Neurocomputational Training to Improve Reward Responsiveness in Veterans With Anhedonia

Anhedonia, a reduction in motivation and in the ability to feel positive emotions, is widespread among Veterans across a range of psychiatric disorders. This impairment is associated with poorer psychosocial functioning and is resistant to first-line medication and psychotherapy treatments. However, interventions to improve anhedonia are sorely lacking. Reward learning supports motivation to seek rewards, and this mechanism can be enhanced by engaging in reward exploration. Our preliminary findings suggest that this approach can help improve reward responsiveness and positive mood among depressed and anxious individuals. Thus, the proposed research will test the preliminary efficacy of a computerized reward learning training in improving reward sensitivity and reducing anhedonia in Veterans. This new intervention could offer a novel remotely accessible treatment and help enhance the efficacy of existing evidence-based treatments for depression and other psychiatric conditions in Veterans.

Study Overview

• Status: Not yet recruiting
• Conditions: Depression; Anhedonia
• Intervention / Treatment: Behavioral: ReLIT (Reward Learning Intensive Training); Behavioral: ST (Sham Training)

Detailed Description

Anhedonia, which is characterized by reduced reward responsiveness and blunted positive affect, is widespread among Veterans across a range of psychiatric conditions, including depression and PTSD. Anhedonia manifests as reduced exploration of rewards in a range of domains, including social connectedness and workforce engagement, and is associated with poorer psychosocial functioning and reduced response to psychiatric treatment. Despite the prominence of anhedonia and these associated deficits, the treatment of impaired reward responsiveness and underlying mechanisms has received relatively little attention compared to punishment sensitivity and negative affect, particularly in Veteran populations. Moreover, pharmacological and behavioral treatments for depression have shown mixed results for anhedonia. Thus, there is a significant need for mechanistically informed interventions targeting anhedonia in Veterans.

Recent advances in computational psychiatry have shown that reward learning is a key top-down mechanism of reward exploration and foraging, which could be leveraged to develop cognitive training interventions for anhedonia. For instance, Bayesian reinforcement learning models have been particularly useful in disentangling various aspects of reward responsiveness, including reward prediction updating (learning) and reward maximization strategy. Within this framework, subjective anhedonia, has been robustly linked to lower learning-based reward maximization in the multi-arm bandit (MAB), a reward exploration task in which one must sample from various unknown options with the goal of maximizing rewards. Critically, a recent randomized clinical trial (RCT) from our group suggests that a MAB experimentally tuned to provide high variance of reward delivery can increase reward learning and associated reward maximization among clinically depressed and anxious individuals with anhedonia.

This proposal will capitalize on this approach to test the effectiveness of a novel neurocomputational cognitive training aimed at boosting reward sensitivity in Veterans with anhedonia. The specific aims are to : 1) examine the degree to which a reward learning training protocol (reward learning intensive training/ReLIT) changes the neurocomputations supporting reward sensitivity in Veterans with anhedonia (Aim 1); 2) test the effectiveness and optimal dosage of ReLIT in improving subjective markers of anhedonia, depression, and psychosocial functioning (Aim2), and 3) assess the degree to which the effects of ReLIT generalize to parallel measures of automatic affective processing (Aim 3).

In a 3-arm double-blind RCT, Veterans (N=120) with moderate to high anhedonia will be randomized to an 8-week protocol of: 1) sham training (non-active), 2) active ReLIT of moderate intensity, or 3) active ReLIT of high intensity. At baseline (pre-treatment), 8-weeks (post-treatment), and 16-weeks follow-up (8 weeks post-treatment), participants will complete an assessment MAB and 2 automatic affective processing tasks (while undergoing functional MRI for a subset of 75 participants). Bayesian computational modeling will be used to derive individual parameters of reward learning and reward maximization and to extract neural activity associated with dynamic updating of reward predictions. Clinical and affective measures will be collected at all 3 assessments and each treatment session.

