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Sleep and circadian biology

Understanding the links between sleep and brain health

Our sleep and circadian biology team focuses on improving our understanding of how changes to our sleep and body rhythms effect diseases of the brain. We're examining interventions for sleep-wake disturbances to improve brain health.

About our research

Studies have shown that sleep-wake disturbance is associated with brain degeneration in ageing and increased mental health disorders. Importantly, and unlike many risk factors associated with these disorders, sleep-wake disturbance is something that can be controlled, which makes it an important target for therapeutics.

The sleep and circadian biology team bring together expert researchers from across the Woolcock Institute and The University of Sydney to:

  • Determine the unique characteristics of sleep and circadian disturbance that are associated with diseases of the brain and mind including psychiatric disorders, mental health, neurodegenerative disorders such as dementia, epilepsy as well as in acquired brain injury
  • Identify and assess better ways of screening for sleep disorders in patients at risk of diseases of the brain and mind 
  • Develop and assess effective drug and non-drug treatments for sleep disorders and sleep and circadian disturbance
  • Determine the usefulness and functionality of new forms of technology, including wearable devices, for assessment, monitoring and delivery of patient care

Our Current Projects

It is increasingly recognised that various disturbances of the sleep or circadian (sleep-wake) systems are linked to brain degeneration in ageing, with recent research suggesting these relationships are likely to be bidirectional. Sleep-wake disturbance can occur decades before the onset of dementia and appears to play a key role in neuro-vascular dysfunction, and the build-up of alpha-synuclein and beta-amyloid in the brain, key proteins that underpin dementia. In addition, obstructive sleep apnoea leads to sleep fragmentation and hypoxaemia in the brain, with adverse effects on alertness, cognition and daytime functioning.

There is relatively little information available on the mechanisms by which sleep-wake disturbance may exert deleterious effects and how it relates to regional structural or brain network dysfunction. There are few established treatments for sleep-wake disturbances in these groups, and there is a need to increase clinical research capacity in this field.

We bring together a world class cross-disciplinary team of researchers in the fields of ageing, dementia, chronobiology, sleep and neuroimaging. Our

collaboration enables us to examine all major forms of dementia and sleep disorders affecting older people and translate these findings into health practice.

Funding

The CogSleep CRE is funded to the value of $2.5million between 2019 – 2023 as part of the NHMRC’s Centre of Research Excellence Program.

Chief Investigators

Sharon Naismith, Ron Grunstein, Simon Lewis, Craig Phillips, Angela D’Rozario, Camilla Hoyos, Glenda Halliday

 

A major source of sleep disruption in older adults is obstructive sleep apnoea (OSA), a disorder characterised by frequent pauses in breathing due to partial or complete airway closure during sleep. These events result in sleep disturbance and oxygen deprivation, which previous studies have shown to be associated with an increased risk of dementia. Therefore, there is an imperative to establish definitively whether treatment of sleep apnoea can prevent dementia. This multi-site feasibility randomised-controlled trial aims to determine whether it is feasible to deploy a targeted intervention to treat sleep apnoea in participants with subjective memory complaints, and determine the magnitude of effect on memory decline. Participants will be randomised to the intervention or control group for 2 years. Participants in the intervention group will receive treatment for their OSA following an algorithm and incorporating key principles of goal setting and behavioural sleep management. Participants in the control group will have their screening results sent to their referring medical practitioner, with recommendations for further investigation. The primary outcome is the feasibility of the trial.  The stop-go criteria to determine feasibility will depend on meeting the prevalence, acceptability, hypoxic burden and tolerability criteria.

Funding

This four year trial is made possible by $1.5m from the NHMRC-funded Boosting Dementia Research Grant.

Chief Investigators

Sharon Naismith, Ron Grunstein, Camilla Hoyos, Craig Phillips, Nathaniel Marshall

 

High-density encephalography (HdEEG) is an innovative neurotechnology that allows the non-invasive investigation of neural activity of the entire brain over prolonged periods of time such as an overnight sleep period. Our unique facility allows us to better understand the impact of sleep disturbance on brain processes and cognitive functioning. Using this new technology we conduct the highest international standard of sleep-related neuroscience research and significantly expand knowledge in the sleep research and medicine field.

So far we have investigated sleep in older people with mild cognitive impairment as sleep wake disturbance is a risk factor for developing dementia. We are also undertaking a large study in healthy relatives of people with non-Alzheimer’s dementia to identify new biomarkers of dementia.

