63. Sleep research in the USA

12 May 2011 at 19:25 | Posted in Circadian rhythm | 6 Comments
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Funding of sleep research by the National Institutes of Health (NIH) is prioritized according to the National Sleep Disorders Research Plan.  The plan resulted from 1993 legislation establishing the National Center on Sleep Disorders Research with the mandate, in part, to:

  • Conduct and support research, training, health information dissemination, and other activities with respect to a basic understanding of sleep and sleep disorders, including research on biological and circadian rhythms, chronobiology, and other sleep-related topics.

The first such plan was dated 1996.  The second and current one is from 2003:  http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/sleep-rplan.pdf  

The present Sleep Disorders Research Advisory Board, chaired by Charles A. Czeisler and with Michael Twery as Executive Director, has been working for a year or so on a revision.  The 2011 research plan will provide a guide for future scientific sleep and circadian research, both basic and clinical.

While the 2003 plan is organized under such headings as Basic sleep science, Enabling technology, and Pediatrics, the 2011 plan will be organized around research goals.

The draft of April 2011 contains five goals.  They are concerned with, in short version:

  1. Sleep and circadian functions and mechanisms
  2. Factors contributing to sleep and circadian disorders and disturbances
  3. Prevention, diagnosis and treatment of sleep and circadian disorders and circadian disruption
  4. Dissemination of sleep and circadian research findings
  5. Sleep and circadian research training, to accelerate the pace of discovery

There appears to be a greatly increased emphasis on circadian disorders and research in this draft.  The word ‘sleep’ appears seldom alone; it’s always ‘sleep and circadian’.

Those of us with circadian abnormalities are perhaps most happy with goal 4.  Health care professionals, educators, policy makers and the general public are at present largely unaware of the results of research to date, and the resulting ignorance leads to misdiagnosis of most of us.  The research community knows a great deal more than the medical community does, and dissemination of that knowledge should have high priority.

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Next post:  64.  Circadian Sleep Disorders Network

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62. Psychiatric misdiagnosis of N24

31 March 2011 at 05:27 | Posted in Circadian rhythm, Melatonin, N24 | 21 Comments
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I’ve been reading an interesting article on a case of psychiatric misdiagnosis of N24 in a 14-year old.  This poor kid was given a long list of severe and pejorative psychiatric diagnoses, all of which resolved completely when his circadian rhythms were normalized with melatonin treatment.  He had dropped out of school for two years and was sent to a child psychiatric hospital.  After treatment was able to return to school and do well.  This case shows how easily N24 (and DSPS) can be misdiagnosed.  The boy was also lucky he responded to melatonin as many N24s do not.

Here is the description of his case before proper diagnosis and treatment:

During the 4 years before referral,
the patient suffered from major functioning difficulties
including conflicts with teachers, parents, and peers. He
was described by a licensed child psychologist as being
extremely introverted with severe narcissistic traits, poverty
of thought, and disturbed thinking, including
thoughts with persecutory content and self-destruction
that led to a paralyzing anxiety, anhedonia, social isolation,
and withdrawal. Assessment of learning disabilities
revealed difficulties with written language and poor
visual and auditory memory. Assessment also revealed
above-average performances in verbal comprehension
and abstract reasoning.

Two years before referral, the patient dropped out of
school and was sent to an inpatient child psychiatry center.
Three months of psychiatric evaluation yielded diagnoses
of atypical depressive disorder with possible
schizotypal personality disorder. He was described as
sleepy and passive, especially in the mornings.

The patient was diagnosed using actigraphy (a wrist monitor that measures movement) and with 24 hour sampling of melatonin and temperature rhythms.  This is his actigraphy chart showing the classic N24 pattern in which the waking period shifts later each day.  The black peaks on the chart show movement, indicating the time of day or night during which he was awake.

Treatment with 5mg of melatonin (a large dose) at 8pm resulted in a normalization of his circadian rhythms within a month.

Here is how he was described after proper diagnosis and treatment:

The patient returned to school after a 1 years absence
and succeeded in filling the gaps of missing studies. At the
end of the first semester, his school report showed excellent
results. His parents also reported an improvement in
the patients relationship with his family and peers.
In a psychiatric evaluation by licensed psychiatrists,
none of the previously described severe diagnoses were
present, and the boy showed no evidence of psychopathology,
as was previously thought.

One wonders how many adolescents — and adults — are misdiagnosed with various severe psychiatric disorders simply because no one looked for a circadian rhythm sleep disorder.   The case was reported by Yaron Dagan and Liat Ayalon two of the best researchers on the clinical manifestations of N24 [1].

1.  Dagan Y, Ayalon L. Case study: psychiatric misdiagnosis of non-24-hours sleep-wake schedule disorder resolved by melatonin. J Am Acad Child Adolesc Psychiatry. 2005 Dec;44(12):1271-5.

–Posted by LivingWithN24 (James Fadden)

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Next post:  63. Sleep research in the USA

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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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60. Charting the course of N24

27 October 2010 at 09:25 | Posted in Circadian rhythm, DSPS, Sleep diary | 26 Comments
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Keeping a sleep log or a sleep chart is one of the keys to getting a proper diagnosis of a circadian sleep disorder.  Oftentimes someone will describe their sleep patterns, but it’s not always clear from the description when exactly they sleep.  For example, someone will say they “keep going to bed later and later.”   Depending on what they mean, that could either describe Non-24 Hour Sleep-Wake Cycle Disorder (N24) or a gradually worsening case of Delayed Sleep Phase Syndrome (DSPS).    But a quick look at a sleep chart will usually clear up the distinction.

