The Nocturnal Brain

by Guy Leschziner

  When I was at medical school, we were taught about the lymphatic system, a series of vessels or channels within the body that drain fluid from the tissues back into the circulation. Roughly three litres of fluid pass through this system a day, helping to remove waste substances and toxins from the tissues, but also flowing through lymph glands to facilitate the immune system. Damage to the lymphatic system after surgery for breast cancer, for example, can cause lymphoedema, swelling of the arm due to inadequate drainage of this fluid. An infection in the foot may cause lymph glands in the groin to swell, as the immune system kicks in to fight that infection and the lymph node enlarges in response. At the time of learning about this aspect of our bodies, we were also told that the one organ that did not have a lymphatic system was the brain. But, in the past few years – and it is truly remarkable that it is so recent – this received knowledge has been overturned.

  Tiny channels within the brain, a network of spaces like the canals draining the lowlands of Holland, have been discovered, and have been termed the glymphatic system. These act like a waste disposal chute for the brain, and there is clear evidence that one of the substances cleared by this network is beta-amyloid. But what has this to do with sleep?

  Well, evidence from sleeping or anaesthetised mice shows that the channels of the glymphatic system expand during sleep, and the flow of fluid through this network increases in both these states compared to mice that are awake. In humans, levels of beta-amyloid in the cerebrospinal fluid, where the fluid inside the glymphatic vessels end up, are highest in the morning, suggesting a similar flushing-out of beta-amyloid overnight. In fact, a recent study in humans has shown that even after a single night of sleep deprivation, levels of beta-amyloid in certain parts of the brain, including the hippocampus, often damaged in Alzheimer’s, go up. So, if you consider that sleep apnoea disrupts sleep sometimes hundreds of times per night, it is easy to understand why this might impair the functioning of the glymphatic system, why beta-amyloid levels in the brain might go up, and why this might predispose to Alzheimer’s.

  However, it may not simply be an issue of glymphatics alone. As with damage to the blood vessels, it may be that the recurrent episodes of low oxygen specific to sleep apnoea also have effects on the brain. As with other parts of the body, sleep apnoea may also give rise to inflammation and oxidative stress in the brain, altering processes that maintain the health of neurones and the way in which circuits are regulated.

  So, why do I refer to this association as exciting? Well, given how common both Alzheimer’s disease and sleep apnoea are, and increasingly so, some researchers have proposed that sleep apnoea is a major modifiable risk factor for Alzheimer’s. We cannot modify our genes (yet!), but if sleep apnoea is identified and treated at an early stage, could this be a preventative treatment for Alzheimer’s disease?

  * * *

  Having raised the diagnosis of sleep apnoea with her GP, Maria was referred to our centre. A simple piece of kit that she wore at home at night to monitor her breathing, heart rate and oxygen levels revealed that her oxygen levels were dipping an alarming eighty-six times every hour over the course of the whole night. I ask her how she felt when she received the diagnosis. ‘The first reaction, I’m ashamed to say, was that when I was told I had to stop driving, I burst into tears, because I rely on my car for work and my husband doesn’t drive. So I was kind of fixated on that. And then, once I’d had time to absorb it, it was a huge relief that it wasn’t anything more serious.’

  Maria works in healthcare, and I ask her if she had previously come across sleep apnoea. ‘I was familiar with it,’ she says, but continues:

  I don’t think people would necessarily jump to it for a diagnosis for somebody like me. Because I’m a woman, I’m not elderly, I haven’t got a particularly large neck. I think that’s why my GP did not think of it. I don’t fit the classic mould of somebody with sleep apnoea. And although doctors asked if I was sleeping okay, they didn’t delve into me getting up frequently in the night, things like that.

  There are various treatments for sleep apnoea. Obviously, weight loss helps, and for selected patients options include keeping them off their back, oral devices to hold the lower jaw forward and open up the airway, or surgery. More recently, for very serious cases, an electronic device can be implanted in the neck to stimulate the nerve that retracts the tongue in sleep. But at this severity of sleep apnoea, there was really only one immediate treatment choice for Maria – CPAP, or continuous positive airway pressure.

