The overall aim of this study has been to understand the long term temporal sequence and familial patterns of mood and other disorders from childhood to adulthood in offspring at high and low risk for depression. This study has had 4 waves of assessments. The last wave began in 12/98, 17 years after the initial assessment. This application is for Wave 5. The sample now includes 3 generations (grandparents, parents, and grandchildren). The basic design is one of families at high and low risk for depression based on the depression status of the original sample (1st generation -- the grandparents). Our previous findings in the offspring (2nd generation -- now the parents) showed both cross-sectionally and longitudinally that the offspring of depressed grandparents were at high risk (3-fold increase) for major depression. Their depression began early, often at puberty, and was preceded by prepubertal onset anxiety. The results for the 3rd generation (the grandchildren) again shows that the grandchildren in the high risk group (i.e., at least one depressed grandparent) are at increased risk of mood and anxiety disorders. These consistent findings across the generations lead directly to this new application which focuses on understanding the brain based correlates of familial depression. These results support the use of the original high and low risk classification which guide this renewal and its hypotheses. A new aim of the current application is to define the neural correlates of familial risk for depression in subjects in the 2nd and 3rd generations of this cohort using anatomical and functional MRI. This sample is uniquely valuable for identifying the neural correlates of familial risk because the study of high-risk populations prior to the onset of illness is likely to be the best way to distinguish cause from compensatory effect in neurobiological studies, and because psychiatric diagnoses established prospectively and across generations will provide the greatest possible confidence in the assessment of multi-generational familial risk. In addition, the availability of MRI data will provide us with the opportunity to understand better the underlying basis, in terms of brain structure and function, of the electrophysiological abnormalities identified in the last cyclic of funding. Our specific aims for this renewal are (1) to complete data analyses of the 4th wave assessment; (2) to acquire and analyze both anatomical and functional MRI in 214 subjects (118 second and 96 third generation) of this cohort; and (3) to conduct data analysis integrating findings of the clinical, psychophysiologic and neuroimaging studies. [unreadable] [unreadable]