One of the rhythms we consider is the ultradian rhythm of sleep. This leads us almost seamlessly into a discussion of the nature and possible explanations of sleep. Sleep is still an enigma. We spend longer practising this behaviour than any other. An adult living to an average age of around 80 years will have spent over 25 of those asleep. So what’s it all about this sleep thing? Dreaming is no longer on the specification but it is a major psychological characteristic of REM sleep and is always worth a brief chat!
Finally we look at sleep disorders. Some of these are common, insomnia being the one most widely suffered. Others are thankfully rare but nevertheless fascinating. The best example of this second category being narcolepsy. Until very recently narcolepsy was a mystery with no known obvious cause. In recent years research has pointed the way to possible future treatments for what is a most debilitating disorder. We shall also consider somnambulism (sleep walking) and sleep apnoea, as a possible secondary cause of insomnia.
You will notice, as we progress, that inevitably there is some overlap between topics. It would be difficult to consider biorhythms without looking at the stages of sleep for example.
Most human and non-human animal functions are cyclic, alternating over a period of time. Obvious examples include the sleep-wake cycle which repeats over a 24 hour cycle, or the hibernation patterns of some creatures that typically rest through the winter months and awaken in spring. The major debate, similar to the nature/nurture in some respects, but without the controversy, is to what extent biological rhythms are determined by internal clocks (endogenous factors) and by environmental factors (so called zeitgebers).
What has become apparent in recent years is the ancient nature of the rhythms. Clocks have been found to exist in the very simplest forms of life, algae. It therefore seems reasonable to assume that they have been around since the beginning of life on Earth. Biological rhythms allow organisms to adapt to the cycle of day and night and they appear to control nearly all behaviours and physiological processes.
In this topic we consider the three main categories of biological rhythms and the extent to which they are controlled by internal and external factors. We then consider what happens when our rhythms are disrupted.
- Circadian Rhythms (about 24 hours)
- Infradian Rhythms (greater than 24 hours)
- Ultradian Rhythms (less than 24 hours at night)
There are others that we might mention en passant:
Circannual rhythms, as the name suggests rhythms that cycle over a period of one year. These are therefore a subset of infradian.
Diurnal rhythms that are less than 24 hours but confined to daytime or waking hours, as opposed to ultradian at night or during sleep.
Variation is a cycle that repeats over an approximate 24 hour period. The word stems from the Latin; circa (meaning ‘about’) and diem (meaning ‘day’). There are some cycles that we are consciously aware of; the sleep/wake cycle being an obvious one, but most cycles we are not usually aware of. For example our core body temperature fluctuates over a 24 hour period. Generally it peaks mid afternoon at about 37.1 C and troughs in the wee small hours at about 36.7 C. This may not sound like a lot but you may nevertheless have noticed the effect and found yourself shivering unexpectedly as you’ve walked home after a late night party, even in August!
Other examples of human circadian rhythm include heart rate, metabolism and breathing. These follow a similar pattern to temperature, which may not seem surprising, since they match our patterns of activity. However, people on shifts, who are sleeping through the day and more active at night still keep the same circadian rhythms with body temperature, metabolism and resting heart rate still peaking mid afternoon!
Blood clotting also shows a circadian rhythm, peaking in the morning and coinciding with increased incidence of heart attack
It is worth mentioning that there are big differences between individuals. The most noticeable being the larks/owls division; larks being morning types and owls preferring the evenings. Typically when studied larks seem to be clock advanced having rhythms about two hours ahead of owls.
Is the circadian rhythm determined by internal mechanisms or external factors?
As second year psychologists you should be able to guess the answer to this one. Whenever faced with an ‘is it nature or is it nurture’ question, it’s always BOTH!
First some terminology:
- Endogenous: refers to internal, physiological factors
- Exogenous: refers to external or environmental/social factors
Zeitgeber: we also have the added complication of this German word that roughly translated means ‘time giver’ and refers to exogenous factors that indicate times of day.
We shall consider the role played by endogenous and exogenous (zeitgebers) in the control of the circadian rhythm.
There is plenty of evidence to suggest that our biological rhythms are inherited. For example although within a species there is variation of rhythm, each individual tends to have a pattern of rhythm that shows little variation over a lifetime. Even the most extreme of environmental factors such as anaesthesia (not the late Russian Princess), alcohol and drug abuse, brain damage and loss of consciousness have little effect on our rhythms.
To study endogenous clocks it is necessary to isolate people from external cues for many months. In 1962 Aschoff and Wever studied a number of volunteers that agreed to spend time cut off from the outside world in a disused WWII bunker in Munich. After a month or so cut off from external cues they adopted a 25 hour daily cycle.
There is internal control of the circadian rhythm, since even in the absence of external cues we are able to maintain a regular daily cycle.
There must usually be some external cue that keeps this cycle to 24 hours. When this is removed we adopt this very strange 24.5 or 25 hour cycle.
Some have criticised this research since it is so artificial. In particular they object to the use of strong artificial light by the participants. On waking the volunteers such as Siffre switch on lights which are likely to artificially re-set the body clock. Czeisler et al (1999) has argued this is the equivalent of providing powerful drugs.
In their own version, Czeisler et al kept 24 participants in constant artificial low-level light for one month and put them on a 28 hour cycle. When readings of body temperature and blood chemicals were analysed they were shown to have adopted a cycle of 24 hours and 11 minutes, much closer to the 24 hours we would expect.
Others however, disagree with Czeisler. In an attempt to find the endogenous clocks’ period volunteers have been exposed to severe variations in clock alteration, for example, exposing participants to artificial lighting simulating a 28 hour day. (So if ‘sunrise’ was at 6am on day 1 it would be at 10am on day 2 and so on). The body cannot adjust to such extremes and the body clocks ‘run free.’ In all cases the cycle is greater than the usual 24 hours but estimates vary as to the exact length. Some put the increase at as little as 11 minutes whereas others claim one hour.
Folkard (1985) showed the limitation of purely exogenous factors in controlling the rhythm. He got 12 volunteers to spend 3 weeks in isolation with no natural light. They were instructed to go to bed when the clock suggested 23.45 and set alarms for 07.45. After a few days the clock was speeded up so that the supposed 24 hours were passing in only 22. Only one of the volunteers kept pace. The other twelve all maintained a 24 hour rhythm, suggesting internal biological factors were over-riding exogenous factors (in this case quite literally ‘time-giver’ in the form of a clock!).
Body clocks are everywhere
The SCN appears to be the location of the main clock but there are certainly others. Yamazaki et al (2000) found that tissues from the liver, lungs and other organs could maintain a constant 24 hour cycle despite being kept in vitro (outside the body).
Biological basis of circadian rhythms
In lower species the pineal gland appears to be the brain structure responsible for regulating bodily rhythms, especially the sleep/wake cycle. The pineal gland lies at the top of the brainstem and in lower species this means it is close to the surface of the skull. As well as having an inbuilt cycle it also has light sensitive cells that receive information through the skull about external light levels and these seem to keep it synchronised with fluctuating environmental conditions. The pineal gland secretes melatonin which is known to have an influence on sleep patterns.
In humans the pineal gland is still situated in the same place, at the top of the brainstem, but we have an extensive cerebral cortex overlying this. (When I say ‘we’ I refer to most of us!). This means the pineal gland is situated deep inside the brain so has no direct contact with conditions outside. (In fact the Greeks considered the pineal gland to be a possible site for the ‘soul’ since it was situated in the centre of the brain)
Work is being carried out apace into biological rhythms. Recent research (Albus et al 2005) has shed light (sorry) on the structure of the SCN.
The hypothalamus crops up all the time in A-level psychology. If there’s a brain area involved chances are it’s gonna be the hypothalamus! To imagine its location, think of a line travelling back from the bridge of your nose. Where this crosses another line from just forward of your ears is approximately where you should find yours! However, it isn’t a unitary structure. Instead this pea-sized bundle of miracles is in fact comprised of a number of distinct areas called nuclei (one of which is the SCN). Like most brain structures it also appears in both hemispheres. Albus added to the complexity of the SCN by splitting each of these into a ventral (forward) and dorsal (back). According to Albus, the ventral portion is more sensitive to light so tends to keep pace with changing environments whereas the dorsal is not so easy to re-set. It is more likely to ‘run free.’ This could provide part of the answer to the issue of desynchronisation (jet lag) that we shall consider later.
