The Sleep and Brain Health Laboratory

at Sunnybrook Health Sciences Centre and the University of Toronto


Andrew Lim, MD - Principal Investigator

Goals

The Sunnybrook Sleep and Brain Health Laboratory is dedicated to unraveling the biological links between sleep and circadian rhythms and neurological diseases in older adults.

We will lay the foundation for 1) sleep-based interventions to prevent neurological diseases, slow progression, and promote recovery, and 2) mechnistically-informed therapies to improve sleep in older adults with neurological diseases

Tools

To achieve these aims we use WEARABLE SENSORS to measure sleep and circadian physiology in 100’s to 1000’s of older adults, with or without sleep and circadian interventions, and relate this to MOLECULAR, HISTOLOGICAL, and IMAGING markers of human brain biology, and to FUNCTIONAL and CLINICAL outcomes including cognition, motor function, and neurological diseases.

Selected Projects

Sleep Apnea as a Cause/Consequence of Dementia

Sleep apnea – the intermittent cessation of breathing in sleep – is common in older adults, particularly in adults with dementia. On the one hand, sleep apnea may contribute to dementia-related brain changes. On the other hand, dementia-related damage to brainstem circuits mediating upper airway and breathing control may predispose to sleep apnea. To disentangle these relationships, we are obtaining detailed measurements of sleep apnea physiology with new wearable sensors, and relating this to imaging and histopathological markers of dementia-related brain changes in mid-life (Ontario Sleep Health Study, n=3200) and late life (Memory and Aging Project, in collaboration with Drs. A. Buchman and D. Bennett at Rush University, n=1000). In the latter we are also relating specific dimensions of sleep apnea physiology (airway obstruction, respiratory drive, arousability) to neuropathology in the circuits hypothesized to subserve them (in collaboration with Dr. V. Vanderhorst at Harvard Medical School). Finally, we are examining how treatment of sleep apnea with continuous positive airway pressure (CPAP) impacts dementia-associated structural and functional imaging changes (in collaboration with Dr. J. Wardlaw, University of Edinburgh).

Non-Neuronal Correlates of Sleep Disruption in Older Adults

A growing body of evidence suggests that non-neuronal cell types (microglia, astrocytes, endothelial cells, pericytes, oligodendrocytes) may play important roles in dementia pathogenesis, and in model organisms, sleep disruption can have dramatic effects on the biology of these cells. Here, we are relating existing and new measurements of sleep physiology in the Rush Memory and Aging Project to bulk (n=400) and single-nucleus human brain RNA-seq to delineate the cellular correlates of various forms of sleep disruption in older adults.

Sleep and Dementia – Chicken and Egg?

Sleep disruption and dementia go hand-in-hand and sleep disruption can precede the onset of clinical cognitive impairment by years. However, is sleep disruption a preclinical marker of dementia-related brain changes, or a contributor to these changes? Observational studies are fundamentally limited in their capacity for causal inference. However, genetic approaches, such as Mendelian randomization (MR), can provide some clues. We are applying MR-based approaches to existing and newly generated sleep physiology, imaging, and genome-wide genotype data in our Ontario Sleep Health Study, the Memory and Aging Project, and other cohorts to shed light on the causal direction of the relationships between various dimensions of sleep and circadian disruption, and dementia-related brain changes.

Bidirectional Interactions between Sleep and Alzheimer’s Disease: Functional Dissection of the Brain Transcriptome in Humans and Drosophila

Sleep disruption affects millions of older Americans and is associated with an increased risk of Alzheimer’s disease (AD); moreover adults with AD have increased sleep disruption. Using an innovative cross-species, human and fly translational approach, and in collaboration with Dr. J. Shulman (Baylor) and Dr. P. Shaw (Washington University) we are identifyng novel gene targets underlying the bi-directional relationship between AD and sleep disruption. We are collecting new human lateral orbitofrontal cortex RNA sequencing data from 500 well-characterized older decedents from the Rush Memory and Aging Project, integrating this with available proteomic data, and relating this to actigraphic sleep metrics, cognitive testing, and post-mortem indices of Aß and Tau pathology to identify candidate brain- expressed genes underlying the bi-directional links between sleep fragmentation, AD pathology and cognition. To move beyond descriptive associations, we are using Drosophila genetics to validate causal roles for these genes in A-beta/Tau-induced neurodegeneration, cognitive plasticity, and sleep. Finally, leveraging available genomic data, we are confirming these causal relationships, observed in Drosophila, in humans using Mendelian randomization.

