Relationship Between Early Functional and Structural Brain Developments and Brain Injury in Preterm Infants.

BACKGROUND: Recent studies explored the relationship between early brain function and brain morphology, based on the hypothesis that increased brain activity can positively affect structural brain development and that excitatory neuronal activity stimulates myelination. OBJECTIVE: To investigate the relationship between maturational features from early and serial aEEGs after premature birth and MRI metrics characterizing structural brain development and injury, measured around 30weeks postmenstrual age (PMA) and at term. Moreover, we aimed to verify whether previously developed maturational EEG features are related with PMA. DESIGN/METHODS: One hundred six extremely preterm infants received bedside aEEGs during the first 72h and weekly until week 5. 3T-MRIs were performed at 30weeks PMA and at term. Specific features were extracted to assess EEG maturation: (1) the spectral content, (2) the continuity [percentage of spontaneous activity transients (SAT%) and the interburst interval (IBI)], and (3) the complexity. Automatic MRI segmentation to assess volumes and MRI score was performed. The relationship between the maturational EEG features and MRI measures was investigated. RESULTS: Both SAT% and EEG complexity were correlated with PMA. IBI was inversely associated with PMA. Complexity features had a positive correlation with the cerebellar size at 30weeks, while event-based measures were related to the cerebellar size at term. Cerebellar width, cortical grey matter, and total brain volume at term were inversely correlated with the relative power in the higher frequency bands. CONCLUSIONS: The continuity and complexity of the EEG steadily increase with increasing postnatal age. Increasing complexity and event-based features are associated with cerebellar size, a structure with enormous development during preterm life. Brain activity is important for later structural brain development.

A perinatal stress calculator for the neonatal intensive care unit: an unobtrusive approach.

OBJECTIVE: Early experience of pain and stress in the neonatal intensive care unit is known to have an effect on the neurodevelopment of the infant. However, an automated method to quantify the procedural pain or perinatal stress in premature patients does not exist. APPROACH: In the current study, EEG and ECG data were collected for more than 3 hours from 136 patients in order to quantify stress exposure. Specifically, features extracted from the EEG and heart-rate variability in both quiet and non-quiet sleep segments were used to develop a subspace linear-discriminant analysis stress classifier. MAIN RESULTS: The main novelty of the study lies in the absence of intrusive methods or pain elicitation protocols to develop the stress classifier. Three main findings can be reported. First, we developed different stress classifiers for the different age groups and stress intensities, obtaining an area under the curve in the range [0.78-0.93] for non-quiet sleep and [0.77-0.96] for quiet sleep. Second, a dysmature EEG was found in patients under stress. Third, an enhanced cortical connectivity and increased brain-heart communication was correlated with a higher stress load, while the autonomic activity did not seem to be associated to stress exposure. SIGNIFICANCE: The results shed a light on the pain and stress processing in preterm neonates, suggesting that software tools to investigate dysmature EEG might be helpful to assess stress load in premature patients. These results could be the foundation to assess the impact of stress on infants' development and to tune preventive care.

Monitoring of Brain Hemodynamics Coupling in Neonates using Updated Tensor Decompositions.

In this paper we explore the use of updated tensor decompositions for the monitoring of brain hemodynamics in neonates. For this study, we used concomitant measurements of heart rate, mean arterial blood pressure, arterial oxygen saturation, EEG, and brain oxygenation - measured using near-infrared spectroscopy. These measurements were obtained from 22 neonates undergoing an INSURE procedure (INtubation, SURfactant and Extubation) and sedation using propofol. To develop the monitoring framework using tensors, we used radial basis kernel function (RBF) to construct a similarity matrix for consecutive segments of the signals. These matrices were concatenated forming a tensor. Updating canonical polyadic decomposition was used to evaluate the impact of propofol in the coupling between the different signals. Results indicate, as previously reported, a drop in the interaction between signals due to propofol administration. This shows that tensor decompositions can be useful in order to monitor the coupling between different physiological signals.

The implementation of an apnea-based perinatal stress calculator.

Early life stress in the neonatal intensive care unit (NICU) predisposes premature infants to adverse health outcomes. Although those patients experience frequent apneas and sleep-wake disturbances during their hospital stay, clinicians still rely on clinical scales to assess pain and stress burden. This study addresses the relationship between stress and apneic spells in NICU patients to implement an automatic stress detector. EEG, ECG and SpO2 were recorded from 40 patients for at least 3 hours and the stress burden was assessed using the Leuven Pain Scale. Different logistic regression models were designed to detect the presence or the absence of stress based on the signals reactivity to each apneic spell. The classification shows that stress can be detected with an area under the curve of 0.94 and a misclassification error of 19.23%. These results were obtained via SpO2 dips and EEG regularity. These findings suggest that stress deepens the physiological reaction to apneas, which could ultimately impact the neurological and behavioral development.

