T32 Program Faculty Research Overview

 
Program Faculty


Full Preceptors
Charles A. Czeisler, PhD, MD (PI)
Radhika Basheer, PhD
Emery N. Brown, MD, PhD
Patrick M. Fuller, PhD
Steven W. Lockley, PhD
Elizabeth B. Klerman, MD, PhD
Dara S. Manoach, PhD
Janet Mullington, PhD
Susan Redline, MD
Clifford M. Saper, MD, PhD
Thomas Scammell, MD
Frank A.J.L. Scheer, PhD
Alexander Schier, PhD
Robert Stickgold, PhD 
Robert E. Strecker, PhD
Charles J. Weitz, MD, PhD

Associate Preceptors
Michael H. Do, PhD
Jeanne F. Duffy, MBA, PhD
Monika Haack, PhD
Takao K. Hensch, PhD
Kun Hu, Ph.D.
Stefanos Kales, MD, MPH
Christopher P. Landrigan, MD, MPH
Jun Lu, PhD
Richa Saxena, PhD
Elsie Taveras, MD, MPH
Rui Wang, PhD
D. Andrew Wellman, MD
John W. Winkelman, MD, PhD


Research Interests

Radhika Basheer, PhD: molecular and cellular mechanisms involved in the regulation of sleep-wake-behavior and sleep homeostasis. Recent work links brain energy metabolism and sleep-wakefulness. Her research strategies combine behavioral studies with molecular, biochemical and state-of-the-art optogenetics to understand the mechanisms regulating sleep-wake behavior. Dr. Basheer trained in the McCarley lab.

Charles A. Czeisler, PhD, MD and colleagues discovered that retinal light exposure, including exposure to ordinary indoor room light, resets the human circadian pacemaker.  They have demonstrated that the resetting response depends on the timing (described in a phase response curve), intensity (described in a dose response curve), duration, continuity and wavelength of the light exposure.  They demonstrated that those findings could be applied to treat shift work disorder; his group has further discovered that retinally-mediated light-induced melatonin suppression is often preserved in otherwise totally blind people who suffer from such severe retinal damage as to result in a complete loss of sight. His group has also demonstrated that the period of the human circadian pacemaker is more stable, precise and closer to 24-hours than previously recognized, remaining stable with age. They have investigated the interaction between circadian and homeostatic regulation of sleep and wake propensity, the manner in which the interaction changes with age, and the influence of these factors and their interaction on neurobehavioral performance.  Clinical trials have revealed the influence of repeated, low-dose caffeine administration on performance; that the impact of exogenous melatonin on sleep is dependent on circadian phase; and that modafinil is effective in the treatment of chronic and severe shift work disorder.  These and other developments from Dr. Czeisler’s program have contributed to the diagnosis and treatment of delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep-wake disorder, and shift work disorder and jet lag disorder.  Moreover, through the Harvard Work Hours, Health and Safety Group, Dr. Czeisler has demonstrated that extended duration (>24 hour) work shifts of hospital interns increase the risk of attentional failures, serious medical errors, adverse events (including fatal adverse events), occupational (percutaneous) injuries, and motor vehicle crashes.

Working with Dr. Czeisler and other colleagues, Emery N. Brown, MD, PhD and his colleagues have developed statistical methods to compute estimates and confidence intervals for circadian phase, amplitude and period from human core-temperature data collected under forced desynchrony, free-run and constant routine protocols. Most recently, Dr. Brown and colleagues have developed statistical methods to estimate circadian, ultradian and pharmacokinetic properties of melatonin and cortisol collected under these protocols.

Michael H. Do, PhD: Broadly stated, our goal is to learn how external signals interact with internal states to generate appropriate action. We take a biophysical approach to neural circuits and conduct our investigations within a conceptual framework established by behavioral experiments. In this manner, we develop a precise understanding of the steps by which system function emerges from its components. Our principal method is patch-clamp electrophysiology, applied to specific cell types in tissues isolated from model organisms. We also employ approaches from optics, molecular genetics, anatomy, and behavior. We study two pathways in the mammalian visual system, from their origin in the retina to their influences downstream. One pathway regulates fundamental aspects of physiology such as the circadian clock, sleep, and hormone levels. It tends to sum photons over broad intervals of time and space for accurate measurement of the overall light level. By contrast, the second pathway initiates most of our conscious visual experience. It parses images with exceptional speed and acuity to produce a detailed representation of the world. We analyze these two visual pathways in parallel to learn how a common signal, light, is diversified by neural circuits to serve a varied palette of behavioral needs.

