De nombreuses études de notre laboratoire ont montré le rôle prépondérant des neurones à histamine (HA) dans le contrôle de l'activation corticale et de l'éveil (Ev). Grâce aux divers modèles de souris knockout (KO), cette thèse a apporté de nouvelles données expérimentales confortant le rôle majeur de l’HA dans le contrôle de l’Ev. D’une part, la comparaison des phénotypes des souris sans HA de fond C57BL/6J à ceux observés précédemment chez les souris sans HA de fond 129/Sv nous a permis de confirmer que la somnolence et le déficit en Ev seraient bien dus à l’absence de l’HA. D’autre part, nous avons montré, grâce aux souris KO pour le gène du récepteur H3, qu’une neurotransmission histaminergique accrue et chronique pourrait, face aux divers défis comportementaux notamment le test de motivation, conduire à une extension exagérée de l’Ev semblable à une restriction volontaire du sommeil. En contrepartie, l’Ev serait déficitaire en absence de stimuli, même aux moments où l’activation corticale et comportementale est habituellement nécessaire (e.g., l’extinction lumineuse). Ces phénotypes ainsi que les perturbations comportementales et métaboliques rapportées (adiposité, obésité) chez la même souris suggèrent que ce modèle pourrait s’apparenter à un modèle de restriction chronique de sommeil. Enfin, nos premiers résultats semblent en mesure de montrer un rôle des récepteurs H2 dans la réactivité face au stress, notamment après un test de suspension. L’ensemble de ce travail contribue à la compréhension de la neurobiologie du système à HA et de sa régulation de l’Ev dans les conditions physiopathologiques / Studies from our laboratory have shown the major role of histamine (HA) neurons in the control of cortical activation and waking (W). Using knockout (KO) mouse models, this PhD study provides new experimental data further supporting the importance of HA in W control. First, the comparison of sleep-wake phenotypes of C57BL/6J mice lacking HA with those of the 129/Sv genetic background allowed us to confirm that somnolence and W deficit are due to the absence of HA rather than the interactions between the genetic background and deleted gene. Second, mice lacking H3-receptors showed signs of enhanced HA neurotransmission and vigilance, e.g., a greater extension of W or sleep restriction during behavioral tasks (new environment, locomotion, and motivation tests). During the baseline dark period, however, they displayed deficient W probably due to decreased HA cell activity and desensitized postsynaptic receptors. These data and the obesity phenotypes reported previously in this mouse suggest that chronic enhancement of HA transmission finally compromises the arousal system per se, leading to sleep-wake, behavioral and metabolic disorders similar to those caused by voluntary sleep restriction in humans. Finally, our preliminary results seem to indicate a role of H2- receptors in the reactivity facing stress, notably after a test of tail suspension. Together, our study contributes to the neurobiology of the HA system and its role in controlling W in pathophysiological conditions

Introdução: A respiração oronasal pode impactar adversamente em pacientes com apneia obstrutiva do sono (AOS) pelo aumento da colapsabilidade da via aérea piorando as apneias ou por influenciar os desfechos de tratamento com a pressão positiva continua de vias aéreas (CPAP). Embora os autorrelatos de respiração oronasal sejam comumente utilizados como uma evidência para prescrição da CPAP oronasal, a associação entre o autorrelato e a mensuração objetiva da via preferencial de respiração ainda é desconhecida. Nós hipotetizamos que a respiração oronasal objetivamente mensurada seja mais comum em pacientes com AOS do que em controles, mas que não esteja associada com o autorrelato de respiração oronasal. Os objetivos do presente estudo foram, portanto, determinar: (1) a via preferencial de respiração em controles e pacientes com AOS na vigília e no sono, (2) a concordância entre a via preferencial de respiração mensurada objetivamente e a via preferencial de respiração autorrelatada, e (3) a associação entre a via preferencial de respiração mensurada objetivamente e os sintomas nasais e fatores em pacientes com AOS. Casuística e Método: Foram incluídos 26 indivíduos não tabagistas recrutados na FMUSP (funcionários) e no Ambulatório de Sono do InCor-HCFMUSP (indivíduos com suspeita de AOS). Para o diagnóstico de AOS os indivíduos foram submetidos a uma polissonografia (PSG). A AOS foi definida como índice de apneia-hipopneia (IAH) >= 15 eventos/hora e determinou a alocação dos indivíduos em dois grupos: grupo controle [idade: 40±10 anos, 4 (44%) homens, índice de massa corpórea (IMC): 25±5 kg/m2, IAH: 5±4 eventos/hora] e grupo AOS (idade: 52±14 anos, 10 (59%) homens, IMC: 31±5 kg/m2, IAH: 56 ± 21 eventos/hora). Para avaliar a via preferencial de respiração (nasal ou oronasal) os indivíduos foram submetidos a uma segunda PSG com uso de uma máscara com 2 compartimentos selados (nasal e oral) e conectados a pneumotacógrafos independentes. A via de respiração preferencial foi determinada durante a vígilia que antecedeu o início de sono e durante o sono. Avaliamos dados clínicos e de função pulmonar. Os indivíduos responderam a questionários sobre a percepção da sua via preferencial de respiração, os sintomas nasais (SNOT-20), a sonolência diurna excessiva (Epworth) e a qualidade do sono (Pittsburgh). Resultados: O grupo controle e AOS foram similares no sexo, co-morbidades e uso de medicamentos. Pacientes com AOS eram mais velhos, tinham maior IMC, pressão arterial sistêmica e circunferência do pescoço. A via preferencial de respiração foi similar na vigília e sono. Observamos que os respiradores oronasais foram mais frequentes nos pacientes com AOS se comparados aos controles (65-71% e 0-22%, respectivamente, p < 0,001). Os controles e pacientes com AOS autorrelataram respiração oronasal em 22% e 59% dos casos, respectivamente (p = 0,110). Entretanto, encontramos pobre concordância entre o autorrelato da via de respiração e a via de respiração identificada no grupo controle (Kappa = 0,36) e nenhum concordância nos pacientes com AOS (Kappa = -0,02). Não houve associação entre os sintomas nasais e a respiração oronasal