Neurobehavioral Consequences of Sleep Dysfunction

October 1, 1999

As chief of the division of sleep and chronobiology in the department of psychiatry at the University of Pennsylvania School of Medicine, David F. Dinges, Ph.D., focuses on ways sleep and the endogenous circadian pacemaker interact to control wakefulness and waking neurobehavioral functions such as physiological alertness, attention, cognitive performance, fatigue, mood, neuroendocrine profiles, immune responses and health. In an interview with Psychiatric Times, Dinges discussed neurobehavioral consequences of sleep loss, factors that impair sleeping, the pervasiveness of sleepiness and new ways to manage sleepiness.

As chief of the division of sleep and chronobiology in the department of psychiatry at the University of Pennsylvania School of Medicine, David F. Dinges, Ph.D., focuses on ways sleep and the endogenous circadian pacemaker interact to control wakefulness and waking neurobehavioral functions such as physiological alertness, attention, cognitive performance, fatigue, mood, neuroendocrine profiles, immune responses and health. In an interview with Psychiatric Times, Dinges discussed neurobehavioral consequences of sleep loss, factors that impair sleeping, the pervasiveness of sleepiness and new ways to manage sleepiness.

Psychiatric Times:

What is the function of sleep?

Dinges: This fundamental question has two levels. An extensive description of the neurobiological mechanisms of sleep will likely reveal multiple functions at a basic, probably subcellular, level. To date, these remain occult. At a more molar level, sleep promotes subsequent wakefulness. The stability of the wake state, alertness, and how well the brain functions cognitively and emotionally all depend upon an adequate duration of quality sleep. If you don't sleep enough, waking is eroded, even though you may not be aware of it.

So if sleep is essential for waking, then how much sleep is needed and for how long? Although the duration of sleep needed for stable waking functions varies among individuals and across the life span, daily sleep in our species is an average duration of eight hours. Because time is viewed in the information age as a commodity that can be bought, sold, traded and generally controlled at will, large segments of modern society have chronically reduced sleep durations. The reasons include sleep loss from occupational demands such as shift work or jet lag, sleep loss associated with aging and other developmental issues and, most pervasively, sleep loss associated with lifestyles that put a premium on waking activities. Because so many of us routinely reduce our sleep, we have created a new societal standard for wakefulness that is suboptimal. Far too many people are sleep-deprived to the point of requiring caffeine, exogenous stimulation and compensatory effort to remain awake. It is not uncommon to hear people attribute their sleepiness and even uncontrolled sleep attacks to a boring or sedentary activity-not appreciating that their own inherent biological drive for sleep overwhelms wakefulness when stimulation or compensatory effort are no longer enough. In contrast, wakefulness following satiation of sleep drive is effortless and requires no stimulation. The neurobiology for wakefulness and the neurobiology for sleep can be thought of as being in opposition [Edgar et al., 1993]. There is evidence that the endogenous circadian pacemaker located in the suprachiasmatic nucleus is a wake-promoting system [Edgar et al., 1993].

Its primary neurobiological effect is to promote wakefulness at the right time of day. In diurnal animals like us, that's when the sun is out. The sleep drive or so-called "sleep homeostat" is in counterregulation to these waking mechanisms. The longer you're awake, or the less sleep you get night after night, the greater the drive to sleep. In reality, the circadian pacemaker and sleep homeostat interact dynamically, tipping the balance toward sleep at night and waking during the day. Even though your circadian system may be promoting wakefulness at the right time of day, if you have too great a sleep debt, your ability to function will be compromised. You will experience problem sleepiness, with its attendant risk for reductions in attention, recall and cognitive throughput, and increased errors and uncontrolled sleep attacks [National Heart, Lung, Blood Institute and National Center on Sleep Disorders Research Working Group, 1999]. My message to psychiatrists and other physicians is simple: Take sleepiness seriously in patients or yourself, as it may have a basis in sleep pathology. Problem sleepiness poses a risk to the patient's safety, (e.g., while driving) and quality of life (e.g., attending school or work).


What do recent studies tell us about the functions of REM [rapid eye movement] and non-REM sleep?