My eponymous co-blogger Delayed2Sleep, who has, of course, DSPS, has posted several of her sleep logs.   Today I am going to post some of my sleep charts.  My name is LivingwithN24 and I have, you guessed it, N24.

One thing I should note to start is that I have always charted my sleep on a vertical chart, whereas D2S has used a horizontal layout, so you’ll need to rotate the charts to compare them.  I have also “double-plotted” some of my sleep charts.  That means each line on the chart encompasses 48 hours.  That’s a standard method in sleep studies as it helps the patterns to stand out more clearly.

I have had N24 for many years.  Here are two pages from a chart of my sleep I compiled in 1991.   In those days I kept my charts on graph paper.

These charts show a textbook case of N24.   The phrase “textbook case” is not a metaphor here; the medical journal articles about my case are commonly cited in reviews of circadian sleep disorders.  So there is no doubt you are looking at a case of N24 sleep.  One can see that the sleep chart of an N24 shows a characteristic diagonal pattern as the bedtime and waking time slides gradually later each day.  Unlike the case of DSPS, the delay does not stabilize at a particular clock time.  Someone with DSPS may for example end up going to bed always around 6am for an extended period.   Someone with N24 who goes to bed at 6am on Monday will likely go to bed at 7am on Tuesday, 8am on Wednesday, 9am on Thursday etc. until  they have gone all the way around the clock.  The delay is not always by one hour — I just chose that for simplicity.  In my case I tended to delay 1.5 hours per day, meaning my “day” was actually 25.5 hours.

One can see in this chart that there is some irregularity in the sleep times, and there may also be daytime naps.  Both of these showed up a lot in January and February of that year.  But there is a nonetheless a clear pattern to the sleep.  In some months such as March, April and May it stands out especially clearly.

It might also be of interest to compare these charts to another type of chart.  In circadian medicine a technique called actigraphy is used. The patient wears a device called an actimeter on their wrist which records movement.  Since people tend to move about a lot more when awake than when asleep, actigraphy can be a way of confirming the sleep times of a patient with N24 or DSPS.  Here is an actigraphic chart of my sleep from around the same time as the sleep logs.   The difference is the black squiggles on the actigraphic chart show time awake, rather than asleep, but the same diagonal pattern is present.

Now those charts are from 1991.  The readers of this blog are clever folks and have no doubt noticed it is now 2010. I did this for a reason.  Most of the studies of N24 have looked the subjects at one point in their lives.   Few, if any, have examined how the sleep patterns of N24 change over the course of many years.  I have noticed a number of changes in my sleep between 1991 and today.

One thing I noticed is that it is much more difficult to control my N24 with lights, darkness and sleeping medications.  In fact, over this summer it became impossible.  So in September I stopped using the lightbox and the sleeping pills to see what my sleep would do on my own.

Here is a sleep chart I made for the last 5 weeks (Sept 18-Oct 25, 2010).  Instead of making the chart by hand I used the SleepChart program from supermemo.com.

This is quite different from the 1991 charts.  While there is still a recognizable diagonal drift of the sleep times, it is much more erratic.  The times of sleep are much less regular.  Also there is a marked tendency to show two or more periods of sleep instead of one for each circadian day.

In some ways this pattern of sleep is in between that of Non-24 Hour Sleep Wake Cycle Disorder and that of Sleep Wake Cycle Disorder – Irregular Type.   In the irregular type of sleep disorder, the person sleeps at almost random times of day or night and for varying lengths of time.  Usually there are several short periods of sleep scattered at various time around the clock.

My sleep has not become completely irregular, but it is getting there.  This is, to put it mildly, not a good thing.  N24, bad as it is, has a least a little predictability to it.  I could never predict my sleep out several weeks as some very regular N24s could do.  But I could at least predict it fairly well 5 or 6 days out.   Now I can barely predict what it will do from one day to the next and the urge to sleep or be awake comes upon me at almost random times.

Usually irregular sleep patterns are associated with conditions involving brain damage (injuries, tumors) or deterioration (dementia).   However I suspect that in cases of severe circadian disorder the circadian system may deteriorate over time, leading to an evolution towards an irregular sleep pattern.   My co-blogger has remarked that her DSPS sleep has some irregular elements as well.

Instead of a static snapshot of sleep which classifies the disorders as DSPS, N24 or irregular, research needs to look at sleep disorders as dynamic, evolving conditions.  If someone has say, heart disease, we understand it will manifest itself differently at age 20 and 40 and 60.  The same may be the case with circadian disorders.  I had some sleep abnormalities from birth, classic DSPS from age 15 to 27, and N24 from then on.  Now I seem to be trending towards irregular sleep.   My approach to coping with this condition will have to change as well, but how that will happen I don’t yet know.

–posted by LivingWithN24 (James Fadden)

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Next post:  61.  Questions and answers about Non-24

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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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