Sleep consists of four distinct stages—Stage 1 (light sleep), Stage 2 (with sleep spindles), Stage 3 (deep slow-wave sleep), and REM sleep—that cycle approximately every 90 minutes throughout the night. The first sleep cycle is critical for memory consolidation, as it involves the release of growth hormone and protein synthesis that encode new learning, while REM sleep in later cycles facilitates schema formation and creativity by connecting old and new information. The locus coeruleus, a brain structure containing norepinephrine-producing neurons, must be suppressed during REM sleep to allow proper memory consolidation and synaptic pruning; dysfunction in this system is associated with conditions like PTSD and addiction.
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Sleep Optimization for Memory, Focus & Mental Health | Dr. Gina PoeAdded:
I've really been looking forward to this conversation because I'm familiar with your work and I know that many people are going to be excited to learn about your work as it relates to sleep, as it relates to problem-solving, creativity, addiction and craving, relapse, and a number of other important topics.
So, to start things off, I would love for you to educate us a bit about this thing that we are all familiar with and yet very few of us understand, which is sleep. And if you would, could you describe the various phases of sleep that exist, what distinguish them, and perhaps frame this within the context of what would a perfect night's sleep look like?
>> Okay. How long would it last, more or less? And what would the biology look like? What What is a perfect night's sleep?
>> Oh, yeah, that's a great question. All right, so sleep is really different from wakefulness and in fact can't be replaced by any state of wakefulness that we've been able to come up with so far.
Um our brain chemistry is completely different and in the different stages of sleep, which there are is non-REM and REM are the two major states of sleep and every animal we've studied so far it seems to have both of those states.
Um anyway, those two states are entirely different from one another, too. And even within non-REM, there are three states. Stage one, which is what you slip into when you first falling asleep, it's dozing. There's kind of an interesting rhythm that goes on in the brain. It's kind of a fast gamma rhythm.
And then there's stage two, which is a really cool state. We sort of used to ignore sleep researchers because it was a transient state between wakefulness and the deep stage three slow wave sleep, which is the most impressively different. And then and between that and REM sleep. So, stage two I'll talk a little bit more about.
And then the deep slow wave sleep state, which is when big slow waves sweep through our brain and now we realize that it cleans our brain. One of the things that those big slow waves do is cleans our brain and does other really important things to restore us um from a day of wakefulness. And then REM sleep, which is the most popular because that's where we have the most active dreams.
And um when you wake up someone out of REM sleep, they'll almost always report having dreamed something really bizarre.
That's called REM sleep, rapid eye movement sleep. So, those are the four states of sleep of human sleep and we cycle through them every 90 minutes or so. When we go to sleep, say 10, 10:30, 11:00, um our first REM sleep period comes about 105 minutes after we fall asleep and um lasts about 20 minutes.
Actually, it comes about 95 minutes and lasts 10 or 15 minutes. And then uh we start over again. And we have about five of those per night for a perfect night's sleep, four or five, something like that. So, a perfect night's sleep is 7 1/2, 8 hours. There was a really great study that um put people [clears throat] in a semi-darkened room with nothing but the bed for 12 hours every day for a month.
And what people did initially is because because we're in a sleep-deprived nation is that they slept a lot more than usual, like 10 or 11 hours of the 12.
And then they leveled off after a week or two to about 8 hours and 15 minutes of sleep. So, you actually can't oversleep. I mean, they had nothing else to do but sleep and they would round off to on average 8 hours and 15 minutes night and then they spend the rest of the time twiddling their thumbs, humming tunes, you know, daydreaming.
>> I want to get back to the contour of a perfect night's sleep, but I'm intrigued by this idea that people can't oversleep. I'm often asked whether or not we can get too much sleep and whether or not sleeping too long long, excuse me, can make us groggy the next day. Um is there anything to that? Um and how does one determine how long they should sleep on >> Right. On average.
>> On average. Yeah, well, that's interesting because different people need seem to need different amounts of sleep, but we don't really even know exactly what sleep is for.
So, what they need is, you know, kind of it's [clears throat] you know, murky murky. Um so, we do know a lot of things that sleep do does now for us, but we don't know how long those things take. So, how long we need to sleep is also just a big question mark, but some people don't feel rested until they've slept 9 hours.
Some people don't feel rested after three or four and a half.
Um but, most people if they consistently deprive themselves of sleep so that they're only sleeping 4 or 4 and 1/2 hours a night, build up uh cognitive deficit that just builds up over time the more nights you have with sleep deprivation, the more cognitive deficit you have. And so, you need sleep again to sleep more to recover. Now, the question you had about um Can you oversleep?
>> oversleep? Right.
>> sleep to the point where it's too much?
You know, that we I growing up um uh when I was in high school, uh my girlfriend's dad had this belief that no one should sleep in past 6:00 a.m. So, he would wake all the There were two children in that home. He would wake up the kids in that house. He had this thing against oversleeping regardless of when people went went to sleep. And I always thought that was um an interesting mentality.
>> Yeah. Um I don't >> terrible, actually, because what That will do is it'll put you make you sleepier the next night to get to bed on time. So, it'll build up your homeostatic need if you wake up too early, but um so, I don't think you can oversleep, but people who sleep a lot, like people who sleep over 9 hours, it's probably indicative of some other problem because in fact, if you have um a lot of different conditions, it will cause you to sleep a lot more, probably because what it does is it interferes with your efficient sleep, the efficiency of your sleep. So, if you find yourself sleeping consistently 9 hours plus every night, then you might want to consult a doctor about maybe what else it might be. It could be cancer. It could be um sleep apnea. That is affects a lot of people. It could be that your sleep is super inefficient because you're snoring a lot more than you know, or you're waking up a lot more than you know every night. So, you might want to sleep study just to see how your sleep is and then see what else might be causing you to sleep so much.
And that wouldn't be if somebody is sleeping 9 or 10 hours you know, every once in a while. You mean if they're consistently sleeping from more than 9 hours.
>> like they need it in order to function cognitively the next day, it it might be that your sleep is just not efficient and you might want to look into why that that's the case. Interesting. Forgive me for the anecdote, but I can't resist.
Years ago, I went to an acupuncturist and um he gave me these red pills um [clears throat] of which I don't know what they contained.
>> Uh-oh. But I took them because he told me they would help with my sleep.
>> Okay. And I would fall asleep about 30 minutes after taking them. Mhm. And I would have incredi- incredibly, excuse me, vivid dreams.
>> Mhm. And I'd wake up 4 or 5 hours after having gone to sleep feeling completely rested. Something that I've never really experienced >> Interesting.
>> on a consistent basis. I wanted to do mass spec on these pills. I still have no idea what was in them whatsoever.
>> mass spec on these pills to see what they are.
>> Some people have thought um that perhaps they had GHB, gamma hydroxybutyrate, which is by the way an illegal drug. It can kill you. It's not a not something you want to take. Um but anyway, if if ever someone can figure out what the red pills were, I'll be very um That's really good. And this is not a red pill of the of the other sort red pill. This is just the red sleep pills. Interesting. I mean, it could have been even a a placebo effect, cuz placebos are extremely strong. So, uh Although I I don't know. There was really something to these red pills. So, [laughter] uh shout out to the acupuncturist and and the Eastern medicine. Um but to return this to this idea of the architecture of a perfect night's sleep.
So, you said um we fall asleep the first 90 minutes of sleep REM sleep, rapid eye movement sleep, will arrive at about 95 minutes in. Does that mean that the rest of that 90 minutes is consumed with slow wave sleep?
>> Yeah, non-REM sleep.
>> Okay. And what about the sleep where we are lightly asleep and we might have a dream that has us somehow thinking about movement or that we jolt ourselves awake. That often happens early in the night, right?
>> Yeah. Yeah, that's the first stage stage one and stage two sleep. And stage two sleep is really cool because that has something called sleep spindles and K complexes. And what sleep spindles are are a little of activity that's 10 to 15 hertz in frequency. It's a conversation between the thalamus and the cortex. The thalamus is the gateway to consciousness and the neocortex, you know, processes all our cognition. And so, it's it's these spindles, they're called sleep spindles.
And if you wake up out of that state, you will often report a dream, like a hallucination style dream. It won't be a long dream report like you have out of REM sleep, but it will be some hallucination state. In during while we're falling asleep, one of the reason we call it falling asleep is because in stage one and stage two our muscles are relaxing.
And if there's part of our brain that's conscious enough to sort of recognize that relaxation, we'll feel like we're falling and we'll jerk awake. So, often that hallucination, it's called hypnagogic hallucination, will feel like it'll be include some falling aspect that we'll wake up out of. That's really interesting to me. I've long felt that sensation of almost like dropping back into my head.
>> Mhm. Um so much so that if I elevate my feet just slightly and I tilt my head back just slightly um in order to go to sleep, I find that I fall asleep much much faster. But it does feel as if I'm going to fall like almost going to do a backward somersault. I actually really like the the sensation and it usually because it precedes falling deeply asleep.
>> Yeah, that's really interesting. I'm somebody has to do a study of elevated feet and Yeah, there there's a little bit on um body position and sleep and some of the washout that we'll talk about. So early in the night, um you get these lighter stages of sleep, less rapid eye movement sleep. What can we say about the dreams that occur during the say first and second um you know, 90-minute cycles of sleep? Are they quite different than the patterns of sleep and dreaming that occur later in the night or toward morning? Well, okay, that's an interesting question. There's a lot of facets to it. Um there is some evidence that the first 4 hours of sleep are very important for memory processing. Um and in fact, if you've learned something new that day or have experienced a new um sensory motor experience, then your early sleep dreams will incorporate that experience much more than the later sleep dreams.
Um later as that memory gets consolidated from the early structures, which are the hippocampus deep in the temporal lobe to the cortex in a distributed fashion, that memory seems to move from that hippocampus to the cortex and also the dreams that incorporate that memory also move later in the night. So, um nobody knows why, but it does There was a great study by Sidarta Ribeiro, who studied the consolidation of memories from the cortex from the hippocampus to the cortex in a rat across the period of a full day sleep because rats sleep in the daytime.
And he found that each subsequent REM sleep period moved that memory from the hippocampus to the first area that projects to it and then the second area and then the third area.
And you can see the memory moving um through the throughout the sleep period, yeah.
>> Very cool. So, I have to read that study. So, um there's a number of different hormones associated with the different stages of sleep. We know that melatonin is a hormone of nighttime that makes us sleepy. Um what about growth hormone release? When does that occur during sleep?
>> So, growth hormone release happens all day long and all night long. But, the deep slow-wave sleep that you get the very first sleep cycle um is when you get a big bolus of growth hormone release and in men and women equally.
