Assessing cognitive abilities in disorders of consciousness (DOC) relies on assessments of overt behaviour, such as the ability to follow commands. Neuroimaging has shown that absence of overt behavior does not necessarily indicate absence of covert cognition, raising questions about behaviour-only assessment. Several electroencephalographic (EEG) markers of higher cognitive functions (event-related potentials; ERPs) have shown the potential to differentiate between DOC states, as well as predict awakening and condition upon emergence. However, no one ERP has emerged with sensitivity and specificity high enough to be widely accepted, showing that further investigation is needed. More recently, evidence has emerged for fluctuations of ERP detectability in DOC over the course of several hours, and for prognostic power of changes in ERP presentation between testing sessions. This investigation builds on such findings towards improving evaluation of cognition in DOC. A testing battery combining several well-known auditory ERPs was administered to a comatose patient over a 24-hour period during two recording sessions one week apart, as well as to a sample of healthy young adults. The patient scored 3 and 6 on the Glasgow Coma Scale (GCS) during the first and second session, respectively. The results show that changes in GCS score were accompanied by changes in ERP detectability. The results also suggest detectability fluctuations over the course of 24 hours, which in turn suggests that repeated testing is necessary for complete evaluation. Future work should validate these findings with a larger sample; additionally, establishing population norms for single-subject prevalence, latency, and amplitude of ERPs would improve confidence in interpreting patient results. With the current understanding of both healthy and DOC ERPs, detecting ERP presence may contribute to a positive DOC prognosis with a degree of confidence, but caution must be exercised in making negative prognoses or high-stakes care decisions based on ERP absence. / Thesis / Master of Science (MSc) / Assessing cognitive abilities in disorders of consciousness such as coma currently relies on assessments of overt behaviour, such as the ability to follow commands or react to a stimulus. Neuroimaging has shown that absence of overt behavior does not necessarily indicate absence of covert cognition, raising questions about behaviour-only assessment. This study describes a neuroimaging testing battery aimed at evaluating a hierarchy of cognitive functions without the need for a behavioural response by measuring brain activity driven by auditory stimulation. This battery was administered to a comatose patient over a 24-hour period during two recording sessions one week apart, as well as to a sample of healthy young adults. The results show that changes in the patient’s condition between testing sessions was accompanied by detectable and quantifiable change in their stimulus-driven brain activity. The results also suggest fluctuations in the patient’s ability to produce detectable responses over the course of 24 hours, which in turn suggests that repeated testing is necessary for a complete evaluation. Overall, neuroimaging provides a promising avenue for non-behavioral assessment of cognition, which will greatly benefit a population whose physical faculties may be compromised.

Finding the neural mechanisms of unconsciousness is a pursuit with significance to both the scientific study of consciousness as well as for the improvement of clinical diagnosis of patients with severe structural brain damage that has resulted in disorders of consciousness (DOC), such as coma or vegetative state . This literature review gives an account for what consciousness studies have contributed to the understanding of the neural mechanisms of unconsciousness, focusing on experiments using anesthetic agents to investigate the loss and return of consciousness. Mechanisms that frequently correlate with the loss of consciousness are modulation of the brainstem, the thalamus, and the cortex, but different anesthetic drugs act on different areas. According to a bottom-up approach unconsciousness can be induced by sleep-circuits in the brainstem, and according to a top-down approach unconsciousness can be induced by cortical and thalamocortical disruption. But the mechanisms involved during loss of consciousness are not the same as for return of consciousness, and this paper includes evidence for the mechanisms involved during the return being closer to what research should be further investigating. The mechanisms involved in return from anesthesia-induced unconsciousness resemble those mechanisms involved in recovery from DOC. Studying mechanisms of unconsciousness can further our understanding of consciousness, as well as improve the diagnosis and treatment of patients with DOC.

Abstract In the 1990s researchers discovered task-deactivated regions in the human brain. Together, these areas make up the default mode network (DMN). It was originally proposed to act as a balancing mechanism between different brain systems, explaining the deactivations, but is now mostly studied with regards to internal awareness, such as daydreaming and mental imagery. The purpose of this thesis is to present a summary of DMN research, focusing on the network’s suggested role in internal awareness. This will be done by reviewing a wide variety of research that either explicitly or indirectly correlate default mode network features with aspects of consciousness and internal awareness. The subjective experience of being conscious have been a source of argument primarily among philosophers, but the qualities we feel are intimately linked to cognitive functions that are supported by the regions found in the DMN. Cognitive neuroscience may therefore be able to contribute to the concept of internal awareness and consciousness.

