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International audience; ObjectiveThe pharmacokinetic/pharmacodynamic (PK/PD) relationship between blood tétrahydrocannabinol (THC) concentrations after smoking and the ability to drive is poorly documented.MethodsTHC and its metabolites were measured in the blood of chronic users (CC, 1–2 joints/day) and 15 occasional users (CO, 1–2 joints/week) 12 times over 24 h after randomized placebo-controlled smoking containing 10 mg or 30 mg of THC. The effects were evaluated 7 times by a vigilance test (reaction time) and a driving simulator during the same period.ResultsThere is no PK/PD relationship. The blood concentration for THC and 11-OH-THC is maximal at the end of the consumption whereas the effects are strongest about 5 h later. After the same dose consumed, the blood concentration of THC is almost twice as high in CC than in CO. CC always have THC in the blood (>1 ng/mL) after 24 h whereas it is < 0.5 ng/mL in CO after approximately 6 h. The effects on reaction time are greater for CO (+19% at 10 mg and +27% at 30 mg) than for CC (+11% at 10 mg and +19% at 30 mg). This is also the case for the ability to drive where there is no dose effect (+25% driving error for CC vs. +34% in CO). The total effect on driving lasts about 8 h in CC and up to 13 h in CO.ConclusionCannabis has a deleterious effect on the ability to drive, delayed in time compared to the blood kinetics of THC.; ObjectifLa relation pharmacocinétique/pharmacodynamique (PK/PD) après une prise fumée de cannabis et l’aptitude à conduire est peu documentée.MéthodesLe tétrahydrocannabinol (THC) et ses deux principaux métabolites ont été mesurés dans le sang de 15 consommateurs chroniques (CC, 1–2 joints/j) et de 15 consommateurs occasionnels (CO, 1–2 joints/semaine) 12 fois pendant 24 h après consommation d’une cigarette contenant de manière randomisée du placebo, 10 mg ou 30 mg de THC. Les effets ont été évalués 7 fois par un test de vigilance (temps de réaction) et un simulateur de conduite durant la même période.RésultatsIl n’existe pas de relation PK/PD. La concentration sanguine en THC et 11-OH-THC est maximale dès la fin de la consommation alors que les effets sont maximums 5 à 6 h après. Après une même dose consommée, la concentration sanguine de THC est pratiquement deux fois plus élevée chez les CC que chez les CO. Les CC ont toujours du THC dans le sang (>1 ng/mL) après 24 h alors qu’il est < 0,5 ng/mL chez les CO après 6 h environ. Les effets sur l’allongement du temps de réaction sont plus importants pour les CO (+19 % à 10 mg et +27 % à 30 mg) que pour les CC (+11 % à 10 mg et +19 % à 30 mg), de même sur l’aptitude à conduire où on ne retrouve pas d’effet dose (+25 % d’erreur pour les CC vs +34 % chez les CO). L’effet total sur la conduite dure environ 8 h chez les CC et jusqu’à 13 h chez les CO.ConclusionLe cannabis a un effet délétère sur la conduite, décalé dans le temps par rapport à la cinétique sanguine du THC.

The coma is the most severe stage of acute brain injury. It is characterized by a global disappearance of consciousness dimensions, including the loss of eyes-opening ability and the absence of reactivity to external stimulus. The relationship between this pathological absence of consciousness – associated to highly heterogeneous aetiologies – and the physiological loss of consciousness during sleep – highly homogeneous in its regulatory mechanisms – has been managed in the current literature in a sleep-like architecture view. However, this analogy seems to perform only for chronic disorders of consciousness that present a behavioural recovery of wakefulness (as chronic coma without any eyes-opening reflex is unusual) classically associated to neurophysiological signs (as the cases of unresponsive wakefulness syndrome without sleep/wake-like alternations are in minority). Because of a stunned arousal oscillatory system, the residual function of the Flip-Flop model assessed during the acute period would not allow attributing a formal stage to each level of fluctuations due to the high variability across patients. A quantitative description of fluctuations should be rather considered. The present thesis has conducted this alternative analysis of wakefulness modulations using neurophysiological markers, related to behavioural clues accessible by eyelid’s movements and to endogenous circadian or exogeneous determinants. Eighteen patients have been included in a multimodal study at the early phase of awakening (after sedation withdrawal and before any response to simple command). It consisted in a 24h polysomnography associated to an infrared video of eyes opening-closing periods, an assessment of urinary hormones (melatonin and cortisol) and the environmental recording of light, sound and nursing. Confronting every analysis has delineated several markers proving an overall respect of the “global state of consciousness” determinants. Despite not currently expressed as recovery, the association to a favourable prognosis would indicate that the basal conditions for a future expression of consciousness have been respected after the following observations: i) neurophysiological fluctuations are broad and have a high long-term predictability for the Alpha and Beta bands; ii) EEG, circadian hormones and behaviour follow a circadian rhythm; iii) the eye-opening periods are associated to a paradoxical reactivity of EEG, expressed as a reduced dominant frequency and an increased spatial variability in the Delta and Alpha bands; iv) the EEG changes induced by sound and nursing are broad and paradoxical; v) these processes appear early, while a late recovery of rhythms and reactivity could be concomitant to a partial cognitive recovery; vi) the Spindles-specific Sigma band power is high and the functional connectivity in Sigma and Beta bands have a rich repertory of night-time modulations. This novel approach apprehends the coma recovery as a dynamic process to be quantified and confronted to the multiplicity of its determinisms rather than between-states leaps associated to poorly defined consciousness levels. Introducing the oscillatory perspective into the natural history of consciousness loss and reappearance may give a non-invasive anatomo-clinical insight into the function of sub-cortical areas regulating sleep-wake cycles by integrating homeostatic and circadian processes. The differential long-term reactivity of EEG and behavioural dimensions provides a complementary information about the afferent brainstem functions modulating the global state of wakefulness (better approximated by EEG measures) – that creates in turn the conditions for local states of consciousness – or an external reflection (assessed by eyes opening) – that could be poorly relevant for some patients. Altogether, assessing the brain function in its bodily determinants alongside its world should offer a pragmatical ecological approach for consciousness embodiment; Stade le plus sévère de l’agression cérébrale aigüe, le coma est caractérisé par une disparition globale de toutes les dimensions de la conscience et s’exprime par une perte de l’ouverture des yeux et de toute réactivité aux stimulations. Les relations entre cette absence de conscience pathologique – de causes hétérogènes – et la perte de conscience physiologique du sommeil – homogène dans ses mécanismes régulateurs – ont été abordées dans la littérature sous l’angle de l’architecture du sommeil. Mais cette analogie ne semble fructueuse que dans les formes chroniques présentant une récupération de la vigilance comportementale (le coma chronique sans ouverture des yeux étant exceptionnel) ou neurophysiologique (les éveils non-répondants sans aucun cycle veille-sommeil étant minoritaires). Au cours de la sidération aigüe du système oscillatoire veille-sommeil, la fonctionnalité résiduelle du Flip-Flop model ne permettrait pas une attribution d’état à chaque période – trop variable entre les patients – mais une description quantitative des fluctuations. Cette thèse propose de conduire cette analyse alternative des modulations neurophysiologiques de la vigilance, en lien avec le comportement accessible par les mouvements des paupières et les déterminants endogènes circadiens ou exogènes. Dix-huit patients ont été inclus dans une étude multimodale à la phase précoce de leur réveil (hors sédation mais sans réponse aux ordres simples) incluant une polysomnographie de 24h, un film infrarouge de l’ouverture et de la fermeture des yeux, des mesures hormonales urinaires (mélatonine et cortisol) et un enregistrement environnemental de la lumière, du son et des soins. Plusieurs marqueurs issus de la confrontation entre ces analyses seraient associés au respect des déterminants de l’état global de conscience. Bien que non encore exprimée, l’association à un pronostic favorable indiquerait que les conditions de l’expression ultérieure de la conscience seraient respectées si : i) les fluctuations neurophysiologiques sont amples et présentent une forte prédictibilité de long terme (Alpha et Beta); ii) l’EEG, les hormones et le comportement suivent tous un rythme circadien; iii) les périodes d’ouverture des yeux sont associées à une réactivité paradoxale de l’EEG s’exprimant par une baisse de la fréquence dominante et une augmentation de la variabilité spatiale (Delta et Alpha); iv) les modifications de l’EEG par le son et les soins sont amples et paradoxales; v) ces processus apparaissent précocement, alors que la récupération tardive des rythmes et de la réactivité pourrait n’être que concomitante à une amélioration cognitive partielle; vi) la puissance dans la bande Sigma (fuseaux de sommeil) est haute et la connectivité fonctionnelle dans le Sigma et le Beta présente un riche répertoire au cours de la nuit. Au total, cette approche permet d’appréhender la récupération du coma comme une dynamique à objectiver et à confronter dans la multiplicité de ses déterminants, plutôt que comme des sauts entre des états correspondant à des niveaux de conscience de définition incertaine. Introduire cette conception oscillatoire de l’histoire naturelle de la perte et du retour à conscience fournirait, dans une optique anatomo-clinique, une mesure non invasive de la fonction des régions sous-corticales régulant les cycles veille-sommeil en intégrant les mécanismes homéostatiques et circadiens. La réactivité de long terme pour l’EEG et le comportement apporte une information complémentaire sur la fonctionnalité du tronc cérébral dans sa fonction afférente pour moduler l’état global de vigilance (mieux évaluée par EEG) – qui détermine les autres états locaux de conscience – ou un reflet externe (indiquée par l’ouverture des yeux) – peu représentatif pour certains patients. Ainsi, mesurer globalement la fonction du cerveau, dans son corps et en relation avec son monde, permettrait une approche écologique pragmatique du concept d’embodiment de la conscience

