Influence of the Main Filter on QRS-amplitude and Duration in Human Electrocardiogram.

Accurate measurement of electrocardiograms (ECG) is critical for effective diagnosis of patient’s cardiac functions. Detailed examination of filters’ effects on ECG accuracy, reproducibility and robustness covering a wide range of available commercial products can provide valuable information on the relationship between quality and effectiveness of filters, and assessments of patients’ cardiac functions. In this study, ECG device with 12 leads and built-in filters used for ECG measurements was assessed on human volunteers. Results showed that with respect to measuring QRS wave duration and R-amplitude variation, there was a 4 % inaccuracy when the main filter was ON and OFF, and R-amplitude variation was most pronounced in the V4 lead. Accordingly, variability of R-amplitude and length of QRS wave can be reduced by the use of appropriate lead, and filter activation during the ECG assessment

Surface mechanomyography and electromyography provide non-invasive indices of inspiratory muscle force and activation in healthy subjects

The current gold standard assessment of human inspiratory muscle function involves using invasive measures of transdiaphragmatic pressure (Pdi) or crural diaphragm electromyography (oesEMGdi). Mechanomyography is a non-invasive measure of muscle vibration associated with muscle contraction. Surface electromyogram and mechanomyogram, recorded transcutaneously using sensors placed over the lower intercostal spaces (sEMGlic and sMMGlic respectively), have been proposed to provide non-invasive indices of inspiratory muscle activation, but have not been directly compared to gold standard Pdi and oesEMGdi measures during voluntary respiratory manoeuvres. To validate the non-invasive techniques, the relationships between Pdi and sMMGlic, and between oesEMGdi and sEMGlic were measured simultaneously in 12 healthy subjects during an incremental inspiratory threshold loading protocol. Myographic signals were analysed using fixed sample entropy (fSampEn), which is less influenced by cardiac artefacts than conventional root mean square. Strong correlations were observed between: mean Pdi and mean fSampEn |sMMGlic| (left, 0.76; right, 0.81), the time-integrals of the Pdi and fSampEn |sMMGlic| (left, 0.78; right, 0.83), and mean fSampEn oesEMGdi and mean fSampEn sEMGlic (left, 0.84; right, 0.83). These findings suggest that sMMGlic and sEMGlic could provide useful non-invasive alternatives to Pdi and oesEMGdi for the assessment of inspiratory muscle function in health and disease.Peer ReviewedPostprint (published version

Extracting heart rate dependent electrocardiogram templates for a body emulator environment

Abstract. Medical device and analysis method developments often include tests on humans, which are expensive, time consuming, and sometimes even dangerous. In order to perform human tests, special safety conditions and ethical and legal requirements must be taken into account. Emulators that can emulate the physiological functions of the human body could solve these difficulties. In this study, the heart rate depended electrocardiogram templates for this kind of an emulator were extracted. The real-life electrocardiogram preprocessing included a high-pass filter and a Savitzky-Golay filter. A beat detection algorithm was developed to detect QRS complexes in the signals and classify beat artefacts based on the RR interval sequences and two adaptive thresholds. Heart rate levels were detected using the K-means clustering technique. Vectorcardiogram signals were converted from the electrocardiogram signals using the inverse Dower’s transformation matrix, and vectorcardiogram templates were extracted to the respective heart rate levels. Finally, a graphical user interface was created for the mentioned methods. The developed beat detection algorithm was tested with the MIT-BIH Arrhythmia Database and the comparison was made with the state-of-the-art algorithms. The beat detection algorithm resulted the sensitivity of 99.77 \%, precision of 99.65 \%, and detection error rate of 0.58 \%. Based on the results, the proposed methods and extracted vectorcardiogram templates were successful.Sykkeestä riippuvien elektrokardiogrammimallien poiminta kehoemulaattoriympäristöön. Tiivistelmä. Lääketieteellisten laitteiden ja analyysimenetelmien kehitystyö sisältää usein ihmisille suoritettavia testejä, jotka ovat kalliita, aikaa vieviä ja joskus jopa vaarallisia. Ihmiskokeiden toteuttamiseksi on otettava huomioon erityisiä turvallisuusehtoja, sekä eettisiä ja laillisia vaatimuksia. Emulaattorit, jotka pystyvät jäljittelemään ihmiskehon fysiologisia toimintoja, voivat olla ratkaisu näihin ongelmiin. Tässä tutkimuksessa sykkeestä riippuvia elektrokardiogrammimalleja poimittiin tämän tyyppiselle emulaattorille. Tosielämän elektrokardiogrammisignaalien esikäsittely sisälsi ylipäästösuodattimen ja Savitzky-Golay suodattimen. Sydämen lyöntien tunnistussalgoritmi kehitettiin tunnistamaan QRS-komplekseja signaaleista ja luokittelemaan lyöntiartefakteja RR-intervallisekvenssien ja kahden adaptiivisen kynnysarvon perusteella. Syketasot tunnistettiin käyttämällä K-means klusterointitekniikkaa. Vektorikardiogrammisignaalit muunnettiin elektrokardiogrammisignaaleista käyttämällä käänteistä Dowerin muunnosmatriisia ja vektorikardiogrammimallit poimittiin vastaaville syketasoille. Lopuksi luotiin graafnen käyttöliittymä mainituille menetelmille. Kehitetty lyöntien tunnistusalgoritmi testattiin MIT-BIH Arrhythmia Database-tietokannalla ja vertailu suoritettiin vastaavien algoritmien kanssa. Algoritmi suoriutui 99,77 % herkkyydellä, 99,65 % spesifsyydellä ja 0,58 % virheprosentilla. Tulosten perusteella ehdotetut menetelmät ja poimitut vektorikardiogrammimallit olivat onnistuneita

