xxxvi. PRC for melatonin

12 July 2007 at 18:36 | Posted in Circadian rhythm | Leave a comment
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Finally! I found a picture of the Phase-Response Curve for Melatonin in humans in a presentation from ten years ago. (If you click the link and find Figure 8, you’ll also see the corresponding curves for lizards and rats.) The peak is maximum 7 hours before bedtime. Taking a melatonin pill 5-6 hours before bedtime should advance one’s circadian rhythms by upwards of an hour. 

Above, I’ve added the melatonin PRC (green) to the old illustration of the light PRC (purple). Clearly, light has the greater effect. However, the effects have been shown to be additive.

Now, for some reason I’ve not seen explained, one is to ignore the rising portion of the curves.  So while it looks as though the period between 4 hours and 2 hours before wake-up would give a phase advance, that is not true.

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Next:  xxxvii. Daylight Saving Time / Summer Time

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xxxv. Can one figure out one’s own rhythms?

11 July 2007 at 12:57 | Posted in Circadian rhythm | 5 Comments
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This will be a lament, mostly without links unless someone insists. 
 
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To properly treat Delayed Sleep-Phase Syndrome (DSPS), one should know the patient’s circadian rhythms. At the least, one should know 

  1. when the natural sleep onset and spontaneous wake-up times are,
  2. when the core body temperature minimum, nadir, occurs during sleep, and
  3. when DLMO (dim light melatonin onset) is and preferably also the midpoint of melatonin in the blood.

Treatment with melatonin “supplement”, a hormone, and bright light therapy are very dependent on knowing these things, on getting (guessing) them right.  

One study I found used eight of the usual subjects: normal, healthy young men. Their rhythms were determined in detail before the start of the study. The final report included results for only seven of them. Why? With all possible expertise and equipment at hand, one factor for one of the young men was determined wrongly by half an hour, so they had to leave him out. I’m glad they admit this sort of thing in the report, but it certainly raises the question of how we ordinary, abnormal mortals are supposed to be able to find these things out.  

One study mentions that the period from nadir to awakening varied in their cohort from 1 to 6.5 hours. One found about a half hour difference in the averages for men and for women.  

Well, if patients haven’t messed up their systems entirely with traditional sleeping pills and long-term coping tactics, number 1 above should be possible to identify. 

 Number 2, nadir, is said to be approximately two hours before spontaneous awakening in normal people, longer that that in DSPS people and even longer in people with Non-24. It should occur approximately seven hours after DLMO. Bright light therapy should be used a couple of hours after nadir to advance circadian rhythms. A few hours later than that, according to the phase response curve (PRC) for light in humans, the light will have almost no effect at all. Am I one of those whose nadir is six hours before wake-up?  If so, using my light box is a waste of time and effort. How to know?  It is also not entirely clear that moving the timing of the sleep-phase also will move the timing of the body’s other circadian rhythms, though in theory it should.  

 Then we have number 3 above, the timing of endogenous (natural) and exogenous (supplemental) melatonin. We all have pineal glands which secrete this hormone at night (whenever our own “night” is). Somehow it can make us sleepy and let us fall asleep. The mechanics of that are not yet well understood.  

There appear to be two schools of thought regarding the timing of supplemental melatonin. The first and most common has been mentioned before. One uses it almost as one would a sleeping pill, a hypnotic in the jargon, one-half to two hours before one wants to go to sleep. This works pretty well for me with 0.5 mg melatonin making me sleepy after about one and one-quarter hours. When I get sleepy, I must get to bed immediately as the effect wears off quickly and I can then stay up til all hours.

It’s hard to find much on the second theory, supplemental melatonin as a chronobiotic, though I see that Wikipedia now tells about the PRC for melatonin as well as the PRC for light, and I’ve seen abstracts from two small studies. One of them, here comes a link to an abstract, in 2005, was done on thirteen DSPS patients in Illinois, USA. Melatonin supplements were tried between 1.5 and 6.5 hours before DLMO (dim light melatonin onset). DLMO is generally considered to occur approximately two hours before bedtime. The study results showed that the earlier melatonin was administered, the greater was the advance in the timing of DLMO. Sleep onset was also advanced some, though to a lesser degree.  

 The other study at a different medical center in Illinois, also in 2005, on normal subjects both male and female, suggests that one should use melatonin much earlier than the traditional timing and “in doses small enough not to feel tired right away” to effectively advance one’s circadian rhythms. They experimented with placebo, with 0.5 mg melatonin five hours before bedtime and with 3 mg administered seven hours before bedtime.  Each of the three groups was also treated with bright light in the morning. They conclude that a nearly one-hour advance, daily, in sleeping time <and> light exposure <and> administration of melatonin did not lead to misalignment of circadian rhythms during the three days of the study.

