Multivariate assessment of linear and non-linear causal coupling pathways within the central-autonomic-network in patients suffering from schizophrenia

Im Bereich der Zeitreihenanalyse richtet sich das Interesse zunehmend darauf, wie Einblicke in die Interaktions- und Regulationsprozesse von pathophysiologischen- und physiologischen Zuständen erlangt werden können. Neuste Fortschritte in der nichtlinearen Dynamik, der Informationstheorie und der Netzwerktheorie liefern dabei fundiertes Wissen über Kopplungswege innerhalb (patho)physiologischer (Sub)Systeme. Kopplungsanalysen zielen darauf ab, ein besseres Verständnis dafür zu erlangen, wie die verschiedenen integrierten regulatorischen (Sub)Systeme mit ihren komplexen Strukturen und Regulationsmechanismen das globale Verhalten und die unterschiedlichen physiologischen Funktionen auf der Ebene des Organismus beschreiben. Insbesondere die Erfassung und Quantifizierung der Kopplungsstärke und -richtung sind wesentliche Aspekte für ein detaillierteres Verständnis physiologischer Regulationsprozesse. Ziel dieser Arbeit war die Charakterisierung kurzfristiger unmittelbarer zentral-autonomer Kopplungspfade (top-to-bottom und bottom to top) durch die Kopplungsanalysen der Herzfrequenz, des systolischen Blutdrucks, der Atmung und zentraler Aktivität (EEG) bei schizophrenen Patienten und Gesunden. Dafür wurden in dieser Arbeit neue multivariate kausale und nicht-kausale, lineare und nicht-lineare Kopplungsanalyseverfahren (HRJSD, mHRJSD, NSTPDC) entwickelt, die in der Lage sind, die Kopplungsstärke und -richtung, sowie deterministische regulatorische Kopplungsmuster innerhalb des zentralen-autonomen Netzwerks zu quantifizieren und zu klassifizieren. Diese Kopplungsanalyseverfahren haben ihre eigenen Besonderheiten, die sie einzigartig machen, auch im Vergleich zu etablierten Kopplungsverfahren. Sie erweitern das Spektrum neuartiger Kopplungsansätze für die Biosignalanalyse und tragen auf ihre Weise zur Gewinnung detaillierter Informationen und damit zu einer verbesserten Diagnostik/Therapie bei. Die Hauptergebnisse dieser Arbeit zeigen signifikant schwächere nichtlineare zentral-kardiovaskuläre und zentral-kardiorespiratorische Kopplungswege und einen signifikant stärkeren linearen zentralen Informationsfluss in Richtung des Herzkreislaufsystems auf, sowie einen signifikant stärkeren linearen respiratorischen Informationsfluss in Richtung des zentralen Nervensystems in der Schizophrenie im Vergleich zu Gesunden. Die detaillierten Erkenntnisse darüber, wie die verschiedenen zentral-autonomen Netzwerke mit paranoider Schizophrenie assoziiert sind, können zu einem besseren Verständnis darüber führen, wie zentrale Aktivierung und autonome Reaktionen und/oder Aktivierung in physiologischen Netzwerken unter pathophysiologischen Bedingungen zusammenhängen.In the field of time series analysis, increasing interest focuses on insights gained how the coupling pathways of regulatory mechanisms work in healthy and ill states. Recent advances in non-linear dynamics, information theory and network theory lead to a new sophisticated body of knowledge about coupling pathways within (patho)physiological (sub)systems. Coupling analyses aim to provide a better understanding of how the different integrated physiological (sub)systems, with their complex structures and regulatory mechanisms, describe the global behaviour and distinct physiological functions at the organism level. In particular, the detection and quantification of the coupling strength and direction are important aspects for a more detailed understanding of physiological regulatory processes. This thesis aimed to characterize short-term instantaneous central-autonomic-network coupling pathways (top-to-bottom and bottom to top) by analysing the coupling of heart rate, systolic blood pressure, respiration and central activity (EEG) in schizophrenic patients and healthy participants. Therefore, new multivariate causal and non-causal linear and non-linear coupling approaches (HRJSD, mHRJSD, NSTPDC) that are able to determine the coupling strength and direction were developed. Whereby, the HRJSD and mHRJSD approaches allow the quantification and classification of deterministic regulatory coupling patterns within and between the cardiovascular- the cardiorespiratory system and the central-autonomic-network were developed. These coupling approaches have their own unique features, even as compared to well-established coupling approaches. They expand the spectrum of novel coupling approaches for biosignal analysis and thus contribute in their own way to detailed information obtained, and thereby contribute to improved diagnostics/therapy. The main findings of this thesis revealed significantly weaker non-linear central-cardiovascular and central-cardiorespiratory coupling pathways, and significantly stronger linear central information flow in the direction of the cardiac- and vascular system, and a significantly stronger linear respiratory information transfer towards the central nervous system in schizophrenia in comparison to healthy participants. This thesis provides an enhanced understanding of the interrelationship of central and autonomic regulatory mechanisms in schizophrenia. The detailed findings on how variously-pronounced, central-autonomic-network pathways are associated with paranoid schizophrenia may enable a better understanding on how central activation and autonomic responses and/or activation are connected in physiology networks under pathophysiological conditions

