A Cross-Recurrence Analysis of the Pupil Size Fluctuations in Steady Scotopic Conditions

Pupil size fluctuations during stationary scotopic conditions may convey information about the cortical state activity at rest. An important link between neuronal network state modulation and pupil fluctuations is the cholinergic and noradrenergic neuromodulatory tone, which is active at cortical level and in the peripheral terminals of the autonomic nervous system (ANS). This work aimed at studying the low- and high-frequency coupled oscillators in the autonomic spectrum (0–0.45 Hz) which, reportedly, drive the spontaneous pupillary fluctuations. To assess the interaction between the oscillators, we focused on the patterns of their trajectories in the phase-space. Firstly, the frequency spectrum of the pupil signal was determined by empirical mode decomposition. Secondly, cross-recurrence quantification analysis was used to unfold the non-linear dynamics. The global and local patterns of recurrence of the trajectories were estimated by two parameters: determinism and entropy. An elliptic region in the entropy-determinism plane (95% prediction area) yielded health-related values of entropy and determinism. We hypothesize that the data points inside the ellipse would likely represent balanced activity in the ANS. Interestingly, the Epworth Sleepiness Scale scores scaled up along with the entropy and determinism parameters. Although other non-linear methods like Short Time Fourier Transform and wavelets are usually applied for analyzing the pupillary oscillations, they rely on strong assumptions like the stationarity of the signal or the a priori knowledge of the shape of the single basis wave. Instead, the cross-recurrence analysis of the non-linear dynamics of the pupil size oscillations is an adaptable diagnostic tool for identifying the different weight of the autonomic nervous system components in the modulation of pupil size changes at rest in non-luminance conditions

Sympathetic and parasympathetic modulation of pupillary unrest

Pupillary unrest is an established indicator of drowsiness or sleepiness. How sympathetic and parasympathetic activity contribute to pupillary unrest is not entirely unclear. In this study, we investigated 83 young healthy volunteers to assess the relationship of pupillary unrest to other markers of the autonomic nervous system. Sample entropy (SE) and the established pupillary unrest index (PUI) were calculated to characterize pupil size variability. Autonomic indices were derived from heart rate, blood pressure, respiration, and skin conductance. Additionally, we assessed individual levels of calmness, vigilance, and mood. In an independent sample of 26 healthy participants, we stimulated the cardiovagal system by a deep breathing test. PUI was related to parasympathetic cardiac indices and sleepiness. A linear combination of vagal heart rate variability [root mean square of heart beat interval differences (RMSSD)] and skin conductance fluctuations (SCFs) was suited best to explain interindividual variance of PUI. Complexity of pupil diameter (PD) variations correlated to indices of sympathetic skin conductance. Furthermore, we found that spontaneous fluctuations of skin conductance are accompanied by increases of pupil size. In an independent sample, we were able to corroborate the relation of PUI with RMSSD and skin conductance. A slow breathing test enhanced RMSSD and PUI proportionally to each other, while complexity of PD dynamics decreased. Our data suggest that the slow PD oscillations ( f < 0.15 Hz) quantified by PUI are related to the parasympathetic modulation. Sympathetic arousal as detected by SCFs is associated to transient pupil size increases that increase non-linear pupillary dynamics

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

Exposing Internal Attentional Brain States using Single-Trial EEG Analysis with Combined Imaging Modalities

The goal of this dissertation is to explore the neural correlates of endogenous task-related attentional modulations. Natural fluctuations in task engagement are challenging to study, primarily because they are by nature not event related and thus cannot be controlled experimentally. Here we exploit well-accepted links between attention and various measures of neural activity while subjects perform simple target detection tasks that leave their minds free to wander. We use multimodal neuroimaging, specifically simultaneous electroencephalograpy and functional magnetic resonance imaging (EEG-fMRI) and EEG-pupillometry, with data-driven machine learning methods and study activity across the whole brain. We investigate BOLD fMRI correlates of EEG variability spanning each trial, enabling us to unravel a cascade of attention-related activations and determine their temporal ordering. We study activity during auditory and visual paradigms independently, and we also combine data to investigate supra modal attention systems. Without aiming to study known attention-related functional brain networks, we found correlates of attentional modulations in areas representative of the default mode network (DMN), ventral attention network (VAN), locus coeruleus norepinephrine (LC-NE) system, and regions implicated in generation of the extensively-studied P300 EEG response to target stimuli. Our results reveal complex interactions between known attentional systems, and do so non-invasively to study normal fluctuations of task engagement in the human brain

