The goal of this research project is to evaluate the role of the cholinergic system in behavioral and cognitive symptoms observed in mood disorders in humans, using functional brain neuroimaging techniques. Specific aspects of behavior and cognition are impaired in mood disorders, including selective attention, set-shifting and memory; and there is also evidence that depressed subjects 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 deficits as well as characterizing the effects of pharmacological manipulation. Attention and memory functions are closely tied to the cholinergic neurotransmitter system. 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. The proposed project investigates the role of cholinergic neurotransmission in the behavioral and cognitive symptoms observed in the depressed phase of both major depressive disorder (MDD) and bipolar disorder (BD). The studies proposed here will identify anatomical correlates of the mood congruent processing bias, working memory, attention and set-shifting deficits observed in depressed subjects. Further, these studies will evaluate the effects of the cholinergic antagonist, scopolamine, both on the performance deficits and on neural activity in brain regions recruited as subjects perform these tasks. This approach is expected to reveal how neuromodulators influence processing in brain structures recruited to perform these tasks, both in healthy subjects and in major depressive disorders. 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. This study was initiated in June 2003. Eleven subjects have completed the study, and four others have been entered. The preliminary results indicate that cholinergic modulation plays a powerful role on the extent to which the emotional salience of sensory stimuli modulates attentional processing in healthy subjects. Additional subjects are being entered to establish the statistical significance of this effect. To determine whether depressives and controls differ with respect to these processes, studies in depressed subjects have been initiated, although no results are available.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Institute of Mental Health
United States
Zip Code
Ellis, Jessica S; Zarate Jr, Carlos A; Luckenbaugh, David A et al. (2014) Antidepressant treatment history as a predictor of response to scopolamine: clinical implications. J Affect Disord 162:39-42
Rosenbaum, R Shayna; Furey, Maura L; Horwitz, Barry et al. (2010) Altered connectivity among emotion-related brain regions during short-term memory in Alzheimer's disease. Neurobiol Aging 31:780-6
Taylor Tavares, Joana V; Clark, Luke; Furey, Maura L et al. (2008) Neural basis of abnormal response to negative feedback in unmedicated mood disorders. Neuroimage 42:1118-26
Furey, Maura L; Tanskanen, Topi; Beauchamp, Michael S et al. (2006) Dissociation of face-selective cortical responses by attention. Proc Natl Acad Sci U S A 103:1065-70
Furey, Maura L; Drevets, Wayne C (2006) Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry 63:1121-9
Freo, Ulderico; Ricciardi, Emiliano; Pietrini, Pietro et al. (2005) Pharmacological modulation of prefrontal cortical activity during a working memory task in young and older humans: a PET study with physostigmine. Am J Psychiatry 162:2061-70
Ibanez, Vicente; Pietrini, Pietro; Furey, Maura L et al. (2004) Resting state brain glucose metabolism is not reduced in normotensive healthy men during aging, after correction for brain atrophy. Brain Res Bull 63:147-54
Pietrini, Pietro; Furey, Maura L; Ricciardi, Emiliano et al. (2004) Beyond sensory images: Object-based representation in the human ventral pathway. Proc Natl Acad Sci U S A 101:5658-63