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

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

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

Brain Computer Interfaces and Emotional Involvement: Theory, Research, and Applications

This reprint is dedicated to the study of brain activity related to emotional and attentional involvement as measured by Brain–computer interface (BCI) systems designed for different purposes. A BCI system can translate brain signals (e.g., electric or hemodynamic brain activity indicators) into a command to execute an action in the BCI application (e.g., a wheelchair, the cursor on the screen, a spelling device or a game). These tools have the advantage of having real-time access to the ongoing brain activity of the individual, which can provide insight into the user’s emotional and attentional states by training a classification algorithm to recognize mental states. The success of BCI systems in contemporary neuroscientific research relies on the fact that they allow one to “think outside the lab”. The integration of technological solutions, artificial intelligence and cognitive science allowed and will allow researchers to envision more and more applications for the future. The clinical and everyday uses are described with the aim to invite readers to open their minds to imagine potential further developments

The functional Role of Gamma-Band Synchronization in selective Routing and Network Configuration within the visual Cortex

First psychophysical experiments performed more than 100 years ago by the German psychologist and physicist Hermann von Helmholtz, showed that visual attention is a central component of perception and, therefore, of substantial relevance for successful behavior. In the decades that followed, much research has been performed to investigate how attention modulates neuronal activity in order to explain the effects of attention on behavior and perception. A well-described finding is that visual neurons responding to the same attended object synchronize their activity in the gamma-frequency range (30 - 100 Hz). In chapter 2, I present the results of an experiment that was designed to find evidence for a causal role of gamma-band synchronization in selective information routing and processing. The underlying idea is that neurons, which synchronize their activity deliver their respective outputs (spikes) more precisely at times the receiving neuron is sensitive for it, i.e. the incoming spikes are more likely to evoke spikes of the receiving neuron. The selective synchronization between input and receiver neurons representing an attended and therefore relevant object could constitute a powerful selection mechanism. To test this gamma recorded neuronal activity in area V4 of two macaque monkeys while applying single electrical pulses to neurons located in area V2. Those V2 neurons delivered afferent input to the recorded V4 population, including the electrically evoked spikes. By relating the effects of these electrically evoked spikes to the gamma-oscillation in V4, I could show that the impact of stimulation on behavior and neuronal activity is causally dependent on the gamma-phase. In chapter 3, I investigated whether the effective processing of a given object requires a specific level of gamma-band synchronization within a local neuronal population. I hypothesized that different objects require different combinations of neurons of the same population to be functionally coupled with one another for effective processing. Furthermore, we hypothesized that this dynamic establishment of functional connections is implemented by gamma-band synchronization, resulting in a specific level of gamma-band synchronization for a specific stimulus. I tested these predictions by first recording neuronal activity in area V4 and quantifying the level of gamma-synchronization in response to two different single stimuli, which had to be attended. Second, I compared these levels to the level of gamma-synchronization when neurons received input of both stimuli simultaneously, and one of them was attended. The level of gamma-synchronization was almost 'as if' the attended stimulus was presented alone, strongly indicating that the processing of this stimulus requires this specific gamma-synchronization level. Chapter 4 describes and characterizes a method that I used for analyzing multi-unit activity in area V4. It does not rely on setting up an amplitude-threshold for separating spikes from background noise as standard procedures do. Thus, this measure takes the entire spike activity into account, which I, therefore, refer to as ESA. I used semi-chronically recorded data of five macaque monkeys in order to quantify the sensitivity of the ESA to detect neuronal responses. The ESA-signal was significantly more sensitive than the standard procedures, especially for data with low signal-to-noise ratio, but preserves information about receptive field sizes and orientation selectivity of the underlying neuronal population. The fifth chapter is describing a method for offline stimulation-artifact removal and restoration of the original broadband neuronal signal. I could show that in contrast to existing methods the here described procedure does not disturb the original signal and therefore allows for analysis of neuronal activity even shortly after electrical stimulation. In summary, the results presented here give further insight into the functional roles of gamma-band synchronization. I could show that (1) gamma-phase synchronization plays a causal role in selective information processing and routing, and (2) that a specific pattern of intra-areal gamma-synchronization is required for effective processing of a given stimulus