Dinges: There is accumulating evidence from animal and human studies that long-term memory consolidation may be one of the primary activities during REM sleep. Without adequate REM sleep, it appears that some memories from the preceding day do not get consolidated.

In contrast, the functions of non-REM sleep remain unknown, although it has been suggested that non-REM has a priority role in recovery. But what's recovered? One theory posits that sleep restores glycogen depleted during waking [Benington and Heller, 1995]. The neurobiological functions of non-REM and REM sleep will likely be discovered in the next five years as the field of basic sleep science completes elucidation of the molecules and brain sites involved in the different sleep states.

There may be parallel functions for sleep in recovery or calibration in emotional processing. However, the relationship of sleep to affect is poorly understood. There is indirect evidence that emotional stability may be a function of obtaining adequate sleep. There is much comorbidity between insomnia and depression. Insomnia symptoms appear to be a risk factor for developing clinically significant depression [Ford and Kamerow, 1989]. Sleep deprivation can acutely relieve depression in some patients and trigger mania in many bipolar patients [Wu and Bunney, 1990]. We've not been able to explain these unexpected effects of sleep loss, but they suggest that the link between loss of sleep and emotional valence may be fundamental to the neurobiology of each. Now we can speculate that every night sleep rebuilds, metaphorically at least, cognitive and emotional capabilities.

Sleep may serve important functions for other physiological systems [Dinges and Chugh, 1997], including immune system integrity and responses. Some of the molecules that turn sleep on-cytokines such as interleukin-1-are active when we develop fever. They not only produce the febrile response, but they also make us sleepy and alter sleep responses [Krueger and Majde, 1994]. There is also evidence that sleep deprivation, especially chronic, may compromise host defense against infection from endogenous pathogens [Everson, 1993]. Therefore sleep may be protective immunologically, either directly or indirectly.

The lethal effects of chronic sleep deprivation have been well-documented in rodents using a yoked control paradigm [Rechtschaffen et al., 1983]. From this model there is evidence that sleep loss involves a progression of ever greater physical debilitation which apparently does not involve failure of a vital organ. Rather, it compromised physiological adaptation reflected in disturbances in thermoregulatory, metabolic and immune systems [Dinges and Chugh, 1997]. Neuroimaging studies of the brains of sleep-deprived rodents, experimentally sleep-deprived humans and patients with fatal familial insomnia [Medori et al., 1992] reveal marked hypometabolism in thalamic regions, among other areas, of the wake brain [Dinges and Chugh, 1997]. Since the thalamus is actively involved with the cortex and reticular formation in the initiation and maintenance of non-REM sleep, these imaging studies may suggest a sustained pressure for, if not outright co-occurrence of, aspects of sleep in the presence of waking.

Sleep may help maintain a range of functions involving health and adaptive behavior. Yet it remains for many people undervalued relative to its role in waking functions. We have had success in making people aware of sleep problems, like obstructive sleep apnea and the ability of medicine to treat these conditions. However, we still have a long way to go to get physicians and patients to understand that identification, prevention and treatment of sleepiness, regardless of its cause, is essential for full behavioral health. The widespread tolerance of sleepiness as an acceptable consequence of modern life, and the failure to appreciate its potentially devastating neurobehavioral effects on children, adolescents, adults and the elderly is an ongoing crisis. As the core specialty for behavioral health, psychiatry has a pivotal role to play in educating the public about sleep, sleep disorders and problem sleepiness. However, too few psychiatrists obtain training in sleep.


What sleep disorders are not related to lifestyle? What do physicians need to know?

Dinges: Every physician should be aware of primary sleep disorders. These include obstructive sleep apnea, insomnias, narcolepsy and periodic leg movements. An excellent source for information is the standard textbook in the field [Kryger et al., 1994]. Sleep apnea involves collapse of the upper airway during sleep and chronic fragmentation of sleep, of which the sleeper is unaware. One of the most prevalent sleep disorders, one study identified apnea in 3% to 5% of the middle-aged adult working population [Young et al., 1993]. A clinical polysomnogram is needed to confirm it but, once diagnosed, apnea is treatable, generally with mechanical airway splints (e.g., CPAP [continuous positive airway pressure]) and increasingly for some patients with dental devices and surgical procedures. Not all treatments are equally effective in all patients, which is why patients need to be evaluated at a sleep disorders center. Apnea has a high correlation with obesity, and studies now also suggest that sleep apnea may contribute to myocardial ischemia and infarct in patients with coronary artery disease. The most common risk from apnea is sleepiness that can result in errors, accidents, motor vehicle crashes and a reduced quality of life [Weaver et al., 1997]. Signs of sleep apnea-which can include obesity, complaints of fatigue or evidence that the patient falls asleep at inappropriate times-need to be taken seriously.

