Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study

• Type of Material: Article
• Authors: Mandakh Bekhbat, Emory University; Zhihao Li, Emory University; Namrataa D. Mehta, Emory University; Michael Treadway, Emory University; Michael Lucido, Emory University; Bobbi J. Woolwine, Emory University; Ebrahim Haroon, Emory University; Andrew Miller, Emory University; Jennifer Felger, Emory University
• Language: English
• Date: 2022-10-01
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Authors 2022, corrected publication 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41380-022-01715-3
• Title of Journal or Parent Work: MOLECULAR PSYCHIATRY
• Volume: 27
• Issue: 10
• Start Page: 4113
• End Page: 4121
• Grant/Funding Information: This work was supported by grants R01MH109637 and R61MH121625 (JCF); R21MH121891 and R01MH128872 (JCF/AHM); R01MH112076 (AHM/EH); R01MH107033 (EH); R01MH108605 and R21MH119622 (MTT); F32MH119750 (MB); and F31MH119745 (NM) from the National Institute of Mental Health, and grants BBRF22296 and BBRF26983 from the Brain and Behavioral Research Foundation and CADF49143 from the Dana Foundation. In addition, the study was supported in part by PHS Grants UL1TR000454, UL1TR002378, KL2TR000455, and TL1TR002382, and P30CA138292 from the National Cancer Institute of the National Institutes of Health.
• Keywords: MECHANISMS; ASSOCIATION; ANTIDEPRESSANT; Biochemistry & Molecular Biology; Science & Technology; INCREASES; OUTPATIENTS; Neurosciences; C-REACTIVE PROTEIN; Life Sciences & Biomedicine; Psychiatry; ACTIVATION; GLUTAMATE; Neurosciences & Neurology; RESTING-STATE FMRI; MARKERS
• Research Categories: Biology, Molecular; Psychology, Clinical; Biology, Neuroscience

Abstract

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine. To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart). The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach. Data available both pre- and post-challenge (n = 31/40) established stability of rsFC across visits and determined CRP > 2 mg/L as a cut-point for patients exhibiting positive FC responses (post minus pre) to L-DOPA versus placebo (p < 0.01). Higher post-L-DOPA FC in patients with CRP > 2 mg/L was confirmed in all patients (n = 40) where rsFC data were available post-challenge (B = 0.15, p = 0.006), and in those with task-based (tb)FC during reward anticipation (B = 0.15, p = 0.013). While effort-based motivation outside the scanner positively correlated with rsFC independent of treatment or CRP, change in anhedonia scores negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r = -0.56, p = 0.012). FC in reward circuitry should be further validated in larger samples as a biomarker of target engagement for potential treatments including dopaminergic agents in MDD patients with increased inflammation.