Jeanne F. Duffy, MBA, PhD (former trainee on the training grant) and colleagues have determined numerous factors influencing inter-individual differences in sleep-wake timing, including aging and the trait of morningness-eveningness.  They are now investigating the mechanisms that underlie these differences among populations, including circadian periodicty, light sensitivity, and "clock" genes.  Dr. Duffy's research team is also investigating novel treatments for circadian rhythm sleep disorders, and investigating the effects of sleep deprivation and chronic sleep restriction on waking performance in aging.

Patrick M. Fuller, PhD's lab is interested in defining the neuronal substrates regulating behavioral state control, including key nodes, their transmitters and their targets.  This work spans a significant continuum and includes lines of investigation involving sleep and circadian regulation to mechanisms of anesthesia to circuitry supporting neurobehavioral and electrocortical arousal (i.e., wakeful consciousness). Investigative approaches include chronic telemetry, ISH, RTqPCR, microarrays, IHC, behavioral recordings, modeling, neuronal tracers, neurotoxic lesions, genetically modified mice (transgenic, knockin, knockout), pharmacogenetics and the development of cre-dependent AAV approaches for the targeted and cell-type specific placement of genetically engineered channel-receptor systems.  The ultimate goal of our work is to link the in vivo activity of defined sets of neurons with neurobehavioral and physiological outcomes in freely behaving animals.

Monika Haack, PhD: My research goals are directed at discovering the mechanisms involved in the relationship between insufficient sleep and the regulation of mood and pain. We study the sleep-pain relationship in experimental models of recurrent patterns of sleep restriction and recovery, as well as in more naturalistic models, i.e. insomnia. I am particularly interested in whether subjective (mood/pain) and inflammatory and stress-related systems responses habituate, or sensitize in the course of repeated insufficient sleep.

Takao K. Hensch, PhD, is joint professor of Neurology, Harvard Medical School at Boston Children’s Hospital, and professor of Molecular and Cellular Biology at Harvard’s Center for Brain Science. After undergraduate studies at Harvard with J Allan Hobson, he trained at the University Tokyo (MPH) and as a Fulbright Fellow at the Max-Planck Institute for Brain Research with Wolf Singer, before receiving a PhD in neuroscience with Michael Stryker at the University of California, San Francisco in 1996. He then helped to launch the RIKEN Brain Science Institute as lab head for Neuronal Circuit Development and served as Group Director for Critical Period Mechanisms Research (and now special advisor) before returning to the United States in 2006. Professor Hensch has received several honors, including the Young Investigator Award from the Society for Neuroscience both in Japan (2001 Tsukahara Prize) and the United States (2005), as well as an NIH Director’s Pioneer Award (2007). He currently directs the NIMH Silvio O. Conte Center for Basic Mental Health Research at Harvard. He serves on the editorial board of various journals, including Neuron, Journal of Neuroscience, Journal of Neurodevelopmental Disorders, Neural Development, Neuroscience Research, and Frontiers in Neural Circuits. Professor Hensch’s research focuses on critical periods in brain development, which impacts not only the basic understanding of brain development, but also therapeutic approaches to devastating cognitive disorders later in life.

Kun Hu, PhD's research interest lies in the emerging interdisciplinary field of fractal physiology and circadian biology, aiming to translate concepts of modern statistical physics and non-linear dynamics to further understanding of behavioral, cardiac and circadian controls and their alterations with aging and under pathological conditions. The current on-going projects include: (1) Identifying the neuronal circutry of the circadian network that is responsible for the fractal regulations of motor activity and cardiac controls; (2) Determining the effects of the endogenous circadian regulation and its disruption on behavioral and cardiovascular controls; (3) Determining the mechanisms underlying the daily patterns of adverse cardiovascaular events such as heart attack and stroke that show much higher occurrences in the morning hours; and (4) Determining the effects of cerebral blood flow regulation and its impairment of neuroanatomical brain structures and functional outcomes in cerebromicrovascular diseases associated with age, hypertension, diabetes and stroke.