The steady state visual evoked potential (SSVEP) tracks “sticky” thinking, but not more general mind-wandering

For a large proportion of our daily lives, spontaneously occurring thoughts tend to disengage our minds from goal-directed thinking. Previous studies showed that EEG features such as the P3 and alpha oscillations can predict mind-wandering to some extent, but only with accuracies of around 60%. A potential candidate for improving prediction accuracy is the Steady-State Visual Evoked Potential (SSVEP), which is used frequently in single-trial contexts such as brain-computer interfaces as a marker of the direction of attention. In this study, we modified the sustained attention to response task (SART) that is usually employed to measure spontaneous thought to incorporate the SSVEP elicited by a 12.5-Hz flicker. We then examined whether the SSVEP could track and allow for the prediction of the stickiness and task-relatedness dimensions of spontaneous thought. Our results show that the SSVEP evoked by flickering words was able to distinguish between more and less sticky thinking but not between whether a participant was on- or off-task. This suggests that the SSVEP is able to track spontaneous thinking when it is strongly disengaged from the task (as in the sticky form of off-task thinking) but not off-task thought in general. Future research should determine the exact dimensions of spontaneous thought to which the SSVEP is most sensitive

The Characterization Of Visual Evoked Feedforward-Feedback Travelling Waves In Mice During Waking And Anesthetized States

A cardinal feature of consciousness is the maintenance of a stable perceptual world. To accomplish this, sensory information must be faithfully relayed and integrated within the brain. General anesthetic agents reliably and reversibly produce states of unconsciousness. However, despite their ubiquitous use in medicine and science, the mechanisms by which anesthetics induce loss of consciousness remains unknown. Over the past 170 years, researchers have searched for the universal targets that anesthetic agents use to ablate perception (Alkire et al., 2008; Kelz and Mashour, 2019). However, there is not yet a common structural motif, receptor target, or sleep/arousal circuit that all known anesthetics interact with (Alkire et al., 2008; Kelz and Mashour, 2019). It was once postulated that anesthetics may ablate perception by disconnecting the cortex from incoming thalamic signals (Alkire et al., 2000; Alkire and Miller, 2005; White and Alkire, 2003); yet under anesthesia, neurons within primary cortical areas are still able to encode features of sensory stimuli, thereby suggesting sensory information is effectively relayed to the cortex (Hubel and Wiesel, 1962). Thus, it has been recently theorized that anesthetics may hinder the ability for sensory responses to faithfully participate in hierarchal, feedback and integrative circuits at a network level (Lee et al., 2009; Mashour, 2006, 2014). In this dissertation, I investigate this theory by analyzing the spatiotemporal features of visual evoked oscillations over multiple hierarchical cortical areas in awake and anesthetized mice presented with simple visual stimuli and answering a series of motivating questions. Are there consistent neurophysiological substrates to coordinate visual evoked activity across the many cortical regions involved in visual processing in awake mice, who have the ability to perceive stimuli? If so, what is the spatiotemporal structure of this activity pattern, and does it coordinate neural firing in disparate cortical areas? Can we identify patterns that may be related to hierarchical visual processing vs feedback signaling? How do mechanistically distinct anesthetic agents disrupt visual evoked patterns seen in the awake brain? Are there agent specific effects? And finally, can we identify a common mechanism by which all tested anesthetic agents breakdown visual evoked activity? While my research does not test perception per se, findings herein will provide the neurophysiological basis for the integration of visual-evoked activity across cortices during wakefulness, and the breakdown of this coordinated pattern of activity during anesthetic induced states of unconsciousness

