Sleepwake Cycles

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According to sleep researcher Alan Hobson, ''Sleep is characterized by a recumbent posture, a raised threshold to sensory stimulation, decreased motor output and a unique behavior, dreaming.'' Sleep is, ironically, one of the least well-understood biological phenomena, yet over one third of our lives are spent in this behavioral state. Various hypotheses of sleep function and the functional significance of sleep have been proposed. These hypotheses have led to the development of a variety of sleep theories, each with evidence of varying quality to support it. For example, there is a restorative sleep theory, an energetic sleep theory, a dream and REM theory, a thermoregulatory theory, an immune theory, and a ethological theory. Whereas each theory most likely holds some truth, a unified sleep theory remains elusive.

The specific physiological processes that control sleep-wake behavior are fairly well-characterized. Collectively, these processes interact to promote and inhibit both sleeping and waking. The nature of these interactions has been described in a number of models for human sleep regulation, of which a circadian consolidation model is one of the most widely accepted at this time. In this model, sleep is timed by the CTS to provide a longer period of uninterrupted sleep. A two-process model of sleep regulation also exists that describes the interaction between a homeostatic sleep drive and a circadian rhythm of alertness. Work in sleep regulation has uncovered a role for the SCN in both the timing of the sleep-wake cycle and the regulation of the internal structure of sleep (Fig. 5). When the SCN was ablated in squirrel monkeys, a loss of sleep-wake consolidation was seen. Furthermore, circadian rhythms in sleep-wake, sleep stages, brain temperature, and drinking were eliminated, and total sleep time was significantly increased in SCN-lesioned monkeys. However, total times in deeper stages of non-rapid eye movement (non-REM; e.g., d sleep) and REM sleep were not significantly affected by SCN lesions. It appears that the circadian timing system promotes waking and alertness while interacting with a homeostatic sleep drive to promote consolidated sleep. In effect, the interaction between the output (amplitude) of the circadian pacemaker and the homeostatic sleep drive is the primary determinant of vigilance and sleep-wake consolidation.

Figure 5 Effects of SCN lesion on sleep-wake behavior in the squirrel monkey. This diurnal nonhuman primate is similar to that of humans in sleep-wake consolidation pattern and sleep architecture. SCN-lesioned monkeys exhibited significantly greater wake and sleep bout counts and a loss of the daily sleep-wake cycle. [Reproduced by permission from Edgar, D. M., Dement, W. C., and Fuller, C. A. (1993). Effect of SCN lesions of sleep in squirrel monkeys: Evidence for opponent processes in sleep-wake regulation. J. Neurosci. 13, 1065-1079.]

Figure 5 Effects of SCN lesion on sleep-wake behavior in the squirrel monkey. This diurnal nonhuman primate is similar to that of humans in sleep-wake consolidation pattern and sleep architecture. SCN-lesioned monkeys exhibited significantly greater wake and sleep bout counts and a loss of the daily sleep-wake cycle. [Reproduced by permission from Edgar, D. M., Dement, W. C., and Fuller, C. A. (1993). Effect of SCN lesions of sleep in squirrel monkeys: Evidence for opponent processes in sleep-wake regulation. J. Neurosci. 13, 1065-1079.]

The circadian rhythm of sleep and waking is tightly coupled to the circadian rhythm of body temperature. Sleep onset occurs on the descending limb of the body temperature cycle. Notably, studies have shown that human subjects in isolation will enter long sleep episodes only at or near the minimum body temperature. In these studies, entry into sleep was not seen at other circadian phases of body temperature. Experimental paradigms utilizing different photoperiods have allowed investigators to artificially separate the sleep-wake and body temperature rhythms. This process is called forced internal desynchronization and results from the inability of one rhythm, usually that of Tb, to entrain to the LD cycle. This rhythm then becomes free-running, whereas the other remains entrained to external time.

VI. CLINICAL RELEVANCE A. Circadian Susceptibility

Circadian rhythmicity is a significant source of variation in many important diagnostic variables (Fig. 6). Taking circadian variation into account can only improve the precision and validity of any clinical test. Furthermore, circadian rhythmicity can substantially affect both susceptibility to trauma and toxins and drug effectiveness and toxicity. Examples include cancer chemotherapy, anesthetics and analeptics, corticosteroid therapy, antiasthmatics, cardiovascular medications, antibiotics, and anabolic steroids. From a pharmacological perspective, a circadian variation in therapeutic response and efficacy is of interest. The effectiveness of a drug is largely a function of the rates of absorption, metabolism, excretion, and, finally, target susceptibility. Documented circadian variations in heart rate, acid secretion, glomerular filtration, renal plasma flow, urine production, pH, gastric emptying time, and blood pressure all, to a great extent, determine absorption, metabolism, excretion, and target susceptibility.