  This device aims to prevent the airway collapsing by holding the airway open in sleep. It does this through a mask strapped to the face to create a seal, attached to a small machine that pumps out air under pressure. This pressurised air splints open the airway. Before this device was invented, patients with extremely severe sleep apnoea would occasionally have tracheostomies, surgical procedures to create a hole in the neck to bypass the obstruction. In comparison, CPAP is very minor. But the prospect of sleeping with a mask strapped to your face is not without difficulties. Some people find it claustrophobic or uncomfortable. Maria tells me:

  The first morning I woke up, I felt like I’d been punched in the face, from the pressure in the mask and everything. So I was thinking, Oh, this isn’t great. But the next day I woke up and it was the first time in eight years that I’d only woken up once in the night. I felt so much better, and I just burst into tears because I was just so pleased that this was something that was going to work.

  Maria has persisted with the mask and machine, and I ask her what the results of ongoing treatment have been. She tells me her sleepiness has completely resolved, and she is driving again. ‘I can focus a lot better. I’ve been able to start reading, which has been fantastic. I used to just come home, switch on the TV – I’d be asleep within half an hour, so I didn’t get to watch anything good. But now I’m able to read and focus on reading an actual novel.’

  Also, whereas previously she found herself unable to cope and less able to tolerate minor upsets, she now laughs. ‘Some people are irritating and you can’t help but react to that. But I feel much more resilient and much more able to cope with things. That part of my personality has returned. I feel much more laid-back and with a bit of perspective on the world.’

  I ask her if she feels that the CPAP has unravelled all the consequences of sleep apnoea.

  I don’t feel back to my old self. But it is eight years later; I’ve got two young children, I’m fat and in my mid-forties. So I don’t feel the same way as I did [before the sleep apnoea], but I feel much better than I did. I feel optimistic about feeling better in the future. The thought of exercising and hopefully losing enough weight that I won’t need to use the CPAP in a couple of years’ time is something that is achievable now. A few months ago, it just wasn’t at all.

  As we chat, Maria expresses something that surprises me. ‘I feel horribly guilty about it now, that I didn’t listen to [my husband] and take it seriously, and investigate it sooner than I did,’ she shrugs. The relief of the diagnosis of sleep apnoea, and its successful treatment with CPAP, has been tainted by regret. She tells me that after she was diagnosed, she researched her condition. ‘I read about it. Obviously I had a look on Google like everybody does. I was shocked at how serious it actually was and the damage that I’ve probably done, having it and not having it treated.’ This is not a sentiment I have often heard, but perhaps stems from Maria’s background as a healthcare professional.

  Maria’s regret should be predicated on the basis that treatment of sleep apnoea with CPAP actually does reverse all the negative effects on health. If sleep apnoea really gives rise to all these other health issues, then surely treating it should reduce your risk, of heart disease, stroke, Alzheimer’s disease, and so on? What seems like a simple question gives rise to a very complicated answer, however. Benefits of CPAP on cognitive functioning, mood and sleepiness in patients with sleep apnoea have clearly been demonstrated. We also know that CPAP results in
an improvement in blood pressure and the endothelial dysfunction that is a marker for blood vessel health, and the effects appear to be more marked in people on multiple drugs for hypertension. But does this translate to a reduction in risk from cardiovascular disease and stroke?

  Despite numerous studies, results have been mixed. Some observational studies have suggested that CPAP reduces the risk of death from cardiovascular disease. More recently, controlled trials, where patients have been randomly assigned CPAP or no CPAP, have not borne these findings out. In the field of dementia, CPAP has been shown to result in changes in brain volume, particularly in the hippocampus, a brain area implicated in memory and Alzheimer’s, after only a few weeks of treatment, but large-scale randomised controlled trials in dementia have not yet been published.

