Background Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for major depressive disorder (MDD). Recent attempts to improve TMS efficacy by individually targeting DLPFC subregions that are functionally connected to the subgenual cingulate cortex (sgACC) appear promising. However, sgACC covers only a small subset of core MDD-related areas. Further, fMRI connectivity of sgACC is poorly repeatable within subjects. Methods Based on an fMRI database analysis, we first constructed a novel core network model (CNM), capturing voxelwise emotion regulation- and MDD-related DLPFC connectivity. Then, in a sample of 15 healthy subjects and 29 MDD patients, we assessed (i) within-subject repeatability of the DLPFC connectivity patterns computed from time segments of varying lengths of individual-level fMRI data and (ii) association of MDD severity with the individual DLPFC connectivity strengths. We extracted group-level connectivity strengths in CNM from individual DLPFC coordinates stimulated with neuronavigated TMS in a separate sample of 25 MDD patients. These connectivity strengths were then correlated with individual TMS efficacy. Results Compared with sgACC connectivity, CNM increased intraindividual repeatability 5-fold. DLPFC connectivity strength from CNM was associated with MDD severity and TMS efficacy. While the locations of CNM-based individual TMS targets remained constant within individuals, they varied considerably between individuals. Conclusions CNM increased repeatability of functional targeting to a clinically feasible level. The observed association of MDD severity and TMS efficacy with DLPFC connectivity supports the validity of the CNM. The interindividual differences in target locations motivate future individualized clinical trials leveraging the CNM.
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