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Gamma-aminobutyric acid (GABA) and glutamate are principal neurotransmitters essential for late gestational brain development and may play an important role in prematurity-related brain injury. In vivo investigation of GABA in the preterm infant with standard proton magnetic resonance spectroscopy (1H-MRS) has been limited due to its low concentrations in the developing brain, and overlap in the spectrum by other dominant metabolites. We describe early postnatal profiles of in vivo GABA and glutamate concentrations in the developing preterm brain measured by using the J-difference editing technique, Mescher-Garwood point resolved spectroscopy. We prospectively enrolled very preterm infants born ≤32 weeks gestational age and non-sedated 1H-MRS (echo time 68 ms, relaxation time 2000 ms, 256 signal averages) was acquired on a 3 Tesla magnetic resonance imaging scanner from a right frontal lobe voxel. Concentrations of GABA + (with macromolecules) was measured from the J-difference spectra; whereas glutamate and composite glutamate + glutamine (Glx) were measured from the unedited (OFF) spectra and reported in institutional units. We acquired 42 reliable spectra from 38 preterm infants without structural brain injury [median gestational age at birth of 28.0 (IQR 26.0, 28.9) weeks; 19 males (50%)] at a median postmenstrual age of 38.4 (range 33.4 to 46.4) weeks. With advancing post-menstrual age, the concentrations of glutamate OFF increased significantly, adjusted for co-variates (generalized estimating equation β = 0.22, p = 0.02). Advancing postnatal weeks of life at the time of imaging positively correlated with GABA + (β = 0.06, p = 0.02), glutamate OFF (β = 0.11, p = 0.02) and Glx OFF (β = 0.12, p = 0.04). Male infants had higher GABA + (1.66 ± 0.07 vs. 1.33 ± 0.11, p = 0.01) concentrations compared with female infants. For the first time, we report the early ex-utero developmental profile of in vivo GABA and glutamate stratified by age and sex in the developing brain of very preterm infants. This data may provide novel insights into the pathophysiology of neurodevelopmental disabilities reported in preterm infants even in the absence of structural brain injury.

Premature babies are subjected to environmental stresses that can affect brain maturation and cause abnormal neurodevelopmental outcome later in life. Better understanding this link is crucial to developing a clinical tool for early outcome estimation. We defined maturational trajectories between the Electroencephalography (EEG)-derived ‘brain-age’ and postmenstrual age (the age since the last menstrual cycle of the mother) from longitudinal recordings during the baby’s stay in the Neonatal Intensive Care Unit. Data consisted of 224 recordings (65 patients) separated for normal and abnormal outcome at 9–24 months follow-up. Trajectory deviations were compared between outcome groups using the root mean squared error (RMSE) and maximum trajectory deviation (δmax). 113 features were extracted (per sleep state) to train a data-driven model that estimates brain-age, with the most prominent features identified as potential maturational and outcome-sensitive biomarkers. RMSE and δmax showed significant differences between outcome groups (cluster-based permutation test, p RMSE had a median (IQR) of 0.75 (0.60–1.35) weeks for normal outcome and 1.35 (1.15–1.55) for abnormal outcome, while δmax had a median of 0.90 (0.70–1.70) and 1.90 (1.20–2.90) weeks, respectively. Abnormal outcome trajectories were associated with clinically defined dysmature and disorganised EEG patterns, cementing the link between early maturational trajectories and neurodevelopmental outcome.

Scientific reports 10, 2373 (2020). doi:10.1038/s41598-020-58761-6, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Very preterm (VPT) infants are at high-risk for neurodevelopmental impairments, however there are few validated biomarkers at term-equivalent age that accurately measure abnormal brain development and predict future impairments. Our objectives were to quantify and contrast cortical features between full-term and VPT infants at term and to associate two key antecedent risk factors, bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), with cortical maturational changes in VPT infants. We prospectively enrolled a population-based cohort of 110 VPT infants (gestational age ≤31 weeks) and 51 healthy full-term infants (gestational age 38–42 weeks). Structural brain MRI was performed at term. 94 VPT infants and 46 full-term infants with high-quality T2-weighted MRI were analyzed. As compared to full-term infants, VPT infants exhibited significant global cortical maturational abnormalities, including reduced surface area (−5.9%) and gyrification (−6.7%) and increased curvature (5.9%). In multivariable regression controlled for important covariates, BPD was significantly negatively correlated with lobar and global cortical surface area and ROP was significantly negatively correlated with lobar and global sulcal depth in VPT infants. Our cohort of VPT infants exhibited widespread cortical maturation abnormalities by term-equivalent age that were in part anteceded by two of the most potent neonatal diseases, BPD and ROP.