Sleep and the Immune System Is Good Health Mediated by Brain-Mind States? by J. Allan Hobson None of the declarations of folk psychology is more widely believed than that linking good sleep and good health. Mothers have exhorted their children to "get a good night's sleep" since time began, it seems. In the early 1970s, studies conducted at the California Human Population Laboratory identified several behaviors that were positively correlated with length of life. Sleep headed the list, followed by exercise (which is known to promote sleep), eating breakfast (commuters take note), and not snacking (icebox raiders beware). Weight watching, not smoking, and moderating alcohol intake were also positive predictors of good health. The subjects in the California study have been followed over time, and those with six of the seven health behaviors listed above have all enjoyed much longer lives than those who violated the rules. But longevity is not the only yardstick that measures the payoff. Positive well-being, or "feeling good," has been linked to all seven factors. It thus appears that not only life itself but wellness is somehow fostered by good sleep. I say "somehow" to emphasize that the encouraging results of these epidemiological studies do not establish causality. For example, it could be that good sleep is not linked to good health at all, but that both are simply the effects of exercise. Or it could be that healthy people just happen to sleep well. It certainly seems that for us to have a sense of well-being, enjoyment, and accomplishment we need energy and a positive mood. And it seems natural that people who are depressed lack energy and have problems with mood. But we cannot feel secure in our well-being or help those who are depressed unless we can uncover the mechanisms that drive energy and mood. Is good health mediated by brain-mind states as they dictate the flow of norepinephrine, which controls waking and the sympathetic nervous system, and acetylcholine, which controls sleep and the parasympathetic nervous system? Let's see what recent research tells us. We all share a common experience when we have the flu; we feel best (or, should I say, least bad) in the morning, when we have "rested." Our symptoms worsen by afternoon and more so by evening. But we improve again after good sleep. Many people, including me, will swear by sleep for the flu until something better comes along. But can sleep actively suppress infection? Can it actually boost the immune system? That is exactly the conclusion reached by James Krueger of the University of Tennessee after fifteen years of research on the effects of sleep deprivation on rabbits, rats, mice, and - believe it or not - goats. Goats were chosen because they had proven useful in studies of cerebrospinal fluid, a rich source of some of the brain chemicals related to sleep. To make a long and fascinating story short, it turns out that when animals are sleep deprived, a protein known as di-muramyl peptide accumulates in their spinal fluid. The peptides do not originate in the brain. Instead, they come from bacteria in the body, suggesting that sleep deprivation may enable bacterial growth and that sufficient sleep impedes bacterial growth. What's even more interesting is that these di-muramyl peptides enhance non-REM sleep (but not REM sleep). [REM=rapid eye movements] The peptides also cause fever. The two effects are dissociable, however; the sleep effect is independent of the fever. More interesting still is the fact that the peptides stimulate cells in the brain and the body to produce interleukin-1, a powerful immune-system molecule that promotes the destruction of both bacteria and tumor cells. Highly significant and desirable health effects are mediated by interleukin's ability to encourage the B lymphocytes to produce antibodies, which kill viruses, and to trigger the proliferation of T lymphocytes, which attack microbial invaders. The net effect is to mobilize the body's defensive forces. It looks as if sleep research has inadvertently stumbled on something of capital importance. By depriving his animals of sleep, Krueger made them more vulnerable to infection, which stimulated their immune system, which made them more sleepy. Having noticed this, it was then possible to show that many immune proteins do, in fact, promote sleep. Taking a shot of sleep for your flu is sounding better and better, isn't it? No needles. No pills. Sleep alone is enough to change the state of the immune system. Now we return to our first question. Why do we feel sleepy when we have an infection? Perhaps because interleukin-1, a protein that is part of the normal bodily response to infection, is also an effective sedative. Like the peptides, interleukin-1 enhances non-REM sleep. It also increases the size of the EEG waves associated with non-REM sleep. Thus both the length and depth of sleep are increased as an integral part of the body's attempt to repulse microbial invaders. The upshot is that there is a positive, circular interaction between the immune response and sleep. Sleep enhances the immune system, and the immune system enhances sleep. Invaders are assaulting our body's portals at all times, not just during winter, when we tend to get sick more, and not just during local outbreaks of viruses. This means that the margin of safety of our health - the degree to which we are resistant to infection, and perhaps even cancer - may be determined by how well our sleep state enhances our immune system. The daily sequencing of normal brain-mind states, therefore, mediates our health. It is non-REM sleep that is enhanced by the chemicals our bodies produce to fight infection. Why is REM sleep absent from the immune response picture? We're not sure, but it seems likely it is because REM sleep involves a loss of temperature control. When we are sick, our body temperature soars and drops, and we cannot risk entering REM sleep and abandoning temperature control. REM as Supersleep We have seen how non-REM sleep helps us battle infection. Once we are healthy, however, it seems that REM sleep is the key to staying on top of our game. We have noted thus far that REM sleep serves to restore our energy system. During REM sleep our memory is consolidated and made permanent. During this unique brain-mind state of REM sleep, then, our circuits are being cleared and our battery is being recharged. We wake up with the insight and