Within the neurones of the suprachiasmatic nucleus, a complex dance occurs on a daily basis, with several genes with names like CLOCK and Period interacting with each other, feeding back to each other, conducting the ticking of our clock. But light, as a Zeitgeber, sways this dance, tweaking it forward or back. In the retina, at the back of the eye, in addition to the rod and cone cells responsible for converting light into vision, are cells known as retinal ganglion cells. A few of these cells have no contribution at all to vision. Their purpose is instead to conduct signals to the suprachiasmatic nucleus, through a direct projection called the retinohypothalamic tract. And it is through this pathway that light influences the rhythm in the suprachiasmatic nucleus, affecting the phase, the relationship of the 24-hour rhythm to the outside world, and the amplitude, the strength with which this rhythm runs. For people without any vision, the control of the circadian rhythm can be problematic, as we will see later.
* * *
The paediatrician’s diagnosis in Vincent of delayed sleep phase syndrome is a common one. For those with this condition, their circadian rhythm runs behind that of the outside world. While most people want to go to sleep between 10 p.m. and midnight and wake between 6 and 8 a.m., people with delayed sleep phase syndrome may want to sleep at 3 a.m., sometimes as late as 7 a.m., and wake up seven or eight hours later. If they get this amount of sleep, then they feel fine. Unfortunately, life often gets in the way of sleep, and within the constraints of modern society, holding down a job or getting an education is difficult, if not impossible, on this sleep schedule.
To some extent, having a tendency to want to wake up early and go to bed early, or wake up late and go to bed late, is normal. There is a broad spectrum of chronotypes – a person’s preference to go to sleep and wake up at a particular time. At the extremes of ‘morningness’ or ‘eveningness’ are those individuals known as ‘morning larks’ or ‘evening owls’. People with delayed sleep phase syndrome can be considered extremes of the extreme, ‘evening owls’ whose circadian rhythm is so delayed that it has negative consequences on their life.
As with many features of our sleep, it appears that what chronotype we are is to some extent determined by our genes. Studies in twins or in families suggest that up to 50 per cent of our chronotype is under genetic control, and variants in the genes that regulate our circadian rhythm have been associated with both extreme ‘eveningness’ and extreme ‘morningness’. In a familial form of what’s known as ‘advanced sleep phase syndrome’, in which sufferers want to go to bed early in the evening and wake up extremely early in the morning, much rarer than delayed sleep phase syndrome, a mutation in one particular circadian gene, called ‘PER’, has been identified. Furthermore, mutations in another one of these circadian genes, called ‘DEC2’, seem to increase the amount of time we spend awake and reduce the amount of sleep required. For most people, however, it is not these few mutations that influence their wake/sleep pattern, but likely the cumulative effect of multiple milder variants in all of these genes.
Moreover, it appears that shifts in our chronotype also occur as the brain matures. Teenage circadian rhythms will typically shift later in the day, before then shifting back in adulthood. I can see this happening in my older daughter. Prising her out of bed in the morning is becoming increasingly difficult – as is getting her to go to sleep at a reasonable time at night. Undoubtedly this shift in the body clock seen in teenagers is compounded by the use of electronic gadgetry late in the evening. Being glued to your tablet, laptop or smartphone while in bed, as many teenagers are, provides a potent source of light to act as a Zeitgeber and makes this delay worse. This is a real problem. The consequence being that many teenagers, still needing to get up early to go to school, are sleep-deprived, and sleep deprivation is correlated with poorer performance at school as well as behavioural issues and anxiety. Individuals with delayed sleep phase syndrome, however, seem to be particularly sensitive to light exposure and its effects on the circadian rhythm. A burst of light in the evening seems to have a much greater delaying effect on the circadian clock in susceptible individuals than on average.
So, maybe the answer to Vincent’s problem is as simple as cutting out the use of electronic devices at night. Or even wearing sunglasses in the evening to stop as much light as possible, especially blue light, from hitting his retinal ganglion cells. There is only one problem with this solution: Vincent does not actually have delayed sleep phase syndrome. What he has is much rarer.
