Multimodal neuroimaging studies combining proton magnetic resonance spectroscopy (1H-MRS) to quantify GABA and/or glutamate concentrations and functional magnetic resonance imaging (fMRI) to measure brain activity non-invasively have advanced understanding of how neurochemistry and neurophysiology may be related at a macroscopic level. The present study aimed to perform a systematic review and meta-analysis of available studies examining the relationship between 1H-MRS glutamate and/or GABA levels and task-related fMRI signal in the healthy brain. Ovid (Medline, Embase, and PsycINFO) and Pubmed databases were systematically searched to identify articles published until December 2019. The primary outcome of interest was the association between resting levels of glutamate or GABA and task-related fMRI. Fifty-five papers were identified for inclusion in the systematic review. A further 22 studies were entered into four separate meta-analyses. These meta-analyses found evidence of significant negative associations between local GABA levels and (a) fMRI activation to visual tasks in the occipital lobe, and (b) activation to emotion processing in the medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC). However, there was no significant association between mPFC/ACC glutamate levels and fMRI activation to cognitive control tasks or to emotional processing, with the relationship to emotion processing related neural activity narrowly missing significance. Moreover, our systematic review also found converging evidence of negative associations between GABA levels and local brain activity, and positive associations between glutamate levels and distal brain activity, outside of the 1H-MRS sampling region. Albeit less consistently, additional relationships between GABA levels and distal brain activity and between glutamate levels and local brain activity were found. It remains unclear if the absence of effects for other brain regions and other cognitive-emotional domains reflects study heterogeneity or potential confounding effects of age, sex, or other unknown factors. Advances in 1H-MRS methodology as well as in the integration of 1H-MRS readouts with other imaging modalities for indexing neural activity hold great potential to reveal key aspects of the pathophysiology of mental health disorders involving aberrant interactions between neurochemistry and neurophysiology such as schizophrenia.

Highlights The neural bases of altered emotion processing in psychosis are still unclear. Systematic review indicated widespread activation decreases to emotion in first-episode psychosis. Evidence in people at clinical high-risk for psychosis lacked convergence. These findings were corroborated by image-based meta-analyses.

Diverse GABAergic interneuron microcircuits orchestrate information processing in the brain. Understanding the cellular and molecular composition of these microcircuits, and whether these can be imaged by available non-invasive in vivo methods is crucial for the study of GABAergic neurotransmission in health and disease. Here, we use human gene expression data and state-of-the-art imaging transcriptomics to uncover co-expression patterns between GABAA receptor subunits and interneuron subtype-specific markers, and to decode the cellular and molecular signatures of gold-standard GABA PET radiotracers, [11C]Ro15-4513 and [11C]flumazenil. We find that the interneuron marker somatostatin is co-expressed with GABAA receptor-subunit genes GABRA5 and GABRA2, and their distribution maps onto [11C]Ro15-4513 binding in vivo. In contrast, the interneuron marker parvalbumin co-expressed with more predominant GABAA receptor subunits (GABRA1, GABRB2 and GABRG2), and their distribution tracks [11C]flumazenil binding in vivo. These results have important implications for the non-invasive study of GABAergic microcircuit dysfunction in psychiatric conditions.

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