Discussion
depression, TBI, primary major depression, depressive symptoms
Our findings suggest that individualized RSNM may be used to reliably identify rTMS targets based on their connectivity profile. We identified subject-specific rTMS targets at the networks that are likely being approximated by sgACC connectivity maps, which have previously been shown to predict efficacy of rTMS for major depressionOur proposed targeting approach was based on individualized mapping of DAN and DMN. The involvement of these networks in depression treatment may be related to dysfunctional interactions between externally-oriented attention-switching, which involves the DAN, and internally-oriented emotion engagement, which involves the DMNNevertheless, our choice of DAN and anti-DMN targeting remains speculative in the absence of a head-to-head trial of antidepressant efficacy in comparison to rTMS applied to other targets. In addition, there are several existing approaches to individualized RSN mappingOur interpretations of treatment-induced changes are limited by small sample size. This may increase the risk of a false negative result due to lack of power or false positive results due to chance. Furthermore, we only assessed bilateral stimulation, and the interactions between the two stimulation sites are uncertain. This does not affect our reliability assessments, but does limit our ability to confirm whether the neurophysiological and clinical effects are consistent with our hypotheses. Prospective studies comparing unilateral stimulation vs. bilateral stimulation will be required to disentangle the neurophysiological effects of the bilateral stimulation employed in this study. It is not known whether the approach to selecting a left excitatory stimulation site should be the same as the approach used to selecting a right inhibitory stimulation site, since stimulation of the two hemispheres may have different effectsFurther research will be required before these findings can be considered generalizable. This study was conducted using cutting-edge MRI scanners and recently-optimized scan protocols, so it remains unclear whether similar results can be achieved using more readily-available equipment. The patient population was also carefully selected as patients with relatively mild TBI and clear major depressive symptoms; its applicability to primary major depression or moderate/severe TBI requires further investigation.Despite these limitations, our results support the emerging notion that variability in effects of rTMS may be related to inter-individual variability in functional topography of the DLPFCIn conclusion, the use of individualized RSN mapping for identification of distinct patient-specific rTMS targets may represent a promising method for reducing variability in targeting rTMS. This lays the foundation for development of more robust approaches for personalized medicine in neuromodulation.