Division of Sleep Medicine @ Harvard Medical School
Program Faculty Research Overview
Program Faculty
Research Interests
The work of Daniel Aeschbach, PhD and colleagues focuses on the neurobiology of sleep-wake regulation in humans, and in particular the homeostatic and circadian processes that regulate the duration and intensity of sleep, as well as the quality of wakefulness. A major part of his work is aimed at understanding the inter-individual differences in sleep duration. By comparing two extreme phenotypic groups – short sleepers and long sleepers – he is investigating whether inter-individual differences in sleep duration have a neurobiological basis in stable trait disparities in homeostatic and circadian sleep regulatory systems. One of the long-range goals of this work is to understand what sleep need is, and whether it has to be defined individually due to intrinsic, and ultimately genetic factors. Furthermore, he and colleagues are investigating whether sleep indeed has an intensity dimension as reflected in a lawful relationship between sleep EEG slow-wave activity on one hand, and learning, cognitive functions, and mood on the other hand.
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.
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 periodicity, 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.
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.
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.
Liming Ling, PhD and colleagues have discovered that chronic intermittent hypoxia enhances the respiratory long-term facilitation and hypoxic response via serotonin receptors. They have also found evidence that sleep fragmentation impairs these respiratory control mechanisms via adenosine receptors. Recently, their research has been extended to investigate upper airway mechanics, intending to better understand the roles of these mechanisms in obstructive sleep apnea.
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.
Atul Malhotra, MD is a pulmonary and critical care physician scientist interested in the pathogenesis of obstructive sleep apnea as well as the pathophysiology of sleep apnea complications. He is PI on 3 NIH grants including studies of upper airway muscle function, pharyngeal structure using MRI, ventilatory control stability, as well as metabolic and cardiac biomarkers important in OSA complications. His projects include collaborations with the Chamberlin laboratory to understand hypoglossal control by defining pharmacological targets and neural pathways mediating respiratory reflexes in a rat model, the development of a finite element model of the upper airway (with Yaqi Huang, PhD), and industry projects to study novel therapeutics for sleep apnea, insomnia and other sleep disorders.
Robert W. McCarley, MD and colleagues have recently characterized the time course of fos-like immunoreactivity associated with cholinergically-induced REM sleep. Furthermore, he and his colleagues discovered that adenosine inhibits mesopontine cholinergic neurons, which has implications for EEG arousal.
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.
Working in collaboration with Dr. McCarley and others, Clifford M. Saper, MD, PhD recently 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.
Steven A. Shea, PhD and colleagues in the Medical Chronobiology Program are determining underlying mechanisms responsible for alterations across the 24-hour period in the severity of many diseases. (e.g., why heart attacks occur most frequently in the morning, and why asthma is worse during the night). In particular Dr. Shea quantifies the separate influences of the internal circadian pacemaker and the behavioral sleep/wake cycle markers of disease severity. These studies provide an insight into the underlying cause of the disease and may lead to better therapy (e.g. appropriately timed medication to target vulnerable circadian phases or behaviors).
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.
J. Woodrow Weiss, MD and his colleagues have shown that patients with obstructive sleep apnea demonstrate both acute and chronic hemodynamic changes attributable to their disease and have demonstrated that airway occlusion during NREM sleep elevates systemic blood pressure.
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.
David P. White, MD and his colleagues have characterized the influence of sleep on a number of the mechanisms controlling both respiration and upper airway muscle activity. The studies have focused on the four primary phenotypic traits that lead to sleep apnea. These include: upper airway anatomy, pharyngeal dilator muscle control asleep, ventilatory control stability (loop gain), and respiratory arousal threshold. These studies have been pivotal in understanding the basic pathophysiology of obstructive sleep apnea and other respiratory disorders of sleep and have the potential to lead to new therapies individualized to the given patient. He has also investigated hormonal influences on respiratory control awake and asleep in an attempt to explain the male predominance in sleep apnea. These combined studies have substantially improved our understanding of these sleep-related respiratory conditions.
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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