These are but two studies experimenting with the concept of the PRC for melatonin. If the theory proves to be valid, we can expect to see many more in years to come. This should be interesting to follow, and we can hope for some studies which will last longer than three days!

I still lament. When is my temperature minimum? My DLMO? Is it possible for me to advance these and all the other rhythms in alignment and keep them there, without detrimental effects on physical and mental health? The more I learn, the less clear it all becomes. Sigh.

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Next:  xxxvi. PRC for melatonin

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xxx. Light Therapy, Practice Parameters, 1999

23 February 2007 at 11:37 | Posted in Circadian rhythm | Leave a comment
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Practice Parameters for the Use of Light Therapy in the Treatment of Sleep Disorders appeared in SLEEP, Vol. 22, No. 5, 1999. The authors, Chesson et al, were all connected to universities and medical institutions in the USA. 

The clinical guidelines developed by the Standards of Practice Committee were reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. The guidelines provide recommendations for the practice of sleep medicine in North America regarding the use of light therapy for treatment of various sleep disorders.  

 “These practice parameters define principles of practice that should meet the needs of most patients in most situations.” 

As the PDF apparently no longer is available on the Internet and the document is found only in Google’s html version, I’m offering some excerpts here. I’m leaving out altogether the sections on shift work and other voluntary shifts of sleep-wake schedules, sleep disturbances in the elderly, jet lag and Seasonal Affective Disorder (SAD).  Update, December 2010:  the PDF is now here, hat tip to ttt.

Almost 10 years old, the guidelines can hardly be said to be up-to-date. Much of the information is, however, correct, and it is interesting to see what doctors “should have known” at the turn of the century, at least in the USA. [Emphasis, bold, is mine.] 

From the INTRODUCTION: Endogenous circadian rhythms are in large part regulated by the hypothalamic suprachiasmatic nuclei (SCN). The SCN are key regulators of sleep, as they regulate rhythms that promote sleep and wakening. It is now recognized that a number of sleep disorders are linked to abnormal circadian rhythms or to a lack of coordination of the sleep-wake cycle with the individual’s circadian rhythms. One of the most potent external factors that can alter the period of the SCN is light exposure. 

From BACKGROUND: Over the past two decades, laboratory studies have demonstrated that scheduled light exposure can produce a dose-dependent phase shift in the endogenous circadian rhythms of a variety of variables. These variables include plasma or saliva melatonin, core body temperature, cortisol and a propensity to sleep. 

The rationale for the use of light therapy evolves from the observation that circadian rhythms in humans can be phase-shifted by scheduled exposure to light. Because of an endogenous pattern of light sensitivity, the direction of the phase shift varies with the timing of the light exposure. The responses of circadian rhythms to light exposure have been summarized in Phase Response Curves (PRC).  The PRC appears phase-locked to the core body temperature and plasma melatonin concentration rhythm. In healthy young subjects, with a normal sleep pattern and temperature curve, the core body temperature minimum typically occurs about two hours before habitual wake time (around 4 to 5 a.m.).

  • Light exposure prior to the endogenous minimum of the core body temperature will shift rhythms to a later clock time (i.e., will delay rhythms).
  • Light exposure just after the endogenous circadian body temperature minimum will shift rhythms to an earlier clock time (i.e., will advance rhythms).

From SAFETY and SIDE EFFECTS:

Light therapy appears to be a generally safe treatment option for some circadian rhythm disorders…  

Rarely, light therapy may provoke a hypomanic state in patients with bipolar affective disorders.

TREATMENT OBJECTIVES, INDICATIONS and FOLLOW-UP: Treatment is indicated only if there is a desire on the patient’s part to resolve symptoms. The objective is to achieve a sleep onset at either a more socially acceptable time or at a time that provides sufficient sleep in keeping with the work schedule or lifestyle. 

Objective documentation is generally limited to a shift in the core body temperature minimum, a shift in the onset of dim light melatonin secretion or in the peak of the melatonin rhythm, information the patient has recorded in diaries, or actigraphic measurement of rest/activity patterns.