And if you miss that first deep slow-wave sleep period, you also miss that big bolus of growth hormone release. And you might get ultimately across the day just as much overall growth hormone release, but endocrinologists will tell you that big boluses do different things than a little bit eked out over time. So, that is well, we know there's also a big push to synthesize pro- proteins. Um so, that's when the protein synthesis this part that builds memories, for example, in our brain happens in that first cycle of sleep. So, you don't want to miss that, especially if you've learned something really big and needs needs more synaptic space to encode it. How would somebody miss that first 90 minutes?
>> themselves. Yeah, so So, let's say I normally go to sleep at um 10:00 p.m.
>> Mhm. Um and then from 10:00 to 11:30 would be this first phase of sleep and that's when the growth hormone big ball of growth hormone would be released.
Does that mean that if I go to sleep instead at 11:30 or midnight that I miss that first phase of sleep? Why is it not the case that I get that first phase of sleep just simply starting later?
>> It is beautiful clock that we have in our body that knows when things should happen and it's every cell in our body has a clock and all those clocks are normally synchronized and the circadian circadian clocks are synchronized and so our cells are ready to respond to that growth hormone release at a particular time and if we miss it and it's a time in relation to melatonin also. So, if you miss it, yeah, you might get some growth hormone release but it's occurring at a time when that your clock is already moved to the next phase and so it's it's just a clock thing. Yeah, I don't think we can overstate the importance of what you just described and to be honest, despite knowing a bit about the sleep research and circadian biology, this is the very first time that I've ever heard this that if you normally go to sleep at a particular time and growth hormone is released in that first phase of sleep that you can't simply initiate your sleep about later and expect to capture that first phase of sleep.
>> Yeah.
That's incredible and I think important and as many listeners are probably realizing also highly actionable. So, what this means is that we should have fairly consistent bedtimes in addition to fairly consistent wake times. Is that right?
>> Exactly. And in fact, one of the best markers of good neurological health when we get older is consistent bedtimes.
Wow. Okay.
I don't want to backtrack but I did write down something that I think is important for me to resolve or for you to resolve. So, I'm going to ask this people that sleep 9 hours or more perhaps that reflecting an issue some underlying issue perhaps. Is um a teenager or an adolescent and undergoing a stage of of of development where there's a lot of bodily and brain growth an exception to that because >> Yes. I don't recall sleeping a ton when I was a teenager. I had a ton of energy, but I know a few teenagers um and they sleep a lot. Like they'll just sleep and sleep and sleep and sleep. Should we let them sleep and sleep and sleep?
>> Okay.
Okay. [laughter] >> So that's the one exception. What about if >> babies. Okay. Uh when you when you're developing something in your brain or the rest of your body, you really need sleep to help organize that. I mean sleep is doing really hard work in organizing our brains and and making it develop right. And if we deprive ourselves of sleep, we will actually also just I like like I said we have a daily clock, we also have a developmental clock and we can miss a developmental window if we don't let ourselves sleep extra like we need to.
What other things inhibit growth hormone release or other components of this first stage of sleep? In other words, if I go to sleep religiously every night at 10:00 p.m.
are there things that I perhaps do in the preceding hours of the preceding day like ingest caffeine or alcohol that can make that first stage of sleep less effective even if I'm going to sleep at the same time? Alcohol definitely will do that because alcohol is a REM sleep suppressant and it even suppresses some of that stage two transition to REM with those sleep spindles. And those sleep spindles we didn't talk about their function yet, but they're really important for moving memories um to our cortex. It's a unique time when our hippocampus, the sort of like the RAM of our brains, um writes it to a hard disk and which is the cortex. And there it's a unique time when they're connected. So if you don't want to miss that, you don't want to miss REM sleep when is also a part of the consolidation process and um schema changing process.
And alcohol in there, you know, before we go to sleep will do that until we've metabolized alcohol and put it out of our bodies, it will affect our sleep badly. So, probably fair to say no ingestion of alcohol within the 4 to 6 hours preceding sleep.
>> Yeah. Given the half-life. Given the half-life. Or at all or at all would be better, but I know some people refuse to go that way.
>> maybe a little bit is okay. I don't know what the dose response is, but um there are studies out there you can look at.
Great. Yeah.
So, we're still in the first stage of sleep and I apologize for slowing us down, but it sounds like it's an incredibly important first phase of sleep. What about the second and third 90-minute blocks of sleep? Is there anything that makes those um unique? What what is their signature uh besides the fact that they come second and third in the night?
>> more and more REM sleep the later the night we get. Um there's also a change in hormones, you know, the growth hormone and um melatonin levels are starting to decline, but other hormones are picking up. So, it is a really different stage that you also don't want to shortchange yourself on. And I think that's the stage many studies are showing that those are the times in sleep when the most creativity can happen. That's when our dreams can incorporate and put together old and new things together into a new way. And um and our schema are built during that time. So, um yeah, we can change our minds best during those phases of sleep.
Could you elaborate a little bit more on schema? Uh no one I don't think anyone on this podcast has ever discussed schema. I'm a little bit familiar with schema from my um courses on psychology, but it's been a while. So, maybe you could just uh refresh your mind and everyone everyone who's listening is familiar.
>> it's still a a concept. Schema is a concept.
>> Right.
>> [laughter] >> I think of schema as um like we have a schema of Christmas, right? We have we we have all kinds of ideas that we sew together and call Christmas, a holiday season in the northern hemisphere, it's cold, we have Santa Claus and reindeer and jingle bells and even things that are false that but we normally associate with Christmas, presents, family gathering, when it is, all of this stuff is sewn together into one there's a thread linking them all and we can just give your ourselves a list of words and um and none of them contain the word Christmas and then ask people later um you know, give them another list of words and include the word Christmas and they'll say, oh yeah, that word was there because in their minds they brought up that word Christmas because it's part of that whole schema. So, that's what it's sort of a related a lot of related concepts, I guess, is what I think about it sort of like on the desktop of my computer um would scare some people, but it's just a ton of folders. But, each of the folder names means something very clear and specific to me.
>> Right. And inside of those folders are collections of things that make sense in terms of how they're batch. Is that kind of one way to think about it?
>> No, that's a great way to think of it.
And and when you're in REM sleep in the later parts of the night and that transition to REM, that's when your computer of your brain is opening folders and comparing documents, seeing if there is there anything the same are these two documents look very much the same, but there's a little bit of difference and it can it can link those conceptually.
So, that that's probably one of the origins of creativity is finding things that are related, maybe just linked a little bit and you can find that link and strengthen it if it you know, makes your schema interesting and different.
Yeah. Very interesting. Um >> [clears throat] >> many people, including myself, tend to wake up maybe once during the middle of the night to use the restroom. I've tried to drink less fluid before going to sleep.
I've I've heard also that um the impulse to urinate, uh forgive the topic, but a lot of people deal with this. So, the impulse to urinate is also dictated by how quickly you drink fluid, not just the total volume. So, I've switched to um sipping fluids more slowly for my last beverage of the day, which seems to help. But, the point here is that I think a lot of people wake up once in the middle of the night, often times to use the restroom, but often times just around 3:00 a.m. and might be up for a few minutes, hopefully not on their phone or viewing any bright light, which can cause more wakefulness, but then go back to sleep.
Is there any known detriment to this middle-of-the-night waking, or should we consider it a normal feature for some people's sleep architecture?
>> we shouldn't worry about it, actually. I think, you know, sleep is really incredibly well homeostatically regulated. And so, really don't worry about how much you're sleeping, as long as you're not intentionally depriving yourself of sleep by doing something really rewarding and exciting, because even that is stressful to your body and deprives you of a lot of things we're talking about. So, don't worry about it.
Um it's absolutely normal to wake up at least once in the middle of the night to go to the bathroom, and as long as you can get back to sleep in a reasonable amount of time, um you know, or even if it takes you an hour, don't worry about it, as long as you have a lifestyle that allows you to then make up that sleep either the next morning or the next night, um going to [clears throat] bed a little earlier. So, if I understand correctly, there's a little bit of asymmetry to sleep, that catching that first phase of sleep, it's like you either get it or you don't, and you have to get it by going to sleep essentially the same time each night, maybe plus or minus 15 minutes or so. Um but then, if I wake up in the middle of the night and go back to sleep, I can not catch up, but I can gather all the sleep that I would have gotten had I just slept the whole way through the night. Is that right?
>> yeah. Yeah, and and we don't know, actually, the answer to whether or not the sleep in the middle between that early sleep and the late sleep is in fact different for another reason and whether depriving yourself of sleep from say 1:00 to 2:30 in the morning is bad in a different way. We don't know. Well, I suppose I am the experiment in that case because I do tend to wake up once per night and I've I've sort of come to recognize it as part of my normal sleep architecture. I don't obsess over it. I do notice that when I go back to sleep and especially toward morning that my sleep is incredibly deep. My dreams are incredibly vivid. I don't always remember them, but what is unique perhaps about the architecture of dreams and sleep in the let's say the last third of the night or the or the second half of the night.
>> Right. Yeah, in the second half of the night we have longer REM sleep periods and those are considered the deepest sleep even though slow wave sleep, big slow wave is considered deep, it is deep, but >> call slow wave sleep deep sleep and REM sleep rapid eye movement, but now you're telling me that REM sleep is actually the deeper sleep. Okay, there needs to be a new nomenclature of sleep researchers.
deeper or not.
The reason why you call slow wave sleep deep sleep is because it's difficult to arouse people out of that state. Um and when you do arouse them out of that state, they are most most often confused and just want to go back into sleep and can go back pretty easily.
If you arouse someone out of REM sleep, they're more likely to report something that was really kind of almost like wakefulness if it was so vivid. But in fact, if you give someone a non- threatening kind of stimulation like somebody dropping keys or um a ping or something like that, instead of waking that same volume will wake someone up out of non-REM sleep, but out of REM sleep and instead lengthen the amount of time or make it even more dense or rapid eye movements more dense and often people will incorporate that sound into their dreams. Hm. So, the body and brain are somehow conscious of the um of the sound and I've heard also smells can even make it into our our dreams and in REM sleep.
But that we it doesn't rouse us from sleep.
>> us as often, yeah. Interesting.
>> And maybe one of the reasons why REM sleep is deeper is especially in adults and older people that deep slow wave sleep goes away. So, it's not as deep, it's not as big, the slow waves aren't as large, which is probably problematic, but we are not sure. And so, then REM sleep becomes the deepest stage.
Actually in children it's kind of a toss-up because they it's really hard to wake them up out of that deep slow wave sleep and in fact um, fire alarms don't wake them up even really loud fire alarms out of that state of sleep. So, that's why they're trying to change fire alarms so that instead of something that the kids don't associate with anything like the whatever they don't associate when it says their name or something else that may be less loud but more salient to them and will wake them up. I don't know having carried sleeping children in from the car, I don't know that I want children to start waking up from sleep cuz that's one of the best things when you get home and the kids are asleep in the backseat, you can literally throw them over your shoulder, gently of course, and put them to sleep and and if they are completely out, they're completely out.
