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Sleep disturbance is a distressing and often poorly treated core symptom of major depression. Physiological sleep abnormalities are one of the few biological markers in depression. Reported here are studies in which sleep has been used to further our understanding of two experimental treatments for patients with treatment refractory depression (TRD). The first is a crossover study of the effect of two bolus infusions of hydrocortisone administered in the afternoon on sleep that night in healthy volunteers. This study was undertaken to help interpret results in a comparable patient study, in which the effects of 3 daily, high doses of hydrocortisone on sleep were assessed on night 3 (after hydrocortisone treatment), and 4 weeks later in patients with TRD. In healthy volunteers, hydrocortisone significantly increased slow wave sleep and, in a dose dependent manner, suppressed rapid eye movement sleep (REM), despite a delay of 8-10 hours between infusion and start of sleep recordings. The low dose increased measures of arousal, resulting in delayed sleep onset. In the patient study, it was not possible to confirm any sleep effects of hydrocortisone at a group level because of low patient numbers and large baseline variations in sleep measures attributable to psychotropic medications with differing effects on sleep architecture. However, the data gave some indication that if sleep improvements were observed directly after hydrocortisone, these were sustained, although not necessarily accompanied by mood alterations. The third study was an investigation of sleep effects of deep brain stimulation (DBS) in patients with TRD. Intracerebral electrodes were implanted in the subgenual cingulate (SGC) and nucleus accumbens (NAcc) regions. Continuous stimulation was commenced in one target brain region (randomised order) which could be switched to the second if no clinical response was observed. The main finding was a striking increase in REM sleep and reduction of REM onset latency after acute SGC stimulation, but not with NAcc stimulation. These results could imply previously unknown cortical mechanisms of REM sleep modulation

The primary aim of this thesis was to evaluate the efficacy of dietary/herbal interventions on sleep, and associated daytime consequences that are often the major complaints of poor sleep in the general population. A secondary aim was to develop appropriate methodology for assessment of such interventions in 'the field.' Poor sleepers participated in two placebo-controlled, double-blind, 3-week field studies that included a baseline week, and were assessed after the first night, over two weeks, and at follow up. Outcomes included objective and self-rated measures of sleep, mood, and daytime cognitive performance, which had initially been assessed using caffeine as a model for poor sleep in good sleepers, and a separate sample of poor sleepers. Previously reported beneficial effects for sleep (or stress and anxiety hypothesised to promote healthy sleep) of hops, lemon balm, L- theanine, and a tryptophan rich protein were largely not replicated here. Nor were any clear beneficial effects observed for next day mood and cognitive performance. Although those with insomnia disorder were excluded, insomnia is often undiagnosed and possibly resulted in a sample of poor sleepers with severe sleep complaints. The selection criteria for poor sleepers are of major importance. Furthermore, different mechanisms must be targeted for short- or long-term sleep problems, and sleep needs to be poor enough to show evidence of daytime impairment. Objective daytime outcome measures are not suitable for daily field testing, as multiple nights of improved sleep are necessary to see measurable changes in performance, and these can be influenced by uncontrolled compensatory mechanisms deployed by participants to manage the effects of their poor sleep. For the purpose of assessing changes associated with improved sleep due to interventions in poor sleepers without insomnia disorder, self-rated performance may be a more appropriate and reliable outcome. Feeling refreshed in the morning may be another important primary outcome variable, as this was found to be associated with both sleep quality and daytime performance.

Chronic lack of sleep has been shown to be deleterious to our health. A variable number tandem repeat (VNTR) polymorphism in PERIOD3 (PER3) gene (rs57875989), has been reported to associate with diurnal preference, sleep propensity, vulnerability to sleep loss, and risk of cancer and mental illnesses. Although sleep loss at the molecular level in animal models has been studied extensively, there is a paucity of data in humans. The aim of the current study was to investigate the dependent and independent effects of the PER3 VNTR polymorphism and sleep loss on gene expression. Men and women homozygous for either the long (P ER35/5) or short (P ER34/4) P ER3 VNTR polymorphism underwent 7 sleep-wake cycles of either sleep restriction (SR) (6 h sleep) or sleep extension (SE) (10 h sleep) in a cross-over design, followed by 40-h constant routine (CR), during which time blood samples for assessing global gene expression were collected 3-hourly. Compared to SE, SR resulted in greater changes in expression in genes involved in neuronal plasticity, immune response, cellular stress response, energy metabolism, sleep-deprivation response, and clock genes in comparison to the effects of CR, suggesting that effects of chronic sleep loss result in more severe consequences than acute lack of sleep. Entrained timing of habitual sleep and wakefulness was shown to correlate with the timing of NRIDl (REV-ERBα), NRID2 (REV-ERBβ), BHLHE41 (DEC2), CSNKl D and TIMELESS expression, suggesting a prominent role for these genes in the regulation of sleep-wake behaviour. Additionally, REV-ERBα and REV- ERBf3 phase of expression showed correlations with sleep-wake timing in P ER34/4, but not in PER35/5. Additional genes identified as differentially expressed between the P ER3 homozygotes were involved m Immune function, phosphorylation/dephosphorylation, chronotype determination, and neurophysiology. A stably expressed reference gene, β-actin, for real-time PCR analysis of circadian time-series data in blood was also identified.