  So why the confusing results in cardiovascular disease? These trials highlight some of the methodological issues surrounding these kinds of studies. Firstly, we know that CPAP compliance – how well people adhere to using CPAP every night for the whole night – is very variable and often limited. In some of these studies, average compliance was very limited, only three hours a night. We don’t know how much usage is optimal, but presumably the more you use CPAP, the more benefit might be expected, so it is difficult to draw conclusions on studies where CPAP usage is short. The second issue is the selection of patients for inclusion into these studies. When someone is very sleepy, it is problematic from an ethical perspective to randomise a patient into no treatment. Some of these trials have therefore been performed on non-sleepy patients, and it has been argued that these are the least likely patients to obtain benefit. Thirdly, it may be that some of the damage done by sleep apnoea is irreversible, so the effect of CPAP on modifying future risk is limited. Finally, there remains uncertainty as to how long these trials need to be. Are the reversible consequences of sleep apnoea apparent immediately, after three months, or three years?

  It is important to recognise that sleep apnoea is not one entity. There is a range of severity, and some people may be sleepy while others are not. Some people have these respiratory events largely in REM sleep, or solely when they are flat on their back. Some may have suffered from it almost their whole lives, while others may have gained weight and started experiencing it very recently. So the impact of sleep apnoea on health, and the consequences of treatment with CPAP, is not likely to be uniform. It is this variability that probably underlies our uncertainty about its effects and the benefits of treatment.

  It is clear, however, as I sit opposite Maria, that the person before me now is not the same person as a few months ago. The grumpy, short-tempered, exhausted Maria that she describes has been replaced by someone smiley, energetic and able to cope with a busy home and working life. ‘I don’t love the mask,’ she says. ‘I’d rather I didn’t have to sleep with it. But the effect it has had on my life has been so positive. I’m very grateful for it.’ For her, the benefits of CPAP, in terms of her sleep, her mood and her function, are evident.

  As for the long-term effects, for Maria and others with sleep apnoea, the hope is that future studies will provide the answer.

  5

  THE SLEEP-TALKING BUS DRIVER

  Things are not always what they appear to be. Very early on in a medical education, one learns to be a bit more circumspect about what is presented. When we learn about general practice in medical school, we are taught to seek out ‘the hidden agenda’, the real reason someone is coming to see their doctor. Is the reason for someone’s visit really about their abdominal pain, or is it because they are depressed and have issues at home? Are their headaches the major problem, or are they being bullied at work? As we progress through our medical careers, we become familiar with circumstances where appearances are deceptive: the child in A&E whose bruises are not consistent with falling off a swing, but are more in keeping with abuse; or the elderly man with dementia, admitted with an acute deterioration, who turns out to have been stable for the past few months, but whose family are simply unable to cope with him at home any more. And, as I have seen on a number of occasions, the person with severe intractable epilepsy, uncontrolled despite many medications, who is repeatedly admitted to intensive care so that prolonged seizures can be treated with general anaesthesia, only to find that when scalp electrodes are attached, the brainwaves are totally normal. These intractable seizures turn out to have a psychological rather than a neurological basis.

  For a few patients, there is a conscious effort to simulate medical conditions, symptoms and signs for some sort of gain. A soldier faking an injury to escape arduous duties, or a prisoner trying to relocate from the main prison onto the hospital wing, known as malingering. Then there is the person with Munchausen’s, a mental disorder where people invent medical symptoms and ailments in an effort to obtain medical attention, desperately trying to convince doctors that one’s abdominal pain is an appendix about to burst, for example. For the vast majority of people, however, this is not ‘swinging the lead’ or ‘putting it on’. These symptoms are very real to them, entirely outside of conscious control; not a malevolent act to pull the wool over the eyes of others.

