Entropy-based nonlinear analysis for electrophysiological recordings of brain activity in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline. As AD progresses, changes in the electrophysiological brain activity take place. Such changes can be recorded by the electroencephalography (EEG) and magnetoencephalography (MEG) techniques. These are the only two neurophysiologic approaches able to directly measure the activity of the brain cortex. Since EEGs and MEGs are considered as the outputs of a nonlinear system (i.e., brain), there has been an interest in nonlinear methods for the analysis of EEGs and MEGs. One of the most powerful nonlinear metrics used to assess the dynamical characteristics of signals is that of entropy. The aim of this thesis is to develop entropy-based approaches for characterization of EEGs and MEGs paying close attention to AD. Recent developments in the field of entropy for the characterization of physiological signals have tried: 1) to improve the stability and reliability of entropy-based results for short and long signals; and 2) to extend the univariate entropy methods to their multivariate cases to be able to reveal the patterns across channels. To enhance the stability of entropy-based values for short univariate signals, refined composite multiscale fuzzy entropy (MFE - RCMFE) is developed. To decrease the running time and increase the stability of the existing multivariate MFE (mvMFE) while keeping its benefits, the refined composite mvMFE (RCmvMFE) with a new fuzzy membership function is developed here as well. In spite of the interesting results obtained by these improvements, fuzzy entropy (FuzEn), RCMFE, and RCmvMFE may still lead to unreliable results for short signals and are not fast enough for real-time applications. To address these shortcomings, dispersion entropy (DispEn) and frequency-based DispEn (FDispEn), which are based on our introduced dispersion patterns and the Shannon’s definition of entropy, are developed. The computational cost of DispEn and FDispEn is O(N) – where N is the signal length –, compared with the O(N2) for popular sample entropy (SampEn) and FuzEn. DispEn and FDispEn also overcome the problem of equal values for embedded vectors and discarding some information with regard to the signal amplitudes encountered in permutation entropy (PerEn). Moreover, unlike PerEn, DispEn and FDispEn are relatively insensitive to noise. As extensions of our developed DispEn, multiscale DispEn (MDE) and multivariate MDE (mvMDE) are introduced to quantify the complexity of univariate and multivariate signals, respectively. MDE and mvMDE have the following advantages over the existing univariate and multivariate multiscale methods: 1) they are noticeably faster; 2) MDE and mvMDE result in smaller coefficient of variations for synthetic and real signals showing more stable profiles; 3) they better distinguish various states of biomedical signals; 4) MDE and mvMDE do not result in undefined values for short time series; and 5) mvMDE, compared with multivariate multiscale SampEn (mvMSE) and mvMFE, needs to store a considerably smaller number of elements. In this Thesis, two restating-state electrophysiological datasets related to AD are analyzed: 1) 148-channel MEGs recorded from 62 subjects (36 AD patients vs. 26 age-matched controls); and 2) 16-channel EEGs recorded from 22 subjects (11 AD patients vs. 11 age-matched controls). The results obtained by MDE and mvMDE suggest that the controls’ signals are more and less complex at respectively short (scales between 1 to 4) and longer (scales between 5 to 12) scale factors than AD patients’ recordings for both the EEG and MEG datasets. The p-values based on Mann-Whitney U-test for AD patients vs. controls show that the MDE and mvMDE, compared with the existing complexity techniques, significantly discriminate the controls from subjects with AD at a larger number of scale factors for both the EEG and MEG datasets. Moreover, the smallest p-values are achieved by MDE (e.g., 0.0010 and 0.0181 for respectively MDE and MFE using EEG dataset) and mvMDE (e.g., 0.0086 and 0.2372 for respectively mvMDE and mvMFE using EEG dataset) for both the EEG and MEG datasets, illustrating the superiority of these developed entropy-based techniques over the state-of-the-art univariate and multivariate entropy approaches. Overall, the introduced FDispEn, DispEn, MDE, and mvMDE methods are expected to be useful for the analysis of physiological signals due to their ability to distinguish different types of time series with a low computation time

Advances in Clinical Neurophysiology

Including some of the newest advances in the field of neurophysiology, this book can be considered as one of the treasures that interested scientists would like to collect. It discusses many disciplines of clinical neurophysiology that are, currently, crucial in the practice as they explain methods and findings of techniques that help to improve diagnosis and to ensure better treatment. While trying to rely on evidence-based facts, this book presents some new ideas to be applied and tested in the clinical practice. Advances in Clinical Neurophysiology is important not only for the neurophysiologists but also for clinicians interested or working in wide range of specialties such as neurology, neurosurgery, intensive care units, pediatrics and so on. Generally, this book is written and designed to all those involved in, interpreting or requesting neurophysiologic tests

