- I'm going to start this talk in a slightly unusual place in a talk about sleep, and I'm going to talk about this man. Some of you will recognize this man, this chap is called Phineas Gage, and he was a worker on a construction gang in New Hampshire, in 1848, when he had an unfortunate mishap. One of his responsibilities whilst creating a cutting for a railway line was to drill holes and tamp down explosives before blasting the hillside away. And unfortunately, on this fateful day, he was a little bit too vigorous in terms of his tamping down, and he must have ignited the explosive at the bottom of the hole as he pushed this tamping iron, this very heavy piece of iron, down into the hole. Unfortunately, the tamping iron, having ignited the explosive, then pierced through his jaw and flew out of the top of his head, and after a brief seizure, with the tamping iron flying several yards through the air, he then sat up. And the first doctor on the scene gave this absolutely grotesque description, which I'm going to read to you in an abbreviated form:"I first noticed the wound upon the head"before I alighted from my carriage,"the pulsations of the brain being very distinct," doctors love this kind of thing, so apologies."The top of the head"appeared somewhat like an inverted funnel,"as if some wedge-shaped body had passed from below, upward."He was relating the manner in which he was injured,"I did not believe his statement."He got up and vomited, and as he did so,"the effort of vomiting"pressed about half a tea cup full of brain,"which fell upon the floor," quite remarkable, firstly remarkable that he even survived and was talking immediately afterwards, in those days, in the era before antibiotics, even more remarkable that he went on to survive. And this is the nature of his injury, you can see this reconstruction, it passed under his cheek bone and basically destroyed an area of the brain called the left frontal lobe. The reason why I'm telling you this is because Mr. Gage is one of the most famous examples of a concept in clinical neurology, which is localization, demonstrating that, far from being this sort of gelatinous mass that does everything, different parts of the brain, in fact, different parts of the nervous system perform very distinct and discreet functions. And the reason why Mr. Gage is such a good illustration of that is because, in many ways, he was completely unchanged, he could walk, he could talk, he could do everything that he could do before. But what had previously been a God-fearing man, somebody who didn't smoke, didn't drink, didn't swear, became this, basically, a completely uncontrollable, whoring, drinking, gambling man who became extremely unpleasant. And if you believe some of the statements of his coworkers after this accident, he was completely transformed, demonstrating, in his case, that the frontal lobe of the brain is really responsible for maintaining our social control, our regulation, our rational thinking, our behavior, and really being a very, very good example of this concept of localization. Now, why am I telling you all of this? Well, what I'm going to try and show you in this lecture is that sleep is of the brain, so it's derived from the brain, it's by the brain, so regulated by the brain, and it's largely for the brain. Now, I'm not the person who first came up with that quote, this relates to a very famous psychiatrist in the world of sleep medicine based in Harvard, but what I'm going to show you is that many of the sleep disorders that we see result from lesions of the brain, and by lesions, once again, I mean damage, or injury, or illness that is related to a particular part of the brain or the nervous system. These lesions that we see in sleep disorders are not necessarily quite as striking as a big, heavy tamping iron, sometimes they are transient, sometimes they're functional, by which I mean they're related to changes in brain chemistry, or changes in electrical activity within the brain, and sometimes they're microscopic, but they are lesions nonetheless, a little bit like that tamping iron. I'm also going to go on to show you what lesioning of sleep itself, so destroying sleep, or somehow impairing sleep, also does to the brain, because that gives us some insights into what the function of sleep, or the functions of sleep really are. We used to think of wake and sleep as being these entirely separate states. I've actually, rather in a prescient manner, I've put in a picture of the Berlin Wall, which seems to be coming back, separating the west of wake from the east of sleep. And historically, it's been put about that sleep is essentially a little death. But of course, we've known that that's not the case, it's not that everything switches off when we go to sleep. In fact, this is one of the earliest descriptions that really gives us an illustration of the knowledge that something goes on in sleep. This is something called the "Egyptian Dream Book," it's a papyrus that resides within the British Library dating back to about 1220-1230 BC, and in it are descriptions of 108 dreams and their prophecies associated with them. So clearly, people were already, at that stage, interested in what the function of sleep, or the function of dreaming was. It was actually this man, Sigmund Freud, who tried to apply some scientific rationale to the functions of sleep or dreaming. He may not have been entirely correct, but this, in many ways, was a landmark in the field of sleep research. What we now know about sleep is that it's not simply wake and sleep, but actually, that sleep comprises of multiple different stages, and this is largely thanks to work by this chap, Eugene Aserinsky, who, in the 1950s, was undertaking a PhD, and as many PhDs go, it was rather successful. He kept on being sent away by his supervisor, failing to do the tasks that he was set, until the supervisor, in a degree of exasperation, basically said, well look, I'm doing some studies on sleeping babies, go and record their sleep. And he went away and started recording the muscle activity and the brainwaves of babies. And what he showed was that, throughout the night, the brainwaves of these sleeping babies changed rather dramatically. At the bottom of the slide, you'll see these rather large waves, these slow brainwaves, that really are a function of the brain slowing down, and represent what we now know as non-REM sleep. But interspersed with this slowing of the brain activity, there were also these periods of time where the brain, and you can see right at the bottom there, there is a slight flattening, a slight increase in the frequency of those oscillations of the brainwaves, that are a feature of what we now term REM sleep, rapid eye movement sleep, which is