Neuroimaging of endogenous lapses of responsiveness,

Attention lapses (ALs) and microsleeps (MSs) are complete lapses of responsiveness in which performance is completely disrupted for a short period of time, but consciousness is retained in the case of ALs. ALs are behaviourally different from MSs, as in an AL the eyes remain open whereas in a MS eyes are partially or completely closed. Both ALs and MSs can result in catastrophic consequences, especially in the transportation sector. Research over the past two decades has investigated the AL and MS phenomena using behavioural and physiological means. However, both ALs and MSs need further investigation to separate the different types of ALs physiologically, and to explore the neural signature of MSs in relation to normal sleep and drowsiness. Hence, the objective of this project was to understand the underlying physiological substrates of endogenous (internal) ALs and MSs which could potentially result in differentiating types of ALs and provide more understanding of MSs. Data from two previous Christchurch Neurotechnology Research Programme (NeuroTech™) studies (C and D) were combined resulting in a total of 40 subjects. During each session, subjects performed a 2-D continuous visuomotor tracking (CVT) task for 50 min (Study C) and 20 min (Study D). For each participant, tracking performance, eye-video, EEG, and fMRI were simultaneously collected. A human expert visually inspected the tracking performance and eye-video recordings to identify and categorize lapses of responsiveness for each participant. Participants performed the 2-D CVT task without interruptions. The repetitive nature of the task and the lack of a motivational factor made the task monotonous and fatiguing. As a result, it was more likely to introduce boredom leading to task-unrelated thoughts (TUTs), which divides attention between the task and the internal thoughts unrelated to the task, also fatigue which will introduce a trend of vigilance decrement over time. The project had hypotheses focusing on the changes in the brain’s activity compared to the baseline of good responsiveness tracking. We expected a decrease in dorsal attention network (DAN) activity during ALs due to a decoupling of attention from the external environment. Furthermore, we hypothesized that the ALs were due to involuntary mind-blanks. As such, we expected no change in default mode network (DMN) activity, as would have otherwise been expected if the ALs were due to mind-wandering. Functional connectivity (FC) of the brain was also investigated between the networks of interest which were the DMN, DAN, frontoparietal network (FPN), sensorimotor network (SMN), visual network (VSN), salience network (SN), eye-movement network (EMN), and working memory network (WMN), by analysing data from fMRI. EEG data were also used to perform analysis on ALs and MSs, by analysing changes in power in the delta, theta, alpha, beta, and gamma bands. Voxel-wise fMRI throughout the whole brain, group-ICA, haemodynamic response (HR) over the regions of interest (ROIs), and FC analyses were performed to reveal the neural signature during ALs. In voxel-wise analysis, a significant increase in activity was found in two regions: the dorsal anterior cingulate cortex (dACC) and the supplementary motor area (SMA). The group-ICA analysis did not show any significant results but did show a trend of increased activity in an independent component (IC) that was spatially correlated with SMN. Dynamic HR analysis was performed to further investigate findings from the voxel-wise analysis. Our results were not significant but there were strong trends of change. There was a trend of increased HR 7.5 s after the onset of the AL in the left intraparietal sulcus (IPS) of the DAN. There was also a decrease of 2.5 s before the onset of the AL in the right posterior parietal cortex (PPC) of the FPN. There was also an increase in the HR 5 s after the onset of the AL in the dACC of the SN. Finally, an increase in the HR 15 s before the onset of ALs in the left inferior parietal lobule (IPL) of the DMN is a major finding, as it is an indication that a lapse is about to happen. The HR analysis provided consistent findings with the voxel-wise analysis. FC analysis showed increases in FC within all networks of interest during the ALs. On looking at FC between networks, there was an increase in FC between the DMN and the FPN, no change between the DAN and the FPN, a decrease in FC between the SMN and the FPN, and an increase in FC between the FPN and the VSN. The EMN had an increased FC with the DMN, while it had both increases and decreases in FC with the DAN. There was also an increase in FC between the SN and the DAN, and no change between the SN and the DMN. Finally, a decrease in FC was found between the WMN and the DMN. These findings indicate an overlap between decoupling due to ALs and the process of recovery from ALs. The EEG analysis showed no significant change in the relative difference between average spectral power during ALs and their average baselines for any band of interest for ALs. During MSs, there was a significant increase in power relative to responsive baselines in the delta, theta, alpha, beta, and gamma bands. However, we could not be completely sure that all motion-related artefacts had been removed. Hence, we investigated this further by removing the effect of the global signal, which left only an increase in gamma activity, in addition to a trend of decreased activity in the alpha band. The significant increase in BOLD seen in the voxel-wise analysis is considered to represent the recovery of responsiveness following ALs. This was also seen in trends in group ICA and HR analyses. Overall, findings from the FC analysis show that, in addition to decoupling during ALs, and recovery from ALs, it is highly likely that the ALs during the 2-D CVT task were due to involuntary mind-blanks. This is supported by three major findings: (1) no significant increase in DMN activity in both voxel-wise and HR analyses, (2) the decrease in the HR in the FPN prior to the onset of the AL, and (3) the decrease in FC between the DMN and the WMN. This is further supported behaviourally by the short average duration of ALs (~ 1.7 s), in contrast to what would be likely during mind-wandering. Finally, the significant results from the EEG analysis of MSs, agreed with the literature in delta, theta, and alpha bands. However, increased power in beta and gamma bands was an important finding. We consider this increased high-frequency activity reflects unconscious ‘cognitive’ activity during a MS aimed at restoring consciousness after having fallen asleep during an active task. This highlights a key behavioural and physiological difference between MSs and sleep. Even after removing the effect of the global signal, we still believe that MSs and sleep are physiologically different in the recovery process. To summarize our key findings: (1) this is the first study to demonstrate that ALs during a continuous task are likely to be due to involuntary mind-blanks, (2) the increase in the HR in the DMN 15 s before the onset of AL could be a predictive signature of these lapses, and finally (3) MSs are physiologically different from sleep in terms of the recovery process. This project has improved our understanding of endogenous ALs and MSs and taken us a step closer to accurate detection/prediction systems which can increase prevention of fatal accidents