Narcolepsy-cataplexy was first described in the late 19th century in Germany and France. Prevalence was established to be 0.05 % and a canine model was discovered in the 1970s. In 1983, a Japanese study found that all patients carried HLA-DR2, suggesting autoimmunity as the cause of the disease. Studies in the canine model established that dopaminergic stimulation underlies anti-narcoleptic action of psychostimulants, while antidepressants were found to suppress cataplexy through adrenergic reuptake inhibition. No HLA association was found in canines. A linkage study initiated in 1988 revealed in hypocretin (orexin) receptor two mutations as the cause of canine narcolepsy in 1999. In 1992, studies on African Americans showed that DQ0602 was a better marker than DR2 across all ethnic groups. In 2000, hypocretin-1/orexin A levels were measured in the cerebrospinal fluid (CSF) and found to be undetectable in most patients, establishing hypocretin deficiency as the cause of narcolepsy. Decreased CSF hypocretin-1 was then found to be secondary to the loss of the 70,000 neurons producing hypocretin in the hypothalamus, suggesting immune destruction of these cells as the cause of the disease. Additional genetic studies, notably genome wide associations (GWAS), found multiple genetic predisposing factors for narcolepsy. These were almost all involved in other autoimmune diseases, although a strong and unique association with T cell receptor (TCR) alpha and beta loci were observed. Nonetheless, all attempts to demonstrate presence of autoantibodies against hypocretin cells in narcolepsy failed, and the presumed autoimmune cause remained unproven. In 2009, association with strep throat infections were found, and narcolepsy onsets were found to occur more frequently in spring and summer, suggesting upper away infections as triggers. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, molecular mimicry with influenza A virus was suggested in 2010. This hypothesis was later confirmed by peptide screening showing higher activity of CD4Narcolepsie : une maladie auto-immune affectant un peptide de l’éveil liée à un mimétisme moléculaire avec des épitopes du virus de la grippe.La narcolepsie et la cataplexie sont décrites pour la première fois à la fin du XIX

Sleep is a physiological condition essential to life, present in all living organisms with a neuronal and glial network. Its functions, not fully understood, include the conservation of energy, the regulation of our immune system and brain function through the modulation of synaptic plasticity and the elimination of substances accumulated during wakefulness. Sleep in human is characterized by two exclusive states, the non-REM and the REM -paradoxical- sleep, whose occurrence is driven by a cyclic organi zation. Sleep and wakefulness result from complex mechanisms involving a hetero geneous transition of different brain structures from one physiological state to another. The sleep duration and distribution of sleep over 24 hours are regulated by complex interconnected mechanisms, involving both the need for sleep accumulated during wakefulness -homeostatic process- and biological rhythm -mainly the circadian process- under the influence of external synchronizers like light-dark cycle. The propensity to sleep at a given moment is regulated by a physiological signal, sleepiness, in connection with the level of vigilance. The characteristics of sleep are relatively stable for a given individual because of a strong genetic determinism, but varies in duration and architecture according to age, individual habits, sleep schedules and environmental constraints. An understanding of the physiology of sleep is important for the clinician, allowing a better understanding of sleep dysfunction, responsible for various and frequent sleep disorders equiring appropriate care.Le sommeil est un état physiologique indispensable à la vie, présent chez tous les organismes vivants disposant d’un réseau neuronal et glial. Ses fonctions, non complètement élucidées, portent notamment sur la conservation de l’énergie, la régulation de notre système immunitaire et le fonctionnement cérébral via la modulation de la plasticité synaptique et l’élimination de substances accumulées lors de la veille. Le sommeil chez l’homme est marqué par deux états exclusifs, le sommeil lent et le sommeil paradoxal, dont l’apparition est régie par une organisation cyclique. L’endormissement et le réveil résultent de mécanismes complexes impliquant une transition hétérogène de différentes structures cérébrales d’un état physiologique vers l’autre. La durée et la répartition du sommeil au cours des 24 heures sont régulées par des mécanismes complexes étroitement intriqués, impliquant d’une part le besoin de sommeil accumulé au cours de la veille -processus homéostatique- et le rythme biologique -principalement le processus circadien- sous l’influence de synchroniseurs externes comme l’alternance lumière-obscurité. La propension au sommeil à un moment donné est régulée par un signal physiologique, la somnolence, en lien avec le niveau de vigilance de l’individu. Les caractéristiques du sommeil sont relativement stables pour un individu donné du fait d’un fort déterminisme génétique, mais varie toutefois en durée et en architecture selon l’âge, les habitudes individuelles, les horaires de sommeil et les contraintes environnementales. Une connaissance de la physiologie du sommeil est importante pour le clinicien, permettant une meilleure compréhension des dysfonctionnements du sommeil, responsables de pathologies diverses et particulièrement fréquentes nécessitant des prises en charge adaptées.

