Les mécanismes neurologiques responsables du déclenchement et de l’homéostasie du sommeil, et du sommeil paradoxal (SP) en particulier, sont l’objet d’un nombre toujours plus important d’études du fait notamment de l’attention croissante portée aux pathologies associées. Les travaux rapportés dans cette thèse s’inscrivent parfaitement dans cette dynamique puisqu’ils ont pour objectif de mieux caractériser les populations neuronales mises en jeu dans la régulation du SP ainsi que leurs interactions. Dans cette optique, nous avons combiné différentes approches techniques complémentaires à savoir : neuroanatomie fonctionnelle, polysomnographie et pharmacologie sur animal libre de se mouvoir. Nous avons ainsi pu démontrer pour la première fois la nature glutamatergique des neurones du SLD, région pontique jouant un rôle central dans la mise en place du SP. De plus, s’il est généralement admis que ces neurones du SLD sont sous le contrôle de neurones GABAergiques situés au niveau de la partie ventrolatérale de la substance grise périaqueducale (VLPAG), le contrôle de ces derniers est encore soumis à controverse. Les résultats que nous avons obtenus suggèrent fortement que l’aire latérale de l’hypothalamus (LH) serait responsable de ce contrôle et donc de celui du SP. En effet, la LH est l’afférence majeure à la VLPAG activée lors d’une hypersomnie de SP. En outre, son inactivation par application locale de muscimol entraine la disparition totale du SP et l’activation des neurones GABAergiques de la VLPAG projetant sur le SLD. En parallèle, nous avons étudié le rôle du noyau réticulé paragigantocellulaire dorsal (DPGi) dans la genèse du SP. Bien que le DPGi fût déjà connu pour être responsable de l’inhibition du locus coeruleus (LC) durant les phases de SP, nous apportons ici un certain nombre d’arguments suggérant que le DPGi pourrait être responsable de l’inhibition, non seulement du LC, mais également de l’ensemble des neurones adrénergiques et noradrénergiques. Cela suggère donc que ce noyau joue également un rôle majeur dans la régulation du SP. Les données rapportées dans cette thèse permettent donc de mieux appréhender les mécanismes neuronaux contrôlant la survenue et la régulation du SP. En particulier, ils apportent de nouvelles données en faveur d’un rôle central de l’hypothalamus dans la régulation du SP puisqu’il constituerait le générateur principal de cet état. / A growing number of studies investigate the neurological mechanisms responsible for paradoxical sleep (PS) genesis and homeostasis. The work presented in this thesis aims to better characterize the neuronal populations implicated in PS regulation and their interrelations. To this purpose, we combined complementary techniques such as functional neuroanatomy, polysomnography and pharmacological approaches on freely moving animals. We thus demonstrated for the first time the glutamatergic nature of SLD neurons which are known to be responsible for muscle atonia and cortical activation characterizing PS. Moreover it is well established that SLD neurons are inhibited by GABAergic cells located inside the ventrolateral part of the periaqueductal gray (VLPAG). Consequently, the control of theses neurons, a crucial step for PS genesis is still a matter of debate. The results we obtained strongly suggest that the lateral hypothalamus (LH) would be responsible for this control and thus for PS. Indeed, LH is the main activated afferent to VLPAG during PS-hypersomnia and its inhibition by muscimol application totally suppresses PS and activates VLPAG GABAergic cells projecting to SLD. We also analyzed the implication of the dorsal part of the paragigantocellular reticular nucleus in PS regulation. Even if it was known that DPGi is responsible for locus coeruleus (LC) inactivation during PS, we brought new evidences showing that DPGi would actually inhibits all noradrenergic and adrenergic cells and not only LC suggesting that DPGi could be of importance for PS genesis. All our data allow us to better understand the PS neuronal network and suggest that, contrary to the classical view that PS is generated by the pons, LH would be the primary PS generator.

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 255-274.

Brain Activation Sequences Abstract INTRODUCTION: This research goes beyond the EEG source localization up to the field of brain connectivity in an attempt to create software tool that eases diagnostic procedures in selected nosologic units by discriminating between patients and healthy controls. METHODS: Experiment 1 - a group of 26 adult patients (14 male, 12 female) suffering from NC and 10 adult controls (5 male, 5 female) participated in the experiment. The experiment contained audio recordings designed to trigger laughter in participants during the EEG recording. Experiment 2 - twenty eight female inpatients diagnosed with ED and ten healthy controls were selected and presented with various stimuli while the EEG was recorded. The Brain Activation Sequences method, applied to all recordings, utilizes nonlinear differential model structure to calculate final output sequence of the brain locations involved substantially in the stimulus processing. RESULTS: Experiment 1 - the BAS results show statistically significant differences in activity between patients and controls namely in gyrus orbitalis, rectus, occipitalis inferior (right), occipitalis medius (right), paracentralis, cinguli, cuneus (right) and parahippocampalis (left). Experiment 2 - the results confirm significant differences in processing the...

