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.
Highlights
Major depressive disorder (MDD) is a common, chronic and debilitating condition characterized by affective, cognitive, and behavioral symptoms [1, 2]
The current study investigated the relationship between inflammatory factors released by peripheral blood mononuclear cells (PBMC) stimulated ex vivo with LPS, anhedonia and neural reactivity to reward anticipation in depression
We found that depressed subjects showed an exaggerated response to the immune challenge with LPS compared to healthy control (HC)
Summary
Major depressive disorder (MDD) is a common, chronic and debilitating condition characterized by affective, cognitive, and behavioral symptoms [1, 2]. Recent work has connected peripheral immune dysfunction to brain systems that mediate key aspects of depression, such as reward processing [20, 21] Despite this evidence, the current data appears heterogenous and the precise nature of inflammatory dysregulation in the context of depression remains unclear. Subjects showing a decrease in vitro lymphocyte activity [24] Building on these data, the current study aimed to translate preclinical findings into humans by investigating a large panel of MRI acquisition, processing, and reward task (incentive flanker task) peripheral immune factors in subjects with depression from All MRI data were acquired with a Siemens 3T MAGNETOM Skyra scanner peripheral blood mononuclear cells (PBMC) stimulated ex vivo with LPS.
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