Sleep and circadian rhythms in the acute phase of moderate to severe traumatic brain injury

Les traumatismes craniocérébraux (TCC) sont la principale cause d’invalidité chez les jeunes adultes, engendrant d’importantes séquelles cognitives, physiologiques et comportementales. Les perturbations du cycle veille-sommeil sont parmi les symptômes les plus persistants à la suite d’un TCC et pourraient nuire à la récupération. En effet, le sommeil est nécessaire à l’apprentissage, la plasticité cérébrale et la génération de nouveaux neurones dans le cerveau adulte. Les observations cliniques suggèrent que ces perturbations apparaissent dès les premières semaines suivant le TCC et pourraient suggérer une altération de l’horloge circadienne. Cependant, aucune étude n’a encore documenté comment les perturbations du cycle veille-sommeil émergent et évoluent dans la phase aiguë du TCC, ni leur association à la récupération fonctionnelle et cognitive à court-terme. Conséquemment, cette thèse vise à caractériser le sommeil et les rythmes circadiens des patients hospitalisés avec un TCC modéré ou sévère et déterminer si les perturbations du cycle veille-sommeil sont causées par un dérèglement de l’horloge circadienne. Pour ce faire, nous avons utilisé des mesures objectives et quantitatives de sommeil et des rythmes circadiens, incluant l’actigraphie, la polysomnographie (PSG) et la mélatonine, dès la phase d’éveil aux soins intensif. Afin de comprendre le rôle du TCC dans ces perturbations, nous avons comparé les patients TCC à des patients hospitalisés avec blessures orthopédiques graves, sans TCC. Ce protocole a mené à cinq articles de recherche. En premier lieu, nous démontrons que le cycle veille-sommeil des patients TCC est sévèrement perturbé, mais s’améliore chez 50% d’entre eux au cours de leur séjour hospitalier. Les patients avec une amélioration de la consolidation du cycle veille-sommeil ont un meilleur fonctionnement cognitif et fonctionnel au congé de l’hôpital. Ensuite, dans une étude de cas, nous démontrons qu’un patient TCC peut avoir un cycle veille-sommeil complètement différent dans un même environnement, selon son stade de récupération. Notre troisième article confirme que la consolidation du cycle veille-sommeil évolue en synchronie avec la récupération de la conscience et des fonctions cognitives dans la phase aiguë du TCC. Notre quatrième article compare le sommeil des patients TCC à celui des blessés orthopédiques graves, sans TCC, en utilisant un système de PSG ambulatoire au chevet. Nous démontrons que, contrairement à notre hypothèse, le sommeil des patients TCC comprend tous les éléments et stades d’un sommeil normal. Cependant, ces patients s’endorment plus tôt et ont un sommeil de plus longue durée, mais plus fragmenté, que les patients sans TCC. Dans les deux groupes, le sommeil est de mauvaise qualité, reflétant probablement l’effet de facteurs non-spécifiques associés avec les blessures physiques et l’environnement hospitalier. Conséquemment, la PSG en phase aiguë permet difficilement de distinguer les patients TCC des patients sans TCC. Notre dernier article confirme que les patients avec TCC ont une consolidation du cycle veille-sommeil et une qualité de sommeil nocturne inférieures à celles des patients sans TCC, ce qui confirme le rôle du TCC dans les perturbations du cycle veille-sommeil. Cependant, malgré ces perturbations plus sévères, les patients TCC ont un rythme normal de la mélatonine et celui-ci n’est pas associé aux perturbations observées. Cet article suggère que des mécanismes neuronaux autres que l’horloge circadienne seraient responsables des perturbations du cycle veille-sommeil à la suite d’un TCC. Cette thèse est la première à évaluer le sommeil et le fonctionnement de l’horloge circadienne de patients hospitalisés avec un TCC modéré ou sévère ayant atteint la stabilité médicale. En isolant le rôle du TCC de celui du traumatisme physique et du milieu hospitalier, ces études contribuent à comprendre les caractéristiques, les conséquences et la pathophysiologie des perturbations du cycle veille-sommeil à la suite d’un TCC, ouvrant la voie à de possibles interventions visant à améliorer le sommeil et optimiser la récupération.Traumatic brain injuries (TBI) are the leading cause of disability among young adults, causing debilitating cognitive, psychological and behavioural impairments. Sleep-wake disturbances (SWD) are among the most persistent sequelae following TBI, and could impede recovery. Indeed, sleep is essential to learning, plasticity and neurogenesis. Clinical observations suggest that these disturbances arise in the first weeks following injury, and could suggest a circadian disturbance. However, no study has yet documented how SWD arise and evolve in the acute phase of TBI, or how they are associated to short-term cognitive and functional recovery. Consequently, this thesis aims to characterize the sleep and circadian rhythms of patients hospitalized with moderate or severe TBI, and determine whether SWD are caused by a deregulation of the circadian clock. To achieve this goal, we used objective and quantitative measures of sleep and circadian rhythms including actigraphy, polysomnography (PSG), and melatonin, beginning in the awakening stage in the Intensive Care Unit. In order to understand the specific role of TBI on SWD, we compared TBI patients to other hospitalized trauma patients, without TBI. Our comprehensive study protocol led to five research articles. First, we show that the sleep-wake cycle of TBI patients is severely disturbed, but improves for 50% of patients during their hospital stay. Patients whose sleep-wake cycle consolidation improves have better cognitive and functional outcome at hospital discharge. Then, in a single case study, we demonstrate how a patient can have drastically different sleep-wake patterns in the same environment, according to recovery stage. In our third research article, we show that the consolidation of sleep and wake states evolves synchronously with the recovery of consciousness and cognition in the acute phase of TBI. Our fourth article compares the sleep of TBI patients to that of non-TBI trauma patients using ambulatory PSG at bedside. Contrary to our hypothesis, TBI patients have normal sleep elements and normal proportions of each sleep stages. However, they have earlier sleep onset and longer nighttime sleep duration, but with greater fragmentation, than non-TBI patients. In both groups, sleep quality is poor, which most likely reflects non-specific factors associated with the physical trauma and hospital environment. Therefore, PSG reveals little information able to distinguish TBI patients from other non-TBI trauma patients at this stage post-injury. Our final article shows that TBI patients have poorer sleep-wake cycle consolidation and nighttime sleep quality than non-TBI patients, confirming the role of the TBI in altering sleep and wake states. However, despite having more severe SWD, TBI patients have a normal melatonin rhythm, and this rhythm is not associated with the observed SWD. This article suggests that neural mechanisms other than the circadian clock may be responsible for post-TBI SWD. This thesis is the first to investigate the sleep and circadian clock of hospitalized moderate to severe TBI patients who are medically stable. By isolating the role of the injured brain from that of overall trauma and the hospital setting, these studies contribute to understanding the characteristics, consequences and pathophysiology of post-TBI SWD, unlocking the possibility to design interventions aiming to improve sleep and optimize recovery