New Wearable Sensors for Sleep Measurement

Accurate measurement of sleep is of critical importance in promoting sleep health, and for studying the relationship between sleep and dementia in aging. It is notoriously difficult to accurately reflect on one’s own sleep because by definition one is unconscious when sleep is occurring. Hence, both over- and under-estimation of sleep are common, and is unawareness of sleep abnormalities. To overcome this, objective sensors are needed. In-lab polysomnography or sleep studies remain the primary clinical tool to diagnose sleep disorders in research and clinical settings. However, polysomnography is difficult for many older adults to tolerate, requires specialized technologists to obtain and analyse the recordings, is labour intensive and expensive. Meanwhile, clinically-used home sleep devices lack crucial sensors (e.g. to accurately measure sleep stages), remain uncomfortable (e.g. requiring breathing sensors on the face) or both, while still being too expensive to deploy at scale. In this project, we are using machine learning and other approaches to develop analytical tools for new low-profile wearable EEG, ECG, accelerometery, and photoplethysmography sensors, comparing these against gold standard in-lab polysomnography, and then deploying them at scale in multiple cohorts (Memory and Aging Project, CAN-Thumbs-Up, COMPASS-ND) to investigate the extent to which the derived metrics are predictive of dementia outcomes.

Current Members

Andrew Lim

Principal Investigator

Andrew Centen

Research Coordinator

Rosa Sommer

PhD Student

Rebecca Wu

MSc Student (Completed 2021)

Mahnoor Hamid

MSc Student

Fardin Islam

BSc Student

Neuroscience

Henson Chen

BSc Student

Computer Science

Lokeesan Kaneshwaran

BASc Student

Engineering

Nasim Montazeri

Postdoctoral Fellow
Biomedical Engineering

Join Us!

Postdoctoral Fellow in Integrative Genomics and Transcriptomics of Sleep and Dementia

We are seeking an exceptional postdoctoral fellow to join the Sleep and Brain Health Laboratory to deliver a high-quality research program combining high dimensional human brain transcriptomic and genomic data with new ambulatory sensor-based measures of human physiology to investigate the impact of sleep and circadian disruption on Alzheimer’s disease and related dementias.

The fellow will play a primary role in two NIH and CIHR-funded projects. The fellow be responsible for analyzing existing (n=1080) and to-be-generated (n=500) human brain bulk RNA-seq and single nucleus RNA-seq data from older adults, and relating this to measures of circadian rhythmicity and sleep derived from ambulatory sensor data to identify genetic and cellular correlates of sleep and circadian rhythm disruption, and their relationship to dementia. The fellow will also analyze existing genomic data from >1000 older adults, and newly generated genomic data from >3000 middle-aged Ontarians with brain imaging and ambulatory sensor-based measures of sleep physiology, and use Mendelian randomization approaches to combine this with existing GWAS and eQTL data to infer causal links between sleep and circadian rhythm disruption and dementia-associated brain changes. There will be opportunities for multiple publications at the interface of sleep, circadian rhythms, genomics/transcriptomics, and dementia. Applicants with expertise in genomics, bioinformatics, informatics, statistics, mathematics, computer science, or computational biology are particularly welcome. More  details can be found here
Postdoctoral Fellow in Machine Learning and Wearables for the Measurement of Human Sleep

For a position to be co-supervised by Dr. Andrew Lim (Neurology) and Dr. Maged Goubran (Medical Biophysics), we are seeking an exceptional postdoctoral fellow to join the Sleep and Brain Health Laboratory to lead development of novel, automated, scalable approaches to the quantification of sleep physiology and identification of sleep disorders from human wearable sensor data in support of several large CIHR and NIH-funded clinical studies of sleep and dementia.

