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 /

Complexity Variability Assessment of Nonlinear Time-Varying Cardiovascular Control

The application of complex systems theory to physiology and medicine has provided meaningful information about the nonlinear aspects underlying the dynamics of a wide range of biological processes and their disease-related aberrations. However, no studies have investigated whether meaningful information can be extracted by quantifying second-order moments of time-varying cardiovascular complexity. To this extent, we introduce a novel mathematical framework termed complexity variability, in which the variance of instantaneous Lyapunov spectra estimated over time serves as a reference quantifier. We apply the proposed methodology to four exemplary studies involving disorders which stem from cardiology, neurology and psychiatry: Congestive Heart Failure (CHF), Major Depression Disorder (MDD), Parkinson?s Disease (PD), and Post-Traumatic Stress Disorder (PTSD) patients with insomnia under a yoga training regime. We show that complexity assessments derived from simple time-averaging are not able to discern pathology-related changes in autonomic control, and we demonstrate that between-group differences in measures of complexity variability are consistent across pathologies. Pathological states such as CHF, MDD, and PD are associated with an increased complexity variability when compared to healthy controls, whereas wellbeing derived from yoga in PTSD is associated with lower time-variance of complexity

Assessment of linear and nonlinear/complex heartbeat dynamics in subclinical depression (dysphoria)

Objective: Depression is one of the leading causes of disability worldwide. Most previous studies have focused on major depression, and studies on subclinical depression, such as those on so-called dysphoria, have been overlooked. Indeed, dysphoria is associated with a high prevalence of somatic disorders, and a reduction of quality of life and life expectancy. In current clinical practice, dysphoria is assessed using psychometric questionnaires and structured interviews only, without taking into account objective pathophysiological indices. To address this problem, in this study we investigated heartbeat linear and nonlinear dynamics to derive objective autonomic nervous system biomarkers of dysphoria. Approach: Sixty undergraduate students participated in the study: according to clinical evaluation, 24 of them were dysphoric. Extensive group-wise statistics was performed to characterize the pathological and control groups. Moreover, a recursive feature elimination algorithm based on a K-NN classifier was carried out for the automatic recognition of dysphoria at a single-subject level. Main results: The results showed that the most significant group-wise differences referred to increased heartbeat complexity (particularly for fractal dimension, sample entropy and recurrence plot analysis) with regards to the healthy controls, confirming dysfunctional nonlinear sympatho-vagal dynamics in mood disorders. Furthermore, a balanced accuracy of 79.17% was achieved in automatically distinguishing dysphoric patients from controls, with the most informative power attributed to nonlinear, spectral and polyspectral quantifiers of cardiovascular variability. Significance: This study experimentally supports the assessment of dysphoria as a defined clinical condition with specific characteristics which are different both from healthy, fully euthymic controls and from full-blown major depression

Complexity index from a personalized wearable monitoring system for assessing remission in mental health

This study discusses a personalized wearable monitoring system, which provides information and communication technologies to patients with mental disorders and physicians managing such diseases. The system, hereinafter called the PSYCHE system, is mainly comprised of a comfortable t-shirt with embedded sensors, such as textile electrodes, to monitor electrocardiogram-heart rate variability (HRV) series, piezoresistive sensors for respiration activity, and triaxial accelerometers for activity recognition. Moreover, on the patient-side, the PSYCHE system uses a smartphone-based interactive platform for electronic mood agenda and clinical scale administration, whereas on the physician-side provides data visualization and support to clinical decision. The smartphone collects the physiological and behavioral data and sends the information out to a centralized server for further processing. In this study, we present experimental results gathered from ten bipolar patients, wearing the PSYCHE system, with severe symptoms who exhibited mood states among depression (DP), hypomania(HM), mixed state (MX), and euthymia (EU), i.e., the good affective balance. In analyzing more than 400 h of cardiovascular dynamics, we found that patients experiencing mood transitions from a pathological mood state (HM, DP, or MX - where depressive and hypomanic symptoms are simultaneously present) to EU can be characterized through a commonly used measure of entropy. In particular, the SampEn estimated on long-term HRV series increases according to the patients' clinical improvement. These results are in agreement with the current literature reporting on the complexity dynamics of physiological systems and provides a promising and viable support to clinical decision in order to improve the diagnosis and management of psychiatric disorders

