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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l(L). A Man with Too Long a Day

14 February 2010 at 01:33 | Posted in Circadian rhythm | 18 Comments
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The Physiological Society is an venerable British scientific society dating from the time of Darwin.   Articles in their journal, Proceedings of the Physiological Society, normally have rather obscure titles like “Synaptic connexions of serotonin-containing neurons in Planorbis Corneus.”  But in 1970 a paper from three scientists at  the University of Manchester appeared with a title that reads more like that of a science fiction story: “A Man with Too Long a Day”.   The man who was the subject of the paper claimed that he was unable to live on a 24-hour day.  Instead his sleep wake cycle followed a 26-hour pattern.  While humans in isolation experiments sometimes followed non-24 hour schedules, this was the first report of someone who followed such a pattern in normal life, and, more importantly to him, he was unable to live on 24 hours however hard he tried.  The scientists were able to confirm the reality of his complaint by a clever experiment.

He was then confined in an isolation unit, without a timepiece, and his
habits were recorded by a remote signalling device; he there followed an
activity cycle of 26 hr. After 5 days a clock, which he knew could be
adjusted to gain or lose several hours a day, was started, and he was asked
to try to conform his habits to the time recorded on the clock; unknown
to the subject, this clock was running at a normal rate, though its absolute
time was in error since it was started at the time which he believed it to be.
He was still unable to conform his habits to a 24 hr cycle, just as when
living in nychthemeral surroundings.

This was the first report of what is now known as Non-24 Hour Sleep Wake Cycle Disorder, more concisely N24.  The authors did not report any attempt to treat his condition.

Eight years later, doctors at the Albert Einstein College of Medicine reported another case of what they called “hypernychthemeral syndrome” after the Greek hyper (over) + nychthemeron (24-hour period of night and day).  Long-term temperature monitoring recorded his rhythms for several months.   In 1980 a third case was reported, this time of a man “John” and his partner “Mary”.  John had N24 while Mary’s sleep had previously been  normal but at times followed Johns N24 schedule.  Charts of their sleep show a kind of circadian dance as their rhythms would coincide for a while and then diverge.

None of these early cases were successfully treated.  In 1983 the Clinical Psychobiology Branch at the US National Institutes of Health reported the first successful treatment of N24, by using vitamin B-12.  Subsequent cases have reported N24s who respond to B-12 although many do not.  (It makes me much worse!)

The next known case, in 1985, responded to clonazepam but the subject reported he felt worse on the drug despite his normalized schedule and chose to stop the drug and resume an N24 schedule.  This was a pattern often found in later N24 cases — sometimes the cure is worse than the disease.

Three reports in the late 80s studied the effects of light, with differing results.   Light successfully treated one person.  Another N24 was initially able to entrain with light, but a later Internet report seems to say she (by the way the first woman with true N24) had to stop it due to migraines.  But a Japanese study found that an N24 person was resistant to the normal phase shifting effects of light, suggesting that some N24s develop the condition due to insensitivity to light.

A few more reports appeared in the early 1990s.  The NIH published a detailed study of a second patient, showing endocrine abnormalities, some of which were corrected by light treatment while others were not.  And researchers in Japan published a growing number of case reports and pioneering studies.

What’s striking about these early cases of N24 is how few of them there were: eight years between the first and second cases!  N24 appeared to be a very rare disorder, and it’s probable no N24 ever met anyone else with N24.

Then came the Internet.

As with many conditions, the Internet has broken the isolation of N24s.  It’s still a rare condition by any measure, but not as rare as once thought.  On Internet sites and mailing lists such as the NiteOwl list for DSPS and N24, more and more N24 people are popping up to say “I’m here” and the talk about the difficulties of living with and/or trying to treat their condition.  And that’s why I’m here on this blog, to talk about N24, what N24 folks say, what the science says.   This post has been about the past of N24, but we are here to make a better future for those whose sleep follows a “different drummer”.  Great thanks to delayed2sleep for inviting me on this blog.  Let’s see what we can do!

Postscript:

I classified “A Man with Too Long a Day” as the first medical report of a person with N24, and that is accurate and how it is generally cited in the medical literature.   However a few years ago I was reading Sylvia Nasar’s biography of John Nash, A Beautiful Mind. She devotes a chapter to Nash’s friend, the brilliant mathematician and game theorist Lloyd Shapley.  Shapley and Nash met at Princeton in 1950 when both were graduate students.  In describing Shapley, Nasar says this:

Shapley’s greatest eccentricity at the time was his claim that he was on a
twenty-five-hour sleep cycle. He worked and slept at extremely odd hours, often
transposing night and day. “Every once in a while he’d disappear from sight.”
another student recalled. “That’s what he said. We accepted anything.”

