Anhedonia has been one of the two key diagnostic criteria for major depressive disorder (MDD) since the publication of The Diagnostic and Statistical Manual of Mental Disorders, Third Edition, yet little is known about its neural substrates. Neuroimaging studies have identified numerous brain regions that are thought to be involved with MDD. Most studies dealt with MDD as a syndromal entity, and not surprisingly, yielded quite variable results with respect to the areas of the brain identified, the nature of the functional changes (i.e., decrease or increase in activities), lateralization, and correlation with clinical symptoms. Clinical heterogeneity and lack of symptom-specific targets are presumably among the factors contributing to the variability. The hypothesis that a functionally impaired mesolimbic dopaminergic pathway may comprise a part of neural substrate underlying core MDD symptoms of anhedonia and loss of motivation has been proposed. Nevertheless, the roles of brain reward mechanisms in mediating anhedonia in MDD remain unclear. Availability of appropriate experimental paradigms that can be used empirically to measure anhedonia is a prerequisite to test such a hypothesis. Recent studies using monetary incentive paradigms coupled with neuroimaging techniques have identified hemodynamic responses in structures that serve as part of the mesolimbic dopaminergic pathway during processing rewards in healthy humans.

We hypothesize that anhedonia in MDD is associated with impairment of brain reward mechanisms such that dysfunction of the orbital and ventromedial frontal cortices involved in the impaired hedonic attribution capacity, while dysfunction of the ventral striatum area that contains the nucleus accumbens is involved with the reduced or lack of reactivity to rewarding environmental stimuli in patients with MDD. Our hypothesis is to link specific neural substrates to the two psychiatric components of anhedonia, i.e., loss of interest and lack of reactivity, as defined in the diagnostic criteria for MDD. We plan to operationally test our hypothesis by using empirical measurement of reward responses in MDD patients with and without significant anhedonia using a conditioning task assessing appetitive and aversive learning without any performance aspects and spatial delayed response task assessing the relationship between reward, performance and mood with the event-related functional magnetic resonance imaging method. We expect to find reduced activation of the ventral striatum, orbital and ventromedial frontal cortices in response to monetary incentive stimuli in MDD patients with significant anhedonia relative to MDD patients without anhedonia and healthy control.

In order to assess the role of dopamine in anhedonia and in reward processing, we propose to assess the effect of dietary tyrosine plus phenylalanine depletion on the neural and behavioral responses associated with the performing of the monetary reward tasks investigated herein in an additional sample of subjects. Dietary depletion of tyrosine and phenylalanine, two DA precursors, is a validated method to induce significant reduction of the brain DA concentration as shown in two previous \[11C\]Raclopride PET studies. We hypothesize that depressed patients will show less activation than controls in brain regions associated with the mesolimbic DA system, such as striatum, amygdala, anterior cingulate gyrus and orbitofrontal cortex in response to reward in the placebo condition. We expect tyrosine and phenylalanine depletion to induce a similar neural impairment to reward in healthy subjects, including a reduction of the neural activation in the striatum, amygdala, anterior cingulate gyrus and orbitofrontal cortex in response to reward. The reduction of the neural activation in those regions will be stronger in healthy controls than in depressed patients. Finally, we hypothesize that tyrosine depletion will influence negatively the valence ratings of rewarding stimuli in healthy subjects. In depressed patients, anhedonia scores will correlate negatively with the valence ratings of rewarding stimuli in the placebo condition already.

The outcome of the proposed work may provide clues for diagnosis, classification, and treatment of MDD, and may also yield leads for identifying the fundamental neural mechanisms underlying anhedonia in other disabling psychiatric conditions such as schizophrenia and addiction.