61. Questions and answers about Non-24

17 February 2011 at 13:56 | Posted in Circadian rhythm | 18 Comments
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About 50% of the totally blind have Non-24-hour Sleep-Wake Cycle Disorder while it is very rare among sighted people.  People with Non-24 cannot adjust to the environmental 24-hour cycle.

If Hayakawa et al. are to be believed, there have been only 96 cases of N24 in sighted people reported in studies, worldwide, ever.  The first 39 were reported in 26 separate studies dated 1970-2003.  Hayakawa’s group reported on 57 cases in a report in 2005*.  These 57 were diagnosed in Japan in 1991-2001.  So what have I learned from that paper?

Are there equally many men and women?  No, there are more than two and a half times as many men.

Is Non-24 about as common as the other Circadian Rhythm Disorders (CRDs)?  No, the other CRDs together, primarily DSPS, are six times as common.

Do people with Non-24 have anything else in common physically?  No.  Eye examinations, blood counts, serum biochemistry, electrocardiography, electroencephalography and brain MRIs show nothing special.

Socially?  89% were unmarried and 39% were unemployed.

Had they any health problems in common before the onset of free-running?  28% had psychiatric problems (obsessive-compulsive, adjustment, schizoprenia, anxiety or depression and often associated social withdrawal), not remarkably higher than the general population.  But more than a fourth had DSPS before developing Non-24.

How old were they at the onset of Non-24?  86% were ten to twenty-nine years old, none younger than ten.  Sex had no effect on the age of onset.  (None of the subjects was over 50.)

Do the hours of sleep correlate to the length of the endogenous circadian cycle?  Most of the subjects’ cycles were between 24.5 and 25.5 hours, with only one having a cycle longer than 26.5 hours.  Subjects slept between less than 7 hours to more than 12, with the majority sleeping 9-11 hours.  But there was no correlation between the period of the sleep-wake cycle and sleep length, and neither was affected by sex nor employment status.

How debilitating is the disorder?  “98% had a history of disturbed social functioning due to inability to regularly attend school or work.”

Do people with Non-24 often develop psychiatric problems after the onset of the disorder.  Yes, but depression only, not the other disorders.  “It is possible that these patients had tried to adapt themselves to their social life and failed, leading to psychological stresses that could have precipitated their depression.”

How does Non-24 in sighted people differ from that of people who are blind?  The blind generally have a shorter circadian period, and it doesn’t fluctuate over time.  In sighted people, the period tends to be longer when sleep onset is in the daytime than when a person falls asleep during nighttime.

*Tatsuro Hayakawa, Makoto Uchiyama, Yuichi Kamei et al.  Clinical Analyses of Sighted Patients with Non-24-Hour Sleep-Wake Syndrome: A Study of 57 Consecutively Diagnosed Cases.   SLEEP 2005;28(8):945-952

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Next post:  62.  Psychiatric misdiagnosis of N24

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xxvii. Two Japanese studies

14 June 2006 at 13:31 | Posted in Circadian rhythm | 6 Comments
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Those of us who can, reset our body clocks daily. The primary cue from the environment is light. The vast majority of us need to advance our phase, that is, shorten our built-in day to match the light/dark cycle in nature. This is what normal people do so easily.  

By definition, people with Delayed Sleep-Phase Syndrome (DSPS) can adjust to a 24 hour day, even though they don’t fall asleep before 2-6 a.m. or even later. People with Non-24-hour Sleep-Wake Syndrome cannot of their own accord.  

M. Uchiyama et al in Japan have studied Non-24 and DSPS people, comparing both with normal controls and with each other. The following table is constructed from two of their reports, published in 2000 and 2002. No blind subjects were included in these two studies. 

* Both the Non-24 and the DSPS people slept longer than the normal ones.

* Non-24 people had a short interval from sleep onset to the melatonin midpoint.

* Both Non-24 and DSPS people had a long interval from the core body temperature trough (nadir) to wake-up.

* DSPS people had a longer interval between sleep onset and nadir than Non-24 people.

 We know that normal people are exposed to morning light about two hours after nadir, as that is their “hard-coded” wake-up time. Light exposure is less and less effective in resetting the body clock in the hours which follow. 

Core body temperature is one marker of an individual’s circadian period.

In the table above, which shows an approximation of the intervals reported, one can see that when DSPS and Non-24 people are allowed to awaken spontaneously, their earliest light exposure occurs much more than the normal two hours after nadir. 

The Japanese researchers conclude that the lack of light two hours after nadir hinders a normal adjustment of the circadian pacemaker. They also postulate that a delayed sleep onset relative to one’s own pacemaker allows for an accelerated light-induced phase-delay. As they put it, “We postulate these alterations in phase relation to be associated with phase changes of the circadian pacemaker via different illumination timings.” 