It is wonderful.
>> of nature's gifts. So, this enhanced volume or or proportion of rapid eye movement sleep in the second half of the night uh, relates to more elaborate dreams. Uh, we are paralyzed during REM sleep, correct?
>> Yes, normally paralyzed and that's really good because that's the time when we're actively dreaming storyline dreams and we could um, hurt ourselves. We're actually really cut off from the outside world in terms of you know, um, responding to say this table or window or a door. And so, different from sleepwalking, which is out of slow-wave sleep. And out of slow-wave sleep, that sleepwalking is a mixture between sleep and wakefulness. So, you actually will respond to the door, you can cook a full meal, um drive your car while you're in deep slow-wave sleep. It's scary because you never know what you're going to do.
You don't have voluntary a voluntary control over it. You have no conscious control over it. But, you can actually safely navigate um some situations in sleepwalking. Um and actually have a conversation, although it may not make much sense when you're sleep-talking. In REM sleep, you're not processing the outside world. And instead, um when you're acting out your dreams, you could be doing things like walking through a plate glass window or falling off of, you know, down the stairs, um things like that. So, you really want your muscles to be inactivated during REM sleep. Otherwise, you will act out those dreams and really hurt yourself or your bed partner.
What about sleep-talking? Or talking in sleep.
>> Mhm. Um I don't know how many relationships have um been saved by sleep-talking, but I'm guessing a few have been destroyed. And I'm guessing that um talking in sleep could have meaning or perhaps has no meaning, just as dreams could have meaning or no meaning as we recall them.
>> Yeah. Do not take sleep-talking seriously, um no matter what people say, it doesn't necessarily reflect truth.
So, it's not like you're being more truthful when you're sleep-talking.
>> You just saved a number of relationships. [laughter] Um I'm not directing this at anyone in particular, but I I guarantee you just did. Um noted. Um so, as people start to approach morning or the time when they normally would wake up, >> Mhm.
I've heard that it's important to, if possible, complete one of these 90-minute cycles prior to waking up.
That is, if you set your alarm for halfway through one of these 90-minute cycles that come late in the night of sleep, that it can lead to um rather groggy patterns of waking.
Um so, I'll just ask you directly, do you use a uh an alarm clock?
>> not. Um thankfully, I'm in a line of work that doesn't require me normally to do anything at any particular time. I do it when I do it. Um unless I have to catch a plane, and then I always set my alarm just in case. Well, as a fellow academic, I can tell you there are plenty of punishing features about being an academic scientist that um that offset the fact that uh you don't have to use an alarm clock, but it is nice that you can often set your own schedule. So, would you recommend that if possible that people not use an alarm clock? Yeah, absolutely. If you can just listen to your body and wake up when you need to wake up, that would be great. Um But, um one of the reasons why we have such a grogginess, it's called sleep inertia when we wake up out of the wrong state, which is um deep slow-wave sleep, is because I liken it to uh like a washing machine cycle.
This 90-minute cycle's like a washing machine cycle. And and um the first part is to add water, right? And um then your clothes are soaking wet. And you don't want to open the washing machine and try and function, put them on, and wear them around while they're soaking wet and full of soap. So, you have to wait until the cycle is through before you can well, actually, let's put it in the dryer, too. Um [laughter] before you want to wear them. Um so, yeah, you can function. It just takes a little while for those clothes, that brain, to dry out so you can actually function well. Um but, it's better to wait through the whole cycle is complete. And so, that's why you want to set that 90 90-minute alarm clock. And again, that's around 90 minutes because the first stage of sleep, the first cycle of sleep, is actually a little longer, more like 105, 110 minutes, but then the second ones and third ones, they get sort of shorter and shorter as the night goes on. And in the last few cycles, you're just doing the N2 REM sleep cycle, which takes less time. And if you wake up out of REM sleep, there's usually no problem cognitively. You get You're good to go.
Are you a fan of of sleep trackers?
Uh sure. Yeah. Yeah. Do you use one? I have one on. I don't take I don't I don't um live my life by them because they are the best ones right now are about 70% effective at staging your sleep. So, 70% is okay. It's okay, but um take it with a grain of salt is what I'm saying.
Yeah, I've tried various ones and I compare the mattress-based one to a actually wear it on my ankle instead of my wrist, but um and I do find it informative, but a um a colleague of mine at Stanford, Ali Crum, who works on mindset and belief effects, um talked to me about a study they did where people often will bias their sense of daytime wakefulness based on their sleep score more than their subjective score. Um in other words, if they were told they got a poor night's sleep, even if they got a great night's sleep in the in and this was of course measured in the sleep lab, so they they're able to compare, people will report feeling more groggy. And the opposite is [clears throat] also true that if it says 100% or 90% on your sleep score, then people go, "Oh, I feel great." even though they might not have slept well. So, this speaks to the I don't want to say placebo effect, but the sort of belief effects that are woven in with a score.
>> Yeah. Um That's right.
>> So, it seems to me that combining subjective and objective data Yeah.
>> Yeah, and I do believe that you should trust your own physiology and the way that your body is telling you to feel um because in fact it used to be that people with insomnia weren't were often not believed because you put them in a sleep lab and they look like they slept great. And you wake them up in the morning, they say, "Oh, I I didn't sleep very well at all." And that's because probably we we just came out with a paper that shows that subcortical structures can be in a completely different sleep state than cortical structures as which is what we measure in the sleep lab, um what the cortex is doing.
>> Interesting. So, it might be that people who say I did not sleep all night long even though the cortex is saying, "Oh, no, you had great sleep." Um was because that they're they're monitoring their subcortical, um hypothalamus, hippocampus, um thalamus, other other structures that the sleep lab just can't access unless you have depth electrodes, which nobody really wants.
>> Right, cuz that requires holes in the skull and wires. Yeah.
>> Wow, so does that mean that the last 50-plus years of sleep science, um it's potentially flawed in some way because they're only recording from um I guess this would be the analogy would be it's like recording from um the surface of the ocean as opposed to the depths of the ocean.
>> trying to ascertain the life moving down deep in the depths.
>> Yeah. Brace yourselves, uh colleagues at Stanford Sleep Lab and elsewhere. Uh but please just tell us cuz I think scientists want to know the truth. Yeah, I mean it's not for nothing that you want to know what the cortex is doing. I mean the cortex is really important for a lot of things, but it doesn't necessarily tell you what a lot of other really important parts of the brain are doing in terms of sleep.
And, um but there's hope uh because in fact it would be great. I think that's possible from the paper if you look at it. It's in PNAS this year that you could detect subtle changes in the cortical EEG that might be able to tell you what the sort subcortical structures are doing. Things like the absolute power uh in that sleep spindle band, that sigma band would change if the hippocampus is in REM sleep and the cortex is in that sleep spindle state, and and vice versa. So, there is some hope um that we can gain from people with depth electrodes or animals um with depth electrodes that we could backwards um machine learn what the cortex might be able to tell us about subcortical structures from the cortical EEG. So, Interesting. This is going to be a a stimula- Yeah, [laughter] stay tuned. That's going to be a stimulus for development of new technology, which is always going to assist in scientific discovery.
>> [snorts] >> Um there's one more thing I wanted to ask about the architecture of the night sleep um in terms of early part of the night.
Earlier you mentioned the washout of debris and um the so-called glymphatic system, I think is what you're referring to. Could you tell us a little bit more about the washout that occurs in the brain during sleep, what what that is, and what roles it's thought to serve, and perhaps if there are any ways to ensure that it happens or to ensure that it doesn't happen?
>> And obviously we want this to happen.
Yeah, yeah.
Um all right, great question. We talked about the circadian clock and how certain things happen at certain times.
Well, one of the things that happens when we're awake and talking to each other is that there's a lot of plasticity.
There's something that I'm learning from you today and you're learning from me, and that changes our synapses and it changes the way our proteins are going to be folded and and changed during sleep. Um it unfolds. This process actually uses a lot of ATP, the power um structure, the fuel of the brain, and uh it unfolds also proteins while we're doing this, while we're using them.
And so, during that first part of the night, uh when we first fall asleep in the first 20 minutes or so, we're building that uh adenosine back into ATP, and that's uh probably why power naps are called power naps, because we're actually rebuilding the power and then we're also cleaning out through the deep slow waves of slow wave sleep we're cleaning out all those misfolded proteins, unfolded proteins, and other things that get broken down and um you know, need to be rebuilt when we're asleep because of its use during wakefulness.
So, I liken that to you know, having a big party during wakefulness and you need all those party goers to leave in order to do the cleanup. And so, what I think the mechanism is and this is still something to be tested is actually slow waves themselves, which is bad news for us as we get older and those slow waves get smaller and slow wave sleep goes away.
So, so what happens when a neuron is firing is that it expands. The membrane expands a little bit, becomes more translucent.
That's how we know one of the ways we know that neurons expand when they fire.
And so, every action potential the membrane expands a little bit as sodium brings water into the cell.
And then when they're silent, they contract. And so, in during slow waves the cool thing is that the reason why you can measure them is that all the neurons at the same time, not all of them but a good portion of them are firing at the same time and silent at the same time. And so, you think about that as contracting and expanding all at the same time, it's kind of like a bilge pump of the brain. So, that can pump out. Glia are also really important for this in terms of cleaning up debris and transferring it to where it needs to go.
So, I so I think of it actually as a bilge pump cleaning out our brain.
Interesting. I've heard about the glymphatic system and the glymphatic washout. I've never thought about the mechanical aspects of it before. I always thought that for some reason that now it's obvious to me that there had to be something mechanical, but only now that you've educated me about this, I thought that for some reason the the cerebral spinal fluid just starts washing through, but here you're talking about literally an expansion and a contraction of the neurons in unison and pushing the fluid through, cleaning out any misfolded proteins or debris that might occur Yeah. on the basis of these metabolic pathways.
>> Yeah.
And the consequence of that is to to what? To leave the brain in a state of a more pristine action for for the next day? Yeah. Is that right?
>> Yeah, you think of it again like a party and if you don't clean up after that party and you try and hold another one the next day, it's going to get more clogged. You know, it's people have a harder time moving around and enjoying themselves.
And um if that builds up day after day, you know, it's going to be cognition that would be the party goers moving around um becomes hard.
Yeah. And so this builds pump that you describe is associated with the big slow waves of of deep well, of slow wave sleep.
>> Yeah. Um so this is going to occur more or less in the first third of the night, is that right?
>> right. And are there things that inhibit this process and are there things that facilitate this process? Yeah.
So, well, one thing to inhibit is not to get it.
>> [laughter] >> But >> Right. And here too, sorry to interrupt, but it and is this similar to the case with growth hormone where if you go to sleep later than you would normally, you miss the wash out. You don't It's not you don't delay it. You miss you miss the wash out.
