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 /

Pathological Heart Rate Regulation in Apparently Healthy Individuals

Cardiovascular diseases are the leading cause of morbidity and mortality in adults worldwide. There is one common pathophysiological aspect present in all cardiovascular diseases—dysfunctional heart rhythm regulation. Taking this aspect into consideration for cardiovascular risk predictions opens important research perspectives, allowing for the development of preventive treatment techniques. The aim of this study was to find out whether certain pathologically appearing signs in the heart rate variability (HRV) of an apparently healthy person, even with high HRV, can be defined as biomarkers for a disturbed cardiac regulation and whether this can be treated preventively by a drug-free method. This multi-phase study included 218 healthy subjects of either sex, who consecutively visited the physician at Gesundheit clinic because of arterial hypertension, depression, headache, psycho-emotional stress, extreme weakness, disturbed night sleep, heart palpitations, or chest pain. In study phase A, baseline measurement to identify individuals with cardiovascular risks was done. Therefore, standard HRV, as well as the new cardiorhythmogram (CRG) method, were applied to all subjects. The new CRG analysis used here is based on the recently introduced LF drops and HF counter-regulation. Regarding the mechanisms of why these appear in a steady-state cardiorhythmmogram, they represent non-linear event-based dynamical HRV biomarkers. The next phase of the study, phase B, tested whether the pathologically appearing signs identified via CRG in phase A could be clinically influenced by drug-free treatment. In order to validate the new CRG method, it was supported by non-linear HRV analysis in both phase A and in phase B. Out of 218 subjects, the pathologically appearing signs could be detected in 130 cases (60%), p < 0.01, by the new CRG method, and by the standard HRV analysis in 40 cases (18%), p < 0.05. Thus, the CRG method was able to detect 42% more cases with pathologically appearing cardiac regulation. In addition, the comparative CRG analysis before and after treatment showed that the pathologically appearing signs could be clinically influenced without the use of medication. After treatment, the risk group decreased eight-fold—from 130 people to 16 (p < 0.01). Therefore, progression of the detected pathological signs to structural cardiac pathology or arrhythmia could be prevented in most of the cases. However, in the remaining risk group of 16 apparently healthy subjects, 8 people died due to all-cause mortality. In contrast, no other subject in this study has died so far. The non-linear parameter which is able to quantify the changes in CRGs before versus after treatment is FWRENYI4 (symbolic dynamic feature); it decreased from 2.85 to 2.53 (p < 0.001). In summary, signs of pathological cardiac regulation can be identified by the CRG analysis of apparently healthy subjects in the early stages of development of cardiac pathology. Thus, our method offers a sensitive biomarker for cardiovascular risks. The latter can be influenced by non-drug treatments (acupuncture) to stop the progression into structural cardiac pathologies or arrhythmias in most but not all of the patients. Therefore, this could be a real and easy-to-use supplemental method, contributing to primary prevention in cardiology.Peer Reviewe

