The cortical mechanisms underlying the analgesic effects of repetitive transcranial magnetic stimulation: Protocol for a Systematic Review and Meta-analysis

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a promising, safe, and non-invasive treatment for pain. However, there is no clear understanding of the cortical mechanisms underlying the analgesic effect of rTMS. One theory is that rTMS-induced analgesia is associated with alterations in corticomotor and cortical excitability, assessed using single-pulse TMS and TMS-electroencephalography (TMS-EEG) respectively. The aim of this systematic review and meta-analysis will be to synthesise the available literature to determine: 1) the effect of rTMS on corticospinal and cortical excitability across experimental pain, and acute and chronic clinical pain conditions; 2) whether changes in cortical/corticospinal excitability correlate with reductions in pain severity for these pain types following rTMS. Methods/Analysis: Electronic databases (Scopus, PubMed, MEDLINE, PsycINFO and Web of Science) will be searched using a predetermined strategy. Studies published before December 2024 that investigated the effects of rTMS on cortical/ corticomotor excitability and pain (experimental, acute or chronic clinical pain) will be included if they meet eligibility criteria. Study identification, data extraction and risk of bias assessment will be conducted by two independent reviewers, with a third reviewer consulted for any disagreements. We will extract the group level and individual level changes in corticomotor excitability (i.e., motor evoked potential amplitude or motor map volume) and/or cortical excitability (TMS-evoked potential peak amplitude) and pain severity, before and after rTMS. Group level effect sizes of rTMS on corticomotor/cortical excitability and the individual level association between changes in pain and corticomotor/cortical excitability for different pain conditions (experimental, acute or chronic clinical pain) will be synthesized using a random effects meta-analysis. Subgroup analyses are planned, separating effect sizes for different pain conditions and different rTMS protocols. Discussion This review will provide the evidence for the cortical and corticomotor mechanisms associated with rTMS-induced analgesia, both at a group and individual level. Registration Number: The systematic review is registered with the International Prospective Register of Systematic Reviews (Insert number)