# Neuroimaging Studies of Reward Processing in Depression

> **NIH NIH R37** · MCLEAN HOSPITAL · 2022 · $785,591

## Abstract

Major Depressive Disorder (MDD) remains a major public health problem with poorly understood 
etiology and pathophysiology. Impairment in reward processing and anhedonia are core features of 
MDD. Findings during the prior award period have shown that MDD and anhedonic phenotypes are 
characterized by functional, structural and molecular abnormalities within a CorticoStriatal 
Valuation Circuit critically implicated in value encoding and reinforcement learning. The main goal 
of the this R37 renewal is to expand this line of work in several fundamental new directions to (1) 
attain a better mechanistic understanding of MDD and anhedonia by focusing on a novel target - 
Nociceptin/Orphanin FQ Receptors - expected to yield molecular abnormalities associated with 
CorticoStriatal Valuation Circuit and stress- induced inflammatory abnormalities (Aims 1 and 2); 
and (2) identify abnormalities that map disease course (Aim 3). This will be achieved through an 
innovative integration of (1) molecular imaging techniques with a novel positron emission 
tomography (PET) NOP tracer ([11C]NOP1A) in unmedicated individuals with current or past MDD, (2) 
state-of-the-art analyses of stress-related pro-inflammatory transcription control pathways, (3) 
behavioral and functional neuroimaging markers of key depressive phenotypes, and (4) a naturalistic 
follow-up design. To differentiate between state- and trait-like markers of vulnerability, 
currently depressed individuals (MDD), remitted individuals with a history of MDD (rMDD), and 
never-depressed healthy controls will be included. Based on findings from the prior project period, 
we hypothesize that, relative to healthy controls, MDD and rMDD participants will show 
significantly higher [11C]NOP1A binding potential in brain regions critically implicated in stress 
regulation and reward processing (Hypotheses 1).
Moreover, among individuals with current or past MDD, N/OFQ abnormalities in brain regions 
implicated in stress regulation and reward processing will be associated with (1) behavioral and 
neural markers of anhedonic phenotypes; (2) lower ability to regulate stress responses; and (3) 
higher stress-related proinflammatory cytokines and transcription control pathways (Hypotheses 2). 
Finally, we expect that N/OFQ abnormalities (and associated behavioral, fMRI, hormonal, and 
inflammatory markers) will predict anhedonic symptoms and poorer general functioning at follow-up 
(Hypothesis 3). Collectively, the proposed research promises to improve our mechanistic 
understanding of stress-induced anhedonia and the pathophysiology of MDD, as well as our ability to 
identify mechanisms that prospectively predict reward deficit-related symptoms, thus opening novel 
avenues for improved treatment and prevention.

## Key facts

- **NIH application ID:** 10307643
- **Project number:** 4R37MH068376-17
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** Diego A Pizzagalli
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $785,591
- **Award type:** 4C
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307643

## Citation

> US National Institutes of Health, RePORTER application 10307643, Neuroimaging Studies of Reward Processing in Depression (4R37MH068376-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10307643. Licensed CC0.

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