External Factors (zeitgebers)
Light appears to be crucial in maintaining 24 hour cycles:
Miles et al (1977) reported the case study of a blind man who had a daily rhythm of 24.9 hours. Other zeitgebers such as clocks, radio etc. failed to reset the endogenous clock and the man relied on stimulants and sedatives to maintain a 24 hour sleep/wake cycle. However, the question remains, how do the majority of blind people still manage to maintain a 24 hour cycle?
Campbell & Murphy (1998), in a bizarre experiment, shone bright lights onto the back of participants’ knees and were able to alter their circadian rhythms in line with the light exposure. The exact mechanism for this is unclear, but it seems possible that the blood chemistry was altered and this was detected by the SCN.
The above study suggests that light detection in the body may be more complex than we might believe. The fact that most blind people seem to be detecting light to reset their body clock also suggests cells other than rods and cones may be responsible.
The rods and cones both contain light sensitive opsin molecules. However, a mutant strain of mice that have retinal degeneration lose their rods and cones but retain their biological rhythms. Severing the optic nerve in mice however, does destroy the rhythm. This appears contradictory, unless we assume that there are receptors in the eye other than rods and cones!
There are a number of possible candidates. Initially Sancar and others suggested that cryptochromes (which detect blue light) might be passing on the information to the body clock. These are particularly interesting since they are also present in plants. Later research has implicated another chemical melanopsin. Eckler et al (2008) found that killing these cells in mice made entrainment impossible. The mice could not adapt to changing light conditions suggesting these cells are the detecting mechanism. This would explain Mile’s blind man study. Although the blind man has lost the ability to detect light using rods and cones (so is unable to consciously perceive light) other cells like those containing melanopsin are still detecting light at an unconscious level and passing on this information to the body clock.
Severing the optic nerve however, would prevent all information from the eyes, be it conscious perception or unconscious reaching the brain. Presumably the case that Miles studied had damage to his optic nerve.
It seems that most people in the industrialised world are out of synchronisation with the natural world and this might be posing all sorts of risks for our physiological and psychological health.
A recent study looked at the extent to which our natural clock might be lagging behind sunrise and sunset and how this can quickly be adjusted. A small group of volunteers were tested. It was found that most were going to sleep after midnight and that as a result their melatonin levels were still high when they woke up in the morning and often were still high two hours after waking. This meant that they were working against their natural cycles.
However, after one week’s camping in Colorado, no artificial light other than campfire allowed, their clocks were back in tune with sunrise and sunset. On average they had shifted backwards by two hours so were sleeping and rising earlier, although total sleep time had not been affected. Melatonin was being secreted earlier and levels were dropping long before waking. Crucial to this shift appeared to be natural light. It was estimated that total exposure to natural light had increased fourfold. (Wright 2013)
Practical applications of research into the body clock
Think back to the Horizon documentary using the body clock to better treat cancers and improve the psychological health of patients with Alzheimer’s.
Dr Reddy’s research at the University of Cambridge (2012):
The body’s immune system is more effective at certain times of the day. For example, patients with blood poisoning are more likely to die between the hours of 2 and 6 am when the body’s defences are at their weakest.
Reddy and his co-workers have found that a protein TLR9 which detects the DNA of microbes such as bacteria and viruses is controlled by the body clock, at least in mice! Immunising mice when their body clock is at its peak is most effective in fighting off a range of infections, much as treatment with chemotherapy we saw in the video.
They have concluded that drugs need to be administered at certain times of the day perhaps longer term, drugs can be administered to alter the body clock to its optimum level.
This is how I’d conclude my essay on biological rhythms, especially one answering the old favourite on internal and external control of rhythms.
Our biological rhythms therefore appear to be internally and externally controlled. Left to their own devices our internal clocks seem to be set to about a 25 hour cycle but external cues, especially light, resets our clocks daily. So why do we need internal and external control? If control was entirely internal we would not be sensitive to external changes such as light levels. Species that hibernate or migrate would not adjust their behaviour. This could be fatal if winter came earlier than expected and animals had failed to prepare for winter in time or were still stuck in colder parts of the World.
If control was entirely external our rhythms would be too erratic and change day to day depending on weather conditions etc. We therefore have an internal mechanism that keeps us relatively stable but is sensitive to environmental factors that allow for adjustments based on weather conditions and available food.
These occur more than once in a 24 hour cycle and at night time. We shall consider the stages of sleep. As you should be aware, a typical night’s sleep takes you from stage 1 to 4 then back to 2 and finally into REM. This whole cycle then repeats itself three or four more times during the night, each cycle lasting about 90 minutes. There are a number of similar cycles during the daytime too. Sometimes these are referred to as diurnal. Examples include eating (approximately every four hours), smoking and drinking caffeine (in those addicted), and urination.
Stages of sleep
This section fits logically into both the ‘biorhythms’ and the ‘sleep’ sections of this particular topic area. We shall cover it as an example of a rhythm but some of the information is also relevant to the section on sleep, particularly a question covering the physiology of sleep.
I know that Henry Ford said that this was ‘bunk’ but the history of sleep is useful from the point of view of research into the stages of sleep.
Until the 1930s there was no scientific or objective way of measuring what was happening in the brain. Following the invention of the electroencephalogram (EEG), it became possible to record the electrical activity of the brain. This was crucial, since as you should be aware by now, the activity of the brain is mainly electrical in nature.
- 1937: Loomis et al discover that during sleep the waves generated by the brain slow and become larger. For the scientists amongst you, the frequency falls as the wavelength increases.
- 1952: Aserinsky was checking to make sure that his newly acquired EEG was working properly. He placed the electrodes of the machine near to the eyes of his eight year old son, Armond whilst he was asleep. At regular intervals he noticed that there were bursts of electrical activity.
- 1953: Aserinsky & Kleitman coin the phrase ‘Rapid Eye Movement’ or REM.
- 1957: Dement & Kleitman realise that there appears to be a link between REM sleep and dreaming. They tested 5 participants, waking them either 5 or 15 minutes into periods of REM sleep. Participants would normally report dreams and the length of the dream would correspond to the time that they had spent in REM.
- 1968: Rechtschaffen & Kales record four other distinct stages of sleep.
All this is important because prior to the 1930s it was assumed that sleep was sleep. Nobody even considered the possibility of different stages or patterns of activity.
Aserinsky and Kleitman (1957)
Nine participants were studies (seven male and two female)
Participants ate normally (excluding coffee and alcohol) then arrived at the laboratory just before their normal bedtime. They went to sleep with electrodes attached beside the eyes (EOG) and on the scalp (EEG). Participants were woken by a doorbell at various times during the night and asked to describe their dream if they were having one, then returned to sleep.
Participants were woken either in REM or NREM (but not told which). They confirmed whether they were having a dream and described the content into a recorder.
The direction of eye movements was detected using electrodes around the eyes. Participants were woken after the persistence of a single eye-movement pattern for more than one minute and asked to report their dream. The eye-movement patterns were either: mainly vertical, mainly horizontal, both vertical and horizontal, very little or no movement.
Uninterrupted dream stages lasted 3-50 minutes (mean approx 20 minutes), were typically longer later in the night and showed intermittent bursts of around 2-100 REMs.
The cycle length varied between participants but was consistent within individuals, eg 70 for one, 104 for another.
When woken in NREM participants returned to NREM, but when woken in REM they typically didn’t dream again until the next REM phase (except sometimes in the final REM phase).
Participants frequently described dreams when woken in REM but rarely did so from NREM sleep (although there were some individual differences) and this differences was marked at the end of the NREM period (within 8 minutes of cessation of REM – only 6 dreams recalled in 132 awakenings). In NREM awakenings, participants tended to describe feelings but not specific dream content.
Accuracy of estimation of 5 or 15 minutes’ of REM was very high (88% and 78% respectively). REM duration and number of words in the narrative were significantly positively correlated.
Eye movement patterns were related to dream content, eg horizontal movements in a dream about throwing tomatoes, vertical ones in a dream about ladders and few movements in dreams about staring fixedly at something.
Dreaming is reported from REM but not nREM sleep, participants can judge the length of their dream duration and REM patterns relate to dream content.
As with most sleep research, sample size is very smalln making generalisations difficult, particularly when there are such great individual differences between participants.
Sleep laboratories are very artificial settings. The participants’ pre-sleep routine is very different to at home, they are in unfamiliar surroundings and covered with a plethora of electrodes and wires. They also know that they’re being observed.
However, sleep studies like this do allow for physiological measurements which are objective and replicable. Unfortunately self-report techniques are just the opposite, subjective and non-verifiable. Given the fragile nature of dreams self report of these must be seen as particularly unreliable.