The fellow will apply contemporary machine/deep learning approaches to address problems in the classification of sleep physiology and the identification of sleep disorders using novel human flexible wearable sensors. (electroencephalography, electrocardiography, accelerometry, photoplethysmography). The fellow will leverage several already-collected lab-based datasets including >3000 nights of gold-standard polysomnography, and >70 nights (200 nights by the middle of 2022) of co-captured wearable sensor + polysomnography data. The resulting analytic approaches will then be applied to several ongoing NIH and CIHR funded cohort studies of older adults (n>1000) to determine if sleep characteristics identified using these approaches can predict dementia outcomes and dementia-related brain changes. In addition to data analysis and algorithm development, the fellow will also be involved in guiding students and staff involved in data collection. More details can be found here.
Postdoctoral Fellow in Advanced Computational Neuroimaging Analysis

For a position to be co-supervised by Dr. Andrew Lim (Neurology) and Dr. Maged Goubran (Medical Biophysics), we are seeking a postdoctoral fellow to lead development of novel, automated, scalable approaches to the analysis of large brain MR imaging datasets in support of a new CIHR-funded project integrating already-collected advanced MR imaging in >3000 adult Ontarians with whole genome genotyping and detailed measurements of sleep physiology to unravel the effects of sleep and circadian rhythm disruption on the human brain and on dementia.

The fellow will apply contemporary machine/deep learning and computational neuroimaging approaches to image segmentation, registration and other problems in the analysis of structural and functional MR data, and will work with others in the laboratory to relate these to genetics, sleep physiology, and cognitive outcomes. The fellow will be interested in developing research questions and optimizing analysis streams tailored to the study aims. New approaches and ideas are encouraged, as are independent projects that dovetail with current studies. More details can be found here.
Graduate and Medical Students

We are currently looking for MSc and MD-GDipHR students. Interested students can apply through the Institute of Medical Science (for MSc students) and GDipHR website (MD students) and also contact Dr. Lim directly (andrew.lim@utoronto.ca). For a list of example projects see here. Applicants should have some programming background. Experience with human genomics, human cardiopulmonary or neuro-physiology, and human neuroimaging are a plus. Dr. Lim is an Associate Professor in the Department of Medicine and an Associate Member in the Institute of Medical Science at the University of Toronto.

Undergraduate Students

We are looking for undergraduate students with 1) a computer science or engineering backgrounds and interest in developing tools for the analysis of human physiological data and 2) a background in human cardiopulmonary and neurophysiology for both paid (through the University of Toronto co-op program) or unpaid (for course credit, or as a volunteer) positions. Students interested in paid positions should apply through the University of Toronto co-op program. Students interested in unpaid positions should email Dr. Lim direct (andrew.lim@utoronto.ca) with a transcript, a few sentences outlining their interest, and a list of relevant coursework.

Publications

2021

 

MRI-visible perivascular space volumes, sleep duration and daytime dysfunction in adults with cerebrovascular disease.

Ramirez J, Holmes MF, Berezuk C, Kwan D, Tan B, Beaton D, Scott CJM, Ozzoude M, Gao F, Yu D, Swardfager W, Lawrence-Dewar J, Dowlatshahi D, Saposnik G, Boulos MI, Murray BJ, Symons S, Bartha R, Black SE, Swartz RH, Lim A.

Sleep Medicine

 

Disrupted Rest-Activity Rhythms and Cerebral Small Vessel Disease Pathology in Older Adults. 

Sommer R, Yu L, Schneider JA, Bennett DA, Buchman AS, Lim ASP.

Stroke

 

Feasibility of unattended home sleep apnea testing in a cognitively impaired clinic population. 

Colelli DR, Black SE, Masellis M, Lam B, Lim ASP, Boulos MI.

Journal of Clinical Sleep Medicine

 

Sleep Fragmentation and Cognitive Trajectories After Critical Illness. 

Wilcox ME, McAndrews MP, Van J, Jackson JC, Pinto R, Black SE, Lim AS, Friedrich JO, Rubenfeld GD.