Examining the Acute and Chronic Effects of Sepsis on the Circadian Clock in the Mouse

Circadian rhythms are recurring patterns (~24hrs) in behaviour and physiology that are driven primarily by an endogenous biological timekeeping system, with the master pacemaker located in the suprachiasmatic nucleus. Studies have indicated bidirectional relationships between the circadian and the immune systems, however while there is much evidence regarding the regulation of immune function by the circadian system, information regarding the impact of immune processes on the timekeeping system is more limited, including that regarding the long-term modulation of the circadian system following immune challenge. The current set of studies address this gap in the literature by examining the long-term impact of sepsis, a substantial immune challenge, on circadian timekeeping processes, following sepsis induction by peripheral treatment with lipopolysaccharide (5mg/kg). Following recovery, post-septic circadian behaviour, SCN molecular oscillations and SCN responsiveness were assessed. SCN neurochemistry was also assessed both in the acute phase and in the long-term post LPS treatment. LPS induced sepsis did not affect core circadian locomotor rhythmicity parameters, but did result in long-term attenuations in post-septic resetting in response to phase advancing photic stimulation, and alterations in re-entrainment to advances of the photoperiod. Perturbations were observed in SCN neurochemistry in the acute phase following septic LPS treatment, and chronic attenuations were also found in post-septic SCN clock gene protein product expression. LPS induced sepsis caused attenuations in SCN functional activation in response to both photic and immune stimulation, as well as alterations in circadian resetting in response to phase resetting immune stimuli. Overall, these data provide further insight into immune circadian communication, and the long-term impact of immune challenge on timekeeping processes, and describe a previously unknown impact of the chronic effects of experimental sepsis on the circadian timekeeping system

Optimizing Circadian Rhythm and Characterizing Brain Function in Disorders of Consciousness

Sleep is a physiological state where memory processing, learning and brain plasticity occur. Patients with prolonged disorders of consciousness (PDOC) show no or minimal signs of awareness of themselves or their environment but appear to have sleep-wake cycles. The main aim of this thesis was to investigate effect of circadian rhythm and sleep optimization on brain functions of patients with PDOC. In the first instance, sleep and circadian rhythms of patients with PDOC were investigated using polysomnography and saliva melatonin measurements. The investigations that were performed at the baseline suggested that both circadian rhythmicity and sleep were severely deranged in PDOC patients. This was followed by the interventional stage of the research where an attempt was made to optimize circadian rhythm and sleep by giving blue light, caffeine and melatonin in a small cohort of patients. To measure the effects of the intervention, we used a variety of assessments: Coma Recovery Scale-Revised (CRS-R) to measure changes in awareness; PSG for assessment of sleep, melatonin for assessment of circadian rhythm; and, event-related potential measures including mismatch negativity (MMN) and subject’s own name (SON) paradigms. Our results showed that it is possible to improve sleep and circadian rhythms of patients with PDOC, and most importantly, this improvement leads to increase in Coma Recovery Scale-Revised scores. Individually, those patients who responded well to the intervention also showed improvements in their functional brain imaging assessments