Our world-class preliminary data has shown for the first-time how the brain recovers during sleep following treatment for obstructive sleep apnea and our next steps are to explore this response in relation to cognitive changes. This is particularly important in light of the growing evidence linking sleep apnea with accelerated cognitive decline as we get older.

We will lead the discovery of new sleep-related biomarkers of dementia risk, and identify novel targets for therapeutics to improve cognition, mood and quality of life.

Collection of HdEEG generates enormous volumes of data collected from the 256 EEG channels during a full night of sleep. For example, there are 3.77 billion data points for one sleep study recording. Specialised computers are required to process this vast amount of data through the use of super computers and data science expertise. With our new super computing power we have been able to cut the processing time down to a third – from 24 hours to 8 hours – improving efficiencies and enabling our capacity to develop new big data analysis approaches, but as this research program grows, our need to increase efficiencies will also be greatly increased.

Our growing Sleep Neurobiology Research Program extends across our collaborative network of researchers from psychology, medicine, nursing, pharmacy, engineering/IT at the University of Sydney, Royal Prince Alfred (RPA) Hospital, NeuRA as well as national (Flinders University, Adelaide; Monash University, Melbourne; University of Sunshine Coast, QLD); and international collaborators (University of California, Irvine; University of Wisconsin, Madison, USA; Inje University, South Korea; University of Surrey, UK).

 

Funding

This program of research is currently being funded from the CogSleep Centre of Research Excellence as well as two NHMRC Project Grants

Chief Investigators

Angela D’Rozario, Ron Grunstein, Sharon Naismith, Tancy Kao Glenda Halliday

 

The research project is testing an adjunct treatment for Major Depressive Disorder.  This adjunct treatment is called Brexpiprazole. Brexpiprazole is an atypical antipsychotic with demonstrated efficacy as an adjunct to antidepressant treatment in Major Depressive Disorder, as evidenced by multiple randomised controlled trials. The exact mechanism of antidepressant action is unknown. This study aims to provide a greater mechanistic understanding of the antidepressant effects of adjunct brexpiprazole in young people with mood syndromes.  More specifically, the primary research question of this study is whether reduction in depressive symptoms following adjunctive brexpiprazole treatment is associated with sleep-wake and circadian rhythm changes.

Funding

This project received an investigator-initiated project grant from Lundbeck.

Chief Investigators

Ian Hickie, Ron Grunstein, Joanne Carpenter, Jacob Crouse

 

A randomised, crossover, placebo-controlled, single-dose study design will be used to test the safety and efficacy of an oral oil solution (‘ETC120’) containing 10 mg Δ9-tetrahydrocannabinol (THC) and 200 mg cannabidiol (CBD) in 20 participants diagnosed with chronic insomnia disorder. Participants aged 25–65 years will be recruited over an 18-month period commencing August 2019. Each participant will receive both the active drug and matched placebo, in a counterbalanced order, during two overnight study assessment visits, with at least a 1-week washout period between each visit. The primary outcomes are total sleep time and wake after sleep onset assessed via

polysomnography. In addition, 256-channel high-density EEG and source modelling using structural brain MRI will be used to comprehensively examine brain activation during sleep and wake periods on ETC120 versus placebo. Next-day cognitive function, alertness and simulated driving performance will also be investigated.

Funding: The Lambert Initiative for Cannabinoid Therapeutics at The University of Sydney, a philanthropically funded research organisation

Co-Chief Investigators: Prof Ronald R Grunstein and Dr Camilla M Hoyos 

Key publications

Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking.

This study demonstrates that prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in Parkinson's disease (PD). 

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Although motor abnormalities have been flagged as potentially the most sensitive and specific clinical features for predicting the future progression to Parkinson's disease, little work has been done to characterize gait and balance impairments in idiopathic rapid eye movement sleep behavior disorder (iRBD).

The objective of this study was to quantitatively determine any static balance as well as gait impairments across the 5 independent domains of gait in polysomnography-confirmed iRBD patients using normal, fast-paced, and dual-task walking conditions.

This study demonstrates that iRBD patients have subtle gait impairments, which likely reflect early progressive degeneration in brainstem regions that regulate both REM sleep and gait coordination. Such gait assessments may be useful as a diagnostic preclinical screening tool for future fulminant gait abnormalities for trials of disease-preventive agents.