the stage of sleep that we most associate with dreaming. And it's during this stage of sleep that the eyes move back and forth, the brainwaves actually look rather similar to the brainwaves of somebody who's awake, which is the top trace there. And whilst the brain appears to be awake, physically, we are completely paralyzed, so something happens in REM sleep that makes all our skeletal muscles paralyzed. The only muscles that continue to have some activity are the diaphragm, which obviously is important from an evolutionary perspective, otherwise we would all stop breathing in our sleep, and the muscles that control our eye movement, hence the term rapid eye movement sleep. And what research has subsequently demonstrated is that we continuously cycle through these various stages of sleep throughout the night, and that the average adult, you can see there in the top, this is something called a hypnogram, which is a graphical representation of an average adult's night sleep, we tend to cycle through the different stages of sleep roughly once every 90 minutes, entering into REM sleep approximately an hour to an hour and a half after sleep onset, and then dipping in and out of REM sleep, with the majority of our very deep non-REM sleep, this is the stage at which the brainwaves are the slowest and largest amplitude, in the first half of the night, and the majority of REM sleep, what we term dreaming sleep, somewhat incorrectly, because we do dream in other stages of sleep, in the latter half of the night. And you can see that those red bars get longer and constitute a higher proportion of sleep in the latter half of the night. So we now have these three stages, we have wake, we have non-REM sleep, which is what we traditionally think of as sleep, where the brain is a little bit less active, and then we have REM sleep, where we're asleep, but the brain seems to be very active indeed. But it gets even more complicated than that because we have a series of sleep disorders that I think very much illustrate that not all is quite so straightforward. I'm going to show you two videos, of two individuals. It's important to stress that both of these individuals are in the deepest stages of sleep, they're in what we term stage three sleep. The brainwaves in this chap are very, very slow, he clearly is, on the basis of the brainwaves that we're recording, in the deepest stages of sleep, but to all intents and purposes, he looks awake, he's moving around, he's interacting with the wires that are attached to his head, he's interacting with the bed. I mean, he's clearly not behaving entirely normally, it's a bit of an odd thing to be doing in the middle of the night, but he is in very deep sleep. This next video is of a young child, who is also in very deep sleep, believe it or not.- No, mum, no! Mum, stop, mum, please, stop me! If I press it, I'm going to die.- [Mother] No, you're not going to die.- No, yes I am!- [Mother] No you're not, sweetheart.- No!- [Guy] So he's clearly interacting(child screams) not in an entirely appropriate way.- Please stop it! But his brainwaves, once again, show that he's in very deep sleep. So how do we explain this, how can we explain the fact that people in very deep sleep can exhibit these kinds of behaviors? Well, what these represent are a range of conditions called non-REM parasomnias. These are a spectrum of behaviors that arise from very deep sleep, as I've already said, and they can range dramatically. They include sleeptalking, confusional arousal, so that's the first video that we saw, where that chap sat up and started looking around, with his eyes open, sleep terrors, which is what we saw in that young child, people can sometimes sleep-eat, so they can get up in the middle of the night, they can cook, they can often eat things that are completely inappropriate, the things that come to mind are raw food, or bird seed, or sometimes things that they shouldn't be eating at all that are highly toxic, sexual behaviors in sleep, a condition called sexsomnias, and of course sleepwalking, occasionally even very complex behaviors like sleep-driving or sleep-motorbiking, I've had patients who have rewired electrical gadgets in the middle of the night without any memory, so these can be very, very complex behaviors. They typically arise in the first half of the night, because that's when we do the majority of our very deep sleep, and as you've seen, the eyes are typically open, there's complex speech, people often interact with their environment, or with people in the room, not in an entirely appropriate way, people often have no recollection at all over these events, they're difficult to wake, although occasionally, they will have some fragments of memory that something is happening that is appropriate to what they were doing. So how do we explain these kinds of events? In a rather remarkable study from 2000, some researchers in Switzerland managed to get a sleepwalker into a type of scanner called a SPECT scanner. What this scanner involves is giving somebody an injection of a radioisotope-labeled tracer, and whilst they're having one of these events, this tracer doesn't last for very long, only a few seconds, and they somehow managed to get this chap into the scanner and give him the injection within a few seconds of the event starting. And what they demonstrated was rather remarkable, that when you look at this tracer, which is really a measure of brain activity, of metabolic activity of the brain, what they demonstrated was that, in the top slide, they showed increased activity in an area of the brain called the cerebellum, which is fundamental to movement, and in a very deep part of the brain which is called the cingulate cortex, which is a part of the brain that's responsible for emotions. So increased activity, suggesting that there were certain parts of the brain that seemed to be more awake than they should be. What they also demonstrated was that other parts of the brain, particularly the frontal lobes, and you'll remember the frontal lobes are responsible for rational thinking, for control, for planning, for executive function, seemed to be asleep, really suggesting that what is happening during these events is that part of the brain appears to be more awake than it should be, and other parts of the brain maintain sleepiness, suggesting that, actually, sleep is not even a simple case of non-REM sleep or wake, but actually that different parts of the brain can exist in different stages of sleep and wake simultaneously. And indeed, further studies have been done. What we will sometimes do in individuals with epilepsy, for example, that we are considering doing surgery on, we will implant electrodes deep into their brain in order to identify precisely