Project Summary Depression affects 1-in-5 individuals in the United States and has a tremendous cost burden for our economy at $210 billion per year. Depression is hard to treat given that it is a heterogeneous illness associated with affective, cognitive and behavioral dysregulation. Around 33% of depressed individuals will not respond to the first two treatments offered. In this context, there is increasing evidence that cognitive functioning in major depression may be an independent factor predicting treatment response, quality of life, disability and suicide, and cognitive control (CC) deficits may persist even when other depression symptoms remit. For instance, FDA-approved therapies for treatment-resistant-depression (TRD) such as repetitive transcranial magnetic stimulation (rTMS) target the dorsolateral prefrontal cortex (DLPFC) brain region that is crucial for CC. But rTMS studies show remission rates of only ~30%, and there is no evidence that rTMS for depression improves CC. This suggests that for individuals with TRD, synergistically targeting CC alongside treatments like rTMS may augment depression treatment response, improve quality of life and potentially reduce morbidity and mortality. While multiple options may exist for targeting CC, based on our preliminary evidence, here we propose to use a digital breath-focused attention training paradigm paired with DLPFC rTMS. We hypothesize that this multimodal neurotherapy will significantly improve CC, and result in better antidepressant treatment response than observed with extant rTMS treatment, particularly by engaging the neural target of default mode network (DMN) activity suppression. Our rationale for pairing digital breath attention training with rTMS is that mindfulness-based interventions that have a core foundation in training attention to internal sensations such as breathing, can improve CC and also ameliorate ruminative symptoms of depression. Digital training, compared to therapist delivered, allows for greater scalability, immediate feedback on performance and application of algorithmic closed-loop training methods tailored to each subject’s performance. From a cognitive neuroscience viewpoint, the CC deficits that occur in depression are linked with impaired top-down control of DMN activity. Both DLPFC rTMS and mindfulness training are hypothesized to work, in part, by enhancing efficacy of top-down/prefrontal suppression of DMN, suggesting potential synergy of these distinct approaches. We therefore hypothesize that our multimodal neurotherapeutic strategy of pairing a digital breath attention training that is akin to mindfulness training, with rTMS will result in improved CC, as well as enhanced antidepressant effects. The R61 phase of the project will focus on dose response of the multimodal therapy for neural target engagement, i.e. DMN activity suppression, while the R33 phase will replicate neural target engagement and also aim to show improvement in CC and greate...