Pathophysiology and Treatment of Circadian Rhythm Sleep Disorders
Charles A. Czeisler, MD, PhD
Circadian Rhythm Sleep Disorders: Jet Lag Syndrome
Slide 1. Pathophysiology and Treatment of Circadian Rhythm Sleep Disorders
Slide 2. Circadian rhythm sleep disorders are a distinct class of sleep disorders. They occur when the pacemaker in the brain that controls the timing of sleep and wake becomes misaligned with the sleep-wake schedule desired by the individual.
This class of disorders is exemplified by a time-zone change or jet lag syndrome. The jet lag syndrome occurs when an individual flies from, for example, New York City to Rome, but their internal clock remains set on the time in New York. They're trying to sleep and wake on the same schedule as everyone else in Italy, which means going to bed and waking up much earlier than they would ordinarily. So, they might be waking up at the equivalent of midnight in New York and attempting to go to bed at the equivalent of 4 PM in New York. That misalignment of the internal time vs the schedule that they're trying to adopt results in this time zone or jet lag syndrome.
Slide 3. In order to understand this syndrome, we have to step back and look at the physiology. There is a pacemaker in the brain that consists of about 50,000 neurons. It's a bilaterally paired structure located on either side of the third ventricle and contains some of the smallest neurons in the brain. This cluster of neurons is called the suprachiasmatic nucleus (SCN) because it sits directly above the optic chiasm in the anterior region of the hypothalamus on either side of the third ventricle. The mammalian circadian pacemaker controls a wide array of physiologic and behavioral variables.
Slide 4. This slide contains data from nearly 30 healthy young subjects who are living on 2 different schedules. The left-hand set of panels shows the temperature cycle, the timing of the release of the pineal hormone melatonin, the adrenal hormone cortisol, urinary volume, thyroid stimulating hormone (TSH), growth hormone, prolactin, parathyroid hormone, and wrist activity. The left-hand series of panels was recorded in individuals who were waking during the day, sleeping at night in the dark, and waking again during the day. You can see that there are robust daily variations in all of these different functions.
The next series of panels is labeled "constant routine." In that series of panels, you can see that the body temperature cycle, for example, is recorded when an individual is continuously awake (hence, the three "W's"). Therefore, they're awake during the day, during the night, and during the following day, and one can see that the body temperature rhythm continues to oscillate in a periodic manner. However, the magnitude of its oscillation is about half of what it is when the person is living on a regular schedule and sleeping at night when it is dark. The timing of the release of the hormone melatonin also continues to be robust and its pattern of release is almost indistinguishable from the pattern of release when the individual is on a regular 24-hour day/night sleep cycle.
Cortisol also maintains a similarly undamped oscillation during the routine of continuous wakefulness. There remains a robust rhythm of urine production and TSH release. All of the different systems in the body that are controlled by the circadian pacemaker continue to oscillate even when activity levels are maintained at a continuous low level throughout day and night and when the person remains continuously awake in constant dim indoor room light throughout the day and night.
The set of panels on the right side of this slide shows that even functions such as short-term memory, cognitive performance, subjective alertness, and body temperature also oscillate when individuals are kept on this kind of a constant routine. For example, the cycle of alertness reaches a nadir just before the habitual wake time and is near its peak just before the habitual bedtime, which is indicated by the vertical dashed line in that figure.
The Body's Regulation of the Sleep-Wake Cycle
Slide 5. The output of the circadian pacemaker, illustrated by the circle in the center of this slide, is entrained or synchronized to the 24-hour day by light information that is conveyed from the retina in the eye to the SCN in the hypothalamus. That pacemaker in turn drives daily variations in a number of rhythms that are summarized here: the melatonin rhythm, temperature, cortisol, the release of growth hormone, somatotropin, thyrotropin, prolactin, and even respiration, and renal function. The photic entrainment of the pacemaker is mediated by a specialized subset of intrinsically photosensitive ganglion cells that are spread throughout the retina rather than having a foveal distribution or concentration.
Those specialized ganglion cells also receive input from rods and cones, acting as a redundant input pathway for synchronizing the circadian system, but can still function even if the rods and cones are so severely damaged that the individual is blind. Light input can still be obtained by the circadian system through these specialized ganglion cells that have a direct monosynaptic pathway to the SCN in the hypothalamus -- that is how our internal clock is ordinarily synchronized to the 24-hour day.
Slide 6. As we all know, the circadian clock is not the only regulatory system that affects sleeping and waking. There is a second process called the sleep homeostat, which also drives daily variation in sleeping and waking tendency. That homeostatic process is what I would call an appetitive process, in that the longer we go without food, the greater the drive and the need for food, and the greater our hunger.
