EEG phase-amplitude coupling to stratify encephalopathy severity in the developing brain

Highlights

• Developed computational quantification of EEG Mean Phase Amplitude Coupling (PACm).

• PACm reflects the maturity of brain development.

• PACm can successfully determine the severity of Hypoxic-Ischemic Encephalopathy.

Abstract

Background

Neonatal hypoxic ischemic encephalopathy (HIE) is difficult to classify within the narrow therapeutic window of hypothermia. Neurophysiological biomarkers are needed for timely differentiation of encephalopathy severity within the short therapeutic window for initiation of hypothermia therapy.

Methods

A novel analysis of mean Phase Amplitude Coupling index, PAC_m, of amplitudes high frequencies (12–30 Hz) coupled with phases of low (1,2 Hz) frequencies was calculated from the 6 h EEG recorded during the first day of life. PAC_m values were compared to identify differences between mild versus higher-grade HIE, respectively, for each of the EEG electrodes. A receiver operating characteristic curve was generated to examine the performance of PAC_m.

Results

38 newborns with different HIE grades were enrolled in the first 6 h of life. Threshold PAC_m 0.001 at Fz, O1, O2, P3, and P4 had AUC >0.9 to differentiate HIE severity and predict the persistence of moderate to severe encephalopathy that requires treatment with hypothermia.

Conclusion

PAC is a promising biomarker to identify mild from higher severity of HIE after birth.

Introduction

Neonatal asphyxia is a worldwide problem that affects 4 million newborns each year [1]. The underlying disturbances in cerebral blood flow and neuronal activity result in an evolving neonatal encephalopathy (NE), the severity of which can be challenging to classify immediately after birth [2,3]. Persistence of moderate to severe encephalopathy is associated with death and or disability and requires treatment with hypothermia therapy [4]. However the 6 h narrow therapeutic window of hypothermia necessitates early recognition with adjunct biomarkers to stratify the evolving encephalopathy severity [5], [6], [7], [8]. The bottle neck in neonatal care has been a lack of quantifiable neurophysiological measures of injury at the bedside which is critically needed for clinicians to make prompt neuroprotective interventions for those at high risk. In particular, this area of research has a timely impact as new trials are targeting those with mild hypoxic ischemic encephalopathy (HIE), a heterogeneous group where a subset has deficits [7,9].

Continuous brain EEG monitoring is routinely used in newborns with HIE to assess brain function [10], [11], [12]. It is known that neuronal activities in the human brain are interconnected and processed among and/or across cerebral regions at distinct spectrum of frequencies [13], [14], [15].

The neonatal brain functions networks are operational especially at very low frequencies [13,16].

In this study, we took an innovative approach by investigating whether the phase amplitude coupling (PAC) indexes derived from an EEG tracing can serve as a physiological biomarker in HIE as it was demonstrated to be sensitive to subtle brain injuries [15,17,18]. PAC can be estimated from intracortical or scalp EEG and refers to the amplitude modulation of a high-frequency brain oscillations by the phase of a low-frequency brain oscillation. PAC has not been measured in the neonatal brain to this date [13,19] but has been reported as critical in encoding, storage, and memory [20], [21], [22], [23] functions that are all affected by an asphyxia insult at birth [24].

Our hypothesis was that PAC measured with a cross-frequency PAC index from scalp EEG in the first six hours of life is associated with encephalopathy severity in a cohort with HIE.