Analysis of consciousness for complete locked-in syndrome patients

This thesis presents methods for detecting consciousness in patients with complete locked-in syndrome (CLIS). CLIS patients are unable to speak and have lost all muscle movement. Externally, the internal brain activity of such patients cannot be easily perceived, but CLIS patients are considered to be still conscious and cognitively active. Detecting the current state of consciousness of CLIS patients is non-trivial, and it is difficult to ascertain whether CLIS patients are conscious or not. Thus, it is vital to develop alternative ways to re-establish communication with these patients during periods of awareness, and a possible platform is through brain–computer interface (BCI). Since consciousness is required to use BCI correctly, this study proposes a modus operandi to analyze not only in intracranial electrocorticography (ECoG) signals with greater signal-to-noise ratio (SNR) and higher signal amplitude, but also in non-invasive electroencephalography (EEG) signals. By applying three different time-domain analysis approaches sample entropy, permutation entropy, and Poincaré plot as feature extraction to prevent disease-related reductions of brainwave frequency bands in CLIS patients, and cross-validated to improve the probability of correctly detecting the conscious states of CLIS patients. Due to the lack a of 'ground truth' that could be used as teaching input to correct the outcomes, k-Means and DBSCAN these unsupervised learning methods were used to reveal the presence of different levels of consciousness for individual participation in the experiment first in locked-in state (LIS) patients with ALSFRS-R score of 0. The results of these different methods converge on the specific periods of consciousness of CLIS/LIS patients, coinciding with the period during which CLIS/LIS patients recorded communication with an experimenter. To determine methodological feasibility, the methods were also applied to patients with disorders of consciousness (DOC). The results indicate that the use of sample entropy might be helpful to detect awareness not only in CLIS/LIS patients but also in minimally conscious state (MCS)/unresponsive wakefulness syndrome (UWS) patients, and showed good resolution for both ECoG signals up to 24 hours a day and EEG signals focused on one or two hours at the time of the experiment. This thesis focus on consistent results across multiple channels to avoid compensatory effects of brain injury. Unlike most techniques designed to help clinicians diagnose and understand patients' long-term disease progression or distinguish between different disease types on the clinical scales of consciousness. The aim of this investigation is to develop a reliable brain-computer interface-based communication aid eventually to provide family members with a method for short-term communication with CLIS patients in daily life, and at the same time, this will keep patients' brains active to increase patients' willingness to live and improve their quality of life (QOL)

Neural Activity of 16p11.2 CNV Human and Mouse

Although rare in the population, individuals affected by deletions or duplications of DNA material at 16p11.2 chromosomal region (within the region ’11.2’ in the short arm of chromosome 16) are at higher risk of myriad clinical features and neurodevelopmental disorders including intellectual disability, developmental delays, and autism spectrum disorder. Whether inherited or appearing for the first time in the family, this 16p11.2 copy number variation (CNV) seems to impact on brain structure and function that may, in turn, drive the profile and severity of 16p11.2 associated phenotypes. As studies of 16p11.2 CNV brain function are scarce, the aim of this thesis is to investigate EEG activity in (human) 16p11.2 CNV carriers and parallel in-vivo electrophysiological activity in 16p11.2 deletion mouse model. Data-sharing platforms and collaborative efforts made it possible to access datasets of this rare population and analyse it for the purpose of this thesis. The thesis is comprised of three studies: 1) an investigation of visual-evoked neural variability, as measured by variability of intra-participant ERP and spectral power, and signal-to-noise ratio, in 16p11.2 CNV carriers; 2) a study of spontaneous neural activity, as measured by multi-scale entropy and conventional spectral power, in 16p11.2 deletion carriers; and 3) a study of spontaneous neural activity in 16p11.2 deletion mouse model. Neural variability was mostly higher in 16p11.2 deletion carriers relative to typical controls and 16p11.2 duplication carriers. Compared to typical controls, higher entropy was found in 16p11.2 deletion carriers and this was associated with certain psychiatric and behavioural traits, e.g., anxiety problems. The 16p11.2 deletion mice showed no group differences in neural activity compared to wild-type control mice. In conclusion, despite the lack of converging evidence from the mouse model, the collective 16p11.2 CNV human findings indicated that neural activity in 16p11.2 deletion carriers, especially, was altered and related to psychiatric traits found in 16p11.2 deletion carriers

Métodos avanzados de procesado de la señal de presión intracraneal durante los estudios de infusión en pacientes con hidrocefalia

