Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial

Abstract

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with 'treatment-resistant depression'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).

Fig. 1. Flowchart of participants through the trial.

CONSORT diagram of all participants who were assessed for eligibility for the trial, randomised to repetitive transcranial magnetic stimulation or connectivity guided intermittent theta burst stimulation and followed up to 26 weeks.

Fig. 2

Mean (s.e.) GRID-HDRS-17 scores over time for analysis of primary ITT (multiple imputation).

Fig. 3

ITT and sensitivity analyses of primary outcome measure following cgiTBS relative to rTMS.

Extended Data Fig. 1. Flow of participants through fMRI protocol.

rTMS, repetitive transcranial magnetic stimulation cgiTBS, connectivity guided intermittent theta burst stimulation.

Extended Data Fig. 2. Sites of TMS stimulation.

Illustration of transcranial magnetic stimulation (TMS) targets, and regions of interest (ROIs) for the baseline brain connectivity analyses. Small dots indicate the connectivity guided intermittent theta burst stimulation (cgiTBS) left dorsolateral prefrontal cortex (DLPFC) target co-ordinates for individual participants – these are the locations with maximal effective connectivity from the right anterior insula (rAI) as a large grey dot. The mean cgiTBS target across participants is shown as a large white dot. The mean repetitive transcranial magnetic stimulation (rTMS) target is shown as a large white dot; this is the F3 target for the group that received rTMS. Plotted with BrainNet Viewer (Xia et al.) on the smoothed ICBM152 atlas.

Extended Data Fig. 3. Percentage of participants who felt somewhat or much better over the 20 TMS sessions.

TMS, transcranial magnetic stimulation. rTMS, repetitive transcranial magnetic stimulation. cgiTBS, connectivity guided intermittent theta burst stimulation. Participant self-rated as somewhat or much improved on modified 5-point clinical global impression scale.

Extended Data Fig. 4. Reduction in baseline net outflow from right anterior insula to left dorsolateral prefrontal cortex in relation to mean improvement in GRID-HDRS-17 score over 26 weeks.

Reduction in GRID version of the 17=item Hamilton Depression Rating Scale (GRID-HDRS-17) total score (improvement) from baseline to follow-up, collapsed across follow-up time points, as a function of baseline net outflow from the right anterior insula (RAI) seed region to the connectivity guided intermittent theta burst stimulation (cgiTBS) target region within the left dorsolateral prefrontal cortex (DLPFC). Each data point is a participant. Lower net outflow (that is, lesser influence of the RAI on the left DLPFC and greater influence of the left DLPFC on the RAI) was associated with greater improvement.

Extended Data Fig. 5. Regions of interest for change in brain connectivity analysis for dorsolateral and dorsomedial prefrontal cortex.

Regions of interest (ROIs) for the change in brain connectivity analyses, plotted on a standard brain image (smoothed ICBM152 atlas), in the sagittal (left) and coronal (right) planes. DMPFC: dorsomedial prefrontal cortex; DLPFC(a): anterior DLPFC site; DLPFC(p): posterior DLPFC site.

Extended Data Fig. 6. Reduction in left dorsolateral prefrontal cortex to left dosrsomedial prefrontal cortex functional connectivity with improvement in PHQ-9 score over 26 weeks.

Reduction in 9-item Personal Health Questionnaire (PHQ-9) total score (improvement) from baseline to follow-up, collapsed across post-treatment time point, as a function of reduction in functional connectivity between the left dorsomedial prefrontal cortex (DMPFC) region and the posterior left dorsolateral prefrontal cortex (DLPFC) region. Each data point is a participant. Greater clinical improvement was associated with greater reduction in functional connectivity between these regions.