The Neuroscience of Sleep and its Disorders

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 so some of you will recognize this man this chap is called phineas gage and he was a a worker on a construction gang in new hampshire in 1848 when he had an unfortunate mishap so one of his responsibilities whilst whilst Creating a cutting for a railway line was to drill holes and tamp down explosives before blasting the hillside away 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 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 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 so you can see this reconstruction it passed under his cheek bone and and basically destroyed an area of the brain called the left frontal lobe now the reason why i'm telling you this is because Uh mr gage is one of the most famous examples of a concept in neurology and clinical neurology which is localization demonstrating that far from being this sort of genetic gelatinous mass that does

everything different parts of the brain in fact different parts of the nervous system perform very distinct and discrete 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 uh a completely uncontrollable whoring drinking gambling man who became extremely unpleasant and if you believe some of the statements of his co-workers 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 and based in 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 now 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 so we used to think of wake and sleep as being these entirely separate states I've um 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 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 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 of sleep or or dreaming he may not have been entirely correct but this in many ways was a landmark in the field of sleep research now 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 and this is largely thanks to work by this chap eugene azerinsky who in the 1950s was under taking a phd and as many phds go It was rather unsuccessful he was he kept on being sent away by his uh supervisor failing to do the tasks that he was set until the supervisor in a degree of exasperation basically said well look you know i'm doing some studies on sleeping babies go and record their sleep and he went away and and

and started recording the uh muscle activity in the brain waves of of babies and what he showed was that throughout the night the Brain waves of these sleeping babies changed rather dramatically so these at the bottom of the slide you'll see these rather large waves these slow brain waves that really are a function of the brain slowing down and represent what we now know as non-rem sleep but interdispersed 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 brain waves 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 brain waves actually look rather similar to the brain waves 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 muscles 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 movements 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 brain waves at 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 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 asleep 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 and but it gets even more complicated than that because we have a series of sleep disorders that i think very much illustrate that naught wall

is quite so straightforward so i'm going to show you two videos of 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 brain waves in this chap are very very slow he clearly is on the basis of the the brain waves that we're recording in 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 of a young child who is also in very deep sleep believe it or not no mom no mom stop no please stop me if i press it I'm gonna die no yes i am but his brain waves 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 sleep talking 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 like 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 sleep walking 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 so these are can be very very complex behaviors um they typically arise in the First half 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 um they're difficult to wake um and but 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 well in a rather remarkable study from 2000 um some researchers in switzerland managed to

get a sleepwalker into a type of scanner called a spect scanner so what this scanner involves is giving somebody an injection of a radio isotope labelled 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 they showed increased activity in an area of the Brain called the cerebellum which is uh fundamental to movement and in a very deep part of the brain which is which is called the 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 so particularly the frontal lobes and You'll remember the frontal

lobes are responsible for rational thinking for control for planning for executive function seem to be asleep so 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 may 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 so 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 try 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 so 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 eeg

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 is in 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 percent of children will have sleep terrors or sleepwalking you know this does not necessarily demonstrate a pathological

state it can be considered part of normal brain development about one to two percent of individuals continue to have these kinds of events into into adulthood but what we have what we demonstrate is that what's the areas of the 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 kinds 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 at 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 so 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 their other half of the 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 now uni hemispheric sleep is well recognized in animals it's Never been recognized in 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 guys hospital people will invariably say well you know 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 when they're in a new environment for the first time but what this study demonstrated is that individuals who have are brought into a sleep lab for two nights will differentially regulate the depth of their sleep in their dominant hemisphere so on the first night Their the 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 be to retain some increased awareness of your environment on that first night so actually it goes even further than that because we now are beginning to

understand that sleep is not only 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 in rats and what they demonstrated was that actually even during full wakefulness these little neuronal units these clusters of nerve cells essentially seem to exhibit silence every so often and as the rats are Tired 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 awakened asleep at the same time and in fact some of you might already be starting to exhibit little islands of of of silence in your cerebral cortex um and indeed when you look at the eegs that the brain waves of humans one star in 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 in different parts of the brain of

humans as they get more tired and it may be that actually when we say oh 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 100th 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 while 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 so 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. the king is dreaming and he's acting out his dreams imagining [Music] this is a this is another example from the same name [Music]