Advances in Ophthalmology

This book focuses on the different aspects of ophthalmology - the medical science of diagnosis and treatment of eye disorders. Ophthalmology is divided into various clinical subspecialties, such as cornea, cataract, glaucoma, uveitis, retina, neuro-ophthalmology, pediatric ophthalmology, oncology, pathology, and oculoplastics. This book incorporates new developments as well as future perspectives in ophthalmology and is a balanced product between covering a wide range of diseases and expedited publication. It is intended to be the appetizer for other books to follow. Ophthalmologists, researchers, specialists, trainees, and general practitioners with an interest in ophthalmology will find this book interesting and useful

Utilisation des mesures ambulatoires pour l’étude des perturbations du rythme circadien veille-sommeil

Thèse de doctorat présenté en vue de l'obtention du doctorat en psychologie - recherche intervention, option neuropsychologie clinique (Ph.D)Les rythmes biologiques sont une caractéristique universelle de la vie sur terre, présents des organismes unicellulaires jusqu’aux humains. Le rythme biologique le plus connu est le rythme circadien, d’environ une journée, reflétant l’alternance jour et nuit sur notre planète. Le rythme circadien est essentiel à la régulation d’une myriade de fonctions biologiques, telles que le sommeil, la température corporelle, la pression artérielle, la sécrétion de nombreuses hormones et bien d’autres. Le rythme circadien est généré intrinsèquement par notre horloge biologique interne, mais dépend aussi des signaux de l’environnement, dont le plus puissant est l’exposition à la lumière, pour son ajustement au cycle jour-nuit. Par ailleurs, des relations étroites existent entre les rythmes circadiens et diverses problématiques de santé physique et mentale. Les troubles du cycle veille-sommeil sont la conséquence la plus manifeste d’un problème de l’horloge biologique ou de l’entrainement de celle-ci avec son environnement. Cette thèse vise à décrire plusieurs des déterminants intrinsèques et environnementaux qui contribuent à l’étiologie des troubles du rythme circadien. Pour y parvenir, des techniques ambulatoires de mesures continues sur plusieurs jours ont été utilisées dans deux populations de jeunes adultes qui présentent une désynchronisation de l’horaire de sommeil par rapport au rythme jour-nuit environnemental. La première étude de cette thèse utilise l’enregistrement continu de l’exposition à la lumière pour illustrer la contribution de l’environnement lumineux au maintien d’un horaire de sommeil inadapté chez des jeunes adultes avec une plainte de sommeil trop tardif, une catégorie sous-clinique du trouble du sommeil en retard de phase. Ces travaux mettent en relief une possible contribution de l’environnement et des habitudes de vie à ces difficultés de sommeil. Plus précisément, les résultats présentés montrent que l’exposition à la lumière bleue tardivement dans la journée, ainsi qu’une diminution du contraste jour-nuit dans le profil quotidien d’exposition à la lumière sont associées à un délai dans l’horaire de sommeil. Dans cette population, l’exposition tardive à la lumière bleue semble liée à l’utilisation d’appareils électroniques en soirée. La deuxième étude porte sur des patients ayant survécu à un traumatisme craniocérébral modéré à grave et hospitalisés dans la phase aiguë de leur traumatisme. Les patients étudiés présentent une désorganisation du rythme veille-sommeil, qui s’apparente au trouble du rythme veille-sommeil irrégulier. Les analyses de mesures continues de l’activité sur plusieurs jours révèlent que des rythmes activité-repos plus courts que 24 heures sont présents après un traumatisme craniocérébral, et que ces rythmes ne semblent pas être une simple conséquence de l’environnement hospitalier. Ces rythmes, appelés « ultradiens », ont une période de 3 à 8 heures et il semble possible de les observer lorsque le rythme circadien d’activité-repos est sévèrement affaibli. Ces rythmes comportementaux pourraient soit refléter une conséquence du traumatisme, tel qu’une augmentation du besoin de sommeil, mais pourraient aussi représenter une composante plus fondamentale de l’organisation du rythme veille-sommeil, tel que la présence d’un rythme intrinsèque ultradien. Cette thèse contribue à la compréhension de l’étiologie des troubles du rythme circadien veille-sommeil en élargissant les facteurs contributifs au-delà d’une dysfonction des mécanismes physiologiques de l’horloge biologique circadienne. Une compréhension plus holistique des déterminants de ces troubles est essentielle au développement de traitements efficaces.From single-cell organisms to humans, biological rhythms are a ubiquitous feature of life on earth. The most well-known biological rhythm is the circadian rhythm with a duration of approximately 24h that reflects the night and day cycle on our planet. Circadian rhythms are essential for multiple biological functions, including sleep, body temperature, arterial pressure, hormone production, and so on. The endogenous circadian rhythm is generated by a central biological clock but also relies on external, environmental cues such as light to stay synchronized to the day-night cycle. Furthermore, strong links have been documented between circadian rhythms and multiple heath and mental health conditions. Circadian rhythm sleep-wake disorders are a consequence of a dysfunction of the biological clock or of its entrainment to the environment. This thesis aims to describe multiple intrinsic and exogenous factors that may contribute to the etiology of circadian rhythm disorders. To achieve this objective, ambulatory measurements on multiple days were used in two clinical populations of young adults suffering from a severe desynchronization of the sleep-wake cycle from the environmental cycle. The first study included in this thesis used continuous light measurements to describe the contribution of light exposure profiles in the maintenance of a delayed sleep schedule in young adults with a complaint of a late sleep schedule, a sub-clinical population of delayed sleep-wake phase disorder. These results highlight the role of the environment and daily habits in delayed sleep-wake phase disorder. More precisely, this study shows that blue light exposure in the later part of the day as well as a reduced amplitude of day-night contrast are associated with a delayed sleep schedule. In this population, light exposure to blue light could be linked to electronic media use in the evening. The second study focuses on patients hospitalized after a moderate or severe traumatic brain injury (TBI) during the acute phase. These patients present a severe disturbance of the sleep-wake cycle that is similar to the irregular sleep-wake rhythm disorder. Analyses of continuous actigraphy data revealed that sleep-wake cycles of shorter duration are present after a traumatic brain injury and that those rhythms don’t seem to be a simple consequence of being in a care unit of a hospital. These rhythms, referred to as ultradian, have a period of 3 to 8h, and they may be observed when the circadian rhythm is weak or absent. These behavioral rhythms could either be a consequence of the trauma, such as an increased need for sleep, or represent a more fundamental component of the organization of the sleep-wake rhythm, for example an intrinsic ultradian rhythm. This thesis contributes to the understanding of the etiology of circadian sleep-wake rhythm disorders by broadening our understanding of their antecedents beyond a mere dysfunction of physiological mechanisms of the circadian biological clock. A more holistic understanding of the determinants of these disorders is essential for the development of effective treatments

