Glutamate connectivity associations converge upon the salience network in schizophrenia and healthy controls

Robert A Mccutcheon,Juan Bustillo,Maria Rogdaki,Oliver D Howes,Toby Pillinger

doi:10.1038/s41398-021-01455-y

Abstract

Alterations in cortical inter-areal functional connectivity, and aberrant glutamatergic signalling are implicated in the pathophysiology of schizophrenia but the relationship between the two is unclear. We used multimodal imaging to identify areas of convergence between the two systems. Two separate cohorts were examined, comprising 195 participants in total. All participants received resting state functional MRI to characterise functional brain networks and proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate concentrations in the frontal cortex. Study A investigated the relationship between frontal cortex glutamate concentrations and network connectivity in individuals with schizophrenia and healthy controls. Study B also used 1H-MRS, and scanned individuals with schizophrenia and healthy controls before and after a challenge with the glutamatergic modulator riluzole, to investigate the relationship between changes in glutamate concentrations and changes in network connectivity. In both studies the network based statistic was used to probe associations between glutamate and connectivity, and glutamate associated networks were then characterised in terms of their overlap with canonical functional networks. Study A involved 76 individuals with schizophrenia and 82 controls, and identified a functional network negatively associated with glutamate concentrations that was concentrated within the salience network (p < 0.05) and did not differ significantly between patients and controls (p > 0.85). Study B involved 19 individuals with schizophrenia and 17 controls and found that increases in glutamate concentrations induced by riluzole were linked to increases in connectivity localised to the salience network (p < 0.05), and the relationship did not differ between patients and controls (p > 0.4). Frontal cortex glutamate concentrations are associated with inter-areal functional connectivity of a network that localises to the salience network. Changes in network connectivity in response to glutamate modulation show an opposite effect compared to the relationship observed at baseline, which may complicate pharmacological attempts to simultaneously correct glutamatergic and connectivity aberrations.

Highlights

Dysfunction of glutamatergic signalling has been proposed as central to the pathophysiology of schizophrenia[1,2]
We investigated whether pharmacologically induced perturbations of glutamatergic signalling in individuals with schizophrenia and healthy controls was linked to perturbations of cortical connectivity, and whether this too localised to the salience network
Blue line in Fig. 3A consisting of connections most strongly associated with glutamate concentrations), we found that this was still disproportionately composed of edges located within the salience network, and this was statistically significant at a wide range of network based statistic (NBS) thresholds with no evidence of overrepresentation of any other network (p < 0.05 all thresholds, Fig. 3C, D)

Summary

Introduction

Dysfunction of glutamatergic signalling has been proposed as central to the pathophysiology of schizophrenia[1,2] This link has been made on the basis of animal work, post-mortem findings, and the fact that drugs which. McCutcheon et al Translational Psychiatry (2021)11:322 cortex, has in particular been suggested as a key mechanism underlying psychotic symptoms[6,7,8,9] It is unclear, whether glutamate signalling is related to the architecture of functional brain networks. Glutamatergic signalling contributes to the balance between excitation and inhibition, which generates synchronised neural oscillations[10,11] These oscillations in turn underlie slow fluctuations of neural activity, which are observable using rs-fMRI, and the co-activation patterns generate well characterised functional brain networks[12,13]. In keeping with this, altered connectivity of functional brain networks has been observed following the administration of drugs such as ketamine that affect glutamatergic signalling[14,15,16]

Methods

Results

Discussion

Conclusion