This is a Veteran's Administration Career Development Award 2 proposal for Colleen Mills-Finnerty, Ph.D., entitled ?Causal brain mechanisms of value-based attentional capture in depression.? The goal of this project is to understand causal brain circuit mechanisms underlying diminished attentional sensitivity to reward in veterans with depression using computational modeling, neuroimaging, and transcranial magnetic stimulation (TMS). This is an important area for study because although depression is a leading cause of disability worldwide, current treatments have limited efficacy. Additionally, TMS is an FDA-approved treatment for depression, but the mechanism by which it works to remediate symptoms remains unclear. Therefore, better understanding of the circuit abnormalities that give rise to behavioral abnormalities and symptoms of depression is needed to spurn development of targeted, neurobiologically informed TMS interventions. Attentional sensitivity to reward is well-studied in the field of visual perception. Stimuli associated with rewards (e.g. money, positive social feedback) capture attention (i.e., serve as a distraction) during tasks even when reward value is not relevant to performance, an attentional bias called value-based attentional capture (VBAC). More limited evidence suggests that the VBAC is behaviorally absent in patients with depression; however no studies have addressed the biological underpinnings causal to this process. Understanding VBAC dysfunction in depression is potentially a critical missing link between reduced reward sensitivity and reward learning deficits widely observed in depression, and therefore the central hypothesis to be tested is that insensitivity to reward stimuli in depression is related to failures of circuit mechanisms underlying integration of attention and subjective value. The current study aims to 1) computationally model VBAC response during neuroimaging in healthy veterans; 2) computationally model VBAC deficits in veterans with depression during neuroimaging; 3) use brain stimulation to probe the causal circuit mechanisms responsible for VBAC in healthy veterans, to model failures of this circuitry in depression. This CDA2 award would allow Dr. Mills-Finnerty to gain proficiency in 1) computational approaches to modeling behavior and brain function; 2) use of brain stimulation as a causal intervention to change behavior and understand brain circuit dysfunction in psychiatric populations; 3) clinical research assessment of depression symptoms; and 4) manuscript/grant writing, professional development, and responsible conduct of research. Training and research for the project will be conducted at both the VA Palo Alto and Stanford University, which offer excellent intellectual and physical resources to complete the proposed work. The PI plans to gain proficiency in proposal domains through: 1) tutorials and meetings with mentors; 2) intensive workshops on modeling information flow within neural circuits and building computational models of behavior; 3) formal coursework; 4) attendance of professional meetings; 5) practical application of skills to research data; and 6) planned submission of grant applications and manuscripts. Insights from the proposed work will improve our understanding of the brain processes underlying VBAC, which will contribute important mechanistic insight to an understudied aspect of circuit dysfunction in depression. This project is intended to lead to a targeted depression intervention using brain stimulation to increase attentional sensitivity to reward in veterans with depression. This approach would constitute a new paradigm for TMS treatment with potential application to other disorders that impact reward functioning, such as obsessive-compulsive disorder, addiction, and depression associated with neurological conditions such as stroke and Parkinson's disease.
Depression is the leading cause of disability worldwide and prevalent in veterans, and current treatments rely on an inefficient trial and error approach for prescribing treatment that is not based on objective biological tests. Better understanding of how changes in the brain are related to symptoms of depression is necessary to develop more targeted treatments. The role of the corticostriatal circuit in approach and avoidance behavior is well characterized in human and animal models, and implicated in symptoms of depression. This proposal tests whether a marker of approach behavior, value-based attentional capture, is a sensitive readout of corticostriatal dysfunction in depression. Brain imaging, brain stimulation, and computational modeling will be used to characterize neurobiobehavioral substrates of depression, with the long term goal of furthering development of novel brain stimulation interventions targeting specific brain circuitry and depressive symptoms.