>> That's right. So, if you go to sleep at 1:00 or 2:00 in the morning, your sleep is still going to be dominated by N2 and REM sleep, not by slow wave sleep. So, you need to you need to get that first bit of sleep. Would a caveat to that be if somebody normally goes to sleep at 1:00 or 2:00 a.m. and wakes up at 10:00 a.m.
>> Yeah.
that if that's their normal sleep cycle Yeah. Um That should be okay. It should be okay.
Um you would probably want to do somebody would want to do a sleep study with people who do that normally and see if also the melatonin release is later and the corticosterone rise that happens normally in the morning also happens later. So, if everything shifted, good.
Um >> Okay. Yeah, there there are a few studies I've come across that really do argue for the fact that waking up circa sunrise, that doesn't mean at sunrise, but within an hour or two, maybe 3 hours of sunrise and going to sleep within 4 hours after sunset or so, okay, these is actually better for the health of all human beings than is being a night owl.
And the night owl, there's almost like a night owl posse out there, especially on social media, they get very upset when you say that you should see morning sunlight that after 10:00 a.m. you kind of missed the boat. Um they get very upset because I think there are about 20 or 30% of people perhaps who um who really feel like they function better staying up late and waking up late and they function much less well waking up early and going to bed early. But the data on health metrics suggests that sorry night owls that they are wrong.
Yeah, sorry me cuz I'm a night owl. Oh boy, okay. Well, then I'm apologizing directly. And here I'm not a really early morning person. I'm kind of more typical if I wake up naturally around 6:30, somewhere between 6:30 and 7:30 a.m. Go to sleep somewhere between 10:00 and 11:00 p.m. These are averages.
Um but I do notice that when I force myself to get up a little earlier and go to sleep a little earlier that my mood and alertness and just overall productivity is much higher. And there could be other variables there, too.
>> right. I'm a night owl. I love staying up late at night doing, you know, writing grants, writing papers, watching movies, whatever it is. I love it.
But, I like you, and like every human being on Earth, do better if I go to bed earlier and wake up earlier. So, one good thing for night owls is to have a child.
Because they will wake you up. Their circadian rhythms are so strong. They will wake up, and even if you deprive them of sleep in the first half of the night, they will still wake up like clockwork because their circadian rhythms are so strong at 6:00 a.m. And so, what you've you haven't done anything good for your kid, you haven't moved their cycle to later and be more in line with yours. In fact, you've just sleep deprived them and made them miss a window and made them cranky the next day, and made your life more miserable.
So, go to bed um soon after your kids go to bed and wake up with them. That's the way to do it.
>> Great. The child alarm clock. Another reason to have children. Um I got a dog, a puppy, and then that became a dog specifically well, for many reasons, but one reason was I wanted to be one of those early morning rise, you know, 5:30 a.m. every morning.
But, I ended up getting a bulldog that would literally sleep 16 hours if he could. A nuclear bomb could go off, >> [laughter] >> and he wouldn't wake up. But, what I started to learn was that bulldogs actually have sleep apnea. They're They're As As far as I know, they're the only species that has a genetically um they're essentially an inbred um sleep defect. And so, I actually don't encourage people to get bulldogs because it's a kind of a cruel breed. They suffer a lot in that body that they're born into. Anyway, um a dog can accomplish some some of this, but get the get the uh the breed of dog that is going to wake up early. So, in other words, don't get a bulldog or a mastiff. Well, you know, interestingly, all all um predatory animals, like dogs and cats and lions and us, um well, more dogs, cats, and lions than us, will can sleep, you you 16 hours a day. Uh ferrets are predatory, they can sleep >> a pet ferret. I used to and uh, sadly I also used to work on ferrets, published a number of papers. Delightful animals.
>> and great because you can study development. It's really cool. Um, because they're born very altricial like we are with brains that are not very well developed and so you can see what happens through development and how important these different phases of development really are.
But yes, um yeah, maybe we're not as predatory as much predators as we think because in fact we our sleep is somewhere between the prey and the predators >> [laughter] >> um, in terms of the amount of sleep that we usually need a night. Um, but those predators can sleep 16 hours um, napping all day long and and they're more crepuscular perhaps like their prey are more >> So dawn and dusk active.
>> Yeah, dawn and dusk active. Um yeah, but anyway, yes, uh, children and dogs actually in if there was a poll done by the National Sleep Foundation to see what the number one thing is that wakes people up at night and number two is going to the bathroom. Um, number three is children because um, you know, you're when your children are young, but that only lasts a few years that they'll wake you up um, when they're babies.
Um, but the number one thing is pets and pets needing to go out um, or cats wanting to curl up with you or whatever it is, pets needs will wake you up more in the middle of the night than anything else. Another reason to not get a nocturnal pet. People who get hamsters pretty quickly realize that they are nocturnal and they want to run on their wheel around.
>> Yeah, you got to put them in the living room away from where you sleep. I vote fish tank, folks. Um, freshwater fish tank. There are all sorts of reasons to not get a saltwater tank. Freshwater fish tank.
>> [laughter] >> Um, or a child.
I appreciate that vote and I appreciate you mentioning ferrets and by the way, folks, they are carnivores, they are not rodents and they are they have very elaborate brain structures. They're very smart.
Um in the same [clears throat] family as the honey badgers and the other mustelids. Anyway, well, I don't I shouldn't geek out too much on on the mustelids or else I'll take the the remainder of all our time.
I'd love for you to tell us about REM sleep and the sleep later in the night as it relates to dreams and emotionality. And this is probably um the appropriate time for you to introduce us to this incredible structure in the brain which is the locus coeruleus. A difficult um structure to spell, but a beautiful a beautifully named structure.
Um I find locus coeruleus to be just fascinating and I know I know a small fraction of what it does and I'm hoping you're going to educate me and and our audience about more what it does and hopefully tell us a little bit about its relationship to epinephrine, aka adrenaline.
>> Yeah, I'm so glad you brought this up because I can totally geek out on the locus coeruleus. Please do. Um locus meaning spot or place and coeruleus meaning blue, so you could just call it the blue spot. Um that's the easiest.
Every um animal with a brain has a blue spot. And um yeah, and I mean every animal with a brain because of course uh there are animals with nervous systems that are not centralized like jellyfish. Um but anyway, we're we're digressing there.
So, um the locus coeruleus is filled with neurons that have in them norepinephrine, which is the brain's version of epinephrine or adrenaline. It's also called noradrenaline. And what it does is it just like adrenaline in the rest of our bodies, it helps prime us to respond to our environment. So, when locus coeruleus neurons fire and fire in a burst, we can switch our attention. Um and they will fire in a burst if for example a loud noise happens in the middle of you're concentrating on something. So, you can it helps it fires and it helps you switch your attention to that thing and then learn quickly from it. So, it's really important in a stress response. It helps us do quick one trial learning. And um and then a tonic activity during the day when you're just you know, doing your normal going about your normal concentration kind of activity activities is really good for um sustained attention. Um it it works with the cholinergic system of our basal forebrain um which is really important for learning and memory also to help us learn about things and put things together. Um but just tonic a level levels are signature of wakefulness and alertness.
So, too much is panic with a locus coeruleus activity. A burst is uh switching attention and then tonic levels are sustained constant attention.
And then when we go to sleep, the locus coeruleus slows and goes from about on average um 2 hertz to about 1 hertz. One cycle per second. Um tonically um and then when we go into REM sleep, it's the only time when it shuts off completely.
And it appears that that complete silence is really really important for a number of things. And the main thing that I think it's important for is the ability to erase and break down synapses that are no longer working for us. So, they encode things that are false now or they are encoding things that we um learned in the novelty encoding pathway in of our of our brain that have now been consolidated other pathways and so we need to now erase them from the novelty encoding pathway. And that is really really important for being able to continue to learn um things all of our lives. So, like erasing that RAM um or that I don't know what do you call those disks that you stick into computers that >> Oh, uh hard drive. Uh no, um Thumb drives.
>> yeah. Erasing your thumb drive, so you That thumb drive is what you carry around all day long, and then during sleep you write that thumb drive to the cortex, to the long-term memory structures, and you need to refresh that thumb drive, and that's what happens during REM sleep when the locus coeruleus is off because whenever it's on and noradrenaline is there, it helps us to put things together, it helps us to learn and strengthen synapses, but it does not allow us to actually weaken synapses that are also really important part for life uh part of life long learning. Um, yeah. I so much more I could say about that.
>> Yeah, locus coeruleus sounds fascinating. So, it's connected to the basal forebrain cholinergic system.
Um, the neurons in locus coeruleus, if I'm not mistaken, release norepinephrine.
Perhaps epinephrine as well? Uh, well, no, the brain's version of epinephrine is norepinephrine. Um, the other thing it also uh the precursor to norepinephrine is dopamine, and so the source of dopamine in the hippocampus seems to be the locus coeruleus, and it's still a mystery as under what conditions the locus coeruleus also releases dopamine, but it's really important when we're learning something new to also release dopamine or to at least activate the dopaminergic receptors in our hippocampus. So, yeah. So, dopamine, norepinephrine, um, and then there's also, um, galanin, which is important for releasing when we're stressed, and it helps also with that rapid learning. Um, it works in concert with norepinephrine and in doing what it needs to do to strengthen synapses so that we learn really quickly.
I I love, um, that there are multiple molecules involved because that signals us to a principle, which is that even if people can't remember all the names, um, that rarely in biology is something handled by just one molecular pathway. That redundancy is the rule because signaling attention to specific events is so important. So that I'm going to use that as a just-so story. I always say, you know, I wasn't consulted at the design phase, but it makes sense to me as to why redundancy would exist in the system.
>> Absolutely. And in fact, when we form hypotheses about the brain, we're always wrong. And the reason why we're always wrong is because it's more complicated than we like to think. And because in our brains, when we're forming hypotheses, it's we fail to account for all of the factors that are involved. You know, the glia, the neuropeptides, the neurotransmitters, the physical structure of synapses. And so, when I was going through grad school 35 years ago, uh we the dogma was that every neuron contains one neurotransmitter and releases one neurotransmitter. And you had excitatory neurotransmitters and inhibitory neurotransmitters and neuromodulatory neurotransmitters, but that's as complicated as it got. And then we started talking about neuropeptides, and people said, "Oh, no, please don't don't complicate it." And then we started talking about how neurons contain both neuropeptides and neurotransmitters and maybe more than one neurotransmitter.
>> even hormones, too.
>> And hormones, and oh lord, you know, it's just so complicated. But I mean, got to admit, that's why it works, right? And every time the brain teaches us something new about itself that we didn't hypothesize, we say, "Oh, of course. That wouldn't work if the way I hypothesized it with it." You know, we actually need redundancy. We need all these systems to work together.
