Neurophysiological signatures reflect differences in visual attention during absence seizures

Objective: Absences affect visual attention and eye movements variably. Here, we explore whether the dissimilarity of these symptoms during absences is reflected in differences in electroencephalographic (EEG) features, functional connectivity, and activation of the frontal eye field. Methods: Pediatric patients with absences performed a computerized choice reaction time task, with simultaneous recording of EEG and eye-tracking. We quantified visual attention and eye movements with reaction times, response correctness, and EEG features. Finally, we studied brain networks involved in the generation and propagation of seizures. Results: Ten pediatric patients had absences during the measurement. Five patients had preserved eye movements (preserved group) and five patients showed disrupted eye movements (unpreserved group) during seizures. Source reconstruction showed a stronger involvement of the right frontal eye field during absences in the unpreserved group than in the preserved group (dipole fraction 1.02% and 0.34%, respectively, p &lt; 0.05). Graph analysis revealed different connection fractions of specific channels. Conclusions: The impairment of visual attention varies among patients with absences and is associated with differences in EEG features, network activation, and involvement of the right frontal eye field. Significance: Assessing the visual attention of patients with absences can be usefully employed in clinical practice for tailored advice to the individual patient.</p

Functional Magnetic Resonance Imaging as an Assessment Tool in Critically Ill Patients

Little is known about whether residual cognitive function occurs in the earliest stages of brain injury. The overarching goal of the work presented in this dissertation was to elucidate the role of functional neuroimaging in assessing brain activity in critically ill patients. The overall objective was addressed in the following four empirical chapters: In Chapter 2, three versions of a hierarchically-designed auditory task were developed and their ability to detect various levels of auditory language processing was assessed in individual healthy participants. The same procedure was then applied in two acutely comatose patients. In Chapter 3, a hierarchical auditory task was employed in a heterogeneous cohort of acutely comatose patients. The results revealed that the level of auditory processing in coma may be predictive of subsequent functional recovery. In Chapter 4, two mental imagery paradigms were utilized to assess covert command-following in coma. The findings demonstrate, for the first time, preserved awareness in an acutely comatose patient. In Chapter 5, functional neuroimaging techniques were used for covert communication with two completely locked-in, critically ill patients. The results suggest that this methodology could be used as an augmentative communication tool to allow patients to be involved in their own medical decision-making. Taken together, the proceeding chapters of this work demonstrate that functional neuroimaging can detect preserved cognitive functions in some acutely comatose patients, which has both diagnostic and prognostic relevance. Moreover, these techniques may be extended even further to be used as a communication tool in critically ill patients

Neural mechanisms of visual awareness and their modulation by social threat

The human brain can extract an enormous wealth of visual information from our surroundings. However, only a fraction of this immense data set ever becomes available to the observer’s awareness. How and why certain information is selected for awareness are questions under active investigation. Following two introductory chapters, this thesis contains six inter-related experimental chapters, through which I will explore two key outstanding questions in this field, using bistable perceptual paradigms to study conscious and non-conscious visual processing in healthy human volunteers. The first major theme focuses on adding new insight into the brain regions and networks that facilitate transfer between non-conscious and conscious modes of visual processing. In Chapters 3 and 4 I will use fMRI, both in task-related and resting-state conditions, to delineate areas, and their interactions (in terms of effective connectivity), which are relevant for transition between different conscious perceptual experiences. In Chapter 5 I will focus on one specific region in the proposed perceptual transition-related network (the frontal eye field) and explore its causal role in access to awareness using repetitive TMS. The second key question explored in this thesis is how social cues in the visual environment influence non-conscious visual processing as well as transition to conscious vision. In Chapter 6 I will study behavioural effects of non-conscious social cues from faces, and the relationship of these effects to focal brain anatomy. Based on finding slower perceptuomotor performance when non-conscious faces contain threatening cues in Chapter 6, I hypothesise that a defensive freezing response is engaged in such situations. The final two experimental chapters will explore the correlates of putative human freezing in the context of non-conscious social threat: using fMRI and psychophysiological measurements to study effects on perceptual transition in Chapter 7, and relating TMS-induced motor-evoked potentials and concurrent psychophysiological measurements to non-conscious perceptuomotor performance in Chapter 8. Taken together, the presented findings shed new light on the network of brain regions involved in transition between non-conscious and conscious modes of visual processing. In addition, they uncover novel mechanisms through which socially relevant visual cues shape our awareness of the visual world, with particular emphasis on the engagement of defensive responses by socially threatening stimuli. The concluding chapter discusses the implications of these findings and explores relevant avenues for future work

