In addition to pervasive sadness, specific aspects of behavior and cognition are impaired in mood disorders, including selective attention, set-shifting and memory. In addition, depressed individuals exhibit a mood congruent processing bias whereby they more readily process negatively toned information as compared to positively toned information. This cognitive pattern lends itself to evaluation with functional brain imaging, both in terms of identifying the anatomical correlates of the specific behavioral and cognitive differences as well as characterizing the effects of pharmacological manipulation. Attention and memory functions are closely tied to the cholinergic neurotransmitter system;drugs that enhance cholinergic function enhance memory and attention tasks while agents that interfere with normal cholinergic function impair performance. Moreover, the cholinergic system is one of the neurotransmitter systems implicated in the pathophysiology of mood disorders. Evidence suggests that during major depressive episodes, the cholinergic system is hypersensitive to acetylcholine. Agents that enhance muscarinic cholinergic receptor function increase depressive symptoms in depressed subjects, and can produce symptoms of depression in healthy subjects. The preclinical literature more specifically implicates the muscarinic receptors and indicates that the use of muscarinic antagonists, in the context of animal models of depression, results in improvement in the behavioral analogs of depression. This on-going project investigates the role of cholinergic neurotransmission in the mood, behavioral and cognitive symptoms observed in the depressed phase of both major MDD and BD. These studies will evaluate the effects of the cholinergic antagonist, scopolamine, on mood in patient populations, as well as performance effects and alterations in neural activity in brain regions recruited to perform cognitive tasks. This approach is expected to reveal how neuromodulators influence processing in brain structures recruited to perform these tasks, and are expected to elucidate the role of cholinergic muscarinic receptors in the mood and cognitive symptoms observed in depression. The combined use of functional brain imaging and pharmacological manipulation to evaluate the role of neurotransmitter dysfunction in depression may direct us to potential therapeutic approaches. Over the past year, functional brain imaging studies have further elucidated the role of the cholinergic system in stimulus processing biases, including emotional processing biases. An affective shift task has been used to identity a network of brain regions that are involved in processing positive versus negative words, as well as shifting emotional stimulus target. The model developed in healthy individuals was applied to a patient group to characterize the extent to which the interaction among the brain regions involved in this network are altered in patients with MDD, with significant differences identified. Group effects focused on differences based on the emotional content of the target stimuli. Preliminary results were presented at the Human Brain Mapping conference in Barcelona. Analyses are currently underway to determine how scopolamine alters network interactions, both within and between groups. We also have continued to follow up on stimulus processing biases uncovered behaviorally using a selective attention task where face and house stimuli compete for attention. Face stimuli generally are favored suggesting that there is an inherent bias towards face processing. Behavioral biases are seen under placebo via faster reaction times to faces than to houses. Behavioral processing biases observed under placebo conditions were modulated by scopolamine, with the face processing bias diminishing during drug while there is no change observed in the responses during houses. Functional brain imaging results show that brain regions in temporal visual processing areas which show a face processing bias (larger response to faces than to houses) during placebo show a reduction in this bias during scopolamine, a result that complements the behavioral finding. In brain regions that show a bias for processing houses during placebo, no change is observed. Moreover, attention regions in parietal cortex show a processing bias for houses, and no change in biases under scopolamine. As faces are salient stimuli that automatically gain attention, the selective effects of cholinergic inhibition during attention to faces on task performance and on BOLD response within visual processing areas, with no effect in parietal attention regions, suggests that the cholinergic influence on selective attention is primarily via stimulus processing mechanisms rather than attention mechanisms. Aspects of these findings have been presented at Human Brain Mapping and Society for Neurosciences. Clinical studies also have continued over the last year to follow up on our earlier finding that scopolamine produces robust antidepressant effects in MDD and BD patients. This work retains the potential to have the greatest impact on public health by providing treatment to a large number of people who suffer from depression. Previously we found that scopolamine produces rapid antidepressant effects in both MDD and BD patients, with over half of participants experiencing remission of symptoms. This past year we completed a study replicating this original finding in an independent group of patients, and published these findings in Biological Psychiatry. We observed equally rapid antidepressant effects, confirming our earlier result. In addition, we considered differential responses based on patient subgroups and found that while men and women both show improvement in symptoms, women show larger antidepressant responses than do men. Other subgroups showed no difference in response magnitude;there was no difference in response magnitude based on diagnosis of MDD vs BD;and there was no difference based on the presence or absence of co-morbid anxiety disorder. The patient sample was extended to complete a group to evaluate gender effects, and a paper currently is in press in Neuropsychopharmacology. Aspects of these clinical findings have been reported at the Society for Neurosciences and Biological Psychiatry. The observed antidepressant effects occurred quickly, within 1 to 3 days, a response that far exceeding the typical three week period that traditional antidepressant agents require. In our estimation, scopolamine has the potential to become a new option for the clinical treatment of depression in MDD and BD, offering a medication that produces a more rapid response than traditional treatments offer.