In that same way, the longer we go without sleep, the greater the drive and the need for sleep. That process is regulated by the sleep homeostat. The neuroanatomical location of the sleep homeostat, unlike that of the circadian pacemaker, is not yet known. It is not known what processes in the brain keep track of the amount of sleep that has been obtained or the amount of sleep that has been lost. However, it is known that there is a complex interaction between the length of time awake and the time of day by which the body determines an individual's alertness, the ability to sleep, the ability to maintain vigilance, and cognitive performance.
We can tease apart those 2 influences -- the circadian one and the wake-dependent one -- using a special protocol in which we schedule individuals to live, in this case, on a 28-hour day. So, every day they go to bed 4 hours later and wake up 4 hours later. That kind of a schedule, a 28-hour day, is outside the range of synchronization or entrainment of the human circadian pacemaker and therefore we can shear apart the influence of length of time awake, a homeostatic system, from the output of the circadian pacemaker.
Slide 7. Using special techniques in analysis, we can look at the magnitude of daily variations in alertness and performance that are related to time of day in the body (left panels), as opposed to the magnitude of those same changes that are associated with the length of time awake averaged across all different circadian phases (right panels). As you can see, they each contribute about equally to the ability to sustain alertness and performance during the course of the day.
In the 2 left-hand panels, the nadir of the alertness and performance cycles occurs just after the nadir of the body temperature cycle (indicated at 0 degrees by the vertical line in the center of each of those diagrams). The body temperature rhythm typically reaches its nadir about 1 to 2 hours before our habitual wake time. The right-hand panels show that there is a similar magnitude of decrease in alertness and performance that occurs over the course of the 16 or 18 hours that we are awake each day. Thus, the longer that we're awake, the greater the drive for sleep relative to this homeostatic process. Therefore, we will become less alert as the day wears on and our performance will deteriorate from the homeostatic point of view.
The circadian system, however, is aligned such that there is an increasing drive for waking as the day wears on. These 2 systems interact to allows us to have a stable level of alertness from the time that we wake up in the morning until the time that we go to bed at night. Just as we would be running out of steam from the length of time we've been awake, the circadian signal sends a strong drive for waking that peaks just before our habitual bedtime and helps us to have a second wind in the latter half of the day.
Slide 8. Those 2 different systems interact to affect our ability to consolidate sleep at night. In the upper panel of this slide, we scheduled subjects to sleep at all different biological times of day. When they try to sleep during their biological daytime -- let's say from 1400 hours to 2200 hours (2 PM until 10 PM) even healthy young subjects will spend 20% of their time awake lying in bed in the dark because they're trying to sleep at a time of day that the brain is trying to wake them up. On the other hand, if we schedule those same individuals to sleep between midnight and 8 AM, their sleep efficiency will be very high and they'll be awake on average only 2% to 4% of the time.
In the lower panel you can see that the percentage of wakefulness also varies with the length of time that an individual is in bed. Once they get past the initial sleep latency, which happens during the first hour of the night when they may be awake 10% of the time, sleep efficiency becomes very high in the second, third, and fourth hour of the night. Then, as the night wears on, there is an increased tendency to be awake. Thus, these 2 different systems interact to determine the ability of an individual to maintain a consolidated bout of sleep at night.
Shift Work Sleep Disorder
Slide 9. Sleeping is particularly difficult for a shift worker. When shift workers work all night while the brain is trying to promote sleep, then attempt to sleep during the daytime, they are going to bed on the rising phase of the body temperature rhythm at a time when there is an increasing drive for wakefulness. Most shift workers can usually fall asleep for 3, 4, or maybe even 5 hours. As the night and the sleep episode wear on, the increasing drive for wakefulness emanating from the circadian pacemaker in the latter third of their sleep episode causes a tremendous amount of wakefulness and many shift workers simply get out of bed at that point because they're sleeping so fitfully.
That brings us to the shift work sleep disorder. Shift work sleep disorder occurs in about a quarter of individuals who are scheduled to work at night. Of course, if all of us tried to work at night and sleep during the daytime, we would have some disruption of our circadian system and some misalignment similar to jet lag. But, just as in the case of jet lag where some individuals are more adversely affected than others when they try to sleep out of sync with the output of their internal clock, a quarter of shift workers, even when they've done it for years, also have a great deal of difficulty sleeping during the day and a great deal of difficulty staying awake at night.