where the epileptic seizure is arising in order to guide further surgery. And in some studies in individuals who've had epilepsy and sleepwalking, what they've clearly demonstrated is that when you implant electrodes deep into the brain, you see something really similar. The SPECT scanner told us about metabolic activity, about physical activity, the EEG, with those electrodes, tells us about electrical activity. And what they've clearly demonstrated, on the basis of the intracranial EEG, is that something very similar occurs, in that you can see, on an electrical basis, different parts of the brain exist in different stages of sleep and wake. So what we now think is going on during these non-REM parasomnias, is that there are particular areas of the brain that, in individuals who are predisposed to these kinds of conditions, and what you have to bear in mind is that these conditions are very common, about 20% of children will have sleep terrors or sleepwalking, this does not necessarily demonstrate a pathological state, it can be considered part of normal brain development, about 1% to 2% of individuals continue to have these kinds of events into adulthood, but what we demonstrate is that whilst the areas of the brain that are responsible for consciousness, for awareness, for judgment, remain asleep, different parts of the brain, particularly those areas of the brain that are responsible for movement, that are responsible for reward and emotions, which is why, sometimes, these events have a very, very strong emotional component, and the parts of the brain that are responsible for memory, like the hippocampus, which is perhaps why these events are very poorly remembered, remain asleep. So sleep is not a universal brain state, that's the first thing that these kind of events tell us. So rather than thinking about these three discrete brain states, actually, what we should be thinking of is that there is a degree of overlap between these three brain states. And in fact, as I'm going to go on to show you, it's that these areas of overlap that many of the sleep disorders that we see, and indeed many of the normal phenomena that some of you may well have experienced in your lives, occur at these points where there is an overlap between the different brain states. I use the term blurred lines because we've actually known that fairly complex organisms can exhibit these kinds of different brain states simultaneously in that there are many animals, particularly aquatic mammals, and certain species of birds and amphibians, that demonstrate a phenomenon called uni-hemispheric sleep, so they can sleep with one half of their brain while the other half of their brain is fully awake, which allows animals to swim and surface, to breathe, particularly important for aquatic mammals, or to continue to fly whilst sleeping with one half of their brain. Uni-hemispheric sleep is well recognized in animals, it's never been recognized in human beings, but a recent paper has suggested that we do exhibit the ability to be able to regulate sleep in the different halves of our brains differentially, because if you take an individual into a sleep lab, which we do about 10 times on every night of the week over at Guy's Hospital, people will invariably say, I didn't sleep as I would at home because I'm covered in wires and I'm in a strange environment, and this is termed the first-night effect, people generally don't sleep quite as well when they're in a new environment for the first time, but what this study demonstrated is that individuals who are brought into a sleep lab for two nights will differentially regulate the depth of their sleep in their dominant hemisphere. On the first night, their very deep sleep, which will be much less deep in their dominant hemisphere than it would be on the second night, and it tends to normalize on the second night, suggesting that there are some mechanisms there that enable us to regulate the different halves of the brain in a different way, even in humans. And this may, of course, be an evolutionary hangover, although one can understand why that would be important, because when you're in a strange environment, there may be threats there, and therefore there is an evolutionary imperative to retain some increased awareness over your environment on that first night. Actually, it goes even further than that, because we now are beginning to understand that sleep, not only is it not a universal brain state, but actually, it can affect very, very small parts of the brain constantly, very small parts of the cerebral cortex. And in this remarkable study from about 10 years ago, what they did was they recorded directly from neuronal units in rats, and what they demonstrated was that actually, even during full wakefulness, these little neuronal units, these clusters of nerve cells, essentially, seemed to exhibit silence every so often. And as the rats become more tired, as they're more sleep-deprived, actually, these little neuronal silences increase in duration and they increase in extent, really demonstrating that these rats appear to be awake and asleep at the same time. And in fact, some of you might already be starting to exhibit little islands of silence in your cerebral cortex. And indeed, when you look at the EEGs, at the brainwaves of humans, in detail, not necessarily in the way that we study in a clinical setting, what we see is we see some changes that occur locally in different parts of the brain of humans as they get more tired. And it may be that, actually, when we say, I had a really bad night, I'm half-asleep, it may not be that far away from the truth, you may not be a half asleep, but you certainly could be a hundredth asleep, there are small islands of your cerebral cortex that are probably constantly dipping in and out of sleep, and that may well be a very good explanation for why our cognitive function, why our performance tends to worsen as we get tired, because those areas of silence increase, so this concept of local sleep is really starting to percolate through into a broad range of sleep research. I talked a little bit about blurred lines, I'm going to give you another example of blurred lines. In fact, what I'm going to show you is, I'm going to show you a really seminal piece of documentation of a neurological disorder, this really is a landmark study. Some of you may recognize this, this is "Cinderella," from 1950, and the king is dreaming,(the king snores and laughs) and he's acting out his dreams. He's imaging his grandson playing with him.(door bangs) And then he wakes up and tumbles out of bed. This is another example from the same movie.(dog growls and whimpers)- Bruno? Bruno?(dog growls) Dreaming again? Chasing Lucifer? Catch him this time? That's bad.