Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis.

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, pFDR < 0.001) and across its subfields (all pFDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all pFDR < 0.001) was significantly reduced (t(69) = -5.1, pFDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, pFDR = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

Are Brain Responses to Emotion a Reliable Endophenotype of Schizophrenia? An Image-Based Functional Magnetic Resonance Imaging Meta-analysis.

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. Functional magnetic resonance imaging 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 functional magnetic resonance imaging literature. METHODS: Functional magnetic resonance imaging studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy control subjects were identified. Frequentist and Bayesian voxelwise meta-analyses were performed separately, by implementing a random-effect model with unthresholded group-level T-maps from individual studies as input. RESULTS: In total, 17 studies with a cumulative total of 677 at-risk individuals and 805 healthy control subjects were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy control subjects. Similar results were observed with Bayesian analyses, which provided 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 instead focus on impaired functional connectivity as an alternative and promising endophenotype.

GABA, Glutamate and Neural Activity: A Systematic Review With Meta-Analysis of Multimodal 1H-MRS-fMRI Studies.

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.