From what we know of these individuals, they are equally sleepy when they're trying to stay awake at night working in factories, power plants, etc. They're as sleepy at that time as narcoleptics. Their sleep latency is generally averaging in the 2-minute range, which is extraordinary given the fact that they're often in very highly responsible jobs such as operating equipment. Night-shift workers in the transportation industry are one of the most vulnerable groups to the consequences of the adverse effects of sleeping during the day and trying to stay awake and work at night.
Slide 10. Driving a truck is a very unforgiving occupation in terms of lapses of attention. If you're sitting in an office answering telephones, a lapse of attention is not going to result in a catastrophic accident. However, if you're driving an 18-wheeler going 70 miles an hour down a highway and you have a 4-, 5-, or 6-second lapse of attention, you can go off the road onto the shoulder and have a catastrophic accident within a very short time. In fact, when the National Transportation Safety Board did a study of fatal-to-the-driver heavy truck accidents, they found that fatigue was the most frequently cited probable cause of accidents among truck drivers.
Slide 11. The distribution of fatigue-related single-vehicle accidents peaks at exactly the time we would expect -- when the greatest drive from the circadian pacemaker for sleep is occurring -- which is typically just before an individual's habitual wake time. This peak of accidents happening around 5 o'clock in the morning is exactly when we would expect based on the laboratory studies that we've reviewed.
Slide 12. Properly timed exposure to bright light and darkness can be used to facilitate adaptation of night-shift workers to their schedules. As illustrated in the left-hand series of panels, the body temperature cycle of an individual on the first night-shift, as we would expect, reaches a nadir in the middle of the night-shift. This indicates that the circadian system is not synchronized with the desired schedule of sleeping during the daytime and staying awake at night. Even after working a week doing night work in standard, ordinary indoor room light, the individual is still not adjusted by the sixth night-shift. The body temperature's rhythm is still reaching its nadir in the middle of the nighttime hours rather than during the daytime.
The right-hand series of panels, D, E, and F, show an individual in the treatment arm of this particular study. On the first night-shift (panel D), this individual is still at the nadir of his or her body temperature cycle during the middle of the night. However, as illustrated in panel E, when the subject is exposed to bright light during nighttime work and darkness during daytime sleep, by the sixth night-shift (panel F), the body temperature rhythm has shifted over so that it's reaching a nadir near the end of the daytime sleep episode at around 3 PM and reaching a peak during the scheduled nighttime work hours. Thus, they have completely adjusted to their inverted sleep-wake schedule required for night-shift work.
Slide 13. In the control group, body temperature, alertness, performance, kidney function, and cortisol rhythms are not shifted because the sleep-wake schedule is not adjusted by working in ordinary indoor room light and exposure to bright outdoor light during the commute home from work.
On the other hand, in the treatment group (illustrated in panels F through J on the right-hand side), you can see that their body temperature rhythm is shifted; their alertness rhythm is shifted so that they're at their peak alertness during their night-shift between midnight (the vertical dashed line), and 8 AM, instead of at poor alertness; their performance rhythm in panel F is at its peak during the nighttime instead of being at its nadir; their urine production rhythm is shifted so that their sleep is less interrupted by visits to the bathroom, and their cortisol rhythm also is shifted. Therefore, night-shift workers can be synchronized to their schedule of nighttime activity and daytime sleep if the light/dark cycle is shifted with them.
Non-24-Hour Sleep-Wake Syndrome
Slide 14. The non-24-hour sleep-wake syndrome is a much rarer condition. There have been perhaps a dozen case reports of cited individuals who are unable to maintain synchrony of their circadian system with the 24-hour day. Much more common, however, are blind people whose circadian system is not synchronized to the 24-hour day. To understand how this might happen, we have to step back and look a bit at the physiology of the circadian pacemaker.
Slide 15. The circadian pacemaker is very sensitive to resetting by exposure to light. Even ordinary indoor room light in the level of 50-100 lux is capable of making significant shifts in the circadian pacemaker. From the point of view of our interaction with the external environment and the function of the circadian pacemaker, we almost have to think of light as a drug because whenever we're exposed to light, even if it is at an inappropriate time, it is going to have an effect on shifting this pacemaker.
Slide 16. When we study subjects in an environment shielded from periodic changes in the outside world and in which we very carefully control their exposure to light and maintain them in very dim light that is evenly distributed across all circadian phases, we can get a precise estimate of the intrinsic period of the circadian oscillator. Unlike some early studies that suggested that this period was around 25 hours, we now know that the period of the circadian pacemaker is actually much closer to 24 hours in humans and has a very narrow range of distribution. It ranges from about 23 3/4 hours to about 24.5 hours when we study people carefully, with an average of 24 hours and 11 minutes.
