Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia

• Type of Material: Article
• Authors: Ebrahim Haroon, Emory University; Xiangchuan Chen, Emory University; Zhihao Li, Emory University; Trusharth Patel, Emory University; Bobbi J. Woolwine, Emory University; Xiaoping P Hu, Emory University; Jennifer Felger, Emory University; Andrew H Miller, Emory University
• Language: English
• Date: 2018-09-10
• Publisher: Springer Nature [academic journals on nature.com]: Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41398-018-0241-4
• Title of Journal or Parent Work: Translational Psychiatry
• ISSN: 2158-3188
• Volume: 8
• Issue: 1
• Start Page: 189
• End Page: 189
• Grant/Funding Information: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.; This work was supported in part by funding from a Shared Instrumentation Grant (S10) grant 1S10OD016413–01 to the Emory University Center for Systems Imaging Core.; In addition, the study was supported in part by PHS Grants UL1TR000454 and KL2TR000455 from the Clinical and Translational Science Award program, and by the NIH/NCI under award number P30CA138292.; This study was supported by grants R01MH H107033 & K23MH091254 (Dr. Haroon), R01MH112076 (Drs. Haroon & Miller), R01MH087604, R25MH101079 (Dr. Miller), and R01MH109637 (Dr. Felger) from the National Institute of Mental Health.
• Keywords: Science & Technology; MAJOR DEPRESSION; BASAL GANGLIA GLUTAMATE; RESTING-STATE FMRI; Psychiatry; QUICK INVENTORY; FUNCTIONAL CONNECTIVITY; DYSFUNCTION; PSYCHOMETRIC EVALUATION; SYSTEM X(C)(-); BIPOLAR DISORDER; Life Sciences & Biomedicine; REPORT QIDS-SR
• Research Categories: Psychology, Physiological

Abstract

Combined increases in peripheral inflammation and brain glutamate may identify a subtype of depression with distinct neuroimaging signatures. Two contrasting subgroups of depressed subjects—with and without combined elevations in plasma C-reactive protein (CRP) and basal ganglia glutamate (high and low CRP-Glu, respectively) were identified by hierarchical clustering using plasma CRP (indexing peripheral inflammation) and magnetic resonance spectroscopy (MRS)-based measurement of left basal ganglia glutamate. High CRP-Glu group status was associated with greater severity of anhedonia and cognitive and motor slowing. Local- and network-level measures of functional integrity were determined using brain oxygen level-dependent (BOLD)-oscillatory activity and graph theory. Greater decreases in concordance of oscillatory activity between neighboring voxels (Regional Homogeneity ‘ReHo’, p < 0.01) within the MRS volume-of-interest was associated with the High CRP-Glu subgroup. Using brain-wide, CRP-Glu ReHo contrast maps, a covariance network of 41 regions-of-interest (ROIs) with similar ReHo decreases was identified in the High CRP-Glu group and was located to brain structures previously implicated in depression. The 41-ROI network was further decomposed into four subnetworks. ReHo decreases within Subnetwork4—comprised of reward processing regions —was associated with anhedonia. Subnetwork4 ReHo also predicted decreased network integrity, which mediated the link between local ReHo and anhedonia in the Low but not High CRP-Glu group. These findings suggest that decreased ReHo and related disruptions in network integrity may reflect toxic effects of inflammation-induced increases in extrasynaptic glutamate signaling. Moreover, local BOLD oscillatory activity as reflected in ReHo might be a useful measure of target-engagement in the brain for treatment of inflammation-induced behaviors.