Sleep & Circadian Research Group

Role

To investigate the neurobiological, physiological and neurobehavioural processes regulated by the sleep and circadian systems that are affected by disturbances in these systems. These disturbances are due to sleep and circadian disorders, other medical disorders and voluntary or lifestyle alterations.

Objectives

To develop, foster and promote Australia’s world-class research and clinical capability in the field of sleep and circadian medicine and research.

Research

Clinical Epidemiology
Evaluation of screening and diagnostic devices for sleep apnea
Obstructive sleep apnea (OSA) is a respiratory based sleep disorder, where patients experience collapse of their airway during sleep and consequently have difficulty breathing, resulting in decreased brain oxygen levels (hypoxia) and multiple arousals from sleep and sleep disturbance. The prevalence of OSA in the general population is about 25% in males and 9% in females. OSA commonly co-occurs with increased weight and obesity, increased risk of cardiovascular disease and alterations in metabolic functioning. OSA is also associated with reductions in daytime alertness levels and neurocognitive performance capabilities, including decreased concentration, memory and slower reaction times.

Current tests to measure OSA require patients to spend a night sleeping in a laboratory. This is both labour-intensive and costly. The Group is examining simple and rapid diagnostic devices that might be used in place of the laboratory sleep study. In the coming year, we will also look at how information about symptoms, age, weight, and the results from a simple screening device might be combined to improve diagnosis of sleep apnea.

Neurobiology
Brain function in sleep apnea study
Despite recognition of the neurobehavioural effects associated with OSA, the brain mechanisms underlying these changes are not widely understood. The aim of this study was to investigate the alterations in brain activity that occurred as a result of OSA, and again following commencement of treatment with continuous positive airway pressure (CPAP).

Effects of CPAP withdrawal on neurobehavioural performance and physiology
CPAP is currently the most popular treatment for OSA. Despite the effectiveness of this treatment, patient compliance tends to vary. Patients who regularly use CPAP are often unable to use their machines for periods of time, such as when they travel or have a respiratory infection. Although there is a high incidence of acute CPAP withdrawal in OSA patients, little is known about the physiological and neurobehavioural effects this has on patients. In this study, we investigated the effects of CPAP withdrawal on neurocognitive performance, physiological variables and sleep. Studies over the coming year will investigate the effects of medications in ameliorating the effects of short-term withdrawal from CPAP therapy.

Investigating sleepiness, driving simulator performance and electroencephalography during sleep deprivation
With increased hours of wakefulness, sleepiness increases and performance on a driving simulator deteriorates. The presence of medical disorders such as sleep apnea might further add to this sleepiness. The Group is studying healthy volunteers and people with sleep apnea to examine the effect of sleep deprivation on reaction time and driving simulator performance. Further studies will assess the suitability of the electroencephalogram (EEG) as a measure of sleepiness.

Respiratory Failure
Obesity Hypoventilation
A significant minority of patients with extreme obesity will develop daytime respiratory failure, with a raised awake carbon dioxide and low level of oxygen in their blood. If inadequately treated, these patients will develop life-threatening breathing problems, for which the usual therapy is either CPAP or bilevel therapy. In this study researchers are investigating if clinical outcomes in these patients vary depending on the type of positive pressure device that is initially prescribed. The results of this study should provide clinicians with a basis for deciding what type of positive pressure should be recommended to patients, and if there are any identifiable factors that distinguish those who will respond to CPAP from those who will not.

Altering inspiratory duration and chinstrap use
The group is also looking at altering inspiratory duration and chinstrap use during non-invasive ventilation to determine if these strategies are effective in reducing mouth leak during sleep. Leak out through the mouth can be a major reason for a poor response to treatment, resulting in inadequate gas exchange or poor sleep quality. While both these techniques have been used clinically in an attempt to improve the effectiveness of therapy, neither approach has previously been tested. This randomised trial is designed to evaluate the impact of controlling inspiratory duration with and without the use of a chinstrap on nocturnal gas exchange and sleep quality. This trial should be completed mid 2006.

Efficacy of using non-invasive ventilation during tests of functional capacity in patients with acute and chronic hypercapnic respiratory failure
As part of her PhD work through the University of Sydney, Collette Menadue is heading a study looking into the efficacy of using non-invasive ventilation during tests of functional capacity in patients with acute and chronic hypercapnic respiratory failure. She is also investigating the effect of early rehabilitation on exercise capacity and quality of life in acutely unwell patients admitted to hospital with hypercapnic respiratory failure.