Consciousness level assessment in completely locked-in syndrome patients using soft-clustering

Brain-computer interfaces (BCIs) are very convenient tools to assess locked-in (LIS) and completely locked-in state (CLIS) patients' hidden states of consciousness. For the time being, there is no ground-truth data in respect to these states for above-mentioned patients. This lack of gold standard makes this problem particularly challenging. In addition to consciousness assessment, BCIs also provide them with a communication device that does not require the presence of motor responses, which they are lacking. Communication plays an important role in the patients' quality of life and prognosis. Significant progress have been made to provide them with EEG-based BCIs in particular. Nonetheless, the majority of existing studies directly dive into the communication part without assessing if the patient is even conscious. Additionally, the few studies that do essentially use evoked brain potentials, mostly the P300, that necessitates the patient's voluntary and active participation to be elicited. Patients are easily fatigued, and would consequently be less successful during the main communication task. Furthermore, when the consciousness states are determined using resting state data, only one or two features were used. In this thesis, different sets of EEG features are used to assess the consciousness level of CLIS patients using resting-state data. This is done as a preliminary step that needed to be succeeded in order to engage to the next step, communication with the patient. In other words, the 'conversation' is initiated only if the patient is sufficiently conscious. This variety of EEG features is utilised to increase the probability of correctly estimating the patients' consciousness states. Indeed, each of them captures a particular signal attribute, and combining them would allow the collection of different hidden characteristics that could have not been obtained from a single feature. Furthermore, the proposed method should allow to determine if communication shall be initiated at a specific time with the patient. The EEG features used are frequency-based, complexity related and connectivity metrics. Besides, instead of analysing results from individual channels or specific brain regions, the global activity of the brain is assessed. The estimated consciousness levels are then obtained by applying two different soft-clustering analysis methods, namely Fuzzy c-means (FCM) and Gaussian Mixture Models (GMM), to the individual features and ensembling their results using their average or their product. The proposed approach is first applied to EEG data recorded from patients with unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) (patients with disorders of consciousness (DoC)) to evaluate its performance. It is subsequently applied to data from one CLIS patient that is unique in its kind because it contains a time frame during which the experimenters affirmed that he was conscious. Finally, it is used to estimate the levels of consciousness of nine other CLIS patients. The obtained results revealed that the presented approach was able to take into account the variations of the different features and deduce a unique output taking into consideration the individual features contributions. Some of them performed better than others, which is not surprising since each person is different. It was also able to draw very accurate estimations of the level of consciousness under specific conditions. The approach presented in this thesis provides an additional tool for diagnosis to the medical staff. Furthermore, when implemented online, it would enable to determine the optimal time to engage in communication with CLIS patients. Moreover, it could possibly be used to predict patients' cognitive decline and/or death

Graph analysis of TMS–EEG connectivity reveals hemispheric differences following occipital stimulation

(1) Background: Transcranial magnetic stimulation combined with electroencephalography (TMS–EEG) provides a unique opportunity to investigate brain connectivity. However, possible hemispheric asymmetries in signal propagation dynamics following occipital TMS have not been investigated. (2) Methods: Eighteen healthy participants underwent occipital single-pulse TMS at two different EEG sites, corresponding to early visual areas. We used a state-of-the-art Bayesian estimation approach to accurately estimate TMS-evoked potentials (TEPs) from EEG data, which has not been previously used in this context. To capture the rapid dynamics of information flow patterns, we implemented a self-tuning optimized Kalman (STOK) filter in conjunction with the information partial directed coherence (iPDC) measure, enabling us to derive time-varying connectivity matrices. Subsequently, graph analysis was conducted to assess key network properties, providing insight into the overall network organization of the brain network. (3) Results: Our findings revealed distinct lateralized effects on effective brain connectivity and graph networks after TMS stimulation, with left stimulation facilitating enhanced communication between contralateral frontal regions and right stimulation promoting increased intra-hemispheric ipsilateral connectivity, as evidenced by statistical test (p &lt; 0.001). (4) Conclusions: The identified hemispheric differences in terms of connectivity provide novel insights into brain networks involved in visual information processing, revealing the hemispheric specificity of neural responses to occipital stimulation