- So the reason why I refer to this as a really seminal piece of medical documentation is that this film came out in 1950, it describes a condition that did not really enter into the diagnostic manuals until 1989, so really, either Disney was a keen observer of nature or he was a great physician, I suspect the former rather than the latter. And what this really exhibits is a condition called REM sleep behavior disorder, which essentially is the acting out of the dreams of REM sleep. You may remember that I said to you that in REM sleep, normally, we're completely paralyzed, that all our muscles are completely weakened, but in this condition, for reasons that I'll go into, that mechanism of paralysis that is a feature of REM sleep doesn't work properly. This is a condition that is often seen in slightly older individuals, although it can be seen in younger individuals, it usually occurs in the latter half of the night, you may recall that when I showed you that hypnogram, the majority of REM sleep occurs in the latter half of the night, and the way that it typically manifests is people lashing out, crying, swearing, or shouting, it's not always violent, but it often is. And those behaviors really represent the context, the narrative of the dreams that individuals are having at the time. The speech, unlike those non-REM parasomnias that I showed you, is usually unintelligible, there's often a few swear words that you hear, or shouting, unlike the non-REM parasomnias, people don't tend to leave the bed, if they are woken, they'll often have that dream recall that's appropriate to the actions that have been witnessed, as I've said, and these can occur every night, several times a night, and can result in really quite significant injuries, injuries to oneself, but also injuries to the bed partner, and there have been well-documented cases of homicide related to this condition, so it is a real problem. What we see in these individuals, without going into too much detail, the bottom traces are measures of muscle activity, and that muscle activity should be completely flat in REM sleep, and what you see in this individual is you see these really big spikes of muscle activity that shouldn't be there, really demonstrating that paralysis is not there during those stages of sleep. This is a non-cartoon version of a REM sleep behavior disorder, just to give you a flavor of what we see in the sleep lab. You can see that chap lashes out against the bedside cabinet. That bedside cabinet weighs about 50 kilos, so to almost topple it over requires really quite significant strength. And if you watch this chap's arms and legs, he is dreaming at the time, he kicks out and then starts waving his arms, and he remembers being on a beach, and being attacked physically. As I said, they're not always violent, and you can see him trying to defend himself with these movements of the arms. This chap is having a dream, I'll let you guess what the dream was. Anybody guess? Gun fight, he was having a gun fight in his dream, so kind of violent. So that's how these kinds of phenomena exhibit themselves. We used to think of this as being what we term an idiopathic condition. the term idiopathic means we don't really know what causes it, it's not associated with anything. But actually, what we've learned over the last few years is that, particularly in older age groups, this can sometimes be a feature, a very early feature of a group of conditions that represent degeneration of the nervous system, in particular conditions like Parkinson's disease. And in fact, there have been documented cases of people having REM sleep behavior disorder up to 35 years before they develop Parkinson's disease. And in this study, which was by one of my colleagues in Barcelona, they followed up a group of older individuals who presented with REM sleep behavior disorder for 15 years, and what they demonstrated was, after 15 years, 91% of those individuals began to exhibit frank features of conditions like Parkinson's disease, or related disorders. So to consider it an idiopathic condition is perhaps not correct, we may want to consider it as part and parcel of this group of conditions, at least for the majority of individuals. Why should this be the case? We know that the areas of the brain that are responsible for generating muscle paralysis reside in this area of the brain, called the brainstem. It's very far away from the parts of the brain that are responsible for the changes in movement that we see in Parkinson's disease, which are up here. So why should people with very early Parkinson's disease develop REM sleep behavior disorder? What we are now beginning to understand is that as well as having REM sleep behavior disorder, one of the very early precursor features of Parkinson's disease is loss of sense of smell. Of course, nowadays, we're all very familiar with the loss of sense of smell, and it's not particularly sensitive as a predictor of Parkinson's disease, particularly post COVID, but when you look at the changes that occur within the nervous system within conditions like Parkinson's disease, we see changes in the nervous system that are actually far beyond the basal ganglia, the area of the brain that we associate with Parkinson's disease, and we see changes in the olfactory bulb, which is responsible for smell, we see changes in terms of looking down a microscope and seeing the histological change, the cellular changes in the gut, which is why many people with Parkinson's disease complain of constipation for many years beforehand, and also in this part of the brain here, the brainstem, which is where those mechanisms of paralysis in REM sleep reside, so really giving us a very clear example of why these kinds of conditions may arise many years before the development of other features of Parkinson's disease. And in fact, we now know that if we look at people with REM sleep behavior disorder in isolation, they exhibit lots of changes that suggest, subtly, that they may be exhibiting one of these neurological problems, so we see abnormalities in smell, in bladder function, in gut function, in the function of the heart. If we do tissue biopsies of various bits of the body, we see deposits of this protein called alpha-synuclein, which is the protein hallmark of Parkinson's disease and related conditions, in the gut, in salivary glands, in various other bits of the body. And so we are perhaps incorrect to consider RBD as idiopathic, we're perhaps even not entirely correct to consider REM sleep behavior disorder as being isolated, and that perhaps we should be considering this condition as part and parcel of the very early stages of some of these neurological disorders. Of course, that's very bad news if you are one of those individuals who exhibits this condition, but actually, it's also a real opportunity, because at the moment, there are ongoing trials looking at drugs that might modify the risk of developing Parkinson's disease, that might slow the progression of Parkinson's disease, and if this is a very strong marker for Parkinson's disease, before you've got any of the other features, then you might be an ideal candidate for this kind of drug, and actually, this gives us a huge opportunity to at least see whether or not some of these drugs may reduce the risk of developing these kinds of conditions. I'm going to move on to another neurological disorder now. I'm just going to introduce you to one of my patients, who was involved in a TV program.

