Integration of Simultaneous Resting-State EEG, fMRI, and Eye Tracker Methods to Determine and Verify EEG Vigilance Measure

Resting-state functional magnetic resonance imaging (rsfMRI) has been widely used for studying the (presumably) awake and alert human brain. Although rsfMRI scans are typically collected while individuals are instructed to focus their eyes on a fixation cross, objective and verified experimental measures to quantify degree of alertness (e.g., vigilance) are not readily available. Concurrent electroencephalography and fMRI (EEG-fMRI) measurements are also widely used to study human brain with high spatial/temporal resolution. EEG is the modality extensively used for estimating vigilance during eyes-closed resting state. On the other hand, pupil size measured using an eye-tracker device could provide an indirect index of vigilance. In this study, we investigated whether simultaneous multimodal EEG-fMRI combined with eye-tracker measurements can be used to determine EEG signal feature associated with pupil size changes (e.g., vigilance measure) in healthy human subjects (n=10) during brain rest with eyes open. We found that EEG frontal and occipital beta power (FOBP) correlates with pupil size changes, an indirect index for locus coeruleus activity implicated in vigilance regulation (r=0.306, p<0.001). Moreover, FOBP also correlated with heart rate (r=0.255, p<0.001), as well as several brain regions in the anti-correlated network, including the bilateral insula and inferior parietal lobule. These results support the conclusion that FOBP is an objective measure of vigilance in healthy human subjects

Magnetic resonance imaging in the study of the Locus Coeruleus and the relationship with the cognitive process of attention: a systematic review

Introdução: A degeneração progressiva dos neurónios do Locus Coeruleus associada à diminuição de recetores adrenérgicos, alvos da Noradrenalina, conduz a uma diminuição da função cerebral, provocando uma baixa resposta hemodinâmica e atividade neuronal. A disfunção noradrenérgica pode, ainda, interromper a capacidade de monitorizar estímulos externos e alterar o processo cognitivo da atenção, como acontece na Doença de Alzheimer e na Doença de Parkinson. Objetivos: A investigação procurou unir estudos estruturais e funcionais do Locus Coeruleus, incluindo estudos pupilométricos na avaliação da atenção seletiva visual, que atendessem à resposta cerebral bem como à progressão da doença, com a finalidade de correlacionar o processo cognitivo de atenção com a imagem obtida por Ressonância Magnética do Locus Coeruleus. Materiais e Métodos: A estratégia de pesquisa foi desenvolvida para encontrar todos os potenciais artigos relevantes num conjunto de fontes, como: as bases de dados bibliográficas de biomedicina; bases de registos de ensaios clínicos randomizados e quase randomizados; repositórios científicos e sites agregadores de bases bibliográficas. Resultados: Estudos que avaliaram o Locus Coeruleus por Ressonância Magnética demonstram variações morfológicas dependentes da idade e estudos funcionais, juntamente com testes pupilométricos, apresentaram alterações na neuromodulação percutindo-se na seletividade da atenção. Conclusão: A compilação da análise dos estudos forneceu dados para o estudo do Locus Coeruleus e a relação com o processo cognitivo de atenção. Cientificamente, todos os aspetos morfológicos e funcionais sugerem possibilitar a análise da disfunção noradrenérgica sob o campo da imagem de Ressonância Magnética para compreender a incapacidade do Locus Coeruleus em monitorizar estímulos externos e alterar o processo cognitivo da atenção.ABSTRACT - Introduction: The progressive degeneration of LC neurons associated with a decrease in adrenergic receptors, targets of NA, leads to a decrease in brain function, causing a low hemodynamic response and neuronal activity. Noradrenergic dysfunction can also interrupt the ability to monitor external stimuli and alter the cognitive process of attention, as in AD and PD. Objectives: The investigation sought to unite LC structural and functional studies, including pupillometric studies in the assessment of visual selective attention, which address the brain response as well as disease progression, in order to correlate the cognitive process of attention with the MR image of the LC. Materials and Methods: The research strategy was developed with high sensitivity to find all potentially relevant articles in a set of sources, such as bibliographic databases on biomedicine; databases of randomized and quasi-randomized clinical trials; scientific repositories and websites aggregating bibliographic bases. Results: Studies that evaluated LC by MRI demonstrate age-dependent morphological variations and functional studies, together with pupillometric tests, showed alterations in neuromodulation affecting the selectivity of attention. Conclusions: The compilation of the analysis of the studies provided data for the study of LC and its relationship with the cognitive attention process. Scientifically, all morphological and functional aspects suggest enabling the analysis of noradrenergic dysfunction under the field of MRI to understand the LC's inability to monitor external stimuli and change the cognitive process of attention.info:eu-repo/semantics/publishedVersio

