Establishing a standardised approach for the measurement of neonatal noxious-evoked brain activity in response to an acute somatic nociceptive heel lance stimulus.

BACKGROUND: Electroencephalography (EEG) can be used in neonates to measure brain activity changes that are evoked by noxious events, such as clinically required immunisations, cannulation and heel lancing for blood tests. EEG provides an alternative approach to infer pain experience in infants compared with more commonly used behavioural and physiological pain assessments. Establishing the generalisability and construct validity of these measures will help corroborate the use of brain-derived outcomes to evaluate the efficacy of new or existing pharmacological and non-pharmacological methods to treat neonatal pain. This study aimed to test whether a measure of noxious-evoked EEG activity called the noxious neurodynamic response function (n-NRF), that was originally derived in a sample of term-aged infants at the Oxford John Radcliffe Hospital, UK, in 2017, can reliably distinguish noxious from non-noxious events in two independent datasets collected at University College London Hospital and at Royal Devon & Exeter Hospital. We aimed to reproduce three published results that use this measure to quantify noxious-evoked changes in brain activity. We used the n-NRF to quantify noxious-evoked brain activity to test (i) whether significantly larger noxious-evoked activity is recorded in response to a clinical heel lance compared to a non-noxious control heel lance procedure; (ii) whether the magnitude of the activity evoked by a noxious heel lance is equivalent in independent cohorts of infants; and (iii) whether the magnitude of the noxious-evoked brain activity increases with postmenstrual age (PMA) in premature infants up to 37 weeks PMA. Positive replication of these studies will build confidence in the use of the n-NRF as a valid and reliable pain-related outcome which could be used to evaluate analgesic efficacy in neonates. The protocol for this study was published following peer review (https://doi.org/10.17605/OSF.IO/ZY9MS). RESULTS: The n-NRF magnitude to a noxious heel lance stimulus was significantly greater than to a non-noxious control heel lance stimulus in both the UCL dataset (n = 60; mean difference .88; 95% confidence interval (CI) .64-1.13; p < .0001) and the Exeter dataset (n = 31; mean difference .31; 95% CI .02-.61; p = .02). The mean magnitude and 90% bootstrap confidence interval of the n-NRF evoked by the heel lance did not meet our pre-defined equivalence bounds of 1.0 ± .2 in either the UCL dataset (n = 72; mean magnitude 1.33; 90% bootstrapped CI 1.18-1.52) or the Exeter dataset (n = 35; mean magnitude .92, 90% bootstrapped CI .74-1.22). The magnitude of the n-NRF to the noxious stimulus was significantly positively correlated with PMA in infants up to 37 weeks PMA (n = 65; one-sided Pearson's R, adjusted for site: .24; 95% CI .06-1.00; p = .03). CONCLUSIONS: We have reproduced in independent datasets the findings that the n-NRF response to a noxious stimulus is significantly greater than to a non-noxious stimulus, and that the noxious-evoked EEG response increases with PMA. The pre-defined equivalence bounds for the mean magnitude of the EEG response were not met, though this might be due to either inter-site differences such as the lack of calibration of devices between sites (a true negative) or underpowering (a false negative). This reproducibility study provides robust evidence that supports the use of the n-NRF as an objective outcome for clinical trials assessing acute nociception in neonates. Use of the n-NRF in this way has the potential to transform the way analgesic efficacy studies are performed.

A machine learning artefact detection method for single-channel infant event-related potential studies.

Objective. Automated detection of artefact in stimulus-evoked electroencephalographic (EEG) data recorded in neonates will improve the reproducibility and speed of analysis in clinical research compared with manual identification of artefact. Some studies use very short, single-channel epochs of EEG data with little recorded EEG per infant-for example because the clinical vulnerability of the infants limits access for recording. Current artefact-detection methods that perform well on adult data and resting-state and multi-channel data in infants are not suitable for this application. The aim of this study was to create and test an automated method of detecting artefact in single-channel 1500 ms epochs of infant EEG.Approach. A total of 410 epochs of EEG were used, collected from 160 infants of 28-43 weeks postmenstrual age. This dataset-which was balanced to include epochs of background activity and responses to visual, auditory, tactile and noxious stimuli-was presented to seven independent raters, who independently labelled the epochs according to whether or not they were able to visually identify artefacts. The data was split into a training set (340 epochs) and an independent test set (70 epochs). A random forest model was trained to identify epochs as either artefact or not artefact.Main results. This model performs well, achieving a balanced accuracy of 0.81, which is as good as manual review of data. Accuracy was not significantly related to the infant age or type of stimulus.Significance. This method provides an objective tool for automated artefact rejection for short epoch, single-channel EEG in neonates and could increase the utility of EEG in neonates in both the clinical and research setting.

