Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia

Abstract

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = −0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = −0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

Clenbuterol Attenuates Immune Reaction to Lipopolysaccharide and Its Relationship to Anhedonia in Adolescents

“…Additionally, this finding fits our prior research reporting relationships between levels of various inflammatory mediators in the blood and anhedonia, as well as their associations with brain function during a reward fMRI task (6,(18)(19)(20). Complementing our works focusing on adolescence, others have shown a correlation between an LPS-induced immune cluster and anticipatory anhedonia, indexed by TEPS-A and a reward fMRI task, in adults (84). The varied cytokines contributing to different immune factors linked to anhedonia across studies is expected from the data-driven nature of factor analyses.…”

“…While anticipatory and consummatory anhedonia quantified with clinical self-reports might share quite some variance, our study supported their divergent immunological correlates across various experimental conditions. Perhaps the distinction between anhedonia subcomponents is more apparent biologically, as suggested by works from our group and others (18,84,90).…”

“…While anticipatory and consummatory anhedonia quantified with clinical self-reports might share some variance, our study supported their divergent immunological correlates across various experimental conditions. Perhaps the distinction between anhedonia sub-components is more apparent biologically, as suggested by works from our group and others [18, 85, 91]. While the effects of β 2 -agonism on hematopoietic growth factors remains mostly undiscerned, CBL might enhance these analytes to act in a compensatory manner, leading to an overall immunosuppressive effect.…”

“…The lack of overlap between immune biomarkers associated with anhedonia in this work and those in our prior work is most likely due to differences in sample size and anhedonia measure (TEPS vs SHAPS). Complementing our works focusing on adolescence, others have shown a correlation between an LPS-induced immune cluster and anticipatory anhedonia, indexed by TEPS-A and a reward fMRI task, in adults [85]. The varied analytes contributing to different immune factors linked to anhedonia across studies is expected from the data-driven nature of factor analyses.…”

Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen

“…Regarding the mechanisms by which inflammation affects the brain, much attention has been paid to the impact of inflammation on neurotransmitter systems and neurocircuits that regulate motivation and motor activity as well as anxiety, arousal, and alarm. Neuroimaging studies examining the impact of inflammation on neurocircuits have largely focused on subjects administered inflammatory stimuli ( Harrison et al, 2009 , 2015 , 2016 ; Eisenberger et al, 2010 ; Capuron et al, 2005 , 2012 ), but increasing data from our group and others have demonstrated that endogenous inflammation in MD (often indexed by blood concentrations of CRP) is also associated with alterations in activity of and functional connectivity (FC) within reward and motor circuits as well as circuits involving threat sensitivity that are in turn related to symptoms of anhedonia, psychomotor retardation and anxiety ( Burrows et al, 2021 ; Felger et al, 2016 ; Mehta et al, 2018 ; Rengasamy et al, 2021 ; Savitz et al, 2013 ; Yin et al, 2019 ; Costi et al, 2021 ). A wealth of evidence from clinical and laboratory animal studies supports the idea that relationships between elevated inflammatory markers and deficits in these neurocircuits are driven by the impact of circulating inflammatory cytokines and peripheral blood immune cells on the brain to reduce availability and release of monoamines, notably dopamine, and increase synaptic and extrasynaptic glutamate in the anterior cingulate cortex and basal ganglia nuclei ( Felger and Treadway, 2017 ; Felger et al, 2013a , 2013b , 2015 ; Yohn et al, 2016 ; Kitagami et al, 2003 ; Haroon et al, 2014 , 2016 , 2018b ; Walker et al, 2013 ; Dantzer and Walker, 2014 ).…”