  For centuries, debates about the nature of these ‘non-organic’ conditions – those that have no basis in biological dysfunction – have raged. Cases of what, in hindsight, represent non-organic neurological disorders have been described as far back as 4,000 years ago in ancient Egyptian texts. In the era of Hippocrates, these conditions were termed hysteria, derived from the Greek for ‘womb’. Hysteria was thought by the male-dominated medical world as a condition of women, caused by shifting of the womb out of its normal position, moving around the body to produce a variety of symptoms. It was only at the tail end of the seventeenth century that hysteria began to be viewed as less of a physical disorder, and more of an emotional problem.

  Proper study of these disorders really began in the nineteenth century with French doctors like Briquet, Janet and Charcot. At that time, hysteria was still seen as a ‘neurodegenerative’ disorder, cured by hypnosis. Jean-Martin Charcot would give public demonstrations of patients with hysteria, with seizures, strange movements, paralysis or numbness, apparently successfully treated in front of the eyes of the paying public. There is a famous painting by Pierre Brouillet that features Charcot displaying a hysterical woman to post-graduate students at the Pitié-Salpêtrière Hospital in Paris, then and now a major neurological centre. In the audience, watching in rapt attention, are famous neurologists like Joseph Babinski, Georges Gilles de la Tourette, Henri Parinaud and Pierre Marie, all of whose names are now associated with a variety of clinical signs or disorders in common usage. Reproductions of this painting, A Clinical Lesson at the Salpêtrière, have adorned the walls of many of the neuroscience units I have worked in.

  However, it is perhaps the work of Sigmund Freud that has had the most impact on our view of these disorders. Working under Charcot, and subsequently in Austria, he viewed hysteria as having a psychological origin, where awful experiences were suppressed and were converted into physical symptoms. Freud essentially described a Catch-22: either you recalled having major trauma, which explained your hysteria, or you repressed it into your unconscious, which also explained your hysteria. This idea of conversion of psychological distress into physical problems led to hysteria being known as ‘conversion disorder’, and to some extent Freud’s views have remained to the present day. But, despite the best efforts of psychiatrists to uncover evidence of psychological trauma, there are patients with this type of problem in whom no such life events can be identified, and it seems that there are in fact multiple reasons people might develop a non-organic disorder.

  The latest iteration of these disorders is now ‘functional neurological disorder’, reflecting our lack of understanding of the origin of these symptoms in many patients, while expressing the view that while the neurological system is structurally normal, there is a disorder of neurological function. A commonly used allegory is that, while the hardware is int
act, there is a problem with the software.

  Historically, the mind and the body have been viewed as separate entities, termed mind–body dualism, with the origins of human experience in the soul, entirely distinct from ‘organic’ or physical dysfunction of the body. This concept of dualism is slowly being chipped away, however, and, if you think about it, this should be of no surprise. We know that one’s psychological state and neurological function are intrinsically linked. People with epilepsy or migraines will often say that stress is a potent trigger for their attacks. And, on a more day-to-day level, we will all be familiar with the goosebumps we get when scared or excited, the hairs on the back of our neck standing up, our pupils dilating. These physical changes are mediated by our nervous systems, but are clearly under the influence of our psychological state.

  On a personal level, a familiar feeling when walking onto the stage to give a big lecture, riven with anxiety, is the sudden sensation that my walking is no longer automatic, but requires concentration. In my nervousness not to trip as I walk up the stairs to the podium, what should be the unconscious act of placing one foot in front of the other becomes a task that needs conscious effort, as my legs become heavy and clumsy. So it seems that our nervous system is vulnerable to our attention being focused upon it; that this awareness of a body part or movement can in itself cause symptoms. In fact, try it for yourself. Sit quietly in a chair, without distraction. Now focus hard on your feet for a few minutes: think about how they feel, the sensation of your socks on your toes, your shoes pressing on your heels or ankles. After a few minutes, you are likely to feel things you didn’t feel before, perhaps a tingling, a numbness or a little discomfort. The mere act of attention can generate symptoms. It is likely that for some patients with non-organic symptoms, especially those without an obvious psychological trigger, it is this mechanism that causes their problems.