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Fetal growth restriction (FGR) is associated with long-term neurodevelopmental disabilities including learning and behavioral disorders, autism, and cerebral palsy. Persistent changes in brain structure and function that are associated with developmental disabilities are demonstrated in FGR neonates. However, the mechanisms underlying these changes remain to be determined. There are currently no therapeutic interventions available to protect the FGR newborn brain. With the wide range of long-term neurodevelopmental disorders associated with FGR, the use of an animal model appropriate to investigating mechanisms of injury in the FGR newborn is crucial for the development of effective and targeted therapies for babies. Piglets are ideal animals to explore how perinatal insults affect brain structure and function. FGR occurs spontaneously in the piglet, unlike other animal models that require surgical or chemical intervention, allowing brain outcomes to be studied without the confounding impacts of experimental interventions. The FGR piglet mimics many of the human pathophysiological outcomes associated with FGR including asymmetrical growth restriction with brain sparing. This review will discuss the similarities observed in brain outcomes between the FGR human and FGR piglet from a magnetic resonance imaging in the living and a histological perspective. FGR piglet studies provide the opportunity to determine and track mechanisms of brain injury in a clinically relevant animal model of FGR. Findings from these FGR piglet studies may provide critical information to rapidly translate neuroprotective interventions to clinic to improve outcomes for newborn babies.

Umbilical cord blood cells have therapeutic potential for neurological disorders, through a paracrine mechanism of action. A greater understanding of the safety and immunological effects of allogeneic donor cord blood cells in the context of a healthy recipient immune system, such as in cerebral palsy, is needed. This study aimed to determine how quickly donor cord blood cells were cleared from the circulation in children with cerebral palsy who received a single intravenous infusion of 12/12 human leucocyte antigen (HLA) matched sibling cord blood cells. Twelve participants with cerebral palsy aged 2-12 years received cord blood cell infusions as part of a phase I trial of umbilical blood infusion for cerebral palsy. Digital droplet PCR analysis of DNA copy number variants specific to donor and recipient was used to assess donor DNA clearance at five timepoints post infusion, a surrogate measure of cell clearance. Donor cells were cleared from 3 months post-infusion in 11/12 participants. When detected, donor DNA was at a fraction of 0.01 - 0.31% of total DNA with no signs of graft-versus-host disease (GvHD) in any participant. The donor DNA clearance times provided by this study have important implications for understanding safety of allogeneic cord blood cell infusion for cerebral palsy and translational tissue engineering or regenerative medicine research in other disorders.

Background and Objective: The mechanism of reported benefits of delayed cord clamping (DCC) are unclear. We aimed to determine whether DCC compared to immediate cord clamping (ICC) in very preterm infants improves cerebral oxygenation in the first 24 h. Study Design: This is a prospective study of a subset of infants at < 30 weeks of gestation who were randomised to DCC (≥60 s) or ICC (< 10 s) and required an indwelling arterial catheter. Regional cerebral oxygenation (rScO2), blood pressure, PI, and peripheral saturation were measured and cerebral fractional tissue oxygen extraction (cFTOE) calculated for the following 3 time intervals: 3–6, 6–12, and 12–28 h of age. Functional ultrasound measures including superior vena cava flow, right ventricular output, ductus arteriosus size and shunt and anterior cerebral artery resistive index were determined. Results: The mean (±SD) gestation and birth weight of the 51 study infants were 27 ± 1 weeks and 1,046 ± 241 g respectively. Twenty infants received DCC and 31 received ICC. Baseline demographics were similar between the 2 groups. Comparing DCC and ICC infants, there was no difference in rScO2 or cFTOE at any time point. Three out of 20 infants did not receive DCC due to clinical concerns. A sensitivity analysis revealed that cord clamping ≥30 s was significantly associated with increased rScO2 and decreased cFTOE at all 3 time points after adjusting for gestation. Conclusion: Although DCC was not associated with changes in cerebral oxygenation overall, sensitivity analysis suggested a possible effect of an increased rScO2 and a decreased cFTOE with ≥30 s of DCC.

