# Early Signatures of Brain Injury in the Preterm Neonatal EEG
###### Abstract  
Reliable prognostic biomarkers are needed to support the early diagnosis of brain injury in extremely preterm infants, and to develop effective neuroprotective protocols that are tailored to the progressing phases of injury. Experimental and clinical research shows that severity of neuronal damage is correlated with changes in the electroencephalogram (EEG) after hypoxic-ischemia (HI). We have previously reported that micro-scale sharp-wave EEG waveforms have prognostic utility within the early hours of post-HI recordings in preterm fetal sheep, before injury develops. This article aims to investigate whether these subtle EEG patterns are translational in the early hours of life in clinical recordings from extremely preterm newborns. This work evaluates the existence and morphological similarity of the sharp-waves automatically identified throughout the entire duration of EEG data from a cohort of fetal sheep 6 h after HI (n = 7, at 103 \(\pm\) 1 day gestation) and in recordings commencing before 6 h of life in extremely preterm neonates (n = 7, 27 \(\pm\) 2.0 weeks gestation). We report that micro-scale EEG waveforms with similar morphology and characteristics (r = 0.94) to those seen in fetal sheep after HI are also present after birth in recordings started before 6 h of life in extremely preterm neonates. This work further indicates that the post-HI sharp-waves show rapid morphological evolution, influenced by age and/or severity of neuronal loss, and thus that automated algorithms should be validated against such signal variations. Finally, this article discusses the need for more focused research on the early assessment of EEG changes in preterm infants to help determine the timing of brain injury to identify biomarkers that could assist in targeting novel therapies for particular phases of injury. neonatal encephalopathy; hypoxia-ischemia; EEG biomarker; deep learning; sharp wave; theta and alpha frequency band +
Footnote †: journal: Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand; [EMAIL_ADDRESS]  
Footnote †: journal: Medical and Health Sciences, University of Auckland, Auckland, Auckland 1023, New Zealand; [EMAIL_ADDRESS]  
Footnote †associated with high amplitude seizures (HAS) (Figure 1a) [7] and failure of mitochondrial function [10]. After 3 days, this may be followed by a long term 'tertiary' phase with remodeling, persistent inflammation, and epigenetic changes [11]. Currently, no specific neuroprotection/neurorepair treatments have been proven to be effective for premature infants. In full-term babies, the first 6 h after hypoxia-ischemia (HI) provides a 'window of opportunity' when therapeutic hypothermia can significantly improve outcomes [12, 13]. It is important to appreciate that the ideal windows for other interventions in the very preterm brain are likely to be different. The development of effective treatments requires accurately targeting the right phases of injury. For example, our animal experiments indicate that early signatures of the injury emerge in the form of micro-scale EEG waveforms superimposed on a suppressed background during the latent phase before the bursts of high-amplitude seizures [6]. Therefore, there is a need to identify biological markers that could indicate the timing of the injury in order to further develop effective treatments associated with different phases of the injury. Currently, we lack reliable early biomarkers while HAS (seen in both experimental and clinical evolving EEG--Figure 1a,b) can be a good indicator of the start of the secondary phase, at least in most cases. Another drawback of HAS are that they are a sign of the closure of the best window of opportunity for treatment in the preterm brain [7, 10]. Nevertheless, encouragingly there is some animal evidence that, in specific situations, very late treatment starting after the secondary phase may be beneficial [14]. Anticonvulsant therapy for HAS may improve outcomes, but this remains surprisingly controversial [2].