The coma is the most severe stage of acute brain injury. It is characterized by a global disappearance of consciousness dimensions, including the loss of eyes-opening ability and the absence of reactivity to external stimulus. The relationship between this pathological absence of consciousness – associated to highly heterogeneous aetiologies – and the physiological loss of consciousness during sleep – highly homogeneous in its regulatory mechanisms – has been managed in the current literature in a sleep-like architecture view. However, this analogy seems to perform only for chronic disorders of consciousness that present a behavioural recovery of wakefulness (as chronic coma without any eyes-opening reflex is unusual) classically associated to neurophysiological signs (as the cases of unresponsive wakefulness syndrome without sleep/wake-like alternations are in minority). Because of a stunned arousal oscillatory system, the residual function of the Flip-Flop model assessed during the acute period would not allow attributing a formal stage to each level of fluctuations due to the high variability across patients. A quantitative description of fluctuations should be rather considered. The present thesis has conducted this alternative analysis of wakefulness modulations using neurophysiological markers, related to behavioural clues accessible by eyelid’s movements and to endogenous circadian or exogeneous determinants. Eighteen patients have been included in a multimodal study at the early phase of awakening (after sedation withdrawal and before any response to simple command). It consisted in a 24h polysomnography associated to an infrared video of eyes opening-closing periods, an assessment of urinary hormones (melatonin and cortisol) and the environmental recording of light, sound and nursing. Confronting every analysis has delineated several markers proving an overall respect of the “global state of consciousness” determinants. Despite not currently expressed as recovery, the association to a favourable prognosis would indicate that the basal conditions for a future expression of consciousness have been respected after the following observations: i) neurophysiological fluctuations are broad and have a high long-term predictability for the Alpha and Beta bands; ii) EEG, circadian hormones and behaviour follow a circadian rhythm; iii) the eye-opening periods are associated to a paradoxical reactivity of EEG, expressed as a reduced dominant frequency and an increased spatial variability in the Delta and Alpha bands; iv) the EEG changes induced by sound and nursing are broad and paradoxical; v) these processes appear early, while a late recovery of rhythms and reactivity could be concomitant to a partial cognitive recovery; vi) the Spindles-specific Sigma band power is high and the functional connectivity in Sigma and Beta bands have a rich repertory of night-time modulations. This novel approach apprehends the coma recovery as a dynamic process to be quantified and confronted to the multiplicity of its determinisms rather than between-states leaps associated to poorly defined consciousness levels. Introducing the oscillatory perspective into the natural history of consciousness loss and reappearance may give a non-invasive anatomo-clinical insight into the function of sub-cortical areas regulating sleep-wake cycles by integrating homeostatic and circadian processes. The differential long-term reactivity of EEG and behavioural dimensions provides a complementary information about the afferent brainstem functions modulating the global state of wakefulness (better approximated by EEG measures) – that creates in turn the conditions for local states of consciousness – or an external reflection (assessed by eyes opening) – that could be poorly relevant for some patients. Altogether, assessing the brain function in its bodily determinants alongside its world should offer a pragmatical ecological approach for consciousness embodiment, Stade le plus sévère de l’agression cérébrale aigüe, le coma est caractérisé par une disparition globale de toutes les dimensions de la conscience et s’exprime par une perte de l’ouverture des yeux et de toute réactivité aux stimulations. Les relations entre cette absence de conscience pathologique – de causes hétérogènes – et la perte de conscience physiologique du sommeil – homogène dans ses mécanismes régulateurs – ont été abordées dans la littérature sous l’angle de l’architecture du sommeil. Mais cette analogie ne semble fructueuse que dans les formes chroniques présentant une récupération de la vigilance comportementale (le coma chronique sans ouverture des yeux étant exceptionnel) ou neurophysiologique (les éveils non-répondants sans aucun cycle veille-sommeil étant minoritaires). Au cours de la sidération aigüe du système oscillatoire veille-sommeil, la fonctionnalité résiduelle du Flip-Flop model ne permettrait pas une attribution d’état à chaque période – trop variable entre les patients – mais une description quantitative des fluctuations. Cette thèse propose de conduire cette analyse alternative des modulations neurophysiologiques de la vigilance, en lien avec le comportement accessible par les mouvements des paupières et les déterminants endogènes circadiens ou exogènes. Dix-huit patients ont été inclus dans une étude multimodale à la phase précoce de leur réveil (hors sédation mais sans réponse aux ordres simples) incluant une polysomnographie de 24h, un film infrarouge de l’ouverture et de la fermeture des yeux, des mesures hormonales urinaires (mélatonine et cortisol) et un enregistrement environnemental de la lumière, du son et des soins. Plusieurs marqueurs issus de la confrontation entre ces analyses seraient associés au respect des déterminants de l’état global de conscience. Bien que non encore exprimée, l’association à un pronostic favorable indiquerait que les conditions de l’expression ultérieure de la conscience seraient respectées si : i) les fluctuations neurophysiologiques sont amples et présentent une forte prédictibilité de long terme (Alpha et Beta); ii) l’EEG, les hormones et le comportement suivent tous un rythme circadien; iii) les périodes d’ouverture des yeux sont associées à une réactivité paradoxale de l’EEG s’exprimant par une baisse de la fréquence dominante et une augmentation de la variabilité spatiale (Delta et Alpha); iv) les modifications de l’EEG par le son et les soins sont amples et paradoxales; v) ces processus apparaissent précocement, alors que la récupération tardive des rythmes et de la réactivité pourrait n’être que concomitante à une amélioration cognitive partielle; vi) la puissance dans la bande Sigma (fuseaux de sommeil) est haute et la connectivité fonctionnelle dans le Sigma et le Beta présente un riche répertoire au cours de la nuit. Au total, cette approche permet d’appréhender la récupération du coma comme une dynamique à objectiver et à confronter dans la multiplicité de ses déterminants, plutôt que comme des sauts entre des états correspondant à des niveaux de conscience de définition incertaine. Introduire cette conception oscillatoire de l’histoire naturelle de la perte et du retour à conscience fournirait, dans une optique anatomo-clinique, une mesure non invasive de la fonction des régions sous-corticales régulant les cycles veille-sommeil en intégrant les mécanismes homéostatiques et circadiens. La réactivité de long terme pour l’EEG et le comportement apporte une information complémentaire sur la fonctionnalité du tronc cérébral dans sa fonction afférente pour moduler l’état global de vigilance (mieux évaluée par EEG) – qui détermine les autres états locaux de conscience – ou un reflet externe (indiquée par l’ouverture des yeux) – peu représentatif pour certains patients. Ainsi, mesurer globalement la fonction du cerveau, dans son corps et en relation avec son monde, permettrait une approche écologique pragmatique du concept d’embodiment de la conscience

A survey carried out in 2004 studied the link between quality of sleep and the nocturnal management of incontinence. This same survey was repeated 10 years later. The results reveal the impact on quality of sleep, the deteriorating management of incontinence with the lenghtening of waiting time and the causes of waking. This discussion process on the quality of sleep must continue.