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Next page:

RECOMMENDATIONS FOR SPECIFIC DISORDERS:

1. Delayed Sleep-Phase Syndrome (DSPS)

2. Advanced Sleep-Phase Syndrome (ASPS)

3. Non-24-Hour Sleep-Wake Syndrome (NON-24)

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Next:  xxxi. Light Therapy Recommendations, 1999

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xix. Phase Response Curve (2)

12 December 2005 at 15:46 | Posted in Circadian rhythm | 2 Comments
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 PRCmelaMIDT-rev
 
 
I can’t yet leave the subject of the PRC, even if it is a bit technical.  Not all researchers say that we have a long “dead zone” mid-day in regard to our response to bright light.  The figure above shows the phase response of melatonin in the blood to light administered at various times.  From a study at Harvard published in 2003, it is somewhat simplified here.
 
21 carefully chosen persons were kept in dim light, then just once exposed to nearly 7 hours of bright light at different points in their personal cycles on the 6th day of a 10-day study.  The timing of each individual’s melatonin secretion was determined at the beginning and again at the end of the experiment.  All results are combined in the curve shown.
 
An interesting point: the midpoints of the individual melatonin profiles were found to be within a range of 2½ to 6 hours prior to these persons’ habitual awakening times. 
 
The horizontal line, about a half an hour below zero, shows how great the delay would have been anyway during the course of the experiment, due to the built-in pacemaker’s longer-than-24-hour period, had there been no light exposure at all. 
   
Phase shifts, from the beginning to the end of the study, are shown in clock time (vertical axis; phase delays are the negative values).  Here, the falling slope in the daytime is only slightly slacker than the rising slope in the night, and the true “dead zone” is only momentary, twelve hours before (or after) the core body temperature minimum. 
 
It is not difficult to explain the long mid-day “dead zone” found by earlier research.  Since bright light has only slight effect in the middle of the day, the effects of light before and after that magic moment will cancel each other out.  Unless, one could imagine, someone consistently is exposed to darkness for an appreciable period just before or just after.  How about someone working in darkness in the projection room of a cinema for the afternoon show, for example — might a phase advance be the result? 
 
The authors state: “These data provide a comprehensive characterization of the human PRC under highly controlled laboratory conditions.”  So this is perhaps the last word on that matter. 
 
Honors for inventing the Phase Response Curve in 1960 go to Patricia DeCoursey.  The “daily” activity rhythms of her flying squirrels, kept in constant darkness, responded to pulses of light exposure.  The response varied according to the time of day — that is, the animals’ subjective “day” — when light was administered.  When DeCoursey plotted all her data relating the quantity and direction (advance or delay) of phase-shift on a single curve, she created the PRC.  It has since been a standard tool in the study of biological rhythms.

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Next post:  xx. Entrainment

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xviii. [CHAPTER TWO] Phase Response Curve

4 December 2005 at 14:59 | Posted in Circadian rhythm | 7 Comments
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“Chapter” One ended, appropriately I think, with a break.  A coffee break…  On to Chapter Two! 
 
A half a year ago, I was struggling to understand what a Phase Response Curve (PRC) is.  Now I’ve drawn one and am going to try to explain it.  In the illustration you can see, obviously, the 24 hours of a day / night on the horizontal, and a good night’s sleep for the person whose PRC is shown.  It’s not mine, not yours, but someone’s Phase Response Curve, similar for all humans.  (Source )  (Another example
 
The hours are clock hours, only if this person’s circadian period happens to be exactly 24 clock hours long.  Most people have a period a bit longer than 24 hours, and will need to advance the phase, shift it earlier, each day. 
 
The human PRC for light
 
This curve shows what light administration does for the timing of the Core Body Temperature in humans.  In general, several other circadian rhythms follow the body temperature rhythm. 
 
The numbers on the vertical axis represent hours of phase shift.  Very bright light to the eyes of this person, immediately upon awakening, will shift her phase two hours earlier, a two-hour advance.  Just a few hours later, light won’t have any effect (in the “dead zone”, where the curve follows the zero-line).  Toward bedtime, exposure to light has the opposite effect; the negative numbers represent a phase delay.  Very bright light just before bedtime will cause a two-hour delay, cancelling out the morning’s advance.  However, the light we usually are exposed to in the evening hours will be considerably less intense.  
 
While the “dead zone” in midday can last for several hours, the “dead zone” in our subjective night lasts for only a moment.  Light exposure shortly thereafter, on the rising portion of the curve, can create a mess according to this chronobiologist.  Exposure to light too many minutes before our spontaneous wake-up time is thus an uncertain business. 
 
Those of us with Delayed Sleep-Phase Syndrome probably have a circadian period which is longer than normal.  We need to phase advance quite a bit each day, just to adjust to nature’s 24 hours.  Advancing even more, in order to awaken at a “normal” time, is impossible without treatment such as that described in my entry no. xvi. 
 
 Have I misunderstood something?  Corrections are welcome! 
 
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Next post:  xix. Phase Response Curve (2) 

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