GABA, glutamate and neural activity: a systematic review with meta-analysis of multimodal 1H-MRS-fMRI studies

TY - JOUR

T1 - GABA, glutamate and neural activity: a systematic review with meta-analysis of multimodal 1H-MRS-fMRI studies

AU - Kiemes, Amanda

AU - Davies, Cathy

AU - Kempton, Matthew

AU - Lukow, Paulina

AU - Bennallick, Carly

AU - Stone, James M.

AU - Modinos, Gemma

N1 - Funding Information: This study was supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society to Dr. Gemma Modinos (202397/Z/16/Z). Publisher Copyright: © Copyright © 2021 Kiemes, Davies, Kempton, Lukow, Bennallick, Stone and Modinos. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/3/8

Y1 - 2021/3/8

N2 - 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.

AB - 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.

KW - Glutamate

KW - GABA

KW - Magnetic resonance spectroscopy (MRS)

KW - functional magnetic resonance imaging

KW - multimodal neuroimaging

UR - http://www.scopus.com/inward/record.url?scp=85102927153&partnerID=8YFLogxK

U2 - 10.3389/fpsyt.2021.644315

DO - 10.3389/fpsyt.2021.644315

M3 - Review article

SN - 1664-0640

VL - 12

JO - Frontiers in Psychiatry

JF - Frontiers in Psychiatry

M1 - 644315

ER -