A brain-age model for preterm infants based on functional connectivity.

OBJECTIVE: In this study, the development of EEG functional connectivity during early development has been investigated in order to provide a predictive age model for premature infants. APPROACH: The functional connectivity has been assessed via the coherency function (its imaginary part (ImCoh) and its mean squared magnitude (MSC)), the phase locking value ([Formula: see text]) and the Hilbert-Schimdt dependence (HSD) in a dataset of 30 patients, partially described and employed in previous studies (Koolen et al 2016 Neuroscience 322 298-307; Lavanga et al 2017 Complexity 2017 1-13). Infants' post-menstrual age (PMA) ranges from 27 to 42 weeks. The topology of the EEG couplings has been investigated via graph-theory indices. MAIN RESULTS: Results show a sharp decrease in ImCoh indices in θ, (4-8) Hz and α, (8-16) Hz bands and MSC in ß, (16-32) Hz band with maturation, while a more modest positive correlation with PMA is found for HSD, [Formula: see text] and MSC in [Formula: see text], θ, α bands. The best performances for the PMA prediction were mean absolute error equal to 1.51 weeks and adjusted coefficient of determination [Formula: see text] equal to 0.8. SIGNIFICANCE: The reported findings suggest a segregation of the cortex connectivity, which favours a diffused tasks architecture on the brain scalp. In summary, the results indicate that the neonates' brain development can be described via lagged-interaction network features.

Sonographic Development of the Pericallosal Vascularization in the First and Early Second Trimester of Pregnancy.

BACKGROUND AND PURPOSE: Anomalies of the corpus callosum are rare. Routine scanning in midtrimester of the pregnancy often fails to identify defective development. The purpose of the study was to identify the pericallosal artery and all its main branching arteries during early gestation from the first trimester onward, to measure the length of the pericallosal artery during its development, and to establish a normal vascular map for each week of development. MATERIALS AND METHODS: We performed a single-center prospective, longitudinal clinical study in 15 patients between 11 and 22 weeks of gestation. The origin and course of the different blood vessels were identified. RESULTS: There was a linear association among gestational age, the biparietal diameter, and the length of the pericallosal artery. The curvature of the developing pericallosal artery increases linearly with the gestational age and biparietal diameter, and 4 variations of branching of the callosomarginal artery were observed. CONCLUSIONS: The pericallosal artery and its branches can be identified and measured from 11 weeks on, and the pericallosal artery takes its characteristic course. A defective course or an abnormal biometry of the pericallosal artery could be an early sonographic marker of abnormal development of the corpus callosum.

Observational study shows that it is feasible to provide neuroprotective treatment for neonatal encephalopathy in low-income countries.

AIM: Perinatal asphyxia is one of the most frequent causes of neonatal morbidity and mortality worldwide, and 96% of the burden of neonatal encephalopathy occurs in low-income countries. This study investigated the feasibility of providing neuroprotective treatment for neonatal encephalopathy in low-income countries. METHODS: Neonates with a gestational age of at least 36 weeks, with signs of perinatal asphyxia, were included in this 2015 observational study in three hospitals in Kinshasa, capital of the Democratic Republic of Congo. Their characteristics were described, including the time to admission and Thompson score on admission. RESULTS: We found that 42 of 134 patients (31.3%) reached the hospital within six hours of birth with a Thompson score of at least seven on admission. Another 15 patients (11.2%) had a five-minute Apgar score of up to five, without a Thompson score, and were eligible for treatment. Of the 57 (42.5%) eligible patients, 31 were discharged (54.4%), 25 died (43.9%) and one (1.8%) remained in hospital at the end of the study. CONCLUSION: Interventional studies are feasible and necessary, especially in countries where the burden of neonatal encephalopathy is largest. A Thompson score of 7-15 might be a useful entry criterion for neuroprotective treatment in low-income countries.

Automatic quiet sleep detection based on multifractality in preterm neonates: Effects of maturation.

This study investigates the multifractal formalism framework for quiet sleep detection in preterm babies. EEG recordings from 25 healthy preterm infants were used in order to evaluate the performance of multifractal measures for the detection of quiet sleep. Results indicate that multifractal analysis based on wavelet leaders is able to identify quiet sleep epochs, but the classifier performances seem to be highly affected by the infant's age. In particular, from the developed classifiers, the lowest area under the curve (AUC) has been obtained for EEG recordings at very young age (≤ 31 weeks post-menstrual age), and the maximum at full-term age (≥ 37 weeks post-menstrual age). The improvement in classification performances can be due to a change in the multifractality properties of neonatal EEG during the maturation of the infant, which makes the EEG sleep stages more distinguishable.