There have been many studies investigating the effect of obstructive sleep apnoea (OSA) on the cardiovascular system, but there are only a few which attempt to correlate these findings to arousals and examine whether continuous positive airway pressure (Cl' AP) treatment is an effective long-term treatment in patients with mild, moderate and severe OSA. The overall aim of this study was to examine these parameters in detail, but also as sleep services in Northep; Ireland are under , ." - - enormous pressure to diagnose, treat and review patients suspected as having OSA, an assessment of the application of the Berlin Questionnaire as a screening tool for use by general practitioners was explored .. This programme of research involved a review of literature which identified several research questions to address inconsistent outcomes with respect to the alteration in cardiovascular markers, following apnoea/hypopnoea events, arousals and the effects of Cl' AP treatment in subjects with OSA. As a result microanalysis of cardiovascular data was performed during five consecutive apnoea/hypopnoea events and compared at early apnoea (EA), onset of apnoea or hypopnoea event and late apnoea (LA) immediately preceeding the onset of arousal. The second output from this thesis was the examination of the effect of 6 weeks and 6 months Cl' AP in subjects with OSA, on apnoea/hypopnoea index (AHI) and Arousal Index (Arl) over a range of cardiovascular markers. The inclusion of data on daytime sleepiness and quality of life was also collected as indicators of improvement in performance, mood, concentration and lifestyle. The third output of this thesis was the application and validation of the Berlin Questionnaire, to help clinicians filter referrals to sleep clinics, improve diagnosis treatment times and prevent further cardiovascular complications. An estimation of the prevalence of OSA in Northern Ireland in a selected population of adults was calculated from the results.

This thesis provides a novel contribution to cognitive and developmental psychology by investigating the relationship between sleep, behaviour and cognition in 41 healthy typically developing (TD) children, 22 children with Down syndrome (OS) and 22 with Williams syndrome (WS). In addition, developmental changes in sleep and cognition, and the importance of sleep for consolidation of new memories were assessed in these groups. Finally, the influence of children's sleep and behaviour on their mothers' sleep and wellbeing were examined. The research used a battery of standardised and novel cognitive tasks, objective measures of sleep, and questionnaires. Sleep problems were syndrome-specific, with poor sleep quality and oxyhaemoglobin desaturation occurring more frequently in OS, suggestive of breathing difficulties during sleep, and long sleep latencies in the WS group. TD children performed well on cognitive tasks of short term memory, working memory and sustained attention compared to children with OS and WS, and their performance generally improved with increasing age, which tended not to be the case for the clinical groups. In the TD group, improved sleep quality and higher, less variable oxyhaemoglobin saturation related to better performance on cognitive tasks and fewer behavioural problems. Few associations between sleep, cognition and behaviour were found in the OS and WS groups. TD children and children with WS showed evidence of sleep-dependent memory consolidation for explicitly learnt material on two tasks. Mothers of children with OS had the poorest sleep and most daytime sleepiness, though not related to children's sleep or daytime behaviour. The findings indicate that sleep problems should be assessed and managed in clinical groups. Educational strategies should be implemented to reinforce sleep-related learning gains. Future research could examine whether sleep-dependent learning occurs in relation to specific aspects of sleep architecture in children with OS and WS, as it does in adults and TD children.