The N400 for Brain Computer Interfacing: complexities and opportunities

The N400 is an Event Related Potential that is evoked in response to conceptually meaningful stimuli. It is for instance more negative in response to incongruent than congruent words in a sentence, and more negative for unrelated than related words following a prime word. This sensitivity to semantic content of a stimulus in relation to the mental context of an individual makes it a signal of interest for Brain Computer Interfaces. Given this potential it is notable that the BCI literature exploiting the N400 is limited. We identify three existing application areas: (1) exploiting the semantic processing of faces to enhance matrix speller performance, (2) detecting language processing in patients with Disorders of Consciousness, and (3) using semantic stimuli to probe what is on a user's mind. Drawing on studies from these application areas, we illustrate that the N400 can successfully be exploited for BCI purposes, but that the signal-to-noise ratio is a limiting factor, with signal strength also varying strongly across subjects. Furthermore, we put findings in context of the general N400 literature, noting open questions and identifying opportunities for further research.Comment: 28 pages, 2 figures, 2 table

Tracking brain dynamics across transitions of consciousness

How do we lose and regain consciousness? The space between healthy wakefulness and unconsciousness encompasses a series of gradual and rapid changes in brain activity. In this thesis, I investigate computational measures applicable to the electroencephalogram to quantify the loss and recovery of consciousness from the perspective of modern theoretical frameworks. I examine three different transitions of consciousness caused by natural, pharmacological and pathological factors: sleep, sedation and coma. First, I investigate the neural dynamics of falling asleep. By combining the established methods of phase-lag brain connectivity and EEG microstates in a group of healthy subjects, a unique microstate is identified, whose increased duration predicts behavioural unresponsiveness to auditory stimuli during drowsiness. This microstate also uniquely captures an increase in frontoparietal theta connectivity, a putative marker of the loss of consciousness prior to sleep onset. I next examine the loss of behavioural responsiveness in healthy subjects undergoing mild and moderate sedation. The Lempel-Ziv compression algorithm is employed to compute signal complexity and symbolic mutual information to assess information integration. An intriguing dissociation between responsiveness and drug level in blood during sedation is revealed: responsiveness is best predicted by the temporal complexity of the signal at single- channel and low-frequency integration, whereas drug level is best predicted by the complexity of spatial patterns and high-frequency integration. Finally, I investigate brain connectivity in the overnight EEG recordings of a group of patients in acute coma. Graph theory is applied on alpha, theta and delta networks to find that increased variability in delta network integration early after injury predicts the eventual coma recovery score. A case study is also described where the re-emergence of frontoparietal connectivity predicted a full recovery long before behavioural improvement. The findings of this thesis inform prospective clinical applications for tracking states of consciousness and advance our understanding of the slow and fast brain dynamics underlying its transitions. Collating these findings under a common theoretical framework, I argue that the diversity of dynamical states, in particular in temporal domain, and information integration across brain networks are fundamental in sustaining consciousness.My PhD was funded by the Cambridge Trust and a MariaMarina award from Lucy Cavendish College

Negative And Positive Attention Bias In Anhedonia And Anxious Arousal: Can Depression And Anxiety Be Distinguished By Patterns Of Engagement And Disengagement Bias?

