On time-frequence analysis of heart rate variability

The aim of this research is to develop a time-frequency method suitable to study HRV in greater detail. The following approach was used: • two known time-frequency representations were applied to HRV to understand its advantages and disadvantages in describing HRV in frequency and in amplitude, over time; • a new method was developed that describes the time-varying fluctuations in the characteristic frequency bands of HRV by means of the instantaneous frequency and the instantaneous amplitude with an optimal time-resolution; • an index was developed to separate the oscillatory from the irregular periods in the instantaneous frequency; • from the instantaneous amplitude and frequency, we derived summarizing parameters which we applied to describe the changes in the instantaneous amplitude and frequency over time for the oscillatory and irregular periods separatel

Measuring Instantaneous Frequency of Local Field Potential Oscillations using the Kalman Smoother

Rhythmic local field potentials (LFPs) arise from coordinated neural activity. Inference of neural function based on the properties of brain rhythms remains a challenging data analysis problem. Algorithms that characterize non-stationary rhythms with high temporal and spectral resolution may be useful for interpreting LFP activity on the timescales in which they are generated. We propose a Kalman smoother based dynamic autoregressive model for tracking the instantaneous frequency (iFreq) and frequency modulation (FM) of noisy and non-stationary sinusoids such as those found in LFP data. We verify the performance of our algorithm using simulated data with broad spectral content, and demonstrate its application using real data recorded from behavioral learning experiments. In analyses of ripple oscillations (100–250 Hz) recorded from the rodent hippocampus, our algorithm identified novel repetitive, short timescale frequency dynamics. Our results suggest that iFreq and FM may be useful measures for the quantification of small timescale LFP dynamics.National Institutes of Health (U.S.) (NIH/NIMH R01 MH59733)National Institutes of Health (U.S.) (NIH/NIHLB R01 HL084502)Massachusetts Institute of Technology (Henry E. Singleton Presidential Graduate Fellowship Award

A Time-Varying Non-Parametric Methodology for Assessing Changes in QT Variability Unrelated to Heart Rate Variability

OBJECTIVE: To propose and test a novel methodology to measure changes in QT interval variability (QTV) unrelated to RR interval variability (RRV) in non-stationary conditions. METHODS: Time-frequency coherent and residual spectra representing QTV related (QTVrRRV) and unrelated (QTVuRRV) to RRV, respectively, are estimated using time-frequency Cohen's class distributions. The proposed approach decomposes the non-stationary output spectrum of any two-input one-output model with uncorrelated inputs into two spectra representing the information related and unrelated to one of the two inputs, respectively. An algorithm to correct for the bias of the time-frequency coherence function between QTV and RRV is proposed to provide accurate estimates of both QTVuRRV and QTVrRRV. Two simulation studies were conducted to assess the methodology in challenging non-stationary conditions and data recorded during head-up tilt in 16 healthy volunteers were analyzed. RESULTS: In the simulation studies, QTVuRRV changes were tracked with only a minor delay due to the filtering necessary to estimate the non-stationary spectra. The correlation coefficient between theoretical and estimated patterns was >0.92 even for extremely noisy recordings (SNR in QTV =-10dB). During head-up tilt, QTVrRRV explained the largest proportion of QTV, whereas QTVuRRV showed higher relative increase than QTV or QTVrRRV in all spectral bands (P<0.05 for most pairwise comparisons). CONCLUSION: The proposed approach accurately tracks changes in QTVuRRV. Head-up tilt induced a slightly greater increase in QTVuRRV than in QTVrRRV. SIGNIFICANCE: The proposed index QTVuRRV may represent an indirect measure of intrinsic ventricular repolarization variability, a marker of cardiac instability associated with sympathetic ventricular modulation and sudden cardiac death

Fog Computing in Medical Internet-of-Things: Architecture, Implementation, and Applications