When individuals are unable to perceive light due to blindness, and their circadian system is not getting the entraining input from the external light/dark cycle, they are then unable to maintain synchrony of their endogenous circadian pacemaker with its intrinsic period (which is not exactly 24 hours), and their internal rhythms are therefore in a perpetual state of slowly drifting jetlag.
Non-24-hour Sleep-Wake Syndrome: Studies on a Blind Individual
Slide 17. This is a calendar of diary data from a totally blind individual showing that individual's nightly sleep and daytime naps over a 15-year period. These were from diary records that this individual kept in Braille. When translated them, you can see a highly periodic process that has a cycle length of about 100 days. We hypothesized that perhaps the circadian system was not synchronized to the 24-hour day, and if it were slipping about a quarter of an hour each day, it would slip an hour every 4 days. If you then multiply every 4 days times the 24 hours that there are in a day, it would take about 96 to 100 days to complete a full cycle if the intrinsic period of this person's oscillator were drifting at a rate of about 24 hours and 15 minutes per day.
Slide 18. Based on that hypothesis, we charted the data. In this slide, you can see that when we lined up every nadir in the ability to sleep during the nighttime hours, we made a little dot. Therefore, when the sleep efficiency was so bad, because the individual was out of sync, that he could only sleep about 4 or 5 hours during the night, we made a little dot. As you can see on this chart, we have almost 6000 days on the vertical axis, and when we chart out each cycle number over that 15-year period, you can see a regular rhythm. He had a very stable period until about cycle number 37 (around 1987), at which point he retired. For reasons that we don't understand, his cycle length changed slightly, so his rhythm deviates off of the diagonal line.
Slide 19. On the next slide you can see that the subject spent 103 consecutive days undergoing sleep recording in our laboratory. The dashed diagonal line represents the timing of the body temperature cycle nadir as it is drifting. It is a function fitted by a least-squares regression method to the timing of the body temperature cycle nadirs over the course of that 3-month period. As you can see, his body temperature and cortisol rhythms exhibited a period of about 24 1/4 hours during the 3.5 months that he spent with us.
Slide 20. This slide shows (by day number) the timing of the phase of the temperature nadir (the filled circles), and the timing of the phase of the cortisol nadir (open boxes), during the more than 100 days that we studied this subject in the laboratory and after he was discharged from the laboratory. As you can see, both parameters display a period that is 24 1/4 hours.
Slide 21. When we align and average the data from that entire experiment with a period of 24 1/4 hours, you can see that the subject's urinary free cortisol excretion, plasma cortisol level, body temperature, urine production, urine sodium excretion, and urinary potassium excretion all line up, indicating that he has a robustly functioning circadian pacemaker that is not synchronized to the 24-hour day.
Non-24-hour Sleep-Wake Syndrome: Further Studies of the Circadian Rhythm
Slide 22. We can produce very similar data in a subject by scheduling the sleep-wake cycle to a duration of daylight that is outside the range of synchronization of the endogenous circadian pacemaker. This graph illustrates when sleep was scheduled by the light grey open bars. The black horizontal thin bars represent the timing of the release of the hormone melatonin, which is normally released during the night-time hours. As you can see, the melatonin rhythm continues to exhibit a near 24-hour oscillation because the intrinsic period of the oscillator in this individual is very close to 24 hours. When we schedule his sleep-wake cycle on a 28-hour day, you can see that when he is scheduled to sleep in phase with the release of the sleep-promoting hormone melatonin, he has very little wakefulness (indicated by the black, filled in portion within the light gray bars). However, when the subject's sleep is scheduled out of phase with the timing of the release of melatonin, you can see there are many filled in black boxes within the scheduled sleep episode, indicating wakefulness within the scheduled sleep episode. It occurs most often in the latter part of the scheduled sleep episode, illustrating beautifully this interaction between the homeostatic drive for sleep and the circadian variation in sleep propensity.
Slide 23. The upper panel shows the percentage of wakefulness in the sleep episode and the lower panel shows the phase of the melatonin rhythm. As we saw in the previous slide, when the subjects are sleeping in phase with the melatonin rhythm there is very little wakefulness during the scheduled sleep episode. Similarly, when the subjects are sleeping out of phase with melatonin secretion (at a time when melatonin is not being released), there is a tremendous amount of wakefulness, typically more than 20%.
Slide 24. This phenomenon continues to occur while our blind subject is trying to live on a 24-hour day even though his internal rhythm is drifting at a 24 1/4 hour cycle length. Since this individual is unable to entrain the output of the circadian pacemaker, he experiences the same daily variation in wakefulness and REM sleep during the scheduled sleep episode that we see in normal subjects scheduled to sleep at various biological times of day.