If you listen carefully to his story, it is readily apparent, because Vincent does not want to go to bed at the same time every night (or day for that matter).
‘Essentially my sleeping pattern shifts constantly, so my body wants to go to sleep an hour later every day,’ Vincent says. ‘So basically if I go to bed at 10 p.m. one day, I’ll be naturally inclined to go to bed at 11 p.m. the next day, and so on.’
For Vincent, this constant shifting in his internal body clock means that bedtime, and by extension waking time, progresses by an hour a day. For a few days of every month, therefore, Vincent is synchronised with the world around him, but he soon shifts out of phase. ‘For a week or so, I will be in social hours, but for the rest of the time, to different extents, I am out of sync.’ At its worst, Vincent is essentially nocturnal and tells me that he can sometimes want to go to sleep at 11 a.m. and wake up at 9 or 10 p.m.
The impact of this shifting pattern is enormous. The result is that Vincent is often incredibly sleep-deprived. For most of the cycle that he shifts through, he finds it difficult to fall asleep at an appropriate time, but is forcing himself to get up in order to go to school. Some days, it is the equivalent of being rudely awakened at 2 or 3 a.m. and then being expected to pay attention in class at 4 or 5 a.m. Essentially, he is almost constantly jet-lagged.
Vincent says: ‘When I’m in school, it can be very difficult to concentrate. One teacher noticed that my reading is particularly slow, and that it affects my processing skills. Sometimes it is almost impossible to stay awake and concentrate, so I could fall asleep during lessons.’
On one of the occasions we meet, it is about 5 p.m., but Vincent is in a phase when he wants to go to bed at 2 or 3 p.m. and wake up at midnight or 1 a.m. For Vincent, his brain is telling him he should be deeply asleep, and according to his body clock it is about 1 or 2 a.m. He struggles to string a sentence together, pausing constantly to find words, trying to get his thoughts in order. It reminds me of times as a junior doctor when I was on call for 24-hour shifts. I would be bleeped in the middle of the night and really have to pull myself together to give a sensible medical opinion. Vincent stumbles over his words: ‘I just feel I’m behind the rest of the world right now. When I’m in sync with the world, I feel pretty good, because then I am able to be the best version of myself, the most articulate version of myself. Whereas right now, I’m not particularly.’
Dahlia’s description of him when he is in sync and out of sync is striking:
When Vincent is on a phase when he wants to sleep all day, when he is awake he is not himself. He looks tired, his responses are delayed, and he is mentally exhausted. Oh, when he is in sync with the world, when he normally wakes up at 6.30 or 7 in the morning, he’s bright, he’s like everyone else. He is passionate about his studies, he engages personally a lot more. He engages better with the world basically.
Unsurprisingly, Vincent’s schooling has suffered terribly. ‘It was getting very difficult to get in [to school] every day because I was constantly late, and teachers weren’t being very understanding about the sleep disorder,’ Vincent tells me. ‘So after a while, I just dropped out because it was getting too difficult. It wasn’t very sustainable.’
Dahlia is clearly bitter at Vincent’s experience at school, and while she does not blame his teachers, she feels that there has been a lack of understanding and flexibility on their part regarding Vincent’s medical issues.
It was not just Vincent’s schooling that suffered; his social life
was devastated too.
Dahlia says, ‘I had to turn his friends away sometimes. When they came to visit him at, say, 7 p.m. to play PlayStation or something, Vincent would have been asleep since 5 p.m. So I had to say to his friends, “Oh, guess what, he’s asleep!” But it is very strange for them, because a teenager never sleeps at 7 p.m.,’ she laughs with a slightly bitter undertone.