In the era when the market segment of Internet of Things (IoT) tops the chart in various business reports, it is apparently envisioned that the field of medicine expects to gain a large benefit from the explosion of wearables and internet-connected sensors that surround us to acquire and communicate unprecedented data on symptoms, medication, food intake, and daily-life activities impacting one's health and wellness. However, IoT-driven healthcare would have to overcome many barriers, such as: 1) There is an increasing demand for data storage on cloud servers where the analysis of the medical big data becomes increasingly complex, 2) The data, when communicated, are vulnerable to security and privacy issues, 3) The communication of the continuously collected data is not only costly but also energy hungry, 4) Operating and maintaining the sensors directly from the cloud servers are non-trial tasks. This book chapter defined Fog Computing in the context of medical IoT. Conceptually, Fog Computing is a service-oriented intermediate layer in IoT, providing the interfaces between the sensors and cloud servers for facilitating connectivity, data transfer, and queryable local database. The centerpiece of Fog computing is a low-power, intelligent, wireless, embedded computing node that carries out signal conditioning and data analytics on raw data collected from wearables or other medical sensors and offers efficient means to serve telehealth interventions. We implemented and tested an fog computing system using the Intel Edison and Raspberry Pi that allows acquisition, computing, storage and communication of the various medical data such as pathological speech data of individuals with speech disorders, Phonocardiogram (PCG) signal for heart rate estimation, and Electrocardiogram (ECG)-based Q, R, S detection.Comment: 29 pages, 30 figures, 5 tables. Keywords: Big Data, Body Area Network, Body Sensor Network, Edge Computing, Fog Computing, Medical Cyberphysical Systems, Medical Internet-of-Things, Telecare, Tele-treatment, Wearable Devices, Chapter in Handbook of Large-Scale Distributed Computing in Smart Healthcare (2017), Springe

Autonomic nervous system biomarkers from multi-modal and model-based signal processing in mental health and illness