The traditional diagnosis of patients with disorders of consciousness relies solely on behavioral responses. In 1996 it was estimated that 43% of patients diagnosed with unresponsive wakefulness syndrome (vegetative state) receive the wrong diagnosis. Assessing consciousness is perhaps the most crucial part of the diagnostic process. The challenging task of identifying covert consciousness in this patient group seems to be the biggest issue. In 2006 willful modulation of brain activity in response to a mental imagery task was discovered in a patient with unresponsive wakefulness syndrome. The brain activity was measured with functional magnetic resonance imaging. It was concluded that consciousness was preserved in this patient and new research investigating this novel method began to take place. The aim of this thesis was to conduct a systematic review of the literature and thereby arrive at the best current estimate of the proportion of patients who receive a diagnosis that wrongfully defines them as “unconscious” although they in fact are “covertly conscious”. In this review, 11 studies were examined. The results showed that patients with unresponsive wakefulness syndrome, who still receive the wrong diagnosis, decreased to 22-28% by the use of neuroimaging. This improvement points to the possible use of neuroimaging methods in the diagnosis of disorders of consciousness. However, this result cannot be taken without reservations. The limitations of the studies have to be taken into consideration. For example, most studies included a limited sample size and healthy controls did not always give the expected response to mental imagery tasks.

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.

Comprendre les mécanismes neurophysiologiques et les bases neurales de la conscience est un défi médico-scientifique majeur. A cette fin, il faut opérer une distinction entre les mécanismes neuraux des états de conscience, et ceux qui sous-tendent l'accès conscient à un contenu mental particulier (ou la prise de conscience). Les données expérimentales ayant contrasté état conscient/ état non conscient (coma, sommeil, sédation) d'une part, et perception consciente/inconsciente d'un même stimulus d'autre part, sont en faveur de l'implication d'un réseau d'aires cérébrales fronto-pariétales à la fois dans l'état et dans l'accès conscient à une information donnée. La comparaison état conscient/ état non conscient est malheureusement limitée par les différences de vigilance existant entre ces états. Nous avons cherché à contourner ce problème en nous focalisant sur deux populations de malades présentant un niveau de vigilance proche mais différant sous l'angle de l'état de conscience : patients éveillés, non conscients (état végétatif) versus patients éveillés et minimalement conscients (état de conscience minimale). Nos résultats, obtenus en utilisant les potentiels évoqués auditifs cognitifs à haute densité spatiale, sont en faveur de l'implication du même réseau d'aires cérébrales fronto-pariétales que celui mentionné ci-dessus, à la fois dans l'état et l'accès conscient. L'activation de ce réseau est contemporaine de l'apparition d'une P300b en potentiels évoqués qui semble constituer un marqueur très spécifique de conscience. Notre travail nous a permis également d'identifier un possible nouveau marqueur de la conscience qu'est la variation contingente négative (CNV). / Understanding the neurophysiological mechanisms and neural bases of consciousness is a major scientific and medical challenge. To do this, one has to distinguish neural mechanisms of conscious state from those subserving conscious access to a given mental state (that is awareness). Experimental data having contrasted conscious / non conscious state (coma, sleep, sedation) on the one hand, and conscious/ unconscious processing of a very same stimulus on the other hand are in favour of the implication of a network of lateral and medial frontal and parietal areas in both conscious state and conscious access. The comparison of conscious/ non conscious state is unfortunately limited by arousal difference between these two states. So, we endeavoured to overcome this problem by exploring two categories of patients with a same level of arousal but a different state of awareness: unaware awaked patients (vegetative state) versus awaked and minimally conscious patients (minimally conscious state). Our results obtained by using high-density auditory event related potentials argue in favour of the implication of the very same network of frontal and parietal areas than the one described above in both conscious state and conscious access to a given information. This network activation is associated with the emergence of a P300b wave, on event related potentials, which seems to be a very specific marker of consciousness. Our work also give us the opportunity to discover a potential new marker of consciousness, namely the contingent negative variation (CNV).

