Infradian Masking Period Phase Phase response curve Phase shift Subjective day Subjective night Suprachiasmatic nuclei Ultradian Zeitgeber

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1 9 Circadian Rhythms Katherine M. Sharkey LEARNING OBJECTIVES On completion of this chapter, the reader should be able to: 1. Define and give examples of circadian rhythms, and be able to describe the various components of circadian rhythms, such as amplitude, phase, and period 2. Describe the neurobiologic basis of the internal circadian pacemaker 3. Understand the effects the light-dark cycle exerts on circadian rhythms and discuss the concept of entrainment 4. Discuss phase shifting and utilize a phase response curve to predict the direction and magnitude of a phase shift 5. Describe circadian rhythm measures including temperature, hormonal, and activity rhythms and the conditions for recording these rhythms KEY TERMS Amplitude Circadian Constant routine Entrainment Free running Infradian Masking Period response curve shift Subjective day Subjective night Suprachiasmatic nuclei Ultradian Zeitgeber CHAPTER OUTLINE Fundamentals of Circadian Rhythms Neurobiologic Basis of the Internal Circadian Clock Effects of the Light-Dark Cycle on Circadian Rhythms Shifting Effects of Light and Light Response Curves -Shifting Effects of Nonphotic Stimuli Measuring Circadian Rhythms References FUNDAMENTALS OF CIRCADIAN RHYTHMS Since ancient times, scientists have observed that most living things have physiological rhythms that parallel the 24-hour rhythm of day and night. These are called circadian rhythms from the Latin circa meaning about, and dia meaning day, a term coined by Franz Halberg in 1959 (1). Circadian rhythms are ubiquitous; they are found in virtually all living things, including one-celled animals and plants. The sleep-wake cycle and hormonal rhythms (e.g., melatonin and cortisol) fluctuating across the twenty-four-hour period are examples of human circadian rhythms. In addition to circadian rhythms, there are other oscillations that are present in humans and animals. Ultradian rhythms are rhythms shorter than twentyfour hours, for instance, the REM-NREM cycles that are observed in sleep. The term infradian rhythms refers to those oscillations that are longer than twenty-four hours. As an example, the menstrual cycle approximates twentyeight days. Typically, circadian rhythms are represented by a sine wave (Figure 9-1). Various terms are used to describe different aspects of the rhythm. The period, also referred to as tau, is the length of the rhythm. This is usually very close to twenty-four hours. The amplitude is the magnitude of the rhythm from its peak to nadir. The amplitude of different circadian rhythms is variable and can be affected 61

2 62 SECTION 2 PHYSIOLOGY OF NORMAL SLEEP Amplitude Period or tau Close to 24 hours Figure 9-1 Circadian rhythms are schematically represented by a sine wave. byage, sex, sleepstate, etc. Thephase refers to the circadian position at any specific instant of time. Depending on what rhythm is measured, different phase markers are utilized. For instance, when the circadian rhythm of temperature is measured, the temperature minimum or maximum is commonly used as a marker of phase. When hormonal rhythms are measured, the onset or peak of hormone secretion is used as a phase marker. NEUROBIOLOGIC BASIS OF THE INTERNAL CIRCADIAN CLOCK Circadian rhythms are endogenously driven by the internal circadian clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus (21,27,30). Information about the lighting conditions of the external environment is conveyed to the SCN from the retina via the retinohypothalamic tract (RHT; Figure 9-2) (16,28). The SCN also receives input from the intergeniculate leaflet of the thalamus and the mid-brain raphé nuclei. These two pathways are thought to transmit both photic (light) and nonphotic information to the circadian clock (16). Figure 9-2 Diagram of the retinohypothalamic tract. Most of the SCN s projections stay within the hypothalamus, although a smaller fraction of SCN neurons terminate in the basal forebrain and midline thalamus (28). Secondary efferents from these three areas project to many brain regions, including the neocortex, hippocampus, basal ganglia, anterior pituitary, hypothalamus, reticular formation, and pineal gland. It is through this expansive network that the SCN exerts control over many physiological functions, including endocrine regulation, body temperature, the sleep-wake cycle, metabolism, autonomic regulation, psychomotor and cognitive performance, attention, memory, and emotion (28). Circadian rhythms researchers measure physiological rhythms that are downstream outputs of the endogenous clock to infer the status or phase position of the circadian rhythms. The circadian rhythms of core body temperature and hormones such as cortisol and melatonin are common measures of circadian phase in humans. EFFECTS OF THE LIGHT-DARK CYCLE ON CIRCADIAN RHYTHMS As mentioned above, sensory receptors in