This proposal aims to assess the preliminary efficacy of a novel intervention for improving healthy reward responsiveness and anhedonic pathology in Veterans, which is currently an underrepresented area of mental health treatment for Veterans. This mechanistically informed intervention could a) provide a scalable and cost-effective treatment for Veterans with anhedonia, relying on technology interface rather than clinician-guided administration, b) be used as an adjunctive training to boost the effectiveness of existing evidence-based treatments for Veterans, such as cognitive behavioral therapy.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Katia Harle, MD; Phone Number: (858) 642-3657; Email: Katia.Harle@va.gov

Study Locations

• United States
  • California
    • San Diego, California, United States, 92161-0002
      • VA San Diego Healthcare System, San Diego, CA
      • Principal Investigator: Katia Harle, MD
      • Contact: Katia Harle, MD; Phone Number: (858) 642-3657; Email: Katia.Harle@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• being a Veteran
• having at least moderate levels anhedonia (Snaith-Hamilton Pleasure Scale score>=20)
• having sufficient vision and reading skills to complete the study protocol
• being willing to attend treatment and assessment sessions

Exclusion Criteria:

• lifetime history of psychotic or bipolar I disorder
• neurological/neurodevelopmental disorders or sensory deficits that may impact cognitive function to preclude completion of study procedure (including past loss of consciousness > 24 hours)
• taking certain psychotropic medications that may impact goal-directed task performance (e.g., benzodiazepines, sedative hypnotics); pre-existing stable doses (same regimen for at least 30 days) of psychotropic medications, such as selective serotonin reuptake inhibitors (SSRIs), will be allowed
• recent (past 3 months) or current severe alcohol or substance use disorder necessitating prioritization of substance use treatment
• recent (past month) or current risk of suicidal/homicidal behavior necessitating urgent higher level of care
• undergoing concurrent neuromodulation or cognitive-behavioral psychotherapy targeting depression, anhedonia, and/or PTSD

