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OBJECTIVE: Separation from loved ones commonly leads to grief reactions. In some individuals, grief can evolve into a major depressive episode. The brain regions involved in grief have not been specifically studied. The authors studied brain activity in women actively grieving a recent romantic relationship breakup. It was hypothesized that while remembering their ex-partner, subjects would have altered brain activity in regions identified in sadness imaging studies: the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex. METHOD: Nine right-handed women whose romantic relationship ended within the preceding 4 months were studied. Subjects were scanned using blood-oxygen-level-dependent functional magnetic resonance imaging while they alternated between recalling a sad, ruminative thought about their loved one (grief state) and a neutral thought about a different person they knew an equally long time. RESULTS: Acute grief (grief minus neutral state) was associated with increased group activity in posterior brain regions, including the cerebellum, posterior brainstem, and posterior temporoparietal and occipital brain regions. Decreased activity was more prominent anteriorly and on the left and included the anterior brainstem, thalamus, striatum, temporal cortex, insula, and dorsal and ventral anterior cingulate/prefrontal cortex. When a more lenient statistical threshold for regions of interest was used, additional increases were found in the lateral temporal cortex, supragenual anterior cingulate/medial prefrontal cortex, and right inferomedial dorsolateral prefrontal cortex, all of which were adjacent to spatially more prominent decreases. In nearly all brain regions showing brain activity decreases with acute grief, activity decreases were greater in women reporting higher grief levels over the past 2 weeks. CONCLUSIONS: During acute grief, subjects showed brain activity changes in the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex, consistent with the hypothesis. Subjects with greater baseline grief showed greater decreases in all these regions except for the cerebellum. Further imaging studies are needed to understand the relationship between normal sadness, grief, and depression.