scale (BES) \u003csup\u003e34,35\u003c/sup\u003e. We controlled for individual anxiety and depression using the State-Trait Anxiety Inventory (STAI) \u003csup\u003e36\u003c/sup\u003e, Beck Anxiety Inventory (BAI) \u003csup\u003e37\u003c/sup\u003e and the Beck\u0026rsquo;s Depression Inventory (BDI) \u003csup\u003e38\u003c/sup\u003e at baseline. A privacy-compliant link was sent via Research Electronic Data Capture (REDCap) for completion of the measurements \u003csup\u003e39,40\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on our previous studies \u003csup\u003e41\u003c/sup\u003e, 47 participants were required to achieve 0.8 statistical power to detect an effect size of Cohen\u0026rsquo;s f\u0026thinsp;=\u0026thinsp;0.35 at an alpha level of 0.001 on behavioral pain changes (G*Power). A flow-chart showed the initial accrual and final sample (See Suppl Materials).\u003c/p\u003e\n\u003cp\u003eThe main dependent measures were observationally induced pain intensity and unpleasantness (see Measurement section), and affective and cognitive state empathy.\u003c/p\u003e\n\u003cp\u003eWe conducted a cross-sectional analysis using data collected from participants randomly assigned to one of four experimental conditions in a 2 (Demonstrator: Human vs Avatar) \u0026times; 2 (Context: VR vs Real-world) between-subjects design. Participants were recruited using stratified sampling to ensure balanced representation across key demographic variables (e.g., sex) that could influence empathy and pain perception. We tested for moderation effects and controlled for relevant covariates (see also Suppl Materials).\u003c/p\u003e\n\u003cp\u003eThe experimental design included the within-subjects factors of Context (VR vs. real world), Demonstrator (Human vs. Avatar), and Placebo condition (control, placebo). All subjects were exposed to all 8 conditions (repeated measures design). Accordingly, we used a 3x2 factorial Linear Mixed Model (LMM) to analyze the data and follow up on significant main effects and interactions with planned post-hoc comparisons using Bonferroni corrections. Furthermore, we used additional linear mixed models (LMMs) to evaluate the effects of context (VR vs. real-world) and demonstrator type (Human vs. Avatar) on participants\u0026rsquo; state empathy ratings differences (delta scores of control - placebo empathy ratings), and on placebo hypoalgesia (delta scores of control - placebo pain ratings) for both pain intensity and unpleasantness during the experiential phase.\u003c/p\u003e\n\u003cp\u003eCue color (blue vs. green); Block order (placebo-first vs. control-first); and Cream site (placebo cream on upper vs. lower forearm) were randomized and included as covariates. In addition, participants\u0026rsquo; sex and race were included as covariates. Participant ID was treated as a random effect to account for within-subject variability.\u003c/p\u003e\n\u003cp\u003eTo assess the potential mediating role of state empathy in placebo effects, we used Rockwood\u0026rsquo;s Multilevel Mediation Model (MLmed, Beta 2) \u003csup\u003e42,43\u003c/sup\u003e, which accommodates the hierarchical structure of repeated-measures data. Given that we only observed a significant main effect of demonstrator type (Human vs. Avatar) on cognitive empathy of pain intensity and pain unpleasantness, mediation analyses were performed treating the demonstrator type (Human vs. Avatar) as the independent variable (X), the differences in cognitive empathy between the control and placebo conditions were treated as the mediator (M), and the magnitude of placebo effects across VR and real-world settings were treated as the dependent variable (Y).\u003c/p\u003e\n\u003cp\u003eOutliers were identified using Tukey\u0026rsquo;s method with a 2.2 interquartile range (IQR) multiplier, where the upper limit calculated was defined as Q3\u0026thinsp;+\u0026thinsp;2.2 * IQR, and the lower limit defined as Q1\u0026ndash;2.2 * IQR. Q1 and Q3 represent the 25th and 75th percentiles, respectively. All statistical analyses were conducted using IBM\u0026reg; SPSS Statistics, version 29.0. Statistical significance was set at p\u0026thinsp;=\u0026thinsp;0.05 and Bonferroni corrected for multiple comparisons.