Translational Model of Anhedonia

A Novel Bench-to-Bedside Translational Model of Anhedonia

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.

Study Overview

• Status: Completed
• Conditions: Anhedonia
• Intervention / Treatment: Behavioral: Emotion Induction

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico - Logan hall

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Men or women aged 18-55
• Free from psychoactive medication for at least 2 weeks

Exclusion Criteria:

• Participants unwilling or unable to give informed consent
• Presence of other known medical or psychiatric comorbidity that in the investigator's opinion would compromise participation in the study
• History of psychosis
• Not fluent in English

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neutral; A neutral mood induction will include reading a dull text while listening to non-evocative music for 5-15 minutes.	Behavioral: Emotion Induction; Described in arm
Experimental: Evocative; A mood induction procedure will be utilized. The procedure consists of a combination of re-experiencing an autobiographical sad personal event while listening to their choice of one of four sad music selections commonly used in mood induction. Visual analogue scale ratings will assess momentary sadness prior to, following, and at subsequent time points around the mood induction procedure.	Behavioral: Emotion Induction; Described in arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reward Positivity Component of the Event-Related Electroencephalogram	The Reward Positivity is a fronto-centrally located positive voltage burst recorded in the EEG from about 200-500 ms following the receipt of a reinforcing outcome (e.g. money, points). Higher voltages (more positive numbers) indicate a larger reward response.	There will only be one day session (on the date of the randomization) where the Reward Positivity amplitude is assessed

Collaborators and Investigators

• Sponsor: University of New Mexico
• Collaborators: National Institute of Mental Health (NIMH)

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: February 21, 2019
• First Submitted That Met QC Criteria: February 26, 2019
• First Posted (Actual): February 27, 2019

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Anhedonia
• Other Study ID Numbers: 1R01MH119382-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No