Coupling of pupil- and neuronal population dynamics reveals diverse influences of arousal on cortical processing

Fluctuations in arousal, controlled by subcortical neuromodulatory systems, continuously shape cortical state, with profound consequences for information processing. Yet, how arousal signals influence cortical population activity in detail has so far only been characterized for a few selected brain regions. Traditional accounts conceptualize arousal as a homogeneous modulator of neural population activity across the cerebral cortex. Recent insights, however, point to a higher specificity of arousal effects on different components of neural activity and across cortical regions. Here, we provide a comprehensive account of the relationships between fluctuations in arousal and neuronal population activity across the human brain. Exploiting the established link between pupil size and central arousal systems, we performed concurrent magnetoencephalographic (MEG) and pupillographic recordings in a large number of participants, pooled across three laboratories. We found a cascade of effects relative to the peak timing of spontaneous pupil dilations: Decreases in low-frequency (2-8 Hz) activity in temporal and lateral frontal cortex, followed by increased high-frequency (>64 Hz) activity in mid-frontal regions, followed by monotonic and inverted U relationships with intermediate frequency-range activity (8-32 Hz) in occipito-parietal regions. Pupil-linked arousal also coincided with widespread changes in the structure of the aperiodic component of cortical population activity, indicative of changes in the excitation-inhibition balance in underlying microcircuits. Our results provide a novel basis for studying the arousal modulation of cognitive computations in cortical circuits

Advancing Multimodal Approaches to Study Human Brain: Improvements in Simultaneous EEG-fMRI Acquisition

The primary aim of the study detailed in this dissertation was improving the quality of simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) experiments. Two common challenges to use concurrent EEG-fMRI tests are addressed herein. The first is the presence of EEG artifacts during simultaneous EEG-fMRI, which require more consideration than EEG data recorded outside the scanner. To mitigate this issue, a fully automated artifact correction pipeline was developed. In the proposed pipeline, magnetic resonance (MR) environmental (i.e., gradient and ballistocardiogram [BCG]) artifacts were reduced using optimal basis sets (OBS) and average artifact subtraction (AAS). Subsequently, independent component analysis (ICA) was leveraged for reducing physiological artifacts (e.g., eye blinks, saccade and muscle artifacts), in addition to residual BCG artifacts. To validate pipeline performance, both resting-state (time/frequency and frequency analysis) and task-based (event related potential [ERP]) EEG data from eight healthy participants were tested. This data was compared with the time/frequency and frequency results achieved by matching meticulously, manually corrected EEG data to the automatically corrected EEG data. No significant difference was found between results. A comparison between ERP results (e.g., amplitude measures and SNR) also showed no differences between manually corrected and fully automated EEG corrected data. The second challenge addressed in this work is the low experimental control over the subject's actual behavior during the eyes-open resting-state fMRI (rsfMRI). This technique has been widely used for studying the (presumably) awake and alert human brain using multimodal EEG-fMRI; however, objective and verified experimental measures to quantify the degree of alertness (e.g., vigilance) are not readily available. To this end, the study reported in this dissertation investigated whether simultaneous multimodal EEG, rsfMRI and eye-tracker experiments could be used to extract objective and robust biomarkers of vigilance in healthy human subjects (n = 10) during cross fixation. Frontal and occipital beta power (FOBP) were found to correlate (r = 0.306, p<0.001) with pupil size fluctuation, which is an indirect index for locus coeruleus activity implicated in vigilance regulation. Moreover, FOBP was also correlated with heart rate (r = 0.255, p<0.001) and several brain regions in an anti-correlated network, including the bilateral insula and inferior parietal lobule. Results support the conclusion that FOBP is an objective and robust biomarker of vigilance in healthy human subjects

Ressonância magnética no estudo do Locus coeruleus e a relação com o processo cognitivo de atenção: revisão sistemática

