Neurocomputational Training to Improve Reward Responsiveness in Veterans With Anhedonia

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.

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 a high dose of the experimental treatment, i.e., ReLIT (Reward Learning Intensive Training).

Behavioral: ReLIT (Reward Learning Intensive Training)

This arm provides a non-training protocol matched for time and reward environment.

Behavioral: ST (Sham Training)

This arm provides an active reward learning training.

This arm provides an inactive reward learning training.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

Measure of anhedonia. Score range from 14 to 56, with higher scores indicating greater anhedonia severity.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

Measures depression severity. Scores range from 0 to 27. Higher scores indicate greater depression severity.

Plazo: Baseline, Post-Treatment (8 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks)

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).

Plazo: Baseline, Post-Treatment (8 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

Assesses the impact of social anxiety on multiple aspects of life. Scores range from 0 to 144, with higher scores indicating greater social anxiety.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

Assess positive and negative mood using a 5-point frequency scale (1-5). Each subscale (positive or negative affect) range from 10 to 50.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks)

Measures performance and computational parameters associated with approach and avoidance biases in a dynamic foraging task.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

This scale measures anxiety severity. Scores range from 0 to 63, with higher scores indicating greater anxiety severity.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

Measures post-traumatic stress disorder (PTSD) severity. Scores range from 0 to 80, with higher scores indicating greater PTSD severity.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Plazo: Baseline , Post-Treatment (8-weeks)

Measures psychological diagnoses, which will be used to assess primary diagnostic category (i.e., depressive vs traumatic stress/anxiety disorder).

Plazo: Baseline, Post-Treatment (8 weeks)

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.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

Computational parameter derived from participants' choices in a reinforcement learning task, capturing the degree to which individuals are updating their dynamic reward predictions.

Plazo: Baseline, Post-Treatment (8 weeks), Follow-Up (16 weeks)

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.

Neurocomputational Training to Improve Reward Responsiveness in Veterans With Anhedonia