Association between autonomic control indexes and mortality in subjects admitted to intensive care unit

This study checks whether autonomic markers derived from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and from their interactions with spontaneous or mechanical respiration (R) are associated with mortality in patients admitted to intensive care unit (ICU). Three-hundred consecutive HP, SAP and R values were recorded during the first day in ICU in 123 patients. Population was divided into survivors (SURVs, n = 83) and non-survivors (NonSURVs, n = 40) according to the outcome. SURVs and NonSURVs were aged-and gender-matched. All subjects underwent modified head-up tilt (MHUT) by tilting the bed back rest segment to 60 degrees. Autonomic control indexes were computed using time-domain, spectral, cross-spectral, complexity, symbolic and causality techniques via univariate, bivariate and conditional approaches. SAP indexes derived from time-domain, model-free complexity and symbolic approaches were associated with the endpoint, while none of HP variability markers was. The association was more powerful during MHUT. Linear cross-spectral and causality indexes were useless to separate SURVs from NonSURVs, while nonlinear bivariate symbolic markers were successful. When indexes were combined with clinical scores, only SAP variance provided complementary information. Cardiovascular control variability indexes, especially when derived after an autonomic challenge such as MHUT, can improve mortality risk stratification in ICU

Linear and nonlinear parameters of heart rate variability in ischemic stroke patients

Introduction Cardiovascular system presents cortical modulation. Post-stroke outcome can be highly influenced by autonomic nervous system disruption. Heart rate variability (HRV) analysis is a simple non-invasive method to assess sympatho-vagal balance. Objectives The purpose of this study was to investigate cardiac autonomic activity in ischemic stroke patients and to asses HRV nonlinear parameters beside linear ones. Methods We analyzed HRV parameters in 15 right and 15 left middle cerebral artery ischemic stroke patients, in rest condition and during challenge (standing and deep breathing). Data were compared with 15 age- and sex-matched healthy controls. Results There was an asymmetric response after autonomic stimulation tests depending on the cortical lateralization in ischemic stroke patients. In resting state, left hemisphere stroke patients presented enhanced parasympathetic control of the heart rate (higher values for RMSSD, pNN50 and HF in normalized units). Right hemisphere ischemic stroke patients displayed a reduced cardiac parasympathetic modulation during deep breathing test. Beside time and frequency domain, using short-term ECG monitoring, cardiac parasympathetic modulation can also be assessed by nonlinear parameter SD1, that presented strong positive correlation with time and frequency domain parameters RMSSD, pNN50, HFnu, while DFA α1 index presented negative correlation with the same indices and positive correlation with the LFnu and LF/HF ratio, indicating a positive association with the sympatho-vagal balance. Conclusions Cardiac monitoring in clinical routine using HRV analysis in order to identify autonomic imbalance may highlight cardiac dysfunctions, thus helping preventing potential cardiovascular complications, especially in right hemisphere ischemic stroke patients with sympathetic hyperactivation