Stage 1 sleep (15 minutes)
This occurs at the start of a nights sleep. It lasts a matter of minutes and you will all be familiar with it since we often wake from this stage. For example sat watching ‘Big Brother’ gradually losing the will to live or certainly to stay awake, we may nod off. We may wake from this stage and think that we’ve been dreaming. In fact these hallucinations are referred to as hypnogogic phenomena and usually comprise fleeting images rather than the bizarre stories more characteristic of dreaming. The eyes may roll slowly. Sometimes we may wake without realising that we’ve even nodded off. Brain waves are slower and are called ‘theta.’ Other times we may wake with a jerk or knee twitch.
Stage 2 sleep (20 minutes)
After about a minute or so we enter stage 2. This is characterised by bursts of high frequency waves called ‘sleep spindles.’ We are still aware of sounds and activity around us and the brain responds to this with K-complexes. At this stage we are still very easily woken.
Stage 3 sleep (15 minutes)
The brain waves start to slow and become higher in amplitude and wavelength. These are called delta waves and are associated with deep sleep. We are now more difficult to wake. First time round in the night this stage is brief, only a few minutes, but we spend longer in it later in the night.
Stage 4 sleep (30 minutes)
In many respects this is a continuation of stage 4, however, delta waves now constitute most of the brain activity and we are now at our most relaxed. At this stage we are very difficult to wake up and even vigorous shaking may not be sufficient to wake some people, me included. However, a quiet but meaningful sound such as a baby crying can be sufficient, again indicating that the brain still retains some degree of awareness to external stimuli! Heart rate and blood pressure fall, muscles are very relaxed and temperature is at its lowest.
We have now been asleep for about an hour. We start to ascend back through these stages in reverse order, i.e. back to level 3 and then to level 2. However, instead of going back to level 1, after just over an hour we enter a very bizarre state of consciousness.
REM sleep (10 minutes at start of night, up to an hour later in the night)
Sometimes referred to rather unimaginatively as stage 5, or more descriptively ‘paradoxical sleep.’ REM is strange. The brain now becomes very active, almost indistinguishable from a waking brain. Remember the activation-synthesis theory of dreaming? The pons in the midbrain throws out bursts of electrical activity into the cortex lighting it up like a Christmas tree. Heart rate and blood pressure increase, as does body temperature, and the eyes twitch rapidly giving this stage its name. But, despite this frantic activity the body remains motionless, cut off from the brain by the pons. We are paralysed and unable to act out the brain’s bizarre thoughts.
REM is now thought by some to be the deepest stage of sleep since it is now that we are most difficult to wake up. However, this could be as a result of being so absorbed in our dreams.
Paralysis appears to be to prevent the body acting out our dreams and endangering our lives. Cats that have had lesions to the pons do in fact appear to act out their dreams. Remember, however, that we have no certain way of knowing whether lower species do dream; it is merely assumed that they do because all warm blooded creatures (birds and mammals), with the exception of the very early egg-laying mammals, have REM sleep.
Our first visit to REM typically lasts about for about 10 minutes and we start our journey back down to stage 2, stage 3 and stage 4 sleep. This cycle repeats throughout the night, however, as the diagram below illustrates, we spend most of the first half of the night in deep sleep (slow wave or NREM), and most of the second half in REM sleep.
The outline above describes a typical or average night’s sleep. Obviously there are large individual differences between people. Some may sleep much shorter periods, others who have been sleep deprived will spend longer in stage 4 and REM, and the pattern changes with age.
These occur over a period of time greater than 24 hours. In humans the best examples are menstrual cycle and PMS (Pre-Menstrual Syndrome) which occurs a few days prior to the onset of bleeding and is characterised (information for the boys), by loss of appetite, stress, irritability and poor concentration. There are a number of rhythms that are cyclic over about one year. A human example would be SAD (Seasonal Affective Disorder), more on this later; and in the animal world migration, mating patterns and hibernation of some species.
Seasonal Affective Disorder (SAD) (Infradian or circadian?)
Although it is apparently normal for most people to feel more cheerful in the summer months than in winter, a small number of people suffer an extreme form of this that appears to be related to the lack of bright light in the winter months.
As hopefully you’ll remember from the stuff we did on the physiology of sleep, light levels, as detected by receptors in the eye, influence levels of melatonin and serotonin. Additionally as you will hopefully recall from your work on depression, serotonin is implicated in mood. See how eventually all these strands knit together! At night low light levels stimulate the production of melatonin, this is what triggers sleepiness. Therefore you would expect the lower light levels of the winter months to have a similar affect.
In areas where light levels are exceptionally low for prolonged periods, such as the Polar regions, you would expect the effects to be particularly noticeable. Terman (1988) found that SAD was five times more common in New Hampshire, a northern state of the USA, than in Florida, obviously a sunnier clime.
The symptoms of SAD can be reduced in polar regions by sitting patients in front of very bright artificial lights for at least one hour per day. This lowers the levels of melatonin in the bloodstream which in turn reduces the feelings of depression. The precise mechanism for this is still unclear. It could be that melatonin (released from the pineal gland) has a direct affect on mood or it could have its influence indirectly through serotonin. Drugs used to treat depression such as Prozac and other MAOIs (monoamine oxidase inhibitors), appear to work by altering serotonin levels. Terman et al (1998) researched 124 participants with SAD. 85 were given 30 minute exposure to bright light, some in the morning, and some in the evening. Another 39 were exposed to negative ions (a placebo group).
60% of the am bright light group showed significant improvement compared to only 30% of those getting light in the evening. Only 5%of the placebo group showed improvement.
The researchers conclude that bright light administered in this way may be acting as a zeitgeber and resetting the body clock in the morning.
Research into SAD has led to effective treatments suggesting that the theory has some validity. However, there does also appear to be a genetic component.
Note: SAD varies over a yearly cycle so can be viewed as an infradian (or circannual) cycle. However, it appears to disrupt the sleep/wake cycle so can also be viewed as circadian. SAD can be discussed in an essay on disruption of biological rhythms.
Obviously a cycle that lasts about one month, so this cycle is infradian. Like other rhythms, the menstrual cycle appears to be under the influence of both internal (endogenous) mechanisms, and external zeitgebers.
The cycle is under the internal control of hormones, particularly oestrogen and progesterone, secreted by the ovaries. These cause a number of physiological changes within the body including the release of at least one egg (ovum) from the ovaries and the thickening of the lining of the womb (uterus), in preparation for the arrival of the egg. If the egg is not fertilised then the lining of womb is shed and menstruation occurs. The contraceptive pill mimics the effects of pregnancy and cons the body into ceasing production of further eggs.
It has long been known that the menstrual cycle can be influenced by external factors, most notably by living with other women. The most likely mechanism for this is by the action of pheromones, chemical substances similar to hormones but which carry messages between individuals of the same species.
Armpit pheromones and the McClintock effect
Martha McClintock (1971) was the first to notice possible synchronisation of menstrual cycles amongst women living in close proximity whilst still an undergraduate student at Wellesley women’ liberal arts college in Massachusetts.
In 1988 McClintock & Stern published their findings of a 10 year longitudinal study into external control of the menstrual cycle. They had followed 29 women (aged 20-35) who had had a history of irregular menstrual cycles. Sweat samples from the armpits of 9 of the women had been collected, sterilised and dabbed onto the upper lip of the other twenty.
On 68% of occasions the recipients of the sweat donation had responded to the pheromones.
Armpit compounds collected from the nine donors in the follicular phase of the menstrual cycle shortened the cycles of 20 recipients by 1.7 ± 0.9 days. Conversely, when the nine donors were in the ovulatory phase, the compounds lengthened the cycles of the same 20 recipients by 1.4 ± 0.5 days.
McClintock’s earlier work as well as the above study are supported by Russell et al (1980) who also placed dabs of sweat taken from the arm pits of sexually inactive women and placed on the upper lips of other women. Four out of five of the women had menstrual cycles that had synchronised to within one day of the sweat-donor.
Due to the small sample size, the entire effect might have been due to just one or two subjects who had a disproportionate effect. Additional questions are raised by the following statement (Stern and McClintock, 1998): `Any condition preventing exposure to the compounds, such as nasal congestion anytime during the mid-cycle period from 3 days before to 2 days after the preovulatory, could weaken the effect. We analysed the data taking this into account'. It would be useful to know what a priori criteria were employed in making such adjustments, and whether the data analysis part of the project was done blind (Strassmann 1998). Wilson (1992) believes her results are due to statistical errors and that when these are corrected the effect disappears.
