A Nonstationary Model of Newborn EEG

The detection of seizure in the newborn is a critical aspect of neurological research. Current automatic detection techniques are difficult to assess due to the problems associated with acquiring and labelling newborn electroencephalogram (EEG) data. A realistic model for newborn EEG would allow confident development, assessment and comparison of these detection techniques. This paper presents a model for newborn EEG that accounts for its self-similar and non-stationary nature. The model consists of background and seizure sub-models. The newborn EEG background model is based on the short-time power spectrum with a time-varying power law. The relationship between the fractal dimension and the power law of a power spectrum is utilized for accurate estimation of the short-time power law exponent. The newborn EEG seizure model is based on a well-known time-frequency signal model. This model addresses all significant time-frequency characteristics of newborn EEG seizure which include; multiple components or harmonics, piecewise linear instantaneous frequency laws and harmonic amplitude modulation. Estimates of the parameters of both models are shown to be random and are modelled using the data from a total of 500 background epochs and 204 seizure epochs. The newborn EEG background and seizure models are validated against real newborn EEG data using the correlation coefficient. The results show that the output of the proposed models has a higher correlation with real newborn EEG than currently accepted models (a 10% and 38% improvement for background and seizure models, respectively)

Modelling neonatal electroencephalogram time series

Creating a model for brain activity is a highly complex task; this is especially true in modelling neonatal electroencephalogram (EEG) signals. Whereas previous work is motivated by improving seizure detection, this research focuses on describing the development of these complicated multivariate signals. Using data collected from inpatients at University College London Hospital at different degrees of prematurity, we propose a model for background and somatosensory response neonatal EEG sig- nals and subsequently make inferences about the observed EEG signals using this model. We construct a univariate model for neonatal EEG by analysing the second order prop- erties of these signals, taking into account time segments which have time-heterogeneous second order properties. To do so we utilise time, frequency and time-frequency domain methods. The presented univariate model is combined with a time domain correlation structure to generate a multivariate representation which is possible, in part, due to the resolution of the data. Furthermore, the parameters and signal components are best described by taking into account not only the age at which testing occurred, but also the age at which an infant was born. This research has attempted to create a model that is not only descriptive of somatosensory responses, but also applicable in other avenues of similar research. We propose to use generalised linear models to describe the age dependence of the ob- served time series, and use these models to simulate EEG observations. When modelling characteristics of the estimated parameters, all models require the age pairing - age at birth and age at test - as variables. Combined with an appropriate time domain corre- lation structure, this allows us to achieve suitable estimates of observed signal structure. The model class presented is a flexible and accurate representation of neonatal back- ground and somatosensory response electroencephalogram signals, and can be used to describe similar multivariate observations

Design of a Simulator for Neonatal Multichannel EEG: Application to Time-Frequency Approaches for Automatic Artifact Removal and Seizure Detection