quando considerados todos os indivíduos do estudo (p = ,267). A respiração oronasal foi associada ao aumento do IAH (r = 0,409 e p = 0,038), aumento da idade (r = 0,597 e p = 0,001) e aumento da circunferência do pescoço (r = 0,464 e p = 0,017). Além disso, mudanças na via de respiração após apneias obstrutivas foram incomuns. Conclusões: Em contraste com os controles, os pacientes com AOS sãos frequentemente respiradores oronasais. Contudo, a auto-percepção da via de respiração e de sintomas nasais não prediz medidas objetivas da via preferencial de respiração. Além disso, a respiração oronasal é associada à gravidade da AOS, ao aumento da idade e da circunferência do pescoço / Background: Oronasal breathing may adversely impact obstructive sleep apnea (OSA) patients either by increasing upper airway collapsibility or by influencing CPAP treatment outcomes. Although self-reported oronasal breathing is commonly used as evidence for oronasal CPAP prescription, the association between self-reported and objectively measured preferential breathing route is unknown. We hypothesized that objectively measured oronasal breathing is more common in OSA patients than in controls but is not associated with self-reported breathing route. The aims of this study were, therefore, to determine (1) the preferential breathing route in controls and OSA patients, (2) the agreements between objective analysis of breathing route and self-reports, and (3) the associations between preferential breathing route objectively measure and nasal symptoms and factors in OSA patients. Methods: We included 26 non-smokers enrolled at FMUSP (employees) and Sleep Laboratory at InCor-HCFMUSP (individuals with suspected AOS). For the diagnosis of OSA, the subjects were submitted a full polysomnography (PSG). OSA was defined as apnea-hypopnea index (AHI) >= 15 events/hour and determined the allocation of individuals in two groups: Control group [age: 40 ± 10 years, 4 (44%) men, body mass index (BMI): 25±5 kg/m2, AHI: 5 ± 4 events / hour] and OSA group (age: 52 ± 14 years, 10 (59%) men, BMI: 31±5 kg/m2, mean AHI: 56 ± 21 events / hour). To evaluate the preferential breathing route (nasal or oronasal) the subjects underwent a second overnight PSG with oronasal mask with 2 sealed compartments attached to independent pneumotacographs. The preferential breathing route was determined during wakefulness before sleep and during sleep. We evaluated clinical data and lung function. Subjects answered questionnaires about perceived preferential breathing route, nasal symptoms questionnaires (SNOT-20), excessive daytime sleepiness (Epworth) and sleep quality (Pittsburgh). Results: Controls and OSA patients were similar in sex, co-morbidities and use of medications. OSA patients were older, had higher BMI and blood pressure as larger neck circumference. Breathing pattern awake and asleep was similar. Compare to controls, oronasal breathers was more frequent in OSA patients (0-22% and 65-71%, respectively, p < 0.001). Controls and OSA patients self-reported oronasal breathing in 22% and 59% of cases, respectively (p = 0.110). There were poor agreements between self-reports and objective analysis in controls (Kappa = 0.36) and no agreement in OSA patients (Kappa = -0.02). No associations were found between nasal symptoms and oronasal breathing when all subjects were considered (p = 0.267). Oronasal breathing was associated with OSA severity (r = 0.409 and p = 0.038), increasing age (r = 0.597 and p = 0.001) and higher neck circumference (r = 0.464 and p = 0.017). Additionally, the changes of breathing route were uncommon during obstructive apneas. Conclusions: In contrast to controls, OSA patients are preferentially oronasal breathers. However, self-perception does not predict objectively measured preferential breathing route. Oronasal breathing is associated with OSA severity, increasing age and higher neck circumference

Introdução: A respiração oronasal pode impactar adversamente em pacientes com apneia obstrutiva do sono (AOS) pelo aumento da colapsabilidade da via aérea piorando as apneias ou por influenciar os desfechos de tratamento com a pressão positiva continua de vias aéreas (CPAP). Embora os autorrelatos de respiração oronasal sejam comumente utilizados como uma evidência para prescrição da CPAP oronasal, a associação entre o autorrelato e a mensuração objetiva da via preferencial de respiração ainda é desconhecida. Nós hipotetizamos que a respiração oronasal objetivamente mensurada seja mais comum em pacientes com AOS do que em controles, mas que não esteja associada com o autorrelato de respiração oronasal. Os objetivos do presente estudo foram, portanto, determinar: (1) a via preferencial de respiração em controles e pacientes com AOS na vigília e no sono, (2) a concordância entre a via preferencial de respiração mensurada objetivamente e a via preferencial de respiração autorrelatada, e (3) a associação entre a via preferencial de respiração mensurada objetivamente e os sintomas nasais e fatores em pacientes com AOS. Casuística e Método: Foram incluídos 26 indivíduos não tabagistas recrutados na FMUSP (funcionários) e no Ambulatório de Sono do InCor-HCFMUSP (indivíduos com suspeita de AOS). Para o diagnóstico de AOS os indivíduos foram submetidos a uma polissonografia (PSG). A AOS foi definida como índice de apneia-hipopneia (IAH) >= 15 eventos/hora e determinou a alocação dos indivíduos em dois grupos: grupo controle [idade: 40±10 anos, 4 (44%) homens, índice de massa corpórea (IMC): 25±5 kg/m2, IAH: 5±4 eventos/hora] e grupo AOS (idade: 52±14 anos, 10 (59%) homens, IMC: 31±5 kg/m2, IAH: 56 ± 21 eventos/hora). Para avaliar a via preferencial de respiração (nasal ou oronasal) os indivíduos foram submetidos a uma segunda PSG com uso de uma máscara com 2 compartimentos selados (nasal e oral) e conectados a pneumotacógrafos independentes. A via de respiração preferencial foi determinada durante a vígilia que antecedeu o início de sono e durante o sono. Avaliamos dados clínicos e de função pulmonar. Os indivíduos responderam a questionários sobre a percepção da sua via preferencial de respiração, os sintomas nasais (SNOT-20), a sonolência diurna excessiva (Epworth) e a qualidade do sono (Pittsburgh). Resultados: O grupo