Stefanos N. Kales, MD, MPH: Occupational Sleep Medicine: Obesity, Metabolic Syndrome, Cardiovascular and Sleep Health Epidemiology He has confirmed that certain emergency duties can precipitate or trigger on-duty heart disease events in firefighters. He uses measures of obesity and cardio-metabolic risk factors to detect sleep disorders in the occupational setting.

Elizabeth B. Klerman, MD, PhD and colleagues utilize mathematical analyses and modeling of human circadian, rhythms and neurobehavioral performance, and their response to light and length of time awake or asleep to understand the underlying physiology, to perform mathematical simulations of different sleep/wake/light schedules and to design countermeasures for times of decreased performance and alertness.

Christopher P. Landrigan, MD, MPH is a pediatric hospitalist and patient safety researcher with a particular interest in the effects of healthcare providers’ work hours, working conditions, and sleep deprivation on safety. Dr. Landrigan was a founding member of the Harvard Work Hours, Health, and Safety Group, and lead author of a 2004 publication in the New England Journal of Medicine that found interns working traditional 24-30 hour shifts made 36% more serious medical errors, and five times as many serious diagnostic errors, as interns whose scheduled work was limited to 16 consecutive hours. He subsequently led a national cohort study published in JAMA in which interns’ compliance with the ACGME duty hour standards was found to be extremely poor, suggesting the need for further efforts to reduce sleep deprivation and fatigue-related errors. Dr. Landrigan currently holds two major grants from the Agency for Healthcare Research and Quality to further support his research in this area. He has been honored with a Young Investigator Award from the Sleep Research Society, the Society of Hospital Medicine’s Excellence in Research Award, and was co-recipient of the National Sleep Foundation’s Healthy Sleep Community Award. He has lectured extensively on the topic of resident sleep deprivation and safety in the United States and abroad, and has been active in efforts to develop policies that promote safer work schedules.

Steven W. Lockley, PhD's research is focused on basic and applied aspects of human circadian and sleep biology, encompassing both highly-controlled laboratory-based studies, and large-scale field and applied studies in research and patient populations. Current active areas of interest include the spectral sensitivity of human circadian photoreception in sighted and blind individuals; the role of non-photic time cues in circadian entrainment, including the effect of melatonin and caffeine on the clock; the relationship between blindness, light exposure, melatonin and breast cancer risk; and, as part of the Harvard Work Hours, Health and Safety group, the impact of extended work hours and sleep disorders on fatigue, health and safety in physicians and police officers.

Jun Lu, PhD's approach to understand sleep-wake behaviors is to dissect out anatomically and physiologically the neuronal groups responsible for spectrum of sleep-wake behaviors in rodent model.  He and his colleagues have been working to identify flip-flop switch control of REM sleep.  He is PI on 3 NIH grants including studies of dopamine control of arousal, pontine motor circuits, and neural circuitry regulating REM sleep.

Dara S. Manoach, PhD: I am a neuropsychologist with a longstanding interest in cognitive neuroscience. I have devoted my career to understanding the neural basis and nature of fundamental cognitive deficits in neuropsychiatric disorders. In ongoing work, my lab is collaborating with Dr. Robert Stickgold to investigate the contribution of abnormal sleep to cognitive deficits in schizophrenia. Sleep plays a critical role in memory consolidation and renders cognitive performance faster, more accurate, and less reliant on limited capacity processing resources (i.e., more efficient and automatic). Recent evidence suggests that sleep-dependent memory consolidation is paralleled by changes in neural activity during task performance resulting in more efficient patiotemporal patterns of brain activation. This led us to hypothesize that sleep plays a critical role in cognitive deficits and associated inefficient brain activation patterns in schizophrenia. We have repeatedly replicated our findings of deficient sleep-dependent memory consolidation schizophrenia, identified a specific mechanism (reduced sleep spindles), and in preliminary work found that eszopiclone can increase spindles and improve memory. Our present projects use electroencephalography, magnetoencephalography and functional MRI to elucidate the links between deficient sleep-dependent memory consolidation and sleep spindles. We are also
studying the mechanisms of the eszopiclone effects. This research program has the potential to (i) substantially enhance our understanding of the mediation of sleep-dependent memory consolidation, (ii) expand current models of cognitive deficits in schizophrenia and (iii) lead to interventions that significantly improve quality of life.