Hypnotics and sedatives are not indicated until sleep apnea has been ruled out. Insomnia, which refers to a complaint that sleep is difficult to initiate or maintain, or that it is neither refreshing nor restorative, is the most common sleep complaint-approximately 10% of adults report chronic insomnia.

Insomnia can present with a variety of daytime sequelae and can result from a range of conditions and disorders (behavioral, psychological, medical, circadian and so forth). Approximately half of all the patients who complain of insomnia chronically have a psychiatric disorder, usually an affective disorder [Buysse et al., 1994]. Most patients with insomnia are not seen in sleep disorders centers, but either seek no treatment or are treated by primary care physicians or psychiatrists. To evaluate and treat insomnia safely and effectively, the psychiatrist must understand how other sleep disorders present (for differential diagnosis), have acumen in the nature of the insomnia being experienced, and understand when treatment should focus on behavioral interventions and/or hypnotic medications. It is also important to appreciate that insomnia complaints in the elderly are less likely to involve psychopathology and more likely to be associated with age-related changes in sleep and physical problems (e.g., pain, nocturia) or behaviors that disrupt sleep, such as too much caffeine intake. Insomnia patients tend to self-medicate-alcohol and "natural" substances such as melatonin are widely used. Several behavioral and pharmacological treatments have been shown to be effective and safe for insomnia. Over-the-counter melatonin is not recommended for insomnia by many sleep experts because too few randomized controlled clinical trials have been completed.

Narcolepsy is a sleep disorder that is serious but much rarer than either sleep apnea or insomnia. A genetically transmitted disorder, narcolepsy involves sleep disruption, waking cataplexy and severe daytime sleepiness with uncontrolled attacks of REM sleep during wakefulness, often triggered by intense affect. Narcolepsy is frequently misdiagnosed, to the detriment of the patient. For example, a psychiatrist misdiagnosed a young adult patient with narcolepsy as having multiple personality disorder-the issue came to a head when the patient kept collapsing into REM sleep during emotionally charged therapy sessions. Subsequent polysomnography confirmed full-blown narcolepsy.

Narcolepsy often begins in adolescent and young adult years like some other severe neurobehavioral disorders. If you have a patient who is excessively sleepy, reports that they get weak in the knees when they experience emotions of any kind and that they have fallen down or had uncontrolled sleep attacks, etc., you need to get them into a sleep disorders center. The clinical markers of narcolepsy include REM sleep during daytime naps. The excessive day-time sleepiness of narcolepsy is now being treated with Provigil (modafinil), a new wake-promoting compound that lacks many of the adverse effects of traditional dopaminergic drugs. There is both hope and concern about the off-label use of Provigil.

Periodic limb movements involve episodes of repetitive limb movements during sleep (usually the legs), which can cause frequent arousals or partially awaken the sleeper or bed partner. Usually patients are unaware of the movements. Like sleep apnea and insomnia, the prevalence of periodic limb movements increases in geriatric populations. It has been reported that as many as one in three persons over the age of 60 may experience this condition [Ancoli-Israel et al., 1991]. Periodic limb movements can be associated with problem sleepiness during the daytime or complaints of nonrefreshing sleep. Like sleep apnea and narcolepsy, polysomnography can be used to objectively confirm the presence of the disorder. Benzodiazepines are often used to treat periodic limb movements.

Other sleep disorders that I have not discussed include parasomnias such as night terrors, nightmares, sleep walking, enuresis and REM behavior disorder. The latter was discovered only a few years ago. Found primarily in elderly men, REM behavior disorder involves the loss of the normal skeletal muscle paralysis of REM sleep. The sleeper suddenly starts pounding and thrashing the bed partner. Psychiatrists should be familiar with the techniques and tests needed to identify and treat all of these sleep disorders.