Slide 25. This slide illustrates 2 different blind individuals. In panel A you see another blind person who is unable to maintain synchrony of his body temperature rhythm, melatonin rhythm, and cortisol rhythm with the 24-hour day even though he is maintaining a regular schedule of bed-times and wake-times. When we expose him to light during the middle of his biological night (panel B), there is no photic input to the circadian system because there is no suppression of melatonin, which normally declines in sighted individuals when they are exposed to light during the night when melatonin is being secreted.
Panel C (right-hand side) illustrates a recording from another blind individual who has no conscious light perception and no electroretinographically detectable changes in response to the brightest light of an ophthalmoscope. However, he has a melatonin rhythm synchronized to the 24-hour day and his sleep-wake schedule. We brought him into the lab, turned on the lights (panel D), and found that we could suppress his secretion of melatonin with exposure to light, even though he could not see.
Slide 26. We're confident that the photic information was reaching the circadian pacemaker through this individual's eyes, because when we covered his eyes there was no suppression of melatonin, and when we exposed his eyes to light, we could suppress the release of the hormone.
The human eye, like that of other mammals, serves 2 different functions. Like the ear, which is responsible for both hearing and balance, the eye is responsible for both conscious light perception, or image formation, and circadian photo reception. Thus, you can lose the ability to perceive light consciously, yet still maintain photic input into the circadian pacemaker because there is a specialized set of intrinsically photosensitive ganglion cells that convey this information to the pacemaker even in the absence of rods and cones.
Slide 27. Another circumstance in which the endogenous period of the circadian pacemaker is manifested is unusual environments, such as living for many months under the sea in a submarine. The Navy maintains enlisted personnel on an 18-hour watch schedule -- working for 6 hours and then off for 12 hours -- throughout their 6-month tour of duty when they're manning a nuclear submarine. We were fortunate enough to be able to study individuals living on such a schedule and to record the timing of their melatonin rhythms throughout the voyage.
During this experiment, we were able to demonstrate that the circadian rhythms of individuals living on this schedule were not synchronized to the 24-hour day. They were drifting, as illustrated in this series of graphs, with a longer than 24-hour period as we would expect under such a situation in which they're not exposed to the synchronizing effect of a periodic light/dark cycle with a 24-hour period.
Additional Circadian Rhythm Sleep Disorders
Slide 28. Circadian Rhythm Sleep Disorders
Slide 29. The delayed sleep phase syndrome, or light sleep phase syndrome, is a condition in which individuals have difficulty falling asleep when they go to bed at their desired time -- let's say 11 PM. They can't fall asleep till 1, 2, or 3 AM. When they finally get to sleep at 3 AM or 4 AM, they then have difficulty waking up at their desired time the following morning. They can sleep on the weekends until about noon, but if it's necessary for them to wake up at 6 or 7 AM, they're exhausted and have difficulty waking up.
Slide 30. The flip side of that disorder is advanced sleep syndrome, which is typically seen in older people, that is the reverse of delayed sleep phase syndrome. Individuals with advanced sleep syndrome experience difficulty staying awake in the evening and a corresponding early morning wakening. They might wake up at 3 or 4 AM, when the patient with delayed sleep phase syndrome is finally falling asleep.
Slide 31. An individual with an advanced phase of their temperature cycle is illustrated in this diagram. In the right-hand portion of this slide, which is when the individual is on the constant routine, the nadir of their body temperature cycle is occurring just before midnight. This is about 5 standard deviations earlier than the rest of the population living in the same city that are reaching the nadir of their temperature cycle at about 6 AM.
This individual's internal clock was on London time even though he or she was living in Boston. Interestingly enough, patients with delayed sleep phase syndrome might be reaching the nadir of their endogenous body temperature cycle, 5 or 6 hours later. When we recorded this patient, we had another patient with delayed sleep phase syndrome who reached a nadir of his temperature cycle at about noon. So we had 2 people living in the same city who's internal circadian clocks were set 12 hours apart. They could have been on opposite ends of the globe even though they were living in the same city. These 2 cases represent the misalignment of the output of the circadian pacemaker with the desired sleep-wake schedule that underlies these circadian rhythm sleep disorders.
Slide 32. The ability to sleep at different phases and the ability to perform cognitive throughput also varies with time of day. Interestingly, the ability to sleep becomes more difficult as we get older (filled circles), compared with younger subjects (open circles). Furthermore, the window of phases at which we're able to maintain sleep, and at which our performance is at its nadir, becomes narrower as we get older. That's why older people are more vulnerable to the effects of misalignment of the circadian phase, related to either jet lag or shift work, in terms of their ability to consolidate sleep.
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