Reward Circuitry and Symptoms of Anhedonia as Modifiable Targets for Therapeutic Interventions in Depressed Patients with High Inflammation

Abstract

A significant portion of patients with depression exhibit increased inflammation, which has been associated with low functional connectivity (FC) in dopamine-modulated ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) reward circuitry in relation to symptoms of anhedonia. Evidence also suggests that inflammation may impact the availability and release of striatal dopamine, which can be reversed by the dopamine precursor levodopa (L-DOPA). We tested the hypothesis that VS-vmPFC FC, at rest and during reward anticipation (Monetary Incentive Delay Task), would be increased by L-DOPA/carbidopa (250/50 mg) versus placebo challenge (double-blind, randomized order ~1-week apart) in 40 medically-stable depressed outpatients with higher versus lower C-reactive protein (CRP). Differential VS-vmPFC FC (during rest and task) was observed in patients with increasing levels of inflammation whereby patients with plasma CRP>2 mg/L (n=19) exhibited a significant L-DOPA-related increase in FC compared to those with CRP≤2 mg/L (n=21, p<0.05). Change in resting FC also correlated with an inflammatory composite factor for cytokines and their soluble receptors (r=0.37, p<0.05). While effort-based motivation outside the scanner positively correlated with resting FC independent of treatment or CRP, change in anhedonia symptoms negatively correlated with FC after L-DOPA only in patients with CRP>2 mg/L (r=-0.56, p<0.05). These data suggest a role for dopamine in inflammation-related circuit deficits and symptoms of anhedonia in patients with high CRP. FC in reward circuitry may serve as a modifiable imaging biomarker for the efficacy of pharmacological and/or behavioral interventions to reverse the impact of inflammation on the brain in depression.