Reliable Detection of Myocardial Ischemia Using Machine Learning Based on Temporal-Spatial Characteristics of Electrocardiogram and Vectorcardiogram

Background: Myocardial ischemia is a common early symptom of cardiovascular disease (CVD). Reliable detection of myocardial ischemia using computer-aided analysis of electrocardiograms (ECG) provides an important reference for early diagnosis of CVD. The vectorcardiogram (VCG) could improve the performance of ECG-based myocardial ischemia detection by affording temporal-spatial characteristics related to myocardial ischemia and capturing subtle changes in ST-T segment in continuous cardiac cycles. We aim to investigate if the combination of ECG and VCG could improve the performance of machine learning algorithms in automatic myocardial ischemia detection. Methods: The ST-T segments of 20-second, 12-lead ECGs, and VCGs were extracted from 377 patients with myocardial ischemia and 52 healthy controls. Then, sample entropy (SampEn, of 12 ECG leads and of three VCG leads), spatial heterogeneity index (SHI, of VCG) and temporal heterogeneity index (THI, of VCG) are calculated. Using a grid search, four SampEn and two features are selected as input signal features for ECG-only and VCG-only models based on support vector machine (SVM), respectively. Similarly, three features (S ( I ), THI, and SHI, where S ( I ) is the SampEn of lead I) are further selected for the ECG + VCG model. 5-fold cross validation was used to assess the performance of ECG-only, VCG-only, and ECG + VCG models. To fully evaluate the algorithmic generalization ability, the model with the best performance was selected and tested on a third independent dataset of 148 patients with myocardial ischemia and 52 healthy controls. Results: The ECG + VCG model with three features (S ( I ),THI, and SHI) yields better classifying results than ECG-only and VCG-only models with the average accuracy of 0.903, sensitivity of 0.903, specificity of 0.905, F1 score of 0.942, and AUC of 0.904, which shows better performance with fewer features compared with existing works. On the third independent dataset, the testing showed an AUC of 0.814. Conclusion: The SVM algorithm based on the ECG + VCG model could reliably detect myocardial ischemia, providing a potential tool to assist cardiologists in the early diagnosis of CVD in routine screening during primary care services

Non-invasive techniques for respiratory information extraction based on pulse photoplethysmogram and electrocardiogram

