Normative Modeling of sgACC-DLPFC Functional Connectivity Identifies a Personalized rTMS Target Associated with Clinical Response in Major Depressive Disorder.

BACKGROUND: Response to repetitive transcranial magnetic stimulation (rTMS) in major depressive disorder (MDD) varies substantially. Normative modeling of functional connectivity can disentangle disease-related pathophysiology from demographic variability, potentially refining personalized targeting. METHODS: We constructed a normative model of subgenual anterior cingulate cortex (sgACC)-dorsolateral prefrontal cortex (DLPFC) functional connectivity using exclusively healthy controls (HCs; DIRECT dataset, n = 1,313). Individual Z-score maps were generated for 1,583 MDD patients; the DLPFC voxel with the most negative Z-score defined the functional connectivity normative deviation (FCND)-guided target. Clinical utility was tested in two independent rTMS cohorts (active: n=39, sham: n=23; accelerated iTBS: n=15) by correlating Euclidean distance from the stimulation site to the FCND target with improvement. We explored whether Z-score normalization statistically mediated this relationship. RESULTS: In the DIRECT dataset, patients with MDD showed significantly more negative values for the most negative Z-score (Min Z-score) than HCs, and this Min Z-score correlated negatively with depressive symptom severity, as measured by the 17-item Hamilton Depression Rating Scale. In the YT active group, shorter distance to the FCND-guided target was associated with greater clinical improvement, while no association was observed in the sham group. This association was also significant in the aiTBS dataset. Exploratory mediation analysis revealed an indirect effect statistically consistent with the hypothesis that distance influences improvement through Z-score normalization in the active group, with a directionally consistent trend in the iTBS dataset. CONCLUSION: The FCND-guided target framework provides a personalized, mechanism-informed strategy for precision neuromodulation in MDD.