Proximity to an SGC-DLPFC Individualized Functional Target and outcomes in large rTMS clinical trials for Treatment-Resistant Depression

Background: Targeting methods for repetitive transcranial magnetic stimulation (rTMS) in patients with depression now include the use of individual functional scans to target specific functional connectivity (FC) patterns obtained from functional magnetic resonance imaging (fMRI). Potential biomarkers of rTMS response include target FC with the subgenual anterior cingulate cortex (SGC) or the causal depression circuit (CDC), each of which may be candidates for individualized functional targets (iFTs). We assessed the relationship of these two approaches to clinical outcomes in two large rTMS clinical trials. Methods: 501 subjects with moderate to severe depression underwent 4-6 weeks of daily rTMS to the left dorsolateral prefrontal cortex (DLPFC), targeted using neuronavigation to a common group-based functional target. Resting-state scans acquired at baseline were used to retrospectively compute iFTs using either SGC-DLPFC or CDC-DLPFC FC. The Euclidean distance from the group-based target used in the trial to the centre of gravity of each iFT was computed and correlated with outcomes. Results: Most subjects' iFTs were within 2cm of their group-based target. Proximity to either the SGC- or CDC-iFT was not associated with better outcomes. Sensitivity analyses accounting for treatment target FC, methodology, data quality, or treatment parameters did not change the results. Conclusions: Proximity to SGC- or CDC-derived iFTs was not associated with better outcomes in patients who received neuronavigated rTMS to a group-based target. Prospective randomized clinical trials comparing neuronavigated group-based target to neuronavigated iFTs are needed.