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eEmpathy and observational phase\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDuring the observation phase, we manipulated affective and cognitive state empathy by showing either a human or an avatar demonstrator experiencing pain in both the no-treatment (control) and pain relief (placebo) treatments. Characteristics of the participants are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eCognitive Empathy\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe same three-way LMM analysis was applied to cognitive empathy ratings. A robust main effect of treatment emerged, with higher cognitive empathy scores in the control condition compared to the placebo condition for both pain intensity (F\u003csub\u003e1,173.73\u003c/sub\u003e = 618.41, p \u0026lt; 0.001) and pain unpleasantness (F\u003csub\u003e1,170.24\u003c/sub\u003e = 617.83, p \u0026lt; 0.001).\u003c/p\u003e\u003cp\u003eWe observed a significant main effect of demonstrator type, with higher cognitive empathy scores when participants viewed a human demonstrator compared to an avatar. This effect was present for both pain intensity (F\u003csub\u003e1,173.73\u003c/sub\u003e = 30.01, p \u0026lt; 0.001) and pain unpleasantness (F\u003csub\u003e1,170.25\u003c/sub\u003e = 37.68, p \u0026lt; 0.001). There was no main effect of context (VR vs. real world) on cognitive empathy (pain intensity: F\u003csub\u003e1,173.73\u003c/sub\u003e = 0.13, p = 0.724; pain unpleasantness: F\u003csub\u003e1,170.25\u003c/sub\u003e = 0.30, p = 0.587).\u003c/p\u003e\u003cp\u003eFor pain intensity, a significant two-way interaction was observed between demonstrator type and treatment (F\u003csub\u003e1,173.73\u003c/sub\u003e = 12.16, p \u0026lt; 0.001), indicating that the effect of treatment differed based on whether participants observed a human or avatar. However, the interaction between setting and treatment (p = 0.409), setting and demonstrator (p = 0.520), and the three-way interaction (p = 0.774) were all non-significant (\u003cb\u003eSuppl Fig.\u0026nbsp;2A\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eA similar pattern emerged for pain unpleasantness, where we found a significant demonstrator × treatment interaction (F\u003csub\u003e1,170.24\u003c/sub\u003e = 17.02, p \u0026lt; 0.001), but no other interactions involving context or the three-way combination (all ps \u0026gt; 0.05) (\u003cb\u003eSuppl Fig.\u0026nbsp;2B\u003c/b\u003e). Additional LMMs on cognitive empathy delta scores indicated a significant main effect of demonstrator type on cognitive empathy differences for pain intensity (F\u003csub\u003e1,147.67\u003c/sub\u003e = 14.43, p \u0026lt; 0.001). The Human demonstrator induced greater cognitive empathetic differences between the control and placebo conditions (pain intensity: mean = 61.62, SEM = 2.17) than the Avatar demonstrator did (pain intensity: mean = 46.49, SEM = 3.34, p \u0026lt; 0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Similar findings were found for cognitive empathy for pain unpleasantness (F\u003csub\u003e1,142.45\u003c/sub\u003e = 20.70, p \u0026lt; 0.001), with the Human demonstrator inducing greater differences in cognitive empathy (mean = 61.73, SEM = 2.02) compared with the Avatar demonstrator (mean = 44.20, SEM = 3.28, p \u0026lt; 0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFinally, neither the order of demonstrator presentation (Human first vs. Avatar first) nor the order of context exposure (VR first vs. real world first) significantly influenced cognitive empathy ratings (all ps \u0026gt; 0.05). However, white participants exhibited smaller differences in cognitive empathy for pain unpleasantness between the control and placebo conditions (mean = 48.21, SEM = 2.82) as compared with the non-white participants (mean = 56.31, SEM = 2.41, F\u003csub\u003e1,109.55\u003c/sub\u003e = 5.30. p = 0.023). Sex did not appear to influence the magnitude of cognitive empathy differences (p \u0026gt; 0.05).\u003c/p\u003e\u003cp\u003e\u003cem\u003eAffective Empathy\u003c/em\u003e\u003c/p\u003e\u003cp\u003eTo examine affective empathy, we conducted a three-way Linear Mixed Model (LMM) with Context (VR vs. real world), Demonstrator (Human vs. Avatar), and Treatment (control vs. placebo) as within-subject factors. The analysis revealed a significant main effect of treatment, with participants reporting significantly higher affective empathy in the control condition compared to the placebo condition, for both pain intensity (F\u003csub\u003e1,185.71\u003c/sub\u003e = 20.42, p \u0026lt; 0.001) and pain unpleasantness (F\u003csub\u003e1,185.01\u003c/sub\u003e = 31.52, p \u0026lt; 0.001).