Cerebral white matter injury is a leading cause of adverse neurodevelopmental outcome in prematurely born infants involving cognitive deficits in later life. Despite increasing knowledge about the pathophysiology of perinatal brain injury, therapeutic options are limited. In the adult demyelinating disease multiple sclerosis the sphingosine-1-phosphate (S1P) receptor modulating substance fingolimod (FTY720) has beneficial effects. Herein, we evaluated the neuroprotective potential of FTY720 in a neonatal model of oxygen-toxicity, which is associated with hypomyelination and impaired neuro-cognitive outcome. A single dose of FTY720 (1mg/kg) at the onset of neonatal hyperoxia (24h 80% oxygen on postnatal day 6) resulted in improvement of neuro-cognitive development persisting into adulthood. This was associated with reduced microstructural white matter abnormalities 4 months after the insult. In search of the underlying mechanisms potential non-classical (i.e. lymphocyte-independent) pathways were analysed shortly after the insult, comprising modulation of oxidative stress and local inflammatory responses as well as myelination, oligodendrocyte degeneration and maturation. Treatment with FTY720 reduced hyperoxia-induced oxidative stress, microglia activation and associated pro-inflammatory cytokine expression. In vivo and in vitro analyses further revealed that oxygen-induced hypomyelination is restored to control levels, which was accompanied by reduced oligodendrocyte degeneration and enhanced maturation. Furthermore, hyperoxia-induced elevation of S1P receptor 1 (S1P1) protein expression on in vitro cultured oligodendrocyte precursor cells was reduced by activated FTY720 and protection from degeneration is abrogated after selective S1P1 blockade. Finally, FTY720s' classical mode of action (i.e. retention of immune cells within peripheral lymphoid organs) was analysed demonstrating that FTY720 diminished circulating lymphocyte counts independent from hyperoxia. Cerebral immune cell counts remained unchanged by hyperoxia and by FTY720 treatment. Taken together, these results suggest that beneficial effects of FTY720 in neonatal oxygen-induced brain injury may be rather attributed to its anti-oxidative and anti-inflammatory capacity acting in concert with a direct protection of developing oligodendrocytes than to a modulation of peripheral lymphocyte trafficking. Thus, FTY720 might be a potential new therapeutic option for the treatment of neonatal brain injury through reduction of white matter damage.

The objective of this paper is to investigate the difference in physiological parameters, EEG and morphology of brain tissues in newborn pigs with different regional oxygen saturations of brain (rSO(2)) and provide a basis for the determination of brain injury and degree of injury with the rSO(2) in clinical practice. A noninvasive near-infrared spectroscopy (NIRS) technique was used to monitor the rSO(2) of 27 newborn pigs. After mechanical ventilation and inhalation of 3-11% oxygen for 30 min by the newborn pigs, the pigs were grouped according to the rSO(2) in the brain caused by inhalation of different concentrations of oxygen. There were six animals each in rSO(2) < 30%, 30-35%, 35-40%, 40-50% groups and three animals in the rSO(2) > 60% group (normal control). The physiological parameters and the EEG were monitored during the experiment. The animals were sacrificed by decollation at 72 hours after brain injury, and light microscope examination and pathological analysis of the ultrastructure were conducted on the brain tissues in the CA1 zone of hippocampi. In rSO(2) > 40% groups, the mean arterial pressure (MAP) was stable and there were no significant changes in blood lactic acid, amplitudes of the EEG, light microscopic findings and ultrastructure after hypoxia. When the rSO(2) was between 30% and 40%, the MAP was stable, the level of blood lactic acid increased, metabolic acidosis occurred, there was no significant change in the amplitudes of the EEG, there were ischemic changes in brain tissues under a light microscope and there was an injury of mitochondria in the neurons in the CA1 zone of hippocampi. When the rSO(2) was less than 30%, circulatory failure occurred, the level of blood lactic acid increased, there was serious metabolic acidosis, the amplitudes of the EEG significantly decreased, there were vacuolization and broken fragments of cells under the light microscope and the mitochondria in the neurons in the CA1 zone of hippocampi were seriously injured. Under varying degrees of hypoxia, when the rSO(2) is between 30% and 40%, brain injury occurs and the functional zones of mitochondria are injured in newborn pigs. When the rSO(2) is less than 30%, the brain functions are seriously abnormal, and the serious morphological impairment in the functional zones of mitochondria is the basis for the disturbance of energy metabolism in brain neurocytes after hypoxia and the sequelae of the nervous system.

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Processing affective prosody, that is the emotional tone of a speaker, is fundamental to human communication and adaptive behaviors. Previous studies have mainly focused on adults and infants; thus the neural mechanisms underlying the processing of affective prosody in newborns remain unclear. Here, we used near‐infrared spectroscopy to examine the ability of 0‐to‐4‐day‐old neonates to discriminate emotions conveyed by speech prosody in their maternal language and a foreign language. Happy, fearful, and angry prosodies enhanced neural activation in the right superior temporal gyrus relative to neutral prosody in the maternal but not the foreign language. Happy prosody elicited greater activation than negative prosody in the left superior frontal gyrus and the left angular gyrus, regions that have not been associated with affective prosody processing in infants or adults. These findings suggest that sensitivity to affective prosody is formed through prenatal exposure to vocal stimuli of the maternal language. Furthermore, the sensitive neural correlates appeared more distributed in neonates than infants, indicating a high‐level of neural specialization between the neonatal stage and early infancy. Finally, neonates showed preferential neural responses to positive over negative prosody, which is contrary to the “negativity bias” phenomenon established in adult and infant studies.

Appropriate processing of human voices with different threat-related emotions is of evolutionarily adaptive value for the survival of individuals. Nevertheless, it is still not clear whether the sensitivity to threat-related information is present at birth. Using an odd-ball paradigm, the current study investigated the neural correlates underlying automatic processing of emotional voices of fear and anger in sleeping neonates. Event-related potential data showed that the fronto-central scalp distribution of the neonatal brain could discriminate fearful voices from angry voices; the mismatch response (MMR) was larger in response to the deviant stimuli of anger, compared with the standard stimuli of fear. Furthermore, this fear–anger MMR discrimination was observed only when neonates were in active sleep state. Although the neonates' sensitivity to threat-related voices is not likely associated with a conceptual understanding of fearful and angry emotions, this special discrimination in early life may provide a foundation for later emotion and social cognition development.