Esta tesis se centra en técnicas de procesado multimodal y basado en modelos de señales para derivar parámetros fisiológicos, es decir, biomarcadores, relacionados con el sistema nervioso autónomo (ANS). El desarrollo de nuevos métodos para derivar biomarcadores de ANS no invasivos en la salud y la enfermedad mental ofrece la posibilidad de mejorar la evaluación del estrés y la monitorización de la depresión. Para este fin, el presente documento se estructura en tres partes principales. En la Parte I, se proporciona unaintroducción a la salud y la enfermedad mental (Cap. 1). Además, se presenta un marco teórico para investigar la etiología de los trastornos mentales y el papel del estrés en la enfermedad mental (Cap. 2). También se destaca la importancia de los biomarcadores no invasivos para la evaluación del ANS, prestando especial atención en la depresión clínica (Cap. 3, 4). En la Parte II, se proporciona el marco metodológico para derivar biomarcadores del ANS. Las técnicas de procesado de señales incluyen el análisis conjunto de la variabilidad del rítmo cardíaco (HRV) y la señal respiratoria (Cap. 6), técnicas novedosas para derivar la señal respiratoria del electrocardiograma (ECG) (Cap. 7) y un análisis robusto que se basa en modelar la forma de ondas del pulso del fotopletismograma (PPG) (Ch. 8). En la Parte III, los biomarcadores del ANS se evalúan en la quantificacióndel estrés (Cap. 9) y en la monitorización de la depresión (Ch. 10).Parte I: La salud mental no solo está relacionada con ese estado positivo de bienestar, en el que un individuo puede enfrentar a las situaciones estresantes de la vida, sino también con la ausencia de enfermedad mental. La enfermedad o trastorno mental se puede definir como un trastorno emocional, cognitivo o conductual que causa un deterioro funcional sustancial en una o más actividades importantes de la vida. Los trastornos mentales más comunes, que muchas veces coexisten, son la ansiedad y el trastorno depresivo mayor (MDD). La enfermedad mental tiene un impacto negativo en la calidad de vida, ya que se asocia con pérdidas considerables en la salud y el funcionamiento, y aumenta ignificativamente el riesgo de una persona de padecer enfermedades ardiovasculares.Un instigador común que subyace a la comorbilidad entre el MDD, la patologíacardiovascular y la ansiedad es el estrés mental. El estrés es común en nuestra vida de rítmo rapido e influye en nuestra salud mental. A corto plazo, ANS controla la respuesta cardiovascular a estímulos estresantes. La regulación de parámetros fisiológicos, como el rítmo cardíaco, la frecuencia respiratoria y la presión arterial, permite que el organismo responda a cambios repentinos en el entorno. Sin embargo, la adaptación fisiológica a un fenómeno ambiental que ocurre regularmente altera los sistemas biológicos involucrados en la respuesta al estrés. Las alteraciones neurobiológicas en el cerebro pueden alterar lafunción del ANS. La disfunción del ANS y los cambios cerebrales estructurales tienen un impacto negativo en los procesos cognitivos, emocionales y conductuales, lo que conduce al desarrollo de una enfermedad mental.Parte II: El desarrollo de métodos novedosos para derivar biomarcadores del ANS no invasivos ofrece la posibilidad de mejorar la evaluacón del estrés en individuos sanos y la disfunción del ANS en pacientes con MDD. El análisis conjunto de varias bioseñales (enfoquemultimodal) permite la cuantificación de interacciones entre sistemas biológicos asociados con ANS, mientras que el modelado de bioseãles y el análisis posterior de los parámetros del modelo (enfoque basado en modelos) permite la cuantificación robusta de cambios en mecanismos fisiológicos relacionados con el ANS. Un método novedoso, quetiene en cuenta los fenómenos de acoplo de fase y frecuencia entre la respiración y las señales de HRV para evaluar el acoplo cardiorrespiratorio no lineal cuadrático se propone en el Cap. 6.3. En el Cap. 7 se proponen nuevas técnicas paramejorar lamonitorización de la respiración. En el Cap. 8, para aumentar la robustez de algunas medidas morfológicas que reflejan cambios en el tonno arterial, se considera el modelado del pulso PPG como una onda principal superpuesta con varias ondas reflejadas.Parte III: Los biomarcadores del ANS se evalúan en la cuantificación de diferentes tipos de estrés, ya sea fisiológico o psicológico, en individuos sanos, y luego, en la monitorización de la depresión. En presencia de estrés mental (Cap. 9.1), inducido por tareas cognitivas, los sujetos sanos muestran un incremento en la frecuencia respiratoria y un mayor número de interacciones no lineales entre la respiración y la seãl de HRV. Esto podría estar asociado con una activación simpática, pero también con una respiración menos regular. En presencia de estrés hemodinámico (Cap. 9.2), inducido por un cambio postural, los sujetos sanos muestran una reducción en el acoplo cardiorrespiratoriono lineal cuadrático, que podría estar relacionado con una retracción vagal. En presencia de estrés térmico (Cap. 9.3), inducido por la exposición a emperaturas ambientales elevadas, los sujetos sanos muestran un aumento del equilibrio simpatovagal. Esto demuestra que los biomarcadores ANS son capaces de evaluar diferentes tipos de estrés y pueden explorarse más en el contexto de la monitorización de la depresión. En el Cap. 10, se evalúan las diferencias en la función del ANS entre elMDD y los sujetos sanos durante un protocolo de estrés mental, no solo con los valores brutos de los biomarcadores del ANS, sino también con los índices de reactividad autónoma, que reflejan la capacidad deun individuo para afrontar con una situación desafiante. Los resultados muestran que la depresión se asocia con un desequilibrio autonómico, que se caracteriza por una mayor actividad simpática y una reducción de la distensibilidad arterial. Los índices de reactividad autónoma cuantificados por cambios, entre etapas de estrés y de recuperación, en los sustitutos de la rigidez arterial, como la pérdida de amplitud de PPG en las ondas reflejadas, muestran el mejor rendimiento en términos de correlación con el grado de la depresión, con un coeficiente de correlación r = −0.5. La correlación negativa implicaque un mayor grado de depresión se asocia con una disminución de la reactividadautónoma. El poder discriminativo de los biomarcadores del ANS se aprecia también por su alto rendimiento diagnóstico para clasificar a