Narcolepsy type 1 (NT1) is a rare neurological disease characterized by an excessive daytime sleepiness and episodes of cataplexy – a sudden loss of muscular tone triggered by strong emotions during wakefulness. In humans, NT1 is due to the specific and postnatal loss of orexin (Orex) neurons involved in wake promotion. It led to describe NT1 as a wake disease. However, clinical observations have suggested a disrupted regulation of paradoxical (or REM) sleep in narcolepsy. Indeed, NT1 patients have shorter latency to enter REM sleep and frequent sleep onset in REM sleep. More, muscular atonia observed in cataplexy is one of the main feature of REM sleep. Together, those data led to the hypothesis that narcolepsy would be also a REM sleep disease. We’ve investigated this hypothesis in two different studies performed on a recognize model of murine narcolepsy: the Orex-KO mouse. In a 1st study, we found that despite an intact REM sleep homeostasic regulation, Orex-KO mice had an increased REM sleep propensity during active phase. We’ve suggested a new role of REM sleep inhibition for the neuropeptide Orex. Then, we aimed to determine whether REM sleep atonia and cataplexy shared the same neuronal network. In contrast to the currently admitted hypothesis, we demonstrate that glutamatergic neurons of the sublaterodorsal nucleus (SLD) are not sufficient to generate cataplexy, and are only partially involved in this symptom. Taken together, data harvested during this thesis help us to better understand the role of Orex in NT1 and to improve our knowledge about the neurobiological mechanisms of cataplexy, La narcolepsie de type 1 (NT1) est une maladie neurologique rare caractérisée par une hypersomnolence diurne et des cataplexies - pertes de tonus musculaire pendant l'éveil provoqué par une émotion forte. Chez l'homme, la NT1 est due à la mort spécifique et postnatale des neurones à orexine (Orex) promoteurs de l'éveil, et est considérée comme une pathologie de l'éveil. Toutefois, les observations cliniques suggèrent une dérégulation du sommeil paradoxal (SP) dans cette pathologie. Les patients NT1 ont une latence d'apparition du SP très courte et de fréquents endormissements en SP. De plus, la similitude entre l'atonie musculaire de la cataplexie et celle caractéristique du SP nous mène à penser que la narcolepsie serait également une pathologie du SP. Cette hypothèse a été testée à travers deux études menées sur un modèle murin de narcolepsie : la souris Orex-KO. Dans une 1ère étude nous avons objectivé que malgré une régulation homéostasique du SP intacte, la souris Orex-KO a une propension élevée à faire du SP pendant la phase active. Nous avons alors suggéré un nouveau rôle pour le neuropeptide Orex, celui d'inhibition du SP. Puis, nous avons cherché à déterminer si le réseau neuronal de l'atonie musculaire du SP était recruté pendant les cataplexies. Nos données suggèrent que contrairement à l'hypothèse généralement admise, les neurones glutamatergiques du noyau sublatérodorsal (SLD) ne sont pas suffisants à la mise place des cataplexies et ne seraient que partiellement impliqués dans ce symptôme. Ce travail de thèse a permis de mieux comprendre le rôle des Orex dans la NT1, et d'approfondir nos connaissances sur les mécanismes neurobiologiques de la cataplexie

There is and Ethical Vigilance. The Levinassian understanding of ‘ vigilance’ is absolutely not intuitive ; more than that, it might even seem to be the opposite of what one usually means when one speaks of vigilance as ‘ sustained attention’. Nevertheless one can put forward the hypothesis that what Levinas describes is in fact faithful to the ‘ thing in itself’, to the phenomenon of ‘vigilance’ as revealed in its essence. The Levinassian description of ‘ vigilance’ is not only a matter of psychology, but also a matter of gnoseology and of ontology once we consider that ‘ vigilance’ gives (access to) what Levinas calls the ‘There is’ (l’il y a). Last but not least, we will see how Levinas, in his latest texts, reveals this core experience as the ultimate test of ethics., L’entente lévinassienne de la « vigilance » n’est pas du tout intuitive ; il pourra même sembler qu’elle s’oppose à ce que l’on entend le plus souvent par « vigilance » , la vigilance comme « attention soutenue » . Pourtant, on peut faire l’hypothèse que ce que Levinas décrit ainsi est en fait fidèle à la « chose même » , au phénomène de la « vigilance » révélé en son essence. La description lévinassienne de la vigilance n’est pas uniquement affaire de psychologie, elle est aussi affaire de gnoséologie et d’ontologie dès lors que la « vigilance » donne (accès à) ce que Levinas nomme l’il y a. Enfin, et ce n’est pas le moins important, nous verrons que Levinas, dans ses derniers textes, révèle que cette expérience fondamentale (la vigilance) est l’épreuve même de l’éthique., Sebbah François-David. Il y a et vigilance éthique. In: Intellectica. Revue de l'Association pour la Recherche Cognitive, n°66, 2016/2. Phénoménologie de la vigilance et de l'attention. Philosophie, sciences et techniques. pp. 57-65.

I am Awake : Husserl on Wakefulness and Attention. The article presents Husserl’s account of wakefulness and shows that, according to Husserl, only a phenomenology of attention is capable of elucidating what characterizes the state of wakefulness. That is, the article shows, from a Husserlian point of view, that attention introduces a distinction between theme and background in our experience and that this accounts for why we are never fully awake when we are awake (section 1 and 2), how the sleep within wakefulness is different from genuine sleep (section 3), and, finally, in what way the intentionality that occurs when genuinely asleep, such as dreaming, is radically different from any awareness that occurs while awake., L’article présente une reconstruction d’analyse husserlienne de l’éveil et démontre que, selon Husserl, seule une phénoménologie de l’attention est en mesure d’élucider les véritables caractéristiques de l’état d’éveil. Plus précisément, l’article démontre que, d’un point de vue husserlien, l’attention introduit une distinction entre thème et arrière-plan dans notre expérience et que cette différence est ce qui nous permettra de déterminer dans quelle mesure nous ne sommes jamais pleinement éveillés lorsque nous sommes éveillés (section 1 et 2), comment le sommeil au sein de l’état d’éveil diffère du sommeil véritable (section 3), et, enfin, comment l’intentionnalité survenant lors du sommeil véritable, à l’instar des rêves, diffère radicalement de toute forme de conscience intentionnelle survenant lors de l’état d’éveil (section 4)., Jacobs Hanne. Je suis éveillée : Husserl sur l’attention et l’éveil. In: Intellectica. Revue de l'Association pour la Recherche Cognitive, n°66, 2016/2. Phénoménologie de la vigilance et de l'attention. Philosophie, sciences et techniques. pp. 37-56.

