The best first-line treatments work for approximately 40-60% of unipolar depressed adults, potentially due to the disorder's complexity and heterogeneity. Basic research on the neural mechanisms of depression, assessed using functional neuroimaging has blossomed in the past decade. The proposed research will combine neuroimaging, behavioral/psychophysiological assessment, and clinical trials to allow rigorous translation of this basic science to the clinic. This work will help to direct patients specifically to treatments that will address their particular mechanisms and could lead to the development of novel neuroscience-based interventions. Such translational research has been done almost exclusively in mid-life adults. Yet, attention has increasingly focused on the extent to which interventions that address relevant brain mechanisms in mid-life individuals (e.g., Cognitive Behavioral Therapy, SSRI's) might be useful with vulnerable or depressed youth and elderly depressed individuals. Increasing research suggests that the same mechanisms which are disrupted in mid-life depression, and which are targeted in therapy, such as increased limbic response to emotional stimuli, are present in anxious youth (Easter et al 2005) who are vulnerable to depression, and may further predict treatment response in these individuals (McClure et al in press-a). Similarly, hallmarks of dysregulated emotion in depression which predict treatment response in mid-life individuals such as decreased prefrontal function are present in a high proportion of elderly depressed adults (e.g., Alexopoulos et al., 2000) and may thus be as, or more important to address in planning treatments in that population. Thus, a life-span developmental perspective will be a key generalization of ongoing translational neuroimaging research. Dr. Siegle is uniquely poised to make significant advances in this type of translational research. Following his training as a clinical psychologist and cognitive neuroscientist, his K01 award yielded computational modeling and neuroimaging data that lead to specific predictions about recovery from depression. Western Psychiatric Institute and Clinic provides a highly collaborative clinical trials environment, allowing him to test these hypotheses. His R01 has begun this work, adding assessments to existing clinical trials and collaborating with established clinical trials researchers. To continue his clinical translations to the high standards of his basic research, Dr. Siegle proposes to receive additional training and supervision in the design, execution, and evaluation of clinical trials for conventional and novel interventions. In addition, Dr. Siegle's research has focused on mid-life depressed individuals, but is increasingly being applied to understanding clinical outcomes in youth and late-life individuals. Obtaining training in potential issues associated with generalizing to the entire lifespan will be important for allowing him to advise such translations.