Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2–Induced Changes for a Randomized Double-blind Controlled Trial
Authors: Pszczolkowski Stefan , Cottam William J , Briley Paul M , Iwabuchi Sarina J , Kaylor-Hughes Catherine , Shalabi Abdulrhman , Babourina-Brooks Ben , Berrington Adam , Barber Shaun , Suazo Di Paola Ana , Blamire Andrew , McAllister-Williams R Hamish , Parikh Jehill , Abdelghani Mohamed , Matthäus Lars , Hauffe Ralf , Liddle Peter , Auer Dorothee P , Morriss Richard 
Published: August 2021

Background
Depression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment—a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses.

Objective
The aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment.

Methods
The study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity.

Results
Recruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023.

Conclusions
This trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients.

Trial Registration
ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644

International Registered Report Identifier (IRRID)
DERR1-10.2196/31925