Resting state electroencephalographic brain activity in neonates can predict age and is indicative of neurodevelopmental outcome.

OBJECTIVE: Electroencephalography (EEG) can be used to estimate neonates' biological brain age. Discrepancies between postmenstrual age and brain age, termed the brain age gap, can potentially quantify maturational deviation. Existing brain age EEG models are not well suited to clinical cot-side use for estimating neonates' brain age gap due to their dependency on relatively large data and pre-processing requirements. METHODS: We trained a deep learning model on resting state EEG data from preterm neonates with normal neurodevelopmental Bayley Scale of Infant and Toddler Development (BSID) outcomes, using substantially reduced data requirements. We subsequently tested this model in two independent datasets from two clinical sites. RESULTS: In both test datasets, using only 20 min of resting-state EEG activity from a single channel, the model generated accurate age predictions: mean absolute error = 1.03 weeks (p-value = 0.0001) and 0.98 weeks (p-value = 0.0001). In one test dataset, where 9-month follow-up BSID outcomes were available, the average neonatal brain age gap in the severe abnormal outcome group was significantly larger than that of the normal outcome group: difference in mean brain age gap = 0.50 weeks (p-value = 0.04). CONCLUSIONS: These findings demonstrate that the deep learning model generalises to independent datasets from two clinical sites, and that the model's brain age gap magnitudes differ between neonates with normal and severe abnormal follow-up neurodevelopmental outcomes. SIGNIFICANCE: The magnitude of neonates' brain age gap, estimated using only 20 min of resting state EEG data from a single channel, can encode information of clinical neurodevelopmental value.

The PiNe box: Development and validation of an electronic device to time-lock multimodal responses to sensory stimuli in hospitalised infants.

Recording multimodal responses to sensory stimuli in infants provides an integrative approach to investigate the developing nervous system. Accurate time-locking across modalities is essential to ensure that responses are interpreted correctly, and could also improve clinical care, for example, by facilitating automatic and objective multimodal pain assessment. Here we develop and assess a system to time-lock stimuli (including clinically-required heel lances and experimental visual, auditory and tactile stimuli) to electrophysiological research recordings and data recorded directly from a hospitalised infant's vital signs monitor. The electronic device presented here (that we have called 'the PiNe box') integrates a previously developed system to time-lock stimuli to electrophysiological recordings and can simultaneously time-lock the stimuli to recordings from hospital vital signs monitors with an average precision of 105 ms (standard deviation: 19 ms), which is sufficient for the analysis of changes in vital signs. Our method permits reliable and precise synchronisation of data recordings from equipment with legacy ports such as TTL (transistor-transistor logic) and RS-232, and patient-connected networkable devices, is easy to implement, flexible and inexpensive. Unlike current all-in-one systems, it enables existing hospital equipment to be easily used and could be used for patients of any age. We demonstrate the utility of the system in infants using visual and noxious (clinically-required heel lance) stimuli as representative examples.

The impact of premature extrauterine exposure on infants' stimulus-evoked brain activity across multiple sensory systems.

Prematurity can result in widespread neurodevelopmental impairment, with the impact of premature extrauterine exposure on brain function detectable in infancy. A range of neurodynamic and haemodynamic functional brain measures have previously been employed to study the neurodevelopmental impact of prematurity, with methodological and analytical heterogeneity across studies obscuring how multiple sensory systems are affected. Here, we outline a standardised template analysis approach to measure evoked response magnitudes for visual, tactile, and noxious stimulation in individual infants (n = 15) using EEG. By applying these templates longitudinally to an independent cohort of very preterm infants (n = 10), we observe that the evoked response template magnitudes are significantly associated with age-related maturation. Finally, in a cross-sectional study we show that the visual and tactile response template magnitudes differ between a cohort of infants who are age-matched at the time of study but who differ according to whether they are born during the very preterm or late preterm period (n = 10 and 8 respectively). These findings demonstrate the significant impact of premature extrauterine exposure on brain function and suggest that prematurity can accelerate maturation of the visual and tactile sensory system in infants born very prematurely. This study highlights the value of using a standardised multi-modal evoked-activity analysis approach to assess premature neurodevelopment, and will likely complement resting-state EEG and behavioural assessments in the study of the functional impact of developmental care interventions.

