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.

Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABA A receptor (GABA A R) α subunits, including α5GABA A R. Positron emission tomography (PET) measures of GABA A R availability in schizophrenia, however, have not revealed consistent alterations in vivo . Animal studies using the GABA A R agonist [ 3 H]-muscimol provide evidence that antipsychotic drugs influence GABA A R availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABA A R radioligands. To address this, we combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed postmortem using the GABA A R subunit-selective radioligand [ 3 H]-Ro15-4513 and the non-subunit selective radioligand [ 3 H]-flumazenil. Chronic haloperidol exposure increased [ 3 H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus ( p <0.01; q <0.01; d =+1.3), which was not dose-dependent. [ 3 H]-flumazenil binding also increased in most rat brain regions ( p <0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABA A R radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABA A R-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABA A R in the context of schizophrenia.

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5GABAA receptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.

Data from post-mortem studies suggest that schizophrenia is associated with abnormal expression of GABAA receptor (GABAAR) a subunits including a5GABAA. Positron emission tomography (PET) measures of GABAAR binding in schizophrenic patients, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [ 3 H]muscimol have provided evidence that antipsychotic drugs used in schizophrenia can influence GABAAR binding, in a region-specific manner, complicating the interpretation of the PET GABA signal in medicated patients. No binding data, however, are available for more subunit-selective ligands. To address this, we combined a rodent model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or vehicle were continuously administered to adult male Sprague-Dawley rats via osmotic pumps to maintain a clinically relevant, steady-state levels of drug exposure for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAA selective radioligand [ 3 H]Ro15-4513 and the non-subunit selective radioligand [ 3 H]flumazenil. Chronic haloperidol exposure increased [ 3 H]Ro15-4513 binding in the CA1 sub-field of the dorsal hippocampus (p<0.01; q<0.01). [ 3 H]flumazenil binding was also increased in most of the explored regions (p<0.05), independently of the dose of haloperidol used. This is the first study to demonstrate a region/dose-specific effect of haloperidol on [ 3 H]Ro15-4513 binding.Although caution needs to be exerted when extrapolating results from animals to patients, collectively these data confirm previous findings that antipsychotic treatment contributes to the heterogeneity observed in PET studies of GABAAR in schizophrenic patients, specifically at the a1/5GABAAR.