The two PET studies, by Mayberg et al. and Smith et al., both used glucose utilization, although the former study also used [15O]water to measure regional cerebral blood flow as an index of neuroactivation. Both studies represent incremental advances in the neurobiology of affective disorders. The Mayberg et al. study is of particular interest for several reasons. First, it provides novel evidence that the brain regions that exhibit changes in activity after provocation of sadness in healthy volunteers are the very same that show opposite changes when depressed patients exhibit clinical recovery after fluoxetine treatment. Second, the circuits identified in both experiments were limbic and cortical sites previously posited to regulate affect, including neocortical and limbic areas (e.g., right dorsolateral prefrontal and inferior parietal cortices and subgenual cingulate and anterior insula regions). Finally, the cingulate-prefrontal circuit model of mood regulation offers a plausible converging point for the separate antidepressant effects of medication, cognitive behavioral, and psychosurgical treatments. Smith and colleagues sought to determine whether total sleep deprivation—a technique demonstrated to result in a rapid, but short-lived, antidepressant effect—combined with paroxetine, a selective serotonin reuptake inhibitor antidepressant, in elderly depressed patients and matched normal comparison subjects provided persistent reductions in glucose utilization in the anterior cingulate cortex, an effect observed after long-term paroxetine treatment. In this study, PET studies were obtained at baseline, after total sleep deprivation, after recovery sleep, and after 2 weeks of paroxetine treatment (patients only). Persistent reductions in glucose metabolism in the anterior cingulate cortex did occur in the depressed patients; no such effects were observed in the comparison subjects. The results suggest that in the depressed patients, improvement in depressive symptom severity associated with the combined treatment was, indeed, associated with reductions in glucose utilization in the right anterior cingulate cortex.