Wilson analyzed the research and data collection methods McClintock and others used in similar studies. He found significant errors in the researchers' mathematical calculations and data collection as well as an error in how the researchers defined synchrony. Wilson's own clinical research and his critical reviews of existing research demonstrated that menstrual synchrony in humans has yet to be proven. Wikipedia
Evolutionary advantages of external control of the menstrual cycle
Bentley (2000) believed that synchronisation between women living in close proximity would ensure that the women would conceive and give birth at similar times. This would be beneficial since they could share breast feeding, a behaviour observed in other species. Similarly, McClintock (1971) found that women who work in a mostly male environment have shorter menstrual cycles. In the past this would be of evolutionary advantage since it would provide more opportunities for pregnancy.
Reinberg (1967) reported the case of a young woman who lived in a cave for three months with the only light being provided by a miner’s lamp. The woman’s daily cycle lengthened to 24.6 hours, (compare to Michael Siffre) and her menstrual cycle shortened to 25.7 days. It took a year before her cycle returned to normal! Reinberg believed that light levels could therefore influence the period of the cycle (no pun intended!). This theory is backed by research on 600 German girls that found that the onset of menstruation (menarche) is more likely in the winter months when light levels are low. The menarche also occurs earlier in girls that are blind. In Finland, during its very long summertime daylight hours, conception rates increase significantly. Perhaps you can think of other contributory factors! No football for example?
Timonen et al (1964) found that women were far more likely to conceive in lighter months of the year than in darker months. This was attributed to the effects of light on the pituitary gland, which exerts its influence on the cycle via the ovaries.
However, much of the research has been carried out on non-human animal species so we have issues of generalisation. Breeding behaviour in humans is far more complex. The females of many species, including rats, simply need to be exposed to the right pheromone for them to adopt the lordotic stance (legs akimbo, bottom raised mating position). Clearly, outside of Essex at least, this is not the case with human females.
When humans participants have been involved they have tended to be case studies of individuals, and very often individuals with medical conditions, so again, generalisation is an issue.
Pre-menstrual Syndrome (PMS)
This is a collection of symptoms that usually occurs four or five days before menstruation. Typically symptoms include irritation, depression, headaches and a decline in alertness. Other possible symptoms, according to Luce (1971) include insomnia, cravings for certain foods and even nymphomania!
However, it is the psychological affects that have been most widely studied. Dalton (1964) alarmingly reported a sharp increase in crimes, suicides, accidents and a decline in schoolwork associated with PMS. More recent studies have played down these findings, for example Keye (1983) concluded that although a small minority of women may suffer in this way, such extreme symptoms are relatively rare.
Janiger reported similar symptoms in other primates.
Disruption of biorhythms
In some respects biorhythms are like stress in that they developed in response to situations we found ourselves in hundreds of thousands of years ago. Like stress, our body’s in built and inherited biorhythms are outdated in a modern world that has a 24 hour culture.
In normal circumstances our in-built body clocks are not in conflict with external zeitgebers. The daily pattern of life, waking in the morning at or around sunrise, working through the day when our metabolism, body temperature etc. are at their peak and going to sleep at night when it gets dark, causes no disruption. However, given modern life there are situations now when our internal clocks do come into conflict with external cues, such as dark/light. The two obvious examples are shift work when we operate on a rotating schedule of hours and jet lag when we travel across time zones either east to west or west to east.
Jet lag or desynchronosis is caused by the body’s internal body clock being out of step with external cues. This results in a number of symptoms including fatigue, insomnia, anxiety, constipation (or diarrhoea), dehydration and increased susceptibility to illness.
Suppose you leave London Heathrow at 6pm (GMT). The flight to New York JFK will take about six hours. However, because time on the east coast of America is five hours behind you will arrive at 5pm local time. However, your body clock assumes that its midnight since the flight has taken six hours. As a result your internal clock is ready for bed, your temperature is starting to fall and your metabolic rate is slowing. External cues however, are telling you something quite different, its still light, people are still shopping, the roads are still busy etc. To overcome this conflict between internal and external effects is not difficult. Provided you keep yourself well stimulated for the next five or six hours you should be able to stay awake ‘til 11pm local time (4am body clock time) and adapt to the new time zone.
But, suppose you leave JFK airport in New York at 12 noon (Eastern Standard Time) heading for London Heathrow. The flight is six hours. You arrive in London at 6pm (New York Time) but this is 11pm GMT (London time). Are you with me so far? Your endogenous clock has just lost five hours! Your body clock still thinking it’s only 6pm, is not ready for bed. Your body temperature, metabolism etc. is still at its peak. To adapt to the new time setting you must now go to bed! This is not as easy as going east to west. Going to sleep when you are wide awake is not as easy as staying awake when you’re tired. As a result flying east to west is more troublesome and takes longer to adapt.
- Phase advance: Getting up or going to bed earlier than usual (flying W to E)
- Phase delay: Getting up or going to bed later than usual (flying E to W)
In general it is easier to adjust to phase delay, possibly because of the reasons mentioned above but also because phase delay is effectively lengthening our day. As we’ve seen our internal rhythm is greater than 24 hours. Phase delay therefore brings external factors closer in line with internal whereas phase advance moves them further away.
Dr de la Iglesia discovered that their SCNs contained two proteins; Per1 and Bmal1 and also that the SCN could be seen as having a top half and a bottom half. Now for the technical bit.
During a normal day the rats would have the protein Perl in both halves of the SCN whereas at night both halve would contain the protein Bmall.
Using melatonin to reset the body clock
Apparently melatonin is used by American military pilots to adapt to differing time zones. Melatonin is the chemical secreted at night and enables us to switch off the RAS (that keeps us awake during the day). Taken just prior to bedtime in the new time zone, melatonin has been shown to be effective in allowing sufferers of jet lag to get to sleep sooner than their body clock would normally allow.
At present the EU has not given natural melatonin a licence in Europe since the potency and purity of the tablets cannot be sufficiently well regulated. However, tasimelteon (a selective agonist for melatonin receptors) i.e. it mimics melatonin has proved effective in early trials. 450 volunteers were kept awake 5 hours past normal bedtime to mimic jet lag. Taking tasimelteon increased eventual sleep duration by up to 2 hours compared with control groups (Klerman 2009).
Recent research (2013)
As we’ve seen, light acts as a sort of reset button for the body clock in the SCN, ensuring it sticks to a 24 hour cycle. A large number of genes in the SCN appear to be light sensitive and adjust their activity depending on whether it is light or dark. They do this quite quickly so should be able to adapt to new time zones. However, recent research at Oxford has found that a protein SIK1 goes round switching all these proteins off again.
The researchers, using mice, found that reducing the activity of this protein allowed the mice to switch their body clocks faster. Using artificial lighting they advanced the mices’ day by six hours, similar to flying from the UK to India. Instead of the usual 6 days it would normally take to adapt the mice were able to adapt in six hours!
Practical applications: A number of psychological disorders such as schizophrenia as well as neurological conditions such as Alzheimer’s, have been linked to disrupted biological clocks. Dr Reddy of Cambridge University suggests that SIK1 is a ‘very drugable target’ and believes drugs may soon be available to allow faster switching to new time zones.
Using fasting to reset the body clock
Recent research has also shown that social factor can play a role in resetting biological rhythms and alleviate some of the symptoms of jet lag. For example a period of fasting before travel followed by eating at times relevant to the new time zone. Apparently food is very good at altering biological rhythms (Fuller et al 2008)
Saper et al (2008) suggests that as well as the main ‘master’ clock in the SCN there is also a ‘feeding clock’ which depends on food intake. In mice, this feeding clock seems to over-ride the master clock and keeps them awake until food has been found.
So if we are flying from London to New York and need to adjust to the new time zone by staying awake longer than the master clock would expect we need to starve ourselves before and during the flight and then eat when we land. This way we can postpone the master clocks drive to get us to sleep. Saper and his team recommend fasting for 16 hours before eating!
Other species abide by natural laws and are governed by their inbuilt biological rhythms. It is only humans with their 24 hour lifestyle that suffer desycnchronisation due to working against biorhythms. Twenty percent of workers in the industrialised world work some form of rotating or permanent unsocial shift pattern.
Shift work results in:
Fatigue, sleep disturbance, digestive problems, lack of concentration, memory loss and mood swings.
