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Supplemental Digital Content 3

Pilot study on TGI

Using our new TGI device, we performed a pre-study on 20 healthy participants (11 females, mean age = 25.10 years, SD = 5.66) examining the perceptions induced by the control

conditions ‘COLD’ (16°C/16°C) and ‘WARM’ (40°C/40°C) as well as the experimental

‘EXP’ condition (16°C/40°C; difference of 24°C). To evaluate the effect of a larger temperature difference, we implemented an additional control condition with a smaller difference (21°C/35°C; difference of 14°C). Each trial consisted of three on-blocks (hand pneumatically pressed against the borosilicate tubes) separated by two off-blocks (hand pneumatically elevated, not touching the borosilicate tubes), lasting for 20 seconds each. This duration allowed enough time for the passive hand lowering towards the borosilicate tubes (approximately 5s) and a sufficiently long stimulation time of approximately 15s. With a starting phase of 5 seconds off-block, one condition lasted for 105s.

We assessed the unpleasantness of the stimulation (using the Self-Assessment Manikin scale [2]) as well as the intensity of pain (using a visual analogue scale (VAS) of 100mm length with the endpoints ‘no pain’ and ‘worst pain imaginable’; the VAS was later transformed into a 100-point scale). The order of conditions was randomized, and there were inter-trial

durations of about 10 minutes each. Performing ANOVAs for repeated measurements, we found significant differences between the conditions related to the VAS ratings (F2.17, 41.30 = 7.24, p = .002) and unpleasantness ratings (F2.28, 43.35 = 6.56, p = .002). By performing post- hoc one-tailed paired t-tests between the EXP and the three control conditions, we found that the EXP condition induced significantly more pain (mean VAS = 21.60, SD = 22.07) and stronger unpleasantness ratings (mean = 5.95, SD = 2.26) than the two conditions controlling for the warm (mean VAS = 4.15, SD = 9.06, t19 = 3.72, p = .002; mean unpleasantness =

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3.65, SD = 1.79, t19 = 3.93, p < .001) and cold (mean VAS: 8.15, SD = 15.82, t19 = 4.09, p <

.001; mean unpleasantness 4.30, SD = 1.95, t19 = 3.12, p = .003) temperatures as well as a smaller temperature difference (mean VAS: 14.30, SD = 21.90, t19 = 2.02, p = .03; mean unpleasantness 5.00, SD = 2.15, t19 = 3.44, p = .001). Successful TGI induction was defined as a positive relative superadditive TGI effect, which is calculated as follows: (VAS EXP - VAS WARM - VAS COLD) / (VAS EXP + VAS WARM + VAS COLD). This results in a value ranging from -1 to +1, with positive values indicating more pain in the EXP condition compared to the linear combination of the COLD and WARM conditions. The EXP condition induced a TGI effect in 70% of participants, which represents an even higher frequency than reported in studies using conventional TGI devices (e.g., [1]). The superadditive effect in the TGI responders ranged from 0.02 to 1.00 and had a mean value of 0.60 (SD = 0.36). Taken together, the results confirm that effects induced by our new device are comparable to effects reported in other studies.

Supplemental References

1. Bouhassira D, Kern D, Rouaud J, Pelle-Lancien E, Morain F. Investigation of the paradoxical painful sensation ('illusion of pain') produced by a thermal grill. Pain 2005;114:160-7.

2. Bradley MM, Lang PJ. Measuring emotion: The Self-Assessment Manikin and the semantic differential. J Behav Ther Exp Psychiat 1994;25:49-59.

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