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

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.

Conflict of interest statement

In the past 3 years, JCF has consulted for Otsuka and Health BioConsulting on topics unrelated to this work. MTT has served as a paid consultant to Blackthorn Therapeutics. MTT is a co-inventor of the EEfRT, which is discussed in this manuscript. Emory University and Vanderbilt University licensed this software to BlackThorn Therapeutics. Under the IP Policies of both universities, MTT receives licensing fees and royalties from BlackThorn Therapeutics. Additionally, MTT has a paid consulting relationship with BlackThorn. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies, and no funding from these entities was used to support the current work. The remaining authors declare no competing interests. All views expressed are solely those of the authors.

© 2022. The Authors.

Figures

Fig. 1. Study design and order of procedures.

Abbreviations: BOLD blood oxygen level dependent, EEfRT effort expenditure for rewards task, fMRI functional magnetic resonance imaging, FC functional connectivity, L-DOPA levodopa, MID monetary incentive delay, SHAPS Snaith-Hamilton Pleasure Scale, vmPFC ventromedial prefrontal cortex, VS ventral striatum.

Fig. 2. Depressed patients with plasma CRP > versus ≤ 2 mg/L had higher VS-vmPFC FC after L-DOPA with respect to placebo.

In patients with VS-vmPFC rsFC available both pre- and post-L-DOPA and placebo (n = 31), rsFC responses (post minus pre) across a range of plasma CRP concentrations revealed that only patients with CRP > 2 mg/L had mean (black bars) positive responses (FC change > 0) after L-DOPA but not placebo (a). The rsFC response to L-DOPA was significantly higher in patients with CRP > versus ≤ 2 mg/L when controlling for response to placebo (b). In the full sample with analyzable rsFC data after both L-DOPA and placebo (n = 40), VS-vmPFC rsFC after L-DOPA with respect to placebo was also higher in patients with CRP > versus ≤ 2 mg/L (c). Similar relationships were observed during reward anticipation in the MID whereby VS-vmPFC tbFC after gain versus neutral cues was higher after L-DOPA with respect to placebo in patients with CRP > 2 mg/L (d). Individual subject data over violin plots with median and IQR. Abbreviations: CRP C-reactive protein, FC functional connectivity, L-DOPA levodopa, rs resting-state, tb task-based, vmPFC ventromedial prefrontal cortex, VS ventral striatum, IQR interquartile range.

Fig. 3. Change in anhedonia scores negatively correlated with VS-vmPFC rsFC after L-DOPA challenge only in patients with CRP > 2 mg/L.

An interaction was observed for treatment and CRP level on the relationship between rsFC and change in anhedonia (SHAPS scores, post minus pre), whereby a decrease in anhedonia was correlated with VS-vmPFC rsFC after L-DOPA but only in patients with CRP > 2 mg/L. CRP C-reactive protein, FC functional connectivity, L-DOPA levodopa, SHAPS Snaith-Hamilton Pleasure Scale, rs resting state, vmPFC ventromedial prefrontal cortex, VS ventral striatum.