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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Background: Impaired emotion processing constitutes a key dimension of schizophrenia and a possible endophenotype of this illness. Empirical studies consistently report poorer emotion recognition performance in patients with schizophrenia as well as in individuals at enhanced risk of schizophrenia ("at risk"). fMRI studies also report consistent patterns of abnormal brain activation in response to emotional stimuli in patients, in particular decreased amygdala activation. In contrast, brain-level abnormalities in at-risk individuals are more elusive. We address this gap using an image-based meta-analysis of the fMRI literature. Methods: fMRI studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy controls were identified. Frequentist and Bayesian voxel-wise meta-analyses were performed separately, by implementing a random effect model with unthresholded group-level T-maps from individual studies as input. Results: Seventeen studies with a cumulative total of 677 at-risk individuals and 805 healthy controls were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy controls. These results were replicated with Bayesian analyses, providing strong evidence for the absence of meaningful brain activation differences across the entire brain. Region of interest analyses specifically focusing on the amygdala confirmed the lack of group differences in this region. Conclusions: These results suggest that brain activation patterns in response to emotional stimuli are unlikely to constitute a reliable endophenotype of schizophrenia. We suggest that future studies rather focus on impaired functional connectivity as an alternative and promising endophenotype.

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Background Behavioural findings suggest that the emotion processing abnormalities typically observed in established schizophrenia are already present in patients with a first episode of psychosis (FEP). Evidence has been less consistent in people at clinical high risk for psychosis (CHRp). While several studies have reported unaltered behavioural performance on emotion identification in people at CHRp compared to healthy controls, some studies have shown poorer negative emotion recognition. A growing number of functional magnetic resonance (fMRI) studies have investigated brain response to emotion processing to elucidate the mechanisms underlying these processes in FEP patients and CHRp individuals. Despite the marked expansion of this field over the last two decades, to date, no systematic review or meta-analysis has attempted to synthesise the evidence on the neural bases of emotion processing in these groups as potential markers of psychosis vulnerability and expression. Methods The PubMed and Ovid MEDLINE databases were searched for published English-language articles applying an emotion processing task during fMRI in a FEP and/or a CHRp sample compared to healthy controls. References of included papers were also screened. For CHRp studies, only those including participants by the basic or attenuated symptom presentation criteria were included. Individual study methodology and results were extracted and systematically reviewed. In addition, at present, statistical parametric mapping contrast maps (‘T-maps’) are being collected from study authors and will be meta-analysed using the Seed-based d Mapping method. The contrasts meta-analysed will be the ones most commonly reported in the studies identified, i.e., of all emotion over comparison conditions and of negative emotion over neutral conditions. These will be meta-analysed separately, as behavioural evidence suggests that emotion recognition performance in these populations might be valence specific. Results For the systematic review, 4,389 papers were identified through the search. 19 relevant fMRI papers were identified and their references were screened. 17 articles were included after full-text screening. Six out of twelve fMRI studies in the FEP population reported lower brain activation to emotion processing tasks compared to healthy controls. Four articles reported region-specific hyper- and hypoactivations and two studies found no significant difference. Of the seven studies in the CHRp population, one study reported lower brain response to emotion relative to healthy controls, two studies found hyperactivations, one study found region-specific increases and decreases, and two studies reported no significant difference. The most consistent finding across studies was lower amygdala activation in FEP participants (n=6). Conversely, in the CHRp population one article found an increase in amygdala response to emotion with age, consistently with one other article but contrasting with another study showing activity decreases in this region. Discussion To our knowledge, no previous systematic review or meta-analysis has synthesised the fMRI findings of emotion processing in both people at CHRp and a FEP. The present systematic review shows that while more consistent hypoactivations are found in the FEP population, results are less consistent in CHRp studies. The undergoing meta-analysis will quantitatively synthesise these findings. Elucidating the nature of emotion processing aberrances in early psychosis may help understand the functional changes across both vulnerability and symptom emergence phases and inform molecular investigations into its underlying mechanisms.

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