677: Prefrontal modulation of placebo analgesia: causal evidence from excitatory and inhibitory TMS

Topic: Experimental (Non-clinical) Human Studies
Subtopic: Non -specific to any diagnosis, Placebo/Nocebo, Electrophysiology/Clinical neurophysiology (e.g. microneurography, EEG, MEG, OPMs, TMS), Pain mechanisms (e.g. descending inhibitory control, placebo, inflammation)

Background and Aims: Placebo analgesia has recently been conceptualized within the Bayesian brain framework, in which the brain integrates prior expectations with incoming nociceptive signals to generate perceptual experience (Buchel et al 2014). Within this view, expectations function as top-down priors that can bias sensory inference, leading to considerable modulations in perceived pain. A growing body of evidence implicates the dorsolateral prefrontal cortex (dlPFC) in the formation and maintenance of placebo-related expectations (Krummenacher et al. 2010, Koban et al. 2012). However, such evidence is largely correlational (Romanella et al., 2023), leaving the causal contribution of dlPFC activity still a matter of debate.

Methods: In the present study, we investigated the role of the dlPFC in enhancing/suppressing placebo analgesia responses using repetitive transcranial magnetic stimulation (rTMS). Participants underwent a placebo induction procedure followed by either sham (control stimulation), inhibitory (1Hz) or excitatory (10Hz) rTMS over the left dlPFC and the Vertex (control site). Thermal pain threshold was assessed before and after stimulation. To quantify placebo-related analgesic responses, difference scores (post - pre, in °C) were analyzed by means of (generalized) linear mixed models with Stimulation and Site as a fixed effects and Subject as a random intercept.

Results: Preliminary results (n = 27) revealed that, compared to sham, inhibitory dlPFC stimulation abolished placebo analgesia (β = -1.7, SE = 0.53, t(51)= -3.3; p < 0.01), whereas excitatory dlPFC stimulation significantly enhanced placebo analgesia (β = +1.4, SE = 0.68, t(51)= +2.1; p < 0.05). Crucially, excitatory/inhibitory stimulation over the Vertex did not significantly modulate the magnitude of placebo responses (ps > 0.1), confirming the anatomical specificity of the dlPFC.

Conclusions: These findings provide preliminary causal evidence that dlPFC activity regulates placebo analgesia, consistent with its proposed function in encoding and maintaining prior expectations. By demonstrating that placebo responses can be selectively suppressed or amplified through targeted neuromodulation, this work advances mechanistic understanding of expectancy-driven pain modulation and highlights the dlPFC as a promising target for improving therapeutic outcomes in both experimental and clinical settings.

References: 1. Büchel C, Geuter S, Sprenger C, Eippert F. Placebo analgesia: a predictive coding perspective. Neuron. 2014;81(6):1223-1239. doi:10.1016/j.neuron.2014.02.042
2. Koban L, Brass M, Lynn MT, Pourtois G. Placebo analgesia affects brain correlates of error processing. PLoS One. 2012;7(11):e49784. doi:10.1371/journal.pone.0049784
3. Krummenacher P, Candia V, Folkers G, Schedlowski M, Schönbächler G. Prefrontal cortex modulates placebo analgesia. Pain. 2010;148(3):368-374. doi:10.1016/j.pain.2009.09.033
4. Romanella SM, Mencarelli L, Burke MJ, Rossi S, Kaptchuk TJ, Santarnecchi E. Targeting neural correlates of placebo effects. Cogn Affect Behav Neurosci. 2023;23(2):217-236. doi:10.3758/s13415-022-01039-3

Presenting Author: Denisa A. Zamfira & Chiara Di Fazio
Submitting Author: Denisa Adina Zamfira

Senior Author: Prof. Elisa Carlino

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Chiara Di Fazio: PhD Student - Department of Psychology, University of Turin
• Alessandro Piedimonte: MSc, PhD - Department of Neuroscience "Rita Levi Montalcini", University of Turin
• Tommaso Fassina: Post-graduate trainee - Department of Neuroscience "Rita Levi Montalcini", University of Turin
• Sara Palermo: MSc, PhD - Department of Psychology, University of Turin
• Elisa Carlino: MSc, PhD - Department of Neuroscience "Rita Levi Montalcini", University of Turin