Multiscale entropy analysis of heart rate variability in neonatal patients with and without seizures

The complex physiological dynamics of neonatal seizures make their detection challenging. A timely diagnosis and treatment, especially in intensive care units, are essential for a better prognosis and the mitigation of possible adverse effects on the newborn’s neurodevelopment. In the literature, several electroencephalographic (EEG) studies have been proposed for a parametric characterization of seizures or their detection by artificial intelligence techniques. At the same time, other sources than EEG, such as electrocardiography, have been investigated to evaluate the possible impact of neonatal seizures on the cardio-regulatory system. Heart rate variability (HRV) analysis is attracting great interest as a valuable tool in newborns applications, especially where EEG technologies are not easily available. This study investigated whether multiscale HRV entropy indexes could detect abnormal heart rate dynamics in newborns with seizures, especially during ictal events. Furthermore, entropy measures were analyzed to discriminate between newborns with seizures and seizure-free ones. A cohort of 52 patients (33 with seizures) from the Helsinki University Hospital public dataset has been evaluated. Multiscale sample and fuzzy entropy showed significant differences between the two groups (p-value < 0.05, Bonferroni multiple-comparison post hoc correction). Moreover, interictal activity showed significant differences between seizure and seizure-free patients (Mann-Whitney Test: p-value < 0.05). Therefore, our findings suggest that HRV multiscale entropy analysis could be a valuable pre-screening tool for the timely detection of seizure events in newborns

Neonatal seizure detection based on single-channel EEG: instrumentation and algorithms

Seizure activity in the perinatal period, which constitutes the most common neurological emergency in the neonate, can cause brain disorders later in life or even death depending on their severity. This issue remains unsolved to date, despite the several attempts in tackling it using numerous methods. Therefore, a method is still needed that can enable neonatal cerebral activity monitoring to identify those at risk. Currently, electroencephalography (EEG) and amplitude-integrated EEG (aEEG) have been exploited for the identification of seizures in neonates, however both lack automation. EEG and aEEG are mainly visually analysed, requiring a specific skill set and as a result the presence of an expert on a 24/7 basis, which is not feasible. Additionally, EEG devices employed in neonatal intensive care units (NICU) are mainly designed around adults, meaning that their design specifications are not neonate specific, including their size due to multi-channel requirement in adults - adults minimum requirement is ≥ 32 channels, while gold standard in neonatal is equal to 10; they are bulky and occupy significant space in NICU. This thesis addresses the challenge of reliably, efficiently and effectively detecting seizures in the neonatal brain in a fully automated manner. Two novel instruments and two novel neonatal seizure detection algorithms (SDAs) are presented. The first instrument, named PANACEA, is a high-performance, wireless, wearable and portable multi-instrument, able to record neonatal EEG, as well as a plethora of (bio)signals. This device despite its high-performance characteristics and ability to record EEG, is mostly suggested to be used for the concurrent monitoring of other vital biosignals, such as electrocardiogram (ECG) and respiration, which provide vital information about a neonate's medical condition. The two aforementioned biosignals constitute two of the most important artefacts in the EEG and their concurrent acquisition benefit the SDA by providing information to an artefact removal algorithm. The second instrument, called neoEEG Board, is an ultra-low noise, wireless, portable and high precision neonatal EEG recording instrument. It is able to detect and record minute signals (< 10 nVp) enabling cerebral activity monitoring even from lower layers in the cortex. The neoEEG Board accommodates 8 inputs each one equipped with a patent-pending tunable filter topology, which allows passband formation based on the application. Both the PANACEA and the neoEEG Board are able to host low- to middle-complexity SDAs and they can operate continuously for at least 8 hours on 3-AA batteries. Along with PANACEA and the neoEEG Board, two novel neonatal SDAs have been developed. The first one, termed G prime-smoothed (G ́_s), is an on-line, automated, patient-specific, single-feature and single-channel EEG based SDA. The G ́_s SDA, is enabled by the invention of a novel feature, termed G prime (G ́) and can be characterised as an energy operator. The trace that the G ́_s creates, can also be used as a visualisation tool because of its distinct change at a presence of a seizure. Finally, the second SDA is machine learning (ML)-based and uses numerous features and a support vector machine (SVM) classifier. It can be characterised as automated, on-line and patient-independent, and similarly to G ́_s it makes use of a single-channel EEG. The proposed neonatal SDA introduces the use of the Hilbert-Huang transforms (HHT) in the field of neonatal seizure detection. The HHT analyses the non-linear and non-stationary EEG signal providing information for the signal as it evolves. Through the use of HHT novel features, such as the per intrinsic mode function (IMF) (0-3 Hz) sub-band power, were also employed. Detection rates of this novel neonatal SDA is comparable to multi-channel SDAs.Open Acces