Mestrado em Radiações Aplicadas às Tecnologias da Saúde. - Área de especialização: Imagem por Ressonância MagnéticaIntrodução: A degeneração progressiva dos neurónios do Locus Coeruleus (LC) associada à diminuição de recetores adrenérgicos, alvos da Noradrenalina (NA), conduz a uma diminuição da função cerebral, provocando uma baixa resposta hemodinâmica e atividade neuronal. A disfunção noradrenérgica pode, ainda, interromper a capacidade de monitorizar estímulos externos e alterar o processo cognitivo da atenção, como acontece na Doença de Alzheimer (AD) e na Doença de Parkinson (PD). Objetivos: A investigação procurou unir estudos estruturais e funcionais do LC, incluindo estudos pupilométricos na avaliação da atenção seletiva visual, que atendessem à resposta cerebral bem como à progressão da doença, com a finalidade de correlacionar o processo cognitivo de atenção com a imagem obtida por RM do LC. Métodos: O desenho de estudo é de carácter descritivo, secundário, de recuperação e análise crítica da literatura. A estratégia de pesquisa foi desenvolvida para encontrar todos os potenciais artigos relevantes num conjunto de fontes, como: as bases de dados bibliográficas de biomedicina; bases de registos de ensaios clínicos randomizados e quase randomizados; repositórios científicos e sites agregadores de bases bibliográficas. Resultados: Após uma pesquisa em diferentes bases de dados, 59 estudos foram selecionados para esta revisão sistemática, dos quais 42 foram incluídos na síntese qualitativa. Estudos que avaliaram o LC por RM demonstram variações morfológicas dependentes da idade e estudos funcionais, juntamente com testes pupilométricos, apresentaram alterações na neuromodulação percutindo-se na seletividade da atenção. Conclusões: A compilação da análise dos estudos forneceu dados para o estudo do LC e a relação com o processo cognitivo de atenção. Cientificamente, todos os aspetos morfológicos e funcionais sugerem possibilitar a análise da disfunção noradrenérgica sob o campo da imagem de RM para compreender a incapacidade do LC em monitorizar estímulos externos e alterar o processo cognitivo da atenção.ABSTRACT - Introduction: The progressive degeneration of Locus Coeruleus (LC) neurons associated with a decrease in adrenergic receptors, targets of Noradrenaline (NA), leads to a decrease in brain function, causing a low hemodynamic response and neuronal activity. Noradrenergic dysfunction can also interrupt the ability to monitor external stimuli and alter the cognitive process of attention, as in AD and PD. Objectives: The investigation sought to unite LC structural and functional studies, including pupillometric studies in the assessment of visual selective attention, which address the brain response as well as disease progression, in order to correlate the cognitive process of attention with the MR image of the LC. Methods: The study design is descriptive, secondary, of recovery, and critical analysis of the literature. The research strategy was developed with high sensitivity to find all potentially relevant articles in a set of sources, such as bibliographic databases on biomedicine; a database of randomized and quasi-randomized clinical trials; scientific repositories, and websites aggregating bibliographic bases. Results: After a search in different databases, 59 studies were selected for this systematic review, and 42 were included in the qualitative synthesis. Studies that evaluated LC by MRI demonstrate age-dependent morphological variations and functional studies, together with pupillometric tests, showed alterations in neuromodulation affecting the selectivity of attention. Conclusions: The compilation of the analysis of the studies provided data for the study of LC and its relationship with the cognitive attention process. Scientifically, all morphological and functional aspects suggest enabling the analysis of noradrenergic dysfunction under the field of MRI to understand the LC's inability to monitor external stimuli and change the cognitive process of attention.N/

Simultaneous pupillometry and functional Magnetic Resonance Imaging (fMRI) for the detection of stress-related endophenotypes

Mental diseases constitute a core health challenge of the 21st century. To date, diagnostics in psychiatry have been primarily based on subjective self-reports, largely bypassing the biological underpinnings and phenotypic heterogeneity of psychiatric disorders. As an effort to implement a more biologically valid classification of mental disorders, recent initiatives like the Research Domain Criteria (RDoC) project aim to identify endophenotypes that reflect transdiagnostic core mechanisms of psychiatric disorders. Stress is known to play a fundamental role in the development of mood and anxiety disorders. One key system involved in the physiological response to stress is the brainstem?s noradrenergic (NA) arousal center located in the locus coeruleus (LC), and previous studies indicate that pupil size provides an indirect index for activity of the LC-NA system. In order to investigate the relationship between spontaneous drifts in autonomic arousal and global brain activity in healthy human subjects, we first determined the fMRI correlates of spontaneous pupil fluctuations during the resting state. We found that pupil dilations are strongly coupled to activation of the dorsal anterior cingulate cortex (dACC) and bilateral insula (salience network [SN]). To assess whether this link between the pupil and the SN would also extend to emotional arousal, we next investigated the neural correlates of reward anticipation-induced pupil dilations in healthy subjects. Here, we could show that a cue signaling the possibility to receive a monetary reward evoked strong pupil dilations, the magnitude of which predicted response time to a target cue. Again, pupil dilations were strongly linked to SN activation. Furthermore, our results suggest that pupillometry is helpful to dissect different phases of reward anticipation and associated brain activity, disentangling reward prediction, arousal modulation and attentionrelated processes. These observations led us to the conclusion that the SN modulates arousal levels to optimize task performance, that is, to counteract drowsiness/ transitions to sleep during the resting state and to facilitate reward-directed behaviors in the reward anticipation task. Taken together, pupillometry appears to provide a reliable index for activity of the SN, a core network related to psychiatric disorders, making it a promising tool for the detection of stress-related endophenotypes