Yeah, it's um it's uh daunting sometimes, but it also ensures many many careers in science and neuroscience in particular. So, um note that uh aspiring scientists, there's plenty of room uh for discovery. Do you want me to talk about norepinephrine and emotion and >> Yes, well, what I'd love what I'd love for you to >> [clears throat] >> um tell us about is, you know, what role this lack of norepinephrine release during rapid eye movement sleep um is thought to achieve and maybe you could also review some of your work describing conditions under which norepinephrine invades Yeah, invades sleep. rapid eye movement sleep and other patterns of sleep and how that can be detrimental.
>> Yeah, so a lot of this is hypothetical but based on a lot of good evidence that we're sewing together into a schema from which these hypotheses come. So a model um schema from which the hypotheses come but one thing that happens to people with post-traumatic stress disorder is that there is a lot of evidence that the locus coeruleus doesn't stop firing in REM sleep. So whereas their levels of norepinephrine might be similar to people without PTSD during the day and even during the first part of the night um during the wee hours of the morning and when you measure norepinephrine levels from metabolites um in the blood or the cerebrospinal fluid you see that people with PTSD it's during the wee hours of the morning when you have the most REM sleep that they have their norepinephrine levels differentiate most from those that don't have PTSD. And so that's evidence that the locus coeruleus is not shutting down during REM sleep like it should. Other evidence is heart rate variability. When our locus coeruleus is firing um our heart rates are generally a little higher and they don't vary as much as they do when the locus coeruleus is not firing. So during slow wave sleep normally have this big juicy variability in heart rate with every breath in and breath out because our noradrenergic levels our norepinephrine levels are lower. During REM sleep that goes away entirely and our heart rate is is um is um dominated by um parasympathetic rather than sympathetic activity and also what our brain is driving you know what we're dreaming about. For example, if we're dreaming we're running our heart rates will go up. But, norepinephrine levels still should be low or off. So, um people with PTSD that noradrenergic we're studying these in rats, too. Is it true that our locus ceruleus doesn't uh shut off when we have post-traumatic stress disorder? And the preliminary evidence is yes, it's true that it doesn't shut off. So, what that would do is um norepinephrine would act at synapses to prevent that um weakening that you really need for example of novelty encoding structures. And it keeps memories in that novelty encoding structure even once it's consolidated to the rest of the brain. So, in the hippocampus, which is important for remembering things throughout our lives and and it's that thumb drive, um we we need it to be erased so that we can learn new things uh once it's been consolidated to the the hard drive of our cortex. And if so, if we're not able to do that, we fill up that RAM um really quickly or that thumb drive really quickly and we're not able to learn new things. So, for example, after a trauma, I talked about the locus ceruleus responding in stressful situations. That's great, it's very adaptive, but then you need it to stop.
Once you've learned what you need to learn from it and you want to go to sleep, you need the locus ceruleus to calm down. And during REM sleep, you want it to stop because then when you've consolidated that traumatic memory to the cortex, you need to erase it from the novelty encoding structures, for example, in the hippocampus. So, that then when you're in the context of safety, you can learn those new things, those new contexts and um and stop responding to those same stimuli as though you're in that original situation. So, if you're not able to erase that thumb drive, you will always feel like that trauma happened that same day, like earlier that same day, and um respond as you would to an early recent trauma, which is with beating heart and all of that. Um so even memories that are years past, if you're never able to downscale that novelty encoding structure and you purged it from that traumatic memory, it will stay fresh and new and then become maladaptive.
What approaches are you aware of that can turn down the output of locus coeruleus during these phases of sleep?
And for that matter, what things can cause ramping up of locus coeruleus during this phase of sleep? Um we've had a couple podcast episodes, solo episodes and with guests talking about trauma. We had Dr. Paul Conti, who's a Stanford-trained, Harvard-trained um psychiatrist who talked a lot about trauma, wrote an excellent book on trauma and um certainly sleep was emphasized as as a key thing, like get enough sleep. But here you're saying even if somebody with trauma gets enough sleep, if locus coeruleus is hyperactive during sleep, those traumas are going to persist. And most of the trauma treatments that I'm aware of are everything ranging from cognitive behavioral therapy, talk therapy, drug therapy, EMDR, hypnosis.
Um nowadays there's a lot of interest and attention on um clinical studies on exploring psychedelics, high-dose psilocybin and MDMA. So there's a vast landscape, none of which as far as I know is really focused on sleep specifically. No, they're not and they should be because actually psychedelics is a sleep-like state and um it's a REM sleep-like state, although of course there are some major differences. So yeah, so much to talk about here.
So antidepressants um are often noradrenergic or serotonergic reuptake inhibitors. So they leave norepinephrine actually out there in the synapses and what that does is it inhibits REM sleep. Um and if you're able to get REM sleep, it would probably be REM sleep with some noradrenergic activity. So actually, I think, anyway, I'm not a physician, that um antidepressants are contraindicated.
You don't want to take them if you've experienced a trauma and you're experiencing PTSD because if anything, it's going to make it worse or at least prevent the type of adaptive REM sleep that you really need in order to resolve those emotions and move on. Um Is that statement specific to antidepressants that um tickle the noradrenergic pathway? So, the the one that comes to mind is um I can never pronounce it, bupropion, which is uh I think brand name is Wellbutrin. It's a dopaminergic and noradrenergic agonist.
That's sort of that's the net effect as opposed to the Prozac, Zoloft variety, which are SSRIs. Yes. Yes, but >> [laughter] >> SSRIs themselves also are problematic because we didn't talk about it yet, but the dorsal raphe nucleus, which produces serotonin, which the specific serotonin specific serotonin reuptake inhibitors block from being reuptaken, um leaves too much serotonin out there.
And what serotonin also is another noradrenergic I mean, sorry, another neurotransmitter that's downregulated during REM sleep. That's specifically off during REM sleep. And what serotonin does is it weights all of our cognition to being able to recognize novelty again. So, it sort of weights um our brain away from a sense of familiarity and toward novelty. And um it might be one reason why it's an effective uh antidepressant because it makes the world feel fresh and new again, right?
Um but you when you have a too much you're holding a novel traumatic memory um in your novelty encoding structure, too strongly already, you don't want to again weight things toward novelty. You need that absence of serotonin also to help you get that sense of familiarity and to start erasing the novelty encoding structures. So, you need both to be absent. It's really interesting.
Um, we hear a lot about serotonin and it's not often discussed in terms of its features related to novelty enough, I think. Um, and what you just described um, cues me to something that uh, Dr. Paul Conti and others have have said in terms of trauma and here I'm paraphrasing, so my apologies to them for not getting this exactly right that that an effective treatment for trauma does not erase the traumatic memory, but it causes a transition of what once was disturbing and invasive and maladaptive to eventually just become kind of a boring old story that has kind of a fuzzy texture to it as opposed to this kind of sharp um, high friction texture that invades our thinking um, and obviously our sleeping states as well. So, um, again and uh, I appreciate the disclaimer the caveats around, you know, not being a clinician etc., but I do think that there's a lot of interest now in whether or not antidepressants are effective for trauma or not and I think these these aspects of neuromodulation as they relate to um, let's call it erasing traumas or changing the emotional load of traumas during sleep um, is something important to take note We have a lot of clinicians that listen to this podcast, so they should also take note. Um, please. So, if I want to reduce the amount of norepinephrine released from locus coeruleus during rapid eye movement sleep to eliminate the troubling or maybe even traumatic memories um, and allow late stages of sleep each night to have their maximum positive effect.
Is there anything that I can do besides avoiding um, avoiding traumas, avoiding serotonergic or noradrenergic compounds? Well, I would also avoid anything just prior to going to sleep that might excite those systems. So, a lot of novelty, a lot of you know, exciting stress-inducing video games.
Try and enter sleep with as much calm as you can. So, maybe deep breathing exercises. That's a beautiful way to calm your sympathetic fight or flight system is deep breathing. And we haven't been able to test this with rats because we can't ask them to do a deep breathing exercise.
>> [laughter] >> There might be a way we can do that, but I haven't found out or figured it out yet.
But if there's a way you can make your sympathetic system nervous system calm down before you go to sleep, might free for you. Meditation or deep breathing exercises might be for some, a warm bath or a comforting book, nothing too exciting, but also nothing too boring. Perhaps just something right in the middle which makes you feel happy and calm is what you should do. And if you instead go to sleep while you're anxious or you're hyped up, then your sleep could become maladaptive. Another thing that happens in rats that we have yet to know if it happens in women is that female rats have three phases of their estrous cycle that their locus coeruleus doesn't seem to calm down during REM sleep as much.
And we don't know why, but during the high estrogen phases of their estrous cycle, the locus coeruleus shuts down just like it does in male rats. But in the other three phases, it doesn't. So, um one thing that might work and in fact there are few studies that show it it could work really well is um giving women after a trauma event something that [clears throat] contains estrogen because estrogen somehow is protective against PTSD and they know that through a retrospective studies where they gave women in emergency room either a pill with estrogen and or without and those that had the pill with estrogen in it were much less likely to get PTSD from that trauma as measured a year later than those that had the pill without. So, um there's some really good studies by Bronwyn Graham. She's out of Australia to really hone in on how much estrogen do you need and also testosterone just so you know gets converted to estrogen in the brain so testosterone also can be protective because it gets converted to estrogen. Um but there's something about estrogen that's really helpful and protective about that from from the high locus coeruleus firing and this is again preliminary data that we don't have full we don't have all the answers yet and um we are looking into it actively right now but it's a really important. The other thing about women is that we are two to four times more susceptible to anxiety related mental health disorders including post-traumatic stress disorder. So, if we could figure out what's happening to the locus coeruleus during sleep in women um that and then figure out a way to normalize that so the locus coeruleus is silent when it needs to be silent, I think we could go a long way in in helping women be more resilient to stress-related disorders.
What are some other sex differences as they relate to sleep? Yeah.
Yeah, that's a really good question.
There have been very few studies unfortunately of women in sleep. Um women and estrous cycle or menstrual cycle and sleep. And but what we have found, which actually largely replicated a study in 1960, um, is that that women, or females, rather, at high estrogen, high hormonal phases of their estrous cycle, or menstrual cycle, sleep a lot less, but that sleep is more efficient. So, that sleep is more dense in those sleep spindles, which I haven't gone into what they might do, except this connection between the hippocampus and cortex, but those sleep spindles are more dense and more coherent across the brain areas. The theta cycle, which is 5 to 10 hertz in the hippocampus, important for one year learning, and also important during REM sleep, is also bigger and juicier, um, during the high hormonal phases.
So, even though there's less sleep, it's more efficient and better, um.
But, uh, so, so all of that efficiency seems to be reduced in those other hormonal phases.