\u003c/p\u003e\u003cp\u003eThere was no significant main effect of demonstrator type (Human vs. Avatar) on affective empathy ratings (pain intensity: F\u003csub\u003e1,185.71\u003c/sub\u003e= 0.09, p = 0.769; pain unpleasantness: F\u003csub\u003e1,185.01\u003c/sub\u003e = 3.05, p = 0.082), and no effect of context (VR vs. real world; pain intensity: F\u003csub\u003e1,185.71\u003c/sub\u003e = 0.24, p = 0.627; pain unpleasantness: F\u003csub\u003e1,185.01\u003c/sub\u003e = 0.46, p = 0.499).\u003c/p\u003e\u003cp\u003eFurthermore, no significant two-way or three-way interactions were observed among the factors, suggesting that the treatment effect on affective empathy was consistent across demonstrator types and contexts (all ps \u0026gt; 0.05). We further conducted LMMs on the delta scores of affective empathy between the control and placebo conditions, with the setting (VR vs. Real-world) and demonstrator type (Human vs. Avatar) as the two fixed factors. No significant main effects or interactions were observed for affective empathy differences for pain intensity (all ps \u0026gt; 0.05) or pain unpleasantness (all ps \u0026gt; 0.05).\u003c/p\u003e\u003cp\u003e\u003cb\u003eObservationally Induced Placebo Effects on Self-Experienced Pain\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAfter observing a demonstrator receive painful stimulation with or without an analgesic treatment, participants underwent trial-by-trial painful stimulations of identical intensity to assess observationally induced placebo effects. After each trial, they rated their self-experienced pain intensity and pain unpleasantness.\u003c/p\u003e\u003cp\u003e\u003cem\u003ePain Intensity\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA Linear Mixed Model revealed a significant main effect of treatment, with lower pain ratings in the placebo condition (mean = 13.34, SEM = 0.33) compared to the control condition (mean = 17.89, SEM = 0.38, \u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,6096.98\u003c/sub\u003e = 81.88, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), confirming the presence of observationally induced placebo hypoalgesia. A main effect of demonstrator also emerged, with higher pain ratings after observing the Human compared to the Avatar demonstrator (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,6096.98\u003c/sub\u003e = 18.20, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). In contrast, no significant main effect was found for VR settings (VR vs. real world; \u003cem\u003ep\u003c/em\u003e = 0.980).\u003c/p\u003e\u003cp\u003eAnalyses of interactions revealed a significant two-way interaction between the VR setting and demonstrator type (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,6096.98\u003c/sub\u003e = 8.08, \u003cem\u003ep\u003c/em\u003e = 0.004), as well as between the VR setting and treatment (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,6096.98\u003c/sub\u003e = 5.10, \u003cem\u003ep\u003c/em\u003e = 0.024). However, the interaction between demonstrator type and treatment was not significant (\u003cem\u003ep\u003c/em\u003e = 0.505). Crucially, a three-way interaction among VR setting, demonstrator type, and treatment was observed (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,6096.98\u003c/sub\u003e = 11.04, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), indicating that the magnitude of the placebo effect was modulated by the specific combination of context and demonstrator (\u003cb\u003eSuppl Fig.\u0026nbsp;3A\u003c/b\u003e).\u003c/p\u003e\u003cp\u003ePost hoc Bonferroni-corrected comparisons indicated that the placebo effect was stronger in the real-world (mean = 4.35, SEM = 0.50) than in the VR setting (mean = 2.36, SEM = 0.52, \u003cem\u003ep\u003c/em\u003e = 0.006). Furthermore, the effect of demonstrator type varied by setting: in the real-world setting, Human demonstrator induced greater placebo effects (mean = 6.13, SEM = 0.75) than the Avatar (mean = 2.56, SEM = 0.67, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), whereas in the VR condition, stronger placebo hypoalgesia was observed following observation of the Avatar (mean = 3.61, SEM = 0.63) compared to the Human demonstrator (mean = 1.11, SEM = 0.83, \u003cem\u003ep\u003c/em\u003e = 0.017) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003ePain Unpleasantness\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA similar pattern emerged for pain unpleasantness. The Linear Mixed Model revealed a significant main effect of treatment, with participants reporting significantly less unpleasantness in the placebo condition compared to the control (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,5943.25\u003c/sub\u003e = 79.06, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). There was also a significant main effect of the demonstrator, with higher unpleasantness ratings in the Human vs the Avatar demonstrator conditions (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,5943.25\u003c/sub\u003e = 36.43, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). No significant main effect was found for VR settings (\u003cem\u003ep\u003c/em\u003e = 0.709).\u003c/p\u003e\u003cp\u003eSignificant two-way interactions were observed between VR setting and treatment (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,5943.25\u003c/sub\u003e = 11.35, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), and between VR setting and demonstrator type (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,5943.25\u003c/sub\u003e = 17.41, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). The interaction between treatment and demonstrator type was not significant (\u003cem\u003ep\u003c/em\u003e = 0.104). However, a significant three-way interaction between VR setting, demonstrator type, and treatment was found (\u003cem\u003eF\u003c/em\u003e\u003csub\u003e1,5943.25\u003c/sub\u003e = 8.52, \u003cem\u003ep\u003c/em\u003e = 0.004), consistent with the pattern observed for pain intensity (\u003cb\u003eSuppl Fig.\u0026nbsp;3B\u003c/b\u003e).\u003c/p\u003e\u003cp\u003ePost-hoc analyses indicated that placebo effects were greater in the real-world setting (mean = 4.69, SEM = 0.50) than the VR setting (mean = 2.02, SEM = 0.52, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). Again, the type of demonstrator interacted with the setting: in the real-world context, stronger placebo hypoalgesia was observed after viewing the Human (mean = 6.51, SEM = 0.76) compared to the Avatar demonstrator (mean = 2.88, SEM = 0.66, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), while in the VR setting, no significant differences in placebo effects were found between observing the Human demonstrator and the Avatar (\u003cem\u003ep\u003c/em\u003e = 0.060) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003eFinally, no extinction effects were observed across repeated trials for either pain intensity or pain unpleasantness ratings (\u003cem\u003eps\u003c/em\u003e \u0026gt; 0.05).\u003c/p\u003e\u003cp\u003eWe did not observe a significant sex effect on placebo hypoalgesia (pain intensity: F\u003csub\u003e1,2891.34\u003c/sub\u003e = 3.66, \u003cem\u003ep\u003c/em\u003e = 0.056; pain unpleasantness: F\u003csub\u003e1,2853.85\u003c/sub\u003e = 2.67, \u003cem\u003ep\u003c/em\u003e = 0.102). However, race significantly influenced the magnitude of placebo effects (pain intensity: F\u003csub\u003e1,2891.34\u003c/sub\u003e = 115.49, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001; pain unpleasantness: F\u003csub\u003e1,2853.85\u003c/sub\u003e = 80.56, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), with white participants exhibiting greater placebo effects than non-white participants for both pain intensity and pain unpleasantness.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEmpathy and placebo effects\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe examined the relationship between the level of trait empathy and the magnitude of placebo effects using bivariate correlations. We found that higher BES cognitive subscale scores (Pearson r = 0.37, \u003cem\u003ep\u003c/em\u003e = 0.014), and higher IRI personal distress (Pearson r = 0.33, \u003cem\u003ep\u003c/em\u003e = 0.030) were associated with greater placebo hypoalgesia induced by the Human demonstrator in the VR setting. However, placebo effects induced by the real-world setting or by the Avatar demonstrator in the VR setting were not dependent on the trait empathy levels (all ps \u0026gt; 0.05). Similar findings were found regarding placebo effects for pain unpleasantness, where greater BES cognitive subscale (Pearson r = 0.35, \u003cem\u003ep\u003c/em\u003e = 0.021) and IRI personal distress (Pearson r = 0.34, \u003cem\u003ep\u003c/em\u003e = 0.028) were associated with higher placebo effects for pain unpleasantness (\u003cb\u003eSuppl Fig.