Narcolepsy is a disabling sleep disorder that is characterized by persistent sleepiness, and cataplexy – an involuntary loss of waking muscle tone. Cataplexy and narcolepsy are caused by the loss of hypocretin containing neurons in the hypothalamus. However, it is hypothesized that dopamine is also involved in sleep and motor control and plays a role in cataplexy. This study investigated how manipulating dopamine affected sleep and cataplexy in narcoleptic mice devoid of hypocretin. We used d-amphetamine to increase endogenous dopamine levels and quinpirole (D2 agonist) to agonize D2 receptor sites. Amphetamine promoted wakefulness while decreasing sleep in wild-type mice, but was less effective in narcoleptic mice. Amphetamine also reduced cataplexy as well as sleep attacks (an indicator of sleepiness) in narcoleptic mice. Quinpirole had no effect on sleep or wakefulness; however, it potently increased cataplexy without affecting sleep attacks in narcoleptic mice.

In this thesis I investigated the neural circuits that trigger cataplexy in mice. Specifically, I first addressed the theory that cataplexy is a REM sleep disorder. I then investigated a role for the noradrenergic and dopaminergic systems in murine cataplexy. Finally, I addressed the role of the amygdala in triggering cataplexy. From this work several specific conclusions can be drawn: 1. Cataplexy does not share a common executive mechanism with REM sleep, although the two may share a common mechanism that generates muscle atonia. Muscle tone during REM sleep and cataplexy is similar, however increasing REM sleep pressure does not increase cataplexy and positive affective stimuli that can increase cataplexy tend to decrease REM sleep. 2. Systemic manipulation of dopamine receptors can modulate cataplexy without affecting behavioral state. Specifically, manipulation of D2-like dopamine receptors at specific doses can modulate cataplexy while having no affect on sleep-wake state or sleep attacks, and manipulation of D1-like receptors potently affects sleep-wake state and sleep attacks without affecting cataplexy. 3. Systemic modulation of noradrenergic activity in orexin KO mice is sufficient to modulate cataplexy. Specifically, activation of excitatory α1 receptors reduces the occurrence of cataplexy while blockade of these receptors exacerbates it. 4. Withdrawal of an endogenous α1-mediated noradrenergic drive from motor neurons during wakefulness contributed to the loss of muscle tone during cataplexy. Re-establishing this excitatory drive exogenously alleviated cataplexy-dependant muscle atonia. 5. The amygdala is a critical part of the neural mechanism that triggers cataplexy in orexin KO mice. Ablation of the amygdala resulted in significant decreases in both baseline cataplexy and emotionally-induced cataplexy. The amygdala may trigger cataplexy through direct projections to brainstem areas that regulate muscle atonia.

Narcolepsy is a disabling sleep disorder that is characterized by persistent sleepiness, and cataplexy – an involuntary loss of waking muscle tone. Cataplexy and narcolepsy are caused by the loss of hypocretin containing neurons in the hypothalamus. However, it is hypothesized that dopamine is also involved in sleep and motor control and plays a role in cataplexy. This study investigated how manipulating dopamine affected sleep and cataplexy in narcoleptic mice devoid of hypocretin. We used d-amphetamine to increase endogenous dopamine levels and quinpirole (D2 agonist) to agonize D2 receptor sites. Amphetamine promoted wakefulness while decreasing sleep in wild-type mice, but was less effective in narcoleptic mice. Amphetamine also reduced cataplexy as well as sleep attacks (an indicator of sleepiness) in narcoleptic mice. Quinpirole had no effect on sleep or wakefulness; however, it potently increased cataplexy without affecting sleep attacks in narcoleptic mice.

In this thesis I investigated the neural circuits that trigger cataplexy in mice. Specifically, I first addressed the theory that cataplexy is a REM sleep disorder. I then investigated a role for the noradrenergic and dopaminergic systems in murine cataplexy. Finally, I addressed the role of the amygdala in triggering cataplexy. From this work several specific conclusions can be drawn: 1. Cataplexy does not share a common executive mechanism with REM sleep, although the two may share a common mechanism that generates muscle atonia. Muscle tone during REM sleep and cataplexy is similar, however increasing REM sleep pressure does not increase cataplexy and positive affective stimuli that can increase cataplexy tend to decrease REM sleep. 2. Systemic manipulation of dopamine receptors can modulate cataplexy without affecting behavioral state. Specifically, manipulation of D2-like dopamine receptors at specific doses can modulate cataplexy while having no affect on sleep-wake state or sleep attacks, and manipulation of D1-like receptors potently affects sleep-wake state and sleep attacks without affecting cataplexy. 3. Systemic modulation of noradrenergic activity in orexin KO mice is sufficient to modulate cataplexy. Specifically, activation of excitatory α1 receptors reduces the occurrence of cataplexy while blockade of these receptors exacerbates it. 4. Withdrawal of an endogenous α1-mediated noradrenergic drive from motor neurons during wakefulness contributed to the loss of muscle tone during cataplexy. Re-establishing this excitatory drive exogenously alleviated cataplexy-dependant muscle atonia. 5. The amygdala is a critical part of the neural mechanism that triggers cataplexy in orexin KO mice. Ablation of the amygdala resulted in significant decreases in both baseline cataplexy and emotionally-induced cataplexy. The amygdala may trigger cataplexy through direct projections to brainstem areas that regulate muscle atonia.

