PROJECT ABSTRACT Major depressive disorder (MDD) in adults across the lifespan is a leading cause of disability worldwide. Cognitive dysfunction is highly prevalent in MDD and is associated with functional impairments and reduced quality of life. Cognitive dysfunction has been noted across non-emotional, “cold” cognitive functions, such as executive function, memory, and attention, as well as emotionally-laden, “hot” cognitive functions, such as emotion processing, negative attentional biases, reward processing, and social cognition. Despite ample evidence of impairments associated with hot cognitive function, behaviors, and associated neural circuity, limited information exists regarding hot cognitive function in adults across the lifespan with MDD. Given the importance of cognitive dysfunction on disease course and overall functioning in MDD, it is critical to identify mechanisms of action and targeted treatment approaches that will improve associated cognitive dysfunction and achieve the ultimate goal of improving overall disease course, functioning, and quality of life. Identification of regional brain network alterations associated with particular hot and cold cognitive functions and treatments that modify these regions will move us closer toward mechanism-based personalized medicine and improved patient outcomes. A first critical step in this long-term endeavor and goal of this R21 study is to better characterize hot cognitive dysfunction in MDD, inform potential effects of age on these dysfunctions, and elucidate associated underlying neurocircuitry in older adults. In the proposed pilot study, we further our prior work in adults across the lifespan with MDD and cold cognitive impairment by examining the understudied area of hot cognitive function. This clinically significant and innovative 2-year preliminary project has two aims: 1) Establish and integrate hot and cold cognitive dysfunction in adults across the lifespan, and 2) Establish and compare specific brain networks underlying hot and cold cognitive tasks. The proposed study engages an interdisciplinary team with diverse expertise including clinical neuropsychology, cognitive/behavioral neuroscience, neuroimaging, and biostatistics. Through the synthesis of clinical metrics, hot and cold cognitive metrics, and resting-state magnetoencephalography (MEG), we will characterize hot cognitive dysfunction in MDD, examine potential effects of age, and inform associated underlying neurocircuitry. The new knowledge gained in this pilot study will allow us to develop a program of research that will then use non-invasive neuromodulation technology (e.g., transcranial magnetic stimulation) to perturb neurocircuitry and confirm the mechanisms underlying both hot and cold cognitive function. Following mechanistic confirmation, subsequent investigations will develop mechanism-based targeted treatment(s) to improve cognitive impairments. These investigations have strong clinical significance and i...