Improved neonatal seizure detection using adaptive learning.

In neonatal intensive care units performing continuous EEG monitoring, there is an unmet need for around-the-clock interpretation of EEG, especially for recognizing seizures. In recent years, a few automated seizure detection algorithms have been proposed. However, these are suboptimal in detecting brief-duration seizures (<; 30s), which frequently occur in neonates with severe neurological problems. Recently, a multi-stage neonatal seizure detector, composed of a heuristic and a data-driven classifier was proposed by our group and showed improved detection of brief seizures. In the present work, we propose to add a third stage to the detector in order to use feedback of the Clinical Neurophysiologist and adaptively retune a threshold of the second stage to improve the performance of detection of brief seizures. As a result, the false alarm rate (FAR) of the brief seizure detections decreased by 50% and the positive predictive value (PPV) increased by 18%. At the same time, for all detections, the FAR decreased by 35% and PPV increased by 5% while the good detection rate remained unchanged.

The Use of Hemodynamic and Cerebral Monitoring to Study Pharmacodynamics in Neonates.

BACKGROUND: Drugs acting on the cardiovascular and central nervous system often display relatively fast clinical responses, which may differ in neonates compared to children and adults. Introduction of bedside monitoring tools might be of additional value in the pharmacodynamic (PD) assessment of such drugs in neonates. METHODS: We aim to provide an overview of the frequently used monitoring tools to assess drug effects on the hemodynamic status as well as the cerebral circulation, oxygenation and cerebral metabolism in neonates. RESULTS: The use of blood pressure measurements, heart rate variability, functional echocardiography, nearinfrared spectroscopy and (amplitude-integrated) electroencephalography in neonates is discussed, as well as new parameters introduced by these tools. Based on the 'brain circulation model', the hemodynamic effects on the brain and their interplay are summarized. In this model, 3 processes (i.e. blood processes, vascular smooth muscle processes and tissue processes) and 3 mechanisms (i.e. autoregulation, blood flow metabolism coupling and cerebral oxygen balance) are distinguished, which all may be influenced by drug administration. Finally, propofol, sevoflurane, midazolam and inotropes are used as examples of which PD has been studied using the available hemodynamic and/or cerebral monitoring tools. CONCLUSION: The implementation of (non-)invasive monitoring tools to document hemodynamic and cerebral PD effects in neonates is of relevance both in a neonatal research and intensive clinical care setting. We highlight the need to integrate these tools in future PD research. Furthermore, besides short-term drug effects, long-term outcome of drug therapy in neonates also warrants further attention.

The role of near-infrared spectroscopy monitoring in preterm infants.

Neurological morbidities such as peri/intraventricular hemorrhage and periventricular leukomalacia largely determine the neurodevelopmental outcome of vulnerable preterm infants and our aim should be to minimize their occurrence or severity. Bed-side neuromonitoring could provide valuable pieces of information about possible hemodynamic disturbances that are significantly associated with neurological morbidities and increased mortality. Near-infrared spectroscopy offers evaluation of regional cerebral oxygenation, which in conjunction with other non-invasive methods may give us a more complete picture about end-organ perfusion. This monitoring tool could help us fully understand the pathophysiology of severe neurological morbidities and guide our management in order to reduce their incidence.

The suppression curve as a quantitative approach for measuring brain maturation in preterm infants.

OBJECTIVES: We apply the suppression curve (SC) as an automated approach to describe the maturational change in EEG discontinuity in preterm infants. This method allows to define normative values of interburst intervals (IBIs) at different postmenstrual ages (PMA). METHODS: Ninety-two multichannel EEG recordings from 25 preterm infants (born ⩽32weeks) with normal developmental outcome at 9months, were first analysed using the Line Length method, an established method for burst detection. Subsequently, the SC was defined as the 'level of EEG discontinuity'. The mean and the standard deviation of the SC, as well as the IBIs from each recording were calculated and correlated with PMA. RESULTS: Over the course of development, there is a decrease in EEG discontinuity with a strong linear correlation between the mean SC and PMA till 34weeks. From 30weeks PMA, differences between discontinuous and continuous EEG become smaller, which is reflected by the decrease of the standard deviation of the SC. IBIs are found to have a significant correlation with PMA. CONCLUSIONS: Automated detection of individual maturational changes in EEG discontinuity is possible with the SC. These changes include more continuous tracing, less amplitude differences and shorter suppression periods, reflecting development of the vigilance states. SIGNIFICANCE: The suppression curve facilitates automated assessment of EEG maturation. Clinical applicability is straight forward since values for IBIs according to PMA are generated automatically.