controle e AOS foram similares no sexo, co-morbidades e uso de medicamentos. Pacientes com AOS eram mais velhos, tinham maior IMC, pressão arterial sistêmica e circunferência do pescoço. A via preferencial de respiração foi similar na vigília e sono. Observamos que os respiradores oronasais foram mais frequentes nos pacientes com AOS se comparados aos controles (65-71% e 0-22%, respectivamente, p < 0,001). Os controles e pacientes com AOS autorrelataram respiração oronasal em 22% e 59% dos casos, respectivamente (p = 0,110). Entretanto, encontramos pobre concordância entre o autorrelato da via de respiração e a via de respiração identificada no grupo controle (Kappa = 0,36) e nenhum concordância nos pacientes com AOS (Kappa = -0,02). Não houve associação entre os sintomas nasais e a respiração oronasal quando considerados todos os indivíduos do estudo (p = ,267). A respiração oronasal foi associada ao aumento do IAH (r = 0,409 e p = 0,038), aumento da idade (r = 0,597 e p = 0,001) e aumento da circunferência do pescoço (r = 0,464 e p = 0,017). Além disso, mudanças na via de respiração após apneias obstrutivas foram incomuns. Conclusões: Em contraste com os controles, os pacientes com AOS sãos frequentemente respiradores oronasais. Contudo, a auto-percepção da via de respiração e de sintomas nasais não prediz medidas objetivas da via preferencial de respiração. Além disso, a respiração oronasal é associada à gravidade da AOS, ao aumento da idade e da circunferência do pescoço / Background: Oronasal breathing may adversely impact obstructive sleep apnea (OSA) patients either by increasing upper airway collapsibility or by influencing CPAP treatment outcomes. Although self-reported oronasal breathing is commonly used as evidence for oronasal CPAP prescription, the association between self-reported and objectively measured preferential breathing route is unknown. We hypothesized that objectively measured oronasal breathing is more common in OSA patients than in controls but is not associated with self-reported breathing route. The aims of this study were, therefore, to determine (1) the preferential breathing route in controls and OSA patients, (2) the agreements between objective analysis of breathing route and self-reports, and (3) the associations between preferential breathing route objectively measure and nasal symptoms and factors in OSA patients. Methods: We included 26 non-smokers enrolled at FMUSP (employees) and Sleep Laboratory at InCor-HCFMUSP (individuals with suspected AOS). For the diagnosis of OSA, the subjects were submitted a full polysomnography (PSG). OSA was defined as apnea-hypopnea index (AHI) >= 15 events/hour and determined the allocation of individuals in two groups: Control group [age: 40 ± 10 years, 4 (44%) men, body mass index (BMI): 25±5 kg/m2, AHI: 5 ± 4 events / hour] and OSA group (age: 52 ± 14 years, 10 (59%) men, BMI: 31±5 kg/m2, mean AHI: 56 ± 21 events / hour). To evaluate the preferential breathing route (nasal or oronasal) the subjects underwent a second overnight PSG with oronasal mask with 2 sealed compartments attached to independent pneumotacographs. The preferential breathing route was determined during wakefulness before sleep and during sleep. We evaluated clinical data and lung function. Subjects answered questionnaires about perceived preferential breathing route, nasal symptoms questionnaires (SNOT-20), excessive daytime sleepiness (Epworth) and sleep quality (Pittsburgh). Results: Controls and OSA patients were similar in sex, co-morbidities and use of medications. OSA patients were older, had higher BMI and blood pressure as larger neck circumference. Breathing pattern awake and asleep was similar. Compare to controls, oronasal breathers was more frequent in OSA patients (0-22% and 65-71%, respectively, p < 0.001). Controls and OSA patients self-reported oronasal breathing in 22% and 59% of cases, respectively (p = 0.110). There were poor agreements between self-reports and objective analysis in controls (Kappa = 0.36) and no agreement in OSA patients (Kappa = -0.02). No associations were found between nasal symptoms and oronasal breathing when all subjects were considered (p = 0.267). Oronasal breathing was associated with OSA severity (r = 0.409 and p = 0.038), increasing age (r = 0.597 and p = 0.001) and higher neck circumference (r = 0.464 and p = 0.017). Additionally, the changes of breathing route were uncommon during obstructive apneas. Conclusions: In contrast to controls, OSA patients are preferentially oronasal breathers. However, self-perception does not predict objectively measured preferential breathing route. Oronasal breathing is associated with OSA severity, increasing age and higher neck circumference

L'histamine(HA) et l'orexine(Ox) jouent des rôles distincts/complémentaires dans l'éveil(Ev) associés à la locomotion, l'exploration, la motivation & l'anticipation. La régulation de l'Ev dépend donc des activités comportementales instantanées et de la participation diverse des systèmes d'éveil. Par une approche intégrée, cette thèse se focalise sur le rôle d'HA et Ox dans l'Ev lié à l'attirance sexuelle (Sexual Arousal), une condition sine qua non pour la reproduction.La présence de la souris femelle entraîne une augmentation de l'Ev chez le mâle. Celle-ci n'est pas significative si un autre mâle est présent. Cet effet dépend d'hormones sexuelles car les souris femelles ovariectomisées ou prétraitées par un antagoniste d'œstrogènes n'entrainent pas d'Ev chez les mâles, alors que les mâles prétraités par un antagoniste d'androgènes n'ont plus cette augmentation. L'inhibition de la synthèse d'HA ou du récepteur Ox1 abolit l'augmentation de l'Ev. Celle-ci est préservée chez la souris sans HA ou sans Ox mais absente chez la souris sans les deux. Ainsi, les systèmes à HA & à Ox, pilotés par les hormones sexuelles, jouent un rôle clé dans Sexual Arousal. Un déficit chronique en HA ou Ox serait compensé par des mécanismes adaptatifs, qui deviennent insuffisants lors de la délétion des deux systèmes. J'ai aussi participé à des études sur : 1) le rôle du récepteur H1 dans l'Ev exploratoire; 2) les neurones à HA, cible de l'acide ursodésoxycholique; 3) les connexines & le mode d'action du modafinil.Cette thèse contribue à qualifier