Negative and positive attention bias (AB) is the preferential allocation of attentional resources to negative and positive stimuli in the environment, respectively. AB has been studied in various clinical and non-clinical populations and the process has been linked to symptoms of depression and anxiety. Findings so far suggest that negative AB is a trait-based factor that predisposes individuals to anxiety and depression. Positive AB appears specific to a depressed state, yet findings generally remain mixed. Measures of AB have been recently critiqued for their poor psychometric properties. This study addresses three gaps in the literature to further our understanding of the relationship between AB and psychopathology. The aims of this study were to determine whether 1) the core symptoms of depression (anhedonia) and anxiety (anxious arousal) are related to differential patterns of negative and positive AB, 2) anhedonia and anxious arousal have incremental utility in predicting AB over and above negative affectivity, 3) AB predicts group membership (clinical vs non-clinical). The dot-probe paradigm was administered to 144 participants from various settings. Mixed effects modeling was used to predict the relationship between Type of Trial (negative or positive vs neutral), Congruence (congruent vs incongruent), and Group (anhedonia, anxious arousal, comorbid, control) on response rate or error rate. Results from random effects analysis showed that inter-subject variability was significant. Fixed effects analyses showed that the present study failed to capture positive and negative AB. Between group differences in raw reaction times were observed. Implications of the findings with regards to methodological differences across studies are discussed

Measuring gaze and pupil in the real world: object-based attention,3D eye tracking and applications

This dissertation contains studies on visual attention, as measured by gaze orientation, and the use of mobile eye-tracking and pupillometry in applications. It combines the development of methods for mobile eye-tracking (studies II and III) with experimental studies on gaze guidance and pupillary responses in patients (studies IV and VI) and healthy observers (studies I and V). Object based attention / Study I What is the main factor of fixation guidance in natural scenes? Low-level features or objects? We developed a fixation-predicting model, which regards preferred viewing locations (PVL) per object and combines these distributions over the entirety of existing objects in the scene. Object-based fixation predictions for natural scene viewing perform at par with the best early salience model, that are based on low-level features. However, when stimuli are manipulated so that low-level features and objects are dissociated, the greater prediction power of saliency models diminishes. Thus, we dare to claim, that highly developed saliency models implicitly obtain object-hood and that fixation selection is mainly influenced by objects and much less by low-level features. Consequently, attention guidance in natural scenes is object-based. 3D tracking / Study II The second study focussed on improving calibration procedures for eye-in-head positions with a mobile eye-tracker.We used a mobile eye-tracker prototype, the EyeSeeCam with a high video-oculography (VOG) sampling rate and the technical gadget to follow the users gaze direction instantaneously with a rotatable camera. For a better accuracy in eye-positioning, we explored a refinement in the implementation of the eye-in-head calibration that yields a measure for fixation distance, which led to a mobile eye-tracker 3D calibration. Additionally, by developing the analytical mechanics for parametrically reorienting the gaze-centred camera, the 3D calibration could be applied to reliably record gaze-centred videos. Such videos are suitable as stimuli for investigating gaze-behaviour during object manipulation or object recognition in real worlds point-of-view (PoV) perspective. In fact, the 3D calibration produces a higher accuracy in positioning the gaze-centred camera over the whole 3D visual range. Study III, eye-tracking methods With a further development on the EyeSeeCam we achieved to record gaze-in-world data, by superposing eye-in-head and head-in-world coordinates. This novel approach uses a combination of few absolute head-positions extracted manually from the PoV video and of relative head-shifts integrated over angular velocities and translational accelerations, both given by an inertia measurement unit (IMU) synchronized to the VOG data. Gaze-in-world data consist of room-referenced gaze directions and their origins within the environment. They easily allow to assign fixation targets by using a 3D model of the measuring environment – a strong rationalisation regarding fixation analysis. Applications Study III Daylight is an important perceptual factor for visual comfort, but can also create discomfort glare situations during office work, so we developed to measure its behavioural influences. We achieve to compare luminance distributions and fixations in a real-world setting, by also recording indoor luminance variations time-resolved using luminance maps of a scenery spanning over a 3pi sr. Luminance evaluations in the workplace environment yield a well controlled categorisation of different lighting conditions and a localisation as well as a brightness measure of glare sources.We used common tasks like reading, typing on a computer, a phone call and thinking about a subject. The 3D model gives the possibility to test for gaze distribution shifts in the presence of glare patches and for variations between lighting conditions. Here, a