Asphyxia or play: who wins the game?

Abstract

Hypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia (PA) affects approximately 1 million neonates worldwide each year and is associated with long-term neurological insufficiency, cognitive impairments, and psychiatric disorders. Approximately 25% of the children with chronic diseases experience psychosocial difficulties and are less likely to engage in play. This is of particular concern, as play is a fundamental behaviour essential for neurological, motor, and socio-emotional development, as well as for establishing a broad behavioural repertoire necessary for adulthood. Long-term effects of PA on play behaviour and cognitive functioning have not previously been investigated in long-term ovine models, which closely mimic the etiology and neuropathology of near-term human HIE. Moreover, effective therapies targeting long-term functional outcomes remain limited. Therefore, the aim of this randomised, blinded laboratory-based animal trial was to investigate the effects of PA and intranasally administered mesenchymal stem cells (MSC) on play behaviour and cognitive functioning. HIE was induced in 35 lambs at 0.89 of gestation by umbilical cord occlusion (UCO) during an ex-utero intrapartum treatment (EXIT) procedure. The lambs were randomly allocated to 4 experimental groups: sham-saline (n = 9), sham-MSC (n = 7), HI-Saline (n = 9), and HI-MSC (n = 9). Neurological milestones were assessed during the first days of life. At 6 to 10 weeks of age, play behaviour was evaluated during a standardised play behaviour trial. Anxiety-related and exploratory behaviour was assessed in an open field trial at four months of age, and cognitive functioning was evaluated using a Y-maze and diamond maze task. The attainment of a full neurological score was significantly later in HI-exposed lambs (Mdn=216.00) than in sham-controls (Mdn=96.00;U=54.50,p=0.005). While total play did not differ among groups, HI-exposed lambs exhibited more locomotor play (Mdn=2.19) compared to controls (Mdn=0.26;U=2.00,p=0.064), most likely due to a delay in neurological development. The open field trial revealed increased anxiety-related behaviour in HI-exposed lambs. The diamond maze trial demonstrated trends of impaired long-term memory retention and reduction of cognitive flexibility in HI-exposed lambs, which need to be further investigated. No significant therapeutic effects of MSC treatment were detected, likely due to limited statistical power. Conversely, these findings demonstrate that PA induces neurobehavioural alterations in an ovine model, emphasizing the need for further investigation into therapeutic strategies targeting long-term functional outcomes.