Um, so even though you might sleep a little more, um, you might need more sleep, in fact, in order to accomplish the same thing that you can get with that short, um, very efficient sleep of high hormonal phases. Very interesting. I think, um, there is a growing trend, at least among, uh, NIH funded grants to, uh, require, um, that, uh, as they refer to it in the grants, a biological sex as a variable. And here we're talk, not here about sex, the, um, the verb, although I'm sure there's studies about that, too, but biological sex is a variable because there is a a dearth of studies exploring sex differences in in most everything. Um, there's there are all sorts of reasons for that, but more importantly, the fortunately, the trend is shifting.
>> Yeah. Um, And even when [clears throat] you study males versus females, a lot of people just say include females in their studies, but then don't track the estrous cycle, or menstrual cycle and hormones [snorts] have huge effects on our behavior. I mean, just think about Well, you said sex.
Um you know, before our hormones come in, we're not interested in it. And suddenly, you know, that's kind of a main driver of our behavior is hormones.
Uh can definitely change who we are and what we do. So, we should be studying hormones, not just sex. I always say that uh puberty is perhaps the most massive transformation and rate of aging that any of us go through in a short amount of time. An individual their cognition changes, their worldview changes, and that's largely hormonal driven and and obviously neural architectures change, too. Um I'm very happy that you mentioned um trying to get into calmer states prior to sleep and some ways to do that. Uh I'm a big fan and I've talked a lot before on this podcast about things like yoga nidra, which is a non-movement based practice, uh sometimes called non-sleep deep rest, where people actually take some time each day to practice how to go into a more parasympathetic, aka relaxed, state deliberately cuz it's a bit of a skill.
Yeah, it's um and there's there's some good data, really, mostly out of a laboratory in Scandinavia showing huge increases in um nigrostriatal dopamine um when people go basically engage in a practice of deliberate um non-movement and that the brain actually enters states of a very shallow sleep. So, sort sort of nap-ish, but the idea is to actually stay awake, but motionless. And it does seem to restore a certain number of features of neurochemistry, but perhaps more importantly, it teaches people to to relax, which is something that most people are not very good at. Um but in any event, um and people who listen to this podcast have heard me say this over and over again, so I sound like a broken record, but this practice as a zero-cost practice that doesn't require any um pharmacology does seem to really enhance people's ability to fall asleep more quickly and to fall back asleep if they wake up in the middle of the night.
So, in any event, another plug for NSDR Yoga Nidra. Well, I just also want to add to that that's one of the reasons why insomnia is so insidious is because when people feel like they haven't gotten enough sleep and they're not getting enough sleep and they become anxious about getting enough sleep and then they're anxious before going to sleep like I'm not going to fall asleep it's going to be 45 minutes and then that's a positive feedback loop. So, you need to break that loop say, "Okay, my body's going to get as much sleep as it needs. I needn't worry about it." And then practice this relaxation to say, "Hey, it's it's all okay.
Um it's going to be all right." And and then concentrate on things that relax you um whether it's concentrating or not concentrating, whatever it is.
Um you men- mentioned um Yoga Nidra and that reminded me of um transcendental meditation which is something that also hasn't been studied well or largely because we can't ask non-human animals to do it and so we don't know what's happening with our neurochemistry and our brain activity it in a deep and meaningful way, but one thing that has has been shown in those that can do it really well is that that theta activity that I said happens when you're learning something or when you're in REM sleep, it it's well established and and increases during the transcendental meditation so it might be that some states of meditation could in some ways replace or mimic some functions of for example REM sleep, but again we don't know if all the neurochemistry is right to do for example the thing that I was talking about which is erasing the novelty encoding structures of the brain. That needs an absence of norepinephrine and serotonin which we don't know if that goes away with with transcendental meditation we just don't know the answer to that yet. Yeah, the the studies on on Yoga Nidra and sleep replacement are kind of interesting. Um, it does seem to be the case that nothing can really replace sleep except sleep, but that if one is sleep deprived or is having trouble falling back asleep that these um, things like and I hear it's I acknowledge this is essentially like yoga Nidra but we now call it non-sleep deep rest or NSDR because often times for um, names like yoga Nidra act as a kind of a barrier for what would otherwise be um, people willing to try a practice. It sounds mystical >> yoga. sounds like flying carpets and you know, it sounds like you have to go to Esalen. By the way, Esalen's a beautiful place, but it sounds like you have to go there or or live in the West Coast to to believe in this stuff, but it's simply not the case. These are practices that that are really just um, self-directed relaxation as a practice that that allows people to get better and better at directing their brain states towards more relaxation and most people have an asymmetry. Like for instance, most people can force themselves to stay up later, Mhm. but they have a hard time going to sleep earlier. Mhm. And that just speaks to the asymmetry that's probably adaptive and survival-based that we can ramp ourselves up far more easily than we can tend to calm ourselves down.
>> And actually, you know, to appeal to other Christians like me, prayer can be a wonderful way to calm yourself down because through prayer you're giving your cares to God and saying, you know, and then you are relaxed, more relaxed. And I just want to say that because the same reason that yoga might put some people off, it might put some people off um, to to talk about prayer, but it's the same process of being able to relax. And um, yeah. And get outside our own experience a little bit.
>> Yeah.
Um, back out, get a world view that might actually also help us to relax.
Um, Well, you you might be surprised at how many um, clinicians and scientists who've come on this podcast um, have mentioned things like prayer from various perspectives, Christianity, Judaism, Muslim traditions and others, that, um, as a as a parallel to all of these things. And I think what it it speaks to is the fact that ultimately the biological architectures that we're all contending with are going to be identical, right? And so different ways to tap into them and and ones that are, um, congruent with people's beliefs, I think is are great. Um, Yeah, because anything non-congruent with your beliefs is also stressful.
>> [laughter] >> And feels forced. And that's why, you know, this idea of calling it non-sleep deep rest in addition to yoga nidra was not to detract from the naming or the history around yoga nidra, but I was finding that it was a barrier, you know, likewise, um, yoga nidra tends to include things like intentions, whereas NSDR scripts, and by the way, we will provide links to some NSDR and yoga nidra scripts, but NSDR has no intentions. It's simply a body scan deep relaxation base. So it's sort of the scientific version of all of this stuff.
And actually we study it in the laboratory and and some of the brain states that people go into, but that's a discussion for another time.
This is a hard nut. My mother used to tell me when I said when I would complain, "I can't go to sleep." She'd say, "Well, you know, start with your toes and relax." So you would clench your muscles around your toes and you relax them and do that all the way from your toes all the way to your head. And I don't know where she got this. It might have been her own common sense or she might have gotten it from this, uh, NP NPR show.
It's called The Mind Can Keep You Well.
She used to listen to, but that's another intentional relaxation that focuses on the body, um, rather than on your own mind mental processes. But There I do a little bit of work with the military and um, there's a method within certain communities of special operations in the US military where if they can't sleep or they're having challenges sleeping, they will deliberately try and relax their facial muscles in particular, like sort of drape the facial muscles and um, use long or exhale emphasize breathing Um, does seem to increase the probability of transitioning back into sleep and those are hallmarks of yoga nidra and non sleep deep rest body scans and and so I think all of these things converge on a common theme you know as neurobiologist we can say all of the things that we are describing certainly move the needle away from locus coeruleus activation and we haven't done that the experiment to really look at that but seems all these things are counter to noradrenaline releasing. Right. Another one is yawning. Yawning in itself is is that kind of sort of tensing of all the muscles in your face and then relaxing them. So it might be why we yawn. We don't know why we yawn yet but it might also have it would be really great. Actually animals yawn too you know. My bulldog was a was a perpetual if he wasn't sleeping he was yawning.
>> [laughter] >> And it would be interesting to see what yawning does to the locus coeruleus.
Does that also calm and switch locus coeruleus activity because it's an interesting that facial nerve like trigeminal nerve you know that through the vagus connects indirectly to the locus coeruleus and has a powerful effect on that.
Interesting. A common I think friend of ours and direct colleague of yours Jack Feldman was a guest on this podcast telling us about all the amazing structures he and others have discovered in the in respiration and breathing.
Sounds like we have a collaboration brewing that the three of us should should definitely carry out.
>> Yeah. I'd love for you to share with us a little bit more about the spindles have come up a few times and I don't know if it's relevant to this so if it's not let's separate it out but I'd love for you to tell us a little bit about the role of sleep in problem solving and creativity. If spindles are involved and I'll consider myself lucky for batching them in the same question and if they're not involved simply feel free to separate them out. I think they could be involved in and the reason why I think they could be involved because we now know a lot more about spindles. First of all the first thing that we knew first of all, we ignored them. Then we thought they had something to do with keeping us asleep and that was their function. It is when the an external stimulus came, they would keep us asleep because they would have arise. But now we know that the density of our sleep spindles, the number that we produce per minute is well correlated with our intelligence in the first place and that no matter what your intelligence is, and no matter what your sleep spindle density is, if you learn something during the day and increase your sleep spindle density, it's really perfectly correlated with our ability to consolidate that information and in and incorporate it into the schema that we already have in our brain. So, if you try and learn something new, even if your sleep spindle density at baseline is great, if you don't increase your sleep spindles that night, you're not going to you know, use sleep to really incorporate it. Interestingly, sleep spindles are poor in those with schizophrenia.
It's one of the characteristic signatures of sleep, um, is that sleep spindles are very few and far between, which might mean that, um, that people with schizophrenia might not be able to incorporate new information into already existing schema and instead it sort of flaps in the breeze out there and can be accessed, um, erroneously at times when you, you know, you don't want it to be in involved.
So, um, I digress. So, sleep spindles and creativity. So, one of the things we now know through some great studies by Julie Seibt and Anita Luethi is that sleep spindles are accompanied by an incredible plasticity out in the distal dendrites, the listening branches of our neurons that listen to other cortical areas. So, there are proximal dendrites in our neurons that listen to the external world and are conducted through the thalamus and then there are distal dendrites which listen to an internal kind of, you know, conversation that's having happening in our brains. It's kind of, you know, our internal state, really. And during sleep spindles, that's when those distal dendrites are able to best learn from other cortical areas and from the hippocampus.
Um it is during sleep spindles that the hippocampus and the cortex are best connected and when that plus incredible plasticity can happen. When I talk about schema, that's a cortical-cortical thing. That's when, you know, the image of Santa Claus and presents, you know, comes together. It's not through some external thing. Once we learn those things together, it's our cortex that that encodes that and brings those images back up together.
And that's during sleep spindles when that's happening, when that um there's big surges of calcium into those um distal dendrites and where plasticity happens in in just huge amounts.
