Brain oscillation-synchronized stimulation for major depression: a randomized controlled trial comparing EEG-triggered repetitive TMS with standard iTBS (Acronym: BOSSFRONT2)

BACKGROUND: Major depressive disorder (MDD) is a common severe mental disorder with enormous socioeconomic costs for the patient and society alike. Current pharmacological and psychotherapeutic treatments are ineffective in a substantial fraction of patients and can be accompanied by unwanted side effects. METHODS: Using a novel non-invasive brain stimulation method to specifically target and modulate dysfunctional brain oscillations with high spatial and temporal precision this study will investigate the efficacy of EEG-triggered transcranial magnetic stimulation (TMS) to alleviate depressive symptoms in 28 patients with MDD in a 1:1-randomized, double blind, standard treatment-controlled pilot trial. In the experimental condition, stimulation will be brain oscillation-synchronized based on the EEG-extracted endogenous theta oscillation over left dorsomedial prefrontal cortex (DMPFC). The control condition will consist of standard TMS therapy following an FDA-approved intermittent theta-burst stimulation (iTBS) protocol over left dorsolateral prefrontal cortex (DLPFC). The treatment will be performed over four consecutive weeks (20 sessions) and the primary outcome will be the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) after the last versus before the first treatment session. DISCUSSION: The aim of the study is to gain exploratory evidence for the feasibility and efficacy of EEG-synchronized TBS of left DMPFC compared to a standard FDA-approved treatment (iTBS of left DLPFC) in a double-blind randomized parallel-design pilot clinical trial. Positive results will pave the way for a larger RCT to prove the superiority of personalized, brain oscillation-synchronized non-invasive brain stimulation therapies as novel, effective and well-tolerated treatment in MDD. TRIAL REGISTRATION: Trial Registration: NCT06345651, date of registration: 2024-01-08, https://clinicaltrials.gov/study/NCT06345651 The trial is conducted in accord with protocol version number 2022-09, Version 3. Recruitment started in January 2024, and recruitment is ongoing. The recruitment phase is projected to conclude by December 2026.