The application of functional neuroimaging techniques to the study of major depressive disorder (MDD) has been successful in identifying its neural correlates as well as in informing neuroaffective models of depression. Two shortcomings of this approach have emerged, however. One is that it has failed to distinguish neural correlates of the disorder from neural factors that are involved more critically in producing and sustaining depressive symptomatology, an essential distinction in creating informative and useful neuroaffective models of depression. Another shortcoming is that functional neuroimaging studies of depression have had limited impact on the quality of life among those suffering from the disorder. In the research plan I present below, I attempt to address these issues by applying real-time functional magnetic resonance imaging (rtfMRI) techniques to the study and treatment of MOD. The primary aim is to explore the impact on depressive symptomatology of learned modulation of the subgenual anterior cingulate cortex (ACC) and the amygdala, two structures that have been demonstrated most frequently to exhibit functional abnormality associated with depression. This will allow both for the roles of these structures in depression to be further elucidated and for the therapeutic efficacy of training depressed individuals to modulate activity in these structures to be assessed. To achieve these objectives, levels of depressive symptomatology in clinically depressed participants will be assessed before and after courses of neurofeedback training designed to teach them to control activity in the subgenual ACC (in one experimental group) and the amygdala (in another experimental group). Changes in depressive symptoms in these experimental groups will be compared to that in control groups who receive either sham neurofeedback training or neurofeedback training with information from somatomotor cortex, not thought to be involved in depression. If depressed participants trained with neurofeedback signals from regions implicated in the disorder show symptom improvement that is greater than that exhibited by participants in the control groups, then the assertion that these regions play an active role in depression will be supported and the viability of an alternative treatment option for depression will be underscored. The proposed program of research could have a direct and positive impact on mental health insofar as it seeks to explore the efficacy of learned modulation of activity in the subgenual ACC and amygdala as a treatment option for depression. Findings from this study could suggest novel treatment options for individuals experiencing this debilitating disorder.