El objetivo principal de esta tesis es el desarrollo de métodos no invasivos para la extracción de información respiratoria a partir de dos señales biomédicas ampliamente utilizadas en la rutina clínica: el electrocardiograma (ECG) y la señal fotopletismográfica de pulso (PPG). La motivación de este estudio es la conveniencia de monitorizar información respiratoria a partir de dispositivos no invasivos que permita sustituir las técnicas actuales que podrían interferir con la respiración natural y que presentan inconvenientes en algunas aplicaciones como la prueba de esfuerzo y los estudios del sueño. Además, si estos dispositivos no invasivos son los ya utilizados en la rutina clínica, la información respiratoria extraída de ellos representa un valor añadido que permite tener una visión más completa del paciente. DESARROLLO TEÓRICO Esta tesis se divide en 6 capítulos. El Capítulo 1 introduce la problemática, motivaciones y objetivos del estudio. También introduce el origen fisiológico de las señales estudiadas ECG y PPG, y cómo y por qué tienen información autonómica y respiratoria que se puede extraer de ellas. El Capítulo 2 aborda la obtención de información respiratoria a partir del ECG. Se han propuesto varios métodos para la obtención de la respiración a partir del ECG (EDR, del inglés ¿ECG derived respiration?). Su rendimiento se suele ver muy afectado en entornos altamente no estacionarios y ruidosos como la prueba de esfuerzo. No obstante, se han propuesto algunas alternativas, como una basada en el ángulo de rotación del eje eléctrico (obtenido del ECG), que es el que mejor funciona en prueba de esfuerzo según nuestros conocimientos. Este método requiere de tres derivaciones ortogonales y es muy dependiente de cada una de ellas, i.e., el método no es aplicable o su rendimiento se reduce significativamente si hay algún problema en alguna de las derivaciones requeridas. En el Capítulo 2 se propone un método EDR nuevo basado en las pendientes del QRS y el ángulo de la onda R. El Capítulo 3 aborda a obtención de información respiratoria a partir de la señal PPG. Se propone un método nuevo para obtener la tasa respiratoria a partir de la señal PPG. Explota una modulación respiratoria en la variabilidad de anchura de pulso (PWV) relacionada con la velocidad y dispersión de la onda de pulso. El Capítulo 4 aborda la extracción de información respiratoria a partir de señales PPG registradas con smarthpones (SCPPG), mediante la adaptación de los métodos basados en la señal PPG presentados en el Capítulo 3. En el Capítulo 5 se propone un método para el diagnóstico del síndrome de apnea obstructiva del sueño (OSAS) en niños basado únicamente en la señal PPG. El OSAS es una disfunción relacionada con la respiración y el sueño que se diagnostica mediante polisomnografía (PSG). La PSG es el registro nocturno de muchas señales durante el sueño, siendo muy difícil de aplicar en entornos ambulatorios. El método que presenta esta tesis está enfocado a diagnosticar el OSAS en niños utilizando únicamente la señal PPG que permitiría considerar un diagnóstico ambulatorio con sus ventajas económicas y sociales. Finalmente, el Capítulo 6 resume las contribuciones originales y las conclusiones principales de esta tesis, y propone posibles extensiones del trabajo. CONCLUSIÓN El método presentado en el Capítulo 2 para estimar la tasa respiratoria a partir de las pendientes del complejo QRS y el ángulo de la onda R en el ECG demostró ser robusto en entornos altamente no estacionarios y ruidosos y por tanto ser aplicable durante ejercicio incluyendo entrenamiento deportivo. Además, es independiente de un conjunto específico de derivaciones y, por tanto, un problema en alguna de ellas no implica una reducción considerable del rendimiento. El método presentado en el Capítulo 3 para estimar la tasa respiratoria a partir de la PWV extraída de la señal PPG está mucho menos afectada por el tono simpático que otros métodos presentados en la literatura que suelen basarse en la amplitud y/o la tasa de pulso. Esto permite una mayor precisión que otros métodos basados en PPG. Además, se propone un método para combinar información de diferentes señales respiratorias, y se utiliza para estimar la tasa respiratoria a partir de la PWV en combinación con otros métodos basados en la señal PPG, mejorando la precisión de la estimación incluso en comparación con otros métodos en la literatura que requieren el ECG o la presión sanguínea. Los métodos propuestos en el Capítulo 4 para estimar la tasa respiratoria mediante señales SCPPG estimaron de forma precisa la tasa respiratoria en sus rangos espontáneos habituales (0.2-0.4 Hz) e incluso a tasas más altas (hasta 0.5 Hz o 0.6 Hz, dependiendo del dispositivo utilizado). El único requerimiento es que el smartphone tenga un luz tipo flash y una cámara para grabar una yema del dedo sobre ella. La popularidad de los smartphones los convierte en dispositivos de acceso y aceptación r¿apidos. Así, para la población general es potencialmente aceptable un método que funciona en smartphones, pudiendo facilitar la medida de algunas constantes vitales utilizando solo la yema del dedo. El método presentado en el Capítulo 5 para el diagnóstico del OSAS en niños a partir de la PPG obtuvo una precisión suficiente para la clínica, aunque antes de ser aplicado en dicho entorno, el método debería ser validado en una base de datos más grande.The main objective of this thesis is to develop non-invasive methods for respiration information extraction from two biomedical signals which are widely adopted in clinical routine: the electrocardiogram (ECG) and the pulse photoplethysmographic (PPG) signal. This study is motivated by the desirability of monitoring respiratory information from non-invasive devices allowing to substitute the current respiration-monitoring techniques which may interfere with natural breathing and which are unmanageable in some applications such as stress test or sleep studies. Furthermore, if these noninvasive devices are those already used in the clinical routine, the respiratory information obtained from them represents an added value which allows a more complete overview of the patient status. This thesis is divided into 6 chapters. Chapter 1 of this thesis introduces the problematic, motivations and objectives of this study. It also introduces the physiological origin of studied ECG and PPG signals, and why and how they carry autonomic- and respiration-related information which can be extracted from them. Chapter 2 of this thesis addresses the derivation of respiratory information from ECG signal. Several ECG derived respiration (EDR) methods have been presented in literature. Their performance usually decrease considerably in highly non-stationary and noisy environments such as stress test. However, some alternatives aimed to this kind of environments have been presented, such as one based on electrical axis rotation angles (obtained from the ECG), which to the best of our knowledge was the best suited for stress test. This method requires three orthogonal leads, and it is very dependent on each one of those leads, i.e., the performance of the method is significantly decreased if there is any problem at any one of the required leads. A novel EDR method based on QRS slopes and R-wave angle is presented in this thesis. The proposed method demonstrated to be robust in highly non-stationary and noisy environments and so to be applicable to exercise conditions including sports training. Furthermore, it is independent on a specific lead set, and so, a problem at any lead do not imply a significantly reduction of the performance. Chapter 3 addresses the derivation of respiratory information from PPG signals. A novel method for deriving respiratory rate from PPG signal is presented. It exploits respiration-related modulations in pulse width variability (PWV) which is related to pulse wave velocity and dispersion. The proposed method is much less affected by the sympathetic tone than other methods in literature which are usually based on pulses amplitude and/or rate. This leads to highest accuracy than other PPG-based method. Furthermore, a method for combining information from several respiratory signals was developed and used to obtain a respiratory rate estimation from the proposed PWV-based in combination with other known PPG-based methods, improving the accuracy of the estimation and outperforming other methods in literature which involve ECG or BP recording. Chapter 4 addresses the derivation of respiratory information from smartphone- camera-acquired-PPG (SCPPG) signals by adapting the methods for deriving respiratory rate from PPG signal presented in Chapter 3. The proposed method accurately estimates respiratory rate from SCPPG signals at its normal spontaneous ranges (0.2-0.4 Hz) and even at higher rates (up to 0.5 Hz or 0.6 Hz, depending on the used device). The only requirement is that these smartphones and tablets contain a flashlight and a video camera to image a fingertip pressed to it. As smartphones and tablets have become common, they meet the criteria of ready access and acceptance. Hence, a mobile phone/tablet approach has the potential to be widely-accepted by the general population and can facilitate the capability to measure some of the vital signs using only fingertip of the subject. Chapter 5 of this thesis proposes a methodology for obstructive sleep apnea syndrome (OSAS) screening in children just based on PPG signal. OSAS is a sleep-respiration-related dysfunction for which polysomnography (PSG) is the gold standard for diagnosis. PSG consists of overnight recording of many signals during sleep, therefore, it is quite involved and difficult to use in ambulatory scenario. The method presented in this thesis is aimed to diagnose the OSAS in children based just on PPG signal which would allow us to consider an ambulatory diagnosis with both its social and economic advantages. Finally, Chapter 6 summarizes the original contributions and main conclusions of the thesis, and proposes possible extensions of the work