Hilbert-Huang Transform: biosignal analysis and practical implementation

Any system, however trivial, is subjected to data analysis on the signals it produces. Over the last 50 years the influx of new techniques and expansions of older ones have allowed a number of new applications, in a variety of fields, to be analysed and to some degree understood. One of the industries that is benefiting from this growth is the medical field and has been further progressed with the growth of interdisciplinary collaboration. From a signal processing perspective, the challenge comes from the complex and sometimes chaotic nature of the signals that we measure from the body, such as those from the brain and to some degree the heart. In this work we will make a contribution to dealing with such systems, in the form of a recent time-frequency data analysis method, the Hilbert-Huang Transform (HHT), and extensions to it. This thesis presents an analysis of the state of the art in seizure and heart arrhythmia detection and prediction methods. We then present a novel real-time implementation of the algorithm both in software and hardware and the motivations for doing so. First, we present our software implementation, encompassing realtime capabilities and identifying elements that need to be considered for practical use. We then translated this software into hardware to aid real-time implementation and integration. With these implementations in place we apply the HHT method to the topic of epilepsy (seizures) and additionally make contributions to heart arrhythmias and neonate brain dynamics. We use the HHT and some additional algorithms to quantify features associated with each application for detection and prediction. We also quantify significance of activity in such a way as to merge prediction and detection into one framework. Finally, we assess the real-time capabilities of our methods for practical use as a biosignal analysis tool

Multimodal image analysis of the human brain

Gedurende de laatste decennia heeft de snelle ontwikkeling van multi-modale en niet-invasieve hersenbeeldvorming technologieën een revolutie teweeg gebracht in de mogelijkheid om de structuur en functionaliteit van de hersens te bestuderen. Er is grote vooruitgang geboekt in het beoordelen van hersenschade door gebruik te maken van Magnetic Reconance Imaging (MRI), terwijl Elektroencefalografie (EEG) beschouwd wordt als de gouden standaard voor diagnose van neurologische afwijkingen. In deze thesis focussen we op de ontwikkeling van nieuwe technieken voor multi-modale beeldanalyse van het menselijke brein, waaronder MRI segmentatie en EEG bronlokalisatie. Hierdoor voegen we theorie en praktijk samen waarbij we focussen op twee medische applicaties: (1) automatische 3D MRI segmentatie van de volwassen hersens en (2) multi-modale EEG-MRI data analyse van de hersens van een pasgeborene met perinatale hersenschade. We besteden veel aandacht aan de verbetering en ontwikkeling van nieuwe methoden voor accurate en ruisrobuuste beeldsegmentatie, dewelke daarna succesvol gebruikt worden voor de segmentatie van hersens in MRI van zowel volwassen als pasgeborenen. Daarenboven ontwikkelden we een geïntegreerd multi-modaal methode voor de EEG bronlokalisatie in de hersenen van een pasgeborene. Deze lokalisatie wordt gebruikt voor de vergelijkende studie tussen een EEG aanval bij pasgeborenen en acute perinatale hersenletsels zichtbaar in MRI

Dynamic classifiers for neonatal brain monitoring

Brain injury due to lack of oxygen or impaired blood flow around the time of birth, may cause long term neurological dysfunction or death in severe cases. The treatments need to be initiated as soon as possible and tailored according to the nature of the injury to achieve best outcomes. The Electroencephalogram (EEG) currently provides the best insight into neurological activities. However, its interpretation presents formidable challenge for the neurophsiologists. Moreover, such expertise is not widely available particularly around the clock in a typical busy Neonatal Intensive Care Unit (NICU). Therefore, an automated computerized system for detecting and grading the severity of brain injuries could be of great help for medical staff to diagnose and then initiate on-time treatments. In this study, automated systems for detection of neonatal seizures and grading the severity of Hypoxic-Ischemic Encephalopathy (HIE) using EEG and Heart Rate (HR) signals are presented. It is well known that there is a lot of contextual and temporal information present in the EEG and HR signals if examined at longer time scale. The systems developed in the past, exploited this information either at very early stage of the system without any intelligent block or at very later stage where presence of such information is much reduced. This work has particularly focused on the development of a system that can incorporate the contextual information at the middle (classifier) level. This is achieved by using dynamic classifiers that are able to process the sequences of feature vectors rather than only one feature vector at a time