the narcolepsy bit is I'm chronically tired, and then the cataplexy, it can manifest itself in me falling to the floor if I experience a strong emotion, like laughing. It's any event that I feel is funny, so it's an emotional connection. The first event that ever happened was trying to put the children to bed, I fell to the floor and wasn't able to get up. The kids were laughing, they thought I was just play acting, and I was just lying there. I could hear them, and I could see them, but I was unable to speak or move, it was bizarre, and I just didn't know what it was.- Narcolepsy is a neurological disorder that is characterized by a number of specific features: people are profoundly sleepy, often to the extent that they will fall asleep sometimes even whilst doing relatively active things like playing football, or at work, in fairly stimulated environments sometimes, and those sleep attacks are relatively brief, they're often associated with very vivid dreaming, people go into REM sleep very early on in those daytime naps. As a result of the REM sleep coming on inappropriately early, they often hallucinate, so that their dream mentation, their dream narrative often enters into wakefulness, another example of one of these blurred lines. So they will often hallucinate as they drift off to sleep or wake up, often seeing people in the room, or having out-of-body experiences, as if they're floating above themselves. They'll often experience sleep paralysis, which is almost the polar opposite of REM sleep behavior disorder, that they will wake up and feel completely paralyzed, because the mechanism of paralysis that is a feature of a REM sleep doesn't switch off. These hallucinations and sleep paralysis are also normal phenomena, a lot of especially the younger people in the crowd will often report experiencing sleep paralysis or hallucinations, it's often related to sleep restriction or chronic sleep deprivation. But in the context of these other features, it's highly suggestive of narcolepsy. And the final feature is cataplexy, which Phil exhibited very clearly there, which is the sudden loss of muscle strength, usually associated with strong emotion, which may represent that mechanism of paralysis being switched on inappropriately during the day, and I'll come on to try and explain why that might be the case. So what do we know about the origins of narcolepsy? Until recently, not a lot. These scans on the left are the scans of a patient with a condition called called encephalitis lethargica, some of you may well be familiar with this condition. This is a condition that essentially presented as an epidemic shortly after the First World war, and resulted in features of conditions similar to Parkinson's disease, but also profound sleepiness, and some of the other features of narcolepsy. We think now that this may well have been a response to the Spanish flu, a post-infectious phenomenon, although its origins still remain a mystery. At that time, famous neurologists and psychiatrists said, well look, actually, narcolepsy, there are features of narcolepsy that a look a little bit similar to encephalitis lethargica, but when we look at the brains of people with narcolepsy, they look normal. But could this be a similar area of the brain, these very deep structures within the brain, that might be damaged in narcolepsy? The story didn't progress much, until this dog and his friends came along to help.- [Narrator] Skeeter is a small dog

no matter how much he struggles to stay awake, he can't. For this 11 pound toy poodle, almost every moment is a disturbing losing battle with the urge to sleep.- Actually, the commentary is wrong there, what this dog is exhibiting is cataplexy, that loss of muscle strength associated with strong emotion. The dog is happy to see its owner, if it's presented with food, it will start collapsing. So why is this of relevance? In the 1970s and '80s, Stanford University, in California, began a breeding program of dogs, because there appeared to be a genetic form of narcolepsy in dogs. And after many, many years, what they identified was that in these dogs, there was a mutation in a particular gene, the function of which was not known. And at about the same time, a chemical within the brain called hypocretin, or orexin, was discovered, and so it was thought that these mutations prevented this chemical, this neurotransmitter from functioning normally within the brains of individuals with narcolepsy. But when they looked in humans with narcolepsy, none of them had these mutations. There has now been one pair of very young children who have been identified who have mutations in this particular gene, but it really focused attention on this particular chemical, this particular neurotransmitter, called hypocretin. And when one looks at the brains of individuals with narcolepsy, and you stain them for this neurotransmitter, what you see is that what should light up, the particular region of the brain, which is called the hypothalamus, in individuals with narcolepsy, all of those neurons producing this particular chemical have disappeared, they've vanished. And in fact, subsequently, it's been demonstrated that, actually, if you measure the spinal fluid of individuals with narcolepsy for this particular chemical, they often have very, very low levels or are completely deficient in this chemical. So why should this arise? Many of you will be increasingly familiar with these, not necessarily this particular diagram, but with the concept of B-cells and T-cells. These are white cells that constitute the core of our immune response. And what we also now know is that in 99% of individuals with narcolepsy and cataplexy, they have a particular genetic marker for something called the HLA type, which is at the core of how our immune system functions. The HLA type defines the way that the immune system presents epitopes, presents bacterial or viral markers to the immune system to generate an immune response. And so what we now think is