Chest

 

 

2020

 

Circadian disturbances in Alzheimer’s disease progression: a prospective observational cohort study of community-based older adults. 

Li P, Gao L, Gaba A, Yu L, Cui L, Fan W, Lim ASP, Bennett DA, Buchman AS, Hu K.

Lancet Healthy Longevity

 

CCCDTD5: Reducing the risk of later-life dementia. Evidence informing the Fifth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD-5). 

Rockwood K, Andrew MK, Aubertin-Leheudre M, Belleville S, Bherer L, Bowles SK, Kehler DS, Lim A, Middleton L, Phillips N, Wallace LMK.

Alzheimers and Dementia

 

CCCDTD5 recommendations on early non cognitive markers of dementia: A Canadian consensus. 

Montero-Odasso M, Pieruccini-Faria F, Ismail Z, Li K, Lim A, Phillips N, Kamkar N, Sarquis-Adamson Y, Speechley M, Theou O, Verghese J, Wallace L, Camicioli R.

Alzheimers and Dementia

 

Fragmentation of Rest/Activity Patterns in Community-Based Elderly Individuals Predicts Incident Heart Failure. 

Gao L, Lim ASP, Wong PM, Gaba A, Cui L, Yu L, Buchman AS, Bennett DA, Hu K, Li P.

Nature and Science of Sleep

 

2019

 

Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer’s dementia. 

Kaneshwaran K, Olah M, Tasaki S, Yu L, Bradshaw EM, Schneider JA, Buchman AS, Bennett DA, De Jager PL, Lim ASP.

Science Advances




 

Actigraphic measures of sleep on the wards after ICU discharge.

Wilcox ME, Rubenfeld GD, Walczak KD, Black SE, McAndrews MP, Lim AS

Journal of Critical Care

 

More random motor activity fluctuations predict incident frailty, disability, and mortality. 

Li P, Lim ASP, Gao L, Hu C, Yu L, Bennett DA, Buchman AS, Hu K.

Science Translational Medicine 

 

Smartphone EEG and remote online interpretation for children with epilepsy in the Republic of Guinea: Quality, characteristics, and practice implications. 

Williams JA, Cisse FA, Schaekermann M, Sakadi F, Tassiou NR, Hotan GC, Bah AK, Hamani ABD, Lim A, Leung ECW, Fantaneanu TA, Milligan TA, Khatri V, Hoch DB, Vyas MV, Lam AD, Cohen JM, Vogel AC, Law E, Mateen FJ.

Seizure

 

Physical activity, common brain pathologies, and cognition in community-dwelling older adults. Buchman AS, Yu L, Wilson RS, Lim A, Dawe RJ, Gaiteri C, Leurgans SE, Schneider JA, Bennett DA. 

Neurology

 

 

2018

 

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts.   

Lim ASP, Gaiteri C, Yu L, Sohail S, Swardfager W, Tasaki S, Schneider JA, Paquet C, Stuss DT, Masellis M, Black SE, Hugon J, Buchman AS, Barnes LL, Bennett DA, De Jager PL.

PLoS Medicine

 

Fractal regulation and incident Alzheimer’s disease in elderly individuals.

Li P, Yu L, Lim ASP, Buchman AS, Scheer FAJL, Shea SA, Schneider JA, Bennett DA, Hu K. 

Alzheimers and Dementia

 

Evaluating the effects of general anesthesia on sleep in children undergoing elective surgery: an observational case-control study. Selvadurai S, Maynes JT, McDonnell C, Cushing SL, Propst EJ, Lorenzo A, Lim A, Meltzer LJ, Lu Z, Horner RL, Narang I.

Sleep

 

Sleep on the ward in intensive care unit survivors: a case series of polysomnography.

Wilcox ME, Lim AS, Pinto R, Black SE, McAndrews MP, Rubenfeld GD. 

Internal Medicine Journal



 

Brain pathology is related to total daily physical activity in older adults.

Buchman AS, Dawe RJ, Yu L, Lim A, Wilson RS, Schneider JA, Bennett DA.

