Investigating the neurophysiological basis of sleep quality

We spend about one third of our life asleep, yet we still do not know why sleep is necessary. The importance of sleep becomes especially apparent in primary sleep disorders such as insomnia, as well as in many other diseases associated with poor sleep. When we do not get sufficient sleep our mood worsens, we make more errors, we have a hard time focusing our attention and make poor judgments. Moreover, poor sleep is often a root cause of major accidents such as Chernobyl, Clapham Junction rail crash, the Challenger, Exxon Valdez oil spill and other tragedies, where sleep loss affected misjudgements probably happened. The UK Health and Safety Executive (HSE) makes the point that fatigue can lead to errors and accidents, ill-health and injury, and reduced productivity and has also been implicated in 20% of accidents on major UK roads and is said to cost the UK £115 - £240 million per year in terms of work accidents alone.

If we go to the doctor with a complaint about sleep problems or associated cognitive deficits while we are awake, we are usually asked to convey our subjective account in some form of an "analogue" scale that may result in an inaccurate assessment. Indeed, while "sleep quality" is a concept widely used in clinical practice, it is defined only vaguely and often only in qualitative terms. Existing quantitative measures of sleep quality, such as a total duration of sleep, measured with polysomnography, while useful in some cases, may often appear not adequate as there is a large variation of sleep parameters from patient to patient and these measures do not correlate well with the patient's experience. Inaccurate assessment of sleep quality may lead to errors in diagnostics, and inadequate or inefficient treatment.

The aim of the current project is to provide an in-depth investigation of the factors that determine sleep quality, focusing for the first time on the electrical activity of many individual cells in the brain. The research strategy we intend to adopt for the current project is based on the recently established concept of "local sleep", according to which some parts of the brain can be "asleep" while other are "awake" at the same time. This pattern of activity may be very useful, because it would allow some parts of the brain to take rest while others continue to work, but in some cases it may be very disruptive for brain function. For example, under certain conditions, some areas of our brain may be unable to "fall asleep" and remain in a "local wakefulness" state, resulting in us experiencing a very bad nights sleep even though from a behavioural perspective or when the brain waves are measured at the level of the scalp, it seems as if we have been asleep all night. The inability to obtain restorative sleep during the night, may, in turn, lead to an intrusion of brief episodes of "local sleep" during the day, resulting in overall poor wake quality, as manifested in attention lapses and many other cognitive deficits.

Therefore our hypothesis is that sleep quality, both in terms of how refreshed we feel in the morning and how well we perform during the day, depends precisely on how much local sleep and local wake occurred in our brain during the night. Testing this hypothesis will be crucial for improving the recognition and treatment of sleep disorders of various origins.

Sleep disorders present a considerable burden on public health and the economy. Diagnostics and treatment of sleep disorders are often based on the assessment of "sleep quality", but, despite its high clinical relevance, this concept has not been rigorously defined. The subjective experience of having poor sleep correlates weakly with objective measures, such as sleep duration, latency or efficiency, which vary between patients, and depend on such factors as age, sex, ethnicity or co-morbidities.

In order to establish objective markers of sleep quality, we will make use of the recent concept that sleep and waking are not global all-or-none phenomena, but have a local aspect, which is not well represented in the scalp EEG. Specifically, it was found that the main defining characteristic of non-rapid eye movement sleep - EEG slow waves and the underlying active (ON) and inactive (OFF) neuronal states often occur locally, and their incidence is determined by preceding sleep-wake history.

We will record cortical neuronal activity in freely-behaving mice during spontaneous and experimentally disrupted (by pharmacological agents, local cortical microstimulation or by the delivery of auditory tones) sleep, and test the animals in a visual discrimination task during subsequent waking. First, we will test the hypothesis that sleep quality, as measured by cognitive performance during subsequent waking, is defined by the proportion of local and global neuronal OFF periods. We suggest that sleep of poor quality corresponds to a state with mostly localised asynchronous patterns of neuronal firing. Second, we will address whether isolated neuronal OFF-periods during waking are directly responsible for poor waking quality, as defined by reduced cognitive performance. Finally, we will test whether waking and sleep quality are interrelated, as manifested in a compensatory increase in "local sleep" during waking after disrupted or insufficient sleep.

This research is of strategic relevance in terms of the extent to which the proposal meets the priorities identified by the MRC Neurosciences and Mental Health Board, as the project proposes research relevant for diagnostics and the treatment of primary and secondary sleep disorders, and will have a potentially high impact for other brain disorders, associated with disturbed sleep and altered cognitive function.

The impact of this project is summarized below in reference to human health, society and the economy.

1. Human Health. This project may lead to the development of novel diagnostic markers. Poor sleep quality during the night and hypersomnolence during the day are typical for many primary and secondary sleep disorders. Several objective markers for sleep disorders have been already established, such as the levels of hypocretin-1 (orexin A) in the cerebrospinal fluid to diagnose narcolepsy-cataplexy (Mignot et al., Archives of Neurology, 2002). However, for many primary and secondary sleep disorders objective markers are not available, and diagnosis is often based on vaguely defined "sleep quality". Currently, it is often assessed based on subjective measures, such as Pittsburgh Sleep Quality Index (Buysse et al., Psychiatry Research, 1989). Existing objective measures, such as based on wrist actigraphy or polysomnography, may be useful in some cases, but provide only gross measures of sleep duration, and correlate poorly with subjective assessment of sleep quality. Establishing a quantitative index of sleep quality, derived from measures of local and global cortical dynamics, has the potential to aid diagnosis, provide a more meaningful assessment of treatment, and provide a better understanding of sleep disorders and the pathophysiological processes underlying them. Establishing a novel conceptual framework for defining sleep quality and introducing a novel mouse model will also facilitate high-throughput drug candidate screening and the development of non-pharmacological interventions.

2. Societal impact. Poor sleep is among the most prevalent complaints observed in many epidemiological studies, and the second most common overall complaint reported in primary care settings after pain. A recent survey revealed that in the English general population, insomnia prevalence and hypnotics use showed a steady increase over a 15-year period (Calem et al., 2012). Sleep problems bring significant challenges to society, including in such key areas as social care, workforce and transport. Establishing better diagnostic markers for the treatment of sleep disorders will decrease the risks associated with inadequate use of pharmacological agents and reduce dangers of side-effects.

3. Economic impact. According to UK Health and Safety Executive (HSE), fatigue can lead to errors and accidents, ill-health and injury, and reduced productivity and has also been implicated in 20% of accidents on major UK roads, and is said to cost the UK £115-£240 million per year in terms of work accidents alone. The proposed research has a high potential to provide a needed stimulus for the pharmaceutical industry to invest more in sleep therapeutics and clinical trials. Thus, this project will have an impact on the pharmaceutical industry and thereby on the economy. Moreover, improved diagnostics of sleep disorders will reduce the costs associated with out-patient visits to the clinics and thereby decrease burden on tax-payers.

Calem, M., Bisla, J., Begum, A., Dewey, M., Bebbington, P.E., Brugha, T., Cooper, C., Jenkins, R., Lindesay, J., McManus, S., et al. (2012). Increased prevalence of insomnia and changes in hypnotics use in England over 15 years: analysis of the 1993, 2000, and 2007 National Psychiatric Morbidity Surveys. Sleep 35, 377-384.