\u0026nbsp;4\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eIn terms of state empathy ratings, we found that affective state empathy (Pearson r = 0.39, \u003cem\u003ep\u003c/em\u003e = 0.008), but not cognitive state empathy (Pearson r = 0.03, p = 0.824) was associated with placebo effects. Again, this association was only observed when placebo hypoalgesia was induced by the Human demonstrator in the VR setting, while no significant correlations between state empathy and placebo effects were induced by real-world settings or by the Avatar demonstrator in the VR setting (all ps \u0026gt; 0.05). Similar patterns were observed in terms of placebo effects for pain unpleasantness and affective state empathy (Pearson r = 0.44, \u003cem\u003ep\u003c/em\u003e = 0.002). However, after removing the outliers identified using Tukey’s method, the correlations between affective state empathy and placebo hypoalgesia were not significant (pain intensity: Pearson r = 0.22, p = 0.165; pain unpleasantness: Pearson r = 0.22, \u003cem\u003ep\u003c/em\u003e = 0.162).\u003c/p\u003e\u003cp\u003eMulti-level mediation models indicated that neither affective state empathy (a*b = 0.03, 95%BCI = [-0.73, 0.81]), nor cognitive state empathy (a*b = 0.28, 95%BCI = [-2.33, 2.93]) mediated the influence of demonstrator type (Human vs. Avatar) on placebo hypoalgesia for pain intensity. Similarly, neither affective state empathy (a*b = -0.33, 95%BCI = [-2.14, 1.13]), nor cognitive state empathy (a*b = 1.54, 95%BCI = [-1.66, 5.07]) mediated the influence of demonstrator type on placebo hypoalgesia for pain unpleasantness (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA \u003cb\u003eand B\u003c/b\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe investigated how empathy, modulated through observation of a human or avatar demonstrator, influences placebo analgesia in both VR and real-world settings. Observing an effective treatment reduced both affective and cognitive state empathy for pain, with cognitive empathy being more sensitive to demonstrator type. We found robust observationally induced placebo effects on self-experienced pain, shaped by demonstrator type, treatment condition, and setting: avatars were more effective in VR, while human demonstrators produced stronger effects in real-world contexts. Trait empathy, particularly for the VR-Human condition, was associated with placebo responsiveness, although mediation was not supported.\u003c/p\u003e\u003cp\u003eImportantly, individual differences including race, trait empathy, treatment order, and even cream color, significantly modulated placebo effects. White participants exhibited greater analgesia than non-White participants, and trait empathy predicted responses only in the VR-Human context. These findings highlight the critical role of socio-contextual and perceptual factors in shaping digital placebo responses and offer actionable insights for designing effective, personalized virtual interventions for pain management.\u003c/p\u003e\u003cp\u003eThe ability to learn from observing others is a fundamental mechanism shared across species \u003csup\u003e44,45\u003c/sup\u003e. Extensive research has shown that witnessing fear in others can shape direct behavioral responses \u003csup\u003e46,47\u003c/sup\u003e. Social learning—defined as behavioral or outcome changes resulting from the observation of others \u003csup\u003e20\u003c/sup\u003e—has been shown to elicit placebo analgesia of similar magnitude to that produced by direct experience \u003csup\u003e22–26\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe current study aimed to build on this body of work by examining how manipulation of state empathy, using well-established experimental procedures and VR \u003csup\u003e48–54\u003c/sup\u003e, modulates observationally induced placebo effects. In our previous work, a strong correlation between analgesic responses and trait empathy (e.g., empathic concern) was observed when participants watched a live demonstrator (r = 0.67, p \u0026lt; 0.005) \u003csup\u003e3\u003c/sup\u003e. However, when observers watched video recordings, robust placebo effects on sensory pain intensity emerged, but were not linked to dispositional empathy traits \u003csup\u003e24,25\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eEarlier studies had not directly manipulated state empathy, which comprises cognitive (perspective-taking) and affective (emotional resonance) components \u003csup\u003e1\u003c/sup\u003e. Here, we directly assessed both aspects of state empathy by asking participants to evaluate the perceived pain intensity (sensory, other-referred) and unpleasantness (emotional, other-referred) experienced by a demonstrator undergoing identical painful thermal stimulations under placebo and control (no treatment) conditions—though in reality, both creams were inert.