low contrast lighting condition with no sun inside and a high contrast lighting condition with direct sunlight inside were compared. When the participants are not engaged in any visually focused task and the presence of the task support is minimal, the dominant view directions are inclined towards the view outside the window under the low contrast lighting conditions, but this tendency is less apparent and sways more towards the inside of the room under the high contrast lighting condition. This result implicates an avoidance of glare sources in gaze behaviour. In a second more extensive series of experiments, the participants’ subjective assessments of the lighting conditions will be included. Thus, the influence of glare can be analysed in more detail and tested whether visual discomfort judgements are correlated in differences in gaze-behaviour. Study IV The advanced eye-tracker calibration found application in several following projects and included in this dissertation is an investigation with patients suffering either from idiopathic Parkinson’s disease or from progressive supranuclear palsy (PSP) syndrome. PSP’s key symptom is the decreased ability to carry out vertical saccades and thus the main diagnostic feature for differentiating between the two forms of Parkinson’s syndrome. By measuring ocular movements during a rapid (< 20s) procedure with a standardized fixation protocol, we could successfully differentiate pre-diagnosed patients between idiopathic Parkinson’s disease and PSP, thus between PSP patients and HCs too. In PSP patients, the EyeSeeCam detected prominent impairment of both saccade velocity and amplitude. Furthermore, we show the benefits of a mobile eye-tracking device for application in clinical practice. Study V Decision-making is one of the basic cognitive processes of human behaviours and thus, also evokes a pupil dilation. Since this dilation reflects a marker for the temporal occurrence of the decision, we wondered whether individuals can read decisions from another’s pupil and thus become a mentalist. For this purpose, a modified version of the rock-paper-scissors childhood game was played with 3 prototypical opponents, while their eyes were video taped. These videos served as stimuli for further persons, who competed in rock-paper-scissors. Our results show, that reading decisions from a competitor’s pupil can be achieved and players can raise their winning probability significantly above chance. This ability does not require training but the instruction, that the time of maximum pupil dilation was indicative of the opponent’s choice. Therefore we conclude, that people could use the pupil to detect cognitive decisions in another individual, if they get explicit knowledge of the pupil’s utility. Study VI For patients with severe motor disabilities, a robust mean of communication is a crucial factor for well-being. Locked-in-Syndrome (LiS) patients suffer from quadriplegia and lack the ability of articulating their voice, though their consciousness is fully intact. While classic and incomplete LiS allows at least voluntary vertical eye movements or blinks to be used for communication, total LiS patients are not able to perform such movements. What remains, are involuntarily evoked muscle reactions, like it is the case with the pupillary response. The pupil dilation reflects enhanced cognitive or emotional processing, which we successfully observed in LiS patients. Furthermore, we created a communication system based on yes-no questions combined with the task of solving arithmetic problems during matching answer intervals, that yet invokes the most solid pupil dilation usable on a trial-by-trial basis for decoding yes or no as answers. Applied to HCs and patients with various severe motor disabilities, we provide the proof of principle that pupil responses allow communication for all tested HCs and 4/7 typical LiS patients. Résumé Together, the methods established within this thesis are promising advances in measuring visual attention allocation with 3D eye-tracking in real world and in the use of pupillometry as on-line measurement of cognitive processes. The two most outstanding findings are the possibility to communicate with complete LiS patients and further a conclusive evidence that objects are the primary unit of fixation selection in natural scenes

The Use of Communication Facilitators With Severely Brain Injured Non-Responsive Adults.

Slow-to-Recover (STR) individuals are a subset of the neurologically impaired population who remain non-responsive for extended periods of time before beginning to demonstrate improvement in cognitive, communicative, or motor function. This investigation focuses on the development and implementation of a facilitator-based intervention program carried out with an STR brain injured adult residing in a long-term care facility. The model involved: (1) sensory stimulation techniques to increase responses to external stimuli, (2) augmentative techniques which enabled the subject to control his immediate environment and, (3) training of qualified residents within the facility to act as communication facilitators. Ethnographic procedures were employed in conjunction with quantitative measures over a six-month period to measure changes in the subject\u27s functional abilities and describe overall changes in the communicative environment. Following eight weeks of communicative intervention, there were positive changes in the cognitive, motor, and communicative abilities of the subject that affected the interactive patterns and behavior of other participants. Results are discussed with regard to the contribution of each intervention technique in bringing about these changes