This thesis presents methods for detecting consciousness in patients with complete locked-in syndrome (CLIS). CLIS patients are unable to speak and have lost all muscle movement. Externally, the internal brain activity of such patients cannot be easily perceived, but CLIS patients are considered to be still conscious and cognitively active. Detecting the current state of consciousness of CLIS patients is non-trivial, and it is difficult to ascertain whether CLIS patients are conscious or not. Thus, it is vital to develop alternative ways to re-establish communication with these patients during periods of awareness, and a possible platform is through brain–computer interface (BCI). Since consciousness is required to use BCI correctly, this study proposes a modus operandi to analyze not only in intracranial electrocorticography (ECoG) signals with greater signal-to-noise ratio (SNR) and higher signal amplitude, but also in non-invasive electroencephalography (EEG) signals. By applying three different time-domain analysis approaches sample entropy, permutation entropy, and Poincaré plot as feature extraction to prevent disease-related reductions of brainwave frequency bands in CLIS patients, and cross-validated to improve the probability of correctly detecting the conscious states of CLIS patients. Due to the lack a of 'ground truth' that could be used as teaching input to correct the outcomes, k-Means and DBSCAN these unsupervised learning methods were used to reveal the presence of different levels of consciousness for individual participation in the experiment first in locked-in state (LIS) patients with ALSFRS-R score of 0. The results of these different methods converge on the specific periods of consciousness of CLIS/LIS patients, coinciding with the period during which CLIS/LIS patients recorded communication with an experimenter. To determine methodological feasibility, the methods were also applied to patients with disorders of consciousness (DOC). The results indicate that the use of sample entropy might be helpful to detect awareness not only in CLIS/LIS patients but also in minimally conscious state (MCS)/unresponsive wakefulness syndrome (UWS) patients, and showed good resolution for both ECoG signals up to 24 hours a day and EEG signals focused on one or two hours at the time of the experiment. This thesis focus on consistent results across multiple channels to avoid compensatory effects of brain injury. Unlike most techniques designed to help clinicians diagnose and understand patients' long-term disease progression or distinguish between different disease types on the clinical scales of consciousness. The aim of this investigation is to develop a reliable brain-computer interface-based communication aid eventually to provide family members with a method for short-term communication with CLIS patients in daily life, and at the same time, this will keep patients' brains active to increase patients' willingness to live and improve their quality of life (QOL).

Le coma, l’état végétatif et l’état de conscience minimale sont classés comme « troubles de la conscience ». La caractéristique commune à ces diagnostics est un état de conscience altéré. La technologie permet désormais de maintenir en vie les individus affligés de ces diagnostics. La nature même de leur condition et les soins disponibles pour ces patients conduisent à des dilemmes médicaux et éthiques importants. Ce mémoire propose une brève introduction des troubles de la conscience suivie d’une recension des écrits sur les enjeux éthiques et sociaux en lien avec ces diagnostics. Force est de constater que certains enjeux perdurent depuis des années comme le retrait de traitement. D’autres sont apparus plus récemment, comme l’enjeu lié à l’usage de la neuroimagerie. Un deuxième volet présente les résultats d’une étude qualitative examinant les perspectives et l’expérience des professionnels de la santé face aux enjeux éthiques lors de la prise en charge des patients atteints de troubles de la conscience. Cette étude a été réalisée par le biais d’un court questionnaire et d’entrevues semi-dirigées qui furent enregistrées puis analysées à l’aide du logiciel Nvivo. Les résultats démontrent entre autres que les répondants éprouvent un niveau de certitude élevé face au diagnostic bien qu’il soit souvent signalé comme un défi important dans la littérature. Le pronostic représente un enjeu crucial, y compris sa divulgation aux proches. Enfin, la relation avec la famille est un élément clé dans la prise en charge des patients et celle-ci est teintée par de multiples facteurs. / Coma, the vegetative state and the minimally conscious state are classified as “disorders of consciousness”. The common characteristic of these diagnoses is an altered state of consciousness. Technological advances now allow us to keep people afflicted with these diagnoses alive. The very nature of their condition and the type of care available to them has lead to important medical and ethical dilemmas. First, this thesis proposes a literature review of the ethical and social issues related to disorders of consciousness. Certain issues have persisted for years and others have emerged more recently as that relating to the use of neuroimaging. The second part proposes a qualitative study examining the perspectives and experiences of healthcare professionals dealing with ethical issues in the management of these patients; these aspects are so far poorly documented. We conducted this study using a short questionnaire and semi-directed interviews. The interviews were taped and analyzed using qualitative analysis software Nvivo. Our study showed that our participants experienced a high degree of certainty about the diagnosis, although the latter is often reported as a major challenge in the literature. The prognosis is a critical challenge, including its disclosure to relatives. Finally, the relationship with the family is a key element in the care of patients and it is influenced by multiple factors.