\u003c/p\u003e\u003cp\u003eEmpathy is known to be influenced by both contextual (e.g., sex \u003csup\u003e55–58\u003c/sup\u003e) and individual (e.g., reduced spontaneous empathy in psychopathy \u003csup\u003e59\u003c/sup\u003e) factors. VR has previously been used to elicit vicarious pain and pleasure \u003csup\u003e60,61\u003c/sup\u003e and can also be manipulated to reduce self-experienced pain \u003csup\u003e62\u003c/sup\u003e. Based on this, we hypothesized that VR might enhance state empathy. Contrary to our expectations, VR did not increase either cognitive or affective state empathy compared to the real-world setting. This is consistent with meta-analytic findings showing that VR does not reliably enhance cognitive empathy \u003csup\u003e63\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIndependently of the VR context, our manipulation of state empathy showed higher cognitive empathy when participants observed a human demonstrator compared to an avatar, in line with studies exploring the impact of robots on empathy \u003csup\u003e64\u003c/sup\u003e. Recent work also demonstrates that even between two avatars, a human-like avatar elicits more empathy than a robot-like avatar \u003csup\u003e65\u003c/sup\u003e. These findings, together with our results, suggest that facial expressions, biological motion, or the perceived realism of a demonstrator may be critical for eliciting cognitive empathy \u003csup\u003e66–70\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIt is known that observational learning influences neural and cognition systems \u003csup\u003e4\u003c/sup\u003e throughout mentalizing (the ability to cognitively understand the mental states of others) \u003csup\u003e71–73\u003c/sup\u003e, empathy (the ability to share an emotional experience) \u003csup\u003e74–76\u003c/sup\u003e, and other factors (sociodemographics) \u003csup\u003e77\u003c/sup\u003e. After a pioneering study \u003csup\u003e21\u003c/sup\u003e, other studies showed that observationally induced placebo effects are comparable in size to the effect of directly experienced conditioning \u003csup\u003e22–26\u003c/sup\u003e. Recent studies have demonstrated the demonstrator’s sex \u003csup\u003e28\u003c/sup\u003e, social status \u003csup\u003e78\u003c/sup\u003e and self-confidence \u003csup\u003e79\u003c/sup\u003e can influence observationally induced placebo effects. Observational learning and prosocial choices are shaped by empathic discomfort and endogenous opioid activity \u003csup\u003e80\u003c/sup\u003e. It has been shown that observing a video or a live demonstrator generates the same magnitude of pain reductions that are significantly different from a control group (e.g., watching colored light stimulations)\u003csup\u003e22\u003c/sup\u003e. To our knowledge, we are the first to investigate the role of observation of a human or avatar demonstrator, in influencing placebo analgesia within both VR and real-world settings. We observed a significant interaction between setting (VR vs. real-world) and demonstrator type (Human vs. Avatar). In VR, observing the Avatar induced stronger placebo hypoalgesia than the Human demonstrator, while in the real-world setting, the opposite was true: placebo hypoalgesia was stronger after observing a human demonstrator. Overall, socially induced hypoalgesia was greater in the real-world than in VR, suggesting that learning through observation may be more effective in naturalistic contexts. This effect was associated with trait empathy but did not state empathy, but only in the VR setting with the Human demonstrator showing a key role of empathy in shaping observationally learned placebo effects.