To explore brain oscillatory activity as key explanatory tool of the neural mechanisms of the placebo effect.

A systematic search based on PRISMA guidelines was conducted in PubMed, Embase, and Cochrane for randomized and crossover trials through August 2023. Our search targeted studies measuring brain oscillations at rest in placebo-controlled neurorehabilitation trials. We conducted qualitative, semi-quantitative, and quantitative anakysis, estimating effect sizes for absolute power differences between sham and active interventions using Hedges' g.

63 studies were included, comprising 180 healthy subjects and 1,758 patients with neurological disorders. In healthy individuals, placebo interventions increased alpha power compared to no intervention (g = 0.45, 95% CI [0.09; 0.8]). Among patients with neurological disorders, sham interventions yielded increases in alpha frontal (g = 0.08, 95% CI [0.07; 0.08]), central (g = 0.55, 95% CI [0.47; 0.65]), and parietal (g = 0.28, 95% CI [0.18; 0.44]) regions, as well as in beta (g = 1.31, 95% CI [1.06; 1.63]) and theta (g = 0.58, 95% CI [0.46; 0.72]) bands in central regions. Interestingly, these effects became non-significant when comparing with the active interventions.

The study reveals enhancement of alpha oscillations in fronto-central regions as a primary neural biomarker of the placebo effect, with increases in beta and theta bands also significant, particularly among patients with neurological disorders. Notably, these placebo-induced modulations appear to be reversed by active rehabilitation interventions, which may incorporate aspects of the placebo effect. Our novel results show, for the first time, that placebo neural effects might depend on the brain oscillatory baseline (healthy vs. patient populations), and they seem to unmask a more homeostatic salutogenic rhythm, such as alpha oscillations in healthy subjects and theta and beta oscillations in patient populations.