It’s not clear if Shapley’s schedule was voluntary or involuntary.  The latter would make him the first known N24.

Posted by LivingwithN24 (James Fadden).

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Next post:  51. Melatonin: Less Is (Sometimes) More

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xlii. Researchers mentioned here

13 June 2009 at 18:05 | Posted in Circadian rhythm | 6 Comments
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Several researchers have been mentioned / cited here, and there’ll surely be more.  They are listed below. 

Bjorvatn, Bjørn (in post vii.), is a sleep researcher at the University in Bergen, Norway, and a co-founder of Bergen Sleep Center.

Czeisler, Charles A. (in post xliii.) has been researching circadian rhythms for several decades.

Dagan, Yaron  (in post xxxviii.) in Israel, often publishing together with Judith Abadi, stated in 2001: “Certain sleep-wake schedule disorders (SWSDs) cannot be successfully managed clinically (…).  …we propose new medical terminology for such cases–SWSD disability. SWSD disability is an untreatable pathology of the circadian time structure…  It is imperative that physicians recognize the medical condition of SWSD disability in their patients and bring it to the notice of the public institutions responsible for vocational and social rehabilitation.”  In almost all of his papers, he emphasizes that people with circadian rhythm disorders often are misdiagnosed because physicians don’t know (enough) about such disorders.  Here is a case study (abstract) about a 14-year-old boy whose other diagnoses fell as soon as his sleep disorder was diagnosed.  It should perhaps be obvious that I appreciate Dagan’s work and his opinion. 

DeCoursey, Patricia (in post xix.), is the grand old, grand old of the field of chronobiology.  In 1960 she invented the Phase Response Curve when 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.

Dijk and Lockley (in post v.).  Derk-Jan Dijk and Steven W. Lockley often publish together.  Dijk, who studies the regulation of sleep and circadian rhythms in humans, is director of the Surrey Sleep Research Centre in the UK.  Lockley, Assistant Professor of Medicine, Harvard Medical School, and Associate Neuroscientist in Sleep Medicine, Brigham and Women’s Hospital in the USA, is particularly interested in the effects of light on the circadian pacemaker in humans.

Horne and Östberg (in post xxxviii.) published their Morningness-Eveningness Questionnaire (MEQ) in 1976.   It is based on O. Öquist’s 1970 thesis at the Department of Psychology, University of Göteborg, Sweden: ”Kartläggning av individuella dygnsrytmer”, “Charting Individual Circadian Rhythms”.  This marks the beginning of modern research into chronotypes.  Olov Östberg modified Öquist’s questionnaire and, together with J. A. (Jim) Horne, he published the MEQ (pmid 1027738, abstract ) which still is used and referred to in virtually all research on this topic. 

Roenneberg, Till (in post xxxvii. and in post xlvii.), professor at the University of Munich, is one of the best-known chronobiologists in Europe, having received international prizes for both his research and his teaching.  He has built up the Centre for Chronobiology at the Munich Medical School with its database on the sleep of over 50 000 Europeans.  In 2008 in India he collaborated with and directed a project in Mangalore chronotyping the south Indian population, with data covering nearly 75 000 participants.  Roenneberg’s work ranges from the cellular/molecular mechanisms of the circadian clock to the consequences of shift work and, as mentioned, huge surveys.

Thorpy, Michael J. (post xxxii.), board certified in sleep medicine, is a sleep researcher and a professor of clinical neurology at the Albert Einstein College of Medicine in New York.  He has held high office in the National Sleep Foundation and in the Sleep Section of the American Academy of Neurology.  Thorpy was for many years editor of The International Classification of Sleep Disorders: Diagnostic and Coding Manual (ICSD) and has been publishing books and articles since the 1980s.

Uchiyama, Makoto (in posts xxxviii. and xxvii.), professor at the Nihon University School of Medicine in Tokyo and managing editor of Sleep and Biological Rhythms, the official English language journal of the Japanese Society of Sleep Research (JSSR), is a prolific co-author of studies on sleep, particularly on DSPS and Non-24, often in cooperation with Masako Okawa, chair of the Asian Sleep Research Society. (ASRS).  This research field is very active in Japan, where study subjects often are people with these disorders.  In the west, in contrast, studies are more often done on healthy, normal people with results extrapolated to effects in people with the disorders.  The Japanese researchers have shown, for example, that the interval between the lowest core body temperature and spontaneous awakening is much longer in people with Non-24 and DSPS than the “about two hours” which is considered normal.

Zivkovic, Bora, aka “Coturnix (in posts xxxvii.xxxiii.xviii. and  xv.), should have had his PhD by now but the ideal job came along and his dissertation isn’t getting done.  He tells about that and about chronobiology and about lots more at ScienceBlogs

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Next:  xliii. Blindfolding the blind

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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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