During the depressed phase of major depressive disorder and bipolar disorder, glucose metabolism is abnormally elevated in the amygdala, a brain structure that is critically involved in associating experiential stimuli with emotional significance and in organizing the endocrine, autonomic and behavioral responses to emotional stimuli. The magnitude of this elevation correlated positively with blood concentrations of the ?stress hormone?, cortisol. This relationship may reflect two phenomena that have been established in studies of rodents: the amygdala?s prominent role in mediating corticosterone (the rodent equivalent of cortisol) secretion during stressful conditions, and the direct enhancement of amygdala function by corticosterone. In response to viewing pictures of human faces showing sad expressions, the neural responses of the amygdala and the prefrontal cortex were abnormal in the depressed phase of both bipolar disorder and major depressive disorder. In both depressed and healthy control subjects the blood flow initially increased in the amygdala in response to sad faces. However, after repeatedly viewing the same sad faces, the amygdala stopped responding in the healthy subjects, but continued to respond in the depressed subjects. This abnormality was associated with abnormal responses of the prefrontal cortex to sad faces in the depressives, such that activity in the anterior cingulate and orbital cortex increased in healthy subjects, but decreased in depressed subjects. These latter regions are known to play important roles in regulating emotional responses generally, including those mediated by the amygdala. During the past one year three new functional imaging experiments have been initiated to pursue these findings. One involves an investigation of the neural basis for the catastrophic response to perceived failure which depressed patients show. This study uses fMRI imaging during a probabalistic reversal learning task to elicit and characterize these phenomena. This study demonstrated initially a significant behavioral difference between depressives and controls, and a manuscript is in preparation to describe these results. In addition, a total of 17 healthy controls, 12 unipolar depressives and 13 bipolar depressives have participated in the fMRI imaging. These results are being analyzed. During the upcoming one year, this study will be completed and the results published. The second investigates the effects of antidepressant drugs on amygdala responses to emotionally valenced faces. A pilot study was completed initially to characterize the optimal stimulus parameters needed to elicit the amygdala responses. These results are of broad interest to the human brain mapping community and have been presented at the Annual Meeting of the Organization for Human Brain Mapping and the Annual Meeting of the Society for Neurosceince. The study of the depressed subjects is expected to be approved by the IRB within the next 2 weeks. The final study has received scientific review and IRB approval, and will examine the rates at which depressives and controls are able to habituate to amygdala responses during repeated stimulation. Finally, a study of the effects of pramipexole on cerbral glucose metabolism has been nearly completed. This study involved 18 bipolar depressives taking lithium, 8 of whom were rescanned following placebo plus lithium and 7 who were rescanned on lithium plus pramipexole. These data showed that the functional anatomical abnormalities present in unmedicated subjects with MDD also are evident in lithium treated bipolar subjects who are currently depressed. Pramipexole treatment resulted in prominent reductions of metabolic activity in these regions. Two manuscripts are in preparation to describe these findings.
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