Bakgrund: I Sverige beräknas över 4000 personer vara drabbade av Narkolepsi. Narkolepsi är en neurologisk kronisk sjukdom som innebär att den drabbade har störd reglering av sömn och vakenhet. Kärnsymtomen är dagtrötthet och kataplexiattacker. Kvantitativa studier har visat att symtomen av narkolepsi påverkar uppfattningen av livskvalitet negativt. Syfte: Att belysa vuxna personers upplevelser av livskvalité efter att ha drabbats av narkolepsi. Metod: Kvalitativ metod där bloggtexter analyseras med innehållsanalys. Resultat: I resultatet framkom två domäner. Domänen ”Möjliggörande av god livskvalité” presenterar en kategori; Strategier för att uppnå god livskvalitet och betydelsen av stöd från omgivningen. Domänen ”Begränsningar av livskvalité” presenterar tre kategorier; Symtom som skapar socialt handikapp, Allmänhetens okunskap och upplevelser av blandade känslor samt Att tvingas planera och prioritera för att orka med vardagen Slutsats: Narkolepsi påverkar upplevelsen av livskvalité negativt. Symtom som okontrollerbar sömnighet dagtid och kataplexier kan orsaka skam och rädsla att vistas i sociala sammanhang. Strategier för att minska symtom, ökad förståelse för de drabbades upplevelser av sjukdomen och stöd från omgivningen kan bidra till att hjälpa de som drabbas till en ökad livskvalité.

Narcolepsia é uma condição neurológica crônica, o principal sintoma é a sonolência diurna excessiva, associada a cataplexia, a paralisia do sono e as alucinações hipnagógicas. Paciente com narcolepsia apresenta dificuldade em manter a atenção e vigilância nas tarefas rotineiras e monótonas, com riscos de acidentes acarretando um sério prejuízo e impacto social nas suas relações de trabalho e sócio-familiares e na percepção da qualidade de vida.Foram avaliados 40 pacientes ( 28 mulheres e 12 homens) com idade média de 42 anos. O presente trabalho teve como objetivo: a) avaliar a percepção da QV em pacientes com narcolepsia b) Avaliar a percepção do impacto social. Este estudo demonstrou que: 1) A narcolepsia acarreta comprometimento na QV dos pacientes, com prejuízo das funções físicas e emocionais, interferindo nas condições de trabalho e dinâmica familiar; 2) A narcolepsia produz um impacto social em várias esferas da vida do pacientes, comprometendo atividades instrumentais da vida diária e a situação de trabalho / Narcolepsy is a chronic neurological condition, whose main symptom is excessive daytime sleepiness, associate the cataplexy, the hypnogogic hallucinations and sleep paralysis. The patient with narcolepsy presents difficulty in keeping the attention and monitoring in the routine and monotonous tasks, with risks of accidents, causing a serious prejudice and social impact its partner-familiar, relations of work and in the perception of the quality of life. The present work had as objective: ) to evaluate the perception of the quality of life in patients with narcolepsy b) To evaluate the perception of the social impact. This study it demonstrated that: 1) The narcolepsy compromises the quality of life of the patients, with prejudice of the physical and emotional functions, intervening with the conditions of work and familiar dynamics; 2) The narcolepsy produces a social impact in some areas of the life of the patients, compromising instrumental activities of the daily life and the situation of work

Aktivitetsbalans innebär hur individen upplever sitt aktivitetsmönster, vilket är mängden av aktiviteter samt variationen av aktiviteter under en dag. Syfte: Syftet med studien var att beskriva hur individer med narkolepsi upplever aktivitetsbalans. Metod: En kvantitativ design användes med deskriptiv tvärsnittsstudie där data samlades in via enkät. Enkäten utgick från instrumentet Occupational Balance Questionnaire [OBQ] och innehöll 11 frågor med fyrgradig skattningsskala samt 4 frågor med fritextsvar. Det var 20 individer som deltog i studien varav 18 stycken är kvinnor och två är män. Deltagarna var mellan åldrarna 18- 56 år. Data analyserades med deskriptiv och analytisk statistik samt innehållsanalys då enkäten gav både kvantitativa och kvalitativa variabler. Resultat: Deltagarna skattade sin aktivitetsbalans som låg. Ingen signifikant skillnad på aktivitetsbalans mellan arbetande/studerande eller arbetslösa/sjukskrivna kunde visas i resultatet. Ingen signifikant skillnad av aktivitetsbalans kunde heller ses mellan ålder och kön på deltagarna, dock var majoriteten av deltagarna kvinnor. Den kvalitativa analysen resulterade i tre kategorier; brist av meningsfulla aktiviteter, aktiviteter som tar och ger energi och brist på vila, sömn samt återhämtning. Det centrala i alla kategorier var att deltagarnas brist på vila och återhämtning påverkar deras aktiviteter i stort och genomsyrar vardagen. Sociala sammanhang blev påverkade samt bortvalda då deltagarna inte hade energi att umgås med andra. Slutsats: Resultatet pekade på att individer med narkolepsi var i behov av mer stöd än det som ges i idag, stödet kan vara strategier och hjälpmedel. Därför finns ett intresse att fortsatt studera vilken typ av insatser eller strategier som kan möjliggöra aktivitet och en vardag i balans för denna grupp.