You know [Music] dreaming again chasing lucifer catch him this time that's bad so so the reason why i refer to this as a really seminal piece of medical documentation is this film came out in 1950 okay it describes a condition that did not really enter into the diagnostic manuals until 1989. So so 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 what this really exhibits is a condition called rem sleep behavior disorder which essentially is the acting out

of the dreams of rem sleep now you may remember that i said to you that in rem sleep normally we're completely paralyzed that all our muscles are 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 and so this is a condition that is often seen in 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 the the and those behaviors really represent the context the narrative of the dreams that individuals are having it happening at that that are having at the time the speech unlike those non-rem parasomnias that i showed you is usually unintelligible it'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 will 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 so what we see in these individuals so this is this is a 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 the the paralysis is not there during those stages of sleep this is a non-cartoon version of a rem sleep behavior disorder just so you ha just to give you a flavor of what we see in the sleep lab so you can see that that chat 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 chaps arms and legs so 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 then as i said they're not always violent and you can see him kind of 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 fights he was having a gunfight in his dream so kind of violent so so that's how these these kinds of phenomena

um exhibit themselves so we used to think of this as being a what we term an idiopathic condition the term idiopathic means we don't really know what causes it and when 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 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 are 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 so why should this be

the case well we know that the areas of the brain that are responsible for generating muscle paralysis reside in this area of the brain called the brain stem 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 With very early parkinson's disease develop rem sleep behavior disorder well what we are now beginning to understand is that 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 now of course nowadays we're all very familiar with the loss of sense of smell and and it's not particularly sensitive as a predictor of parkinson's disease Particularly postcovid 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 with parkinson's disease 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 the histological changes 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 and 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 various bits of the body we see deposits of this protein called alpha synuclein which is the 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 now 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 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 so i'm going to move on to another um another neurological disorder now so i'm just going to introduce you to one of my patients who was involved in a tv program there's two sides to it the narcolepsy bit is is i'm chronically tired and then cataplexy it can manifest Itself in me falling to

the floor if i experience a strong emotion like laughing it's any event that that i feel is funny so it's an emotional uh connection the first event that ever happened was trying to put the children to bed i fell to the floor and i 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 just didn't know what it was so so 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 going to rem sleep very early on in those 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 rem sleep doesn't switch off now these hallucinations and sleep paralysis Are also normal phenomena a lot of especially the younger people in the crowd will often uh report

experiencing sleep paralysis or 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 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 to try and explain why that might be the case so what do we know about the origins of narcolepsy well until recently not a lot

these scans on the on the left are the scans of a patient with a Condition 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 resulted in features of of conditions similar to parkinson's disease but also profound sleepiness and some of the other features of narcolepsy and we think now that this may well have been a 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 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 in narcolepsy the story didn't progress much until this dog and his friends came along to help skeeter is a small dog with a very big problem no matter how much he struggles to stay awake he can for this 11 pound

toy poodle almost every moment is a disturbing losing battle with the urge to sleep so Actually the the the commentary is wrong though what this dog is why is this of of relevance well in the 1970s and 80s stanford university in california began a breeding programme 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 erection was discovered and so it was thought that these mutations prevented this chemical this neurotransmitter from functioning normally within the brains of individuals in narcolepsy but when they looked in humans with narcolepsy none of them had These mutations there have 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 be should light up a 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're off they often have very very low levels or are completely Deficient in this chemical so why should this arise well many of you will be increasingly familiar with these not necessarily this particular diagram but with the concept of b

cells and t cells so 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 a very high risk of generating an immune response to a particular environmental trigger that looks very similar to hypercretine or erectin 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 flu 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 vaccine called pandemics

has been very strongly associated with new cases of of of narcolepsy with cataplexy so what does this substance do well it has very wide projections this this system that really is largely responsible for making sleep 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 with narcolepsy well you can see here this is a hypnogram of somebody with narcolepsy that this this purpley pink bar is rem sleep and you can see that in this individual

with the 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 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 these this sleep paralysis they often experience very vivid dreams indeed and they experience these sleep Attacks well what about cataplexy well the honest answer

is we don't know why these individuals get cataplexy but we think that this may well be an evolutionary um 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 and their response to threats 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 Now the other thing that people with narcolepsy experience a lot of is lucid dreaming some of you may well have lucid dreamed yourself so 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 so in this study that was done in 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 line the 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 hat left hand for 10 seconds then make a particular sequence of eye movements to signal that they were doing that they were switching sides and then clenched

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 the hand area on the co on the other side because of course our representation of our bodies is crossed lit up and when they Switched over the other side the hand area on the other side lit up they then got them to get into the scanner and while they were awake to imagine that they were doing this rather than 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 pre-arranged 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 you know it's quite a remarkable study if you think about it so 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 areas of the in the frontal body frontal area of the brain comes up a lot in this talk but areas of the of the frontal lobes that seem to demonstrate some wakeful type behavior within lucid dreaming now implying that perhaps these areas of the brain in the in the frontal region might be important in awareness In consciousness although a very recent study has thrown some doubt onto these studies now why is this relevant to insomnia well many people with insomnia