GABA is a major neurotransmitter in the mammalian brain. In the mature brain GABA exerts inhibitory actions via the GABAA receptor (GABAAR); however, in the immature brain GABA provides much of the excitatory drive. We examined the expression of 3 predominant GABAA α-subunit proteins in the pig brain at various pre- and postnatal ages. Brain tissue was collected from piglets born via caesarean section at preterm ages 91, 97, 100, and 104 days' gestational age (GA), at term equivalent (114 days' GA, caesarean section) and at term, postnatal day 0 (P0) (spontaneous delivery, term = 115 days). Tissue was obtained from piglets at P4 and P7. Adult tissue from sows was collected postmortem after caesarean section. In all cortical regions and basal ganglia (1) α3 exhibited a significant increase in protein expression at 100 days' GA, (2) α3 expression decreased with age after 100 days' GA, (3) α1 increased with age, with peak expression at P7 in cortices, hippocampus, and thalamus, and (4) α2 protein expression remained relatively constant across the ages examined. The subunit expression of α3 was most abundant at preterm ages, with α1 the predominant subunit expressed postnatally. Immunofluorescent labelling revealed α1 expression on the somatic membranes of pyramidal cells in the cortex and hippocampus, and in the cerebellar Purkinje cells. Positive α3 labelling was apparent on interneurones in the cortex and hippocampus. The switch between dominant α-subunits may coincide with the functional change in GABAergic neurotransmission from excitation to inhibition. Brain growth in the pig closely reflects that in the term human, making the pig a valuable non-primate model for studying development and the effects of insults on the perinatal brain.

The principal function of the γ-aminobutyric acid (GABA) system in the adult brain is inhibition; however, in the neonatal brain, GABA provides much of the excitatory drive. As the brain develops, transmembrane chloride gradients change and the inhibitory role of GABA is initiated and continues throughout juvenile and adult life. Previous studies have shown that GABAA receptor subunit expression is developmentally regulated, and it is thought that the change in GABA function from excitation to inhibition corresponds to the changeover in expression of ‘immature’ to ‘mature’ subunit isoforms. We examined the protein expression pattern and distribution of GABA type A (GABAA) receptor α1-, α3- and β2-subunits in the parietal cortex and hippocampus of the developing piglet brain. Four perinatal ages were studied; 14 days preterm (P–14), 10 days preterm (P–10), day of birth (P0) and at postnatal day 7 (P7). Animals were obtained by either caesarean section or spontaneous birth. Protein expression levels and subunit localization were analysed by Western blotting and immunohistochemistry, respectively. In the cortex and hippocampus, GABAA receptor α1-subunit showed greatest expression at P7 when compared to all other age groups (p < 0.05). In contrast, α3 expression in the cortex was elevated in preterm brain, peaking at P0, followed by a significant reduction by P7 (p < 0.05); a similar trend was observed in the hippocampus. GABAA receptor β2-subunit protein expression appeared relatively constant across all time points studied in both the cortex and hippocampus. Immunolabelling of the α1-, α3- and β2-subunits was observed throughout all cortical layers at every age. GABAA receptor α3-subunit appeared to show specific localization to layers V and VI whilst labelling for the β2-subunit was observed in layer IV. In the hippocampus of all animals, the α1- and β2-subunits were shown to immunolabel various cells and processes in the dentate gyrus (DG), CA1 and CA3; the α3-subunit was barely observed except at the stratum moleculare of the DG. We report for the first time the ontogenesis of GABAA receptor subunits α1, α3 and β2 in the perinatal pig brain.

Background: Very preterm neonates can have severe lung disease and are prone to brain injury if cerebral blood flow fluctuates. Partial liquid ventilation (PLV) may benefit the lung disease, but it is unknown whether the administration of intratracheal perfluorocarbon when starting PLV affects haemodynamics or cerebral blood flow. Objectives: To determine if haemodynamics or cerebral blood flow are affected in preterm lambs receiving a dose of perfluorocarbon when starting PLV. Methods: Sixteen preterm lambs were randomised to either PLV or conventional mechanical ventilation. An intratracheal loading dose of 30 ml/kg of perfluorocarbon liquid (PLV group) or air (sham group) was instilled over 20 min. Data were collected continuously for 30 min from the start of dosing. Results: Cortical cerebral blood flow velocity, measured continuously with laser Doppler, was increased in the PLV group during the administration of perfluorocarbon and immediately thereafter (p = 0.0026); the highest mean increase in the PLV group was 27%. There was no difference in cortical cerebral blood flow variability (p = 0.96). There was a slightly lower mean arterial blood pressure in the PLV group; the heart rate did not differ between groups. The PaCO2 was higher in the PLV group at 30 min – the difference between groups was not statistically significant (difference between means = 5.5 mm Hg, 95% confidence interval –2.7 to 13.7). Conclusions: Preterm lambs receiving a dose of tracheal perfluorocarbon at the start of PLV have an increased cortical cerebral blood flow velocity, but no change in cortical cerebral blood flow variability.