Shift work is usually more troublesome than jet lag since it involves prolonged conflict between internal clocks and external stimuli. As a result during the day when metabolism etc. is at its peak the person is expected to sleep. At night when body temperature is low the person is expected to be working. This situation is often compounded by 1. the person reverting to ‘normal’ sleep/wake cycles at the weekend and 2. shifts altering from one week to the next. As a result the person never adapts to a new rhythm, leaving their biorhythms in a permanent state of desynchronisation! It is estimated that 20% of Western employees work shifts.
In the very least this can result in reduced productivity and reduced employee morale. In extreme cases it can have catastrophic consequences. Major disasters such as Chernobyl and Three-mile Island, Bhopal (explosion at a chemical plant in India), Exxon Valdez (oil tanker spillage in Alaska and many other major incidents have occurred in the early hours of the morning and been attributed to tiredness. Additionally on the roads in Britain there are a disproportionately high number of fatal accidents in the early hours of the morning
In addition to accidents and disasters there are also health risks associated with regular shift work. These include increased risk of heart disease and digestive disorders and regular tiredness. Twenty percent of shift workers report falling asleep whilst at work. This clearly has implications both for safety and for productivity and efficiency.
Shifts can follow a number of patterns:
Rotating of fixed
A rotating pattern involves working different hours each week or month. A typical three shift system covering a 24 hour period would involve people working
- 6am to 2 pm
- 2pm to 10pm
- 10pm to 6am
Clockwise or anticlockwise
In addition the rotation can be clockwise or anticlockwise. In the example above, week 1 would be 6am to 2pm in the first week and moving to the pm to 10pm in week to…and so on. This is clockwise. A backward (or anticlockwise) rotation would involve starting at am to 2pm in week one and then moving to the 10pm to 6am in week two…and so on. With a rotating shift pattern there can be permanent desynchronisation between internal and external factors with the person never fully adjusting to the new shift.
Fast or slow rotation
Although most research suggests a clockwise rotation is to be preferred, there is disagreement over the speed of rotation. Czeisler (main man in this area) recommends a slow rotation, for example spending at least three weeks on each shift. Bambra (2008) however, prefers a faster rotation of just 3 to 4 days on each pattern so the body never has time to adjust to the new cycle.
Fixed shifts tend to be rarer, mostly because of the unsociable hours involved. For example working a permanent 10pm to 6am shift. Although this allows time for resynchronisation with the worked adjusting to the shift pattern it does create problems at weekends when people revert back to a normal sleep-wake pattern.
Czeisler et al (1982) were called in to sort out shift related problems at a chemical plant in Utah, USA. Having implemented the changes suggested above a number of benefits were reported. These included greater productivity, fewer accidents, increased morale and improvements to the health of workers.
It is worth mentioning that work by Monk & Folkard (1983) reported that rapidly rotating shifts (i.e. working 2 or 3 days on any one shift) were preferable to slower rotation of shifts. This seemingly contradicts the work of Czeisler.
Even with a constant shift pattern such as 10pm to 6am (night shift) there are issues. Although the worker will adapt to this pattern by experiencing a shift in biological rhythm there will be disruption at the weekend when presumably, not being at work, they will adopt a more sociable day pattern of recreation before restarting the night shift the following week.
Using artificial light to reset the body clock
Boivin et al (1996) put 31 male participants on an inverted sleep pattern (so they were awake at night and slept during the day). This lasted for three days. Each day when they woke they were sat in front of dim lights for 5 hours and then placed in one of four conditions:
- Very bright light
- Bright light
- Ordinary room light
- Continued dim light
After three days:
- Group 1 had advanced by five hours (they were adapting to the new pattern best)
- Group 2 had advanced by three hours
- Group 3 had advanced by one hour
- Group 4 had drifted backwards by one hour (were failing to show any signs of adapting).
Artificial light, even ordinary room light can help us adapt our biological rhythms to suit the environment; however, brighter light is even more effective. Clearly this could be useful in the workplace to help shift workers to adapt to changing sleep-wake cycles.
Delayed sleep phase syndrome (DSPS)
Like desynchronisation (as experienced in jet lag) this results in a mis-match between the body’s internal biological rhythm and the external world (light, social activities etc). However, this failing seems to be due to a delayed internal mechanism that results in the endogenous clock being three or four hours behind what would be expected. As a result patients with this ‘disorder’ find it difficult to get to sleep before 2am and typically wake about 10am. Amount of sleep is therefore not an issue. Problems arise with social expectations, particularly schooling and work. Often referred to as ‘owls’ (as opposed to the ‘larks’ that are early risers), the condition is thought to affect about 7% of teenagers and is a major contributory factor to cases of chronic insomnia.
The specification states that you need to know about disruption of biological rhythms… clearly suggesting more than one. The two obvious ones suggested above are the effects shift work and of jet lag. However, SAD is a disrupted biorhythm that can be seen as either circadian or infradian so can also be discussed in a question on disruption of rhythms.
What the board expects you to know:
· The nature of sleep
· Functions of sleep, including evolutionary explanations and restoration theory
· Lifespan changes in sleep
All birds and mammals sleep and other creatures have a dormant period during the 24 hour cycle, suggesting that sleep must perform some vital purpose. Some herbivores such as horses and giraffes can sleep whilst standing but must lie down for REM when muscle paralysis sets in, otherwise they’d fall over. Birds tend to have a much shorter cycle of sleep, and according to Wikipedia do not lose muscle tone to the same extent as mammals when they enter REM.
However, in humans the amount of sleep needed by individuals does show considerable variation. Meddis (1979) reported the case of a woman who only slept for one hour per night but showed no ill effects. This case however is unusual and it is estimated that in the UK with an average of 7.5 hours sleep per night, that most of us are in a state of mild sleep deprivation. Sleep deprivation studies highlight the need for sleep to maintain normal levels of awareness and cognitive ability as well as psychological health. Three or four nights without sleep can result in symptoms of mild paranoia and hallucinations. Yet, even in the most extreme cases, such as Randy Gardner’s eleven nights without sleep, the effects are not long lasting.
The nature of sleep
It is possible that you will be faced with a short question on the nature of sleep. If so use the material on the stages of sleep (see the biorhythms booklet) covering stages 1 to 4 and REM and the characteristics of each. Later in this booklet we will also look at lifespan changes and the way in which sleep patterns alter with age. If this wasn’t enough it might also be possible to include material on sleep disorders, again to be covered later in this booklet.
Theories of sleep
Why then do we sleep, and why do we spend almost one third of our lives in this state of reduced consciousness? There are two main theories:
- Sleep helps to protect us from harm at night
- Sleep helps us to conserve energy
- Sleep helps us to repair damage done to our bodies during the day
- Sleep restores the brain’s levels of neurotransmitters
Evolutionary (ecological) theory
1. Protection (Meddis 1975)
In our evolutionary past night time would have been a time of great danger. Since as a species we have poor night vision we would have been unable to forage, likely to fall and hurt ourselves and wide open to predation from species with better night sight. Sleep would have been an evolutionary advantage since it would have kept us out of harm’s way. As a result, those members of the species that slept would have been more likely to have survived to maturity and passed on their genes, ensuring that as an activity, sleep would have been retained in our behavioural repertoire. The theory also considers the metabolic rates of other species, predicting that animals with high metabolic rates will need to spend more time eating so have less time to sleep.
Animals such as the shrew are safer since they have a burrow to return to, but due to their high metabolic rate (heart rate of 800 beats per minute) and need to be eating constantly only have time to sleep for two hours per day. Generally speaking smaller species have higher metabolic rates because of their large surface area to volume ratio. This results in loss of a lot of heat energy in comparison to species that are larger.
Larger preyed-upon species, e.g. ground squirrel, have burrows where they are safe, similar to the shrew, but since they are larger and have a lower metabolic rate, they need to eat less often and so can spend longer tucked away in their burrows asleep.
However, there are some glaring anomalies. On the face of it you would expect species most at risk to sleep longer (in order to get added protection) but often the opposite is the case. Species most at risk such as herbivores sleep least (a few hours a day in brief naps), whilst species that are at little risk such as big cats sleep for most of the day! Since this can’t be explained by one aspect of the theory (protection), food intake and metabolic rate is used instead. The lion has a large protein-rich intake every few days. Because of its size it has a relatively low metabolic rate. As a result it has time to sleep for over twenty hours a day.
Herbivores with their impoverished diet of grass need to be eating all the time so don’t have the time to sleep.