Um during that sleep spindle stage of sleep, which is N2 stage, there's also some another excitatory uh event that comes all the way from the brain stem and projects everywhere in our cortex, which is called PGO waves. That's P for pons, G for geniculate nucleus of the thalamus, which is where they were first discovered, and O for occipital area, which is our visual area, which is again where they were first discovered. But in fact, it's now been shown that PGO waves, which we should generalize to P waves cuz they come from the pons and go to the thalamus and then the cortex, happens all over the brains and that is where um glutamate, which is a major excitatory neurotransmitter involved in learning and plasticity, is being released in big amounts also in those distal dendrites. So, P waves and spindles work together to cause plasticity and so our schema together, which could be the origins for um insight and creativity. Now, when PGO waves or P waves were first discovered, it was thought to be random because this small area that generates P waves all over the brain, you know, gen- uh projects all the all over the thalamus and causes P waves all over and you don't measure P waves all over the brain at the same time. In fact, it's just seems sporadic and random. So, that's probably and P waves also happening even more during REM sleep, rapid eye movement sleep. So, that's probably that's why people think that REM dreams are so random is because these P waves are random and they could generate dreams because they're an internal source of excitation that kind of replaces the outside world during our dream state. And so, these P waves, if they are random, could could function or could be the underlying reason why REM sleep dreams are random. And it might also be why creativity can happen there is because we're randomly activating, co-activating different things in our brain that we can then sew together. Um, but it might not be as random as we think. So, that's a caveat there. Well, I just learned a lot from you because I I teach brain stem to medical students and um, I talk about the pons. And the pons is like this dense collection of all these different nuclei involved in a bunch of different things and it's close by a bunch of interesting things and um, it's still kind of a mysterious brain area.
But when I learned about PGO waves, I thought pons geniculate occipital because occipital is most commonly associated with the visual cortex. I thought it was the origin of the visual component of dreams.
>> is. I'm very happy to learn that they should be called P waves because they include lots of different areas of the brain and it makes really good sense to me why the kind of pseudo randomness of dreams, especially these late night and early morning um, later in sleep I should say and early morning dreams seem to be cobbled together from kind of disparate experiences. I mean, you know, you walk through a door and suddenly it's a completely different context and landscape. Yes. Beautiful.
Yeah, I I I like this idea a lot. I mean, it makes intuitive sense, it makes biological sense, it also gives me something to talk about uh to the medical students next quarter when I talk about pons. And you want to talk about where in the pons it's right below the locus ceruleus. It's called the subceruleus. They're glutamatergic. It's also called uh nucleus. So.
Love it. Uh so, um note to any aspiring neurobiologist, there's a a vast landscape of yet to be undiscovered structure and functions in the pons. You want to work on something that is sure to reveal something novel, work on the pons because it's in every textbook, it's a a clinically very important structure.
Um sadly, uh gliomas can and and other uh cancers of the brain can sometimes uh can often surface in the in the pons, but but we still know very little about it. Um I read a paper this last year or and I think it was covered in a bit of popular press that during rapid eye movement sleep people can solve problems or respond to external stimuli. Like, for instance, they would give them math problems.
They'd whisper in their ear while they were in REM sleep, you know, "What's 2 + 2?" And people would say, even though they were paralyzed, apparently they could still move their mouth because they'd say, "Four." Or something like [laughter] that. Or they'd say, "You know, what's your name?" And people could respond. And so, that in REM sleep perhaps people um some elements of cognition are still um active.
>> I'm glad you brought that up. That What do you think of And I don't know the authors of that study and um and uh listen, if ever I say something wrong, it's great on this podcast because someone will tell us in the YouTube comments. It's one of the great uh uses of YouTube comments. But I'd love to know your thoughts on that study. I mean, is that just kind of a a uh an odd feature that Or does this have meaning? Should we actually care about this result? There's no just about it.
It's really actually intriguing and interesting and might relate to this paper that I talked about where we where we said different areas of the brain can be in different states at the same time.
So, lucid dreaming is another thing we can't ask animals to do or can't ask them if they've done it, but um we can certainly ask humans to do it and some people can do it really well. And it would be really interesting to see in those people who could lucid dream really well whether they spend more or less time in this um asymmetrical state where one area of the brain is in one state and another area of the brain is in another. And it might be that those people can respond to questions during REM sleep best are those that have the most asymmetry or or dissimilarity or dissociation between subcortical and cortical structures. Or it might be that they're the ones with the most symmetry.
We don't know. Um I do worry a little bit about lucid dreaming cuz people are it's a fad. People are really excited about it and to be able to remember one's dreams is fun often unless they're nightmares. And but it's really interesting or to be able to direct one's dreams if they are nightmares is really wonderful power to have and to be able to redirect a nightmare that has been repeated to something else and then kick yourself out of that um repetitive nightmare is really nice.
But um I worry a little bit about it because we know so little about what's actually going on in the brain. And if this lucid dreaming state is preventing us from for example from the locus coeruleus from calming down or the serotonergic system from silencing like it should.
And maybe what we're doing during this state is yeah, we're activating the learning and memory structures but in a way that's maladaptive in terms of the erasure that we need to do. So, maybe one of the reasons why most people don't remember most of their dreams is for good reason.
Your hippocampus is in a state where it's not writing new memories. In In it's writing out it's the memories it learned during the day to the cortex and it's um immune from incoming new information.
So, um so maybe lucid dreaming is bad because you're you're activating the hippocampus in a way that's writing new memories and it might be really maladaptive for things like, you know, PTSD. On the other hand, >> [laughter] >> let me just argue myself right out of this. Um when I used to have a repeated nightmare when I was a kid, my mother, who's so wise, would tell me, "Well, listen, just next time you're in that dream, you know, say, 'Hey, I'm in a dream' and then change something about it." So, she and I rehearsed what the horrible dream that it was. It was a big monster, you know, running after me and my legs were like mud and I couldn't run away and it was just terrifying. And that was a dream I would have, you know, time and time again. She said, "Okay, next time what are you going to do when that monster comes after you?" I was like, "I'm going to run away." "No, you That's what you do every time and it's always the same outcome. You can't run. So, let's do different. Like, what what could you do that's different?" So, I came up with a I could turn around and punch it in the nose. She said, "Yeah, that's great." Um so, the next time I had that dream, I did recognize this is that same old dream, which means that there's part of my brain that's conscious enough to know that this that I'm in a dreaming state and then I didn't have the courage in my dream cuz I was still terrified to punch, you know, or touch the monster in any way, but I did have the courage to turn around and look it in the eye and say, "No." That was enough. I said, "No." And that was enough to knock me out of that rut of that dream so that I never had it again. I never had that same dream again. And in fact, it gave me peace about dreaming because I knew that if ever there was a nightmare that was just too scary, I could probably do something to change it and knock myself out of it. So, even though I don't recommend lucid dreaming on a normal day-to-day basis, if it's enough that can knock you out of a rut, um one thing that happens with people with PTSD is they have the same repeated horrible nightmare, which is often a reliving of the day's trauma that that they that they had. So, maybe lucid dreaming can be used on occasion to be a powerful tool because there's so much plasticity that happens during REM sleep to knock you out of that rut of of reliving that event. And and just change it, you know, and you could probably practice that during wakefulness.
Um rehearse the event that happened that was so traumatic, and then just introduce a new element, like, you know, "Now I'm safe. Now, you know, the sound that was associated with that really traumatic thing, I should now associate with something else, and next time I have that dream, I'm going to change it so that sound is now this new thing that it should be associated with safety."
And that might be enough, maybe, I hope, um to knock you out of that repeated nightmare, and maybe even start you on the path to recovery because if you can calm down about those nightmare states of sleep, then maybe your locus coeruleus, which is involved in stress, can also relax, and you can do the erasure parts that need to be done.
>> [clears throat] >> I love it. I seem to recall a paper, and I'll have to find the reference and and um send it to you we will also put it in the show note captions that described a protocol essentially matches this um uh idea. And well, I think what they had people do was either cue themselves to a particular smell or tone in wakefulness, then to try and recall a recurring nightmare, then during the night's sleep they had the tone playing in the background, which would then cue them to the wakeful state. They're still asleep, mind you, but in the pseudo lucid or lucid state, and then try and change some variable, as you're describing. Some either look the the um predator in the eyes or do something different.
>> Yeah. And then in the waking state take a little bit of time to try and script out a different um narrative altogether.
And it took several nights as I recall or more, but that they were able to escape this recurring nightmare.
>> a week or something. Yeah.
>> Right. Oh, so you're familiar with this study.
>> a beautiful study. I loved it. Yeah.
>> will um put a reference to that. I um I need to revisit that study. It was pretty recent, but I I need to dive into it again um because I think I I didn't go as deep into it as I I should have.
>> No, no, but the one thing that you that you well, you said many right things, but one of the things you said is that they were able to cue the dreamer um when they knew when they were going to REM sleep, and then they played the sound or had the odor. Now, when you're normally asleep alone in your bed, you're not going to be able to cue yourself, but it might be that rehearsal enough before you go to sleep is enough to, you know, help cue you um to that repeated nightmare. Remembering what the nightmare is, and then figuring out how to cue yourself to do something different. Yeah.
>> For years I had the same recurring nightmare >> Yeah. over and over and over again, and it was so salient and so clear, and I'm not going to share what it is cuz it's um it's not that it's that disturbing.
It was just it I think it was the emotional load of it and just how salient certain features were. Like one person in um who's a real-life person had a particular um clothing on, and it's like and that just served as this cue, and I don't know if I ever did any direct work to try and deal with it, but now it almost seems silly to describe it.
>> Mhm. Oh, yeah. Well, dreams are usually silly to describe.
>> pretty silly, but it was a pretty violent dream.
>> Yeah, and your emotional system is so geared up during REM sleep, which is another thing we could talk about.
>> [laughter] >> Yeah, please. Um I would love to Yeah, so locus coeruleus is ideally suppressed, so we can't release norepinephrine. We can't act out our dreams. Um this uh during these very emotionally laden um thoughts and and storylines during sleep. It's almost like starts to sound like a little bit of a built-in while sleeping trauma therapy. Because most trauma therapies involve trying to get people into states of Counter to what most people think you actually want to get close to the trauma in terms of the narrative, but try and suppress the emotional activity of it or I guess that's the motivation for ketamine-based therapies for trauma. Or I've also heard, and this is still perplexing to me, that other waking-based trauma therapies involve taking people the other way, making it very cathartic. Take them to the peak of the emotional response, but then allow that to finally cycle down into a more relaxed response. So, please if there's anything about locus coeruleus and and dreams and that can help people basically extinguish traumas or traumatic features to to real-life events, we definitely want to know about that. Yeah, yeah. Well, I think one of the things that people thought might help after a trauma, like a school shooting or whatever, you know, a car accident, is to talk about it and in but in fact that ended up being counterproductive. And I think one of the reasons why it was counterproductive is cuz it didn't take you them back down.