Le coma, l’état végétatif et l’état de conscience minimale sont classés comme « troubles de la conscience ». La caractéristique commune à ces diagnostics est un état de conscience altéré. La technologie permet désormais de maintenir en vie les individus affligés de ces diagnostics. La nature même de leur condition et les soins disponibles pour ces patients conduisent à des dilemmes médicaux et éthiques importants. Ce mémoire propose une brève introduction des troubles de la conscience suivie d’une recension des écrits sur les enjeux éthiques et sociaux en lien avec ces diagnostics. Force est de constater que certains enjeux perdurent depuis des années comme le retrait de traitement. D’autres sont apparus plus récemment, comme l’enjeu lié à l’usage de la neuroimagerie. Un deuxième volet présente les résultats d’une étude qualitative examinant les perspectives et l’expérience des professionnels de la santé face aux enjeux éthiques lors de la prise en charge des patients atteints de troubles de la conscience. Cette étude a été réalisée par le biais d’un court questionnaire et d’entrevues semi-dirigées qui furent enregistrées puis analysées à l’aide du logiciel Nvivo. Les résultats démontrent entre autres que les répondants éprouvent un niveau de certitude élevé face au diagnostic bien qu’il soit souvent signalé comme un défi important dans la littérature. Le pronostic représente un enjeu crucial, y compris sa divulgation aux proches. Enfin, la relation avec la famille est un élément clé dans la prise en charge des patients et celle-ci est teintée par de multiples facteurs. / Coma, the vegetative state and the minimally conscious state are classified as “disorders of consciousness”. The common characteristic of these diagnoses is an altered state of consciousness. Technological advances now allow us to keep people afflicted with these diagnoses alive. The very nature of their condition and the type of care available to them has lead to important medical and ethical dilemmas. First, this thesis proposes a literature review of the ethical and social issues related to disorders of consciousness. Certain issues have persisted for years and others have emerged more recently as that relating to the use of neuroimaging. The second part proposes a qualitative study examining the perspectives and experiences of healthcare professionals dealing with ethical issues in the management of these patients; these aspects are so far poorly documented. We conducted this study using a short questionnaire and semi-directed interviews. The interviews were taped and analyzed using qualitative analysis software Nvivo. Our study showed that our participants experienced a high degree of certainty about the diagnosis, although the latter is often reported as a major challenge in the literature. The prognosis is a critical challenge, including its disclosure to relatives. Finally, the relationship with the family is a key element in the care of patients and it is influenced by multiple factors.

Chez les patients présentant un trouble de la conscience l'évaluation de leurs fonctions cognitives résiduelles est un enjeu clinique majeur, limité par la faible sensibilité des tests. La musique en tant que stimulation émotionnelle en lien avec la mémoire autobiographique pourrait représenter une stimulation cognitive de choix chez cette population. De nombreuses études ont rapporté les effets bénéfiques d'une exposition à la musique sur le fonctionnement cognitif, à la fois normal et pathologique, mais aucune n'a permis de déterminer objectivement de tels effets chez les patients en état de conscience altérée. Ce travail de thèse s'articule en trois études principales : 1) la présentation d'extraits musicaux préférés chez des patients en éveil de coma est liée à une importante connectivité cérébrale au sein de structures corticales participant à la perception de la musique et à la récupération d'informations autobiographiques ; 2) la réponse cognitive au propre prénom P300 obtenue chez des patients en éveil de coma est évoquée plus souvent lorsque ce dernier est précédé d'un extrait musical préféré ; 3) un contexte musical personnel familier entraîne l'activation de multiples structures cérébrales notamment celles impliquées dans l'analyse de stimulations autobiographiques. L'ensemble de ces travaux témoigne du recrutement de nombreux réseaux cérébraux lors de l'écoute musicale que ce soit chez les sujets sains et les patients en éveil de coma et suggère l'existence d'un possible amorçage autobiographique par la musique. Ainsi, l'emploi de la musique permettrait de favoriser l'expression des capacités cognitives et conscientes des patients en coma et en éveil de coma / Evaluating the residual cognitive functions in patients with disorders of consciousness is a major clinical challenge, restricted by the poor sensitivity of clinical tests. Music as a highly familiar and emotional stimulus in close relationship with autobiographical memory may be constitute a relevant tool for cognitive stimulation. Numerous studies have demonstrated that music listening conveys beneficial effects on cognitive processes as well as both normal and pathologic cerebral functioning. Surprisingly, no quantitative study has evaluated the potential effects of music on cognition and consciousness in comatose and post-comatose patients. The present thesis revolves around three studies: 1) an increased functional connectivity during exposure of favourite music is shown in cortical structures linked to music perception and memory search processes for post-comatose patients; 2) the cerebral response to the first name, the P300 component, is more often observed in post-comatose patients when its presentation was preceded by a preferred musical excerpt; 3) listening to personally relevant music is associated to activations in many cerebral structures, particularly in regions linked to autobiographical memory retrieval and self-processing. The whole of this work reveals that listening music involves numerous cerebral networks whether it be in healthy subjects or post-comtaose patients. These results also suggest the presence of an autobiographical priming by music. Finally, the use of music in clinical context can be boost the cognition in comatose and post-comatose patients