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ReLIT - Moderate Intensity; This arm provides a moderate dose of the experimental treatment, i.e., ReLIT (Reward Learning Intensive Training).	Behavioral: ReLIT (Reward Learning Intensive Training); This arm provides an active reward learning training.
Experimental: ReLIT - High Intensity; This arm provides a high dose of the experimental treatment, i.e., ReLIT (Reward Learning Intensive Training).	Behavioral: ReLIT (Reward Learning Intensive Training); This arm provides an active reward learning training.
Sham Comparator: ST (Sham Training); This arm provides a non-training protocol matched for time and reward environment.	Behavioral: ST (Sham Training); This arm provides an inactive reward learning training.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Snaith-Hamilton Pleasure Scale (SHAPS)	Measure of anhedonia. Score range from 14 to 56, with higher scores indicating greater anhedonia severity.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Reward Maximization	Computational parameter derived from participants' choices in a reinforcement learning task, capturing the degree to which individuals select the options they predict to be most rewarding.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Neural Activation to Reward Prediction Errors (RPEs)	Average BOLD (Blood-Oxygenation-Level Dependent) % signal change (i.e., activation) associated with individuals' model-based RPE (difference between expected probability of reward and actual outcome received) during reinforcement learning.	Baseline, Post-Treatment (8 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
World Health Organization Quality of Life Scale (WHOQOL-BREF)	Measures quality of life and life satisfaction. Includes 4 domain subscales: physical health (range 7-35), psychological health (range 6-30), social relationships (range 3-15), and environment (range 8-42). Higher scores indicate higher quality of life.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Patient Health Questionnaire-9 (PHQ-9)	Measures depression severity. Scores range from 0 to 27. Higher scores indicate greater depression severity.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Approach Bias	This metric assesses the degree to which individuals display an implicit approach bias towards positive/rewarding cues in an approach-avoidance task. It is computed as the mean response time difference between approach-positive and avoid-positive choices.	Baseline, Post-Treatment (8 weeks)
Automatic Positive Affective Processing	A measure of implicit bias towards positive relative to negative cues in an affective go/no-go task, as measured but the standardized rate of hits (accurate identification of positive cues) minus standardized rate of false alarms (inaccurate identification of negative cues as positive).	Baseline, Post-Treatment (8 weeks)
Neural Activation Associated with Implicit Processing of Positive Cues	Average BOLD (Blood-Oxygenation-Level Dependent) % signal change (i.e., activation) associated with the contrast of positive-Go vs negative-Go trials in an affective go/no-go task.	Baseline, Post-Treatment (8 weeks)
Neural Activation Associated with Approach Bias	Average BOLD (Blood-Oxygenation-Level Dependent) % signal change (i.e., activation) associated with the contrast of (positive-approach vs positive-avoid) minus (neutral-approach vs neutral-avoid) in an approach-avoidance task.	Baseline, Post-Treatment (8 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inventory of Psychosocial Functioning (IPF)	The scale measures the degree of impairment in ability to interact effectively with others, fulfill social roles (e.g., work), and meet personal and societal expectations. It is comprised of 7 subscales. Each item ranges from 0 to 6. Higher scores indicate greater degree of impairment in psychosocial functioning.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Mood and Anxiety Symptoms Questionnaire (MASQ-D30)	Measure of anhedonic depression, anxiety, and stress symptoms. The scale has three subscales (general distress, anhedonic depression, and anxious arousal) , with each score ranging from 10 to 50. Higher scores indicate greater severity of symptoms.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Reaction to Treatment Questionnaire	Measure of treatment satisfaction and credibility of treatment rationale. Total scores range from 3 to 27, with higher scores indicating greater satisfaction and credibility in the treatment.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Liebowitz Social Anxiety Scale (LSAS)	Assesses the impact of social anxiety on multiple aspects of life. Scores range from 0 to 144, with higher scores indicating greater social anxiety.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Positive and Negative Affect Schedule (PANAS)	Assess positive and negative mood using a 5-point frequency scale (1-5). Each subscale (positive or negative affect) range from 10 to 50.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Social Connectedness Scale - Revised (SCS-R)	Measures the degree to which individuals feel connected to others in their social environment. Scores range from 20 to 120, where higher scores indicate a stronger, healthier sense of social connectedness.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Foraging Task	Measures performance and computational parameters associated with approach and avoidance biases in a dynamic foraging task.	Baseline, Post-Treatment (8 weeks)
Beck Anxiety Inventory (BAI)	This scale measures anxiety severity. Scores range from 0 to 63, with higher scores indicating greater anxiety severity.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
PTSD Checklist-5 (PCL-5)	Measures post-traumatic stress disorder (PTSD) severity. Scores range from 0 to 80, with higher scores indicating greater PTSD severity.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Behavioral Activation for Depression Scale (BADS)	This scale measures changes in activation and avoidance behaviors. Items are measured on a 7-point Likert scale (0-6). Scores range from 0 to 150, with higher scores indicating greater behavioral activation.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Quick Structured Clinical Interview for DSM-5 (QuickSCID-5)	Measures psychological diagnoses, which will be used to assess primary diagnostic category (i.e., depressive vs traumatic stress/anxiety disorder).	Baseline , Post-Treatment (8-weeks)
Neural Activation to Anticipated Reward	Average BOLD (Blood-Oxygenation-Level Dependent) % signal change (i.e., activation) associated with individuals' model-based reward prediction/anticipation for chosen options during reinforcement learning.	Baseline, Post-Treatment (8 weeks)
Learning Rate	Computational parameter derived from participants' choices in a reinforcement learning task, capturing the degree to which individuals are updating their dynamic reward predictions.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)
Specific Loss of Interest and Pleasure Scale (SLIPS)	This is a measure of social anhedonia, i.e., hypo-responsiveness to social rewards, such as positive human interactions. Scores range from 0 to 69. Higher scores indicate greater severity of social anhedonia.	Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Katia Harle, MD, VA San Diego Healthcare System, San Diego, CA

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2027
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): March 31, 2031

Study Registration Dates

• First Submitted: November 4, 2026
• First Submitted That Met QC Criteria: November 4, 2026
• First Posted (Actual): November 10, 2026

Study Record Updates

• Last Update Posted (Actual): November 10, 2026
• Last Update Submitted That Met QC Criteria: November 4, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Keywords: Motivation; Cognitive Training; Reward; Anhedonia
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Behavioral Symptoms; Neurobehavioral Manifestations; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Depression; Anhedonia
• Other Study ID Numbers: MHBC-006-26S

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

One or more data sets without personal identifiers will be generated during the data analysis phase of this study. The data sets will include all data underlying any publications generated by this study as well as statistical code, and therefore these will be sufficient to reproduce or verify any published findings.

Any HIPAA identifiers, or combinations of variables that could be used for re-identification, will be excluded, as will any proprietary information. The plan does not include any access to individually identifiable or proprietary data. Therefore, this plan will ensure the protection of personal privacy, the confidentiality of individually identifiable private information, and the security of proprietary data and information.

IPD Sharing Time Frame

IPD and supporting information will become available upon completion of the study and publication of the the results.

IPD Sharing Access Criteria

Final de-identified datasets in machine-readable format will be submitted to and accessed from PubMed Central (and similar sites); care will be taken to ensure that individuals cannot be re-identified using other publicly available information.

• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No