Potential Epigenetic Mechanisms of High-Frequency rTMS in the Treatment of Major Depression: A Brief Report of Current Evidence.

INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS) is an FDA-approved, non-invasive neuromodulation technique with clinically supported efficacy in the management of treatment-resistant major depressive disorder (TRD). Although the clinical effectiveness of high-frequency rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) is well established, the molecular mechanisms underlying its long-term therapeutic effects remain incompletely understood. The aim of this brief report is to examine the possible epigenetic modifications (DNA methylation, histone modifications, microRNA) associated with the antidepressant effects of rTMS in light of current literature, and to evaluate the dose-response relationship that may affect treatment response within the framework of homeostatic plasticity. METHODS: A summary of current literature from the PubMed, Web of Science, and Google Scholar databases is presented using the keywords "rTMS," "major depression," "epigenetics," "histone modifications," "DNA methylation," "miRNA," and "homeostatic plasticity." Clinical and preclinical studies specifically investigating the molecular effects of rTMS on synaptic plasticity were included. RESULTS: The reviewed studies suggest that rTMS may not merely provide transient electrical stimulation but may also operate through an "epigenetic regulatory" mechanism capable of permanently altering neuronal gene expression. In preclinical studies, changes in histone acetylation (e.g., regulation of CDK5 and PSD-95) and specific microRNAs (e.g., miR-146a-5p) have been observed to modulate synaptic plasticity. Furthermore, it has been proposed that the dose-response relationship of rTMS is non-linear; excessive stimulation may activate "homeostatic plasticity" mechanisms, thereby reducing synaptic sensitivity. DISCUSSION: Current findings indicate that rTMS may exert an antidepressant effect by reorganizing synaptic plasticity through epigenetic modifications. Enhancing treatment efficacy depends on optimizing the dosage by considering homeostatic balances and integrating epigenetic biomarkers capable of predicting treatment response into clinical practice. Future personalized treatment protocols should be designed based on these molecular and neurophysiological insights.