Effects of Personalized Transcranial Magnetic Stimulation on Social Cognitive Network Functional Connectivity in Schizophrenia Spectrum Disorders: A Double-Blind, Randomized, Sham-Controlled Target Engagement Trial

BACKGROUND: Schizophrenia spectrum disorders (SSDs) often feature debilitating social cognitive impairments, with limited treatment options. This study used a target engagement approach to examine the effects of individually-targeted repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex (DMPFC) on social cognitive network functional connectivity (i.e., mentalizing and simulation networks) in individuals with SSDs. METHODS: We conducted a double-blind, randomized, sham-controlled trial in adults with SSDs (NCT04418011). Participants received two weeks of DMPFC stimulation with 10 Hz rTMS, intermittent theta burst stimulation (iTBS), or sham stimulation. They completed pre- and post-treatment functional magnetic resonance imaging, including a social processing task. Treatment was personalized using functional connectivity mapping and electric field modelling. Primary outcomes were changes in individualized within-mentalizing and between mentalizing-simulation network functional connectivity after active stimulation versus sham, compared using effect sizes. Secondary outcomes were safety and tolerability. RESULTS: Analyses included 46 participants who completed treatment (10 Hz rTMS: n=15; iTBS: n=15; sham: n=16). iTBS produced a significantly greater increase in within-mentalizing network connectivity, with a large effect size, while 10 Hz rTMS did not differ from sham. Effects on between-network connectivity were negligible-to-small for both active conditions. Participants receiving iTBS reported higher pain ratings, but adverse event and discontinuation rates did not differ across groups. CONCLUSIONS: Individualized DMPFC-targeted iTBS demonstrated target engagement via increased mentalizing network connectivity relative to sham, and was feasible, safe, and well-tolerated in adults with SSDs. A larger and longer clinical trial powered to assess change in social cognitive outcomes is ongoing (NCT06118268).