The electroencephalogram (EEG) is used to noninvasively monitor brain activities; it is the most utilized tool to detect abnormalities such as seizures. In recent studies, detection of neonatal EEG seizures has been automated to assist neurophysiologists in diagnosing EEG as manual detection is time consuming and subjective; however it still lacks the necessary robustness that is required for clinical implementation. Moreover, as EEG is intended to record the cerebral activities, extra-cerebral activities external to the brain are also recorded; these are called “artifacts” and can seriously degrade the accuracy of seizure detection. Seizures are one of the most common neurologic problems managed by hospitals occurring in 0.1%-0.5% livebirths. Neonates with seizures are at higher risk for mortality and are reported to be 55-70 times more likely to have severe cerebral-palsy. Therefore, early and accurate detection of neonatal seizures is important to prevent long-term neurological damage. Several attempts in modelling the neonatal EEG and artifacts have been done, but most did not consider the multichannel case. Furthermore, these models were used to test artifact or seizure detection separately, but not together. This study aims to design synthetic models that generate clean or corrupted multichannel EEG to test the accuracy of available artifact and seizure detection algorithms in a controlled environment. In this thesis, synthetic neonatal EEG model is constructed by using; single-channel EEG simulators, head model, 21-electrodes, and propagation equations, to produce clean multichannel EEG. Furthermore, neonatal EEG artifact model is designed using synthetic signals to corrupt EEG waveforms. After that, an automated EEG artifact detection and removal system is designed in both time and time-frequency domains. Artifact detection is optimised and removal performance is evaluated. Finally, an automated seizure detection technique is developed, utilising fused and extended multichannel features along a cross-validated SVM classifier. Results show that the synthetic EEG model mimics real neonatal EEG with 0.62 average correlation, and corrupted-EEG can degrade seizure detection average accuracy from 100% to 70.9%. They also show that using artifact detection and removal enhances the average accuracy to 89.6%, and utilising the extended features enhances it to 97.4% and strengthened its robustness.لمراقبة ورصد أنشطة واشارات المخ، دون الحاجة لأي عملیات (EEG) یستخدم الرسم أو التخطیط الكھربائي للدماغ للدماغجراحیة، وھي تعد الأداة الأكثر استخداما في الكشف عن أي شذوذأو نوبات غیر طبیعیة مثل نوبات الصرع. وقد أظھرت دراسات حدیثة، أن الكشف الآلي لنوبات حدیثي الولادة، ساعد علماء الفسیولوجیا العصبیة في تشخیص الاشارات الدماغیة بشكل أكبر من الكشف الیدوي، حیث أن الكشف الیدوي یحتاج إلى وقت وجھد أكبر وھوذو فعالیة أقل بكثیر، إلا أنھ لا یزال یفتقر إلى المتانة الضروریة والمطلوبة للتطبیق السریري.علاوة على ذلك؛ فكما یقوم الرسم الكھربائي بتسجیل الأنشطة والإشارات الدماغیة الداخلیة، فھو یسجل أیضا أي نشاط أو اشارات خارجیة، مما یؤدي إلى -(artifacts) :حدوث خلل في مدى دقة وفعالیة الكشف عن النوبات الدماغیة الداخلیة، ویطلق على تلك الاشارات مسمى (نتاج صنعي) . 0.5٪ولادة حدیثة في -٪تعد نوبات الصرع من أكثر المشكلات العصبیة انتشارا،ً وھي تصیب ما یقارب 0.1المستشفیات. حیث أن حدیثي الولادة المصابین بنوبات الصرع ھم أكثر عرضة للوفاة، وكما تشیر التقاریر الى أنھم 70مرة أكثر. لذا یعد الكشف المبكر والدقیق للنوبات الدماغیة -معرضین للإصابة بالشلل الدماغي الشدید بما یقارب 55لحدیثي الولادة مھم جدا لمنع الضرر العصبي على المدى الطویل. لقد تم القیام بالعدید من المحاولات التي كانتتھدف الى تصمیم نموذج التخطیط الكھربائي والنتاج الصنعي لدماغ حدیثي الولادة, إلا أن معظمھا لم یعر أي اھتمام الى قضیة تعدد القنوات. إضافة الى ذلك, استخدمت ھذه النماذج , كل على حدة, أو نوبات الصرع. تھدف ھذه الدراسة الى تصمیم نماذج مصطنعة من شأنھا (artifact) لإختبار كاشفات النتاج الصنعيأن تولد اشارات دماغیة متعددة القنوات سلیمة أو معطلة وذلك لفحص مدى دقة فعالیة خوارزمیات الكشف عن نوبات ضمن بیئة یمكن السیطرة علیھا. (artifact) الصرع و النتاج الصنعي في ھذه الأطروحة, یتكون نموذج الرسم الكھربائي المصطنع لحدیثي الولادة من : قناة محاكاة واحده للرسم الكھربائي, نموذج رأس, 21قطب كھربائي و معادلات إنتشار. حیث تھدف جمیعھا لإنتاج إشاراة سلیمة متعدده القنوات للتخطیط عن طریق استخدام اشارات مصطنعة (artifact) الكھربائي للدماغ.علاوة على ذلك, لقد تم تصمیم نموذجالنتاج الصنعيفي نطاقالوقت و (artifact) لإتلاف الرسم الكھربائي للدماغ. بعد ذلك تم انشاء برنامج لكشف و إزالةالنتاج الصناعينطاقالوقت و التردد المشترك. تم تحسین برنامج الكشف النتاج الصناعيالى ابعد ما یمكن بینما تمت عملیة تقییم أداء الإزالة. وفي الختام تم التمكن من تطویر تقنیة الكشف الآلي عن نوبات الصرع, وذلك بتوظیف صفات مدمجة و صفات الذي تم التأكد من صحتھ. (SVM) جدیدة للقنوات المتعددة لإستخدامھا للمصنفلقد أظھرت النتائج أن نموذج الرسم الكھربائي المصطنع لحدیثي الولادة یحاكي الرسمالكھربائي الحقیقي لحدیثي الولادة بمتوسط ترابط 0.62, و أنالرسم الكھربائي المتضرر للدماغ قد یؤدي الى حدوث ھبوطفي مدى دقة متوسط الكشف عن نوبات الصرع من 100%الى 70.9%. وقد أشارت أیضا الى أن استخدام الكشف والإزالة عن النتاج الصنعي (artifact) یؤدي الى تحسن مستوى الدقة الى نسبة 89.6 %, وأن توظیف الصفات الجدیدة للقنوات المتعددة یزید من تحسنھا لتصل الى نسبة 94.4 % مما یعمل على دعم متانتھا

