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OBJECTIVE: Prior studies showed that subjects with major depression have deficits in hippocampal-based verbal declarative memory (e.g., recall of a paragraph) and in hippocampal and prefrontal cortical functioning and structure. The purpose of the present study was to assess hippocampal and prefrontal functioning during performance of a verbal declarative memory task in subjects with midlife major depression. METHOD: Subjects with midlife major depression (N=18) and healthy subjects (N=9) underwent positron emission tomography imaging during a control task and verbal encoding of a paragraph. RESULTS: During the verbal memory encoding task the comparison subjects, but not the subjects with depression, activated the right hippocampus and prefrontal cortex (anterior cingulate), as well as the cuneus and cerebellum. CONCLUSIONS: These results are consistent with a failure of hippocampal and anterior cingulate activation in depression, and they support the hypothesis of deficits in hippocampal and anterior cingulate functioning in depression.