Brain Regulation of Emotions in People With Depression and Anhedonia
Condition: Major Depressive Disorder
MeSH terms: Anhedonia; Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Observational

Summary: 
      This study will use magnetic resonance imaging (MRI) to examine how the brain regulates
      emotions in healthy people and in patients who have major depression and anhedonia (loss of
      feeling of pleasure in things that normally give pleasure).

      Healthy normal volunteers and patients between 18 and 50 years of age with major depression,
      with or without significant anhedonia, are eligible for this study. Candidates will be
      screened with a psychiatric interview, a physical examination that will include blood and
      urine samples, and an electrocardiogram, and a questionnaire about their emotions.

      Participants will perform a monetary reward task while lying in an MRI scanner. The task is
      similar to playing a computer video game with the possibility of winning cash. The amount of
      cash is largely dependent on the subject's performance. The accumulated amount of cash earned
      in a session will fluctuate depending on the subject's continuing performance level. That is,
      during a single session, a subject could lose money earned early in the session if his or her
      performance later in the session is not as good as earlier.

      MRI pictures will be taken during performance of the task. MRI uses a magnetic field and
      radio waves to produce images of body tissues and organs. The patient lies on a table that is
      moved into the scanner (a narrow cylinder) and wears earplugs to muffle loud knocking and
      thumping sounds that occur during the scanning process. The procedure will last about 1 to
      1-1/2 hours.
    

Detailed description: 
      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.
    

Keywords: Reward; Cortex; Dopamine; Neuroimaging; Strirtum; Major Depressive Disorder (MDD); Melancholic Features; Brain Imaging; Functional Magnetic Resonance Imaging (fMRI); Dopaminergic Mechanisms; Anhedonia; Depression; Major Depressive Disorder; MDD; Healthy Volunteer; HV