Reflex syncope : an integrative physiological approach

Síncope, a forma mais comum de perda temporária de consciência é responsável por até 5% das idas aos serviços de emergência e até 3% dos internamentos hospitalares. É um problema médico frequente, com múltiplos gatilhos, incapacitante, potencialmente perigoso e desafiante em termos diagnósticos e terapêuticos. Assim, é necessária uma anamnese detalhada para primeiro estabelecer a natureza da perda de consciência, mas, após o diagnóstico, as medidas terapêuticas existentes são pouco eficazes. Embora a fisiopatologia da síncope vasovagal ainda não tenha sido completamente esclarecida, alguns mecanismos subjacentes foram já desvendados. Em última análise, a síncope depende de uma falha transitória na perfusão cerebral pelo que qualquer factor que afecte a circulação sanguínea cerebral pode determinar a ocorrência de síncope. Assim, o objectivo do presente estudo é caracterizar o impacto hemodinâmico e autonómico nos mecanismos subjacentes à síncope reflexa, para melhorar o diagnóstico, o prognóstico e a qualidade de vida dos doentes e dos seus cuidadores. Para isso, desenhámos e implementámos novas ferramentas matemáticas e computacionais que permitem uma avaliação autonómica e hemodinâmica integrada, de forma a aprofundar a compreensão do seu envolvimento nos mecanismos de síncope reflexa. Além disso, refinando a precisão do diagnóstico, a sensibilidade e a especificidade do teste de mesa de inclinação (“tilt test”), estabelecemos uma ferramenta preditiva do episódio iminente de síncope. Isso permitiu-nos estabelecer alternativas de tratamento eficazes e personalizadas para os doentes refractários às opções convencionais, sob a forma de um programa de treino de ortostatismo (“tilt training”), contribuindo para o aumento da sua qualidade de vida e para a redução dos custos directos e indirectos da sua assistência médica. Assim, num estudo verdadeiramente multidisciplinar envolvendo doentes com síncope reflexa refractária à terapêutica, conseguimos demonstrar uma assincronia funcional das respostas reflexas autonómicas e hemodinâmicas, expressas por um desajuste temporal entre o débito cardíaco e as adaptações de resistência total periférica, uma resposta baroreflexa atrasada e um desequilíbrio incremental do tónus autonómico que, em conjunto, poderão resultar de uma disfunção do sistema nervoso autónomo que se traduz por uma reserva simpática diminuída. Igualmente, desenhámos, testámos e implementámos uma plataforma computacional e respectivo software associado - a plataforma FisioSinal –incluindo novas formas, mais dinâmicas, de avaliação integrada autonómica e hemodinâmica, que levaram ao desenvolvimento de algoritmos preditivos para a estratificação de doentes com síncope. Além disso, na aplicação dessas ferramentas, comprovámos a eficácia de um tratamento não invasivo, não disruptivo e integrado, focado na neuromodulação das variáveis autonómicas e cardiovasculares envolvidas nos mecanismos de síncope. Esta terapêutica complementar levou a um aumento substancial da qualidade de vida dos doentes e à abolição dos eventos sincopais na grande maioria dos doentes envolvidos. Em conclusão, o nosso trabalho contribuiu para preencher a lacuna entre a melhor informação científica disponível e sua aplicação na prática clínica, sustentando-se nos três pilares da medicina translacional: investigação básica, clínica e comunidade.Syncope, the most common form of transient loss of consciousness, accounts for up to 5% of emergency room visits and up to 3% of hospital admissions. It is a frequent medical problem with multiple triggers, potentially dangerous, incapacitating, and challenging to diagnose. Therefore, a detailed clinical history is needed first to establish the nature of the loss of consciousness. However, after diagnosis, the therapeutic measures available are still very poor. Although the exact pathophysiology of vasovagal syncope remains to be clarified, some underlying mechanisms have been unveiled, dependent not only on the cause of syncope but also on age and various other factors that affect clinical presentation. Ultimately, syncope depends on a failure of the circulation to perfuse the brain, so any factor affecting blood circulation may determine syncope occurrence. Thus, the purpose of the present study is to understand the impact of the hemodynamic and autonomic functions on reflex syncope mechanisms to improve patients diagnose, prognosis and general quality of life. Bearing that in mind, we designed and implemented new mathematical and computational tools for autonomic and hemodynamic evaluation, in order to deepen the understanding of their involvement in reflex syncope mechanisms. Furthermore, by refining the diagnostic accuracy, sensitivity and specificity of the head-up tilt-table test, we established a predictive tool for the impending syncopal episode. This allowed us to establish effective and personalised treatment alternatives to patient’s refractory to conventional options, contributing to their increase in the quality of life and a reduction of health care and associated costs. In accordance, in a truly multidisciplinary study involving reflex syncope patients, we were able to show an elemental functional asynchrony of hemodynamic and autonomic reflex responses, expressed through a temporal mismatch between cardiac output and total peripheral resistance adaptations, a deferred baroreflex response and an unbalanced, but incremental, autonomic tone, all contributing to autonomic dysfunction, translated into a decreased sympathetic reserve. Through the design, testing and implementation of a computational platform and the associated software - FisioSinal platform -, we developed novel and dynamic ways of autonomic and hemodynamic evaluation, whose data lead to the development of predictive algorithms for syncope patients’risk stratification. Furthermore, through the application of these tools, we showed the effectiveness of a non-invasive, non-disruptive and integrated treatment, focusing on neuromodulation of the autonomic and cardiovascular variables involved in the syncope mechanisms, leading to a substantial increase of quality of life and the abolishment of syncopal events in a vast majority of the enrolled patients. In conclusion, our work contributed to fill the gap between the best available scientific information and its application in the clinical practice by tackling the three pillars of translational medicine: bench-side, bedside and community