Assessment of the dynamics of atrial signals and local atrial period series during atrial fibrillation: effects of isoproterenol administration

BACKGROUND: The autonomic nervous system (ANS) plays an important role in the genesis and maintenance of atrial fibrillation (AF), but quantification of its electrophysiologic effects is extremely complex and difficult. Aim of the study was to evaluate the capability of linear and non-linear indexes to capture the fine changing dynamics of atrial signals and local atrial period (LAP) series during adrenergic activation induced by isoproterenol (a sympathomimetic drug) infusion. METHODS: Nine patients with paroxysmal or persistent AF (aged 60 ± 6) underwent electrophysiological study in which isoproterenol was administered to patients. Atrial electrograms were acquired during i) sinus rhythm (SR); ii) sinus rhythm during isoproterenol (SRISO) administration; iii) atrial fibrillation (AF) and iv) atrial fibrillation during isoproterenol (AFISO) administration. The level of organization between two electrograms was assessed by the synchronization index (S), whereas the degree of recurrence of a pattern in a signal was defined by the regularity index (R). In addition, the level of predictability (LP) and regularity of LAP series were computed. RESULTS: LAP series analysis shows a reduction of both LP and R index during isoproterenol infusion in SR and AF (R(SR )= 0.75 ± 0.07 R(SRISO )= 0.69 ± 0.10, p < 0.0001; R(AF )= 0.31 ± 0.08 R(AFISO )= 0.26 ± 0.09, p < 0.0001; LP(SR )= 99.99 ± 0.001 LP(SRISO )= 99.97 ± 0.03, p < 0.0001; LP(AF )= 69.46 ± 21.55 LP(AFISO )= 55 ± 24.75; p < 0.0001). Electrograms analysis shows R index reductions both in SR (R(SR )= 0.49 ± 0.08 R(SRISO )= 0.46 ± 0.09 p < 0.0001) and in AF (R(AF )= 0.29 ± 0.09 R(AFISO )= 0.28 ± 0.08 n.s.). CONCLUSIONS: The proposed parameters succeeded in discriminating the subtle changes due to isoproterenol infusion during both the rhythms especially when considering LAP series analysis. The reduced value of analyzed parameters after isoproterenol administration could reflect an important pro-arrhythmic influence of adrenergic activation on favoring maintenance of AF

Concomitant evaluation of cardiovascular and cerebrovascular controls via Geweke spectral causality to assess the propensity to postural syncope

The evaluation of propensity to postural syncope necessitates the concomitant characterization of the cardiovascular and cerebrovascular controls and a method capable of disentangling closed loop relationships and decomposing causal links in the frequency domain. We applied Geweke spectral causality (GSC) to assess cardiovascular control from heart period and systolic arterial pressure variability and cerebrovascular regulation from mean arterial pressure and mean cerebral blood velocity variability in 13 control subjects and 13 individuals prone to develop orthostatic syncope. Analysis was made at rest in supine position and during head-up tilt at 60°, well before observing presyncope signs. Two different linear model structures were compared, namely bivariate autoregressive and bivariate dynamic adjustment classes. We found that (i) GSC markers did not depend on the model structure; (ii) the concomitant assessment of cardiovascular and cerebrovascular controls was useful for a deeper comprehension of postural disturbances; (iii) orthostatic syncope appeared to be favored by the loss of a coordinated behavior between the baroreflex feedback and mechanical feedforward pathway in the frequency band typical of the baroreflex functioning during the postural challenge, and by a weak cerebral autoregulation as revealed by the increased strength of the pressure-to-flow link in the respiratory band. GSC applied to spontaneous cardiovascular and cerebrovascular oscillations is a promising tool for describing and monitoring disturbances associated with posture modification

Development of new signal analysis methods as preoperative predictors of the Cox-Maze procedure outcome in atrial fibrillation