Animals sleep for short periods if:
1. They high metabolic rates so need to be constantly eating.
2. They are likely to be eaten.
Animals sleep longer if:
1. They have low metabolic rate, eat less and therefore have more time available to sleep.
2. They have no natural predators
Other obvious evaluation comments
If the only purpose of sleep is to protect from harm, then why do species that face the most risk when asleep bother to sleep at all. Surely it would make more sense to stay awake and alert to danger. Research in India for example has suggested that given a choice, lions are happier tucking into a sleeping human than a more active one! Evans (1984) sums it up nicely: ‘The behaviour patterns involved in sleep are glaringly, almost insanely, at odds with common sense.’
Sleep can also be dangerous in other respects as these two dolphin examples illustrate:
The Indus dolphin is at constant risk from being hit by logs and other big river debris being swept down the River Indus. Clearly, loss of consciousness is life threatening since it means loss of vigilance. However, despite this it still grabs quick naps of a few seconds at a time. In effect, this dolphin is risking its life to sleep. How can this be protective?
The Bottlenose dolphin sleeps with one hemisphere of its brain at a time (unihemispheric slow wave sleep) so it can remain partly conscious and return to the surface to breathe. This takes place in two hourly cycles with one half of the brain always remaining fully conscious. The fact that it has evolved such a bizarre sleep pattern suggests sleep is serving an essential purpose.
Meddis’ theory does try to explain the diverse sleep patterns found across various species, unlike the restoration theory that we’ll look at in a while.
This has always been one of my favourite topics, both to study and to teach. We begin with a look at biological rhythms in general, looking at research into the different types. We then consider what happens when these rhythms get disrupted, most likely through jet lag or shift work.
These notes are now available to download in booklet form
Background info for interest only!
French geologist (and speleologist) Michael Siffre is the daddy! Over the past 40 years or so he has regularly spent extended periods of time in various caves around the World and agreed to be studied during the process. His first stint was in 1962 when he spent 61 days in a cave in the Alps. He emerged on September 17th but thought it was August 20th! He receives no unsolicited contact with the outside World, but does shout to co-workers at the cave entrance when he wakes, prior to sleep and before meals.
In 1972 he was monitored by NASA in the caves of Texas and in 1999 he missed the millennium celebrations in a cave in some part of the World. He spent new year’s eve eating foie gras and quaffing champagne. He subsequently discovered that his celebrations were over three days late! Each time his body clock extended form the usual 24 to around 24.5 hours. Occasionally this extended to 48 hours, 36 hours awake and 12 to 14 hours asleep. However, as he points out, these days appeared no longer at the time!
Working with other volunteers he has also noticed a correlation between day length and REM duration. For every 10 minutes that a day extends, REM seems to lengthen by one minute.
Krishnan et al (1999) reported that the fruit fly has body clocks in its antennae. In an ingenious experiment on fruit flies Kay et al (1997) paired what they termed the ‘period gene’ (a gene they believe responsible for body clocks) with a gene from jelly fish that produces a green fluorescent dye. They then exposed the flies to different patterns of light and found that all parts of the body were developing green spots. They concluded that genes responsible for the internal clocks of fruit flies are found in all of their tissues.
Recent evidence provided by Hall (1999) suggests these peripheral clocks may also be present in humans. The adrenal glands secrete a hormone cortisol each morning just before dawn, (‘the darkest hour’ according to Mama Cass!). Cortisol therefore must be controlled by a clock mechanism. Hall removed tissue from the gland and grew it in culture and found that it continued to secrete cortisol at the same time each day. Hall concludes that the tissue in our adrenal glands must possess an endogenous clock.
In humans the suprachiasmatic nuclei (SCN) appears to take over the role. This is situated in the hypothalamus and just behind the eyes and receives sensory input about light levels through the optic nerve. The SCN then appears to regulate melatonin production from the pineal gland. Removal of the SCN in rats causes the usual sleep/wake cycle to disappear. Studies of the electrical activity of the SCN show it to have a cyclic activity varying over a 24.5 hour cycle. This cycle persisted even after the SCN had been removed from the brain (so called ‘hypothalamic island’).
Humans certainly have a bunch of fibres (the retino-hypothalamic tract) that connects, as the name suggests, the retina of the eye to the hypothalamus. As early as 1929 Bailey found that patients with brain tumours close to the hypothalamus suffered from odd sleep/wake cycles.
Luce & Segal (1966), however, have shown that light levels can be over ridden. In the Arctic Circle people still maintain a reasonably constant sleep pattern, averaging 7 hours a night, despite 6 months of darkness in the winter months, followed by six months of light in the summer. In these conditions it appears to be social factors that act to reset endogenous rhythms rather than light levels
EEG is recording brain activity
EMG is recording muscle activity
EOG is recording eye activity
The most noticeable features are how similar the eye and brain recordings are between awake and REM sleep and the loss of muscle activity in REM sleep.
The menstrual cycle is divided into two phases--the follicular phase; and the luteal or ovulatory phase. The follicular phase includes the time when menstruation occurs and is followed by proliferation or the growth and thickening of the endometrium. This phase typically lasts from 10 to 14 days, starting with the first day of menstruation. Oestrogen and progesterone levels are at their lowest during menstruation. When bleeding stops, the follicular phase begins causing the endometrium to grow and thicken in preparation for pregnancy. During the next (approximately) two weeks, FSH levels rise causing maturation of several ovarian follicles and the size of the eggs triple.
FSH also signals the ovaries to begin producing estrogen which stimulates LH levels to surge at around day 14 of your cycle triggering one of the follicles to burst, and the largest egg is released into one of the fallopian tubes. This premenstrual period lasts approximately 14 days. After ovulation, LH causes the corpus leuteum to develop from the ruptured follicle. The corpus leuteum produces progesterone. Together estrogen and progesterone stimulate the endometrium to prepare a thick blanket of blood vessels that will support a fertilized egg should pregnancy occur. When pregnancy occurs, this blanket of blood vessels becomes the placenta which surrounds the fetus until birth.
Research evidence provided by Schwartz et al (1995) supports this theory. They studied the results of baseball games involving teams on the west and east coasts of America. The time difference here is three hours. They found that east coast teams travelling to play away games on the west coast won significantly more games that west coast teams travelling to the east.
According to the song
‘The lion sleeps tonight’
…in fact it sleeps for most of the day too!
If sleep is there to protect us from predation why would a creature at the top of the food chain with no natural predators spend up to 22 hours a day asleep?
The pineal gland is a neuroendocrine organ located in the midline of the brain. Melatonin, thought to be the output hormone of the pineal gland, plays a central role in the co-ordination of circadian rhythms and the circadian system.
Circadian rhythms are centrally co-ordinated and physiological, psychological and behavioural processes, which in humans follow approximately a 24- to 25-hour alternating cycle. In humans, circadian rhythms are genetically programmed to synchronise with night and day.
Over a period of ten years there has been an expansion of interest in circadian systems, how their disruption impacts on health and how they can be manipulated to improve health and optimise treatment.
The circadian system
The circadian system consists of a central 'biological master clock' (located in the suprachiasmatic nucleus (SCN) of the hypothalamus) and peripherally located biological clocks (found in most tissues such as the heart and liver).
This system has an endogenous rhythmicity of approximately 24 hours. Peripheral 'clocks' can work independently of the external light/dark cycle but are synchronised by the 'master clock' in the SCN of the hypothalamus. Physiological cues from the SCN entrain or reset the peripheral clocks, and the master clock responds to external cues such as the light/dark cycle, exercise and nutrient intake.
The system creates a biological night and a biological day so that:
Physiological and behavioural activities best suited for night time (such as rest, memory processing, cellular repair and brain development) take place at night.
Those activites best suited for daytime (such as alertness and the availability of glucose, take place during the day. The prolonged disruption of the circadian synchrony leads to an array of disorders, including insomnias, impaired glucose tolerance and obesity and decreased life expectancy.
Synchronisation of the circadian system
The biological clock within the SCN is thought to be the pacemaker of the circadian system, since lesions to the SCN alter circadian physiology and behaviour. The SCN co-ordinates circadian rhythms via endocrine and neural pathways. These include melatonin, the renin-angiotensin system, the hypothalamic-pituitary-adrenal axis including cortisol, and the hypothalamic-pituitary-thyroid axis and adrenaline (epinephrine). Animal studies have revealed neurological connections of the SCN to the pineal gland, heart, kidneys, adrenal cortex, liver, pancreas, spleen and white and brown adipose tissue.
How is the circadian system synchronised with night and day?
Circadian clocks communicate with, and can be 'reset' or entrained by, our external environment via photic and non-photic signals such as melatonin, feeding and exercise. Light is, however, the most potent 'Zeitgeber' ('time giver'), or cue, for the SCN.