happening is that individuals with this particular genetic marker, that defines how their immune system works, seem to be at very high risk of generating an immune response to a particular environmental trigger that looks very similar to hypocretin, or orexin, and that the immune system is actually attacking the brain and causing this damage. And in fact, what we have now clearly demonstrated is that the H1N1 swine flue, which was around in 2009-2010, is one of those environmental triggers that seems to be particularly good at generating this kind of immune response. And in fact, both the the flu itself and the vaccine for that flu, a vaccine called Pandemrix, has been very strongly associated with new cases of narcolepsy with cataplexy. So what does this substance do? It has very wide projections, this system, that really is largely responsible for making wake stable, so it's a wake-promoting neurotransmitter, but it also stabilizes non-REM sleep, so it prevents people from going into REM sleep. So what happened in individuals with narcolepsy? You can see here, this is a hypnogram of somebody with narcolepsy, this purply-pink bar is REM sleep, and you can see that in this individual with narcolepsy, they're constantly flicking in and out of dreaming sleep, from wake, from deeper stages of sleep, but it's very fragmented. And so in these individuals, because they are flicking in and out of dreaming sleep, because those switches between wake, and sleep, and REM sleep, and non-REM sleep are unstable, and the whole of sleep is destabilized, that explains many of the phenomena that they experience. So they experience these hallucinations, they experience this sleep paralysis, they often experience very vivid dreams indeed, and they experience these sleep attacks. Well what about cataplexy? The honest answer is we don't know why these individuals get cataplexy, but we think that this may well be an evolutionary throwback, in that there are many species that play dead when they're under threat, they exhibit something called tonic immobility, possums, snakes, amphibians, birds, and some researchers have speculated that the reason why strong emotions, and even things like laughter, which has its origins in a response to threat if one looks at primates, may be triggering these vestigial pathways that mediate this process of losing muscle strength, of playing dead, and that somehow, this loss of this chemical unveils, or unmasks these evolutionary-old circuits, but that's very speculative. The other thing that people with narcolepsy experience a lot of is lucid dreaming. Some of you may well have lucid dreamed yourself, this describes the phenomenon of dreaming, but being aware that you're dreaming, sometimes even being able to control your dreams, which must be a magical thing, if you can actually decide where you go and what you do in your dreams. This used to be thought of as being a bit of a figment of people's overactive imaginations, but actually, we now have some really quite amazing evidence that lucid dreaming is a real phenomenon. In this study that was done in Germany a few years ago, they got a few people who said that they could lucid dream into a scanner. And they asked them to lie in this scanner, something called a functional MRI scanner, which tells us a little bit about the activity within the brain, and they asked them to clench their left hand for 10 seconds, then make a particular sequence of eye movements to signal that they were switching sides, and then clench their other side, and do that repeatedly. And what they showed was that, obviously, when they clenched their right hand, this area of the brain, which is the hand area on the other side, because, of course, our representation of our bodies is crossed, lit up, when they switched over, the hand area on the other side lit up. They then got them to get in the scanner, and while they were awake, to imagine that they were doing this rather then physically doing this, and once again, those same areas of the brain lit up. They then got these people to fall asleep in the scanner, to signal with this prearranged sequence of eye movements when they had begun to lucid dream, and in their dream, to clench their hand, their left hand, then their right hand. And sure enough, once again, similar areas of the brain lit up, really demonstrating very clearly that lucid dreaming has an underlying neurobiological origin. It's quite a remarkable study, if you think about it. And in fact, when people have looked at lucid dreamers, what they've demonstrated is that there are areas of the brain that seem to be in slightly less consistent REM sleep than others. The frontal area of the brain comes up a lot in this talk, but areas of the frontal lobes that seem to demonstrate some wakeful-type behavior within lucid dreaming, implying that, perhaps, these areas of the brain in the frontal region might be important in awareness, in consciousness, although a very recent study has thrown some doubt onto these studies. Why is this relevant to insomnia? Many people with insomnia, many people who say, I didn't sleep a wink, when you bring them into the sleep laboratory, actually, what you record is seven or eight hours of fantastic sleep. And this is a phenomenon that used to called sleep state misperception, it's now termed paradoxical insomnia, so individuals who complain of very bad insomnia, but actually, when their sleep is objectively measured, they demonstrate very good quality sleep. But actually, rather than this being psychological, as was previously termed, what we now know is that individuals with paradoxical insomnia, with this sleep state misperception, also exhibit some changes on their EEG, on the electrical activity of their brain, demonstrating that different parts of the brain demonstrate some slightly more waking behavior than the rest of the brain, so another example of these blurred lines. What about lesioning of sleep itself? There are a wide range of conditions that damage, or lesion sleep, chronic sleep deprivation is probably the commonest, but one of the very common conditions that we see in a clinical sleep setting is a condition called obstructive sleep apnea. This is a condition whereby, usually for anatomical reasons, the airway, in sleep, obstructs. Our airway is kept patent by multiple muscles that maintain the rigidity of the airway, and as we drift off to sleep, the airway becomes a bit more floppy, and it begins to reverberate, which is why most of us snore. But if your airway is a little bit more narrowed, or a little bit more floppy, then it can sometimes collapse in on itself and completely obstruct, and that disrupts sleep because your oxygen levels drop, your brain detects the fact that there is increased