Improvements in Neonatal Brain Monitoring after Perinatal Asphyxia

Perinatal hypoxic ischemic encephalopathy (HIE) is a major cause of morbidity and mortality world-wide. Common sequelae in survivors include cerebral palsy (CP), epilepsy and sensory as well as cognitive problems. The consequences of HIE impose significant long-term personal and financial burden on the affected families and the society. The most cost-effective approach to reducing neonatal mortality world-wide would be to improve access to antenatal care4. However, even in developed countries, the exact factors triggering perinatal asphyxia as well as the time of onset of brain injury are often difficult to determine, and it remains a major clinical problem. Seizures commonly occur in the neonate with HIE and are often the only sign of serious underlying brain dysfunction6. Animal studies have shown that neonatal seizures in the context of HIE may cause additional brain injury and that their pharmacological suppression may improve outcome9. Monitoring of brain function using the electroencephalogram (EEG), continuously or by serial EEGs is well-suited to give insight into brain function and its dynamic changes in neonatal HIE and helps to guide treatment as well as prognostication. A good understanding of the pathophysiology of HIE is needed not only in the selection of suitable diagnostic tests and treatment methods, but also to develop new therapeutic strategies

Intelligent monitoring and interpretation of preterm physiological signals using machine learning

Every year, more than one in ten babies are born prematurely. In Ireland of the 70000 babies delivered every year, 4500 are born too early. Premature babies are at a higher risk of complications, which may lead to both short-term and long-term adverse health outcomes. The neonatal population is especially vulnerable and a delay in the identification of medical conditions, as well as delays in the initiating the correct treatment, may be fatal. After birth, preterms are admitted to the neonatal intensive care unit (NICU), where a continuous flow of information in the form of physiological signals is available. Physiological signals can assist clinicians in decision making related to the diagnosis and treatment of various diseases. This information, however, can be highly complex, and usually requires expert analysis which may not be available at all times. The work conducted in this thesis develops a decision support systems for the intelligent monitoring of preterms in the NICU. This will allow for an accurate estimation of the current health status of the preterm neonate as well as the prediction of possible long-term complications. This thesis is comprised of three main work packages (WP), each addressing health complication of preterm on three different stages of life. At the first 12 hours of life the health status is quantified using the clinical risk index for babies (CRIB). This is followed by the assessment of the preterm’s well-being at discharge from the NICU using the clinical course score (CCS). Finally, the long-term neurodevelopmental follow-up is assessed using the Bayley III scales of development at two years. This is schematically represented in Figure 1 along with the main findings and contributions. Low blood pressure (BP) or hypotension is a recognised problem in preterm infants particularly during the first 72 hours of life. Hypotension may cause decreased cerebral perfusion, resulting in deprived oxygen delivery to the brain. Deciding when and whether to treat hypotension relies on our understanding of the relation between BP, oxygenation and brain activity. The electroencephalogram (EEG) is the most commonly used technology to assess the ‘brain health’ of a newborn. The first WP investigates the relationship between short-term dynamics in BP and EEG energy in the preterm on a large dataset of continuous multi-channel unedited EEG recordings in the context of the health status measured by the CRIB score. The obtained results indicate that a higher risk of mortality for the preterm is associated with a lower level of nonlinear interaction between EEG and BP. The level of coupling between these two systems can potentially serve as an additional source of information when deciding whether or not to intervene in the preterm. The electrocardiogram (ECG) is also routinely recorded in preterm infants. Analysis of heart rate variability (HRV) provides a non-invasive assessment of both the sympathetic and parasympathetic control of the heart rate. A novel automated objective decision support tool for the prediction of the short-term outcome (CCS) in preterm neonates who may have low BP is proposed in the second WP. Combining multiple HRV features extracted during hypotensive episodes, the classifier achieved an AUC of 0.97 for the task of short-term outcome prediction, using a leave-one-patient-out performance assessment. The developed system is based on the boosted decision tree classifier and allows for the continuous monitoring of the preterm. The proposed system is validated on a large clinically collected dataset of multimodal recordings from preterm neonates. If the correct treatment is initiated promptly after diagnosis, it can potentially improve the neurodevelopmental outcome of the preterm infant. The third WP presents a pilot study investigating the predictive capability of the early EEG recorded at discharge from the NICU with respect to the 2-year neurodevelopmental outcome using machine learning techniques. Two methods are used: 1) classical feature-based classifier, and 2) end-to-end deep learning. This is a fundamental study in this area, especially in the context of applying end-to-end learning to the preterm EEG for the problem of long-term outcome prediction. It is shown that for the available labelled dataset of 37 preterm neonates, the classical feature-based approach outperformed the end-to-end deep learning technique. A discussion of the obtained result as well as a section highlighting the possible limitations and areas that need to be investigated in the future are provided