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Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD

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This study aimed to investigate associations between obstructive sleep apnoea (OSA) and cortical thickness in older adults with subjective and objective cognitive difficulties, who are considered "at-risk" for dementia.83 middle-aged to older adults (51-88 years) underwent neuropsychological testing, polysomnography assessment of OSA and a structural magnetic resonance imaging brain scan.

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Sleep disordered breathing (SDB) is common in older adults and is strongly associated with cognitive decline, with increasing evidence suggesting that it may represent a risk factor for dementia. Given that SDB is characterized by intermittent episodes of hypoxemia during sleep, it is possible that cognitive impairment may relate to cerebral oxidative stress. This study aimed to examine the relationship between nocturnal markers of hypoxemia and proton magnetic resonance spectroscopy ((1)H-MRS) markers of oxidative stress within the anterior cingulate cortex (ACC) of the brain.

Markers of nocturnal hypoxemia and SDB are associated with cerebral oxidative stress in older people at-risk for dementia, suggesting a potential mechanism by which SDB may contribute to brain degeneration, cognitive decline, and dementia. Further work focused on utilizing this biomarker for the early identification and treatment of this possible modifiable risk factor in older persons is now warranted.

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The present study investigated Default Mode Network (DMN) functional connectivity in subjects with a lifetime history of major depression, comparing those with and without current sleep disturbance. Controls were included to assess DMN abnormalities specific to depression.

Current sleep disturbance together with depression is associated with distinct abnormalities in DMN functioning incorporating regions responsible for self-reflection and declarative memory processes. Impaired sleep is associated with increased connectivity between these regions. Future studies may augment these findings with complementary imaging techniques including cortical thickness and diffusion tensor imaging, as well as high density electroencephalogram recording.

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Patients with obstructive sleep apnea (OSA) unable to tolerate standard treatments have few alternatives. They may benefit from weight loss, but the major symptom of daytime performance impairment may remain during weight loss programs.

Armodafinil did not improve driving task performance at the primary endpoint of 6 months. Armodafinil might be a useful adjunctive to weight loss in patients with OSA rejecting conventional treatments but this needs to be directly tested in a specifically designed, properly powered clinical trial. Clinical trial registered with Australian and New Zealand Clinical Trials Registry (ACTRN 12611000847910).

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This is the first systematic review and meta-analysis comparing objectively-measured sleep in people with mild cognitive impairment to age-matched controls.

This paper showed that there are significant alterations in the architecture of sleep in people with mild cognitive impairment and that these changes are exacerbated beyond what is seen in healthy ageing.

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Digital cognitive behavioral therapy (dCBT) is a scalable and effective intervention for treating insomnia. Most people with insomnia, however, seek help because of the daytime consequences of poor sleep, which adversely affects quality of life.

Use of dCBT is effective in improving functional health, psychological well-being, and sleep-related quality of life in people reporting insomnia symptoms. A reduction in insomnia symptoms mediates these improvements. These results confirm that dCBT improves both daytime and nighttime aspects of insomnia, strengthening existing recommendations of CBT as the treatment of choice for insomnia.

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To empirically derive and evaluate potential clusters of Insomnia Disorder through cluster analysis from polysomnography (PSG). We hypothesized that clusters would differ on neurocognitive performance, sleep-onset measures of quantitative (q)-EEG and heart rate variability (HRV).

Two insomnia clusters derived from cluster analysis differ in sleep onset HRV. Preliminary data suggest evidence for three clusters in insomnia with differences for sustained attention and sleep-onset q-EEG.

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Connection between sleep and dementia

Our team

  • Dr Catriona Ireland
  • Dr Henry Ainge Allen
  • Clinical Research Manager, Dr Julia Chapman - julia.chapman@sydney.edu.au
  • Kathleen Franklin - kathleen.franklin@sydney.edu.au
  • Jun Teh
  • Dr Keith Johnson
  • Aaron Lam
  • Anastasia Suraev
  • Carla Haroutonian
  • Dexiao (Shawn) Kong
  • Johannes Michaelian
  • Jonathon Pye
  • Melissa Aji
  • Yun Hwang
  • Zoe Menczel Schrire
  • Bradley Skinner
  • Andrea Ricciardello
  • Madelaine Pankhurst
  • Teha Pun
  • Jake Palmer

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