Contexte : La structure du sommeil évolue grandement dans les premières années de vie. Les réveils nocturnes occasionnels chez les enfants d'âge préscolaire font partie d’un processus normal de développement et de maturation du sommeil. Ils sont cependant considérés comme anormalement fréquents lorsqu’ils surviennent une nuit sur deux ou plus. La littérature suggère que les réveils nocturnes fréquents sont associés de manière transversale à des difficultés comportementales du jeune enfant. Or, l’évolution des réveils nocturnes dans la petite enfance, les facteurs associés à leurs trajectoires et les liens longitudinaux avec le comportement sont peu connus. Objectifs : Modéliser l’évolution des réveils nocturnes entre l’âge de 2 et 5-6 ans et explorer leurs liens avec des facteurs précoces familiaux et de l’enfant. Analyser les associations entre les trajectoires de réveils nocturnes et le comportement de l’enfant avant l’entrée à l’école. Population et méthode : Nos analyses ont porté sur les données de l’étude EDEN. Il s’agit d’une cohorte mère enfant, qui a recruté 2 002 femmes enceintes entre 2003 et 2006 dans les maternités de Nancy et Poitiers. Les réveils nocturnes et le comportement ont été mesurés par des questionnaires parentaux à l’âge de 2, 3 et 5-6 ans. La méthode du « group-based trajectory modeling » nous a permis de modéliser l’évolution des réveils nocturnes et de difficultés d’attention, et ainsi d’identifier des trajectoires, décrivant différentes histoires développementales entre l’âge de 2 et 5-6 ans. Les analyses statistiques pour mesurer les associations entre les trajectoires de réveils nocturnes, les facteurs précoces et le comportement de l’enfant, ont été faites par régressions logistiques, ajustées sur les facteurs de confusion potentiels. Résultats : Deux trajectoires distinctes de réveils nocturnes ont été identifiées chez les enfants entre 2 et 5-6 ans. L’une, nommée “réveils nocturnes rares”, représentait 77% des enfants. Ce groupe suivait une trajectoire linéaire proche de zéro et légèrement décroissante avec le temps. La seconde trajectoire, nommée « réveils nocturnes communs », représentait 23% des enfants. Elle était plus haute que la première trajectoire à chaque point de suivi, et présentait un pic à l’âge de 3 ans. Les facteurs de risque d’appartenir à la trajectoire de « réveils nocturnes communs » étaient essentiellement environnementaux : l’exposition au tabagisme passif, un mode de garde collectif et le temps passé devant la télévision. Les enfants appartenant à la trajectoire de réveils nocturnes communs présentent un risque accru de présenter des symptômes émotionnels, des problèmes de conduite et des problèmes d'hyperactivité/inattention à l’âge de 5-6 ans. Aucune association n'a été trouvée avec le comportement pro-social ou avec les problèmes de relations avec les pairs. Trois trajectoires d’inattention/hyperactivité ont été identifiées, une trajectoire basse, intermédiaire et une haute, toutes trois stables au cours du temps. Le risque d’appartenir à une trajectoire haute d’inattention/hyperactivité, par rapport à une trajectoire basse, était quatre fois plus important pour les enfants avec une trajectoire de « réveils nocturnes communs » comparativement à ceux avec trajectoire de « réveils nocturnes rares ». Conclusion : Les réveils nocturnes et les troubles d’inattention/hyperactivité persistent dans la petite enfance. Une trajectoire de réveils nocturnes communs durant cette période est un facteur de risque de plusieurs troubles du comportement : symptôme émotionnel, troubles de conduites et inattention/hyperactivité. Ces derniers co-évoluent avec les troubles du sommeil. Nos résultats soulignent l’importance d’identifier et de prendre en charge les difficultés de sommeil dès le plus jeune âge, surtout en présence de difficultés de comportement. / Context: The structure of sleep evolves greatly in the first years of life. Occasional nightwaking is thus normal in young children, but waking-up every other night or more is considered adversely frequent. The scientific literature suggests that frequent night-waking is associated with concomitant behavioral difficulties in children. Yet, little is known about the evolution of night-waking in preschool years and its longitudinal association with behavior. Objectives: To model the evolution of night-waking between the age of 2 and 5-6 years and explore the association with family and child related factors. To analyze the associations between night-waking trajectories and behavior before school entry. Population and methods: Analyses were based on the French birth-cohort study EDEN, which recruited 2 002 pregnant women between 2003 and 2006 in the maternity of Poitiers and Nancy. Information regarding night-waking and behavior were assessed using parental questionnaires at the ages of 2, 3 and 5-6 years. The « group based trajectory modeling » method allowed us to model the evolution of night-waking and of inattention/hyperactivity, describing different developmental trends between the age of 2 and 5-6 years. The associations between night-waking trajectories, family and child related factors and behavior, were analyzed using logistic regressions, adjusted on potential confounding factors. Results: Two distinct night-waking trajectories were identified in children between the age of 2 and 5-6 years. One, named « rare night-waking », represented 77% of the children. This group followed a linear trajectory, which was close to zero and slightly declining with time. The second trajectory, named « common night-waking », represented 23% of the children. It was higher than the first trajectory at each time-point, and a peak was observed at age 3. Risk factors for belonging to the « common night-waking » trajectory were life-style related factors: exposures to second hand smoking, collective care arrangement, and time spent in front of the television. Children belonging to the common night-waking trajectory had higher risk of having emotional symptoms, conduct problems and inattention/hyperactivity at age 5-6. No associations were found with prosocial behavior nor peer-relationship problems. Three trajectories of inattention/hyperactivity were identified, a low, an intermediate and a high one, all stable in time. The risk of belonging to a high inattention/hyperactivity trajectory, compared to a low one, were four time more important for children with a « common night-waking » trajectory. Conclusion: Night-waking and inattention/hyperactivity persist in preschool years. A common night-waking trajectory during this period is a risk factor of diverse behavioral difficulties: emotional symptoms, conduct problems and inattention/hyperactivity. The latter co-evolves with night-waking. Our results highlight the importance of identifying sleep problems in early years, especially in the presence of behavioral difficulties.