Individualized Connectivity-Guided Versus Conventional Targeting of Accelerated Theta-Burst Stimulation in Depression: A Randomized, Double-Blind, Parallel-Design Trial.

Authors

Mingzhu Li, Zijia Wu, Xuefeng Lu, Andrew Zalesky, Xinle Cheng, Yuyanan Zhang, Robin F H Cash, Fang Jin, Shidong Jia, Yang Xiao, Gangliang Zhong, Xiao Zhang, Weihua Yue, Zhengyi Yang, Tianzi Jiang, Hao Yan

Published in

The American journal of psychiatry. Pages appiajp20251084. Aug 12, 2026. Epub Aug 12, 2026.

Abstract

Scalp-based repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) does not account for interindividual variability. This trial was designed to determine whether individualized connectivity-guided intermittent theta-burst stimulation (iTBS) improves antidepressant outcomes compared with 5-cm targeting.
In this single-center, randomized, double-blind, three-arm trial (February 2023-March 2025), adults ages 18-65 years with major depressive disorder or bipolar II depression (≥1 antidepressant failure) were randomly assigned to receive 20 sessions of iTBS over 2 weeks using robotic neuronavigation with one of three targeting strategies: 5-cm rule, functional connectivity (FC)-guided targeting showing negative resting-state connectivity with the subgenual anterior cingulate cortex (sgACC), or structural connectivity (SC)-guided sites defined by probabilistic tractography to the sgACC. The primary outcome was percentage reduction in 17-item Hamilton Depression Rating Scale (HAM-D) score at week 2. Secondary outcomes included HAM-D score reduction at weeks 6 and 12, response or remission, self-reported symptoms, performance on a cognitive battery, and adverse events.
Of 123 randomized participants, 119 were included in the modified intention-to-treat analyses (5-cm, N=40; SC-guided, N=39; FC-guided, N=40). SC-guided iTBS produced significantly greater HAM-D score reduction than the 5-cm rule at week 2 (least squares mean difference [LSMD]=8.79 percentage points, 95% CI=2.19, 15.40; Cohen's d=0.70). At week 6, both SC-guided and FC-guided groups showed significantly greater improvement than the 5-cm group (SC-guided LSMD=12.87 percentage points, 95% CI=6.21, 19.54; Cohen's d=1.03; and FC-guided LSMD=9.41 percentage points, 95% CI=2.84, 15.98; Cohen's d=0.75). By week 12, between-group differences were no longer significant. Adverse events were comparable across groups, with no seizures or mania.
SC-guided iTBS produced promising preliminary evidence of improved antidepressant response compared with 5-cm targeting, supporting sgACC-based connectivity-guided precision neuromodulation in depression.

PMID:
42581396
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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