Hormonal secretion, cognitive performance, motor activity, metabolic processes, the sleep wake cycle and, most recently shown, cell division and ADN repair show a 24 h rhythmicity that is driven by the circadian timing system (the biological clock). Their appropriate activity over the 24 h requires appropriate entrainment of the circadian clock, which is achieved through the synchronizing effects of ocular light exposure. The activation of melanopsin-expressing ganglion cells in the retina depends on timing, quality, intensity, and history of light exposure. Inappropriate lighting leads to inappropriate synchronization of the clock, and activation of non-visual functions (mood, wakefulness, cognition, etc.). In turn, a deficit of circadian entrainment to the 24 h is responsible for alterations of a large number of functions, and leads to altered sleep, wake, mood, neurobehavioral processes and cell division, but also to pathologies. The crucial role of the circadian clock and the nature of the non-visual functions activated by light give rise to the concept that light is a biological need fundamental to health. Without an appropriate light hygiene, the clock receives an odd tempo, and it is cacophony!

Most living organisms possess a circadian clock (24 h period) which allows them to adapt to environmental conditions. Numerous studies in Drosophila allowed to discover various key clock genes, such as period and timeless. The powerful tools of drosophila genetics have shown that the molecular clock relies on negative feedback loops that generate oscillations of the clock genes mRNA. A delay between the accumulation of mRNAs and proteins is required for the feedback loop. It is generated by post-translational modifications as phosphorylations and ubiquitinations, which control protein stability and determine the period of their oscillations. Clock cells are present in brain as well as in multiple peripheric tissues where they run autonomously. The synchronisation of clock cells by light relies on cryptochrome in both brain and peripheral tissues. In the brain, synchronisation also involves the eye photoreceptors. The clock that drives sleep-wake rhythms is controlled by different groups of neurons in the brain. Each group has a distinct function in the generation of the behavioral rhythm and this function is modulated by environmental conditions.

The hypothalamic hypocretin (orexin) system plays a crucial role in the regulation of sleep and wakefulness. The strongest evidence is the fact that the primary sleep disorder narcolepsy is caused by disrupted hypocretin signaling in humans as well as in various animal models. Today there is growing interest in the role of hypocretin defects in sleep disorders associated with neurodegenerative diseases. One of the most controversial issues is the functional relevance of partial hypocretin defects in these disorders.

By combining brain section/lesion studies and sleep analysis, neurophysiologists have identified the brain areas responsible for regulating sleep and wakefulness during the first half of the 20th century. Identification of the phenotypic nature of the neurons underlying the regulation of vigilance, as well as their anatomical and functional connections led to a theoretical model based on mutual inhibitory interactions between sleep-on neurons (namely GABAergic neurons of the hypothalamic preoptic region) and wake-on neurons (mainly monoaminergic and cholinergic neurons). In addition to the corresponding neurotransmitters (serotonin, acetylcholine and GABA), other neuroactive molecules that play key roles in sleep and wakefulness regulation have recently been discovered, leading to an updated model. Hypocretin, also known as orexin, is a key neuropeptide involved in the sleep disorder narcolepsy. Extensive characterization of the respective roles of these neurotransmitters has led to the identification of novel therapeutic targets for the treatment of sleep disorders. For example, blockade of hypocretin receptors has hypnotic effects.

The recent development of awake surgery in neuro-oncology allowed a conceptual change, i.e. the realization of resection for invasive brain tumors according to functional and not anatomic boundaries. This paradigmatic shift enabled a significant improvement of results in surgery for gliomas, by opening the door to resections within eloquent areas classically considered as "inoperable", while preserving and even improving the quality of life of patients. In addition, the extent of resections has been maximized, leading to an increase of median survival - especially in low-grade gliomas. Strong relationships between the different teams (surgeons, neuropsychologists, anaesthesiologists) are crucial for the development and improvement of awake surgery. Thus, it seems important that anesthesiologists can benefit from a clear and accurate knowledge of the real contribution of this procedure, in order to better evaluate the balance between the theoretical risks of surgery under local anesthesia versus the actual risk of not performing resection with a maximum of safety and efficiency for the patients. The purpose of this plea is to advocate the spread of awake surgery in routine practice, due to its major impact on both functional and survival outcomes, by nonetheless keeping in mind that a multidisciplinary staff is mandatory for selection of patients as well as into the operating room. In this state of mind, anaesthesiologists have to play a central role, through an increased involvement in this field.

Brain tumor surgery is at risk when lesions are located in eloquent areas. The interindividual anatomo-functional variability of the central nervous system implies that brain surgery within eloquent regions may induce neurological sequelae. Brain mapping using intraoperative direct electrical stimulation in awake patients has been for long validated as the standard for functional brain mapping. Direct electrical stimulation inducing a local transient electrical and functional disorganization is considered positive if the task performed by the patient is disturbed. The brain area stimulated is then considered as essential for the function tested. However, the exactitude of the information provided by this technique is cautious because the actual impact of cortical direct electrical stimulation is not known. Indeed, the possibility of false negative (insufficient intensity of the stimulation due to the heterogeneity of excitability threshold of different cortical areas) or false positive (current spread, interregional signal propagation responsible for remote effects, which make difficult the interpretation of positive or negative behavioural effects) constitute a limitation of this technique. To improve the sensitivity and specificity of this technique, we used an electrocorticographic recording system allowing a real time visualization of the local. We provide here evidence that direct cortical stimulation combined with electrocorticographic recording could be useful to detect remote after discharge and to adjust stimulation parameters. In addition this technique offers new perspective to better assess connectivity of cerebral networks.

Insomnia is the most prevalent sleep disorders and affects severely 10% of adults worldwide. From poor sleep to insomnia, the severity of sleep disorders should be assessed clinically and by the use of validated questionnaires based on international consensual definitions. One main sign of insomnia is impaired daytime functioning. Insomnia may be treated with hypnotics only for a limited duration. Behavioural and cognitive therapies have been found efficient on chronic insomnia. Sleepiness is also a common sleep disorders due to altered sleep schedules, sleep deprivation, sleep disorders or as an adverse effect of some treatments. The risk of car accidents and the impaired quality of daytime functioning are the main consequences of sleepiness. The aim of this paper is to give some recommendations for the diagnosis and treatment of insomnia and sleepiness.

This article describes the two-process model of sleep regulation. The 24-hour sleep-wake cycle is regulated by a homeostatic process and an endogenous, 2 oscillators, circadian process, under the influence of external synchronisers. These two processes are partially independent but influence each other, as shown in the two-sleep-process auto-regulation model. A reciprocal inhibition model of two interconnected neuronal groups, "SP on" and "SP off", explains the regular recurrence of paradoxical sleep. Sleep studies have primarily depended on observation of the subject and have determined the optimal conditions for sleep (position, external conditions, sleep duration and need) and have studied the consequences of sleep deprivation or modifications of sleep schedules. Then, electrophysiological recordings permitted the classification of sleep stages according to the observed EEG patterns. The course of a night's sleep is reported on a "hypnogram". The adult subject falls asleep in non-REM sleep (N1), then sleep deepens progressively to stages N2 and N3 with the appearance of spindles and slow waves (N2). Slow waves become more numerous in stage N3. Every 90minutes REM sleep recurs, with muscle atonia and rapid eye movements. These adult sleep patterns develop progressively during the 2 first years of life as total sleep duration decreases, with the reduction of diurnal sleep and of REM sleep. Around 2 to 4 months, spindles and K complexes appear on the EEG, with the differentiation of light and deep sleep with, however, a predominance of slow wave sleep.