Improved multi-stage neonatal seizure detection using a heuristic classifier and a data-driven post-processor.

OBJECTIVE: After identifying the most seizure-relevant characteristics by a previously developed heuristic classifier, a data-driven post-processor using a novel set of features is applied to improve the performance. METHODS: The main characteristics of the outputs of the heuristic algorithm are extracted by five sets of features including synchronization, evolution, retention, segment, and signal features. Then, a support vector machine and a decision making layer remove the falsely detected segments. RESULTS: Four datasets including 71 neonates (1023h, 3493 seizures) recorded in two different university hospitals, are used to train and test the algorithm without removing the dubious seizures. The heuristic method resulted in a false alarm rate of 3.81 per hour and good detection rate of 88% on the entire test databases. The post-processor, effectively reduces the false alarm rate by 34% while the good detection rate decreases by 2%. CONCLUSION: This post-processing technique improves the performance of the heuristic algorithm. The structure of this post-processor is generic, improves our understanding of the core visually determined EEG features of neonatal seizures and is applicable for other neonatal seizure detectors. SIGNIFICANCE: The post-processor significantly decreases the false alarm rate at the expense of a small reduction of the good detection rate.

Early development of synchrony in cortical activations in the human.

Early intermittent cortical activity is thought to play a crucial role in the growth of neuronal network development, and large scale brain networks are known to provide the basis for higher brain functions. Yet, the early development of the large scale synchrony in cortical activations is unknown. Here, we tested the hypothesis that the early intermittent cortical activations seen in the human scalp EEG show a clear developmental course during the last trimester of pregnancy, the period of intensive growth of cortico-cortical connections. We recorded scalp EEG from altogether 22 premature infants at post-menstrual age between 30 and 44 weeks, and the early cortical synchrony was quantified using recently introduced activation synchrony index (ASI). The developmental correlations of ASI were computed for individual EEG signals as well as anatomically and mathematically defined spatial subgroups. We report two main findings. First, we observed a robust and statistically significant increase in ASI in all cortical areas. Second, there were significant spatial gradients in the synchrony in fronto-occipital and left-to-right directions. These findings provide evidence that early cortical activity is increasingly synchronized across the neocortex. The ASI-based metrics introduced in our work allow direct translational comparison to in vivo animal models, as well as hold promise for implementation as a functional developmental biomarker in future research on human neonates.

Current research suggests that the future looks brighter for cerebral oxygenation monitoring in preterm infants.

UNLABELLED: Brain injuries remain a significant problem for preterm infants, despite extensive physiological monitoring. Near infrared spectroscopy (NIRS) monitoring in the neonatal intensive care unit has to date remained limited to research activities. CONCLUSION: This review highlights the increasing clinical application of NIRS in delivery suites and neonatal units. Four randomised controlled trials incorporating NIRS monitoring suggest that the future may indeed be brighter for this technology in the care of very preterm infants.

Outcome of 12 antenatally diagnosed fetal arachnoid cysts: case series and review of the literature.

OBJECTIVES: To investigate the natural history, associated abnormalities and outcome of 12 fetuses with arachnoid cyst diagnosed antenatally by ultrasound and magnetic resonance imaging and to compare the outcome with cases in the literature. METHODS: A retrospective study of all cases of antenatally detected fetal arachnoid cysts was performed in patients referred to a tertiary unit between 2007 and 2013. Associated abnormalities, pregnancy outcome and postnatal follow-up were analyzed. All papers about prenatally diagnosed arachnoid cysts, of the last 30 years, were evaluated (search terms in Pubmed: "prenatal diagnosis", "Arachnoid Cysts"). RESULTS: Fetal arachnoid cysts were diagnosed in 12 fetuses, 9 were females. The mean gestational age of diagnosis was 28 1/7 (range 19 1/7-34 2/7 weeks). A total of 9 cases were supratentorial, 3 were located in the posterior fossa. In 10 cases a fetal MRI was performed which confirmed brain compression in 4 out of 5 supratentorial arachnoid cyst. MRI did not reveal other malformations nor signs of nodular heterotopia. Only one fetus presented with additional major anomalies (bilateral ventricumomegaly of >20 mm and rhombencephalosynapsis) leading to a termination of pregnancy. Two neonates underwent endoscopic fenestration of the arachnoid cyst in the first week of life with no additional intervention in childhood. All but one (10/11) had a favorable postnatal outcome. This child suffered from visual impairment at autism was diagnosed at the age of 5. One child had a surgical correction of strabismus later in childhood. In one child the infratentorial arachnoid cyst regressed spontaneously on ultrasound and MRI in the postnatal period. CONCLUSIONS: The majority of arachnoid cysts in this series are of benign origin and remain stable. Based on the current series and the review of the literature, in the absence of other associated anomalies and when the karyotype is normal, the postnatal overall and neurological outcome is favorable. Large suprasellar arachnoid cysts however, may cause visual impairment and endocrinological disturbances. Rarely associated cerebral or cerebellar malformations are present. Modern postnatal management of suprasellar arachnoid cyst consists of endoscopic cystoventriculostomy.