The 'master clock' in the SCN is affected by light and darkness via the retino-hypothalamic tract, which connects the retinal ganglion cells (RGCs) of the retinae to the SCN in the hypothalamus. This connects with the pineal gland via the superior cervical ganglion (SCG).
Sunlight (or light at 480 nm) stimulates the RGCs to produce the photoreceptor melanopsin. Melanopsin 'signals' daytime to the SCN, which in turn induces the pineal gland to suppress melatonin production.
RGCs → melanopsin → SCN → SCG → pineal gland → melatonin supression
In the absence of light or melanopsin, melatonin is produced by the pineal gland. In humans, it induces an almost irresistible urge to sleep. Its primary function is to signal day length to the SCN so that it can synchronise the day/night cycle with:
- Endocrine rhythms
- Body temperature
- Glucose homeostasis
- Locomotor activity
Disruption of the circadian system
It can occur as a result of external factors of conditions such as light at night during shift work or crossing meridian time zones (jet lag), genetic predisposition or abnormalities which affect the functioning of the retino-hypothalamic system, the production of melatonin, or the sensitivity of the system to light (for example, seasonal affective disorder (SAD)), physical damage or tumours of the pineal gland or the SCN.
- Age and ageing: the pineal gland is large in children but shrinks at puberty and has diminished activity in the elderly.
- Jet lag, shift work and exposure to bright light at night: these result in desynchrony between the internal clock and the external light-dark cycle brought on by rapid travel across time zones or by working a non-standard schedule.
- Genetic aberrations to 'clock' genes: for example, in SAD and possibly in rheumatoid arthritis.
- Tumours or lesions to the SCN or pineal gland: there has been a continuous interest in the use of melatonin as a marker for neoplasms of the pineal region. Melatonin decreases following pinealectomy and can cause alterations in the sleep/wake cycle. However, because these tumours are extremely rare, it has been difficult to find conclusive evidence for the effect of pineal tumours on circadian rhythms.
- Damage to the retino-hypothalamic tract or pineal gland: severely sight impaired people with no conscious or unconscious light perception frequently display free-running rhythms.
Changes of the pineal gland with age
The pineal gland is large in children but shrinks at puberty; however, the roles of the pineal gland and melatonin in human pubertal development remain unclear.
Treatment of children with sleep disorders with melatonin for an average of three years was not found to be associated with alterations in pubertal development in children. However, there is a report in the literature of juvenile hamartoma of the pineal gland being associated with melatonin deficiency and precocious puberty.
The activity of the pineal gland declines with advancing age:
- Elderly people with sleep disturbance have impaired melatonin production compared with age-matched controls.
- Campaigns aiming to reduce the use of benzodiazepines failed when they were not associated with the availability and market uptake of prolonged-release (PR) melatonin. The reimbursement of PR melatonin supports better penetration rates and a higher reduction in sales for benzodiazepine drugs.
- In one study, outpatients with mild cognitive impairment exhibited significant improvements in cognitive function, sleep profiles and depression compared with those given placebo.
- Sundown syndrome - characterised by agitation, confusion, aggressiveness and anxiety occurring in the late afternoon in patients with dementia. It is thought to be due in part to impaired circadian rhythmicity and is associated with degeneration in the SCN. Reduced melatonin levels are seen in several neurodegenerative disorders, including Alzheimer's disease and Pick's disease.
Jet lag, shift work and exposure to bright light at night
These can result in desynchrony between the internal clock and the external light-dark cycle (brought on by rapid travel across time zones or by working a non-standard schedule) and reduce melatonin levels.
Short-term exposure can result in sleep disorders, gastrointestinal symptoms, poor concentration and irritability. Long-term exposure, however, has been associated with an increased risk of cancers, cardiovascular disorders and diabetes.
Short-term treatment of jet lag
Short-term, intermittent jet lag symptoms can be avoided by manipulating the circadian system's ability to be reset or entrained by bright light, melatonin, exercise, or the use of sleeping agents or stimulants.
Bright light therapy for jet lag
- The human core temperature tends to dip to its lowest point 2-3 hours before we are due to wake up.
- Exposure to bright light before this dip causes a phase delay, and encourages later sleep (desirable for westward travel across time zones).
- Exposure to bright light after this dip causes a phase advance, and encourages sleep earlier than usual (desirable for eastward travel across time zones).
- Exposure to bright light can be avoided by wearing dark glasses or by remaining in a darkened room.
- In order to avoid inadvertently phase advancing or delaying, web tools can be used to aid travellers to optimise light exposure or avoidance to prevent jet lag.
Melatonin for jet lag
- Melatonin is indicated for travel across more than five time zones but may be used in those travelling across two to four time zones if needed.
- 0.5 mg of melatonin is equally as effective as 5 mg, although 5 mg results in quicker, more effective sleep. More than 5 mg is not more effective than 5 mg.
- Timing of melatonin is essential in order to optimise its effects - taking it earlier in the day induces drowsiness and delays effective sleep at night.
- In travellers crossing seven to eight time zones the administration of melatonin on arrival at the destination area is enough; however, when more time zones are crossed, melatonin should be administered for two to three days before the flight, its hypnotic and sedative action being appropriately managed.
Hypnotics for jet lag
- The use of hypnotics in the treatment of jet lag is common but poorly researched.
- They appear to be effective in improving sleep in patients with jet lag; however, their effects on other symptoms are unknown.
- Data comparing the effects of melatonin and hypnotics (zolpidem) for jet lag are equivocal; however, melatonin has fewer side-effects.
Stimulants and jet lag
- Stimulant medications such as caffeine 300 mg or modafinil may improve sleepiness associated with jet lag but they may be associated with more nocturnal sleep complaints.
Reducing circadian disruption for long-term shift workers
- Fewer than 3% of permanent night workers show complete adaptation of their circadian system to their imposed work schedule and fewer than 25% adjust to a point that some benefit would be derived from the adaptive shift that they have made.
- Partial re-entrainment to a permanent night shift schedule, with the following activities, is associated with greatly reduced impairment of the circadian rhythm during night shifts:
- Intermittent bright light pulses during night shifts.
- Wearing dark sunglasses outside.
- Scheduled sleep episodes in darkness.
- In one study of rotating shift-work female nurses with clinical insomnia, higher intensity and briefer duration of bright light exposure during the first half of their evening/night shift, with a daytime darkness procedure, improved their insomnia, anxiety and depression.
- Circadian realignment has not yet been associated with a reduction in the long-term effects of shift work.
Consequences of prolonged circadian disruption
- A reduction in melatonin level is associated with a number of tumours, including prostate, endometrial and breast cancers. The reason for this is unclear.
- In 2007, the International Agency for Research on Cancer classified shift work that involves circadian disruption "as a probable carcinogen". However, to date this has not been conclusively proved by epidemiological studies. A meta-analysis found that night-shift work had little or no effect in the incidence of breast cancer in women.
- Abberations in clock genes affecting the action of melatonin in various tissues have been associated with cancers (for example, non-Hodgkin's lymphoma).
- Melatonin inhibits human cancer cell growth in cultures and has been shown to exert oncostatic activity by antiproliferative actions, stimulation of anticancer immunity, modulation of oncogene expression and anti-inflammatory, antioxidant and anti-angiogenic activity.
- The administration of melatonin alone or in combination with aldesleukin (interleukin-2) in conjunction with chemoradiotherapy and/or supportive care in cancer patients with advanced solid tumours, has been associated with improved outcomes of tumour regression and survival.
- Chemotherapy has been shown to be better tolerated in patients treated with melatonin.
Hypertension and cardiovascular disease
- In healthy individuals, there is a circadian variation of BP with a nocturnal fall of 10-20% during the sleep period.
- In hypertensive patients, this circadian rhythm may disappear or even become inverted. Patients have been classified as:
- 'Dippers' when the mean night-time BP is ≥10% lower than the mean daytime BP
- 'Non-dippers' when the reduction is <10%
- 'Risers' when it is higher
- Non-dippers and risers are at an increased risk for target organ damage and cardiovascular events. Non-dippers have been found to have lower melatonin levels at night.
- The renin angiotensin system (RAS) is considered to be the most important endocrine regulator of cardiovascular homeostasis.
- Pineal RAS modulates the synthesis of melatonin.
- Accumulating evidence suggests that angiotensin not only interferes with melatonin synthesis and release but also that both hormones interact at several levels, having opposing effects in cardiovascular and metabolic pathophysiology.