resistance to sleeping, your depth of sleep rises, and then the muscle strength returns and the airway becomes more patent. And in people with very bad sleep apnea, they can obstruct sometimes as often as 120 times an hour throughout the night, so you can imagine that this is very, very disruptive to sleep itself. And we now know that conditions like obstructive sleep apnea, and some forms of insomnia, although not all forms of insomnia, are associated with a whole range of negative health consequences, conditions like high blood pressure, conditions like heart disease, stroke, and importantly, cognitive decline, conditions like dementia. Why should that be the case? If you look at the protein that is deposited in the brain in conditions like Alzheimer's, a protein called beta-amyloid, and you measure beta-amyloid in the spinal fluid of individuals, even after a single night of sleep deprivation, you see a fundamental alteration in terms of levels of beta-amyloid in the spinal fluid. You can see here, this is somebody who's left to sleep, their beta-amyloid is a little bit lower, and then they're left to sleep throughout the night, and in the morning, their beta-amyloid levels drop down. In this individual, who clearly has been kept awake all night because they've had spinal taps all the way through the night, what you see is you see a dramatic deviation in terms of their levels of beta-amyloid in their spinal fluid, it's much higher than it would have been if they had been left to sleep. And in fact, when imaging studies have been done looking at markers of beta-amyloid in the brain, even after a single night of sleep deprivation, levels of this protein, and once again, I would stress that this protein is one of the fundamental culprits that are thought to underlie Alzheimer's disease, change within areas of the brain that are implicated in Alzheimer's disease, like the hippocampus, which is fundamental to memory, so suggesting at least one explanation for why sleep disruption or sleep deprivation may be associated with these conditions. And in fact, why this may be the case has become apparent in recent years as well. When I was at medical school, we were taught that the lymphatic system, which is a drainage system that brings extracellular fluid back into the circulation, exists everywhere apart from the brain, but in the early 2010s, actually, it was demonstrated that whilst there isn't a lymphatic system within the brain, there is a very, very similar system on a microscopic level, and they demonstrated that there are a series of channels, microscopic channels, that run through the brain, whose function is actually to cleanse the brain of toxins or metabolites that have accrued over the course of the day, and that, actually, these channels open up by about 60% in deep sleep or under conditions of anesthesia. And the degree to which, the speed at which beta-amyloid, and other associated byproducts of wakefulness are cleansed from the brain is fundamentally altered by disruption of sleep, giving us a very clear idea of why sleep disturbance might result in conditions like Alzheimer's disease. And in fact, in sleep apnea, it's a bit more complicated, because in sleep apnea, essentially, you're being strangled up to 120 times an hour, so your oxygen levels are bouncing up and down, and so your brain not only is vulnerable to the effects of your sleep being disrupted, but it's also vulnerable to the effects of being starved of oxygen repeatedly throughout the night, and that may well generate some inflammatory changes within the brain. So sleep apnea in particular may be a very important modifiable risk factor for conditions like dementia, which, in the current climate, is gaining increasing attention. I'm going to stop there. I hope that I've demonstrated to you that sleep is not a single brain state, that sleep is not even a global brain state, that when you look at the conditions that afflict us, or indeed, some of the phenomena that afflict us, even if we don't have any particular health issues, then these give us some really important insights into the regulation and the functions of sleep, and that these phenomena can very much be explained in terms of blurred lines. Thank you.(audience applauds)- Thank you, Guy, thank you. We've got some time for questions, about 10 minutes for questions. I'm going to take a few questions from the online audience, and then a few questions in the hall. The most popular question we have online is what can we do ourselves to manage apnea and combat drowsiness during the day?- Specifically to apnea, sleep apnea is associated, in some individuals, with increased weight. When we put on weight, first of all, it causes some changes in terms of the movement of our chest, but fat is deposited in our neck, and also in the muscles of our neck, and so obesity has a very strong association with obstructive sleep apnea. That's not to say that if you are slim, you can't have sleep apnea, because if you have a specific anatomical abnormality, then you can, but certainly, losing weight would significantly help sleep apnea. There are a number of different strategies that also help, there is a treatment called APAP, which is a mask-like device that generates positive pressure, and it stops the airway from collapsing down, and this is an extremely good treatment for sleep apnea, and can transform lives, actually, when it comes to people who are really very severely afflicted by sleepiness.- What happens to brain chemistry after long periods of wakefulness, building up so-called sleep debt?- There are a number of different chemicals that regulate sleepiness. There are two processes that define how sleepy you are, there's something called the homeostatic mechanism, which is essentially a glorified way of saying the longer you've been awake, the more sleepy you are, and we think that that is mediated by a chemical called adenosine, which is how caffeine works, because caffeine interacts with the adenosine system. But there's also the circadian rhythms. We all, within us, have a master clock in a part of the brain called the suprachiasmatic nucleus that defines when we want to go to sleep and when we want to wake up. And so, when our homeostatic mechanism, so how long we've been awake for, and our circadian rhythm are aligned, that's when we sleep at an appropriate time and wake up at an appropriate time, and perhaps feel a bit drowsy after lunch, because that's part of the circadian rhythm as well, but it's when those are misaligned, then sleep can really go awry.- [Questioner] Thanks for the interesting talk. I've got a question about the impact of exercise on sleep, because usually, I've read many positive things, but personally, if I exercise in the evening, I would, after half an hour after falling asleep, have the hallucinations you described, so I guess in this kind of overlap time, and I wonder if there's anything chemical happening?