What can be done to evaluate and manage problem sleepiness?

Dinges: Sleepiness has to be recognized. Problem sleepiness can be easily missed. An article has recently appeared in the American Family Physician-a leading journal for primary care physicians-based on the report of a NIH [National Institutes of Health] National Center for Sleep Disorders Research Working Group on problem sleepiness [National Heart, Lung, Blood Institute and National Center on Sleep Disorders Research Working Group, 1999]. In it, we encourage physicians to ask patients about behavioral signs of excessive sleepiness, sleep disorders, and the quantity and quality of sleep. For example: Does the patient report dozing off or having difficulty staying awake during routine tasks, especially while driving?

Having identified excessive sleepiness in a patient, you should then attempt to determine why the patient is sleepy, in order to ensure effective treatment of the underlying cause (e.g., sleep apnea, narcolepsy, insomnia). Diagnosis and treatment may ultimately require evaluation in a sleep disorders center. Prescription of sedating or stimulant compounds should not be done until the cause of and treatment for excessive sleepiness are determined. All patients should be advised that pre-existing sleepiness heightens the sedative effects of alcohol. Stimulants do not play a major role in the treatment of problem sleepiness except for patients with narcolepsy.


What are you working on now?

Dinges: While much is known about acute total sleep loss, little is known about chronic partial sleep deprivation, which afflicts millions of people as a result of medical and psychiatric conditions, and lifestyle. We are currently investigating the effects of chronic sleep restriction on neurobehavioral functions and emotional, physical and psychological responses. This NIH-supported project involves having people live in the laboratory for 20 days, with random assignment to a limited amount of sleep (four, six or eight hours per day). Our initial experiments have demonstrated that [restricting] sleep...even to six hours per day, results in accumulating cognitive deficits that reach severe levels of impairment within one week, without subjects being aware of their levels of problem sleepiness. We are also continuing our experiments on the use of brief daytime (prophylactic) naps to enhance both neurobehavioral functioning and growth hormone secretion when nocturnal sleep is restricted, which occurs during space flight. This work is being done for NASA [National Aeronautics and Space Administraion] through support from the National Space Biomedical Research Institute.

As part of our studies for the U.S. Air Force Office of Scientific Research, we are investigating the effects of sustained low-dose caffeine and naps during severe total and partial sleep loss. This research is focused on novel ways to safely promote wakefulness through pharmacological countermeasures, other than amphetamines, in emergency personnel who must undergo prolonged waking demands (e.g., military operations). It is in collaboration with projects of Charles Czeisler, M.D., at Harvard Medical School and Dale Edgar, M.D., at Stanford Medical School.

We are also studying human-centered technologies that purport to detect a person's alertness or drowsiness level. These experiments, which are being done for the U.S. Department of Transportation and NASA Ames Research Center, are intended to identify ways to reliably track a person's sleepiness level while driving, flying or during other activities. We've tested in a double-blind, controlled trial a number of biobehavioral technologies that claim to be able to detect drowsiness while driving. These devices detect changes in head movements, various measures of brain wave activity, eye blink rate, slow eyelid closures, eye movements, pupil responses, heart rate changes and so forth.

Many of these technologies continue to be marketed, but few have been validated. Thus far, we have only found one technique that reliably detected drowsiness-induced vigilance failures with a high level of accuracy. This approach involves monitoring the cumulative duration of slow eyelid closures [PERCLOS]. An unobtrusive automated PERCLOS system is currently being developed by Richard Grace, Ph.D., at Carnegie Mellon University. Our goal is to ensure that technologies that end up in the workplace, automobile or clinic meet scientific criteria for validity and reliability, practical criteria for implementation and proper use, and legal policy criteria for protecting individual rights. I am certain that unobtrusive, online monitoring of human alertness and performance in the workplace and most transportation modes will grow and become normative early in the next century, as other technologies permit flexibility in time utilization beyond a fixed biologically driven period for sleep. I am equally certain that problems with sleep and sleepiness will accompany these developments and remain important behavioral health issues.




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