Neurology



 

Association Between Quantitative Gait and Balance Measures and Total Daily Physical Activity in Community-Dwelling Older Adults. 

Dawe RJ, Leurgans SE, Yang J, Bennett JM, Hausdorff JM, Lim AS, Gaiteri C, Bennett DA, Buchman AS

J Gerontol A Biol Sci Med Sci



 

Actigraphy Detects Greater Intra-Individual Variability During Gait in Non-Manifesting LRRK2 Mutation Carriers.

van den Heuvel L, Lim AS, Visanji NP, Huang J, Ghate T, Mestre TA, AlDakheel A, Connolly BS, Gasca-Salas C, Kern DS, Jain J, Slow EJ, Pondal M, Faust-Socher A, Rogaeva E, Tomlinson G, Lang AE, Marras C. 

Journal of Parkinsons Disease

 

 

2017

 

Sleep fragmentation and Parkinson’s disease pathology in older adults without Parkinson’s disease.

Sohail S, Yu L, Schneider JA, Bennett DA, Buchman AS, Lim ASP

Movement Disorders

 

Restless legs syndrome after high-risk TIA and minor stroke: association with reduced quality of life. 

Boulos MI, Wan A, Black SE, Lim AS, Swartz RH, Murray BJ.

Sleep Medicine 

 

 

A study protocol for an observational cohort investigating COGnitive outcomes and WELLness in survivors of critical illness: the COGWELL study. 

Wilcox ME, Lim AS, McAndrews MP, Wennberg RA, Pinto RL, Black SE, Walczak KD, Friedrich JO, Taglione MS, Rubenfeld GD.

BMJ Open

 

Circadian alterations during early stages of Alzheimer’s disease are associated with aberrant cycles of DNA methylation in BMAL1.

Cronin P, McCarthy MJ, Lim ASP, Salmon DP, Galasko D, Masliah E, De Jager PL, Bennett DA, Desplats P. 

Alzheimers and Dementia

 

Validation of a smartphone-based EEG among people with epilepsy: A prospective study. 

McKenzie ED, Lim AS, Leung EC, Cole AJ, Lam AD, Eloyan A, Nirola DK, Tshering L, Thibert R, Garcia RZ, Bui E, Deki S, Lee L, Clark SJ, Cohen JM, Mantia J, Brizzi KT, Sorets TR, Wahlster S, Borzello M, Stopczynski A, Cash SS, Mateen FJ.

Scientific Reports

 

Diurnal and seasonal molecular rhythms in human neocortex and their relation to Alzheimer’s disease. 

Lim AS, Klein HU, Yu L, Chibnik LB, Ali S, Xu J, Bennett DA, De Jager PL.

Nature Communications

 

 

2016

 

Periodic Limb Movements and White Matter Hyperintensities in First-Ever Minor Stroke or High-Risk Transient Ischemic Attack.

Boulos MI, Murray BJ, Muir RT, Gao F, Szilagyi GM, Huroy M, Kiss A, Walters AS, Black SE, Lim AS, Swartz RH. 

Sleep

Self-Reported Sleep in Older African Americans and White Americans.

Turner AD, Lim AS, Leurgans SE, Bennett DA, Buchman AS, Barnes LL.

Ethnicity and Disease

 

Incident parkinsonism in older adults without Parkinson disease. 

Buchman AS, Leurgans SE, Yu L, Wilson RS, Lim AS, James BD, Shulman JM, Bennett DA.

Neurology 

 

Medication prescribing and patient-reported outcome measures in people with epilepsy in Bhutan.

McKenzie ED, Nirola DK, Deki S, Tshering L, Patenaude B, Clark SJ, Cash SS, Thibert R, Zepeda R, Leung EC, Lam AD, Lim AS, Mantia J, Cohen J, Cole AJ, Mateen FJ. 

Epilepsy and Behavior 

 

The effect of melatonin on sleep and quality of life in patients with advanced breast cancer.

Innominato PF, Lim AS, Palesh O, Clemons M, Trudeau M, Eisen A, Wang C, Kiss A, Pritchard KI, Bjarnason GA.