le rôle synergique d'HA & Ox dans le contrôle des multiples facettes de l'Ev & soutient l'hypothèse que le contrôle de l'Ev est comportement-dépendant / Our previous work showed that histamine (HA) and orexin (Ox) neurons play distinct, but complementary roles in wakefulness(W) associated with locomotion, exploration, motivation and anticipation, leading to the hypothesis that the regulation of W, a highly heterogeneous brain state, depends on the instantaneous ongoing behavioral activities and diverse participation of various arousal systems. Using an integrative approach, this thesis focused on the role of HA and Ox in sexual arousal, a prerequisite for reproduction.The presence of a female mouse elicited in a male a marked increase in W. This increase was not significant if another male was introduced. Ovariectomized or estrogen receptor antagonist-treated female mice did not elicit sexual arousal in males. Male mice pretreated with an androgen receptor antagonist did not show any increased W facing a female. Acute inhibition of HA synthesis or Ox1-receptor antagonist abolished sexual arousal. Whereas sexual arousal was intact in knockout(KO) mice lacking either HA or Ox, it was totally absent in double KO mice. Thus, both the HA and Ox systems, driven by sex hormones, promote sexual arousal. Chronic HA or Ox loss could be compensated by up-regulated adaptive mechanisms, which became ineffective when both systems were deleted.During my thesis, I was also involved in the studies of 1) role of HA H1-receptor in W associated with exploration; 2) HA neurons as target of ursodeoxycholic acid; 3) astroglial connexins and modafinil mode of action.This thesis contributes to qualify the synergistic role of HA and Ox in controlling the multiple facets of W and supports the hypothesis that the control of W is behavior-dependent

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 / 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

<p>Uzroci gubitka svesti su različiti i te&scaron;ko ih je diferencirati. Razlikovanja epileptičkih od neepileptičkih gubitaka svesti je od krucijalnog značaja za ispitivanje, lečenja i prognoze ovih poremećaja. Elektroencefalografija (EEG) je standardna, neinvazivna metoda koja se koristi u ispitivanju nakon gubitka svesti. Inicijalni EEG nalaz nakon prvog gubitka svesti može biti normalan, specifičan ili nespecifičan. Procenat patolo&scaron;kog EEG nalaza je veći kod rano urađenog EEG pregleda. Kod dece rani EEG pregled u roku od 48h ne pokazuje statistički značajne abnormalnosti. Spontanim spavanjem ili EEG pregledom nakon deprivacije spavanja se beleži značajno veća prisutnost epileptiformnih promena kod dece starije od 3 godine, čak i kada je prvi EEG u budnom stanju normalan. Kombinacijama pregleda u budnom stanju i spavanju povećava prisutnost patolo&scaron;kih promena u EEG zapisu. Materijal metode: Istraživanje je obuhvatilo 198 dece uzrasta od 3-12 godine života nakon prvog gubitka svesti. Ispitanici su klasifikovani u dve grupe na osnovu otpusne dijagnoze: na grupu dece kod kojih dijagnoza epilepsije nije postavljena i na grupu dece kod kojih je dijagnoza epilepsije potvrđena. Korelirani su nalazi EEG-a u budnom stanju i spavanju (spontanom ili nakon deprivacije spavanja) sa anamnestičkim i kliničkim podacima o gubitku svesti, podacima o dužini trajanja gubitka svesti i vremena oporavka, vremenom kada je urađen prvi EEG u odnosu na gubitak svesti kao i sa podacima o ličnoj i porodičnoj anamnezi, a koji su navedeni u protokolu istraživanja. Ispitanici su potom podeljeni prema uzrastu u pet grupa u intervalima od 2 godine (3-4; 5-6; 7-8; 9-10; 11-12). Rezultati: Nakon prvog gubitka svesti specifičan (epileptiformni) nalaz EEG u budnom stanju imalo je 41,97% ispitanika, a 58,03% je imalo nespecifičan ili uredan EEG nalaz u budnom stanju, dok je specifičan nalaz EEG u spavanju imalo je 73,57% ispitanika, a 26,43% je imalo nespecifičan ili uredan EEG nalaz u spavanju. Ispitanici koji su imali specifičan EEG nalaz u budnom stanju imali su i specifičan nalaz u spavanju, a 45,07%, nakon deprivacije sna. Ispitanici koji su u budnom stanju imali nespecifičan ili uredan EEG nalaz u budnom stanju su u 35,92% nakon deprvacije spavanja imali specifičan EEG nalaz u spavanju, za razliku od 1,41% dece koji su imali specifičan EEG nalaz u spontanom spavanju. Sumarno gledano bolesnici koji su &ldquo;aktivirani&rdquo; odnosno oni kod kojih je deprivacija spavanja uticala na dobijanje specifičnog nalaza (epileptiformnih pormena) u spavanju čine 37.32% od svih ispitanika sa specifičnim (epileptiformnim) promenama u EEG-u u spavanju Zaključak: Kod većine pacijenata nakon prvog gubitka svesti EEG nalaz u budnom stanju je bio nespecifičan ili uredan. Procenat specifičnih EEG nalaza (epileptiformnih promena) se značajno povećao prilikom snimanja EEG u spavanju. Naročito velika korist od deprivacije spavanja kao metode aktivacije potvrđena kod onih pacijenata koji su imali inicijalni EEG u budnom stanju uredan ili nespecifičan. Dobijeni rezultati nesumljivo ukazuju na efikasnost deprivacije spavanja kao provokacione metode i povećanja procenta interiktalnihepileptiformnih EEG promena. Neprovociranih prvi gubitci svesti su se če&scaron;će javljali u grupi dece kod kojih je dijagnoza epilepsije potvrđena, dok su se provocirani gubitci svesti javljali če&scaron;će u grupi dece kod kojih dijagnoza epilepsije nije postavljena. Uzrast dece nije uticao na postavljanje dijagnoze epilepsije kao ni na inicijalne nalaze EEGa u budnom stanju i spavanju ali se registrovalo povećanje specifičnih nalaza (epileptiformnih promena) EEG-a, nakon deprivacije spavanja , sa porastom godina života.