Restless legs syndrome (RLS) diagnosis is clinically ascertained on four associated essential criteria according to the recommendations of the workshop at the National Institute of Health published in 2003. Supportive clinical features can help to resolve any diagnosis uncertainty. RLS severity is assessed by a validated rating scale also useful for therapeutic decision and evaluation. Idiopathic forms (familial or sporadic) are the most frequent. Nevertheless secondary forms must be recognized, and etiology, associated pathologies and risk factors investigated. Periodic leg movements (PLM) during wakefulness and more frequently during sleep are present in almost 80 % of patients with RLS. These PLM can be recorded during a suggested immobilization test or during a polysomnography. Deleterious consequences of RLS are important: attention-deficit hyperactivity or tiredness and asthenia, cognitive deficit, psychiatric illness and detrimental impact on quality of life. This high prevalent syndrome is actually better defined but still under-diagnosed probably due to the patients' difficulties to describe their feelings. Practitioners would benefit to interview more systematically their patients complaining of poor sleep about legs discomfort and movements in the evening and at night.

Circadian rhythms are periodic variations over approximately 24hours in many biological and physiological processes and are controlled by the internal clock. The environment can influence or even synchronise rhythms over a different phase than the internal clock, although a specific phase relationship exists between the rhythms. Measuring circadian rhythms involves mathematical modelling which defines different parameters (amplitude, period phase, mean level or mesor). To identify these parameters, different protocols need to be applied which remove the impact of external factors liable to change the variable being measured. Markers of circadian rhythms are the wake/sleep cycle examined by the sleep diary and polysomnographic recording, the rest/activity cycle investigated by actimetry, chronotype, body temperature and melatonin secretion in particular with pre-sleeping measurements (DMLO), cortisol secretion and activity of clock genes. Improved knowledge of circadian rhythm parameters particularly stability is essential to understand the pathophysiological mechanisms underpinning some psychiatric diseases.

Ontogenesis of circadian rhythms in human beings, the history of the development of synchronisation of the daily rhythm describes the deployment of an adaptive capacity providing vital biological linkage to the environment. Methods for dating the stages in this temporal organisation have advanced and the genetics approach to the circadian cycle is dominated by studies of the maturation of the awake-asleep cycle. Disease involves the functional regression to one of the different stages of genesis or alternatively will involve a pathological lesion. Circadian dysfunction is characterised by loss of amplitude and multi-day fragmentation, correction of which requires control of multi-day pressure and within-day stabilisation.

This paper is a review of the use of drugs in sleep and wakefulness disorders. Insomnia is more often a symptom than an autonomic disorder. Good knowledge of the clinical facts is required before prescribing hypnotics. Sedative drugs are potentially hypnotics; yet, melatonin is not sedative and may be considered to resynchronise of sleep phases. Stimulant drugs are prescribed in attention disorders; methylphenidate is the more frequently used. Narcolepsy, which is characterized by daytime sleepiness and irresistible episodes of sleep, is treated by an alpha1 noradrenergic stimulant modafinil which has no amphetaminic properties.

Sports and military environments have many common features - intense physical activity, rigorous physical environment (heat, cold, high or low pressure, hypoxia, acceleration...), specific psychosocial atmosphere, team spirit. If combined with jet lag syndrome, these specific conditions can favor altered physical and mental performance. There is always the temptation to use drugs as a simple way to reduce the penalizing effects. The available compounds known to affect sleep and wakefulness include hypnotics, benzodiazepines and non benzodiazepines such as temazepam, zolopidem, and zopiclone, stimulants such as amphetamine and amphetamine-like agents, adrafinil, modafinil, caffeine and chronobiotics substances such as melatonin and, more recently, slow release caffeine. In the sports area, all of these substances except caffeine are on the list of forbidden products, although special authorizations linked to known disease conditions are allowed. In the military setting, the environment may be similar, but the context of use is very different. In the context of a rescue mission, the current practice in the French military organization is to place modafinil pills in the ejection seat of fight planes and in rescue boats. A second context is the use of anti-sleep agents under orders; the debate continues on this and the appropriate recommendations in this context. Self-medication is a third condition, in which case no rules have been defined.

Normal waking mentation is the outcome of the combined action of both electrophysiological and neurochemical antagonistic and complementary activating and inhibitory influences occurring mainly in the cerebral cortex. The chemical ones are supported principally by acetylcholine, and noradrenaline and serotonin, respectively. During rapid eye movement (REM) sleep, the monoaminergic silence - except dopaminergic ongoing activity - disrupts this equilibrium and seems to be responsible for disturbances of mental activity characteristic of dreaming. This imbalance could cause disconnectivity of cortical areas, failure of latent inhibition and possibly the concomitant prefrontal dorsolateral deactivation. Moreover, the decrease of prefrontal dopaminergic functioning could explain the loss of reflectiveness in this sleep stage. All these phenomena are also encountered in schizophrenia. The psychotic-like mentation of dreaming (hallucinations, delusions, bizarre thought processes) could result from the disinhibition of dopamine influence in the nucleus accumbens by the noradrenergic and serotonergic local silence and/or the lifting of glutamate influence from the prefrontal cortex and hippocampus. We hypothesize that, during REM sleep, the increase of dopamine and the decrease of glutamate release observed in nucleus accumbens reach the threshold values at which psychotic disturbances arise during wakefulness. Whatever the precise mechanism, it seems that the functional state of the prefrontal cortex and nucleus accumbens is the same during dreaming sleep stage and in schizophrenia. The convergent psychological, electrophysiological, tomographic, pharmacological and neurochemical criteria of REM sleep and schizophrenia suggest that this sleep stage could become a good neurobiological model of this psychiatric disease.

We studied the nyctohemeral cortisol secretion rhythm and the cortisol response to 1-24 corticotropin during Ramadan in 11 healthy, male volunteers aged 20-35 years. Their response to 250 mg 1-24 corticotropin was investigated 2 weeks before Ramadan by testing daily at 08:00 and 20:00 hours. After 16-22 days of fasting, their cortisol levels were measured at 08:00 hours and their response to 1-24 corticotropin at 20:00 hours. Before Ramadan, the baseline cortisol level was significantly higher at 08:00 hours than at 20:00 hours and the cortisol response to 1-24 corticotropin was also higher at 08:00 hours but this difference was not significant. During Ramadan, the cortisol level at 08:00 hours was lower than at the same time before Ramadan; the level at 20:00 hours was slightly higher than at the same time before Ramadan. There was no significant difference between the cortisol response to 1-24 corticotropin at 20:00 hours during Ramadan and the responses before Ramadan at 20:00 hours and 08:00 hours.