Atrial fibrilation (AF) is the most common cardiac arrhythmia, however, the knowledge about its causes and mechanisms is still uncompleted. Several studies suggest that atrial structural and electrophysiological remodeling are directly related to its development and perpetuation. To this respect, ECG and preoperative clinical data have been studied to analyze different aspects of atrial remodeling. Nonetheless, there is a lack of studies using ECG parameters to provide valuable clinical information in the study of AF aggressive treatments, such as the Cox-Maze surgery. In this work, ECG parameters such as fibrillatory (f) waves organization and amplitude are studied to predict patient's rhythm from the discharge after the Cox-Maze surgery until a twelve months follow up period. On the other hand, widely used clinical parameters such as age, AF duration and left atrial size (LA size) are studied to assess electrocardiographic results. In addition, clinical information known as a risk factor to develop AF such as weight and body mass index has also been analyze. After assess the individual indices, classification models were created in order to optimize the prediction capability. The results obtained reported that the ECG indices outperform the cinical indices. Nevertheless, the information contained in both types of indices is complementary as the generation of a classification model combining the indices shows. This model exceeded 90% accuracy in each period analyzed. In conclusion, studying the AF information contained in an ECG could provide new data to understand the AF and also could help to develop a reliable method to predict preoperatively the Cox-Maze outcome.La fibrilación auricular (FA) es la arritmia cardiaca más comúnmente encontrada en la práctica clínica diaria, sin embargo, todavía no se comprenden completamente los mecanismos fisiológicos que causan el inicio y la perpetuación de la FA. Diversos estudios sugieren que el remodelado estructural y electrofisiológico de la aurícula está relacionado directamente con el desarrollo y perpetuación de la FA. En este sentido, se ha estudiado el ECG e información clínica preoperatoria para analizar distintos aspectos del remodelado. Sin embargo, hay una falta de estudios usando parámetros electrocardiográficos para proporcionar información clínica valiosa en el estudio de tratamientos agresivos de la FA como la cirugía Cox-Maze. En este trabajo, se estudian parámetros electrocardiográficos como la organización de las ondas fibrilatorias y su amplitud para predecir el ritmo de los pacientes desde el momento del alta, tras la cirugía Cox-Maze hasta 12 meses después de la operación. Por otro lado, para evaluar la capacidad de dichos índices, se han utilizado parámetros clínicos ampliamente utilizados como la edad, el tamaño de la aurícula izquierda y el tiempo en FA. Además, se han estudiado también parámetros clínicos conocidos como factores de riesgo para desarrollar FA como son el peso y el índice de masa corporal. Tras analizar la capacidad predictiva de los índices individualmente, éstos se han combinado mediante la generación de modelos de predicción para optimizar la precisión de las predicciones. Los resultados obtenidos señalan que la información contenida en el ECG obtuvo resultados estadísticamente significativos y predicciones más precisas que los índices clínicos. No obstante, el desarrollo de modelos de predicción combinando ambos tipos de índices superó al uso de éstos por separado, con resultados por encima del 90% en todos los períodos estudiados. En conclusión, el análisis del ECG podría aportar nuevos enfoques a la hora de estudiar la FA, y su uso como herramienta de predicción podría ayudar a desarrollar tratamientos más eficientes y personalizados.La fibril·lació auricular (FA) és l'arítmia cardíaca més comunament trobada en la pràctica clínica diària, no obstant això, encara no es comprenen completament els mecanismes fisiològics que causen l'inici i la perpetuació de la FA. Diversos estudis suggerixen que el remodelat estructural i electrofisiològic de l'aurícula està relacionat directament amb el desenrotllament i perpetuació de la FA. En este sentit, s'ha estudiat l'ECG i informació clínica preoperatòria per a analitzar distints aspectes del remodelat. No obstant això, hi ha una falta d'estudis usant paràmetres electrocardiográficos per a proporcionar informació clínica valuosa en l'estudi de tractaments agressius de la FA com la cirurgia Cox-Maze. En este treball, s'estudien paràmetres electrocardiográficos com l'organització de les ones fibrilatorias i la seua amplitud per a predir el ritme dels pacients des del moment de l'alta, després de la cirurgia Cox-Maze fins a 12 mesos després de l'operació. Per un altre costat per a avaluar la capacitat dels dits índexs, s'han utilitzat paràmetres clínics àmpliament utilitzats com l'edat, la grandària de l'aurícula esquerra i el temps en FA. A més, s'han estudiat també paràmetres clínics coneguts com a factors de risc per a desenrotllar FA com són el pes i l'índex de massa corporal. Després d'analitzar la capacitat predictiva dels índexs individualment, estos s'han combinat per mitjà de la generació de models de predicció per a optimitzar la precisió de les prediccions. Els resultats obtinguts assenyalen que la informació continguda en l'ECG va obtindre resultats estadísticament significatius i prediccions més precises que els índexs clínics. No obstant això, el desenrotllament de models de predicció combinant ambdós tipus d'índexs va superar a l'ús d'estos per separat, amb resultats per damunt del 90% en tots els períodes estudiats. En conclusió, l'anàlisi de l'ECG podria aportar nous enfocaments a l'hora d'estudiar la FA, i el seu ús com a ferramenta de predicció podria ajudar a desenrotllar tractaments més eficients i personalitzats.Hernández Alonso, A. (2017). Development of new signal analysis methods as preoperative predictors of the Cox-Maze procedure outcome in atrial fibrillation [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/90491TESI

