Structural Connectivity–Guided iTBS Improves Early Depression Outcomes
Key Clinical Summary
- A randomized, double-blind trial compared 3 targeting strategies for accelerated intermittent theta-burst stimulation (iTBS) in 123 adults with major depressive disorder (MDD) or bipolar II depression.
- Structural connectivity-guided targeting produced greater improvement than the conventional 5-cm rule at weeks 2 and 6.
- Functional connectivity-guided targeting showed an advantage at week 6, but differences between groups were no longer significant at week 12.
A connectivity-guided approach to accelerated iTBS produced greater short-term reductions in depression severity than conventional scalp-based targeting, according to a randomized trial published in The American Journal of Psychiatry. However, the differences between targeting strategies did not remain statistically significant at 12 weeks.
Study Findings
The single-center, randomized, double-blind, 3-arm trial enrolled 123 participants aged 18 to 65 years with MDD or bipolar II depression who had experienced at least 1 antidepressant treatment failure. Investigators randomly assigned participants to receive 20 iTBS sessions over 2 weeks.
Stimulation targeted the left dorsolateral prefrontal cortex using robotic neuronavigation and 1 of 3 methods: the conventional 5-cm scalp rule, functional connectivity with the subgenual anterior cingulate cortex (sgACC), or structural connectivity defined through probabilistic tractography to the sgACC. Modified intention-to-treat analyses included 119 participants.
At week 2, structural connectivity-guided treatment produced a significantly greater percentage reduction in 17-item Hamilton Depression Rating Scale scores than the 5-cm method (least squares mean difference [LSMD] = 8.79 percentage points, 95% confidence interval [CI] 2.19 to 15.40; Cohen's d = 0.70).
At week 6, both connectivity-guided groups demonstrated significantly greater improvement than the conventional-targeting group (structural targeting: LSMD = 12.87 percentage points, 95% CI = 6.21 to 19.54, Cohen’s d = 1.03; functional connectivity: LSMD = 9.41, 95% CI = 2.84 to 15.98, Cohen’s d = 0.75). No significant between-group differences remained at week 12. Adverse events were comparable, with no seizures or manic episodes reported.
Clinical Implications
The findings suggest that individualized connectivity mapping may improve early antidepressant outcomes from accelerated iTBS, particularly when structural connections to the subgenual anterior cingulate cortex guide target selection.
For clinicians, however, the disappearance of significant differences by week 12 limits conclusions about sustained benefit. Connectivity-guided targeting also requires neuroimaging, neuronavigation, and specialized analysis beyond the fixed scalp-based method commonly used in clinical practice.
Expert Commentary
“Structural connectivity-guided iTBS produced promising preliminary evidence of improved antidepressant response compared with 5-cm targeting,” Hao Yan, PhD, and colleagues at Peking University Sixth Hospital in Beijing concluded. The investigators said the results support further study of subgenual anterior cingulate cortex-based precision neuromodulation for depression.
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