Time-frequency Analysis of Biomedical Signals

Tato diplomová práce je zaměřena na vytvoření výukového modulu pro zkoumání metod časově-frekvenční analýzy biomedicínských signálů. V rámci práce jsou představeny základní metody analýzy biomedicínských signálů v časově-frekvenční oblasti s cílem analýzy biomedicínských signálů vykazujících frekvenční nestacionaritu. V teoretické části jsou představeny metody spektrální analýzy a vyplývající metody analýzy v časově-frekvenční oblasti. V praktické části jsou popsány demonstrační algoritmy pro výpočty frekvenčních spekter pomocí Rychlé Fourierovy transformace a je provedena analýza jejich časové výpočetní náročnosti. Pro výpočet časově-frekvenčních spekter jsou vybrány metody Krátkodobé Fourierovy transformace, Vlnkové transformace a Winger-Ville rozdělení. Jsou představeny algoritmy výpočtu těchto metod a je provedena kvantitativní analýza dynamické intenzity šumu v kontextu časově-frekvenční analýzy. V rámci práce bylo vytvořeno graficko-uživatelské prostředí pro výuku problematiky časově-frekvenční analýzy bio signálů a byla vytvořena databáze testovacích biomedicínských signálů.This diploma thesis is focused on the creation of a learning module for the investigation of time-frequency analysis methods. Basic methods of analysis of biomedical signals in time-frequency domain with are presented. In the theoretical part are introduced spectral analysis methods and time-frequency analysis methods. In the practical part are described demonstration algorithms for calculation of frequency spectra by Fast Fourier transform. An analysis of their computational complexity is performed. For calculation of time-frequency spectra, the methods of Short-time Fourier transform, Wavelet transform and Winger-Ville distribution are selected. Algorithms of calculation of these methods are presented and quantitative analysis of dynamic noise intensity in context of time-frequency analysis is performed. In this thesis a graphical-user interface for teaching time-frequency analysis of bio signals was created and a test database of biomedical signals was created.450 - Katedra kybernetiky a biomedicínského inženýrstvívýborn

Contributo da monitorização do sistema nervoso autónomo para a abordagem do doente com instabilidade hemodinâmica em ambiente de cuidados intensivos