Quantification of Cerebral Blood Flow and Oxidative Metabolism in Infants with Post-Hemorrhagic Ventricular Dilatation

Post-hemorrhagic ventricular dilatation (PHVD) is highly predictive of mortality and morbidity among very low birth weight preterm infants. Impaired cerebral blood flow (CBF) due to elevated intracranial pressure (ICP) is believed to be a contributing factor. In this study, a hyperspectral near-infrared spectroscopy (NIRS) method of measuring CBF and the cerebral metabolic rate of oxygen (CMRO2) was used to investigate perfusion and metabolism changes in patients receiving a ventricular tap (VT) based on clinical signs of elevated ICP. To improve measurement accuracy, the spectral analysis was modified to account for compression of the cortical mantle caused by PHVD and the possible presence of blood breakdown products. From 9 patients (27 VTs), a significant increase in CBF was measured (15.6%) following VT (14.6 ± 4.2 to 16.9 ± 6.6 ml/100g/min), but no corresponding change in CMRO2 (1.02 ± .41 ml O2/100g/min) was observed. Post-VT CBF was in good agreement with a control group of 13 patients with patent ductus arteriosus and no major cerebral pathology (16.5 ± 7.7 ml/100g/min), while StO2 was significantly lower in these patients (58.9 ± 12.1 versus 70.5 ± 9.1% for controls). This study demonstrates that PHVD impedes CBF; however, no change in CMRO2 was observed

Approaches to Quantifying EEG Features for Design Protocol Analysis

Recently, physiological signals such as eye-tracking and gesture analysis, galvanic skin response (GSR), electrocardiograms (ECG) and electroencephalograms (EEG) have been used by design researchers to extract significant information to describe the conceptual design process. We study a set of video-based design protocols recorded on subjects performing design tasks on a sketchpad while having their EEG monitored. The conceptual design process is rich with information on how designer’s do design. Many methods exist to analyze the conceptual design process, the most popular one being concurrent verbal protocols. A recurring problem in design protocol analysis is to segment and code protocol data into logical and semantic units. This is usually a manual step and little work has been done on fully automated segmentation techniques. Also, verbal protocols are known to fail in some circumstances such as when dealing with creativity, insight (e.g. Aha! experience, gestalt), concurrent, nonverbalizable (e.g. facial recognition) and nonconscious processes. We propose different approaches to study the conceptual design process using electroencephalograms (EEG). More specifically, we use spatio-temporal and frequency domain features. Our research is based on machine learning techniques used on EEG signals (functional microstate analysis), source localization (LORETA) and on a novel method of segmentation for design protocols based on EEG features. Using these techniques, we measure mental effort, fatigue and concentration in the conceptual design process, in addition to creativity and insight/nonverbalizable processing. We discuss the strengths and weaknesses of such approaches

Neural and socio-cognitive sequelae of congenital visual impairment during midchildhood

Previous studies identified cognitive difficulties in individuals with congenital visual impairment that significantly impacted on wellbeing and educational attainment. However, factors leading to adverse outcome remained unclear. The current study aimed to identify associations and mechanisms of specific cognitive deficits associated with visual impairment from a neurodevelopmental perspective. Based on recent theoretical advances (Johnson, 2011), it was assumed that visual impairment leads to differences in cognition by influencing experience-driven brain maturational processes, which support the integration between cortical areas to support cognitive processes. In order to explore this hypothesis, children with visual impairment due to disorders that were thought to only affect peripheral sensory parts of the visual system were assessed on neuropsychological instruments covering a range of functional domains. Further, structural and functional neurophysiological methods were employed to establish the impact of visual impairment on brain organisation. The results of the present work confirm earlier reports of specific deficits in spatial memory, social understanding, and aspects of executive function, despite typical performance in other domains. In addition, the current study is the first study to indicate dosage-dependence with some aspects of social communication being even impaired in children with only mild to moderate visual impairment, while aspects of executive function and spatial memory were only found to be deficient in children with more severe forms of visual impairment. Further, neurophysiological investigations indicated differences in structural and functional brain organisation in children with VI that related to differences in behavioural performance. In general, the results of the present study suggest that visual sensory impairment impacts on brain and cognitive development with important implications for education and clinical treatment of children with visual impairment

