Salience network glutamate and brain connectivity in medication-naïve first episode patients - A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study

Jose O Maximo, Frederic Briend, William P Armstrong, Nina V Kraguljac, Adrienne C Lahti, Jose O Maximo, Frederic Briend, William P Armstrong, Nina V Kraguljac, Adrienne C Lahti

Abstract

Background: Salience network (SN) connectivity is altered in schizophrenia, but the pathophysiological origin remains poorly understood. The goal of this multimodal neuroimaging study was to investigate the role of glutamatergic metabolism as putative mechanism underlying SN dysconnectivity in first episode psychosis (FEP) subjects.

Methods: We measured glutamate + glutamine (Glx) in the dorsal anterior cingulate cortex (dACC) from 70 antipsychotic-naïve FEP subjects and 52 healthy controls (HC). The dACC was then used as seed to define positive and negative resting state functional connectivity (FC) of the SN. We used multiple regression analyses to test main effects and group interactions of Glx and FC associations.

Results: dACC Glx levels did not differ between groups. Positive FC was significantly reduced in FEP compared to HC, and no group differences were found in negative FC. Group interactions of Glx-FC associations were found within the SN for positive FC, and in parietal cortices for negative FC. In HC, higher Glx levels predicted greater positive FC in the dACC and insula, and greater negative FC of the lateral parietal cortex. These relationships were weaker or absent in FEP.

Conclusions: Here, we found that positive FC in the SN is already altered in medication-naïve FEP, underscoring the importance of considering both correlations and anticorrelations for characterization of pathology. Our data demonstrate that Glx and functional connectivity work differently in FEP than in HC, pointing to a possible mechanism underlying dysconnectivity in psychosis.

Trial registration: ClinicalTrials.gov NCT03442101 NCT02034253.

Keywords: Brain network; Dorsal anterior cingulate; First episode psychosis; Functional connectivity; Glutamate; Medication-naïve.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
A) Example voxel placement in the dorsal anterior cingulate cortex in one subject and its spectrum. The black line is a collected spectrum and the blue line is a model fit; B) Boxplot of Glx levels in antipsychotic-naïve FEP compared to HC. Each dot corresponds to one participant. The red line indicates the mean dACC Glx level for each group. HC, healthy controls; FEP, first episode psychosis; Cr, creatine; Cho, choline; Glx, glutamate + glutamine; NAA, N-acetyl aspartate; dACC, dorsal anterior cingulate cortex; and I.U., institutional unit. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
A) Clusters of significant group differences in positive FC which indicate HC > FEP. Boxplot of FC where each dot corresponds to one participant. The red line indicates the mean FC value for each group. Clusters of significant group differences were combined and FC was extracted for data visualization purposes on the scatterplot below. All analyses were TFCE corrected. HC, healthy controls; FEP, first episode psychosis; FC, functional connectivity; dACC, dorsal anterior cingulate cortex. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
A) Clusters where main effects and interaction between Glx and FC in the SN mask were found; B) clusters where main effects and interaction between Glx and FC in the SN anticorrelation mask were found. Clusters of group interactions in Glx-FC associations were combined and FC was extracted for data scatterplot visualization purposes. All analyses were TFCE corrected. HC, healthy controls; FEP, first episode psychosis; FC, functional connectivity; dACC, dorsal anterior cingulate cortex; Glx, glutamate + glutamine; TFCE, threshold-free cluster enhancement; and I.U., institutional unit.

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