Reward-related activation of fronto-striatal regions scaled negatively with C-reactive protein but showed no association with anhedonia in depression.

Depression is characterized by divergent changes in positive and negative affect. Emerging roles of inflammation in depression portend avenues for novel immunomodulator-based monotherapy, targeting mechanistically distinct symptoms such as anhedonia and pessimism. To investigate fundamental links between these divergent affective components and inflammation, we used a probabilistic reinforcement-learning fMRI paradigm, testing for evidence of hyposensitivity to reward, and hypersensitivity to punishment in low-inflammation depression cases (loCRP depression; CRP [≤] mg/L; N=48), high-inflammation depression cases (hiCRP depression; CRP > 3mg/L; N=31), and healthy controls (HC; CRP [≤] mg/L; N=45). We aimed to (i) determine whether depression cases with high and low inflammation showed aberrant neural activation to monetary gains and losses compared to controls; (ii) examine if these alterations correlated with a continuous measure of C-reactive protein (CRP) in depression, (iii) test if neuroimaging responses to rewards and punishments scaled with indices of anhedonia and pessimism derived from behavioral instruments in depression. Voxel-wise activation was observed in key brain regions sensitive to monetary reward (ventromedial prefrontal cortex, vmPFC; nucleus accumbens, NAc) and punishment (insula) outcomes across all three groups. However, there was no significant difference in activation between groups. Within depression cases, increasing CRP scaled negatively with activation in the right vmPFC and left NAc but not insula cortex. However, there was no significant association between regional activation and severity of anhedonia or pessimism. Our results support the previously reported association between CRP and striatal reward reactivity in depression but do not extend this to processing of negatively valenced information.