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GABA and glutamate in the preterm neonatal brain: In-vivo measurement by magnetic resonance spectroscopy.

ABSTRACT: Cognitive and behavioral disabilities in preterm infants, even without obvious brain injury on conventional neuroimaging, underscores a critical need to identify the subtle underlying microstructural and biochemical derangements. The gamma-aminobutyric acid (GABA) and glutamatergic neurotransmitter systems undergo rapid maturation during the crucial late gestation and early postnatal life, and are at-risk of disruption after preterm birth. Animal and human autopsy studies provide the bulk of current understanding since non-invasive specialized proton magnetic resonance spectroscopy (¹H-MRS) to measure GABA and glutamate are not routinely available for this vulnerable population due to logistical and technical challenges. We review the specialized ¹H-MRS techniques including MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS), special challenges and considerations needed for interpretation of acquired data from the developing brain of preterm infants. We summarize the limited in-vivo preterm data, highlight the gaps in knowledge, and discuss future directions for optimal integration of available in-vivo approaches to understand the influence of GABA and glutamate on neurodevelopmental outcomes after preterm birth.

SUBMITTER: Basu SK

PROVIDER: S-EPMC8404144 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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GABA and glutamate in the preterm neonatal brain: In-vivo measurement by magnetic resonance spectroscopy.

Basu Sudeepta K SK Pradhan Subechhya S du Plessis Adre J AJ Ben-Ari Yehezkel Y Limperopoulos Catherine C

NeuroImage 20210528

Cognitive and behavioral disabilities in preterm infants, even without obvious brain injury on conventional neuroimaging, underscores a critical need to identify the subtle underlying microstructural and biochemical derangements. The gamma-aminobutyric acid (GABA) and glutamatergic neurotransmitter systems undergo rapid maturation during the crucial late gestation and early postnatal life, and are at-risk of disruption after preterm birth. Animal and human autopsy studies provide the bulk of cur ...[more]

PMID: 34058332

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Project description:Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder. Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T. The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites. Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

Project description:IntroductionConverging evidence suggests that ketamine elicits antidepressant effects via enhanced neuroplasticity precipitated by a surge of glutamate and modulation of GABA. Magnetic resonance spectroscopic imaging (MRSI) illustrates changes to cerebral glutamate and GABA immediately following ketamine administration during dissociation. However, few studies assess subacute changes in the first hours following application, when ketamine's antidepressant effects emerge. Moreover, ketamine metabolites implicated in its antidepressant effects develop during this timeframe. Thus, this study aimed to investigate subacute changes in cerebral Glx (glutamate + glutamine), GABA and their ratio in seven brain regions central to depressive pathophysiology and treatment.MethodsTwenty-five healthy subjects underwent two multivoxel MRS scans using a spiral encoded, MEGA-edited LASER-localized 3D-MRSI sequence, at baseline and 2 h following intravenous administration of racemic ketamine (0.8 mg/kg bodyweight over 50 min). Ketamine, norketamine and dehydronorketamine plasma levels were determined at routine intervals during and after infusion. Automated region-of-interest (ROI)-based quantification of mean metabolite concentration was used to assess changes in GABA+/total creatine (tCr), Glx/tCr, and GABA+/Glx ratios in the thalamus, hippocampus, insula, putamen, rostral anterior cingulate cortex (ACC), caudal ACC, and posterior cingulate cortex. Effects of ketamine on neurotransmitter levels and association with ketamine- and metabolite plasma levels were tested with repeated measures analyses of variance (rmANOVA) and correlation analyses, respectively.ResultsFor GABA+/tCr rmANOVA revealed a measurement by region interaction effect (puncorr < 0.001) and post hoc pairwise comparisons showed a reduction in hippocampal GABA+/tCr after ketamine (pcorr = 0.02). For Glx/tCr and GABA+/Glx neither main effects of measurement nor measurement by region interactions were observed (all puncorr > 0.05). Furthermore, no statistically significant associations between changes in any of the neurotransmitter ratios and plasma levels of ketamine, norketamine, or dehydronorketamine were observed (pcorr > 0.05).ConclusionThis study provides evidence for decreased hippocampal GABA+/tCr ratio 2 h following ketamine administration. As MRS methodology measures total levels of intra- and extracellular GABA, results might indicate drug induced alterations in GABA turnover. Our study in healthy humans suggests that changes in GABA levels, particularly in the hippocampus, should be further assessed for their relevance to ketamine´s antidepressant effects.

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Dataset Information

GABA and glutamate in the preterm neonatal brain: In-vivo measurement by magnetic resonance spectroscopy.

Publications

GABA and glutamate in the preterm neonatal brain: In-vivo measurement by magnetic resonance spectroscopy.

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