Non-24 patients have a significantly more faulty phase angle between sleep onset and the circadian pacemaker than DSPS patients have.

Uchiyama M, Okawa M, Shibui K, Kim K, Tagaya H, Kudo Y, Kamei Y, Hayakawa T, Urata J, Takahashi K. Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep-wake syndrome in humans. Neurosci Lett. 2000 Nov 17;294(2):101-4.

Shibui K, Uchiyama M, Okawa M. Melatonin rhythms in delayed sleep phase syndrome. J Biol Rhythms. 1999 Feb;14(1):72-6.

Okawa M, Uchiyama M. Circadian rhythm sleep disorders: characteristics and entrainment pathology in delayed sleep phase and non-24-h sleep-wake syndrome. Sleep Med Rev. 2007 Dec;11(6):485-96. Epub 2007 Oct 25.

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Next:  xxviii. Some good news

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xii. Circadian rhythm disorders

27 November 2005 at 11:14 | Posted in Circadian rhythm | 6 Comments
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There are a great many sleep disorders. I read recently that an official list of them had been pared down to about 70. Many have to do with not getting enough sleep, or getting sleep of poor quality by several criteria. Some have obvious causes, such as chronic pain, frequent stops in breathing etc.

My interest is in the timing of sleep as my sleep seems otherwise normal. As the experts put it, I have normal “sleep architecture”. (For a good, short explanation of sleep architecture — stages and brain waves — see this page from Feinberg School of Medicine at Northwestern University in the USA.)

Nearly all of us can reset our clocks daily, adjusting the various rhythms to 24 hours. As much as I’ve read about it, I’ve not found a good enough explanation for being able to adjust to 24 hours while not being able to adjust to sleeping midnight to eight or so.

I’m not immune to the light/dark cycle. I need to get up at noon. I fly 8 hours east or west, go through jet lag like anyone else and within days I need to get up at noon in the new location. This is built in. I’m not the only one. I’d just like to understand it better.

A Japanese paper (2004) suggests these possible mechanisms:

  • reduced sensitivity of the oscillator to photic entrainment,
  • an intrinsic period beyond the range of entrainment to the 24 hour day, and
  • abnormal coupling of the sleep/wake cycle to the circadian rhythm.

 

The least common and most debilitating circadian disorder is the one where body temperature, melatonin secretion, sleep and other rhythms vary several times a day, in and out of phase with one another, so called Irregular Sleep/Wake Disorder. This has been reported in humans who’ve been in accidents and had physical injuries to the hypothalamus. It’s also been provoked by surgery in lab animals.

One of the most rare disorders which occurs naturally is called Non-24. Sufferers simply(?) live on a 23, 25 or 26 hour cycle, getting up one hour later each day for example, thus coming in sync with the earth’s rotation every few weeks. Their rhythms are in sync internally, just not with the light/dark cycle outside. Most, but not all, of these people are blind. 

ASPS, Advanced Sleep-Phase Syndrome, is also rare. These people fall asleep and awaken much earlier than normal. The disorder runs in families, and an American family has been studied intensively the last few years. Research on their genetic mutation was published in 2001. “Detailed sequence studies of the candidate human gene, hPer2, in the affected family members, revealed a key change in a single amino acid — from serine to glycine — at position 662 in the hPer2 protein.” The alteration “occurred in the portion of the hPer2 protein that governed binding to an enzyme called casein kinase one-epsilon (CK1e ).” In animal models, this enzyme regulates “proteins involved in controlling the length of circadian rhythms.”

Now this is beyond me, but it would appear that these disorders may be genetically programmed. Though ASPS is rare, it seems reasonable that researchers start there, since one can compare the DNA of people who are related to one other.

DSPS, Delayed Sleep-Phase Syndrome, is a bit more common. Studies indicate that somewhat more than one in a thousand adults have DSPS (Japan 0.13%, Norway 0.17%). It runs less commonly in families, but it doesn’t seem unreasonable to guess that its cause may be similar to that of ASPS.
 
Clearly, anyone whose health cannot tolerate frequent forced awakening earlier than 10 a.m., will have few real choices in our society. Thus, hardcore (inflexible) DSPS must be considered a disability.

Another disorder which may be related to the others is Seasonal Affective Disorder, SAD. Sufferers are normal in summer, have problems of mood, weight gain etc. when days get shorter and can often be treated successfully by bright light therapy. It seems likely that they may have a mild form of ASPS or DSPS which is “treated” by morning/evening daylight when days are long.

Diurnal preference, spoken of as “morningness”, larks, and “eveningness”, owls, is also a subject of study, the field of chronobiology. This is, reasonably enough, connected to one’s circadian rhythms. However, it does not appear that ASPS is an extreme morningness chronotype nor DSPS an extreme eveningness chronotype. The internal relationships among the various rhythms do not place these conditions on a simple continuum.

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Next post:  xiii. DSPS-sleep

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