Functional Connectivity Mapping for rTMS Target Selection in Depression

Objective: Repetitive transcranial magnetic stimulation (rTMS) protocols increasingly use subgenual anterior cingulate cor-tex (sgACC) functional connectivity to individualize treatment targets. However, the efficacy of this approach is unclear, with conflicting findings and varying effect sizes across studies. Here, the authors investigated the effect of the stimulation site's functional connectivity with the sgACC (sgACC-StimFC) on treatment outcome to rTMS in 295 patients with major depression.Methods: The reliability and accuracy of estimating sgACC functional connectivity were validated with data from indi-viduals who underwent extensive functional MRI testing. Electric field modeling was used to analyze associations be-tween sgACC-StimFC and clinical improvement using stan-dardized assessments and to evaluate sources of heterogeneity.Results: An imputation-based method provided reliable and accurate sgACC functional connectivity estimates. Treatment responses weakly but robustly correlated with sgACC-StimFC (r=-0.16), but only when the stimulated cortex was identified using electric field modeling. Surprisingly, this association was driven by patients with strong global signal fluctuations stemming from a specific periodic respiratory pattern (r=-0.49). Conclusions: Functional connectivity between the sgACC and the stimulated cortex was correlated with individual differences in treatment outcomes, but the association was weaker than those observed in previous studies and was accentuated in a subgroup of patients with distinct, respiration -related signal patterns in their scans. These findings indicate that in a large representative sample of patients with major depressive disorder, individual differences in sgACC-StimFC explained only ;3% of the variance in out-comes, which may limit the utility of existing sgACC-based targeting protocols. However, these data also provide strong evidence for a true-albeit small-effect and highlight op-portunities for incorporating additional functional connec-tivity measures to generate models of rTMS response with enhanced predictive power.