los sujetos como MDD o sanos, con una precisión de 80.0%. Por lo tanto, se puede concluir que los biomarcadores del ANS pueden usarse para evaluar el estrés y que la distensibilidad arterial deteriorada podría constituir un biomarcador de salud mental útil en el seguimiento de la depresión.This dissertation is focused on multi-modal and model-based signal processing techniques for deriving physiological parameters, i.e. biomarkers, related to the autonomic nervous system (ANS). The development of novel approaches for deriving noninvasive ANS biomarkers in mental health and illness offers the possibility to improve the assessment of stress and the monitoring of depression. For this purpose, the present document is structured in three main parts. In Part I, an introduction to mental health and illness is provided (Ch. 1). Moreover, a theoretical framework for investigating the etiology of mental disorders and the role of stress in mental illness is presented (Ch. 2). The importance of noninvasive biomarkers for ANS assessment, paying particular attention in clinical depression, is also highlighted (Ch. 3, 4). In Part II, themethodological framework for deriving ANS biomarkers is provided. Signal processing techniques include the joint analysis of heart rate variability (HRV) and respiratory signals (Ch. 6), novel techniques for deriving the respiratory signal from electrocardiogram (ECG) (Ch. 7), and a robust photoplethysmogram(PPG)waveform analysis based on amodel-based approach (Ch. 8). In Part III, ANS biomarkers are evaluated in stress assessment (Ch. 9) and in the monitoring of depression (Ch. 10). Part I:Mental health is not only related to that positive state ofwell-being, inwhich an individual can cope with the normal stresses of life, but also to the absence of mental illness. Mental illness or disorder can be defined as an emotional, cognitive, or behavioural disturbance that causes substantial functional impairment in one or more major life activities. The most common mental disorders, which are often co-occurring, are anxiety and major depressive disorder (MDD). Mental illness has a negative impact on the quality of life, since it is associated with considerable losses in health and functioning, and increases significantly a person’s risk for cardiovascular diseases. A common instigator underlying the co-morbidity between MDD, cardiovascular pathology, and anxiety is mental stress. Stress is common in our fast-paced society and strongly influences our mental health. In the short term, ANS controls the cardiovascular response to stressful stimuli. Regulation of physiological parameters, such as heart rate, respiratory rate, and blood pressure, allows the organism to respond to sudden changes in the environment. However, physiological adaptation to a regularly occurring environmental phenomenon alters biological systems involved in stress response. Neurobiological alterations in the brain can disrupt the function of the ANS. ANS dysfunction and structural brain changes have a negative impact on cognitive, emotional, and behavioral processes, thereby leading to development of mental illness. Part II: The development of novel approaches for deriving noninvasive ANS biomarkers offers the possibility to improve the assessment of stress in healthy individuals and ANS dysfunction in MDD patients. Joint analysis of various biosignals (multi-modal approach) allows for the quantification of interactions among biological systems associated with ANS, while the modeling of biosignals and subsequent analysis of the model’s parameters (model-based approach) allows for the robust quantification of changes in physiological mechanisms related to the ANS. A novel method, which takes into account both phase and frequency locking phenomena between respiration and HRV signals, for assessing quadratic nonlinear cardiorespiratory coupling is proposed in Ch. 6.3. Novel techniques for improving the monitoring of respiration are proposed in Ch. 7. In Ch. 8, to increase the robustness for some morphological measurements reflecting arterial tone changes, the modeling of the PPG pulse as amain wave superposed with several reflected waves is considered. Part III: ANS biomarkers are evaluated in the assessment of different types of stress, either physiological or psychological, in healthy individuals, and then, in the monitoring of depression. In the presence of mental stress (Ch. 9.1), induced by cognitive tasks, healthy subjects show an increment in the respiratory rate and higher number of nonlinear interactions between respiration and HRV signal, which might be associated with a sympathetic activation, but also with a less regular breathing. In the presence of hemodynamic stress (Ch. 9.2), induced by a postural change, healthy subjects show a reduction in strength of the quadratic nonlinear cardiorespiratory coupling, whichmight be related to a vagal withdrawal. In the presence of heat stress (Ch. 9.3), induced by exposure to elevated environmental temperatures, healthy subjects show an increased sympathovagal balance. This demonstrates that ANS biomarkers are able to assess different types of stress and they can be further explored in the context of depression monitoring. In Ch. 10, differences in ANS function between MDD and healthy subjects during a mental stress protocol are assessed, not only with the raw values of ANS biomarkers but also with autonomic reactivity indices, which reflect the ability of an individual to copewith a challenging situation. Results show that depression is associated with autonomic imbalance, characterized by increased sympathetic activity and reduced arterial compliance. Autonomic reactivity indices quantified by changes, from stress to recovery, in arterial stiffness surrogates, such as the PPG amplitude loss in wave reflections, show the best performance in terms of correlation with depression severity, yielding to correlation coefficient r = −0.5. The negative correlation implies that a higher degree of depression is associated with a decreased autonomic reactivity. The discriminative power of ANS biomarkers is supported by their high diagnostic performance for classifying subjects as having MDD or not, yielding to accuracy of 80.0%. Therefore, it can be concluded that ANS biomarkers can be used for assessing stress and that impaired arterial compliance might constitute a biomarker of mental health useful in the monitoring of depression.<br /