* * *
Dahlia’s determination to get to the bottom of Vincent’s condition finally resulted in a referral to one of my sleep colleagues in the children’s hospital. The history that Vincent and his mother give is absolutely typical of a condition called non-24-hour rhythm disorder, and this was confirmed using actigraphy – prolonged tracking of Vincent’s sleep patterns using a wearable device, a medical version of some of the wrist activity trackers now widely available. Essentially, Vincent’s circadian clock is running at twenty-five hours, rather than twenty-four. Somehow, Vincent’s suprachiasmatic nucleus has become immune to or detached from the Zeitgebers – the external influences that normally nudge the clock to remain synchronised with the outside world.
In otherwise healthy individuals, non-24-hour rhythm disorder is really rather rare, but is much more common in people who are completely blind. It is easy to understand why. In the absence of any vision at all, that most important of influences on the circadian rhythm, light, is completely abolished as an input to the suprachiasmatic nucleus. The effects of other Zeitgebers, such as physical activity or eating, are magnified in its absence. The pathway from the retinal ganglion cells at the back of the eye via a dedicated bundle of fibres, the retinohypothalamic tract, is no longer intact. In fact, between half and two-thirds of patients who are unable to perceive any light have problems with sleep consistent with a circadian rhythm disorder. In one recent study, 40 per cent of totally blind individuals had a non-24-hour rhythm. In normally sighted individuals like Vincent, however, it is incredibly rare and poorly understood, though we do know that it typically starts in early teenagehood and is much more common in males.
We know that much of the influence of the intrinsic clock on the brain is mediated via a hormone called melatonin. This hormone is secreted by the pineal gland, a tiny pine-cone-shaped structure deep within the centre of the brain. René Descartes proposed this tiny area as the seat of the soul, though in reality its role is rather less glamorous, although still important. Under the influence of the suprachiasmatic nucleus, it churns out melatonin in a cyclical pattern.
For people with a normal sleep/wake cycle, melatonin levels rise in the early evening, stay elevated in the night and then drop back down a couple of hours before waking. The melatonin acts as a chemical signal to the rest of the brain that it is time to sleep, acting on melatonin receptors distributed very widely, not only in the brain, but also in multiple other tissues like the kidneys, gut, heart, lungs, skin and reproductive organs. So, by studying the rise and fall in melatonin levels in the blood, we can monitor someone’s circadian rhythm, and the length of their cycle. But it is not quite as simple as that, because we know that a burst of bright light in the evening can suppress and delay this rise in melatonin before sleep. So, environmental factors can significantly alter the rise and fall of this hormone.
In order to understand someone’s internal clock, they need to be kept in constant dim lighting conditions, bright enough to see but dark enough so as not to influence the pineal gland’s secretion of melatonin. Looking at this pattern of melatonin in sighted individuals with non-24-hour rhythm disorder confirms that the sleep patterns seem to be internally driven, with an average cycle length of 25.2 hours – much longer than the 24.2 hours most people have. So maybe it is just having a cycle length that is so far off from the norm that is at least part of the problem. The effect of light and other Zeitgebers may simply not be strong enough to correct for such a big discrepancy.
Or it may be that there is just an insensitivity to the effects of light. Perhaps the suprachiasmatic nucleus is blind to the signals that the retinal ganglion cells send, like in patients who cannot see. In Vincent’s case, his sleeping problems certainly get much worse in the winter months, and this might be directly associated with the lower intensity of light. A reduced effect of light on melatonin secretion has not been demonstrated in these patients, however, nor has a reduced sensitivity of the retinal ganglion cells ever been proven.
There seem to be some commonalities between people with non-24-hour rhythms and those with delayed sleep phase syndrome. In both, the natural rhythm is slightly longer than normal individuals, and analysis of the genes that define the circadian clock has shown variants in a gene called PER3 to be associated with both patterns of sleep. So maybe it is the case that, if your rhythm is slightly longer than twenty-four hours, you have a tendency to run later, but eventually your rhythm is stabilised by the effects of Zeitgebers, causing delayed sleep phase syndrome. But if you run very long, and the drift is too great for the Zeitgebers to correct for, or the Zeitgebers simply don’t work very well, then you end up free-running, like Vincent. This is still a hypothesis, and remains to be proven, but it is curious that there have been a few reports of non-24-hour rhythm disorder starting after the manipulation of sleep/wake patterns in patients with delayed sleep phase syndrome.