</p> / <p>The reasons for the loss of consciousness are various and difficult to be differentiated. It is of utmost importance to differentiate between epileptic and non-epileptic losses of consciousness for the purpose of testing, treating and giving prognosis related to this disorder. Electroencephalography (EEG) is a standard, non-invasive method used in testing after the loss of consciousness. The initial EEG after the first loss of consciousness can be normal, specific and non-specific. The percentage of pathological EEG findings is higher in EEG exams performed at an earlier stage. In children, an early EEG exam within 48 hours does not reveal any statistically relevant abnormalities. Spontaneous sleeping or an EEG examination after sleep deprivation leads to a significantly higher number of epileptiform changes in children above the age of 3, even in cases when the first EEG in the awake state was normal. Combinations of examinations in the awake state and during sleep lead to an increased presence of pathological changes in the EEG recording. Material and methods: The research included 198 children aged 3-12 who have experienced their first loss of consciousness. The subjects were classified into two groups, based on their discharge diagnosis: children who have not been diagnosed with epilepsy and children who have had epilepsy confirmed. A correlation was established between EEG findings in the awake state and sleep (spontaneous or following sleep deprivation) and medical history and clinical data related to the loss of consciousness, the information about the length of the loss of consciousness and recovery time, the time when the first EEG examination was performed in relation to the loss of consciousness, as well as the data from the personal and family history. The subjects were further divided into five groups, depending on their age, with each group covering a 2-year period (3-4; 5-6; 7-8; 9-10; 11-12). Results: Following the first loss of consciousness, specific (epileptiform) EEG findings were noticed in 41.97% subjects, while 58.03% of them had non-specific, i.e. regular findings in the awake state. When it comes to the findings during sleep, 73,57% were specific, while 26,43% were non-specific, i.e. regular. The subjects who had specific EEG findings in the awake state also had specific findings during sleep, while that percentage was 45,07% after sleep deprivation. The subjects who had non-specific, i.e. regular EEG findings in the awake state had specific EEG findings during sleep in 35.92% of the cases following sleep deprivation, while 1.41% of the children had specific EEG findings during spontaneous sleep. In total, the patients who were &ldquo;activated&rdquo;, i.e. those whose sleep deprivation contributed to specific findings (epileptiform changes) during sleep comprise 37.32% of all subjects with specific (epileptiform) changes in the EEG findings during sleep. Conclusion: In most patients suffering from the first loss of consciousness the EEG findings were non-specific, i.e. regular. The percentage of specific EEG findings (epileptiform changes) was significantly increased when the EEG examination was performed during sleep. Sleep deprivation, as an activation method, was particularly useful in patients whose initial EEG findings in the awake state were regular, i.e. non-specific. The results obtained undoubtedly confirm the efficiency of sleep deprivation as a provoking method and the increase of the percentage of interictal epileptiform EEG changes. Unprovoked first losses of consciousness were more common in the group of children who have had the diagnosis of epilepsy confirmed, while provoked losses of consciousness were more common in the group of children who have not been diagnosed with epilepsy. The age of children did not affect the process of establishing a diagnosis of epilepsy, nor did it affect the initial EEG findings in the awake state or during sleep, but it was observed that the number of specific EEG findings (epileptiform changes) following sleep deprivation increased with the increase of the age of the patients.</p>

Le sommeil est un besoin vital et le bon fonctionnement de l’organisme dépend de la quantité et de la qualité du sommeil. Le sommeil est régulé par deux processus : un processus circadien qui dépend de l’activité des noyaux suprachiasmatiques de l’hypothalamus et qui régule le moment durant lequel nous allons dormir, et un processus homéostatique qui dépend de l’activité neuronale et se reflète dans l’intensité du sommeil. En effet, le sommeil dépend de l’éveil qui le précède et plus l’éveil dure longtemps, plus le sommeil est profond tel que mesuré par des marqueurs électroencéphalographiques (EEG). Des études ont montré que le bon fonctionnement de ces deux processus régulateurs du sommeil dépend de la plasticité synaptique. Ainsi, les éléments synaptiques régulant la communication et la force synaptique sont d’importants candidats pour agir sur la physiologie de la régulation du sommeil. Les molécules d’adhésion cellulaire sont des acteurs clés dans les mécanismes de plasticité synaptique. Elles régulent l’activité et la maturation des synapses. Des études ont montré que leur absence engendre des conséquences similaires au manque de sommeil. Le but de ce projet de thèse est d’explorer l’effet de l’absence de deux familles de molécule d’adhésion cellulaire, les neuroligines et la famille des récepteur Eph et leur ligand les éphrines dans les processus régulateurs du sommeil. Notre hypothèse est que l’absence d’un des membres de ces deux familles de molécule affecte les mécanismes impliqués dans le processus homéostatique de régulation du sommeil. Afin de répondre à notre hypothèse, nous avons étudié d’une part l’activité EEG chez des souris mutantes n’exprimant pas Neuroligine‐1 (Nlgn1) ou le récepteur EphA4 en condition normale et après une privation de sommeil. D’autre part, nous avons mesuré les changements moléculaires ayant lieu dans ces deux modèles après privation de sommeil. Au niveau de l’activité EEG, nos résultats montrent que l’absence de Nlgn1 augmente la densité des ondes lentes en condition normale et augment l’amplitude et la pente des ondes lentes après privation de sommeil. Nlgn1 est nécessaire au fonctionnement normal de la synchronie corticale, notamment après une privation de sommeil, lui attribuant ainsi un rôle clé dans l’homéostasie du sommeil. Concernant le récepteur EphA4, son absence affecte la durée du sommeil paradoxal ainsi que l’activité sigma qui dépendent du processus circadien. Nos résultats suggèrent donc que ce récepteur est un élément important dans la régulation circadienne du sommeil. Les changements transcriptionnels en réponse à la privation de sommeil des souris n’exprimant pas Nlgn1 et EphA4 ne sont pas différents des souris sauvages. Toutefois, nous avons montré que la