Analysis and Modelling of Multimodal Interactions in Renal Autoregulation

By maintaining the volume and composition of the body fluids within narrow bounds and by producing a set of hormones that affect the blood vessels, the kidneys provide important long-term regulation of the blood pressure. Disturbances of kidney function can cause hypertension, a prevalent disease in modern societies. The kidneys protect their own function against short-term variations in the blood pressure. At the level of the individual functional unit (the nephron), pressure and flow control involves two different mechanisms: the tubuloglomerular feedback, which regulates the incoming blood flow in response to variations of the NaCl concentration of the tubular fluid near the terminal point of the loop of Henle (macula densa), and a myogenic mechanism by which the afferent arteriole regulates its diameter in response to variations in its transmural pressure. Experimentally, both of these mechanisms are found to produce oscillations. In the present study, analysis of experimental data of the tubular pressure and arteriole blood flow in combination with mechanism-based modelling has been used to answer the following questions: (i) How to reveal and characterize interactions between the two mechanisms of renal autoregulation? (ii) To what extend does nephron-to-nephron communication lead to cooperative behaviour? and (iii) How do intra- and inter-nephron interactions differ in normotensive and hypertensive rats? Analysis of experimental data revealed the presence of amplitude and frequency modulation, i.e. the regulation is provided not only by a change in the diameters of the active parts of the vessels, but also by an adjustment of the frequency of the myogenic oscillations. Interaction between the two mechanisms of renal autoregulation was found to be significantly stronger in spontaneously hypertensive rats than in normotensive rats. Synchronization phenomena in neighbouring nephrons were evaluated by measuring both frequency and phase entrainment. Statistical analysis showed that synchronization among mechanisms of renal autoregulation is reduced in hypertensive rats. With a probability exceeding 80%, normotensive rats demonstrated full entrainment in neighbouring nephrons where the oscillatory modes associated with two mechanisms of autoregulation were synchronized. Hypertensive rats displayed about half the probability of full synchronization and about twice the probability of partial synchronization, i.e. a state where neighbouring nephrons synchronize their slow tubuloglomerular feedback dynamics, while the fast myogenic dynamics remain desynchronized, or vice versa. Spontaneously hypertensive rats generally remained in synchrony for only 1/3 to 1/2 as long as the normotensive ones. Numerical simulations with a model of superficial nephrons connected via a flow mediated hemodynamic coupling and a vascular propagated coupling reproduced the experimentally observed patterns of behaviour. Lack of synchronization may be responsible for the development of irregular dynamics in the tubules of rats with experimental hypertension. The model has been extended by including deep nephrons for which it has not yet been possible to perform similar experimental measurements. Using available anatomical and physiological information we constructed a model of an nephron-vascular ensemble including superficial as well as deep nephrons with different length of loop of Henle. The computer simulation suggested that irregular dynamics of nephron ensemble increases at higher arterial pressures and values of the coupling strength. The model showed that, for physiologically reasonable parameter values, the deep nephrons do not synchronize with the superficial nephrons even though they are coupled via the same blood supply

Investigations of the neural mechanisms of cardiac stability

Electrical instability of the heart is known to precede the onset of lethal arrhythmias and the autonomic nervous system (ANS) is a primary factor in this process. However, the exact mechanisms of failure remain poorly understood. This work aims to better understand how ANS activity affects the electrical properties of the heart by investigating the effect of autonomic rhythms on the ventricular action potential duration (APD) recorded at tissue level using unipolar electrograms (UEGs). Studying dynamic behaviour of APD was associated with large data-sets of UEGs. Methods were developed to improve accuracy of automatic detection of APD, like narrow search windows and correlation filters to detect ambiguous activity. A simulation study was conducted to generate realistic UEG recordings to examine the effect of signal quality and filtering on tracking of APD dynamics. New insights were provided in how signal quality and filtering affect the accuracy of APD tracking. The proposed improvements were found to reduce the detection error substantially. The effect of autonomic rhythms on ventricular APD was explored using existing clinical data. By employing techniques to determine causality and time-frequency coherence, evidence was found that the ANS modulates ventricular electrophysiology: (1) with respiratory behaviour via a direct causal pathway, and (2) at a lower frequency and related to signs of enhanced sympathetic activity in blood pressure observed during mental stress. Further investigations were undertaken by designing and conducting a clinical experiment to study the effect of baroreceptor control on APD. Novel methodologies to determine the statistical significance of response curves were used to demonstrate for the first time that ventricular APD can be influenced by baroreceptor stimulation independent of heart rate. Identification of the neural mechanisms controlling cardiac stability may ultimately contribute to the development of new diagnostic tools and treatments to prevent thousands of deaths each year