To evaluate target controlled infusion anesthesia (TCI) with propofol for conscious intubation [(Ramsay score equal to 3 (RS 3)] through the Fastrach laryngeal mask airway (LMA).17 consenting and unpremedicated patients, who showed criteria for difficult intubation (score developed by Arne et al.or = 11), were monitored and received supplemental oxygen. Propofol was administered by TCI, with successive targets of 0.6 and 1 microg x mL(-1), while the RS was evaluated: if = 3, LMA intubation was attempted, if3 the TCI was increased by steps of 0.2 microg x mL(-1) until an RS of 3 was reached. Local anesthesia (lidocaine 5%) of the oropharynx was carried out at 0.6 and 1 microg x mL(-1), together with local anesthesia of the nasopharynx at 1 microg x mL(-1). A standardized questionnaire evaluated memory of and satisfaction with the technique (score/10) on postoperative day 1.The LMA was inserted in 100% of cases and intubation was successful in 16 out of 17 cases (one failure). The propofol target concentration to obtain a RS of 3 was 1.25 +/- 0.07 microg x mL(-1). Amnesia occurred as soon as the target concentration of propofol exceeded 1 microg x mL(-1). The patients found the technique very satisfactory (median satisfaction score = 9.4/10). Incidents of coughing or nausea were observed in 47% and 5% of cases respectively. There was no oesophageal intubation and no desaturation (SpO295%).Propofol administered by TCI to achieve a RS of 3 allows conscious intubation to be performed through a LMA under satisfactory conditions. A LMA could be a possible alternative to a "conscious" fibroscopy.

Genetic manipulation of the 5-HT system leads to alterations of 5-HT neurotransmission and provides new opportunities to investigate the role of 5-HT in sleep regulations. Indeed, it represents an alternative to the use of pharmacological tools and, to some extent, of localized lesions of the 5-HT system, which have been, from the 1960s until recently, the main approaches to investigate this question. Homologous recombination knocking-out genes encoding various proteins involved in 5-HT neurotransmission in the mouse has recently allowed further assesment of the role of the serotonin transporter (5-HTT), the monoamine oxidase A (MAO-A), and the 5-HT1A, 5-HT1B and 5-HT2A receptors in the regulation of sleep. In 5-HT1A -/- and 5-HT1B -/- knock-out mice, Rapid Eye Movement sleep (REMs) was enhanced. Pharmacological blockade of these receptors had the same effects in wild-types. Thus, both receptor types exert a tonic inhibitory influence on REMs. In addition, 5-HT1A -/- and 5-HT1B -/- mutants were hypersensitive to 5-HT1B and 5-HT1A receptor agonists, respectively, which suggests that adaptive changes at 5-HT neurotransmission develop in knock-out animals. In the same manner, 5-HTT-/- knock-out mice exhibited increased REMs. This may be accounted for by a decrease in 5-HT1A and 5-HT1B receptor-mediated sleep regulations. In contrast, decreased REMs was observed in MAOA -/- knock-outs, a phenomenon that mimics the effect of pharmacological MAO inhibition. Finally, 5-HT2A -/- and 5-HT2C -/- mice exhibited more wakefulness and less slow wave sleep (SWS) than wild-types. These effects could not be reproduced by 5-HT2A or 5-HT2c receptor blockade in wild-types. To conclude, constitutive knock-outs undergo adaptive processes involving other proteins than those encoded by the invalidated gene, which renders interpretation of the corresponding sleep phenotype difficult. Inducible knock-outs will probably help to overcome this difficulty. Finally, combination of genetic manipulations with relevant pharmacological ones should allow further progress in the understanding of sleep mechanisms.

The uncertainty of the future of the territory obliges to take into account a treatment different from the piece of information within the premises.The ruling of industrial site ( Métaleurop), the appearance of mortal epidemics of type SRAS (syndrôme respiratory severe), the explosion of the factory AZF of Toulouse or still the reproduction of legionnaires' disease make of the territory place of the threats anticipate. In return of regional action of economic intelligence on the Nord-Pas de Calais since 2002, we propose a second reading of support points necessary for the implemented a territorial plan of intelligence. It leans on the works that we engaged since 2001 with the the territory but does not claim to be a model directly transposable. it explains a initiative of mutualization of the signals and the elaboration of the guesses between the people capable of thwarting the traps of future., L'incertitude des futurs du territoire oblige à prendre en compte un traitement différent de l'information au sein du local. L'arrêt brutal de site industriel (Métaleurop), l'apparition d'épidémies mortelles de type SRAS (syndrôme respiratoire aigu sévère), l'explosion de l'usine AZF de Toulouse ou encore la multiplication de cas de légionellose font du territoire un lieu des menaces à anticiper. En retour d'action du plan régional d'intelligence économique Nord-Pas de Calais mis en œuvre dès 2002, nous proposons une relecture des points d'appui nécessaires à la mise en œuvre d'un schéma d'intelligence territoriale. Il s'adosse aux travaux que nous avons engagé depuis 2001 avec les acteurs du territoire mais ne prétend pas être un modèle directement transposable. Il expose une démarche de mutualisation des signaux et d'élaboration des conjectures entre les acteurs aptes à déjouer en partie les pièges du futur.

It has been known since the sixties that a habituation phenomenon is present in polysomnographic analyses of sleep, the first night including more awakenings and less Rapid Eye Movement sleep (REM) than consecutive ones. Results about Non-Rapid Eye Movement sleep (NREM) are less clear. The study presented here attempted to classify the variables in function of their sensitivity to this phenomenon by comparing inter-night and inter-subject effects in a series of ANCOVA analyses and on the other hand, to group the same variables in function of a factorial analysis on the differences between the two first nights. The study included 26 subjects with no somatic nor psychiatric disorder and was performed at their homes for four consecutive nights. The most sensitive variables were, in descending order: Ultra-Slow spectral power band, REM sleep, Sleep Efficiency Index, Delta spectral power band, number of awakenings, duration of awakenings, number of ultradian sleep cycles and Total Sleep Time. The factorial analysis showed 7 factors, grouping separately the two series of results from the spectral analysis (corresponding to visually-scored NREM and REM sleep), awakenings, sleep duration variables, variables linked to REM sleep, microarousals and deep sleep.

The respiratory disorders expressed by obstructive hypopneas and apneas during sleep, as well as the sequences of crescendo in respiratory effort without hypopneas or apneas which define the upper airway resistance syndrome, terminate with (thanks to) an arousal, defined by EEG changes. In some cases, the activation of the central nervous system is restricted to a sympathetic activation, which has been mainly studied in the cardiovascular area, and is not always accompanied by a cortical arousal. Various approaches (heart rate, blood pressure, pulse transit time, peripheral arterial tonometry) make the identification of sympathetic activation possible. Sympathetic activation seems to be more sensitive than cortical arousal to the stimulations generated by the respiratory system via an activation of mechanoreceptors stimulated by the increased respiratory effort in response to total or partial occlusion of the upper airway. The mechanisms of the cortical or autonomic arousal are not fully understood, but their detection could be a diagnostic tool for the identification of such disorders. Such tools are currently under validation.