RESUMO: O Sistema Nervoso Autónomo, funcionalmente composto pelo Sistema Nervoso Autónomo Intrínseco, Sistema Nervoso Autónomo Extrínseco Simpático e Sistema Nervoso Autónomo Extrínseco Parassimpático, é um dos sistemas mais primitivos que garante a sobrevivência da espécie humana. A harmonia do funcionamento dos vários órgãos e sistemas depende em grande medida do equilíbrio entre os diversos componentes do Sistema Nervoso Autónomo, bem como da sua adequada interação com os restantes sistemas. Existem diversos métodos para testar o seu funcionamento: testes dos reflexos autonómicos cardiovasculares, análise da variabilidade da frequência cardíaca, determinação sérica de neurotransmissores, microneurografia e testes da função sudomotora. Na prática clínica é usual fazer-se uso dos reflexos autonómicos cardiovasculares, da análise da variabilidade cardíaca e dos testes da função sudomotora; todavia, a sua aplicabilidade nos doentes internados em ambiente de Cuidados Intensivos tem-se restringido, quase em exclusivo, à análise da variabilidade da frequência cardíaca; e, dentro da comunidade científica da Medicina Intensiva, especialidade médica com alicerces sólidos na fisiopatologia, o Sistema Nervoso Autónomo tem-se mantido à margem do interesse científico dos seus profissionais. A dúvida é legítima: não é um tema intelectualmente estimulante ou, não terá aplicabilidade na atividade clínica? No capítulo “Estudo do Sistema Nervoso Autónomo em ambiente de cuidados intensivos – estado da arte” faz-se uma revisão da literatura sobre a aplicabilidade da sua monitorização nos doentes críticos. Dessa revisão conclui-se que o estudo da correlação da variabilidade da frequência cardíaca com o prognóstico é o tema de excelência, sendo unânimes que a variabilidade da frequência cardíaca varia de forma inversa com o prognóstico. Existem igualmente alguns trabalhos que estudam a variabilidade da pressão arterial, nomeadamente o estudo do barorreflexo, uma vez mais o foco incide no prognóstico, apresentando pior prognóstico os doentes com baixa sensibilidade do barorreflexo. A pupilometria e a resposta pupilar à luz, apresentam-se como exceções ao cenário anterior, já que são utilizadas como ferramenta para titular a analgesia nos doentes críticos e para inferir as alterações da pressão intracraniana; são igualmente utilizadas para inferir o prognóstico nos doentes vítimas de anoxia cerebral e no estado de mal não convulsivo. Focando-se os estudos da avaliação do Sistema Nervoso Autónomo como ferramenta de prognóstico, sem aplicabilidade clínica direta para modificar o outcome dos doentes, este poderá ser um dos fatores limitativos à sua introdução como instrumento de monitorização na prática clínica diária das Unidades de Cuidados Intensivos. O capítulo “Monitorização do Sistema Nervoso Autónomo em ambiente de Cuidados Intensivos como ferramenta de prognóstico. Revisão sistemática” surgiu como uma necessidade natural do trabalho previamente desenvolvido. Face à evidência dos múltiplos estudos, que abordavam a avaliação da variabilidade da frequência cardíaca, havia a necessidade de se proceder a uma revisão sistemática dos mesmos. Todos os estudos publicados em ambiente de cuidados intensivos são de coorte, prospetivos ou retrospetivos, focando-se no trauma, sépsis grave e choque sético, disfunção multiorgânica, na paragem cardiorrespiratória, acidente vascular cerebral e doentes neurocirúrgicos; independentemente das variáveis estudadas, foi unânime que a variabilidade da frequência cardíaca varia de forma inversa com a gravidade clínica e com o prognóstico. Após terminar o capítulo anterior surgiram algumas dúvidas metódicas resultantes da constatação de que: não existe padronização das variáveis estudadas, nem dos métodos estudados e, é quase inexistente a aplicação dos métodos no domínio tempo-frequência nos doentes internados em ambiente de cuidados intensivos. O capítulo “Avaliação do Sistema Nervoso Autónomo pela monitorização da frequência cardíaca em ambiente de Cuidados Intensivos. Comparação de métodos” tem como objetivo fornecer um contributo para minorar estas dúvidas. Estudou-se a variabilidade da frequência cardíaca no domínio do tempo, no domínio da frequência (pelo método de Welch, pelo modelo autorregressivo e pelo método de Lomd-Scargle) e no domínio tempo-frequência (pelo método de Burg, pelo método de Lomb-Scargle, pela transformada de Wavelet e pela transformada de Hilbert-Huang) em 324 blocos de sinal eletrocardiográfico estável, obtidos em 82 doentes. Foram identificadas correlações fortes, e muito fortes, entre variáveis no domínio do tempo e variáveis no domínio da frequência, essas mesmas correlações foram replicadas com as variáveis no domínio tempo-frequência. Apesar da correlação positiva muito forte, entre os vários métodos e modelos disponíveis para estudar o balanço do Sistema Nervoso Autónomo, não existe entre eles concordância, o que reforça a necessidade de ser padronizada a metodologia do seu estudo. Durante a colheita, e o tratamento dos dados para o capítulo anterior, constatou-se que existia, em alguns doentes, uma subestimação do poder da banda HF, pelo facto dos doentes admitidos nas Unidades de Cuidados Intensivos apresentarem valores elevados da frequência respiratória. Frequências respiratórias superiores a 24 cpm ficam fora do limite superior do espectro da banda HF, não sendo por esse motivo quantificado. Esta observação deu origem a um pequeno capítulo intitulado “Variabilidade da frequência cardíaca. O espectro das bandas de alta frequência não está adequado para todos os doentes adultos internados em Cuidados Intensivos”. O capítulo “Manobra de Valsalva. Uma nova proposta para a sua utilização em doentes submetidos a ventilação mecânica invasiva” tem o objetivo de transformar a monitorização do Sistema Nervoso Autónomo num instrumento útil de orientação terapêutica nos doentes internados em ambiente de cuidados intensivos com instabilidade hemodinâmica. Apresenta-se um pequeno estudo piloto, sobre a adaptação da manobra de Valsalva durante a manobra da pausa inspiratória nos doentes submetidos a ventilação mecânica invasiva. Apesar do reduzido número de observações apresentadas, pode-se afirmar que a manobra de Valsalva é replicável nestes doentes e, que existe uma concordância da monitorização contínua do Sistema Nervoso Autónomo com as várias fases da manobra, nomeadamente na modelação vagal, a e b-adrenérgica. Por último, e de forma a dar destaque à importância da introdução da monitorização contínua do Sistema Nervoso Autónomo nas Unidades de Cuidados Intensivos, pelos métodos de monitorização no domínio tempo-frequência, apresenta-se o capítulo “Monitorização de eventos”. Neste capítulo são apresentados fenómenos