Investigating the neurophysiological basis of sleep quality
Lead Research Organisation:
University of Oxford
Department Name: Physiology Anatomy and Genetics
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
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.
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.
Organisations
Publications
Ang G
(2021)
Deletion of AMPA receptor GluA1 subunit gene (Gria1) causes circadian rhythm disruption and aberrant responses to environmental cues.
in Translational psychiatry
Ang G
(2018)
Absent sleep EEG spindle activity in GluA1 (Gria1) knockout mice: relevance to neuropsychiatric disorders
in Translational Psychiatry
Ang Gauri
(2021)
Deletion of AMPA receptor GluA1 subunit gene (
Gria1) causes circadian rhythm disruption and aberrant responses to environmental cues
in TRANSLATIONAL PSYCHIATRY
Bocchio M
(2016)
Sleep and Serotonin Modulate Paracapsular Nitric Oxide Synthase Expressing Neurons of the Amygdala.
in eNeuro
Cui N
(2014)
Long-term history and immediate preceding state affect EEG slow wave characteristics at NREM sleep onset in C57BL/6 mice.
in Archives italiennes de biologie
Fisher SP
(2016)
Stereotypic wheel running decreases cortical activity in mice.
in Nature communications
Fisher SP
(2014)
Local sleep taking care of high-maintenance cortical circuits under sleep restriction.
in Sleep
Guillaumin MCC
(2018)
Cortical region-specific sleep homeostasis in mice: effects of time of day and waking experience.
in Sleep
Hasan S
(2021)
Modulation of recognition memory performance by light and its relationship with cortical EEG theta and gamma activities.
in Biochemical pharmacology
McKillop LE
(2018)
Effects of Aging on Cortical Neural Dynamics and Local Sleep Homeostasis in Mice.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
McKillop LE
(2020)
Sleep and ageing: from human studies to rodent models.
in Current opinion in physiology
McKillop LE
(2021)
Diazepam effects on local cortical neural activity during sleep in mice.
in Biochemical pharmacology
Meisel C
(2017)
The Interplay between Long- and Short-Range Temporal Correlations Shapes Cortex Dynamics across Vigilance States.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Milinski L
(2021)
Waking experience modulates sleep need in mice.
in BMC biology
Northeast RC
(2019)
Sleep homeostasis during daytime food entrainment in mice.
in Sleep
Thomas C
(2022)
Psilocin acutely alters sleep-wake architecture and cortical brain activity in laboratory mice
in Translational Psychiatry
Thomas CW
(2020)
Global sleep homeostasis reflects temporally and spatially integrated local cortical neuronal activity.
in eLife
Thomas, Christopher W
(2020)
Global sleep homeostasis reflects temporally and spatially integrated local cortical neuronal activity
Vyazovskiy VV
(2014)
The dynamics of cortical neuronal activity in the first minutes after spontaneous awakening in rats and mice.
in Sleep
Vyazovskiy VV
(2017)
Sleep homeostasis, habits and habituation.
in Current opinion in neurobiology
Yamagata T
(2021)
The hypothalamic link between arousal and sleep homeostasis in mice
in Proceedings of the National Academy of Sciences
Title | An arts and science collaboration with a visual artist and neuroscientist. |
Description | Evocative visual expression of neural activity recorded in a dreaming mouse, rendered in real-time, using a 3D game engine. |
Type Of Art | Film/Video/Animation |
Year Produced | 2015 |
Impact | presented at several art exhibitions |
URL | https://vimeo.com/130114366 |
Description | Contributed a research spotlight to The Physiological Society's report Growing Older, Better: Physiology's role in meeting the Government's healthy ageing mission |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Impact | I contributed a 'research spotlight' article to The Physiological Society's report Growing Older, Better: Physiology's role in meeting the Government's healthy ageing mission. This was a report put forward to the UK government to highlight the importance of understanding Physiology in improving the quality of life in later years - the so called healthspan. The Government has included healthy ageing as a key factor in their 'Government Industrial Strategy' but this report aims to highlight the important role of physiology in addressing this. The piece I wrote focused on the research I carried out during my PhD, investigating the association between sleep and ageing. |
URL | https://www.physoc.org/policy/healthyageing/ |
Description | Ariadna |
Amount | € 25,000 (EUR) |
Organisation | European Space Agency |
Sector | Public |
Country | France |
Start | 05/2015 |
End | 06/2016 |
Description | Fasting-induced torpor in mice: effects on sleep and behaviour |
Amount | £90,000 (GBP) |
Funding ID | NC/S001689/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 10/2019 |
End | 09/2022 |
Description | John Fell OUP Research Fund |
Amount | £98,700 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2014 |
End | 12/2015 |
Description | Local sleep homeostasis and single cell rest |
Amount | £945,072 (GBP) |
Funding ID | MR/S01134X/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 08/2024 |
Description | Measuring metabolic rates in freely behaving laboratory rodents |
Amount | £58,130 (GBP) |
Funding ID | 0007851 |
Organisation | University of Oxford |
Department | John Fell Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2021 |
Description | Oxford McGill ZNZ Partnership in the Neurosciences pilot grant |
Amount | £8,205 (GBP) |
Organisation | University of Oxford |
Department | Oxford McGill ZNZ Partnership in the Neurosciences |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2014 |
End | 10/2015 |
Description | Article for The Conversation |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I wrote an article entitled 'Can humans hibernate?' for The Conversation. In this article I discussed state of the art of the research on sleep and hibernation, and the relevance of human hibernation for space travel. It was read by >33,000 readers. |
Year(s) Of Engagement Activity | 2016 |
URL | https://theconversation.com/could-humans-hibernate-54519 |
Description | Article for The Conversation: 'Why running could keep you awake at night' |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I wrote an article 'Why running could keep you awake at night' where I discussed our recent findings published in Nature Communications. In this article we found unexpected suppression of brain activity during intense running. |
Year(s) Of Engagement Activity | 2016 |
URL | https://theconversation.com/why-running-could-keep-you-awake-at-night-69320 |
Description | Article in the Phenotype magazine |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | We published an article entitled "Unravelling the complexity of sleep" in the Phenotype magazine. This article was read by a student Josephine Bates from the Henrietta Barnett School, London, who subsequently contacted me and came for a one week work experience in our group in the summer 2016. |
Year(s) Of Engagement Activity | 2016 |
URL | http://oxphenotype.wix.com/oxphenotype15 |
Description | interview for The John Batchelor show |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I was interviewed by The John Batchelor show on the topic of sleep, based on the editorial I wrote for Science magazine |
Year(s) Of Engagement Activity | 2016 |
URL | https://audioboom.com/search?utf8=%E2%9C%93&q=vyazovskiy |
Description | presentation at Oxford Brain Day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The thirteenth Oxford Brain Days was devoted to the sleeping brain. The expert speakers were all members of the Oxford-based Sleep and Circadian Neuroscience Institute. They covered topics ranging from basic sleep science to the management of sleep disorders. The event was aimed at the general public and was open to all. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.conted.ox.ac.uk/F900-35 |