privation de sommeil affectait la distribution des marques épigénétiques sur le génome, tels que la méthylation et l’hydroxyméthylation, et que l’expression des molécules régulant ces changements est modifiée chez les souris mutantes pour le récepteur EphA4. Nos observations mettent en évidence que les molécules d’adhésion cellulaire, Nlgn1 et le récepteur EphA4, possèdent un rôle important dans les processus homéostatique et circadien du sommeil et contribuent de manière différente à la régulation du sommeil. / Sleep is a vital need and the proper functioning of the body depends on the amount and quality of sleep. Sleep is regulated by two processes: a circadian process that depends on the activity of suprachiasmatic nuclei of the hypothalamus and regulates the time of day during which we are going to sleep, and a homeostatic process that seems to depend on neuronal activity and that reflects sleep intensity. The homeostatic process controls a pressure for sleep as a function of the amount of time spent awake. Indeed, sleep quality depends on the duration of preceding wakefulness, the more one is awake, deeper the sleep afterwards as measured by electroencephalographic markers (EEG). Studies have shown that the proper functioning of these two sleep regulatory processes depends on synaptic plasticity. Thus, elements that regulate synaptic communication and synaptic strength are important candidates to act upon the physiology of sleep regulation. Cell adhesion molecules are key elements regulating synaptic plasticity. They control synapse activities and maturation. Studies have shown that their absence leads to consequences similar to sleep deprivation. The aim of this study is to explore the effect of the absence of two different cellular adhesion molecule, Neuroligin‐1 and EphA4 receptor in sleep regulatory processes. Our hypothesis is that the absence of either of these molecules will affect sleep regulation and more specifically sleep homeostasis. To address our hypothesis, we first studied EEG activity in mice which do not express Nlgn1 and EphA4 in normal condition or after sleep deprivation. Secondly, we measured the molecular changes that occur in these two models after sleep deprivation. At the level of EEG activity, our results show that the absence of Nlgn1 increases the density of slow waves under baseline condition, and that the amplitude and slope of slow waves are increased after sleep deprivation. We concluded that Nlgn1 is required for normal functioning of cortical synchrony especially after sleep deprivation, thereby giving it a key role in sleep homeostasis. Regarding the EphA4 receptor, its absence affects the duration of paradoxal sleep and sigma activity which are known to depend on the circadian process. These results suggest that the EphA4 receptor is an important element in the circadian regulation of sleep. The transcriptional response after sleep deprivation in mice not expressing Nlgn1 or EphA4 is not different from that in wild‐type mice. However, we found that sleep deprivation affects the distribution of specific epigenetic markers like methylation and hydroxymethylation and the expression of molecules regulating these changes is altered in EphA4 null mice. Our observations show that two cell adhesion molecules, Nlgn1 and EphA4 receptor, have an important role in the homeostatic and circadian sleep process and contribute differentially to sleep regulation.

INTRODUÇÃO: A apneia obstrutiva do sono (AOS) é comum na população geral e é caracterizada pelo colapso recorrente da via aérea superior. Há um interesse crescente no desenvolvimento de métodos para melhor entendimento da fisiopatologia da AOS. A técnica da pressão negativa expiratória (NEP) é um método relativamente simples que avalia a colapsabilidade da via aérea superior durante a vigília. Porém, a metodologia varia muito e a maioria dos estudos utilizou o bocal, que pode não retratar de forma adequada o comportamento da nasofaringe e pode interferir na posição da língua. Adicionalmente, não existem estudos que avaliaram a associação da NEP com variáveis anatômicas da via aérea superior. A pressão crítica de fechamento da faringe (Pcrit) é um método bem estabelecido que reflete o componente anatômico da AOS, porém é realizada durante o sono e envolve metodologia complexa. OBJETIVOS: Realizamos 2 estudos em indivíduos normais e portadores de AOS com o objetivo de: Estudo 1) Determinar a influência da interface e posição sobre a medida da colapsabilidade da via aérea superior durante a vigília avaliada pela NEP. Estudo 2) Avaliar a associação entre a colapsabilidade da via aérea superior durante a vigília medida pela NEP com máscara nasal na posição supina e durante o sono medida pela Pcrit com variáveis anatômicas da via aérea superior avaliadas pela tomografia computadorizada (TC). MÉTODOS: Foram recrutados indivíduos com idade entre 18 e 65 anos com suspeita de AOS referidos do Laboratório do Sono do InCor. Os indivíduos foram submetidos a prova de função pulmonar, polissonografia e NEP em 4 situações: posição sentada e supina utilizando tanto bocal como máscara nasal. A NEP foi avaliada pelo parâmetro V0,2SB/V0,2NEP (relação entre o volume expirado a 0,2 s durante a respiração espontânea (3 expirações precedentes à aplicação da NEP) sobre o volume expirado a 0,2 s durante a aplicação da NEP). Um subgrupo dos indivíduos realizou o exame de Pcrit e TC de via aérea superior. RESULTADOS: Estudo 1) Foram estudados um total de 86 indivíduos (72 homens, idade: 46 ± 12 anos, índice de massa corpórea (IMC): 30,2 ± 4,4 kg/m2, índice de apneia/hipopneia (IAH): 32,9 ± 26,4 eventos/hora). Encontramos uma interação entre interface e posição sobre a colapsabilidade da via aérea superior na análise multivariada (p=0,007), sendo que a via aérea superior foi mais colapsável com bocal do que com máscara nasal na posição sentada. A colapsabilidade da via aérea superior foi maior na posição supina do que sentada quando a NEP foi realizada com máscara nasal. Em contraste, a NEP não foi influenciada pela posição quando avaliada com bocal. A resistência expiratória foi significativamente maior e independente da posição com bocal do que máscara nasal (20,7 cmH2O/L.s-1 vs 8,6 cmH2O/L.s-1 respectivamente, p=0,018). Estudo 