many people who say oh 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 a phenomenon that used to be called sleep state misperception it's Now termed um paradoxical insomnia so individuals who complain of a very bad insomnia but actually when they are objective 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 so what about lesioning of sleep itself well there are a wide range of conditions that damage or lesion sleep so chronic sleep deprivation is probably the commonest but one of the very common Conditions that we see in in a clinical sleep setting is a condition called obstructive sleep apnea so this is a condition whereby

some 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 poor of negative health consequences conditions like high blood pressure conditions like heart disease stroke and importantly Cognitive decline conditions like

dementia now why should that be the case well 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 so you can see here this is somebody who is 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 lump punctures all the way spinal taps all the way through the night and 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 is is one of the fundamental culprits that are thought to underlie alzheimer's disease um change within areas of the brain that Are implicated in alzheimer's disease like the hippocampus which is 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 um The lymphatic system which is a 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 percent in deep sleep or under conditions of

anesthesia and and the the the degree to which the speed at which beta amyloid and other associated products byproducts of wakefulness are cleansed from the brain is fundamentally altered by disruption of sleep so 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 of um

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 increa is gaining increasing attention so 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 um that when you look at the conditions that afflict us

or indeed some of the phenomena that afflicts 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 [Applause] [Applause] 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 um the most popular question we have online is what can we do

ourselves to manage apnea and combat drowsiness during the day Well specific specifically to to apnea so sleep apnea is associated in in some individuals with increased weight so when we put on weight first of all it causes some changes in terms of the movement of our of our chest but it also um fat is deposited in our neck and also in the muscles of our neck and so obesity is this obesity is 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 then then you can but certainly losing weight would significantly help sleep apnea there are a number of different strategies that also help so 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 yeah so there

are a number of different um there are a number of different chemicals that regulate um sleepiness So there are two processes that define how sleep you are there's 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 what how caffeine works because caffeine interacts with the with the adenosine system um but there's also the the Circadian rhythm so we all within us have a master clock in a part

of the brain called the supracharismatic 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 this that's part of the Circadian rhythm as well but it's when those are misaligned then then sleep can really go awry thanks for the interesting talk um 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 or yeah so so there is evidence that aerobic exercise improves sleep it increases the proportion of deep sleep of slow wave sleep um and perhaps improves the the quality of sleep as well um now 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 creates lots of chemicals endorphins but it also things like adrenaline and noradrenaline your heart rate goes up your body temperature goes up and therefore that all of that can be Conducive to a poor sleep initiation so if you are one of those individuals and certainly exercising within the hour two before bed is perhaps something that you might like to

avoid thank you professor here we are in electric light does the fact that we don't live by daylight and night time anymore affect our sleep generally and lead to more of the sleep disorders that you've been talking about yes i mean this is a rather this is a Rather controversial area um so so historically it was said that if you expose yourself to environmental light at inappropriate times then it can generate insomnia uh 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 you pass your brain called your pineal gland pushes out that is a 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 universities to get to work and that can result in chronic sleep deprivation how reversible is this sleep damage as to speak Um is it permanent um i i think the answer to that is we don't know yet this is a very

short answer you know 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 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 you know 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 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 you mentioned briefly about circadian rhythms can you just say a bit more about whether the uh mediterranean pattern of having a siesta and 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 sort of the western european pattern of having one so i think that uh it's always difficult to unravel the effects of changes in 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 a siesta type nap your blood pressure in the afternoon is significantly lower um so so so so there is there is um uh some rationale for for that kind of pattern i i think that

um you know people often say well should i be having an afternoon nap and the question is really well why are you having an afternoon nap because if you're having An afternoon nap because you're getting eight hours a night 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 you know living life to the full in a sort of mediterranean style and going to bed at 2 a.m getting six hours at night but then getting an extra two hours at lunch time then

certainly some evidence points to that as being quite quite Helpful uh so you said that the cd4 proteins and cd8 proteins are involved in the genetic mutations and i know that hiv patients and age sufferers have lower levels of cd4 proteins so does that mean that people who've got hiv typically have like sleep problems and also i know that some people on antipsychotics such as chlorpromazine results in a granulosa granulocytosis which again lowers levels of xenophils And cd4 proteins yeah so i think so the the the immune the immune mechanisms that underly narcolepsy are rather

different from what is seen in hiv but but it's important to understand that obviously your specific question which was do people with hiv have uh uh have an increased risk of sleep disorders yes they do but they have multiple reasons as to why that might be the case The effects of the medication that they're taking pain which is associated with some of the older uh 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 the psychological consequences of being diagnosed with hiv

so so that's a little bit more difficult to unravel similarly actually you know the a granulocytosis within antipsychotic drugs is is quite a rare phenomenon um 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 movement disorder so there are multiple reasons once again why people on these drugs might have sleep issues but

it is separate from narcolepsy um Thank you professor lesnar for a really interesting lecture and thank you to the audience for coming um 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 rosser and the last thing to do is to thank professor lesnar thank you very much [Applause]