Janet Mullington, PhD and her colleagues investigate the role of sleep in host protection and have characterized the neuroendocrine, neuroimmune and EEG spectral qualities of sleep in response to varying doses of experimental bacterial challenge in healthy human subjects. In addition, they have found that C-reactive protein and IL-6, acute phase markers known to be predictive of future cardiovascular risk, are increased during sleep deprivation. They are currently investigating the contribution of age, autonomic and metabolic factors involved in these inflammatory changes and are also investigating individual differences in body composition.

Susan Redline, MD focuses on: 1)  conducting epidemiological studies designed to elucidate the etiologies of sleep disorders, including the role of genetic and early life developmental factors, and 2) conducting epidemiological and clinical trials aimed at understanding the health outcomes, particularly the cardiovascular consequences, of sleep disorders and the role of sleep interventions in improving health.  She attempts to integrate physiology, clinical medicine, and genetics in epidemiological designs that include: 1) genetic epidemiological studies of sleep apnea and related traits; 2) development/participation in large multicenter observational studies of adult populations; 3) development of pediatric cohort studies to study subclinical markers of cardiovascular disease in relationship to sleep disorders; and 4) intervention trials. 

Working in collaboration with Dr. McCarley and others, Clifford M. Saper, MD, PhD  discovered that ventrolateral preoptic neurons in the hypothalamus that innervate the tuberomammilary nucleus are activated during sleep, as reflected at the molecular level by c-fos expression. His neuroanatomical research on the brainstem and basal forebrain circuitry involved in regulating arousal and in controlling cycles of sleep and wakefulness has delineated some of the ascending cholinergic and peptidergic pathways to the cerebral cortex and thalamus that are involved in the sleep process.

Thomas Scammell, MD and colleagues discovered that orexin (hypocretin)-containing neurons of the hypothalamus are active during wakefulness and help stabilize wakefulness. Their current research focuses on how orexin regulates sleep and wakefulness, and how a loss of orexin gives rise to the symptoms of narcolepsy.

Frank A.J.L. Scheer's research is primarily focused on medical chronobiology, including investigations of the underlying physiological mechanisms and therapeutic strategies to treat chronobiological disorders.  His work focuses on circadian and behavioral influences (including the sleep/wake cycle) on cardiovascular, pulmonary, and metabolic regulation and disease. 
Furthermore, he is interested in fundamental properties of the human circadian timing system, with work focusing on the effects of light. He has shown that endogenous melatonin production is important for sleep quality and that melatonin supplementation may be a logical therapy in certain patient populations. Furthermore, he has demonstrated that circadian misalignment, typical for shift work, leads to suppressed leptin, insulin resistance, and elevated blood pressure, providing possible physiological mechanisms to explain the increased risk for obesity, diabetes, and cardiovascular disease in shift workers.

Alexander F. Schier, PhD and colleagues wish to find genes and circuits that regulate the mechanisms that control sleep and wake states by studying zebrafish as a model system for sleep research. Zebrafish have the basic hallmarks of sleep-like behaviors. Sleeping fish require stronger stimuli than awake fish to initiate movement (increased arousal threshold), and sleep deprivation is followed by increased sleep (sleep rebound). In addition, the zebrafish brain expresses peptides that have been implicated in human sleep disorders.

Robert Stickgold, PhD and his colleagues investigate sleep-dependent aspects of cognition, focusing on the roles of sleep and dreaming in off-line memory reprocessing. In examining the role of sleep in cognitive processes, Dr. Stickgold’s work aims to define, delineate, and demonstrate sleep's role in perception, learning, memory, and emotions, with a focus on sleep as a process that evolved to enhance the consolidation and integration of memories. More recently, this work has been extended into fMRI studies of the sleep onset period and of sleep-dependent learning, alterations in sleep-dependent learning in schizophrenics and cocaine addicts, and dreaming in amnesiacs. We now are also studying sleep-dependent learning in elderly subjects and insomniacs, and will be looking at the effect of a drug that increases deep, slow wave sleep on sleep-dependent learning.

