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. ### Competing Interest Statement ETB serves on the advisory board of Sosei Heptares and as a consultant for GlaxoSmithKline. All other authors declare no competing interests. ### Funding Statement This study was funded by an award from the Wellcome Trust (grant number: 104025/Z/14/Z) for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA) Consortium in partnership with Janssen, GlaxoSmithKline, Lundbeck and Pfizer. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The national research ethics service (NRES) committee of East of England, Cambridge Central, University of Cambridge gave ethical approval for this work. All procedures were approved by an independent national research ethics service (NRES) committee (NRES: East of England, Cambridge Central, UK; Reference: 15/EE/0092) and all participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study will be made available upon reasonable request to the authors following peer-reviewed publication.