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 greater depressive symptom response to treatment in a randomized controlled trial.