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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.

Schizophrenia is often characterized by dysconnections in the brain, which can be estimated via functional connectivity analyses. Commonly measured using resting-state functional magnetic resonance imaging (fMRI) in order to characterize the intrinsic or baseline function of the brain, fMRI functional connectivity has significantly contributed to the understanding of schizophrenia. However, these measures may not capture the full extent of functional connectivity abnormalities in schizophrenia as fMRI is temporally limited by the hemodynamic response. In order to extend fMRI functional connectivity findings, the complementary modality of magnetoencephalography (MEG) can be utilized to capture electrophysiological functional connectivity abnormalities in schizophrenia that are not obtainable with fMRI. Therefore, we implemented a multimodal functional connectivity analysis using resting-state 7 Tesla fMRI and MEG data in a sample of first-episode patients with schizophrenia (n = 19) and healthy controls (n = 24). fMRI and MEG data were decomposed into components reflecting resting state networks using a group spatial independent component analysis. Functional connectivity between resting-state networks was computed and group differences were observed. In fMRI, patients demonstrated hyperconnectivity between subcortical and auditory networks, as well as hypoconnectivity between interhemispheric homotopic sensorimotor network components. In MEG, patients demonstrated hypoconnectivity between sensorimotor and task positive networks in the delta frequency band. Results not only support the dysconnectivity hypothesis of schizophrenia, but also suggest the importance of jointly examining multimodal neuroimaging data as critical disorder-related information may not be detectable in a single modality alone. Keywords: Functional connectivity, Functional magnetic resonance imaging, Magnetoencephalography, First-episode, Schizophrenia, Independent component analysis