Quantitative analyses in basic, translational and clinical biomedical research: metabolism, vaccine design and preterm delivery prediction

2 t.There is nothing more important than preserving life, and the thesis here presented is framed in the field of quantitative biomedicine (or systems biomedicine), which has as objective the application of physico-mathematical techniques in biomedical research in order to enhance the understanding of life's basis and its pathologies, and, ultimately, to defend human health. In this thesis, we have applied physico-mathematical methods in the three fundamental levels of Biomedical Research: basic, translational and clinical. At a basic level, since all pathologies have their basis in the cell, we have performed two studies to deepen in the understanding of the cellular metabolic functionality. In the first work, we have quantitatively analyzed for the first time calcium-dependent chloride currents inside the cell, which has revealed the existence of a dynamical structure characterized by highly organized data sequences, non-trivial long-term correlation that last in average 7.66 seconds, and "crossover" effect with transitions between persistent and anti-persistent behaviors. In the second investigation, by the use of delay differential equations, we have modeled the adenylate energy system, which is the principal source of cellular energy. This study has shown that the cellular energy charge is determined by an oscillatory non-stationary invariant function, bounded from 0.7 to 0.95. At a translational level, we have developed a new method for vaccine design that, besides obtaining high coverages, is capable of giving protection against viruses with high mutability rates such as HIV, HCV or Influenza. Finally, at a clinical level, first we have proven that the classic quantitative measure of uterine contractions (Montevideo Units) is incapable of predicting preterm labor immediacy. Then, by applying autoregressive techniques, we have designed a novel tool for premature delivery forecasting, based only in 30 minutes of uterine dynamics. Altogether, these investigations have originated four scientific publications, and as far as we know, our work is the first European thesis which integrates in the same framework the application of mathematical knowledge to biomedical fields in the three main stages of Biomedical Research: basic, translational and clinical

Examining the development of brain structure in utero with fetal MRI, acquired as part of the Developing Human Connectome Project