Identification of myocardial infarction by high-frequency serial ECG measurement

The purpose of this study is to attempt to identify acute myocardial infarction with high frequency serial electrocardiogram. High-frequency ECG and serial ECG are both unique ECG analysing techniques. The idea in this study is to combine these two and see if changes between different ECGs from the same person can provide us some information, whether it being in the high-frequency or normal frequency range of the ECG. To answer the questions, an existing database which contained multiple ECGs for each person with high sampling frequency was used. 5 different machine learning models were trained and tested with this database. The results of the machine learning methods were good, producing the mean accuracy of 91.9%, while the best model was the Extra Trees machine learning model. It produced the accuracy of 97.9% when applying cross-validation to the database. After these results, high-frequency serial ECG could be stated to be relevant. However, having ECG measured regularly can be expensive and time consuming. Therefore, the possibility of using a wearable ECG device was also studied. With a device called SAFE, developed by the University of Turku, a new high-frequency serial ECG database was gathered. The already existing machine learning model trained with the previous data was applied to this database and produced a mean accuracy of 90%. The quality of the ECGs gathered with the device were also deemed to be viable. Both high-frequency ECG and serial ECG were found to be relevant methods. A wearable device could be used for AMI detection if the ECG is sufficient enough. Future studies could include increasing the dataset size of the wearable device, investigate other myocardial diseases and exploring the possibilities of high-frequency ECG further

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 /