Major Depressive Disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet prior resting state fMRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to conduct the first investigation of the relationship between directed rs-fMRI activity, MDD, and treatment response to a novel FDA-approved neurostimulation paradigm termed Stanford Neuromodulation Therapy (SNT). We find that SNT over left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pre-treatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD.
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