- There is evidence that aerobic exercise improves sleep, it increases the proportion of deep sleep, of slow wave sleep, and perhaps improves the quality of sleep as well. Whether it disrupts your sleep if you exercise late in the evening is very much a personal thing, but by and large, what, historically, people have recommended is that you shouldn't really exercise within an hour or two of going off to sleep, because what exercise does, obviously, it creates lots of chemicals, endorphins, but also things like adrenaline, and noradrenaline, your heart rate goes up, your body temperature goes up, and therefore all of that can be conducive to poor sleep initiation. So if you are one of those individuals, then certainly, exercising within the hour or two before bed is perhaps something that you might like to avoid.- [Questioner] Thank you, professor. Here we are in electric light, does the fact that we don't live by daylight and nighttime anymore affect our sleep generally, and lead to more of the sleep disorders that you've been talking about?- This is a rather controversial area. Historically, it was said that if you expose yourself to environmental light at inappropriate times, then it can generate insomnia, it can generate difficulty sleeping, because we know that if you expose yourself to very bright light, then that interferes with your circadian clock, it suppresses a chemical called melatonin, which is a chemical signal that a part of your brain called your pineal gland pushes out, that is a signal to the rest of the brain to go to sleep. Actually, it's probably not the case that a quick burst of playing on your mobile phone necessarily does that on a night by night basis, but certainly, if you expose yourself regularly to bright light in the evenings, what that can do is it can shift your body clock back, it can cause something called a delayed sleep phase, where you start wanting to go to bed later and wake up later. And that's fine if you don't have to get up for work, or school, or anything else, because you go to bed later and you wake up later, but for most of us, we have to get up in order to get to school, to get to university, to get to work, and that can result in chronic sleep deprivation.- [Questioner] How reversible is this sleep damage, as to speak, is it permanent?- I think the answer to that is we don't know yet, is a very short answer. I think there are many areas of this that we don't fully understand, I think the relationship between sleep disruption or deprivation and conditions like Alzheimer's disease is just in its infancy in terms of our understanding of it, because we also know that, for example, those circuits that regulate sleep probably degenerate quite early on in Alzheimer's disease, so some of the associations may be related. In the same way that REM sleep behavior disorder might be part of the prodrome of Parkinson's disease, sleep disruption may be part of the prodrome of Alzheimer's disease. And so these are all works in progress, and I think that we'll hopefully have those kind of answers in the next 10 to 20 years, but we don't have those answers now I'm afraid.- [Questioner] You mentioned briefly about circadian rhythms, can you just say a bit more about whether the Mediterranean pattern of having a siesta, and a bit of sleep of a reasonably substantial length in the afternoon and a shorter sleep in the night, both in terms of quality of sleep, and also whether the conclusions around some of these conditions are any different in that sort of environment compared to the Western European pattern of having one long sleep?- I think that it's always difficult to unravel the effect of changes in lifestyle related to sleep from other aspects of lifestyle. What we do know, there was a very recent study that was done in Greece, I think, which demonstrated that, actually, after a siesta-type nap, your blood pressure in the afternoon is significantly lower, so there is some rationale for that kind of pattern. People often say, should I be having an afternoon nap, and the question is, really, why are you having an afternoon nap. Because if you're having an afternoon nap because you're getting eight hours a night of sleep but you're waking up feeling completely exhausted, then you should probably be looking at why you're feeling so exhausted; if you are living life to the full in a Mediterranean style and going to bed at two a.m., getting six hours at night, but then getting an extra two hours at lunchtime, then certainly, some evidence points to that as being quite helpful.- [Questioner] You said that the CD4 proteins and CD8 proteins are involved in the genetic mutations, and I know that HIV patients and AIDS sufferers have lower levels of CD4 proteins, so does that mean that people who've got HIV typically have sleep problems? And also, I know that some people are on antipsychotics, such as chlorpromazine, results in agranulocytosis, which again lowers levels of eosinophils and CD4 proteins-- I think the immune mechanisms that undermine narcolepsy are rather different from what is seen in HIV, but it's important to understand that, obviously, your specific question, which was, do people with HIV have an increased risk of sleep disorders, yes they do, but they have multiple reasons as to why that might be the case, the effect of the medication that they're taking, pain, which is associated with some of the older antiviral drugs, so a lot of patients who have been on antiviral drugs for a long time have a painful neuropathy, there's obviously the psychological consequences of being diagnosed with HIV, so that's a little bit more difficult to unravel. Similarly, actually, agranulocytosis with antipsychotic drugs is quite a rare phenomenon, but certainly, people who are on antipsychotic drugs have a very wide range of sleep disorders, in part related to their underlying reason for being on those drugs, and in part related to the fact that a lot of these drugs do cause conditions like restless leg syndrome and an associated condition called periodic limb movement disorder. So there are multiple reasons, once again, why people on these drugs might have sleep issues, but it is separate from narcolepsy.- Thank you, Professor Leschzhner, for a really interesting lecture, and thank you to the audience for coming. Do join us on Tuesday, the 5th of April at 6 o'clock for the last lecture in this neuroscience series, Is Dementia Inevitable, from Professor Martin Rossor, and the last thing to do is to thank Professor Leschzhner, so thank you very much.(audience applauds)