Targeting Network Dysfunction in Apathy of Late-life Depression Using Digital Therapeutics

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PROJECT SUMMARY/ABSTRACT This K23 Career Development Award is designed to provide the conceptual knowledge and technical skills necessary for the PI to pursue a career as an independent investigator evaluating brain network targets to optimize non-pharmacologic interventions for difficult-to-treat mood and cognitive disturbances in aging. Apathy is a persistent and disabling disorder of motivation that afflicts 30-50% of patients with late-life depression (LLD). Apathy worsens clinical outcomes in LLD, as apathetic depressed patients have poor response to existing treatments and higher rates of hospitalization, functional decline, and increased caregiver burden. Functional network abnormalities in a core set of brain circuits that interact to support motivated behavior (salience, executive control, and reward networks) may underlie apathy of LLD. Options for the efficacious treatment of apathy of LLD are limited, and novel interventions are urgently needed. This proposal is based on the premise that customizing interventions based on theorized brain mechanisms of apathy may increase the potency and scalability of promising therapies. This K23 proposes to conduct a randomized controlled trial evaluating the potential of a customized digital cognitive training (DCT) intervention to target brain network abnormalities in apathy of LLD and reduce symptoms of apathy and related cognitive and behavioral deficits. Eighty-four older adults with major depressive disorder and clinically significant apathy will be randomized to four weeks of a home-based DCT intervention or an active expectancy-matched control. The DCT will involve a suite of exercises designed to engage brain networks disrupted in apathy by targeting cognitive processes (i.e., salience processing, sustained attention, cognitive control) supported by these networks. Aligned with NIMH’s experimental therapeutics approach, we will examine the extent to which a targeted DCT program modulates functional network disturbances in apathy of LLD and improves apathy and associated cognitive deficits. The proposed study will generate preliminary data regarding network targets of a customized digital therapeutic that may translate to mood and cognitive benefits, and may guide future personalization of treatments for motivational disturbances in older adulthood. The training provided through this K23 will advance my knowledge and skillsets in: 1) the design and delivery of a neuroscience-informed, virtually-delivered intervention targeting a distinct subtype of depressed older adults; 2) use of functional MRI to probe mechanisms of action of the proposed DCT; 3) advanced longitudinal modeling of clinical trial data to assess trajectories of change and identify predictors of response and; 4) generating an R-series experimental therapeutics target engagement application. This training will prepare me for an independent research career developing and refining neuroscience-based interventions targeting traditionally intractable and functionally impairing mood and cognitive disturbances in older adulthood.