energy needed to tackle problems that seemed insoluble the night before. As the conservator of the aminergic system, REM sleep is more than twice as effective as non-REM sleep. The firing rates of neurons containing norepinephrine and serotonin drop to half their waking levels in non-REM sleep, but the output drops by far more than half again in REM sleep. Thus REM sleep is at least five times more conservative of the amines than non-REM sleep and ten times more conservative than waking. These calculations are based on the assumptions that the release of the chemical modulators is directly proportional to the firing rate of the neurons and that there is no release when the cells don't fire at all. Both assumptions have not been proven directly, but the general conclusion that far fewer amines are released in REM sleep than in either non-REM sleep or waking has been proven by experiments that measure their concentration in the brain. The same methods have also shown reciprocal increases in acetylcholine. REM, it seems, is some sort of supersleep. The first reason for according it this status is that, although it normally occupies only about 20 percent of the total time we sleep each night, it takes only six weeks of deprivation of REM sleep alone to kill rats compared with four weeks for complete sleep deprivation. Based on its relative duration of only 20 percent of sleep time, we would predict that five times as long a deprivation period would be required if both states were equally life-enhancing. On these terms, one minute of REM sleep is worth five minutes of non-REM sleep. The second reason supporting the idea of REM as supersleep is one that is attractive for the nappers of the world: there is a surprisingly beneficial nature of short naps if they occur at times in the day when REM sleep probability is high. Daytime naps are different from night sleep in that we may fall directly into a REM period and stay there for the duration of the nap. Since the time of peak REM probability is greatest in the late morning, the tendency of naps to be composed of REM sleep is highest then and falls thereafter till the onset of night sleep (about twelve hours later). The implication is that a little bit of sleep, at the right time of day, may be more useful than the same amount later on. The third reason is that, following the deprivation of even small amounts of REM sleep, there is a prompt and complete repayment. The subject who has been denied REM sleep launches into extended REM periods as soon as he is allowed to sleep normally. In recent drug studies, when REM sleep was prevented the payback seemed to be made with interest. More REM sleep was paid back than was lost. Of course, all these considerations have ignored the prospect that we might derive benefits from the rise of acetylcholine during REM sleep too. Unfortunately, how acetylcholine might confer its positive trophotropic benefits is as yet obscure. One possibility is that exposure to high levels of acetylcholine might affect cell metabolism. If so, this would indicate a link between brain-mind states and genetics, an exciting scientific prospect. The field of brain-mind research is on the threshold of an inevitable union with molecular biology. Since both REM sleep and DNA were discovered in 1953, this is a rather late marriage. The neuromodulator molecules - norepinephrine, serotonin, and acetylcholine - operate on the membrane surface of cells. Genes are large molecules that lie deep in the nucleus of the cell. Genes communicate via messenger molecules that ferry information from cell membranes to the nucleus. There is evidence that the neuromodulators may affect this communication. If this is the case, then norepinephrine, serotonin, and acetylcholine may affect the communication between genes. And since they affect the brain-mind states, they would provide a link between our genes and our states. Thus we can contemplate a very intimate conjunction in biology: the coupling of sleep to our genes. From such a union the fathers of DNA and REM sleep, Francis Crick, James Watson, Eugene Aserinsky, and Nathaniel Kleitman, could expect a bevy of beautiful scientific grandchildren. My hypothesis, and that of many sleep scientists, is that each of the three major brain-mind states - waking, sleeping, and dreaming - will prove to be quite different states at a very deep level, that of gene expression. Genes operate by making enzymes, and enzymes are essential to synthesizing norepinephrine, serotonin, and acetylcholine. We might expect, then, that in REM sleep the genetic manufacture of enzymes that synthesize the norepinephrine molecule would be turned on when acetylcholine interacts with the messenger cells communicating with the genes. A related concept would be that the disappearance of norepinephrine during REM sleep might signal genes to crank out more of the enzymes that make it. Either way, by the time we wake up enough norepinephrine will have been manufactured so that the aminergic system is ready to go. What scientists need, now, are ways to study the genetic biology of sleep. As genetics and brain-mind theory come together, we will find better explanations of how states affect energy, mood, and health. J. Allan Hobson, M.D., is professor of psychiatry at Harvard Medical School, director of the Laboratory of Neurophysiology at the Massachusetts Mental Health Center, and a member of the MacArthur Foundation Mind-Body Network who lectures regularly around the world. The author of The Dreaming Brain and Sleep, he lives in Brookline, Massachusetts. Reprinted with permission. "Sleep and the Immune System" is an excerpt from The Chemistry of Conscious States: How The Brain Changes Its Mind by J. Allan Hobson. Copyright © 1994. Published by Little, Brown (a Time Warner Co.), Time & Life Bldg., 1271 Avenue of the Americas, New York, NY 10020. ISBN 0-316-36754-0, 300pp; hardback $22.95. Table of Contents | 1995 Issues | Subscribe Truth Seeker | Feedback | Freethought.com Webmaster Credit card Orders call: 800-321-9054 or fax: (619)676-0433 Or send check or money order to: Truth Seeker / 16935 W. Bernardo Drive, Suite 103 / San Diego, CA 92127 $20.00 annual U.S. subscription ($35.00 international). Individual issues—$10.00 + $2.50 postage and handling Or be a committed freethinker and send $35.00 for a two year subscription. Truth Seeker is published by Truth Seeker Co., Inc. (ISSN 0041-3712) © 1996