Epigenetic mechanisms of Non-Invasive Brain Stimulation: A Systematic Review of Human and Preclinical Evidence
Abstract
Non-invasive brain stimulation (NIBS) produces clinical and behavioural effects persisting weeks to months beyond stimulation. This persistence is typically attributed to LTP- and LTD-like synaptic plasticity, yet short-lived synaptic events alone cannot explain it; epigenetic mechanisms, the leading candidate substrate, have never been systematically evaluated. Following PRISMA 2020, we searched PubMed/MEDLINE and Europe PMC to June 2026 (2,089 records; 1,941 de-duplicated). Twenty-two studies were eligible: ten human, ten preclinical, and two invasive cervical-VNS studies retained for sensitivity analysis. Among 18 interventional studies, 17 reported significant epigenetic change (94%; p = 1.45×10⁻⁴), driven by the controlled animal tier (10/10; p = 0.002); the human stream alone (5/6) was non-significant (p = 0.22). Adjusting for publication bias, the pooled signal held under a moderately conservative null (p₀ = 0.7, p = 0.020) but not a strongly conservative one (p₀ = 0.8, p = 0.15). Effects spanned histone modifications, DNA methylation, non-coding RNAs, and epigenetic enzymes. Histone acetylation was the most compelling pathway, supported by causal pharmacological rescue in rodent rTMS and tDCS models. DNA methylation showed an "epigenetic homeostat" pattern, normalising stress-induced aberrations at promoters including BDNF and COMT. Non-coding RNAs formed the largest stream, with circulating miR-146a-5p recurring across rTMS trials. BDNF emerged as a convergent node,…
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Evidence Hub reads this as a systematic review. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid.
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