Functional brain maturation and sleep organisation in neonates with congenital heart disease.

OBJECTIVE: Neonates with Congenital Heart Disease (CHD) have structural delays in brain development. To evaluate whether functional brain maturation and sleep-wake physiology is also disturbed, the Functional Brain Age (FBA) and sleep organisation on EEG during the neonatal period is investigated. METHODS: We compared 15 neonates with CHD who underwent multichannel EEG with healthy term newborns of the same postmenstrual age, including subgroup analysis for d-Transposition of the Great Arteries (d-TGA) (n = 8). To estimate FBA, a prediction tool using quantitative EEG features as input, was applied. Second, the EEG was automatically classified into the 4 neonatal sleep stages. Neonates with CHD underwent neurodevelopmental testing using the Bayley Scale of Infant Development-III at 24 months. RESULTS: Preoperatively, the FBA was delayed in CHD infants and more so in d-TGA infants. The FBA was positively correlated with motor scores. Sleep organisation was significantly altered in neonates with CHD. The duration of the sleep cycle and the proportion of Active Sleep Stage 1 was decreased, again more marked in the d-TGA infants. Neonates with d-TGA spent less time in High Voltage Slow Wave Sleep and more in Tracé Alternant compared to healthy terms. Both FBA and sleep organisation normalised postoperatively. The duration of High Voltage Slow Wave Sleep remained positively correlated with motor scores in d-TGA infants. INTERPRETATION: Altered early brain function and sleep is present in neonates with CHD. These results are intruiging, as inefficient neonatal sleep has been linked with adverse long-term outcome. Identifying how these rapid alterations in brain function are mitigated through improvements in cerebral oxygenation, surgery, drugs and nutrition may have relevance for clinical practice and outcome.

A Deep Shared Multi-Scale Inception Network Enables Accurate Neonatal Quiet Sleep Detection With Limited EEG Channels.

In this paper, we introduce a new variation of the Convolutional Neural Network Inception block, called Sinc, for sleep stage classification in premature newborn babies using electroencephalogram (EEG). In practice, there are many medical centres where only a limited number of EEG channels are recorded. Existing automated algorithms mainly use multi-channel EEGs which perform poorly when fewer numbers of channels are available. The proposed Sinc utilizes multi-scale analysis to place emphasis on the temporal EEG information to be less dependent on the number of EEG channels. In Sinc, we increase the receptive fields through Inception while by additionally sharing the filters that have similar receptive fields, overfitting is controlled and the number of trainable parameters dramatically reduced. To train and test this model, 96 longitudinal EEG recordings from 26 premature infants are used. The Sinc-based model significantly outperforms state-of-the-art neonatal quiet sleep detection algorithms, with mean Kappa 0.77 ± 0.01 (with 8-channel EEG) and 0.75 ± 0.01 (with a single bipolar channel EEG). This is the first study using Inception-based networks for EEG analysis that utilizes filter sharing to improve efficiency and trainability. The suggested network can successfully detect quiet sleep stages with even a single EEG channel making it more practical especially in the hospital setting where cerebral function monitoring is predominantly used.

Applying a data-driven approach to quantify EEG maturational deviations in preterms with normal and abnormal neurodevelopmental outcomes.

Premature babies are subjected to environmental stresses that can affect brain maturation and cause abnormal neurodevelopmental outcome later in life. Better understanding this link is crucial to developing a clinical tool for early outcome estimation. We defined maturational trajectories between the Electroencephalography (EEG)-derived 'brain-age' and postmenstrual age (the age since the last menstrual cycle of the mother) from longitudinal recordings during the baby's stay in the Neonatal Intensive Care Unit. Data consisted of 224 recordings (65 patients) separated for normal and abnormal outcome at 9-24 months follow-up. Trajectory deviations were compared between outcome groups using the root mean squared error (RMSE) and maximum trajectory deviation (δmax). 113 features were extracted (per sleep state) to train a data-driven model that estimates brain-age, with the most prominent features identified as potential maturational and outcome-sensitive biomarkers. RMSE and δmax showed significant differences between outcome groups (cluster-based permutation test, p < 0.05). RMSE had a median (IQR) of 0.75 (0.60-1.35) weeks for normal outcome and 1.35 (1.15-1.55) for abnormal outcome, while δmax had a median of 0.90 (0.70-1.70) and 1.90 (1.20-2.90) weeks, respectively. Abnormal outcome trajectories were associated with clinically defined dysmature and disorganised EEG patterns, cementing the link between early maturational trajectories and neurodevelopmental outcome.