Robert E. Strecker, PhD and colleagues have confirmed the role of adenosine as an endogenous sleep factor that mediates the sleepiness associated with prolonged wakefulness. These data indicate that adenosine acts as an inhibitory neuromodulator, inhibiting the wakefulness promoting neurons of the basal forebrain region. This work also provides a mechanism to understand the alertness promoting effects of caffeine and related compounds, since these agents are adenosine receptor antagonist.

Rui Wang, PhD: My research interests include the development and application of statistical methodologies in the area of sleep medicine epidemiology. Sleep disorders impact large fractions of the population. I am interested in developing methods to elucidate the complex inter‐relationship between cardiovascular disease and sleep disorders, and to identify novel targets for cardiovascular disease reduction that relate to common, treatable sleep disorders, using data from clinical trials and epidemiological studies. In the analysis of clinical trials, it is often important to investigate whether treatment effects vary among group of patients defined by patient characteristics. Currently I am working on developing statistical methodologies to recommend treatment that optimizes the outcome for each individual. In addition, I am also interested in the design and analysis of cluster randomized trials, where a group of subjects, as opposed to individuals, are randomized to each of the treatment arms in the trial. The particular questions I am addressing include how the complex correlation structure within clusters affects the sample size and power of the trial, and how to analyze data from such trials efficiently, taking into account the correlation structure and the issue of missing data.

Charles J. Weitz, MD, PhD and colleagues use molecular biology, biochemistry, and genetics to investigate the mammalian circadian system.  The focus of their efforts has been to identify and characterize components of the circadian clock mechanism and to identify molecular output pathways by which the central circadian clock of the suprachiasmatic nucleus drives rhythms in behavioral activity. Most recently the Weitz laboratory has generated mouse lines in which circadian clock function can be conditionally ablated or conditionally rescued in a background otherwise lacking clock function, allowing them to investigate the specific physiological roles of circadian clocks in various brain regions and in peripheral tissues.

Andrew Wellman, MD: Pathophysiology of OSA; control of ventilation. Dr. Wellman has RO1 funding to study the phenotype traits of OSA including: upper airway anatomy/collapsibility, ventilatory control sensitivity, pharyngeal muscle responsiveness, and respiratory arousal threshold. Dr. Wellman is a product of our training grant, having trained in the White/Malhotra lab., MD: Epidemiology of sleep habits and sleep disorders and the potential effects on metabolism. Dr. Patel studies health effects of curtailed sleep including defining effects on weight, diabetes, heart disease, and mortality. He is PI on 2 RO1 grants, including a novel comparative effectiveness study comparing bariatric surgery to CPAP. Dr. Patel is a product of the White/Malhotra laboratory and developed further with Dr. Redline while she was in Cleveland.

John Winkelman, MD, PhD’s research addresses physiological manifestations, descriptive phenomenology, epidemiology, and clinical trials in sleep-related movement disorders (particularly restless legs syndrome, RLS), sleep-related eating disorder (SRED), and insomnia. He published the first demonstration of a neurochemical abnormality in insomnia, and then replicated this finding of reduced GABA with anatomical specificity in the anterior cingulate and occipital cortices.  This work is now supported by an RO1 from the NIMH to assess GABA in insomnia and major depression.  He published the first papers on the autonomic consequences of periodic leg movements of sleep (PLMS), the elevated risk of cardiovascular disease in RLS, and the elevated risk that RLS confers for mortality in patients with end stage renal disease (ESRD); each of these findings has been replicated multiple times.  He was the lead author on the American pivotal trial for pramipexole in RLS.  He was senior author of the first long-term comparative treatment trial in RLS, published in NEJM, which assessed efficacy and augmentation over 1 year.  He documented the phenotype, including polysomnographic findings, of SRED, and reported the first studies of the use of topiramate, which is now the first line therapy.

Faculty Committees
Several faculty committees oversee this Training Program, including an Education and Training Committee consisting of all preceptors, and four standing sub-committees: Trainee Selection, Curriculum Development, Minority Recruitment and Tracking and Evaluation. For more information on committee structure and responsibilities, please visit the Faculty Committees of the Training Program page.


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