2) Vinte e oito indivíduos realizaram a NEP com máscara nasal na posição supina, Pcrit e TC da via aérea superior (idade: 45 ± 13 anos, IMC: 29.4±4.9 kg/m2 e IAH: 30 ± 26 eventos/hora). A NEP e a Pcrit se associaram de maneira semelhante com a área da língua (r=0,646 e r=0,585), volume da língua (r=0,565 e r=0,613), comprimento da faringe (r=0,580 e r=0,611) e IAH (r=0,490 e r=0,531), respectivamente (p < 0,05 para todas as correlações). A NEP e a Pcrit foram significativamente piores em pacientes com AOS grave do que no restante da população (p < 0,05). CONCLUSÕES: Estudo 1) A interface e a posição influenciam a colapsabilidade da via aérea superior medida pela NEP. Propomos que a NEP seja realizada com máscara nasal na posição supina em estudos futuros de avaliação da colapsabilidade da via aérea superior em pacientes sob investigação de AOS. Estudo 2) A NEP avaliada com máscara nasal na posição supina é um método simples e promissor que reflete o componente anatômico da colapsabilidade da via aérea superior de forma similar a Pcrit / INTRODUCTION: Obstructive sleep apnea (OSA) is common in the general population and is characterized by recurrent collapse of the upper airway. There is a growing interest in developing methods for better understanding of OSA pathophysiology. Negative expiratory pressure (NEP) technique is a simple method that evaluates upper airway collapsibility during wakefulness. However, the method of NEP determination varies among published studies and is mostly evaluated with a mouthpiece, which could inadequately reflect the behavior of nasopharynx and also interfere on the tongue position. In addition, there are no studies evaluating the association between NEP and upper airway anatomy. Pharyngeal critical closing pressure (Pcrit) is a well established technique that reflects the anatomical component of OSA, however, it is performed during sleep and requires a complex methodology. OBJECTIVES: We performed 2 studies in OSA and normal subjects with the objectives of: Study 1) To determine the influence of interface and position on the measurement of upper airway collapsibility while awake evaluated by NEP. Study 2) To evaluate the association among upper airway collapsibility while awake evaluated by NEP with nasal mask in supine position and during sleep evaluated by Pcrit with upper airway anatomy evaluated objectively by upper airway computed tomography (CT) scan. METHODS: We recruited subjects with age between 18 and 65 years with suspect OSA referred to the outpatient sleep clinic at the Heart Institute, University of São Paulo. Subjects underwent pulmonary function test, polysomnography and NEP evaluations in four conditions: sitting and supine position either with mouthpiece or with nasal mask. NEP was evaluated by the parameter V0.2SB/V0.2NEP (ratio between the volume exhaled at 0.2 s during stable breathing (3 expirations prior to NEP application) over the volume exhaled at 0.2 s during NEP application). A subgroup of subjects performed Pcrit and upper airway CT evaluations. RESULTS: Study 1) We studied a total of 86 subjects (72 male, age: 46 ± 12 years, body mass index (BMI): 30.2 ± 4.4 kg/m2, apnea/hypopnea index (AHI): 32.9 ± 26.4 events/hour). We found an interaction between interface and position on upper airway collapsibility in multivariate analysis (p=0.007), with the upper airway being more collapsible with mouthpiece than with nasal mask in sitting position. Upper airway collapsibility was higher in supine than in sitting position when NEP was performed with nasal mask. In contrast, NEP was not influenced by position when evaluated with mouthpiece. Expiratory resistance was significantly higher and independent of position with mouthpiece than with nasal mask (20.7 cmH2O/L.s-1 vs 8.6 cmH2O/L.s-1 respectively, p=0.018). Study 2) Twenty-eight subjects performed NEP with nasal mask in supine position, Pcrit and upper airway CT scan (age: 45±13 years, BMI: 29.4 ± 4.9 kg/m2, and AHI: 30 ± 26 events/h). NEP evaluated with nasal mask in supine position and Pcrit were similarly associated with tongue area (r=0.646 and r=0.585), tongue volume (r=0.565 and r=0.613), pharyngeal length (r=0.580 and r=0.611), and AHI (r=0.490 and r=0.531) respectively (p < 0.05 for all comparisons). NEP and Pcrit were significantly worse in patients with severe OSA than the remaining population (p < 0.05). CONCLUSIONS: Study 1) Interface and position influence upper airway collapsibility measured by NEP. We propose NEP to be performed with nasal mask in supine position in future studies of upper airway collapsibility evaluation in patients under investigation for OSA. Study 2) NEP evaluated with nasal mask in supine position is a simple and promising method that is associated with the anatomical component of upper airway collapsibility similarly to Pcrit

INTRODUÇÃO: A apneia obstrutiva do sono (AOS) é comum na população geral e é caracterizada pelo colapso recorrente da via aérea superior. Há um interesse crescente no desenvolvimento de métodos para melhor entendimento da fisiopatologia da AOS. A técnica da pressão negativa expiratória (NEP) é um método relativamente simples que avalia a colapsabilidade da via aérea superior durante a vigília. Porém, a metodologia varia muito e a maioria dos estudos utilizou o bocal, que pode não retratar de forma adequada o comportamento da nasofaringe e pode interferir na posição da língua. Adicionalmente, não existem estudos que avaliaram a associação da NEP com variáveis anatômicas da via aérea superior. A pressão crítica de fechamento da faringe (Pcrit) é um método bem estabelecido que reflete o componente anatômico da AOS, porém é realizada durante o sono e envolve metodologia complexa. OBJETIVOS: Realizamos 2 estudos em indivíduos normais e portadores de AOS com o objetivo de: Estudo 1) Determinar a influência da interface e posição sobre a medida da colapsabilidade da via aérea superior durante a vigília avaliada pela NEP. Estudo 2) Avaliar a associação entre a colapsabilidade da via aérea superior durante a vigília medida pela NEP com máscara nasal na posição supina e durante o sono medida pela Pcrit com variáveis anatômicas da via aérea superior avaliadas pela tomografia computadorizada (TC). MÉTODOS: Foram recrutados