Improvement of an automated neonatal seizure detector using a post-processing technique.

Visual recognition of neonatal seizures during continuous EEG monitoring in neonatal intensive care units (NICUs) is labor-intensive, has low inter-rater agreement and requires special expertise that is not available around the clock. Development of an accurate automated seizure detection system with a low false alarm rate will support clinical decision making and alleviate significantly the workload. However, this is an ongoing difficult challenge for engineers as the neonatal EEG signal is non-stationary and often includes complex patterns of seizures and artifacts. In this study, we show an improvement of our previously developed neonatal seizure detector (developed using heuristic if-then rules). In order to improve the detection accuracy, mean phase coherence as a new feature is used to characterize artifacts and also support vector machine is applied to perform the post-processing step to remove false detections. As a result, the false alarm rate drops 42% (from 2.6 h(-1) to 1.5 h(-1)), whereas the good detection rate reduces only by 4%.

Cognitive assessment of very low birth weight infants using the Dutch version of the PARCA-R parent questionnaire.

OBJECTIVE: Very low birth weight (VLBW) infants are at an increased risk of long-term cognitive impairment. Early identification and timely interventions are important. We aimed to validate the Dutch version of the revised Parent Report of Children's Abilities (PARCA-R) questionnaire. METHODS: The subjects were survivors from the Belgian participating centers to the NIRTURE trial. As part of a study-related follow-up, PARCA-R was sent out at the age of 2 years. As part of a normal hospital follow-up, these infants were assessed by the Bayley Scales of Infant Development - second edition (BSID-II) at the age of 9, 18 and 36 months. MRI was performed at term in the group of VLBW infants of ZOL Genk as standard care. RESULTS: PARCA-R was sent out to 193 surviving infants. BSID-II was performed in 36% (n=70) at 9 months, in 30% (n=58) at 18 months and in 12% (n=23) at 36 months. MRI was available for 32 infants. We received 86 responses to the PARCA-R. Parent report composite (PRC) scores were significantly correlated with the Mental Development Index (MDI) (p<0.0001 (9 months); p=0.003 (18 months); p=0.01 (36 months)). PRC scores were significantly lower in those with an abnormal MRI (92 vs.124; p=0.04). CONCLUSION: We support the use of the PARCA-R as a time and cost efficient alternative for identifying cognitive delay. PRACTICE IMPLICATIONS: We suggest that the combination of BSID-II, MRI at term and PARCA-R would be the ideal testing method for identifying VLBW infants at risk for cognitive developmental delay by two years of age.

Management of hypotension in preterm infants (The HIP Trial): a randomised controlled trial of hypotension management in extremely low gestational age newborns.

BACKGROUND: Extremely preterm babies (delivered at <28 completed weeks of gestation) are frequently diagnosed with hypotension and treated with inotropic and pressor drugs in the immediate postnatal period. Dopamine is the most commonly used first-line drug. Babies who are treated for hypotension more frequently sustain brain injury, have long-term disability or die compared to those who are not. Despite the widespread use of drugs to treat hypotension in such infants, evidence for efficacy is lacking, and the effect of these agents on long-term outcomes is unknown. HYPOTHESIS: In extremely preterm babies, restricting the use of dopamine when mean blood pressure (BP) values fall below a nominal threshold and using clinical criteria to determine escalation of support ('restricted' approach) will result in improved neonatal and longer-term developmental outcomes. RESEARCH PLAN: In an international multi-centre randomised trial, 830 infants born at <28 weeks of gestation, and within 72 h of birth, will be allocated to 1 of 2 alternative treatment options (dopamine vs. restricted approach) to determine the better strategy for the management of BP, using a conventional threshold to commence treatment. The first co-primary outcome of survival without brain injury will be determined at 36 weeks' postmenstrual age and the second co-primary outcome (survival without neurodevelopmental disability) will be assessed at 2 years of age, corrected for prematurity. DISCUSSION: It is essential that appropriately designed trials be performed to define the most appropriate management strategies for managing low BP in extremely preterm babies.