Cognitive Enhancement in Recurrent Depression

Late-life depression (LLD) is a heterogeneous neuropsychiatric disorder that can take a chronic and recurrent course. Executive dysfunction (i.e., difficulties with complex mental tasks and planning) is prominent in recurrent LLD, persists despite remission of depressive symptoms, and corresponds with increased risk of cognitive decline and transition to dementia. Past work demonstrates executive function deficits are related to changes in the underlying structure and function of the brain’s executive control network (ECN). Combining targeted cognitive-enhancing interventions aimed at promoting neuroplasticity may strengthen the underlying ECN, thereby improving executive function performance. Multi-modal approaches using cognitive training and non- invasive neuromodulation (i.e., transcranial direct current stimulation; tDCS) support cognitive benefits in older adults. However, previous research used more general executive function-based cognitive training, while the current study proposes a targeted cognitive training (TCT) intervention that was created to specifically address executive function deficits found in LLD. Combining this with tDCS applied to the frontal lobes may help to maximally engage and benefit executive function-based cognitive and neural functions. The proposed study aims to identify cognitive and neural changes elicited by a multi-modal cognitive- enhancing intervention using a randomized clinical trial pilot study design. Sixty non-demented older adults presenting with executive dysfunction and recurrent LLD will undergo a 4-week daily intervention contrasting the effects of three conditions (bifrontal active tDCS+TCT, sham tDCS+TCT, and sham tDCS+non-targeted control cognitive training (CT)) on measures of executive functioning and ECN brain connectivity pre- and post- intervention. Specific aims are to determine whether stepwise ECN engagement across randomized groups (active tDCS+TCT > sham tDCS+TCT > sham tDCS+control CT) results in progressively greater benefit to executive functions (Aim 1) and functional connectivity between ECN regions (Aim 2). We will also explore whether intervention-related changes in ECN relates with executive function performance (Exploratory Aim) and changes in depressive symptoms. Resultant data will enhance understanding of mechanisms underlying this multi-modal cognitive-enhancing intervention in recurrent LLD and inform a more definitive randomized, mechanistically-focused clinical trial via an R01. This K23 will support my career development goals of building expertise in 1) delivery and optimization of multi-modal non-pharmacological interventions to enhance cognition, 2) functional connectivity neuroimaging analysis in LLD, and 3) clinical trials development, implementation, and management. Study results will establish the necessary groundwork for my development as an independent investigator focused on multi-modal targeting of the ECN (via TCT, tDCS) to enhance brain and cognitive functions in LLD, with goals of understanding mechanism, personalizing treatments, and altering the trajectory of cognitive decline to reduce dementia risk. Project Number: 1K23MH140069-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Sarah Szymkowicz | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $186,624 | Activity Code: K23 | Study Section: Special Emphasis Panel[ZRG1 CN-F (91)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301402