Circadian rhythms and antihypertensive treatment
- Melatonin: PR melatonin improves nocturnal BP.
- Chronotherapy (timing of BP therapy): among patients with a non-dipping BP profile, a once-daily evening (in comparison to morning) ingestion schedule of the angiotensin-II receptor antagonists (AIIRAs) irbesartan, olmesartan, telmisartan, and valsartan, exerted a greater therapeutic effect on nocturnal BP, with normalisation of the circadian BP profile toward a more dipping pattern.
Melatonin and ischaemic heart disease
One study reported an association between lower melatonin levels and myocardial infarction in women with high BMI.
Insulin and metabolic syndrome
The interaction between melatonin, circadian rhythms and the RAS has also been implicated in the pathophysiology of type ll diabetes and metabolic syndrome. There is accumulating evidence that the RAS plays a major role in the development of dyslipidaemias, in altered glucose homeostasis and in hypertension of the metabolic syndrome.
- Angiotensin II causes insulin resistance through activation of angiotensin receptors and increased production of mineralocorticoid.
- Treatment with AIIRAs and angiotensin-converting enzyme (ACE) inhibitors has beneficial effects in patients with diabetes.
- The underlying mechanisms through which it does this remain unknown.
- Lower melatonin secretion has been independently associated with an increased risk of developing type 2 diabetes.
Seasonal affective disorder (SAD)
SAD is a subtype of depression, which characteristically occurs during the winter months and is more common in northern latitudes:
- It is associated with genetic abberations which cause abnormalities along the retino-hypothalamic tract.
- It is thought that these lead to a 'phase shift' in the circadian cycle, which worsens as sunlight hours reduce.
- However, the evidence supporting the use of melatonin in the prevention and treatment of SAD is equivocal.
- Likewise, the newer antidepressant drug, agomelatine, which combines melatonergic and serotonergic activity, has been associated with positive outcomes for this disorder; however, further research is needed.
Other mental health disorders
- Melatonin levels at night have been found to be decreased in patients with depression and dysthymia and increased in those with mania.
- Treatment with melatonin has not been found to improve defining features of these disorders but helps to improve the insomnia associated with it.
Patients with rheumatoid arthritis have disturbances in the hypothalamic-pituitary-adrenal axis. These are reflected in altered circadian rhythm of circulating serum cortisol, melatonin and interleukin-6 (IL-6) levels and in chronic fatigue.
Timing of medications for rheumatoid arthritis according to these changes has been associated with beneficial treatment effects.
Zhao M, Wan J, Zeng K, et al; The Reduction in Circulating Melatonin Level May Contribute to the Pathogenesis of Ovarian Cancer: A Retrospective Study. J Cancer. 2016 Apr 277(7):831-6. doi: 10.7150/jca.14573. eCollection 2016.
Sun H, Gusdon AM, Qu S; Effects of melatonin on cardiovascular diseases: progress in the past year. Curr Opin Lipidol. 2016 Aug27(4):408-13. doi: 10.1097/MOL.0000000000000314.
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Kolla BP, Auger RR; Jet lag and shift work sleep disorders: how to help reset the internal clock. Cleve Clin J Med. 2011 Oct78(10):675-84. doi: 10.3949/ccjm.78a.10083.
de Almeida EA, Di Mascio P, Harumi T, et al; Measurement of melatonin in body fluids: standards, protocols and procedures. Childs Nerv Syst. 2011 Jun27(6):879-91. doi: 10.1007/s00381-010-1278-8. Epub 2010 Nov 21.
Tolson KP, Chappell PE; The Changes They are A-Timed: Metabolism, Endogenous Clocks, and the Timing of Puberty. Front Endocrinol (Lausanne). 20123:45. doi: 10.3389/fendo.2012.00045. Epub 2012 Mar 28.
van Geijlswijk IM, Mol RH, Egberts TC, et al; Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Psychopharmacology (Berl). 2011 Jul216(1):111-20. doi: 10.1007/s00213-011-2202-y. Epub 2011 Feb 22.
Hardeland R; Neurobiology, pathophysiology, and treatment of melatonin deficiency and dysfunction. ScientificWorldJournal. 20122012:640389. doi: 10.1100/2012/640389. Epub 2012 May 2.
Clay E, Falissard B, Moore N, et al; Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and Z-drugs consumption in nine European countries. Eur J Clin Pharmacol. 2013 Apr69(4):1-10. doi: 10.1007/s00228-012-1424-1. Epub 2012 Nov 1.
Cardinali DP, Vigo DE, Olivar N, et al; Therapeutic application of melatonin in mild cognitive impairment. Am J Neurodegener Dis. 20121(3):280-91. Epub 2012 Nov 18.
Khachiyants N, Trinkle D, Son SJ, et al; Sundown syndrome in persons with dementia: an update. Psychiatry Investig. 2011 Dec8(4):275-87. doi: 10.4306/pi.2011.8.4.275. Epub 2011 Nov 4.
Hardeland R; Chronobiology of Melatonin beyond the Feedback to the Suprachiasmatic Nucleus-Consequences to Melatonin Dysfunction. Int J Mol Sci. 2013 Mar 1214(3):5817-41. doi: 10.3390/ijms14035817.
Jet lag plan; Jet Lag Rooster
Kostoglou-Athanassiou I; Therapeutic applications of melatonin. Ther Adv Endocrinol Metab. 2013 Feb4(1):13-24. doi: 10.1177/2042018813476084.
Choy M, Salbu RL; Jet lag: current and potential therapies. P T. 2011 Apr36(4):221-31.
Suhner A, Schlagenhauf P, Hofer I, et al; Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med. 2001 Jul72(7):638-46.
Smith MR, Eastman CI; Shift work: health, performance and safety problems, traditional countermeasures, and innovative management strategies to reduce circadian misalignment. Nat Sci Sleep. 2012 Sep 274:111-32. doi: 10.2147/NSS.S10372. Print 2012.
Smith MR, Fogg LF, Eastman CI; A compromise circadian phase position for permanent night work improves mood, fatigue, and performance. Sleep. 2009 Nov32(11):1481-9.
Cutando A, Lopez-Valverde A, Arias-Santiago S, et al; Role of melatonin in cancer treatment. Anticancer Res. 2012 Jul32(7):2747-53.
Erren TC, Falaturi P, Morfeld P, et al; Shift work and cancer: the evidence and the challenge. Dtsch Arztebl Int. 2010 Sep107(38):657-62. doi: 10.3238/arztebl.2010.0657. Epub 2010 Sep 24.
Travis RC, Balkwill A, Fensom GK, et al; Night Shift Work and Breast Cancer Incidence: Three Prospective Studies and Meta-analysis of Published Studies. J Natl Cancer Inst. 2016 Oct 6108(12). pii: djw169. Print 2016 Dec.
Hermida RC, Ayala DE, Fernandez JR, et al; Circadian rhythms in blood pressure regulation and optimization of hypertension treatment with ACE inhibitor and ARB medications. Am J Hypertens. 2011 Apr24(4):383-91. doi: 10.1038/ajh.2010.217. Epub 2010 Oct 7.
Grossman E, Laudon M, Zisapel N; Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vasc Health Risk Manag. 20117:577-84. doi: 10.2147/VHRM.S24603. Epub 2011 Sep 15.
McMullan CJ, Rimm EB, Schernhammer ES, et al; A nested case-control study of the association between melatonin secretion and incident myocardial infarction. Heart. 2016 Nov 2. pii: heartjnl-2016-310098. doi: 10.1136/heartjnl-2016-310098.
McMullan CJ, Schernhammer ES, Rimm EB, et al; Melatonin secretion and the incidence of type 2 diabetes. JAMA. 2013 Apr 3309(13):1388-96. doi: 10.1001/jama.2013.2710.
Verster GC; Melatonin and its agonists, circadian rhythms and psychiatry. Afr J Psychiatry (Johannesbg). 2009 Feb12(1):42-6.
Kaminski-Hartenthaler A, Nussbaumer B, Forneris CA, et al; Melatonin and agomelatine for preventing seasonal affective disorder. Cochrane Database Syst Rev. 2015 Nov 11(11):CD011271. doi: 10.1002/14651858.CD011271.pub2.
Buttgereit F, Smolen JS, Coogan AN, et al; Clocking in: chronobiology in rheumatoid arthritis. Nat Rev Rheumatol. 2015 Jun11(6):349-56. doi: 10.1038/nrrheum.2015.31. Epub 2015 Mar 24.