Novel photoreceptor cells, pupillometry and electrodiagnosis in orbital, vitreo-retinal and refractive disorders

Imperial Users onl

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 365)

This bibliography lists 211 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during July 1992. Subject coverage includes: aerospace medicine and physiology, life support systems and man/system technology, protective clothing, exobiology and extraterrestrial life, planetary biology, and flight crew behavior and performance

Cortical thickness and neuropsychological applications: morphometric differences in cortical thickness associated with cognitive variances in ageing and circadian chronotypes

Although rapidly emerging, the field of Neuroscience is still in its infancy. With in-vivo imaging rapidly emerging and novel analysis methods being developed and improved all the time, the neural substrates of behaviour and cognition can be observed like never before. A relatively new method in the anatomical analysis of neuroimaging is cortical thickness analysis. A sensible and intuitive measure of brain morphology and cytoarchitecture, the thesis explores which role cortical thickness measurements can take, when combined with neuropsychological methods. This thesis examines several approaches to neuropsychology with traditional face to face assessments like the Wechsler Scales, to more modern computerised testing, like CANTAB, through to novel approaches and psychometric testing. Whilst combining neuroimaging with neuropsychological methods, this thesis will also account for two of the most inevitable confounding factors in neuropsychology - Ageing and diurnal sleep preference. Though cortical thickness, much like comprehensive neurocognitive batteries like the WAIS and its overall summary score FSIQ, is often expressed through a single composite measure (e.g., global cortical thickness, or mean cortical thickness), this thesis will examine the complexities in developmental trajectories and differences across the brain, when interpreting cortical thickness analysis and explain why the key is really in the detail. This thesis closely examines possible new modulating factors in neuroscientific research, namely circadian chronotype, the role of neuropsychology as a gold standard in the evaluation of cognition, the importance of choosing the correct assay, and how caution must be exercised as brain imaging methods and their measurements are more dynamic than previously thought

Aerospace medicine and biology: A cumulative index to the continuing bibliography of the 1973 issues

A cumulative index to the abstracts contained in Supplements 112 through 123 of Aerospace Medicine and Biology A Continuing Bibliography is presented. It includes three indexes: subject, personal author, and corporate source