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 ( 1 H-MRS) to measure GABA and glutamate are not routinely available for this vulnerable population due to logistical and technical challenges. We review the specialized 1 H-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.

Regional Differences in Gamma-Aminobutyric Acid and Glutamate Concentrations in the Healthy Newborn Brain

“…Post hoc ROI tests were conducted using contrasts. Potential confounding from clinical variables with previously reported (sex) 7 or biologically plausible (mode of delivery) 11 associations with brain metabolites or neonatal outcomes was examined. Separate mixed-regression models were used to investigate the influence of PMA (model 1, adjusted for sex and mode of delivery) and postnatal age (model 2, adjusted for gestational age, sex, and mode of delivery) on metabolites on the day of MR imaging.…”

“…Our data meet the quality parameters recommended in recent expert consensus statements, 24,26,27 though one-fifth of the spectra had to be excluded due to motion or low SNR, inherent challenges with neonatal acquisitions. 11 Regional differences in 1 H-MR spectroscopy acquisition parameters like voxel size and SNR (Online Supplemental Data) may also influence these measurements, though if contributing, they would affect all metabolite measurements and would be nullified for metabolite ratios. The metabolite concentrations are expressed in international units due to their dependence on acquisition parameters and are not generalizable in terms of absolute concentrations across studies using different parameters.…”

“…lower SNR from a limited voxel volume in the small neonatal brain, to name a few. [7][8][9][10][11] Important knowledge gaps remain in our understanding of the normal temporal trajectory of in vivo GABA and glutamate concentrations during the critical perinatal transition and early postnatal maturation, which, in turn, limit the ability to detect abnormalities following premature birth. 11 Animal and adult human studies have characterized the temporal trajectories of brain metabolites, their regional and sex-based variations, and the influence of mode of delivery; early postnatal studies, however, are currently limited.…”

“…[7][8][9][10][11] Important knowledge gaps remain in our understanding of the normal temporal trajectory of in vivo GABA and glutamate concentrations during the critical perinatal transition and early postnatal maturation, which, in turn, limit the ability to detect abnormalities following premature birth. 11 Animal and adult human studies have characterized the temporal trajectories of brain metabolites, their regional and sex-based variations, and the influence of mode of delivery; early postnatal studies, however, are currently limited. [12][13][14][15][16] Conventional neonatal 1 H-MR spectroscopy allows measurement of NAA and Cr (markers of neuronal integrity and metabolic activity), Cho (lipid membrane component), and mIns (cytoplasmic osmotic agent).…”

GABAB Receptor-Mediated Impairment of Intermediate Progenitor Maturation During Postnatal Hippocampal Neurogenesis of Newborn Rats

“…In line with this, GABAergic transmission changes from excitatory to inhibitory also during the end of the first postnatal week (Rivera et al, 1999;Khirug et al, 2005). Neurobehavioral disorders, including autism, are more common in survivors of preterm birth and have been associated with decreased GABA concentrations, underscoring the importance of in vivo examination of GABA changes during early postnatal life in preterm infants (Ream and Lehwald, 2018;Basu et al, 2021). Peerboom and Wierenga (2021) postulated that the postnatal shift from depolarizing to hyperpolarizing GABA is a pivotal event in brain development and its timing affects brain function throughout life.…”