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).

Dose-response of intermittent theta burst stimulation of the prefrontal cortex: A TMS-EEG study.

OBJECTIVE: Using concurrent transcranial magnetic stimulation (TMS) and electroencephalography (TMS-EEG), this study aims to compare the effect of three intermittent theta-burst stimulation (iTBS) doses on cortical activity in the left dorsolateral prefrontal (DLPFC) cortex. METHODS: Fourteen neurotypical participants took part in the following three experimental conditions: 600, 1200 and 1800 pulses. TMS-EEG recordings were conducted on the left DLPFC pre/post iTBS, including single-pulse TMS and short- and long-interval intracortical inhibition (SICI, LICI). TMS-evoked potentials (TEP) and event-related spectral perturbation (ERSP) were quantified. Linear mixed models were used to assess the effect of iTBS on brain activity. RESULTS: The effects of iTBS on DLPFC activity did not significantly differ between the three doses. Specifically, regardless of dose, iTBS modulated the amplitude of most TEP components (P30, N45, P60, P200), reduced SICI and LICI ratios of P30 and P200, and decreased ERSP power of theta oscillations. CONCLUSIONS: In neurotypical individuals, doubling or tripling the number of iTBS pulses does not result in stronger potentiation of prefrontal activity. However, all iTBS conditions induced significant modulations of DLPFC activity. SIGNIFICANCE: Replicating the study in clinical populations could help define optimal parameters for clinical applications.

No aftereffects of high current density 10 Hz and 20 Hz tACS on sensorimotor alpha and beta oscillations.

Application of transcranial alternating current stimulation (tACS) is thought to modulate ongoing brain oscillations in a frequency-dependent manner. However, recent studies report various and sometimes inconsistent results regarding its capacity to induce changes in cortical activity beyond the stimulation period. Here, thirty healthy volunteers participated in a randomized, cross-over, sham-controlled, double-blind study using EEG to measure the offline effects of tACS on alpha and beta power. Sham and high current density tACS (1 mA; 10 Hz and 20 Hz; 0.32 mA/cm2) were applied for 20 min over bilateral sensorimotor areas and EEG was recorded at rest before and after stimulation for 20 min. Bilateral tACS was not associated with significant changes in local alpha and beta power frequencies at stimulation sites (C3 and C4 electrodes). Overall, the present results fail to provide evidence that bilateral tACS with high current density applied over sensorimotor regions at 10 and 20 Hz reliably modulates offline brain oscillation power at the stimulation site. These results may have implications for the design and implementation of future protocols aiming to induce sustained changes in brain activity, including in clinical populations.