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 COVID-19 induced changes for a Randomised Double-blind Controlled Trial (BRIGhTMIN

Abstract

Background: \n \nDepression is a significant health and economic burden. In approximately one third of patients, depression is resistant to first line treatments and therefore it is essential that alternative treatments are found. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the UK and the US in treatment resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness and mechanism of action between standard treatment repetitive TMS (rTMS) targeted at the F3 EEG 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 the brain imaging acquisition and analysis for the BRIGhTMIND trial that is used to create personalised TMS targets and answer the proposed mechanistic hypotheses. \n \nObjective: \n \nThe objectives of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and cgiTBS and to identify imaging-based markers predicting response to treatment. \n \nMethods: \n \nThe study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of a) TBS or b) standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired per participant at baseline (prior to TMS treatment) with T1-weighted and task-free functional MRI during rest (rsfMRI) utilised to estimate TMS targets. For participants enrolled in the mechanistic substudy additional diffusion-weighted, sequences are acquired at baseline and at post-treatment follow-up 16 weeks after treatment randomisation. Core datasets of T1-weighted and task-free functional MRI during rest (rsfMRI) are acquired for all participants and utilised to estimate TMS targets. Additional sequences of arterial spin labelling, magnetic resonance spectroscopy and diffusion-weighted images are acquired dependent on recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex whilst 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 a level of MRI-guidance but only TBS is provided with precision targeting based on functional brain connectivity. \n \nResults: \n \nRecruitment began January 2019 and is ongoing. Data collection is expected to continue until January 2023. \n \nConclusions: \n \nThis trial will determine the impact of precision MRI guidance on rTMS treatment, and furthermore, assess the neural mechanisms underlying this treatment in treatment resistant depressed patients. Clinical Trial: International Standard Randomized Controlled Trial Number (ISRCTN) 19674644; https://www.isrctn.com/ISRCTN19674644. Registered 2nd October 2018.