The hippocampus, amygdala, and ventral anterior cingulate are each implicated in the pathophysiology of mood disorders. The volume of the subiculum of the hippocampus is abnormally decreased in MDD and bipolar disorder. Subtle decreases in hippocampal volume were previously reported by some MRI studies of mood disorders, although many other studies were unable to confirm this difference. Two studies of the hippocampus performed post mortem provided clues that the reduction in volume may be confined to only discreet subregions of the hippocampus, namely the subiculum and the adjacent CA1 region. The subiculum is known to play major roles in guiding reward-directed behavior and in modulating endocrine responses to stress, and is the portion of the hippocampus that shares the heaviest anatomical connections with other brain regions implicated in regulating emotional behavior. A method for imaging the human brain at a very high spatial resolution, developed by a collaboration between NIMH and NINDS, permitted reliable volumetric measures of the subiculum and adjacent CA1 cortex. Application of this technique revealed a marked reduction in the volume of the subiculum exists in mood disorders, and demonstrated this abnormality can be noninvasively detected using MRI. Secondly, the amygdala has an abnormal reduction of glial cells in major depressive disorder (MDD). Glial cells were previously shown to be decreased in other brain regions of the prefrontal cortex which share extensive anatomical connections with the amygdala in both MDD and bipolar disorder. The glial cells play a variety of important roles in assisting the function of the neurons, the cells responsible for carrying signals from one brain region to another. This abnormality could thus interfere with the normal functioning of the amygdala, which plays major roles in the regulation of emotional behavior. Finally, lithium treatment of bipolar disordered subjects is associated with increases (toward normal) in the volume of the left ventral anterior cingulate cortex, a structure where the grey matter volume was previously shown to be abnormally reduced in bipolar disorder. Studies performed in experimental animals or humans have suggested that this brain structure plays a major role in inhibiting or regulating the autonomic and endocrine responses to threat or stress, and the emotional feelings that occur in response to internally generated sad or anxious thoughts and memories. The abnormal reduction in volume may indicate this region's function is impaired in bipolar disorder, dysregulating emotional expression and experience. Lithium has been shown to increase the genetic expression of proteins that exert neuroprotective and neurotrophic effects, so correcting this brain abnormality may play an integral role in lithium's mood stabilizing effect. Effects of other psychotropic medications such as pramipexole are currently being persued.