the retina provide information about the light-dark cycle to the endogenous clock (SCN). The light-dark cycle helps the organism remain synchronized or entrained to the twentyfour-hour day of the external environment (Figure 9-3). In the absence of a light-dark cycle and other time cues, circadian rhythms free run at a rate not equal to twentyfour hours, but equal to the endogenous period length, or tau. The period (tau) is close to, but not exactly, twenty-four hours. Free running is observed in humans when they have no photic (light) stimuli, for instance in blind people (1,31,32,34), or when the light-dark cycle to which they are exposed is outside of the time range of possible biologic entrainment, for instance, astronauts in orbit. During free running, the time when an organism exhibits its usual nocturnal behavior sleep in a diurnal (day active) animal, activity in a nocturnal (night active) animal is called subjective night, and the time when the organism exhibits its typical daytime behavior is called subjective day. Wever and colleagues performed some of the first experiments using bright light to entrain human circadian rhythms (37), confirming an important principle of human circadian rhythms: The light-dark cycle is one of the most powerful synchronizers of the endogenous circadian pacemaker in humans. More recent studies have tested various intensities of light (5) and have shown that in humans, as in animals, the brighter the light is, the stronger it is as an entrainer. Whether free running or entrained, circadian rhythms can be reset to a new time. This process is called phase

3 CHAPTER 9 CIRCADIAN RHYTHMS 63 6 P.M. 6 A.M. 6 P.M. Figure 9-3 Examples of entrainment and free running. The gray bars represent time when the body temperature is low and the triangles represent the temperature minimum. The black and white bars represent the lighting conditions. The top half of the figure depicts entrainment. When a changing light-dark cycle is present, the internal circadian clock uses the photic cues to synchronize or entrain to the twenty-four-hour light-dark cycle. The bottom half of the figure depicts free running. When there is no change in the light-dark cycle, the circadian rhythms free run at a period length (tau) determined by the endogenous circadian clock. In this case, the period length is longer than twenty-four-hours, which causes the circadian rhythms to delay (move later) because each day starts and ends slightly later than the previous day. shifting. Humans frequently are faced with situations in which their rhythms must phase shift, such as adapting to jet lag, daylight savings time, and shift work. A phase shift occurs when an organism is exposed to stimuli that affect the biological clock. Various external stimuli, called zeitgebers (from the German time giver ), act as time cues and can impinge on the internal clock, causing a resetting or phase shifting of circadian rhythms. Photic information about the light-dark cycle is the strongest stimuli for the biological clock (35). shifts differ in direction and magnitude depending on where in the circadian cycle (at what circadian phase) the zeitgeber is administered. PHASE SHIFTING EFFECTS OF LIGHT AND LIGHT PHASE RESPONSE CURVES The relationships between circadian rhythms, phase shifting, and various time cues or zeitgebers are described using phase response curves (PRCs). A PRC is derived by administering a stimulus at many different times or circadian phases and measuring the resulting shift in the circadian clock. The multiple phase shift data points are then plotted on a curve that can help predict the magnitude and direction of a phase shift given a particular stimuli. The first PRC to light was described by Hastings and Sweeney in a single-cell organism, Gonyaulax polyedra, in 1958 (15). In 1960, Patricia DeCoursey constructed the first PRC to light in mammals (11). She recorded the activity of flying squirrels free running in constant darkness before and after administration of brief light pulses. The squirrels were nocturnal and thus they started to become active as soon as they woke up, at the beginning of their subjective night, and would remain active until it was time to go to sleep, at the beginning of their subjective day. Because the squirrels were free running according to their internally generated period lengths (tau), the daily onset of activity in an individual squirrel could be predicted from day to day. shifts resulting from the light exposure could be measured by calculating the difference between the actual time of activity onset and the time predicted by extrapolating from the previous days activity onset. DeCoursey found that when these nightactive animals were exposed to light at the beginning of their daily activity (the beginning of their subjective night), the time of the onset of activity was phase delayed (it began later) on subsequent days. Conversely, when the animals received light pulses at the end of their activity bouts, their activity onset was phase advanced (it began earlier) on subsequent days. Light exposure during the subjective day resulted in no phase shifting of activity. In the 1980s several light PRCs were published in humans (9,17,25,37); all showed that despite being diurnal, humans responded to bright light exposure similar to the way DeCoursey s rodents responded. A schematic PRC for light in diurnal mammals is shown in Figure 9-4 (10); as it illustrates, when humans are exposed to light at the end of the subjective day and beginning of the subjective night, phase delays are produced. When light exposure occurs at the end of the subjective night and beginning of the subjective day, phase advances are produced. Minimal phase shifting occurs when humans are exposed to light in the middle of the subjective day. PHASE-SHIFTING EFFECTS OF NONPHOTIC STIMULI In addition to light, other nonphotic stimuli have been shown to affect circadian rhythms. For instance, exogenous administration of the hormone melatonin leads to phase shifts in the circadian clock. Lewy and colleagues produced a PRC for melatonin that demonstrates that circadian phase delays of about an hour are produced when melatonin is administered in the later hours of sleep and in the morning, and phase advances of similar magnitude are

4 64 SECTION 2 PHYSIOLOGY OF NORMAL SLEEP advance A C phase shifts produced with exercise appears to be related to the duration and intensity of the physical activity. delay B = delay B Subjective night A = No phase change C = advance Figure 9-4 Schematic light phase response curve. The horizontal black bars in A, B, and C indicate the timing of whatever behavior is normal for that organism during its subjective night the sleep time in diurnal (day active) animals or the activity time in nocturnal (night active) animals. Within each inset, the effect of a single stimulus (e.g., a light pulse in otherwise constant darkness) on a free-running rest-activity pattern is shown. The effects of stimuli (open circles) presented during the subjective day (A), the early part of the subjective night (B), and late in the subjective night (C) are shown. Note the very different effects which these identical stimuli have at those different phases. Those results are then plotted at the corresponding points (labeled A, B, and C) in the central diagram, which is a phase response curve (PRC). The boxed area represents the subjective night of the organism, and the remaining area represents subjective day. (Adapted from Czeisler CA, Richardson GS, Coleman RM, Zimmerman JC, Moore-Ede MC, Dement WC, Weitzman ED: Chronotherapy: Resetting the circadian clocks of patients with delayed sleep phase insomnia. Sleep 4: 1 21, Used with permission.) MEASURING CIRCADIAN RHYTHMS Circadian rhythms are measured in both clinical and research situations. For instance, if circadian rhythms are believed to be aberrant, they are measured in order to diagnose and treat a potential circadian rhythm disorder. Or, if a circadian phase shift intervention is planned, the baseline circadian phase is determined in order to time the intervention correctly. Similarly, the rhythms are measured after the intervention to measure the magnitude of the shift in circadian rhythms. Rhythms are also measured when a researcher wants to demonstrate that an intervention did not affect circadian rhythms. In humans, the endogenous clock (SCN) cannot be monitored directly; thus, marker rhythms that are controlled by the circadian clock are used to estimate circadian phase. Several markers are employed in studies of human circadian rhythms, including the rhythm of core body temperature, hormonal rhythms, and sleep/activity rhythms. Each of these has its advantages and disadvantages vis àvis cost, invasiveness, precision, labor intensity, influences of confounding variables, and duration of monitoring. One difficulty in measuring circadian rhythms is that rhythms can be affected by other aspects of the organism s physiology and by the techniques used to measure the rhythms. This is called masking. For instance, as shown in Figure 9-5, human core body temperature has a robust circadian rhythm it is high during the day, peaking in the midafternoon, and lower at night, with its nadir about two hours before wakefulness. However, core body temperature varies because of things other Core body temperature ( C) Temperature minimum 36.8 produced when melatonin is administered in the afternoon and early evening (19,20). Physical activity or exercise has also been shown to phase shift the human circadian clock (2,6,12,36). advances in circadian rhythms occur after exercise in the evening and phase delays are produced with exercise in the middle of the night (6). The magnitude of the circadian Noon 6:00 P.M. Midnight 6:00 A.M. Noon Figure 9-5 Circadian rhythm of core body temperature in a young adult male recorded in constant conditions. Temperature is high during the daytime hours and low at night. The fitted temperature minimum, indicated by the black triangle, serves as a marker of circadian phase.