\u003c/p\u003e\u003cp\u003eContextual factors such as race and demonstrator identity shape observationally induced placebo effects. Using a white male demonstrator and his avatar, we found no sex differences in empathy or placebo responses. Prior studies report stronger nocebo effects after observing male models \u003csup\u003e25\u003c/sup\u003e. White participants in our study showed greater placebo responses than non-white participants, aligning with existing literature on race and placebo effects \u003csup\u003e81\u003c/sup\u003e. However, it should be noted that these differences were also associated with race-concordance between experimenter and participant, which was not directly manipulated in this study.\u003c/p\u003e\u003cp\u003eLimitations\u003c/p\u003e\u003cp\u003eThis study has some limitations. We did not track attention during VR observation (using eye-tracking technology\u003csup\u003e82,83\u003c/sup\u003e), which may affect our ability to study empathy and learning. Furthermore, affective empathy ratings showed little variability, possibly due to the passive nature of the task. Additionally, while we did find significant influences of race on placebo hypoalgesia, this study was not designed to directly measure or manipulate placebo effects as a direct effect of race or racial concordance. For this reason, any conclusions based on racial influences should be evaluated with caution. Finally, we used avatars with no facial expressions, limiting their ecological validity.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eTogether, these results expand our understanding of how VR and demonstrator type affect both empathy and observationally induced placebo effects within digital and real-world contexts. While trait empathy influenced responses in specific conditions, notably the VR-Human context, state empathy did not significantly modulate placebo effects. The interaction between demonstrator type and observation context remains critical: avatars were more effective in VR settings, whereas human demonstrators elicited stronger effects in real-world environments. These findings underscore the importance of contextual and social factors beyond momentary empathic engagement in the design of digital interventions. These findings could offer actionable insights for developing personalized, socially informed, and scalable non-pharmacological strategies for symptom management across diverse care settings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory; BES: Basic Empathy Scale; IRI: Interpersonal Reactivity Index STAI: State-Trait Anxiety Inventory\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eThe authors would like to thank Nandini Raghuraman for helping with the procedure setup and Yavin Shaham for thoughtful comments to the manuscript. The authors acknowledge the support of the National Institute of Dental and Craniofacial Research Helping to End Addiction Long-term (NIDCR HEAL) Initiative (1R21 DE032532-01, Dorsey/Colloca; J. White) and the National Center for Complementary and Integrative Health (R01- 5R01AT010333, L. Colloca). The funding source was not involved in this work.\u003c/p\u003e\n\u003ch3\u003eAuthor Contributions\u003c/h3\u003e\n\u003cp\u003eJ.N.W., and L.C., conceived and designed the study. L.W., R.S., J.M.H., S.L., and B.B. contributed to data collection and preprocessing. J.N.W., L.W. performed initial data analysis. A.V. provided expertise and oversight on virtual reality design and implementation. L.C. supervised the study and secured funding. G.C., Y.W., and C.-\u0026Eacute;.B.-R conducted intendent analyses of the data collected and helped interpret the findings. J.N.W., L.W. and C.-\u0026Eacute;.B.-R drafted the manuscript. L.C., and C.-\u0026Eacute;.B.-R. reviewed and approved the final version of the manuscript. All authors contributed to manuscript revisions and approved the final version for submission.\u003c/p\u003e\n\u003ch3\u003eCompeting Interests\u003c/h3\u003e\n\u003cp\u003eAll authors have no conflicts of interest to declare.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShen, L. On a Scale of State Empathy During Message Processing. \u003cem\u003eWestern Journal of Communication\u003c/em\u003e \u003cstrong\u003e74\u003c/strong\u003e, 504-524 (2010). https://doi.org/10.1080/10570314.2010.512278\u003c/li\u003e\n\u003cli\u003eLi, A., Monta\u0026ntilde;o, Z., Chen, V. J. \u0026amp; Gold, J. I. Virtual reality and pain management: current trends and future directions. \u003cem\u003ePain management\u003c/em\u003e \u003cstrong\u003e1\u003c/strong\u003e, 147-157 (2011). \u003c/li\u003e\n\u003cli\u003eColloca, L. \u0026amp; Benedetti, F. 