La narcolepsie, une maladie neurologique rare débute dans 50% des cas avant l'âge adulte, est caractérisée par la somnolence diurne excessive, cataplexie, la paralysie du sommeil et les hallucinations hypnagogiques. Ces manifestations affectent les aspects psychologiques, sociaux et scolaires des enfants. Sa physiopathologie est décrite par la perte de neurones à hypocrétine dans l'hypothalamus postérieur, probablement dû d'une attaque auto-immune, ainsi que par les systèmes à histamine. Au contraire de la narcolepsie adulte, les études pédiatriques ne sont pas nombreuses et peuvent être la lumière pour la compréhension de sa pathogenèse et de son évolution. L'objectif principal de la thèse est de caractériser la maladie et sa prise en charge dans population pédiatrique. Nous avons utilisé des bases de données clinique, anthropométriques, électrophysiologiques et pharmacologiques des enfants, adolescents et adultes narcoleptiques suivis dans les cinq Centres de Référence Nationale de Narcolepsie et d'Hypersomnie. Nous avons montré que la narcolepsie chez l'enfant peuvent avoir différents phénotypes, tels de da prise de poids rapide, de l'obésité, du TDAH, de la dépression, des allergies et autres, ainsi que les caractéristiques de la narcolepsie plus sévères que la population adulte, principalement l'obésité et le TDAH. Nous décrivons nos expériences du traitement et par le Pitolisant dans la narcolepsie. En conclusion, il existe un aspect distinctif de la narcolepsie adulte et pédiatrique (obésité et symptômes du TDAH plus sévères). L'obésité affecte environ 60% des enfants narcoleptiques, la plupart chez les jeunes au début de la maladie, et a un impact néfaste sur la qualité du sommeil et l'absentéisme scolaires. Le Pitolisant ont été efficace pour traiter la somnolence avec des améliorations sur la cataplexie, et bien que ont présenté un bon rapport risques/bénéfices / Narcolepsy is a rare neurological disease and it starts, in 50% of cases, before adulthood. It is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis and hypnologic hallucinations, events that affect the psychological, social and school children. This pathophysiology is described by the loss of neurons in the posterior hypothalamus hypocretin, probably due to an autoimmune attack, and by histamine systems. Instead of narcolepsy adult, pediatric studies aren’t numerous and can be a light to the understanding of this pathogenesis and her evolution. The main objective of the thesis is to characterize the disease and her treatment in pediatric population. This rechearch used clinical databases, anthropometric, electrophysiological and pharmacological in children’s, adolescents and adults, with narcolepsy followed within five Centers National Reference Narcolepsy and hypersomnia. The results have shown that narcolepsy in children may have different phenotypes (rapid weight gain, obesity, ADHD, depression, allergies and others) and It can be most severe than adult population, principality obesity and ADHD. The thesis describes our experience of treatment and the utilization of pitolisant in narcolepsy (effective for treating sleepiness with improvements on cataplexy, has been presented a good risk/benefit ratio). In conclusion, there is a distinctive aspect of adult and pediatric narcolepsy (obesity and symptoms of more severe ADHD, in the way that obesity affects about 60% of narcoleptic children, most youth early in the disease, and has a negative impact on sleep quality and school absenteeism

Manual sleep scoring, executed by visual inspection of the EEG, is a very time consuming activity, with an inherent subjective decisional component. Automatic sleep scoring could ease the job of the technicians, because faster and more accurate. Frequency information characterizing the main brain rhythms, and consequently the sleep stages, needs to be extracted from the EEG data. The approach used in this study involves a wavelet filter bank for the EEG frequency features extraction. The wavelet packet analysis tool in MATLAB has been employed and the frequency information subsequently used for the automatic sleep scoring by means of an artificial neural network. Finally, the automatic sleep scoring has been employed for epoching the fMRI data, thus allowing for studying brain resting state networks during sleep. Three resting state networks have been inspected; the Default Mode Network, The Attentional Network and the Salience Network. The networks functional connectivity variations have been inspected in both healthy and narcoleptic subjects. Narcolepsy is a neurobiological disorder characterized by an excessive daytime sleepiness, whose aetiology may be linked to a loss of neurons in the hypothalamic region.

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