Non-invasive ventilation workshop
The Sleep & Circadian Group was involved in the development and presentation of a two-day non-invasive ventilation workshop, which attracted participants from throughout NSW and interstate. Feedback suggested that this workshop was highly regarded and of great benefit to participants, and likely to become a regular fixture on our education calendar.

Cardio-Metabolic & Endocrine
Vascular Reactivity to Isocapnic Hypoxia
Researchers from the Sleep & Circadian Group have previously observed an acute blood pressure response to intermittent hypoxia in subjects with OSA, that is absent in control subjects. Our studies show that large conduit arterial stiffness falls when control subjects are exposed to sustained isocapnic hypoxia, and that large arteries may play an important role in buffering blood pressure during hypoxic exposure. Subsequent work using the nitric oxide synthase inhibitor L-NMMA suggests that vasodilatation is mediated by an endothelial dependent mechanism. We now intend to establish if this mechanism is compromised in subjects with OSA, and if treatment with CPAP improves vascular reactivity.

Vascular Reactivity to Mental Stress
Abnormal cardiovascular responses to mental stress have been observed in subjects with established cardiovascular disease and evidence now suggests that this may represent an early marker of cardiovascular disease. This work will aim to establish whether blood pressure and arterial stiffness can be increased by mental stress and to what extent these responses are altered by OSA. Preliminary results in control subjects indicate that both blood pressure and arterial stiffness acutely increase in response to mental stress.

OSA and metabolic syndrome
Metabolic (or insulin resistance) syndrome occurs in many patients with OSA and is defined by central obesity, hypertension, glucose intolerance/insulin resistance and dyslipidemia. Many studies now suggest that OSA may exacerbate the metabolic syndrome by promoting insulin resistance. Ongoing studies using magnetic resonance spectroscopy (MRS) look at how OSA may alter lipid metabolism and storage. Our work also aims to establish whether post-prandial lipidemia (PPL) is increased in OSA and whether CPAP improves lipid handling by reducing PPL. These studies will help to assess whether hepatic lipotoxicity is increased in OSA and whether it is reduced following treatment with CPAP.

The influence of the menstrual cycle on breathing during sleep
It is believed that the sex hormones alter the pattern of breathing, and may contribute to a decreased prevalence of sleep apnea in women before menopause. What is not known is how fluctuations in hormones across the menstrual cycle might affect measurement of sleep-disordered breathing. To examine this effect we are undertaking a study in a group of young and healthy women. The results of this project may suggest that sleep studies involving women should be planned so as to consider the effects of the menstrual cycle on breathing.

Circadian & Sleep Physiology
Circadian rhythms are biological rhythms that fluctuate across the 24 hour day and repeat every 24 hours. In humans the biological clock is located in the brain, and coordinates the activities of nearly all our behavioural and physiological processes, including endocrine, thermoregulatory, immune, cardiovascular, respiratory, gastrointestinal, renal, neurobehavioural and sleep-wake activities. Circadian disruption results from misalignment in the timing of circadian rhythms in relation to either the environment or to each other, as experienced by shiftworkers and travellers suffering from jet lag.

The effects of circadian disruption and sleep loss in patients suffering from medical disorders, such as asthma and sleep apnea, have not been widely studied and remain poorly understood. There is also little known about the relative contributions of the circadian and sleep systems on understanding of disease severity and pathways, as well as optimal treatment regimes for these disorders. Our current research work is focused in the following areas:

• understanding the interaction of sleep disturbance due to sleep apnea and asthma with further challenges to the sleep system by chronic sleep restriction and how the effects may differ in healthy, well sleeping individuals
  
• understanding the interaction of sleep disturbance due to sleep apnea and asthma with circadian disruption due to simulated jet lag, and how the effects may differ in healthy, well sleeping individuals
  
• understanding the profile and time course of neurobehavioural changes induced by acute periods of total sleep deprivation in individuals with sleep apnea and healthy, well sleeping individuals

Measures in these studies include assessment of neurocognitive function using a range of computerised performance tests and subjective assessments, sleep physiology, waking EEG, respiratory symptoms and body temperature.