Chronotherapy involves delaying the bedtime by a certain number of hours every day in an effort to bring someone with delayed sleep phase syndrome back into sync. The rationale is that it is easier to stay awake for an additional few hours than to force your body to go to sleep earlier. By pushing your sleep pattern around the clock, you eventually get in line with everyone else. However, it seems that doing this can push the circadian clock to the limit, and in rare cases may result in the loss of control that one finds in non-24-hour rhythm disorder. In Vincent’s case, perhaps it was the hip operations and the recovery period that were the initial disrupters of his sleep cycle.
* * *
Some of the effects of battling against your own body clock are readily apparent. The sleepiness or insomnia are obvious, as are the effects on cognitive ability, alertness and vigilance. The nurse at the workstation who briefly dozes off on their third night shift in a row is not a rare sight on the wards. It is not a reflection of laziness, but a direct function of their underlying circadian rhythm. The effects of the natural shift in the circadian rhythm in teenagers has even led some scientists and educationalists to propose that secondary school should start later in the day, to maximise the potential of pupils who are otherwise left sleep-deprived by waking earlier than their circadian rhythm dictates.
We are now beginning to understand that there are far-reaching and long-lasting implications of chronic disruption of the circadian clock, however. To comprehend the impact of this, studying the health of people who have been working shifts for long periods of time is a good place to start. For over twenty years now, we have been aware of some of the possible risks. A study in 1996 suggested higher levels of breast cancer in Norwegian radio and telegraph operators, and since then this finding has been reproduced several times. There is also evidence to point to an increased risk of colorectal and prostate cancers in shift-workers. The evidence is robust enough for the World Health Organization to add ‘circadian disruption’ to the list of probable carcinogens; and the Danish government to provide compensation to shift-workers with breast cancer. Moreover, it appears that shift work is also associated with gastrointestinal disorders, cardiovascular disease and diabetes.
So why should shift-workers have increased rates of certain cancers? One hypothesis is centred around the exposure to light at night. As we’ve discussed, light exposure at night suppresses the production of melatonin by the pineal gland, and it is argued that melatonin may have some anti-cancer activity above and beyond its role as a hormone – specifically, to absorb toxic by-products of oxygen metabolism that are thought to damage our DNA and predispose us to cancer. So, by regular exposure to light at night, perhaps we are lessening our resistance to cancer. This h
ypothesis is supported by the fact that people who are totally blind are less likely to develop breast cancer than normally sighted individuals, and in one experiment mutant mice predisposed to breast cancer were more likely to develop tumours when their circadian rhythms were disrupted. But there are lots of potential confounders.
We know that sleep deprivation in itself causes changes to appetite and promotes weight gain, a risk factor for breast cancer. And maybe shift work makes it more likely for you to take up an unhealthy lifestyle like smoking or exercising less. Also, very recently, a study has shown that even after three days of simulated shift work, the circadian clocks in the brain and in other organs become misaligned. The researchers found that markers of the brain’s circadian clock in the suprachiasmatic nucleus remained relatively stable, but simultaneously there were dramatic changes in levels of the breakdown products of food. It could therefore be that this misalignment of brain rhythms and other 24-hour cycles in the body, usually tightly regulated, has fundamental consequences for how these products of food metabolism are processed, increasing our risk of diabetes, obesity and other medical issues. Furthermore, through this clash in the rhythms of various physiological processes in our bodies, our normal processes of cell replication and DNA repair may be impaired, giving rise to increased cancer risk. While the precise nature of the mechanisms underlying disrupted circadian rhythms and ill health remains poorly understood, certainly this association raises some very broad implications for us. Are we causing ourselves long-term harm through our exposure to light indoors and the use of electronic gadgets late into the night?
The Nocturnal Brain Page 3