The human brain is an incredibly complex organ, and the study of it traverses many scales across space and time. The development of the brain is a protracted process that begins embryonically but continues into adulthood. Although neural circuits have the capacity to adapt and are modulated throughout life, the major structural foundations are laid in utero during the fetal period, through a series of rapid but precisely timed, dynamic processes. These include neuronal proliferation, migration, differentiation, axonal pathfinding, and myelination, to name a few. The fetal origins of disease hypothesis proposed that a variety of non-communicable diseases emerging in childhood and adulthood could be traced back to a series of risk factors effecting neurodevelopment in utero (Barker 1995). Since this publication, many studies have shown that the structural scaffolding of the brain is vulnerable to external environmental influences and the perinatal developmental window is a crucial determinant of neurological health later in life. However, there remain many fundamental gaps in our understanding of it. The study of human brain development is riddled with biophysical, ethical, and technical challenges. The Developing Human Connectome Project (dHCP) was designed to tackle these specific challenges and produce high quality open-access perinatal MRI data, to enable researchers to investigate normal and abnormal neurodevelopment (Edwards et al., 2022). This thesis will focus on investigating the diffusion-weighted and anatomical (T2) imaging data acquired in the fetal period, between the second to third trimester (22 – 37 gestational weeks). The limitations of fetal MR data are ill-defined due to a lack of literature and therefore this thesis aims to explore the data through a series of critical and strategic analysis approaches that are mindful of the biophysical challenges associated with fetal imaging. A variety of analysis approaches are optimised to quantify structural brain development in utero, exploring avenues to relate the changes in MR signal to possible neurobiological correlates. In doing so, the work in this thesis aims to improve mechanistic understanding about how the human brain develops in utero, providing the clinical and medical imaging community with a normative reference point. To this aim, this thesis investigates fetal neurodevelopment with advanced in utero MRI methods, with a particular emphasis on diffusion MRI. Initially, the first chapter outlines a descriptive, average trajectory of diffusion metrics in different white matter fiber bundles across the second to third trimester. This work identified unique polynomial trajectories in diffusion metrics that characterise white matter development (Wilson et al., 2021). Guided by previous literature on the sensitivity of DWI to cellular processes, I formulated a hypothesis about the biophysical correlates of diffusion signal components that might underpin this trend in transitioning microstructure. This hypothesis accounted for the high sensitivity of the diffusion signal to a multitude of simultaneously occurring processes, such as the dissipating radial glial scaffold, commencement of pre-myelination and arborization of dendritic trees. In the next chapter, the methods were adapted to address this hypothesis by introducing another dimension, and charting changes in diffusion properties along developing fiber pathways. With this approach it was possible to identify compartment-specific microstructural maturation, refining the spatial and temporal specificity (Wilson et al., 2023). The results reveal that the dynamic fluctuations in the components of the diffusion signal correlate with observations from previous histological work. Overall, this work allowed me to consolidate my interpretation of the changing diffusion signal from the first chapter. It also serves to improve understanding about how diffusion signal properties are affected by processes in transient compartments of the fetal brain. The third chapter of this thesis addresses the hypothesis that cortical gyrification is influenced by both underlying fiber connectivity and cytoarchitecture. Using the same fetal imaging dataset, I analyse the tissue microstructural change underlying the formation of cortical folds. I investigate correlations between macrostructural surface features (curvature, sulcal depth) and tissue microstructural measures (diffusion tensor metrics, and multi-shell multi-tissue decomposition) in the subplate and cortical plate across gestational age, exploring this relationship both at the population level and within subjects. This study provides empirical evidence to support the hypotheses that microstructural properties in the subplate and cortical plate are altered with the development of sulci. The final chapter explores the data without anatomical priors, using a data-driven method to extract components that represent coordinated structural maturation. This analysis aims to examine if brain regions with coherent patterns of growth over the fetal period converge on neonatal functional networks. I extract spatially independent features from the anatomical imaging data and quantify the spatial overlap with pre-defined neonatal resting state networks. I hypothesised that coherent spatial patterns of anatomical development over the fetal period would map onto the functional networks observed in the neonatal period. Overall, this thesis provides new insight about the developmental contrast over the second to third trimester of human development, and the biophysical correlates affecting T2 and diffusion MR signal. The results highlight the utility of fetal MRI to research critical mechanisms of structural brain maturation in utero, including white matter development and cortical gyrification, bridging scales from neurobiological processes to whole brain macrostructure. their gendered constructions relating to women

3D motion : encoding and perception

The visual system supports perception and inferences about events in a dynamic, three-dimensional (3D) world. While remarkable progress has been made in the study of visual information processing, the existing paradigms for examining visual perception and its relation to neural activity often fail to generalize to perception in the real world which has complex dynamics and 3D spatial structure. This thesis focuses on the case of 3D motion, developing dynamic tasks for studying visual perception and constructing a neural coding framework to relate neural activity to perception in a 3D environment. First, I introduce target-tracking as a psychophysical method and develop an analysis framework based on state space models and the Kalman filter. I demonstrate that target-tracking in conjunction with a Kalman filter analysis framework produce estimates of visual sensitivity that are comparable to those obtained with a traditional forced-choice task and a signal detection theory analysis. Next, I use the target-tracking paradigm in a series of experiments examining 3D motion perception, specifically comparing the perception of frontoparallel motion with the perception of motion-through-depth. I find that continuous tracking of motion-through-depth is selectively impaired due to the relatively small retinal projections resulting from motion-through-depth and the slower processing of binocular disparities. The thesis then turns the neural representation of 3D motion and how that underlies perception. First I introduce a theoretical framework that extends the standard neural coding approach, incorporating the environment-to-retina transformation. Neural coding typically treats the visuals stimulus as a direct proxy for the pattern of stimulation that falls on the retina. Incorporating the environment-to-retina transformation results in a neural representation fundamentally shaped by the projective geometry of the world onto the retina. This model explains substantial anomalies in existing neurophysiological recordings in primate visual cortical neurons during presentations of 3D motion and in psychophysical studies of human perception. In a series of psychophysical experiments, I systematically examine the predictions of the model for human perception by observing how perceptual performance changes as a function of viewing distance and eccentricity. Performance in these experiments suggests a reliance on a neural representation similar to the one described by the model. Taken together, the experimental and theoretical findings reported here advance the understanding of the neural representation and perception of the dynamic 3D world, and adds to the behavioral tools available to vision scientists.Neuroscienc