On Arousal and the Internal Regulation of Brain Function: Theory and Evidence across Modalities and Species

The brain is an organ. It is subject to the same physiological regulatory processes that engage the rest of the body’s organs, sculpted over hundreds of millions of years to sustain life so effectively. The central message of this thesis is that the holistic functioning of the brain, rather than operating at some level above or independent from these systemic regulatory processes, is deeply related to them. In short, as our limited attention spans might suggest: brain function is internally regulated. I propose that this internal regulation is a primary function of intrinsic brain activity. Chapter 2 provides a theoretical treatment of this issue, recasting intrinsic activity as an internal regulatory process operating on the brain’s temporal “states” and spatial “networks”. After establishing this framework, Chapters 3 and 4 provide tests of specific predictions. Thus, Chapter 3 confirms, in humans and macaque monkeys, the presence of topographically organized traveling waves occurring in synchrony with ongoing arousal fluctuations, with propagation occurring in parallel within the neocortex, striatum, thalamus, and cerebellum. This process is argued to provide a heretofore lacking physiological account of “resting-state functional connectivity” and related phenomenology. Chapter 4 extends this observation by demonstrating a continuous and tightly coordinated temporal evolution of brain, body, and behavioral states along a latent arousal cycle. Across multiple recording techniques and species, this cyclic trajectory is shown to be coupled to the traveling wave process described in Chapter 3, thus providing a parsimonious and integrative account of intrinsic brain activity and its spatiotemporal dynamics. Taken together, this thesis argues for the existence of an intrinsic regulatory process for global brain function

Simultaneous pupillometry and functional Magnetic Resonance Imaging (fMRI) for the detection of stress-related endophenotypes

Mental diseases constitute a core health challenge of the 21st century. To date, diagnostics in psychiatry have been primarily based on subjective self-reports, largely bypassing the biological underpinnings and phenotypic heterogeneity of psychiatric disorders. As an effort to implement a more biologically valid classification of mental disorders, recent initiatives like the Research Domain Criteria (RDoC) project aim to identify endophenotypes that reflect transdiagnostic core mechanisms of psychiatric disorders. Stress is known to play a fundamental role in the development of mood and anxiety disorders. One key system involved in the physiological response to stress is the brainstem’s noradrenergic (NA) arousal center located in the locus coeruleus (LC), and previous studies indicate that pupil size provides an indirect index for activity of the LC-NA system. In order to investigate the relationship between spontaneous drifts in autonomic arousal and global brain activity in healthy human subjects, we first determined the fMRI correlates of spontaneous pupil fluctuations during the resting state. We found that pupil dilations are strongly coupled to activation of the dorsal anterior cingulate cortex (dACC) and bilateral insula (salience network [SN]). To assess whether this link between the pupil and the SN would also extend to emotional arousal, we next investigated the neural correlates of reward anticipation-induced pupil dilations in healthy subjects. Here, we could show that a cue signaling the possibility to receive a monetary reward evoked strong pupil dilations, the magnitude of which predicted response time to a target cue. Again, pupil dilations were strongly linked to SN activation. Furthermore, our results suggest that pupillometry is helpful to dissect different phases of reward anticipation and associated brain activity, disentangling reward prediction, arousal modulation and attentionrelated processes. These observations led us to the conclusion that the SN modulates arousal levels to optimize task performance, that is, to counteract drowsiness/ transitions to sleep during the resting state and to facilitate reward-directed behaviors in the reward anticipation task. Taken together, pupillometry appears to provide a reliable index for activity of the SN, a core network related to psychiatric disorders, making it a promising tool for the detection of stress-related endophenotypes