Medical Psychology
This year has seen the formation of Medical Psychology within the Sleep and Circadian Research Group. The main role of this section is to provide psychological services for the whole sleep group but with a focus on the treatment and research of individuals with insomnia. Dr Delwyn Bartlett and Ms Lynne Paisley (clinical psychologist) have now been running educational and cognitive behavioural treatment (CBT) groups for over three years. They have shown that of those individuals who are able to complete the 3-4 CBT sessions they have significantly reduced time for sleep onset, reduced number of wakenings and increased total sleep times. Scores for depression, anxiety and stress have also shown significant reductions. Medical psychology has also been involved in a joint CBT programme with Ms Dianne Richards at Royal North Shore Hospital. The aim of this research study was to improve the knowledge and understanding of individuals with OSA in order to encourage at least a trial of CPAP. Not even starting treatment is a problem and there is often a 50% drop out rate. Further work is planned in this area.

Sleep psychology training is an important component of the section. Dr Brett Toelle and Ms Suyen Moncado have made an invaluable contribution as interns over the last two years, and there are new internships planned for the year ahead.

Also in 2006, Medical Psychology will collaborate with Newcastle University to establish a joint educational intervention programme for individuals with chronic pain and sleep difficulties.

Upper Airway Structure & Function
This new group was established at the end of 2005, following the appointment of Prof Peter Cistulli in the Department of Respiratory Medicine at Royal North Shore Hospital. His group has a long-standing interest in the structure and function of the upper airway in the context of sleep-disordered breathing and the implications for treatment modalities. The current research programme is focused on the use of mandibular advancement devices (oral devices worn during sleep to protrude the lower jaw) to treat OSA, as an alternative to CPAP therapy. Their previous published work has proven that this novel treatment modality is efficacious in a substantial number of patients, but not all. Work completed this year using sophisticated physiological recordings during sleep has identified that primary oropharyngeal (tongue) collapse of the upper airway during sleep is highly predictive of a good response to treatment. The current project, funded by the NHMRC, is aimed at identifying more clinically useful predictors of treatment outcome by undertaking detailed evaluations of upper airway structure (using MRI scans) and function (using resistance and flow-volume measurements) and examining the response of the airway to mandibular advancement.

Preliminary data indicate that while baseline anatomical features do not differ between responders and non-responders, the response to mandibular advancement in quite different. With regard to functional properties of the upper airway during wakefulness, a difference in flow volume loops has been identified, and this may have clinical application in stratifying patients who are more appropriate for treatment with mandibular advancement devices. The group will expand with the addition of two PhD students in 2006, and their work will revolve around complimentary projects examining the diagnostic and therapeutic implications of upper airway structure and function in OSA.

Sleep Clinical Trials
In addition to investigator-initiated research, the Woolcock is engaged in a wide range of research studies or clinical trials for new and more effective ways to treat sleep disorders. The Sleep and Circadian Research Group’s Clinical Trials Unit (CTU) is one of the few facilities of its kind in Australia. It is involved in a number of international, multi-centre clinical trials evaluating potential pharmacological and device-based treatments for sleep disorders including insomnia, restless legs syndrome, obstructive sleep apnea and narcolepsy. The facilities include a fully equipped eight bed sleep laboratory based at a university teaching hospital, where research studies are performed in tandem with hospital -based sleep investigations, and direct access to several other Woolcock affiliated sleep laboratories throughout Sydney for additional Sleep Laboratory investigations or patient visits. The Sleep and Circadian Research Group’s Clinical Trials Unit has a dedicated and experienced clinical trials team, including a Medical Director Sleep Physician, several other experienced Sleep Physicians, a full time senior clinical trials co-ordinator, several research assistants and an administration officer.

Over the past year, we have been involved in a number of trials for large pharmaceutical and device manufacturers. These studies have included the following:

• A trial investigating the effectiveness of a weight loss medication in overweight and obese patients with OSA in promoting weight loss and decreasing OSA severity. This study also examined the effect of weight loss on metabolic, cardiovascular and respiratory function variables in obese severe OSA patients.
  
• Several proof-of-concept clinical trials examining drugs in combination or as mono-therapy as primary treatments for OSA.
  
• Several International, multi-centre clinical trials investigating the effectiveness and safety of novel stimulant treatments in improving sleepiness and daytime function in patients with narcolepsy and residual sleepiness associated with sleep apnea despite using CPAP treatment.