A naturalistic study comparing the efficacy of unilateral and bilateral sequential theta burst stimulation in treating major depression - the U-B-D study protocol.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. METHODS: In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4-6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. DISCUSSION: Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. TRIAL REGISTRATION: The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

Electrophysiological and behavioral effects of unilateral and bilateral rTMS; A randomized clinical trial on rumination and depression.

BACKGROUND: Rumination is significantly frequent in major depressive disorder (MDD). However, not a lot of studies have investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on rumination. METHODS: 61 participants with a minimum Hamilton Depression Rating Scale (HAM-D) score of 20 were randomly assigned to sham, bilateral stimulation (BS) or unilateral stimulation (US) groups. EEG, The Ruminative Response Scale (RRS), and HAM-D were administered before and after the 20 sessions of rTMS. Phase locked values (PLV) were calculated as a measure of connectivity. RESULTS: There was a significant decrease in HAM-D scores in both BS and US. In responders, BS and US differed significantly in RRS total scores, with greater reduction in BS. PLV significantly changed in the default mode network (DMN) in delta, theta, alpha, and beta in BS, in responders of which PLV decreased in the DMN in beta and gamma. Positive correlations between PLV and brooding in delta and theta, and negative correlations between PLV and reflection were found in theta, alpha, and beta. In US, connectivity in the DMN increased in beta, and PLV increased in theta and beta, and decreased in alpha and beta in its responders. Positive correlations between PLV and brooding in the delta and theta, as well as negative correlations between PLV and reflection in theta were observed in the DMN. CONCLUSION: US and BS resulted in different modulations in the DMN, however, both could alleviate both rumination and depression. Reductions in the beta and alpha frequency bands in the DMN can be considered as potential EEG-based markers of response to bilateral and unilateral rTMS, respectively.