Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression |
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Affiliation: | 1. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, United States;2. Biomarker Core Laboratory, Foundation for Atlanta Veterans Education and Research, Atlanta VAHSC, Decatur, GA 30033, United States;3. School of Psychology, Shenzhen University, Shenzhen, Guangdong 518060, China;4. Center for Brain Disorders and Cognitive Neuroscience, Shenzhen University, Shenzhen, Guangdong 518060, China;5. The Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States;1. School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China;2. Shenzhen Key Laboratory of Functional Polymer, College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518060, China;3. Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China;1. Shenzhen Key Laboratory of Polymer Science and Technology, College of Materials Science and Engineering, Shenzhen University, Shenzhen 518060, China;2. CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, China;1. Shenzhen Key Laboratory of Polymer Science and Technology, College of Materials Science and Engineering, Shenzhen University, Shenzhen 518060, China;2. Department Chemistry, The University of Akron, Akron, OH 44325, USA;3. Department of Biology, The University of Akron, Akron, OH 44325, USA;4. Department of Chemical & Biomolecular Engineering, The University of Akron, Akron, OH 44325, USA;1. Functional Thin Films Research Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;2. College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060, China |
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Abstract: | Bidirectional relationships between inflammation and metabolic dysfunction may contribute to the pathophysiology of psychiatric illnesses like depression. Metabolic disturbances drive inflammation, which in turn exacerbate metabolic outcomes including insulin resistance. Both inflammatory (e.g. endotoxin, vaccination) and metabolic challenges (e.g. glucose ingestion) have been shown to affect activity and functional connectivity (FC) in brain regions that subserve reward and motor processing. We previously reported relationships between elevated concentrations of endogenous inflammatory markers including C-reactive protein (CRP) and low corticostriatal FC, which correlated with symptoms of anhedonia and motor slowing in major depression (MD). Herein, we examined whether similar relationships were observed between plasma markers related to glucose metabolism (non-fasting concentrations of glucose, insulin, leptin, adiponectin and resistin) in 42 medically-stable, unmedicated MD outpatients who underwent fMRI. A targeted, hypothesis-driven approach was used to assess FC between seeds in subdivisions of the ventral and dorsal striatum and a region in ventromedial prefrontal cortex (VS-vmPFC), which was previously found to correlate with both inflammation and symptoms of anhedonia and motor slowing. Associations between FC and gene expression signatures were also explored. A composite score of all 5 glucose-related markers (with increasing values reflecting higher concentrations) was negatively correlated with both ventral striatum (VS)-vmPFC (r = −0.33, p < 0.05) and dorsal caudal putamen (dcP)-vmPFC (r = −0.51, p < 0.01) FC, and remained significant after adjusting for covariates including body mass index (p < 0.05). Moreover, an interaction between the glucose-related composite score and CRP was observed for these relationships (F[2,33] = 4.3, p < 0.05) whereby significant correlations between the glucose-related metabolic markers and FC was found only in patients with high plasma CRP (>3 mg/L; r = −0.61 to −0.81, p < 0.05). Insulin and resistin were the individual markers most predictive of VS-vmPFC and dcP-mPFC FC, respectively, and insulin, resistin and CRP clustered together and in association with both LV-vmPFC and dcP-vmPFC in principal component analyses. Exploratory whole blood gene expression analyses also confirmed that gene probes negatively associated with FC were enriched for both inflammatory and metabolic pathways (FDR p < 0.05). These results provide preliminary evidence that inflammation and metabolic dysfunction contribute jointly to deficits in reward and motor circuits in MD. Future studies using fasting samples and longitudinal and interventional approaches are required to further elucidate the respective contributions of inflammation and metabolic dysfunction to circuits and symptoms relevant to motivation and motor activity, which may have treatment implications for patients with psychiatric illnesses like depression. |
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Keywords: | Glucose metabolism Inflammation Insulin C-reactive protein Functional connectivity fMRI Gene expression |
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