本研究旨在探討猝睡症患者生活品質受症狀變化及神經認知功能改變的影響情況，以及不同層次影響因素對患者生活品質的初始狀態及後續變化軌跡的影響效果。 本研究於北部一所醫學中心睡眠障礙科及兒童心智科募集確診為猝睡症之患者，經同意後進行為期五年的長期研究，募集總人數168人，完成五年資料收集人數85人。本研究使用睡眠多項檢驗（polysomnography, PSG）、多段入睡測試（multiple sleep latency test, MSLT）、人類白血球抗原檢驗（human leukocyte antigen, HLA）為基本檢驗工具，以電腦化第二版康氏持續注意力測驗（Continuous Performance Test- II）及威斯康辛卡片分類測驗（Wisconsin Card Sorting Test, WCST）為檢測神經認知功能之工具，以自填艾普渥斯嗜睡程度量表（Epworth sleepiness scale, ESS）、史丹佛睡眠問卷（Stanford sleep inventory, SSI）及簡式生活品質量表（short from-36 items of health related quality of life, SF-36）做為症狀嚴重度及生活品質的依據。資料分析以描述統計及階層線性模式（hierarchical linear models , HLM）統計方法進行。主要結果如下： 一、 猝睡症患者生活品質分為生理與心理兩個層面，患者生理層面在五年期間維持相對穩定沒有顯著變化；心理層面中之不同向度則有不同變化趨勢，心理健康與活力向度隨時間有逐漸提高的趨勢，患者此二向度生活品質接受治療後有穩定上升的趨勢，而社會功能及情緒角色限制則呈現二次方曲線變化，以及呈現先增後減的發展軌跡，患者此二向度接受治療後顯著上升，第三年後有逐年下降的趨勢。 二、 患者嗜睡程度及猝倒嚴重度變化隨時間有顯著成長軌跡，呈二次方曲線發展，轉折點在第三年，接受治療前三年症狀呈現穩定降低的軌跡，但自第三年起逐年增加，此結果與藥物治療初期症狀獲得顯著改善，後期改善幅度相對減少，及藥物效果具有關聯。 三、 個體間層次變項僅疾病持續時間、HLA對患者生活品質具顯著解釋力，其中疾病持續時間越長，患者可能發展因應症狀之策略，從而降低疾病對生活品質之衝擊。而HLA則對症狀有不同影響，HLA陽性患者初始嗜睡程度較陰性者為低，且接受治療後改善效果較陰性者顯著，猝倒嚴重度起始值較陰性者高，且接受治療後的趕善幅度較陰性者小。 四、 疾病嚴重度變化對生活品質具顯著影響，完整模式分析中，時間主效應未達顯著，但可由症狀變化及神經認知功能改變進行更佳的解釋。嗜睡程度變化僅對身體疼痛向度變化不具有解釋力外，對其餘七個向度均具顯著影響；猝倒影響層面不及嗜睡程度，但亦可解釋生理量表、生理角色限制、心理量表、心理健康、情緒角色限制、活力等向度上的變化。 五、 神經認知功能改變與否對患者生活品質具有加成效果，分析顯示患者神經認知功能改善時，其生活品質提升速率較未改善者高，影響較顯著的包括注意力、警覺度及概念反應，此結果與下視丘泌素參與的維持注意力及前額葉功能有關。 本研究依據分析結果提出猝睡症患者生活品質受嗜睡症狀及猝倒嚴重度改變直接影響，同時受人類白血球抗原屬性及神經認知功能改變調節之假設模型，作為未來研究參考依據。並根據研究結果與限制，提出對臨床實務的應用與心理介入的建議，並對未來提升猝睡症患者生活品質相關研究提供建議。 / The current study aims to: (1) examine the change of eight domains of quality of life in narcoleptics within five years, (2) investigate the impact of the change of symptom severity on different dimension of quality of life, as well as the influence associated with the change of neuro-cognitive function. There were 168 participants recruited from a medical center in northern Taiwan. 85 of them completed the 5-year annual follow-up data collection. During the follow-ups, polysomnography (PSG), multiple sleep latency test (MSLT) and human leukocyte antigen (HLA) test were conducted. Computerized neuropsychological tests of Conners’ Continuous Performance Test- II (CPT-II) and Wisconsin Card Sorting Test (WCST) were also administered to obtain attention and executive function data. The short from-36 items of health related quality of life (SF-36), Stanford sleep inventory (SSI) and Epworth sleepiness scale were applied to assess quality of life and symptom severity. Descriptive statistics and hierarchical linear models were applied for data analysis. The main results were: 1. The quality of life was divided into physical and psychological domains. The physical domain kept relatively stable during the 5-year follow up as opposed to the psychological domain. In psychological domain, the vitality and psychological health showed increasing tendency overtime. However, the social function and role functioning-emotion increased during the first 3 years then declined afterward. 2. The symptom severity also showed a tendency corresponded to quadratic curve. The daytime sleepiness together with cataplexy severity reduced immediately after treatment but rose after the third year. 3. The variables of individual characteristics that showed significant impact on quality of life were disease duration and HLA type. The longer the duration, the better quality of life one had. Positive HLA typing seemed to be a protective factor on severity of sleepiness. It also predicted better treatment outcomes, but worsen the severity of cataplexy and treatment effects. 4. The symptom severity could be a good explanation as a variable of quality of life. The daytime sleepiness altered all domain of SF-36 expect body pain. Cataplexy affected only psychological domain of SF-36. 5. The neuro-cognitive function was also found to affect quality of life. Those who improved in attention and executive function test got greater improvement on SF-36 as well. The vigilance on CPT-II and conceptualized response on WCST had most significant impact. I proposed a model of change of quality of life in patients with narcolepsy based on the results obtained. Several suggestions were also proposed for clinical and psychological intervention for narcolepsy to improve their quality of life.

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