Translational Model of Anhedonia
Condition: Anhedonia
MeSH terms: Anhedonia
Study type: Interventional

Summary: 
      The proposed research addresses a major mental health issue (anhedonia) with a novel
      computationally-inspired translational technique in both humans and mice. This approach
      greatly increases the likelihood that a positive animal model result will be successfully
      translated to humans. This research plan thus offers a novel way to address the NIMH's
      mission of defining mechanisms of complex behaviors.
    

Detailed description: 
      Although considered a trans-diagnostic phenotype, anhedonia can emerge from deficits in
      motivation, valuation, or hedonic appreciation, each of which reflect different neural
      processes and are differently expressed across individuals. There is a critical need to
      refine the construct of anhedonia in order to improve treatment. The long-term goal of this
      project is to combine computational, imaging, and causal manipulations to define a
      translational biomarker of diminished valuation in anhedonia. This proposal aims to identify
      how the EEG response known as the Reward Positivity (RewP) is a candidate biomarker specific
      to value-based deficiencies in anhedonia. The RewP is only elicited by the presentation of a
      rewarding outcome, it is decreased in depression, and it scales with the central feature of
      reinforcement learning models, the positive reward prediction error (+RPE). Importantly, this
      same neural response can be elicited in rodents using the same learning task as in humans.
      The objective of this proposal is to test whether induced emotion, depressed mood, and
      learned helplessness (in mice) directly diminish +RPE coding in the RewP. The rationale for
      this approach is that electrophysiology is a highly promising tool for identifying mechanisms
      of complex behaviors and translating these mechanisms between species. Aim 1 will determine
      if induced emotion and +RPE have independent or interactive effects on the RewP. Aim 2 will
      recruit depressed participants and determine if anhedonia and +RPE have independent or
      interactive influences on the source-level generators underlying the RewP (using MEG). Aim 3
      will use the same task in a mouse model with infralimbic recordings; this will then test the
      causal diminishment (learned helplessness) and recovery (fluoxetine) of this mechanism. This
      proposed research is innovative because it identifies a computational function tightly tied
      to a neural response that directly addresses the disease-specific phenotype in human patients
      and is capable of being assessed, manipulated, and recovered within a rodent model. This
      contribution is expected to be significant because it will advance a translational mechanism
      for deficient valuation in anhedonia. Upon completion of these aims, the expected outcome
      will validate the RewP as a sensitive and specific mechanism of aberrant valuation in
      anhedonia. In line with the Research Domain Criteria framework, the use of computational
      modeling will facilitate algorithmic contrasts between multiple sub-constructs of approach
      motivation in the positive valence systems domain. The translational computational psychiatry
      approach advanced here links circuit-level dysfunction, aberrant computations, and
      trans-diagnostic behavioral phenotype. The successful completion of the aims advanced here
      will create a highly promising path for combining these strengths into a
      computationally-inspired, mechanistically tested, translatable model of aberrant valuation in
      anhedonia. This novel candidate biomarker will be translatable between species and testable
      in an outpatient clinic.
    

Intervention name(s): Emotion Induction
Intervention type(s): Behavioral
Intervention description(s): Described in arm
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomly assigned into neutral or emotionally evocative conditions prior to assessing EEG brain signals of reward.
Masking: Single (Investigator)
Primary purpose: Basic Science