de curta duração, que ocorrem com elevada frequência nas Unidades de Cuidados Intensivos, nomeadamente a troca de seringas com aminas vasoativas, a tosse e a aspiração de secreções brônquicas, e que a observação da resposta adaptativa do Sistema Nervoso Autónomo face à provocação a que é submetido, poderá nos indicar o seu estado de equilíbrio e, eventualmente na sua ausência, quais as medidas a adotar.ABSTRACT: The Autonomic Nervous System, functionally composed by the Intrinsic Autonomic Nervous System, Sympathetic Extrinsic Autonomic Nervous System and Parasympathetic Extrinsic Autonomic Nervous System, is one of the most primitive systems that is responsible for the survival of the human species. The harmony of the various organs and systems depends in a large scale on the balance between the various components of the Autonomic Nervous System, as well as their proper interaction with the other systems. There are several methods to test its functioning: cardiovascular autonomic reflex tests, heart rate variability analysis, serum determination of neurotransmitters, microneurography and sudomotor function tests. In clinical practice, it is usual to use the autonomic cardiovascular reflexes, heart rate variability analysis and sudomotor function tests; however, its applicability in patients hospitalized in the Intensive Care setting has been restricted, almost exclusively, to the analysis of heart rate variability; and among the scientific community of Intensive Medicine, a medical specialty with solid foundations in pathophysiology, the Autonomic Nervous System has been kept out of the scientific interest of its professionals. Doubt is legitimate: is it not an intellectually stimulating subject, or is it not appropriate for clinical practice? In the chapter "Study of the Autonomic Nervous System in Intensive Care Environment - State of the art" a critical review of the literature on the applicability of its monitoring in critical patients is made. This review concludes that studying the correlation between heart rate variability and prognosis is the focus, and all studies indicate that lower the heart rate variability, worse the prognosis. There are also some studies on the blood pressure variability, namely studying the baroreflex, once again the focus is on the prognosis, presenting worse prognosis the patients with low baroreflex sensitivity. Pupillometry and pupil light response is an exception to the previous scenario, since it is used as a tool to titrate analgesia in critical patients and to infer changes in intracranial pressure; it is also used as a prognostic tool in patients suffering from cerebral anoxia and in non-convulsive status epilepticus. Focusing the studies in evaluation the Autonomic Nervous System as a prognostic tool, without direct clinical applicability to modify the outcome of the patients, may be one of the limiting factors for its introduction as a monitoring instrument in the daily clinical practice of the Intensive Care Units. The chapter "Monitoring the Autonomic Nervous System in an Intensive Care environment as a prognostic tool. Systematic review "emerged as a natural need for previously developed work. Considering the multiple studies that addressed the evaluation of heart rate variability, there was a need for a systematic review of the studies, to evaluate if the results were consistent. All studies published in intensive care settings are cohort, prospective or retrospective, focusing on trauma, severe sepsis and septic shock, multiorgan dysfunction, cardiorespiratory arrest, stroke and neurosurgical patients; regardless of the variables studied, it was unanimous that heart rate variability is inversely related with clinical severity and prognosis. After finishing the previous chapter, some methodological doubts emerged: there is no standardization of the variables studied, nor of the methods, and there is almost no application of the time-frequency methods in patients hospitalized in intensive care units. The chapter "Evaluation of the Autonomic Nervous System by monitoring the heart rate variability in Intensive Care environment. Comparison of methods" try to answer those questions. Heart rate variability was studied in time domain, in frequency domain (Welch method, autoregressive model and Lomd-Scargle method) and in timefrequency domain (Burg method, Lomb-Scargle method, Wavelet transform and Hilbert- Huang transform) in 324 blocks of electrocardiographic stable signal, obtained in 82 patients. Strong and very strong correlations were identified between variables in the time domain and variables in the frequency domain, these same correlations were replicated with the variables in the time-frequency domain. Despite the very strong positive correlation between the various methods and models available to study the Autonomic Nervous System balance, there was no concordance between them, which reinforces the need to standardize the methodology of Autonomic study. During collection and treatment of data for the previous chapter, it was found that, in some patients there was an underestimation of the power of the HF band, because patients admitted to the Intensive Care Unit had higher respiratory rate values. Respiratory frequencies above 24 cpm are outside the upper limit of the HF band spectrum and are therefore not quantified. This observation originated a short chapter entitled "Variability of heart rate. The spectrum of high frequency bands is not suitable for all adult patients admitted in Intensive Care. The chapter "Valsalva maneuver. A new proposal for its use in patients submitted to mechanical ventilation" has the objective to transform the Autonomic Nervous System monitoring into a useful instrument for therapeutic orientation in Intensive Care patients with hemodynamic instability. A small pilot study was performed, to adapt the Valsalva maneuver during the inspiratory pause maneuver in patients submitted to mechanical ventilation. Despite the small number of observations presented, it can be stated that the Valsalva maneuver is replicable in these patients and there is a concordance of the continuous Autonomic Nervous System monitoring with the various phases of the maneuver, namely in the vagal, a and b-adrenergic modulation. Lastly, and to highlight the importance of the introduction of the continuous Autonomic Nervous System monitoring in Intensive Care Units, through the methods of timefrequency domain, I present the chapter "Monitoring of events". In this chapter, observation the adaptive response of the Autonomic Nervous System when exposed to short-term phenomena, like vasoactive syringes exchange, coughing and tracheal aspiration, may indicate its balance and, if necessary, what measures to take