It is possible to increase the therapeutic efficacy and minimize the toxic side effects of drug treatments by providing treatment at a certain time of day. One medically relevant disease for chronotherapy is cancer, as many drugs used in chemotherapy affect the mitotic replication of normal and malignant cells. By treating the normal cells at times when DNA synthesis is low, higher levels of chemotherapeutic agents can be tolerated. Conversely, limitation of exposure to chemotherapy drugs during times when DNA synthesis is high can reduce the side effects. Moreover, cancer patients have been receiving adjuvant immunother-apy. Because both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner, chronodiagnostics and treatments may prove to dramatically increase the efficacy of immunotherapy in cancer treatment. Figure 7A illustrates the effects of cyclophosphamide and 1-b-d-arabinofuranosylcytosine administered to mice previously given injections of L1210 leukemia cells. Mean survival time and cure rate exhibited a marked circadian phase dependency. For example, the cure rate was 94% in mice treated at one circadian phase but only 44% in those treated at another phase.

Figure 6 Normal limits for a diagnostically useful variable plotted (A) without and (B) with regard to the time of day. When the time of day is taken into account, the detection of abnormal values is improved, so that not only value x but also value y can be identified as being outside the normal range. [Reproduced by permission from Moore-Ede, M. C., Sulzman, F. M., and Fuller, C. A. (1982). The Clocks That Time Us: Physiology of the Circadian Timing System. Harvard University Press, Cambridge, MA].

Figure 6 Normal limits for a diagnostically useful variable plotted (A) without and (B) with regard to the time of day. When the time of day is taken into account, the detection of abnormal values is improved, so that not only value x but also value y can be identified as being outside the normal range. [Reproduced by permission from Moore-Ede, M. C., Sulzman, F. M., and Fuller, C. A. (1982). The Clocks That Time Us: Physiology of the Circadian Timing System. Harvard University Press, Cambridge, MA].

Figure 7 Circadian phase dependency for toxicity and efficacy of exogenous agents. Three different experiments demonstrate the marked circadian variation in the tolerance, susceptibility, and the rate of cure for (A) chemotherapuetic agents, (B) radiation, and (C) bacterial infection. [Modified from Moore-Ede, M. C., Sulzman, F. M., and Fuller, C. A. (1982). The Clocks That Time Us: Physiology of the Circadian Timing System. Harvard University Press, Cambridge, MA].

Figure 7 Circadian phase dependency for toxicity and efficacy of exogenous agents. Three different experiments demonstrate the marked circadian variation in the tolerance, susceptibility, and the rate of cure for (A) chemotherapuetic agents, (B) radiation, and (C) bacterial infection. [Modified from Moore-Ede, M. C., Sulzman, F. M., and Fuller, C. A. (1982). The Clocks That Time Us: Physiology of the Circadian Timing System. Harvard University Press, Cambridge, MA].

As previously mentioned, circadian variation in susceptibility has been documented for a number of exogenous challenges. Figure 7B illustrates a dramatic example of circadian susceptibility in mice injected with a bacterial endotoxin. Here, over 80% of the mice who received the toxin during the late subjective day died, whereas less than 20% of the mice who received the toxin during the mid-subjective night died. Figure 7C illustrates an even more dramatic example of circadian susceptibility with direct relevance to cancer therapy. In this study, mice were exposed to 550 R of whole-body X irradiation. Strikingly, 8 days after exposure all mice irradiated at the midpoint of the subjective night were dead, whereas all those exposed during the late subjective day were still alive. Similar studies have examined the minimum alveolar concentration (MAC) for effectiveness of inhalant anesthetics. Not surprisingly, both the concentration necessary to achieve an adequate plane of anesthesia and the lethal effects of the same drug vary widely and predictably over the 24-hr day. One area of clinical relevance that has not been adequately explored is homeostatic regulatory capacity, which can be severely compromised in conditions without temporal cues (Fig. 8). This condition unfortunately is very similar to the environment experienced by patients in the intensive care units (ICUs) of some hospitals.

The onset and symptoms of pathologies such as myocardial infarction, stroke, acute pulmonary embolism, sudden cardiac death, thoracic aortic rupture, and paroxysmal supraventricular tachycardia all exhibit marked circadian phase dependency. Thus, circadian time is an important parameter to be considered during the diagnosis and treatment of any patient.

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Healthy Sleep

Healthy Sleep

A Guide to Natural Sleep Remedies. Many of us experience the occasional night of sleeplessness without any consequences. It is when the occasional night here and there becomes a pattern of several nights in arow that you are faced with a sleeping problem. Repeated loss of sleep affects all areas of your life The physical, the mental, and theemotional. Sleep deprivation can affect your overall daily performance and may even havean effecton your personality.

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