Neonatal EEG sleep stage classification based on deep learning and HMM.

OBJECTIVE: Automatic sleep stage scoring is of great importance for investigating sleep architecture during infancy. In this work, we introduce a novel multichannel approach based on deep learning networks and hidden Markov models (HMM) to improve the accuracy of sleep stage classification in term neonates. APPROACH: The classification performance was evaluated on quiet sleep (QS) and active sleep (AS) stages, each with two sub-states, using multichannel EEG data recorded from sixteen neonates with postmenstrual age of 38-40 weeks. A comprehensive set of linear and nonlinear features were extracted from thirty-second EEG segments. The feature space dimensionality was then reduced by using an evolutionary feature selection method called MGCACO (Modified Graph Clustering Ant Colony Optimization) based on the relevance and redundancy analysis. A bi-directional long-short time memory (BiLSTM) network was trained for sleep stage classification. The number of channels was optimized using the sequential forward selection method to reduce the spatial space. Finally, an HMM-based postprocessing stage was used to reduce false positives by incorporating the knowledge of transition probabilities between stages into the classification process. The method performance was evaluated using the K-fold (KFCV) and leave-one-out cross-validation (LOOCV) strategies. MAIN RESULTS: Using six-bipolar channels, our method achieved a mean kappa and an overall accuracy of 0.71-0.76 and 78.9%-82.4% using the KFCV and LOOCV strategies, respectively. SIGNIFICANCE: The presented automatic sleep stage scoring method can be used to study the neurodevelopmental process and to diagnose brain abnormalities in term neonates.

A convolutional neural network outperforming state-of-the-art sleep staging algorithms for both preterm and term infants.

OBJECTIVE: To classify sleep states using electroencephalogram (EEG) that reliably works over a wide range of preterm ages, as well as term age. APPROACH: A convolutional neural network is developed to perform 2- and 4-class sleep classification in neonates. The network takes as input an 8-channel 30 s EEG segment and outputs the sleep state probabilities. Apart from simple downsampling of the input and smoothing of the output, the suggested network is an end-to-end algorithm that avoids the need for hand-crafted feature selection or complex pre/post processing steps. To train and test this method, 113 EEG recordings from 42 infants are used. MAIN RESULTS: For quiet sleep detection (the 2-class problem), mean kappa between the network estimate and the ground truth annotated by EEG human experts is 0.76. The sensitivity and specificity are 90% and 88%, respectively. For 4-class classification, mean kappa is 0.64. The averaged sensitivity and specificity (1 versus all) respectively equal 72% and 91%. The results outperform current state-of-the-art methods for which kappa ranges from 0.66 to 0.70 in preterm and from 0.51 to 0.61 in term infants, based on training and testing using the same database. SIGNIFICANCE: The proposed method has the highest reported accuracy for EEG sleep state classification for both preterm and term age neonates.

A Bayesian parametric model for quantifying brain maturation from sleep-EEG in the vulnerable newborn baby.

Newborn babies, particularly preterms, can exhibit early deviations in sleep maturation as seen by Electroencephalogram (EEG) recordings. This may be indicative of cognitive problems by school-age. The current 'clinically-driven' approach uses separate algorithms to first extract sleep states and then predict EEG 'brain-age'. Maturational deviations are identified when the brain-age no longer matches the Postmenstrual Age (PMA, the age since the last menstrual cycle of the mother). However, the PMA range where existing sleep staging algorithms perform optimally, is limited, which subsequently limits the PMA range for brain-age prediction. We introduce a Bayesian Parametric Model (BPM) as a single end-to-end solution to directly estimate brain-age, modelling for sleep state maturation without requiring a separately optimized sleep staging algorithm. Comparison of this model with a traditional multi-stage approach, yields a similar Krippendorff's $\alpha = 0.92$ (a performance measure ranging from 0 (chance agreement) to 1 (perfect agreement)) with the BPM performing better at younger ages <30 weeks PMA. The BPM's potential to detect maturational deviations is also explored on a few preterm babies who were abnormal at 9 months follow-up.

Automated EEG sleep staging in the term-age baby using a generative modelling approach.