An optimization method based on genetic algorithm for heart rate variability analysis in the prediction of the onset of cardiac arrhythmia

Heart rate variability (HRV) is one of the common biological markers for developing a diagnostic system of cardiovascular disease. HRV analysis is used to extract statistical, geometrical, spectral and non-linear features in such diagnostic system. The diagnostic accuracy can be maximized by applying a feature selection step that selects an optimal feature subset from the extracted features. However, there are shortcomings in using only the feature selection for optimizing a diagnostic system that is based on HRV analysis. One of the main limitations is that the parameters of HRV feature extraction algorithms are not optimized for maximal performance. In addition, the feature selection process does not consider the feature cost and misclassification error of the selected optimal feature subset. Therefore, this thesis proposes a multi-objective optimization method that is based on the non-dominated sorting genetic algorithm to overcome these shortcomings in a cardiac arrhythmia prediction system. It optimizes the HRV feature extraction parameters, selects the best feature subset, and tunes the classifier parameters simultaneously for maximum prediction performance. The proposed optimization algorithm is applied in two cardiac arrhythmia cases, namely the prediction of the onsets of paroxysmal atrial fibrillation (PAF) and ventricular tachyarrhythmia (VTA). In the proposed approach, trade-off between multiple optimization objectives that contradict to each other are also analyzed. The optimization objectives include the feature count, measurement cost, prediction sensitivity, specificity and accuracy rate. The following results prove the effectiveness of the proposed optimization algorithm in the two arrhythmia cases. Firstly, the PAF onset prediction achieves an accuracy rate of 89.6%, which significantly outperforms most of the previous works. This accuracy rate is achieved even with the HRV signal length being reduced from the typical 30 minutes to just 5 minutes (a reduction of 83%). In the case of VTA onset prediction, the accuracy rate of 78.15% is achieved with 5-minute signal length. This result outperforms previous works. Another significant result is the sensitivity rate improvement with the tradeoff of lower specificity and accuracy rate for both PAF and VTA onset predictions. For instance, the sensitivity rate of the VTA onset prediction system improved from 81.48% to 92.59% while the accuracy rate reduced from 78.15% to 72.59%

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias: use the right tool for the right outcome, in the right population

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European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias: use the right tool for the right outcome, in the right population.

In clinical practice and for scientific purposes, cardiologists and primary care physicians perform risk assessment in patients with cardiac diseases or conditions with high risk of developing such. The European Heart Rhythm Association (EHRA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) set down this expert consensus statement task force to summarize the consensus regarding risk assessment in cardiac arrhythmias. Objectives were to raise awareness of using the right risk assessment tool for a given outcome in a given population, and to provide physicians with practical proposals that may lead to rational and evidence-based risk assessment and improvement of patient care in this regard. A large variety of methods are used for risk assessment and choosing the best methods and tools hereof in a given situation is not simple. Even though parameters and test results found associated with increased risk of one outcome (e.g. death) may also be associated with higher risk of other adverse outcomes, specific risk assessment strategies should be used only for the purposes for which they are validated. The work of this task force is summarized in a row of consensus statement tables