# Reward processing and depressive subtypes:  Identifying neural biotypes related to suicide risk, resilience, and treatment response

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2023 · —

## Abstract

Anhedonia and amotivation are common in depressive presentations, and putatively thought to be
caused by alterations in the ways in which the brain anticipates, evaluates, and adaptively uses reward-related
information. However, reward processing is a complex, multi-circuit phenomenon, and the precise neural
mechanisms that contribute to the absence or reduction of typical hedonic and motivational outputs seen in
the clinic are still being elucidated. Heterogeneity in the clinical presentation of depression has long been a
rule rather than an exception, including individual variation in symptoms, severity, and treatment response.
This heterogeneity complicates understanding of depressive pathophysiology and thwarts progress toward
personalized disease classification and treatment planning. If the goal of personalized medicine in psychiatric
care is to be realized, biomarkers that account for the full range of depressive presentations need to be
developed (and ultimately validated). Discovery of biomarkers that go beyond the level of aggregate disease
definitions to account for neurobiological variation that presumably underlies distinct clinical manifestations
is critical to this larger effort.
 The proposed work combines clinically motivated questions with in-depth study of neurobiological
mechanisms to evaluate how reward system neurobiology contributes to expression of reward-related deficits,
such as anhedonia and amotivation in major depressive disorder (MDD), with a particular emphasis on
understanding depressive heterogeneity. Conceptually, we will use a multi-measure approach, by studying
Veterans with i) a passive slot machine reward task to isolate brain responses to reward anticipation and
receipt in the absence of confounding higher-order cognitive demands, and ii) a delay-discounting task to
assess higher-order aspects of reward processing necessary for reward valuation and decision-making.
Methodologically, we will use a multi-modality approach by combining fMRI, EEG, and behavioral
assessment, to more fully characterize reward-related brain functions and their clinical correlates. In addition
to evaluating reward effects between Veterans with MDD and healthy controls (HC), and examining
depressive heterogeneity within a large (n=150) MDD group, we will also focus on understanding the
relationship between reward processing and clinical features of high relevance to depression, with an
emphasis on suicidality. Specific Aim 1 will establish MDD deficits in reward processing at the level of
group averages (i.e., case-control comparisons of MDD vs. HC). Specific Aim 2 will examine the extent to
which data-driven subtyping of MDD can derive “biotypes” in Veterans, based on our EEG and fMRI reward
processing metrics, that segregate clinically relevant features. Specific Aim 3 will compare subgroups of
MDD with varying levels of suicidality.

## Key facts

- **NIH application ID:** 10595485
- **Project number:** 5I01CX001980-03
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** SUSANNA FRYER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595485

## Citation

> US National Institutes of Health, RePORTER application 10595485, Reward processing and depressive subtypes:  Identifying neural biotypes related to suicide risk, resilience, and treatment response (5I01CX001980-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10595485. Licensed CC0.

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