OBJECTIVE: We develop a method for automated four-state sleep classification of preterm and term-born babies at term-age of 38-40 weeks postmenstrual age (the age since the last menstrual cycle of the mother) using multichannel electroencephalogram (EEG) recordings. At this critical age, EEG differentiates from broader quiet sleep (QS) and active sleep (AS) stages to four, more complex states, and the quality and timing of this differentiation is indicative of the level of brain development. However, existing methods for automated sleep classification remain focussed only on QS and AS sleep classification. APPROACH: EEG features were calculated from 16 EEG recordings, in 30 s epochs, and personalized feature scaling used to correct for some of the inter-recording variability, by standardizing each recording's feature data using its mean and standard deviation. Hidden Markov models (HMMs) and Gaussian mixture models (GMMs) were trained, with the HMM incorporating knowledge of the sleep state transition probabilities. Performance of the GMM and HMM (with and without scaling) were compared, and Cohen's kappa agreement calculated between the estimates and clinicians' visual labels. MAIN RESULTS: For four-state classification, the HMM proved superior to the GMM. With the inclusion of personalized feature scaling, mean kappa (±standard deviation) was 0.62 (±0.16) compared to the GMM value of 0.55 (±0.15). Without feature scaling, kappas for the HMM and GMM dropped to 0.56 (±0.18) and 0.51 (±0.15), respectively. SIGNIFICANCE: This is the first study to present a successful method for the automated staging of four states in term-age sleep using multichannel EEG. Results suggested a benefit in incorporating transition information using an HMM, and correcting for inter-recording variability through personalized feature scaling. Determining the timing and quality of these states are indicative of developmental delays in both preterm and term-born babies that may lead to learning problems by school age.

Review of sleep-EEG in preterm and term neonates.

Neonatal sleep is a crucial state that involves endogenous driven brain activity, important for neuronal survival and guidance of brain networks. Sequential EEG-sleep analysis in preterm infants provides insights into functional brain integrity and can document deviations of the biologically pre-programmed process of sleep ontogenesis during the neonatal period. Visual assessment of neonatal sleep-EEG, with integration of both cerebral and non-cerebral measures to better define neonatal state, is still considered the gold standard. Electrographic patterns evolve over time and are gradually time locked with behavioural characteristics which allow classification of quiet sleep and active sleep periods during the last 10weeks of gestation. Near term age, the neonate expresses a short ultradian sleep cycle, with two distinct active and quiet sleep, as well as brief periods of transitional or indeterminate sleep. Qualitative assessment of neonatal sleep is however challenged by biological and environmental variables that influence the expression of EEG-sleep patterns and sleep organization. Developing normative EEG-sleep data with the aid of automated analytic methods, can further improve our understanding of extra-uterine brain development and state organization under stressful or pathological conditions. Based on those developmental biomarkers of normal and abnormal brain function, research can be conducted to support and optimise sleep in the NICU, with the ultimate goal to improve therapeutic interventions and neurodevelopmental outcome.

An Automated Quiet Sleep Detection Approach in Preterm Infants as a Gateway to Assess Brain Maturation.

Sleep state development in preterm neonates can provide crucial information regarding functional brain maturation and give insight into neurological well being. However, visual labeling of sleep stages from EEG requires expertise and is very time consuming, prompting the need for an automated procedure. We present a robust method for automated detection of preterm sleep from EEG, over a wide postmenstrual age ([Formula: see text] age) range, focusing first on Quiet Sleep (QS) as an initial marker for sleep assessment. Our algorithm, CLuster-based Adaptive Sleep Staging (CLASS), detects QS if it remains relatively more discontinuous than non-QS over PMA. CLASS was optimized on a training set of 34 recordings aged 27-42 weeks PMA, and performance then assessed on a distinct test set of 55 recordings of the same age range. Results were compared to visual QS labeling from two independent raters (with inter-rater agreement [Formula: see text]), using Sensitivity, Specificity, Detection Factor ([Formula: see text] of visual QS periods correctly detected by CLASS) and Misclassification Factor ([Formula: see text] of CLASS-detected QS periods that are misclassified). CLASS performance proved optimal across recordings at 31-38 weeks (median [Formula: see text], median MF 0-0.25, median Sensitivity 0.93-1.0, and median Specificity 0.80-0.91 across this age range), with minimal misclassifications at 35-36 weeks (median [Formula: see text]). To illustrate the potential of CLASS in facilitating clinical research, normal maturational trends over PMA were derived from CLASS-estimated QS periods, visual QS estimates, and nonstate specific periods (containing QS and non-QS) in the EEG recording. CLASS QS trends agreed with those from visual QS, with both showing stronger correlations than nonstate specific trends. This highlights the benefit of automated QS detection for exploring brain maturation.