Connectivity- vs Scalp-Based Targeting of Accelerated Transcranial Magnetic Stimulation for Depression

Importance: Neuroimaging is prevalent in psychiatric research, but there is limited evidence that it improves clinical outcomes. Functional connectivity neuroimaging was recently used to target individualized brain circuits with accelerated transcranial magnetic stimulation (aTMS), with rapid antidepressant effects and US Food and Drug Administration clearance, but the importance of connectivity-based targeting remains unclear. Objective: To estimate the effect size of connectivity- vs scalp-based targeting of aTMS for treatment-resistant depression. Design, Setting, and Participants: This randomized clinical trial comparing connectivity- to scalp-based aTMS treatment was conducted between July 2023 and March 2025 with the primary outcome assessed at 1 month posttreatment and follow-up every 3 months for 1 year. Participants, TMS technicians, and study physicians were blinded. The study took place at the Center for Brain Circuit Therapeutics at Mass General Brigham and Harvard Medical School in Boston, Massachusetts. Forty adults aged 22 to 80 years with a primary diagnosis of major depressive disorder with moderate to severe depression per Montgomery-Åsberg Depression Rating Scale (MADRS) score and moderate to severe treatment resistance per Maudsley Staging Method were included. Key exclusion criteria included contraindications to TMS or magnetic resonance imaging, primary psychiatric diagnoses other than major depressive disorder or anxiety disorders, recent rapid-acting antidepressant treatments, and significant neurological or substance use disorders. Interventions: All participants underwent a 41-minute multiecho resting-state functional connectivity scan prior to aTMS, and half of them received treatment guided by these data. The connectivity-based target was defined as the left dorsolateral prefrontal cortex region with the greatest correlation to a published and publicly available convergent depression circuit. This circuit includes multiple brain regions linked to depression, including negative connectivity to the subgenual cingulate cortex. The scalp-based target was identified with the Beam F3 method. Main Outcomes and Measures: MADRS score 1 month after treatment, adjusted for baseline. Results: In total, 40 participants (22 female [55%]; mean [SD] age, 45.7 [15.2] years) were randomized and treated. The median (IQR) MADRS score reduction was 24 (19-28) vs 18 (10-23) points with connectivity- vs scalp-based targeting, respectively (P = .02). Connectivity-based targeting had an effect size of 0.8 (Cohen d analog) and 95% CI of 0.26-1.54, with a number needed to scan of 5 individuals. Individualized targets were reproducible within an individual (4.47 mm split-half distance) and different between individuals (12.97 mm) (P < .001). Conclusions and Relevance: In this randomized clinical trial, individualized, connectivity-based targeting of the convergent depression circuit enhanced the antidepressant effects of high-dose aTMS. These results could facilitate cost-effectiveness analyses and help to power a confirmatory efficacy trial. Trial Registration: ClinicalTrials.gov Identifier: NCT05680727.