indivíduos com idade entre 18 e 65 anos com suspeita de AOS referidos do Laboratório do Sono do InCor. Os indivíduos foram submetidos a prova de função pulmonar, polissonografia e NEP em 4 situações: posição sentada e supina utilizando tanto bocal como máscara nasal. A NEP foi avaliada pelo parâmetro V0,2SB/V0,2NEP (relação entre o volume expirado a 0,2 s durante a respiração espontânea (3 expirações precedentes à aplicação da NEP) sobre o volume expirado a 0,2 s durante a aplicação da NEP). Um subgrupo dos indivíduos realizou o exame de Pcrit e TC de via aérea superior. RESULTADOS: Estudo 1) Foram estudados um total de 86 indivíduos (72 homens, idade: 46 ± 12 anos, índice de massa corpórea (IMC): 30,2 ± 4,4 kg/m2, índice de apneia/hipopneia (IAH): 32,9 ± 26,4 eventos/hora). Encontramos uma interação entre interface e posição sobre a colapsabilidade da via aérea superior na análise multivariada (p=0,007), sendo que a via aérea superior foi mais colapsável com bocal do que com máscara nasal na posição sentada. A colapsabilidade da via aérea superior foi maior na posição supina do que sentada quando a NEP foi realizada com máscara nasal. Em contraste, a NEP não foi influenciada pela posição quando avaliada com bocal. A resistência expiratória foi significativamente maior e independente da posição com bocal do que máscara nasal (20,7 cmH2O/L.s-1 vs 8,6 cmH2O/L.s-1 respectivamente, p=0,018). Estudo 2) Vinte e oito indivíduos realizaram a NEP com máscara nasal na posição supina, Pcrit e TC da via aérea superior (idade: 45 ± 13 anos, IMC: 29.4±4.9 kg/m2 e IAH: 30 ± 26 eventos/hora). A NEP e a Pcrit se associaram de maneira semelhante com a área da língua (r=0,646 e r=0,585), volume da língua (r=0,565 e r=0,613), comprimento da faringe (r=0,580 e r=0,611) e IAH (r=0,490 e r=0,531), respectivamente (p < 0,05 para todas as correlações). A NEP e a Pcrit foram significativamente piores em pacientes com AOS grave do que no restante da população (p < 0,05). CONCLUSÕES: Estudo 1) A interface e a posição influenciam a colapsabilidade da via aérea superior medida pela NEP. Propomos que a NEP seja realizada com máscara nasal na posição supina em estudos futuros de avaliação da colapsabilidade da via aérea superior em pacientes sob investigação de AOS. Estudo 2) A NEP avaliada com máscara nasal na posição supina é um método simples e promissor que reflete o componente anatômico da colapsabilidade da via aérea superior de forma similar a Pcrit / INTRODUCTION: Obstructive sleep apnea (OSA) is common in the general population and is characterized by recurrent collapse of the upper airway. There is a growing interest in developing methods for better understanding of OSA pathophysiology. Negative expiratory pressure (NEP) technique is a simple method that evaluates upper airway collapsibility during wakefulness. However, the method of NEP determination varies among published studies and is mostly evaluated with a mouthpiece, which could inadequately reflect the behavior of nasopharynx and also interfere on the tongue position. In addition, there are no studies evaluating the association between NEP and upper airway anatomy. Pharyngeal critical closing pressure (Pcrit) is a well established technique that reflects the anatomical component of OSA, however, it is performed during sleep and requires a complex methodology. OBJECTIVES: We performed 2 studies in OSA and normal subjects with the objectives of: Study 1) To determine the influence of interface and position on the measurement of upper airway collapsibility while awake evaluated by NEP. Study 2) To evaluate the association among upper airway collapsibility while awake evaluated by NEP with nasal mask in supine position and during sleep evaluated by Pcrit with upper airway anatomy evaluated objectively by upper airway computed tomography (CT) scan. METHODS: We recruited subjects with age between 18 and 65 years with suspect OSA referred to the outpatient sleep clinic at the Heart Institute, University of São Paulo. Subjects underwent pulmonary function test, polysomnography and NEP evaluations in four conditions: sitting and supine position either with mouthpiece or with nasal mask. NEP was evaluated by the parameter V0.2SB/V0.2NEP (ratio between the volume exhaled at 0.2 s during stable breathing (3 expirations prior to NEP application) over the volume exhaled at 0.2 s during NEP application). A subgroup of subjects performed Pcrit and upper airway CT evaluations. RESULTS: Study 1) We studied a total of 86 subjects (72 male, age: 46 ± 12 years, body mass index (BMI): 30.2 ± 4.4 kg/m2, apnea/hypopnea index (AHI): 32.9 ± 26.4 events/hour). We found an interaction between interface and position on upper airway collapsibility in multivariate analysis (p=0.007), with the upper airway being more collapsible with mouthpiece than with nasal mask in sitting position. Upper airway collapsibility was higher in supine than in sitting position when NEP was performed with nasal mask. In contrast, NEP was not influenced by position when evaluated with mouthpiece. Expiratory resistance was significantly higher and independent of position with mouthpiece than with nasal mask (20.7 cmH2O/L.s-1 vs 8.6 cmH2O/L.s-1 respectively, p=0.018). Study 2) Twenty-eight subjects performed NEP with nasal mask in supine position, Pcrit and upper airway CT scan (age: 45±13 years, BMI: 29.4 ± 4.9 kg/m2, and AHI: 30 ± 26 events/h). NEP evaluated with nasal mask in supine position and Pcrit were similarly associated with tongue area (r=0.646 and r=0.585), tongue volume (r=0.565 and r=0.613), pharyngeal length (r=0.580 and r=0.611), and AHI (r=0.490 and r=0.531) respectively (p < 0.05 for all comparisons). NEP and Pcrit were significantly worse in patients with severe OSA than the remaining population (p < 0.05). CONCLUSIONS: Study 1) Interface and position influence upper airway collapsibility measured by NEP. We propose NEP to be performed with nasal mask in supine position in future studies of upper airway collapsibility evaluation in patients under investigation for OSA. Study 2) NEP evaluated with nasal mask in supine position is a simple and promising method that is associated with the anatomical component of upper airway collapsibility similarly to Pcrit

No description available.