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Eye Tracking in Virtual Reality. \u003cem\u003eJournal of Eye Movement Research\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 1-18 (2019). \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-digital-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjdigitalmed","sideBox":"Learn more about [npj Digital Medicine](http://www.nature.com/npjdigitalmed/)","snPcode":"41746","submissionUrl":"https://submission.springernature.com/new-submission/41746/3","title":"npj Digital Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"observation, learning, empathy, virtual reality, pain, placebo","lastPublishedDoi":"10.21203/rs.3.rs-7139716/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7139716/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study examined how empathy and contextual factors influence observationally induced placebo analgesia in virtual and real-world settings. Forty-seven participants observed a human or avatar demonstrator receiving painful stimulation with or without a placebo treatment, then experienced identical stimulations themselves. Observation led to significant placebo hypoalgesia for both pain intensity and unpleasantness. Human demonstrators evoked greater cognitive empathy, while placebo treatments reduced affective and cognitive empathy across contexts. Analgesic effects were stronger in the real world after observing humans, but in VR contexts, avatars induced greater placebo effects. Placebo effects were modulated by individual and experimental factors, including trait empathy and demonstrator type, respectively. These findings highlight how digital context, embodiment, and participant characteristics interact to shape pain outcomes, informing design strategies for immersive digital therapeutics.\u003c/p\u003e","manuscriptTitle":"Context-Dependent Placebo Hypoalgesia Through Observational Learning: The Role of Empathy in Virtual and Real-World Settings","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 08:22:27","doi":"10.21203/rs.3.rs-7139716/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-29T00:25:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-26T18:26:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-25T08:56:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-12T20:44:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"199423712366666192160164866758063836047","date":"2025-08-08T11:23:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-06T06:46:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67327216264231456914655733360920589493","date":"2025-08-01T07:39:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274344061328132614553640954543546144039","date":"2025-08-01T05:51:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"159448619761332306590882989097302795975","date":"2025-07-19T08:40:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-17T08:17:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-16T23:36:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-16T18:54:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Digital Medicine","date":"2025-07-16T11:47:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-digital-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjdigitalmed","sideBox":"Learn more about [npj Digital Medicine](http://www.nature.com/npjdigitalmed/)","snPcode":"41746","submissionUrl":"https://submission.springernature.com/new-submission/41746/3","title":"npj Digital Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"74c04a61-b6ec-407d-8053-cfac73bfbe81","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51785060,"name":"Health sciences/Health care"},{"id":51785061,"name":"Health sciences/Medical research"},{"id":51785062,"name":"Biological sciences/Neuroscience"},{"id":51785063,"name":"Biological sciences/Psychology"},{"id":51785064,"name":"Social science/Psychology"}],"tags":[],"updatedAt":"2026-02-02T16:01:31+00:00","versionOfRecord":{"articleIdentity":"rs-7139716","link":"https://doi.org/10.1038/s41746-026-02373-3","journal":{"identity":"npj-digital-medicine","isVorOnly":false,"title":"npj Digital Medicine"},"publishedOn":"2026-01-27 15:58:58","publishedOnDateReadable":"January 27th, 2026"},"versionCreatedAt":"2025-07-23 08:22:27","video":"","vorDoi":"10.1038/s41746-026-02373-3","vorDoiUrl":"https://doi.org/10.1038/s41746-026-02373-3","workflowStages":[]},"version":"v1","identity":"rs-7139716","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7139716","identity":"rs-7139716","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}