Supportive Care in Cancer

 

Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People.

Lim AS, Yu L, Schneider JA, Bennett DA, Buchman AS. 

Stroke

 

Regional Neocortical Gray Matter Structure and Sleep Fragmentation in Older Adults.

Lim AS, Fleischman DA, Dawe RJ, Yu L, Arfanakis K, Buchman AS, Bennett DA. 

Sleep

 

Common variants in DRD2 are associated with sleep duration: the CARe consortium.

Cade BE, Gottlieb DJ, Lauderdale DS, Bennett DA, Buchman AS, Buxbaum SG, De Jager PL, Evans DS, Fülöp T, Gharib SA, Johnson WC, Kim H, Larkin EK, Lee SK, Lim AS, Punjabi NM, Shin C, Stone KL, Tranah GJ, Weng J, Yaffe K, Zee PC, Patel SR, Zhu X, Redline S, Saxena R. 

Human Molecular Genetics

 

 

2015





Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans.

Wang JL, Lim AS, Chiang WY, Hsieh WH, Lo MT, Schneider JA, Buchman AS, Bennett DA, Hu K, Saper CB. 

Annals of Neurology

 

Irregular 24-hour activity rhythms and the metabolic syndrome in older adults. Sohail S, Yu L, Bennett DA, Buchman AS, Lim AS.

Chronobiology International

 

 

2014

 

Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer’s disease.

Lim AS, Ellison BA, Wang JL, Yu L, Schneider JA, Buchman AS, Bennett DA, Saper CB. 

Brain

 

Sleep complaints and incident disability in a community-based cohort study of older persons.

Park M, Buchman AS, Lim AS, Leurgans SE, Bennett DA. 

American Journal of Geriatric Psychiatry

 

 

2013

 

Modification of the relationship of the apolipoprotein E ε4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep.

Lim AS, Yu L, Kowgier M, Schneider JA, Buchman AS, Bennett DA. 

JAMA Neurology

 

Sleep Fragmentation and the Risk of Incident Alzheimer’s Disease and Cognitive Decline in Older Persons.

Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. 

Sleep

 

Sex difference in daily rhythms of clock gene expression in the aged human cerebral cortex. 

Lim AS, Myers AJ, Yu L, Buchman AS, Duffy JF, De Jager PL, Bennett DA.

Journal of Biological Rhythms

 

 

2012

 

Locus coeruleus neuron density and parkinsonism in older adults without Parkinson’s disease. Buchman AS, Nag S, Shulman JM, Lim AS, VanderHorst VG, Leurgans SE, Schneider JA, Bennett DA.

Movement Disorders

 

A common polymorphism near PER1 and the timing of human behavioral rhythms. 

Lim AS, Chang AM, Shulman JM, Raj T, Chibnik LB, Cain SW, Rothamel K, Benoist C, Myers AJ, Czeisler CA, Buchman AS, Bennett DA, Duffy JF, Saper CB, De Jager PL.

Annals of Neurology



 

Increased fragmentation of rest-activity patterns is associated with a characteristic pattern of cognitive impairment in older individuals. 

Lim AS, Yu L, Costa MD, Leurgans SE, Buchman AS, Bennett DA, Saper CB.

Sleep



 

Quantification of the fragmentation of rest-activity patterns in elderly individuals using a state transition analysis.

Lim AS, Yu L, Costa MD, Buchman AS, Bennett DA, Leurgans SE, Saper CB.

Sleep

 

Latest News

Welcome Henson and Fardin

I’d like to welcome Henson Chen (Computer Science) and Fardin Islam (Molecular Biology and Biotechnology) who are new undergraduate students joining us for the fall term!

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Welcome Mahnoor

I’d like to welcome Mahnoor Hamid to the lab, who will be joining us as a new MSc student.  Mahnoor completed a BSc in Biology at the University of Toronto[…]

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Rosa awarded CIHR Doctoral Scholarship

Congratulations to Rosa on being awarded a prestigious doctoral scholarship from the Canadian Institutes of Health Research for her project “Associations between the physiological consequences of sleep apnea and cerebral[…]

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