Most pharmacotherapeutic treatments designed to treat insomnia target GABAergic activity globally in the brain. Development of new molecules having a more specific activity pathway should improve treatment efficacy and acceptance. Both subjective and objective criteria are needed to study drug efficacy. Data regarding drug effects on polysomnographic recordings are mandatory for the development of hypnotics. Whether the drug-induced sleep is comparable to normal sleep is tackled with the spectral analysis of the sleep EEG. Residual drug effects are assessed with a package of psychomotor and neurocognitive tests, and with the driving simulator test Clinical studies investigating drug efficacy and tolerability have to be conducted on large groups of patients carefully selected using polysomnographic recordings. Our knowledge about sleep will undoubtedly soon become available for treatment of insomnia.

The starting point of the French conference of consensus concerning arousal after coma was to answer the following question: "How can we define the ways of going from coma to arousal and their clinical levels?A team of readers have picked up in the literature one hundred and fifty papers, out of which fifty six have been analysed.From this analysis, three points emerged: The concepts of coma and arousal; The conditions of evolution from coma to arousal; Various groups of patients depending on their expressing arousal. One could not find any consensual model concerning the different ways of going from coma to arousal. The variability of the technics and the changing validity of all scores did not allow the conditions of arousal to reach a satisfactory level of proof. The Glasgow Coma Scale (GCS) is the recognised standard for severe wakefulness' impairment, but it is not sensitive enough while patients' arousing. The Glasgow Outcome Scale (GOS) takes into account the patients' situations far later and does not include situations such as Minimally Conscious States (MCS). That's why we face multiple scores, either ordinal, or categorial, all tending to evaluate the slow levels of arousal.Clinical findings concerning arousal are to be completed by non-clinical data. This would be greatly helpful to define appropriate management concerning individualized groups of patients. At this stage, another challenge for clinicians is to make the difference between emerging wakefulness and growing conscious activity.

Mandibular advancement device provide a therapeutic option for obstructive sleep apnea syndrome (OSAS). Clinical improvement has been proven in the different available studies, mainly on nocturnal respiratory events and quality of sleep. Less snoring have been noted by bed partners and objective studies have demonstrated a decrease in snoring frequency and intensity. The effects of these appliances on upper airways resistance syndrome is not yet well documented. The significant clinical improvement is secondary to the decrease in the occurrence of apneas and hypopneas. Polysomnographic improvement criteria with an apnea hypopnea index less than 10 per hour has been noted in certain cases, although no improvement or even worsening was noted in other cases. Sleep architecture has also changed in these patients, with a decrease in the time spent in stages 1 and 2, and an increase in the time spent in stages 3, 4 and rapid eye movement sleep. Micro-arousals are also reduced in number. Somnolence and loss of attention are improved; these have been evaluated subjectively or by a well known and approved somnolence scale. In some cases a test for vigilance was done. Our results are identical to those published in the different studies concerning respiratory events and sleep architecture.

We investigated the effect of adapted management of sleep on the duration and quality of sleep in shift workers working the night shift. Twenty-nine shift workers suffering from insomnia were included and treated with zopiclone (7.5mg/day) or placebo according to a random double-blind protocol. Patients completed a sleep diary and a wrist actigraph was used to evaluate episodes of rest/activity. A self-administered subjective sleep questionnaire was filled out just after awakening. Zopicone was found to increase the duration of sleep significantly (p0.05) over the baseline duration after the first and second night on duty. Subjective estimation of sleep was better in patients taking zopiclone who exhibited a smaller number of shorter awakening episodes.zopiclone improves the quality and duration of sleep in shift workers suffering from insomnia.

Through a polygraphic and pharmacological approach conducted in the rat, it is established that L-NAME (N-nitro-L-arginine methyl ester; an inhibitor of the endothelial and neuronal NO-synthases), administered intraperitoneally (i.p., 100 mg/kg) increases significantly slow wave sleep (SWS) and paradoxical sleep (PS). On the contrary, 7-NI (7-Nitro-indazole; an inhibitor of the neuronal NO-synthase), when administered locally in the nRD (n. raphe dorsalis), decreases PS without SWS changes. Finally, SIN-1 (molsidomine, a NO donor), also administered locally in the nRD (200 ng/0.2 microliter), increases PS without effects on SWS. According to the fact that L-NAME is not efficient on the cerebral NO fraction when administered i.p., it appears likely that this compound, mainly through its vascular effects, might inhibit SWS and PS. On the contrary, the effects, respectively inhibitory and facilitatory, observed on PS after nRD local injection of 7-NI and SIN-1 1 indicate that the NO-ergic component of this nucleus might facilitate PS.

The genetic approach of the sleep-wake cycle allowed the identification of several genes involved in the paradoxical sleep regulation and in narcolepsy. Concerning insomnia, a genetic study is more complex. Insomnia is indeed a wakefulness disorder defined by non quantitative biological parameters. The genetic approach of insomnia needs a more precise definition.

Brain microdialysis coupled with EEG recording allowed us to track dynamic neurochemical changes every 3 or 6 minutes in relation to sleep/wake cycles. We chose to investigate prostaglandins (PG) and monoamines (catecholamines, serotonin and metabolites) because of their respective role in the states of vigilance, mainly suggested by pharmacological approaches, and because of the known interactions between PGs and monoamines. We focused on the paraventricular and ventromedial nuclei of the hypothalamus for their involvement in the relationships between feeding, metabolic rate and sleep, and the prefrontal cortex for its role in vigilance. These studies revealed a few changes in prostaglandin or monoamine levels as a function of a given state of vigilance. In particular, serotonin levels were higher during wakefulness than during sleep in both hypothalamus and cortex. Both hypothalamic and cortical PGE2 levels were higher during wakefulness than during slow wave sleep and still higher during paradoxical sleep in the cortex. Cortical PGD2 showed an exactly reverse profile of PGE2. These changes are in agreement with the described awaking action of PGE2 and with the hypnogenic action of PGD2. Our most informative findings were the sequential changes around transitions from one state to another that allow to predict the moment of onset of both sleep and wakefulness. Both in hypothalamus and in cortex, ondulatory patterns of PGE2 were encountered around the transitions between states. PGE2 was high in the middle of wakefulness, then regularly dropped announcing the occurrence of sleep, where the drop persisted before giving place to a rise in prediction to the next period of wakefulness. A similar profile was also observed for cortical serotonin, but its low levels reached a plateau during sleep. Cortical dopamine levels showed sudden and dramatic drops during short periods of wakefulness closely surrounding slow wave sleep. In some instances, as in the case of PGE2, similar profiles of variations could be found both in the hypothalamus and cortex. But in most cases, different and even opposite profiles were encountered in those two structures. Interestingly, in some instances, the pattern of changes in both prostaglandins and monoamines were similar, as for example between hypothalamic PGE2 and dopamine as well as between cortical PGE2 and serotonin. These similarities support the idea of the suggested interaction between prostaglandins and monoamines, in particular concerning their involvement in the regulation of sleep/wake cycles.