FEATURE EXTRACTION AND CLASSIFICATION THROUGH ENTROPY MEASURES

Entropy is a universal concept that represents the uncertainty of a series of random events. The notion \u201centropy" is differently understood in different disciplines. In physics, it represents the thermodynamical state variable; in statistics it measures the degree of disorder. On the other hand, in computer science, it is used as a powerful tool for measuring the regularity (or complexity) in signals or time series. In this work, we have studied entropy based features in the context of signal processing. The purpose of feature extraction is to select the relevant features from an entity. The type of features depends on the signal characteristics and classification purpose. Many real world signals are nonlinear and nonstationary and they contain information that cannot be described by time and frequency domain parameters, instead they might be described well by entropy. However, in practice, estimation of entropy suffers from some limitations and is highly dependent on series length. To reduce this dependence, we have proposed parametric estimation of various entropy indices and have derived analytical expressions (when possible) as well. Then we have studied the feasibility of parametric estimations of entropy measures on both synthetic and real signals. The entropy based features have been finally employed for classification problems related to clinical applications, activity recognition, and handwritten character recognition. Thus, from a methodological point of view our study deals with feature extraction, machine learning, and classification methods. The different versions of entropy measures are found in the literature for signals analysis. Among them, approximate entropy (ApEn), sample entropy (SampEn) followed by corrected conditional entropy (CcEn) are mostly used for physiological signals analysis. Recently, entropy features are used also for image segmentation. A related measure of entropy is Lempel-Ziv complexity (LZC), which measures the complexity of a time-series, signal, or sequences. The estimation of LZC also relies on the series length. In particular, in this study, analytical expressions have been derived for ApEn, SampEn, and CcEn of an auto-regressive (AR) models. It should be mentioned that AR models have been employed for maximum entropy spectral estimation since many years. The feasibility of parametric estimates of these entropy measures have been studied on both synthetic series and real data. In feasibility study, the agreement between numeral estimates of entropy and estimates obtained through a certain number of realizations of the AR model using Montecarlo simulations has been observed. This agreement or disagreement provides information about nonlinearity, nonstationarity, or nonGaussinaity presents in the series. In some classification problems, the probability of agreement or disagreement have been proved as one of the most relevant features. VII After feasibility study of the parametric entropy estimates, the entropy and related measures have been applied in heart rate and arterial blood pressure variability analysis. The use of entropy and related features have been proved more relevant in developing sleep classification, handwritten character recognition, and physical activity recognition systems. The novel methods for feature extraction researched in this thesis give a good classification or recognition accuracy, in many cases superior to the features reported in the literature of concerned application domains, even with less computational costs