THROUGHOUT the past 20 years, findings from studies of functional brain imaging have coalesced in the identification of regions of abnormal functional activity during major depressive episodes (MDE).^1-5 In studies performed during the resting state (no physiological or cognitive challenge), patients with MDE typically show reduced activity in the dorsolateral prefrontal cortex. At least 15 studies have found covariation between the magnitude of this reduction (or that of larger prefrontal areas) and the magnitude of depression severity,^6-8 with the suggestion that reduced dorsolateral prefrontal cortex activity is tied to psychomotor retardation or cognitive disturbance.^9,10 In contrast, the ventral prefrontal cortex has been found to show increased activity in some studies,⁴ with the exception that an area ventral to the genu of the corpus callosum may be subject to perfusion and metabolic reduction, which has been linked to neuronal loss.¹¹ Abnormal functional activity has been observed in several studies of the anterior cingulate gyrus. This is an important observation since, paradoxically, responders to sleep deprivation almost invariably show increased cingulate activity, and reduced activity in the medial prefrontal cortex and the anterior cingulate gyrus is associated with clinical improvement following sleep deprivation.¹² In addition, there are findings that during MDE, patients have reduced functional activity in the basal ganglia, particularly in the caudate nuclei^1,13 and in some areas of the parietal and temporal lobes.¹⁴