5 CHAPTER 9 CIRCADIAN RHYTHMS 65 than the circadian cycle. Sleep and wakefulness, activity, drugs, fever, and menstrual phase are a few of the things that can alter the true circadian rhythm of core body temperature. These exogenous activities obscure or mask the endogenous temperature rhythm produced by the circadian pacemaker. Core body temperature recordings collected outside of a laboratory are relatively inexpensive, but they require subjects to be instrumented with an indwelling thermistor, usually a rectal temperature probe, which many subjects find unpleasant. Typically, this measure also requires several days of monitoring, as several days of phase estimates are usually averaged to obtain a more accurate measure. In addition, deriving circadian phase from temperature recordings collected outside of a laboratory is somewhat labor intensive because it requires extensive data analysis and because subjects must meet with researchers frequently to download the temperature recorders and assure compliance. Furthermore, circadian phase estimates from this temperature measure are subject to error due to masking produced by exercise, rest, sleep, and eating. Masking interferes with estimations of circadian phase from temperature rhythms by changing where the phase (temperature maximum or minimum) is estimated during a curve-fitting procedure. Because the temperature minimum normally occurs at night, the largest masking effect occurs if sleep occurs during the day or wakefulness occurs at night. If sleep occurs at its usual time at night, it increases the amplitude of the usual endogenous decrease in core body temperature, but the times of the temperature maximum and minimum are not displaced very much from their usual times (3). The size and timing of the exogenous or evoked component(s) of the daily temperature rhythm can be estimated and mathematically removed from the raw temperature recording to reveal an estimate of the endogenous core temperature rhythm. There is an extensive literature on mathematical and statistical techniques that can be used to demask data so that other physiological variables do not interfere with measuring the true circadian rhythm (4,7,12 14,22,26,33). Critics of these methods contend that mathematically demasking temperature recorded outside of the laboratory to derive circadian phase is invalid because the degree of masking differs depending on what phase of the circadian cycle the masking behavior occurs (18). In fact, several studies have demonstrated extremely small differences in masking effects at different circadian times (24). As with many physiologic variables, it is very difficult to measure circadian rhythms without also affecting the rhythm you are attempting to measure. Masking effects on core body temperature recordings can be decreased by the use of constant routine protocols (8,23). This method of determining circadian phase position is usually used in a research setting and subjects are in the laboratory for a complete circadian cycle. Conditions are kept as consistent as possible: Typically participants are kept awake in dim lighting, small isocaloric meals are given at frequent, regular intervals, and activity is minimized. It is more expensive to record temperature during a constant routine because of the personnel and laboratory costs. In addition, usually only one day is used to determine circadian phase. Some of the other drawbacks of measuring temperature in constant routine conditions are similar to those that occur when temperature is measured outside the laboratory core temperature monitoring requires placement of an indwelling thermistor and extensive data processing before phase can be determined. Furthermore, although constant routines are meant to minimize masking, constant routine temperature data are still subject to masking secondary to sleep deprivation. Nevertheless, temperature data from a constant routine is felt to be fairly reliable. Another advantage, is that it can be interpreted on line if necessary. Another method for estimating circadian phase is to derive it from rhythms of hormone secretion. The onset of melatonin and the peak of cortisol are frequently used as circadian phase markers. These hormonal measures are thought to be quite reliable. Nevertheless, hormonal secretion is also subject to masking. For instance, stress can mask the circadian rhythm of cortisol, and light can mask the circadian rhythm of melatonin. In addition, hormonal measures require radioimmunoassays that can be expensive and require specialized training and equipment to perform. Hormonal measures can also be invasive depending on which body fluid (saliva, serum, urine) is used to determine the hormone levels. Another disadvantage to measuring circadian phase using hormonal rhythms is that there is usually a time delay between data collection and determination of phase. Activity monitoring is one of the simplest ways to measure circadian rhythms. In humans, activity-based measures of circadian rhythms typically come from sleep diaries or wrist activity monitors. In rodents, activity is measured using wheel running recordings and is considered the gold standard. Activity methods are relatively inexpensive and noninvasive. However, they usually require several days of monitoring in order to establish the typical pattern of activity. Furthermore, in humans, activity rhythms are subject to extensive masking because of volitional activity. Nevertheless, these measures may be all that is needed to diagnose severe circadian rhythm disorders. As described here, there are multiple methods for measuring circadian rhythms. Each has advantages and disadvantages depending on budget, population being studied, time frame and required precision. Because each method also has some error inherent in its measurement, those who are recording circadian rhythms for research

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