Abstract
BACKGROUND: Precise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression. OBJECTIVE: To use imaging data from a "failed" clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations. METHODS: An imaging substudy of 49 Veterans (mean age, 56 years; range, 27-78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks. RESULTS: The average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P < .001) while the nonresponder location did not (P = .17), a finding replicated in independent cohorts of 84 depressed and 35 neurotypical participants. The responder and nonresponder stimulation locations evoked different seed based networks (FDR corrected clusters, all P < .03), revealing additional brain regions related to rTMS treatment outcome. CONCLUSION: These results provide evidence from a randomized controlled trial that clinical response to rTMS is related to accuracy in targeting the region within DLPFC that is negatively correlated with subgenual cingulate. These results support the validity of a neuro-functionally informed rTMS therapy target in Veterans.