Blunted autonomic reactivity to mental stress in depression quantified by nonlinear cardiorespiratory coupling indices

In this study, differences in autonomic reactivity to mental stress between Major Depressive Disorder (MDD) patients and healthy control (HC) subjects are assessed by nonlinear cardiorespiratory coupling indices derived from the Real Wavelet Biphase. The degree and strength of Quadratic Phase Coupling (QPC) between interacting oscillations of Heart Rate Variability (HRV) and respiration are quantified before, during and after the execution of acognitive task. Results show that the QPC strength and QPC degree between the respiration and the respiratory sinus arrhythmia component of HRV were lower in HC compared to MDD during stress, suggesting that the parasympathetic branch was less inhibited in MDD patients. During recovery, only in HC group, this degree of QPC increased, while the respiratory rate was reduced, compared to the basal stage. The degree of QPC between the respiration and components of HRV in the low frequency band ([0.04, 0.15] Hz) increased in HC during stress, compared to the basal stage, while remained unchanged in MDD patients. These results imply that depression is associated with blunted autonomic reactivity to mental stres

When Heart Beats Differently in Depression: Review of Nonlinear Heart Rate Variability Measures

Background: Disturbed heart dynamics in depression seriously increases mortality risk. Heart rate variability (HRV) is a rich source of information for studying this dynamics. This paper is a meta-analytic review with methodological commentary of the application of nonlinear analysis of HRV and its possibility to address cardiovascular diseases in depression. Objective: This paper aimed to appeal for the introduction of cardiological screening to patients with depression, because it is still far from established practice. The other (main) objective of the paper was to show that nonlinear methods in HRV analysis give better results than standard ones. Methods: We systematically searched on the web for papers on nonlinear analyses of HRV in depression, in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 framework recommendations. We scrutinized the chosen publications and performed random-effects meta-analysis, using the esci module in jamovi software where standardized effect sizes (ESs) are corrected to yield the proof of the practical utility of their results. Results: In all, 26 publications on the connection of nonlinear HRV measures and depression meeting our inclusion criteria were selected, examining a total of 1537 patients diagnosed with depression and 1041 healthy controls (N=2578). The overall ES (unbiased) was 1.03 (95% CI 0.703-1.35; diamond ratio 3.60). We performed 3 more meta-analytic comparisons, demonstrating the overall effectiveness of 3 groups of nonlinear analysis: detrended fluctuation analysis (overall ES 0.364, 95% CI 0.237-0.491), entropy-based measures (overall ES 1.05, 95% CI 0.572-1.52), and all other nonlinear measures (overall ES 0.702, 95% CI 0.422-0.982). The effectiveness of the applied methods of electrocardiogram analysis was compared and discussed in the light of detection and prevention of depression-related cardiovascular risk. Conclusions: We compared the ESs of nonlinear and conventional time and spectral methods (found in the literature) and demonstrated that those of the former are larger, which recommends their use for the early screening of cardiovascular abnormalities in patients with depression to prevent possible deleterious events. ©Milena Čukić, Danka Savić, Julia Sidorova

Heart Rate Fractality Disruption as a Footprint of Subthreshold Depressive Symptoms in a Healthy Population

Psychopathology (and depression in particular) is a cardiovascular risk factor independent from any co-occurring pathology. This link is traced back to the mind-heart-body connection, whose underlying mechanisms are still not completely known. To study psychopathology in relation to the heart, it is necessary to observe the autonomic nervous system, which mediates among the parts of that connection. Its gold standard of evaluation is the study of heart rate variability (HRV). To investigate whether any association exists between the HRV parameters and sub-threshold depressive symptoms in a sample of healthy subjects

Intelligent Advanced User Interfaces for Monitoring Mental Health Wellbeing

It has become pressing to develop objective and automatic measurements integrated in intelligent diagnostic tools for detecting and monitoring depressive states and enabling an increased precision of diagnoses and clinical decision-makings. The challenge is to exploit behavioral and physiological biomarkers and develop Artificial Intelligent (AI) models able to extract information from a complex combination of signals considered key symptoms. The proposed AI models should be able to help clinicians to rapidly formulate accurate diagnoses and suggest personalized intervention plans ranging from coaching activities (exploiting for example serious games), support networks (via chats, or social networks), and alerts to caregivers, doctors, and care control centers, reducing the considerable burden on national health care institutions in terms of medical, and social costs associated to depression cares