El análisis espectral y la dinámica no lineal han permitido mejorar la capacidad diagnóstica de varias señales biomédicas. Durante los últimos años han surgido nuevas propuestas de análisis de la señal de presión intracraneal (PIC) basadas en la dinámica no lineal con unos resultados preliminares prometedores. Más concretamente, la regularidad y la complejidad del trazado de esta señal fisiológica disminuyen durante los periodos de hipertensión intracraneal en pacientes que han sufrido un traumatismo craneoencefálico (TCE) grave. El test de infusión es una prueba complementaria para el estudio de pacientes con hidrocefalia. Permite calcular la resistencia a la reabsorción de líquido cefalorraquídeo (ROUT), un parámetro que aumenta en las formas arreabsortivas de hidrocefalia. Al margen de su utilidad clínica, los estudios de infusión ponen a prueba los mecanismos de compensación del sistema craneoespinal infundiendo volumen. Este escenario permite investigar el comportamiento de la PIC en su tránsito desde un estado basal fisiológico hasta que se saturan los mecanismos de compensación y aparece hipertensión intracraneal. En esta memoria se pretende cuantificar y caracterizar el comportamiento de la señal PIC en el amplio rango de presiones que recorren los estudios de infusión, con métodos avanzados de procesado de señales derivados de la dinámica no lineal y el análisis espectral.Departamento de Medicína, Dermatología y Toxicologí

Quantitative texture analysis in MR imaging in the assessment of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease which is clinically characterized by cognitive impairment and memory loss. Anatomically, AD initially affects specific structures within the Medial Temporal Lobe (MTL), which are essential for declarative memory. A definitive diagnosis of AD relies on post-mortem biopsy therefore, clinical assessment and cognitive tests are currently used. However, these tests are not sensitive to detect AD in an early stage. The aim of this research was to investigate the usefulness of quantitative Magnetic Resonance Imaging (MRI) and specifically of texture features in the assessment of Mild Cognitive Impairment (MCI) which is the pre-dementia stage and AD. Firstly, two types of magnetic fields where investigated in order to examine whether, a stronger MR magnetic field would benefit quantitative imaging analysis derived from texture features. Secondly, texture features were extracted from the entorhinal cortex and evaluated in the diagnosis and prediction of MCI and AD. To the best of our knowledge this is the first research that investigated how the MR field strength affects texture features and used entorhinal cortex texture features on the assessment of AD. The main results of this PhD showed that (1) texture features could provide more sensitive measures when they are extracted from stronger MRI magnetic field, such as 3T, compared to 1.5T. From a disease classification and prediction perspective, (2) entorhinal cortex texture features provide better classification between Normal Controls (NC), MCI and AD subjects, and (3) better prediction of the conversion from MCI to AD. In conclusion, this research has shown for the first time in the literature that entorhinal cortex texture features from MRI could contribute towards the early classification of AD

Characterising evoked potential signals using wavelet transform singularity detection

This research set out to develop a novel technique to decompose Electroencephalograph (EEG) signal into sets of constituent peaks in order to better describe the underlying nature of these signals. It began with the question; can a localised, single stimulation of sensory nervous tissue in the body be detected in the brain? Flash Visual Evoked Potential (VEP) tests were carried out on 3 participants by presenting a flash and recording the response in the occipital region of the cortex. By focussing on analysis techniques that retain a perspective across different domains - temporal (time), spectral (frequency/scale) and epoch (multiple events) - useful information was detected across multiple domains, which is not possible in single domain transform techniques. A comprehensive set of algorithms to decompose evoked potential data into sets of peaks was developed and test ed using wavelet transform singularity detection methods. The set of extracted peaks then forms the basis for a subsequent clustering analysis which identifies sets of localised peaks that contribute the most towards the standard evoked response. The technique is quite novel as no closely similar work in research has been identified. New and valuable insights into the nature of an evoked potential signal have been identified. Although the number of stimuli required to calculate an Evoked Potential response has not been reduced, the amount of data contributing to this response has been effectively reduced by 75%. Therefore better examination of a small subset of the evoked potential data is possible. Furthermore, the response has been meaningfully decomposed into a small number (circa 20) of constituent peaksets that are defined in terms of the peak shape (time location, peak width and peak height) and number of peaks within the peak set. The question of why some evoked potential components appear mor e strongly than others is probed by this technique. Delineation between individual peak sizes and how often they occur is for the first time possible and this representation helps to provide an understanding of how particular evoked potentials components are made up. A major advantage of this techniques is the there are no pre-conditions, constraints or limitations. These techniques are highly relevant to all evoked potential modalities and other brain signal response applications - such as in brain-computer interface applications. Overall, a novel evoked potential technique has been described and tested. The results provide new insights into the nature of evoked potential peaks with potential application across various evoked potential modalities