Multimodal Investigation of Brain Network Systems: From Brain Structure and Function to Connectivity and Neuromodulation

The field of cognitive neuroscience has benefited greatly from multimodal investigations of the human brain, which integrate various tools and neuroimaging data to understand brain functions and guide treatments for brain disorders. In this dissertation, we present a series of studies that illustrate the use of multimodal approaches to investigate brain structure and function, brain connectivity, and neuromodulation effects. Firstly, we propose a novel landmark-guided region-based spatial normalization technique to accurately quantify brain morphology, which can improve the sensitivity and specificity of functional imaging studies. Subsequently, we shift the investigation to the characteristics of functional brain activity due to visual stimulations. Our findings reveal that the task-evoked positive blood-oxygen-level dependent (BOLD) response is accompanied by sustained negative BOLD responses in the visual cortex. These negative BOLD responses are likely generated through subcortical neuromodulatory systems with distributed ascending projections to the cortex. To further explore the cortico-subcortical relationship, we conduct a multimodal investigation that involves simultaneous data acquisition of pupillometry, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). This investigation aims to examine the connectivity of brain circuits involved in the cognitive processes of salient stimuli. Using pupillary response as a surrogate measure of activity in the locus coeruleus-norepinephrine system, we find that the pupillary response is associated with the reorganization of functional brain networks during salience processing. In addition, we propose a cortico-subcortical integrated network reorganization model with potential implications for understanding attentional processing and network switching. Lastly, we employ a multimodal investigation that involves concurrent transcranial magnetic stimulation (TMS), EEG, and fMRI to explore network perturbations and measurements of the propagation effects. In a preliminary exploration on brain-state dependency of TMS-induced effects, we find that the propagation of left dorsolateral prefrontal cortex TMS to regions in the lateral frontoparietal network might depend on the brain-state, as indexed by the EEG prefrontal alpha phase. Overall, the studies in this dissertation contribute to the understanding of the structural and functional characteristics of brain network systems, and may inform future investigations that use multimodal methodological approaches, such as pupillometry, brain connectivity, and neuromodulation tools. The work presented in this dissertation has potential implications for the development of efficient and personalized treatments for major depressive disorder, attention deficit hyperactivity disorder, and Alzheimer's disease