It brought them up and continued to reactivate the emotions of it, but then didn't, you know, emphasize the safety of fact that it's over or help them work through how they might avoid it again in the future to calm the sympathetic nervous system down again before they went to sleep. And in and in any none of these studies has sleep ever been considered, but to me that's the key part is bringing down your sympathetic nervous system before you go to sleep so that your sleep can be adaptive, your locus coeruleus can shut off like it normally does or should do, and then able to erase the novelty of it. The other thing that Um, I just mentioned a minute ago was that the emotional system is highly activated in REM sleep and that's definitely true. And that might seem counterproductive in terms of you know, the nightmares and and how to help REM sleep be a therapeutic thing rather than a um than a um in reinforcing the emotionality of the trauma. And I think the key to that again is the absence of norepinephrine.
So, even though the emotional system is in high gear without norepinephrine, you can actually um divorce those highly activated emotions from the cognitive parts of the memory that you have just written out in that N2 stage of sleep when the sleep spindles are going. So, um so, you've just now consolidated the information that you'll need to survive and to you know, to make that adaptive and now you need to divorce from that schema and from that semantic parts of memory the emotional part because whenever you remember something it's fine if you remember the being emotional at the time, but you don't want to bring back and sew into that memory all of the same emotional systems. You don't want to bring back you know, the heart rate changes and the sweating and and all of that. You want to be able to remember all the parts of it and even remember that you were traumatized and that you did cry and that you did have you know, your heart was racing, but when you're talking about it years later, you don't want to have to relive all that. Otherwise, you who would ever want to recall a traumatic memory because you're basically putting yourself through the same trauma, which is what people with PTSD have. They don't want to recall this traumatic memory because it's reliving it it like it's just happening again. So, that's what we're thinking is that um the emotional parts are no longer are not able to be divorced because the norepinephrine system is not downscaled during REM sleep and so that REM sleep serves to instead reinforce and in fact amplify the emotions because your your emotional system is up, locus coeruleus says hi, re-sewing in every night the emotionality of those memories and with the memory itself.
You've um told us a lot about locus coeruleus and norepinephrine from locus coeruleus. Is there any role for um norepinephrine, epinephrine, and cortisol released from the adrenals?
Uh, my understanding is that norepinephrine and epinephrine will not cross the blood-brain barrier, which is probably why we have a brain-based noradrenergic system, locus coeruleus and other and other neurons as well.
Actually, that's a question I should ask you. Are there other sites in the brain where norepinephrine is released from or is it just locus coeruleus?
>> Um, so there are seven Oh, okay.
>> nine different adrenergic Yes, there's nine different adrenergic structures.
>> I'm sorry. I did not ask but but it just occurred to me that um in some cases like with raphe, there are other sources of serotonergic drive in the brain but raphe is like the main site.
>> the one that goes to the cortex and and and the locus coeruleus is also the one that goes to the cortex. But there are other adrenergic sources, some that from the brainstem that descend and help us to ignore pain, for example, when we're stressed and needing to run away from the tiger, right? We don't want to be thinking, "Oh, my ankle hurts." You know, you want to just be able to ignore it and go do what you need to do. So, um yeah, so there are lots of other noradrenergic nuclei but the locus coeruleus is the main one that projects all over the brain. They actually the only place it doesn't project is the dorsal striatum. You talked about ventral striatum and addiction. The dorsal striatum is the only place the locus coeruleus doesn't project to and that's involved in procedural learning, motor learning, um kinds of learning that take over when your hippocampus, for example, is compromised bilaterally. If you don't have a good hippocampus, you can still do procedural learning and do and it's great. It's a redundant system. And so, um if your locus coeruleus is not working, if you don't have it anymore, you can still do if you if you don't have a good hippocampus, you can still do learning through this dorsal striatum structure. So, it might be for those kinds of learning uh functions.
Um sleep deprivation, where you never let the locus coeruleus stop firing, is okay because it doesn't have any receptors for norepinephrine anyway, so um yeah. And what about bodily um like adrenals? Um you know, I I often remind people there's no such thing as adrenal burnout, per se, that adrenals don't actually um burn out. Um but some people have um adrenal insufficiency syndrome, other people have adrenals that are just chronically cranking out um epinephrine, norepinephrine, and cortisol at the wrong times, in particular. Yeah. Yeah.
So, that those are great questions and I think the answers to them have yet to be discovered, the connections between our periphery and our central nervous system. But we know that there are beautiful connections and it's untapped source of being able to manipulate our brains is to work through our bodies. And so, um our adrenals do great things. They constrict our blood vessels, causing higher blood pressure, which help blood rush out to all the extremities that need blood, um you know, our muscles, for example, for running away from the lion, um or the tiger, Or meeting a grant deadline.
Or catching a train. Or catching a train, yeah. Um the adrenals help our hearts pump faster, our muscles get perfused with the um blood it needs.
It diverts blood and everything away from our parasympathetic system, which is rest and digest. We don't really need to digest that croissant when we're running for a train. We can do that later.
So, it's doing really important things. What we don't know, because it doesn't cross the blood-brain barrier, is how that affects the brain and whether our if we can independently activate our adrenals when a time when our brain thinks that we should be fine and calm and asleep, how our brain detects that. Is it a feedback through your heart is racing and then our brain stem says, "What's going on? My heart is racing." and then wakes us up.
Then our hearts are racing together with our brain racing.
We We just don't know the answers to these questions yet. There are some good good studies, old studies, but we need a lot more.
All right. Well, another another nod to the fact that there's lots of great work ongoing and still to do.
I'd love for you to tell us about some of the work that you're doing more recently on the relationship between sleep and opiate use, withdrawal, relapse, and craving, just addiction generally.
I get a lot of questions about people trying to come off benzodiazepines or people's challenges with benzodiazepine and other types of addiction. Um yeah, what what is the role of sleep in addiction and recovery from addiction and opiates in particular?
>> Yeah, this is a very young area. And in fact, my laboratory has just started. I have a graduate student who's been in my lab for just 1 year. She's done amazing work already, but completely groundbreaking work. And what she has discovered already, we don't have the paper out yet, but we're working on it, is that um when animals withdraw from opiates and this has been sort of replicated in other ways with other types of things um our sleep is disturbed. Our sleep is terribly disturbed and the amount of sleep disturbance predicts relapse behaviors. Um and you might think, well, of course you're going to relapse if you can't sleep because opiates calm you down. Well, one of the reasons why opiates calm you down is because the locus coeruleus again, the blue spot, is covered with opiate receptors and that are normally really responsive to our endogenous opiates. Um and so what what happens when we're pleased, for example, or laughing or whatever, our endogenous opiates um activate those receptors in the locus coeruleus and calm it down. It it actually um suppresses locus coeruleus activity, makes us happy and relaxed. One of the things reasons why opiates are so addictive is because it also calms us down and makes us relaxed. Um but the problem with exogenous opiates is that they really bind strongly bind these receptors on our locus coeruleus and if you take an exogenous opiates again and again like you're recovering from surgery, for example, take these pain medications is that our locus coeruleus struggles to do what it's supposed to do, which is keep us awake and learning and and concentrating on things. So it will down regulate, it will internalize these receptors that are normally only occupied by endogenous opiates and and and it will do this, it will change our genes that are associated with producing these receptors. So you actually have very many fewer receptors. So the locus coeruleus, at least during wakefulness, can fire and help us to do these things like learn about our environment. And so if you long-term reduce the number of receptors out there, um then when you withdraw the exogenous opiates, there's not enough of your endogenous opiates to uh to be able to re-occupy those few receptors that are there and our locus coeruleus has nothing to calm it down anymore, no pacifier, and it just fires and fires and fires, and that phasic and tonic high activity stresses us out because it's normally associated with stress. And so, any exogenous stressor that adds to that and it also activates our locus coeruleus, there's nothing to calm it down again. And so, it just keeps firing, it disturbs our sleep, um and so, that's why maybe sleep disturbance is a an indicator of a hyperactive locus coeruleus, and um and such a good predictor of relapse behaviors because nobody likes to live in that high stress state, and they will do anything um to get back to normal.
So, the problem with with um taking these drugs is that it it leaves you re-excited and or I'm sorry, excited, relaxed and happy, but then when you come off of it, you're worse than when you when you were at baseline. You take it again, um it only brings you up this far because you have fewer receptors.
When you come off it, you're down even more depressed and and anxious, and I depressed is a word I use loosely, and that's not that's not what I should say.
>> central nervous system depression. I mean, sleepier, less motivated, lower mood. Yeah, I mean, our locus coeruleus is actually it it's a it's a the anxiety kind of depression, actually, the anxiety-related depression. So, um yeah, so, we don't know yet what and there's some good research going on right now, what could restore our own endogenous receptors so that our endogenous opiates can properly calm our locus coeruleus um once that they have been tamped down by exogenous opiates, but that would be really one way that you can access um the sleep disturbance. So, we talked about sleep and the importance of sleep in terms of learning and memory, the importance of the structure of the 90-minute cycle for all of that. So, you can imagine if your sleep is disturbed by too much locus coeruleus activity, the the the structure and the function of those sleep spindles and that theta during REM sleep and the and the lack of norepinephrine, all of those structures all those functions for for learning something new like a new behavior that has as an involved the drug becomes um compromised. And so, that's something that Tanya Lugos in collaboration with Pamela Kennedy at UCLA that we're we're looking at. How is learning and memory affected by the sleep disturbance? Is there a way we can um in animals that are coming off of opiates, can we restore their sleeps to normal so that then they are less likely to um do relapse kinds of behaviors.
Yeah. Fascinating and I'm I will certainly have to have you back on to tell us the results of those studies.
Meanwhile, I think for anyone who's trying to um come off opiates, um exogenous opiates and restore these systems, um what I'm hearing is that it's going to take some time, but that any and all things that people can do to buffer their healthy normal sleep architecture like morning and daytime sunlight, limiting bright light exposure, lowering the temperature at night, a number of things that we've talked about on this podcast.
>> deep breathing exercises, meditation, whatever it is that helps you calm yourself before sleep. Yeah. Right, would would facilitate not just sleep, but perhaps even accelerate the the recovery and um and shorten this period of withdrawal, which from the questions I get and from what I hear, um can be absolutely brutal.
>> Yeah. Um so, >> can imagine. I had to take opiates for I only took it for 3 days after giving birth to my um first son, I think, second son, one of them. And um and just I just said after 3 days, this is enough. I'm just going to try Tylenol and um so I I weaned myself not weaned.
I just did a sudden sharp cut off and even though I felt I didn't get the high of opiates when I was taking the um Tylenol codeine um when I went off it boy it was like PMS times 100. I was so anxious and upset at little things and thankfully only lasted a few hours but if I had taken it for a week or 2 weeks who knows if my indulgence opiate receptors would have been permanently down regulated and I would have been an addict you know an addict I would have been addicted I shouldn't say an addict there's negative connotations. It's just a really physiological state so um no judgments at all associated with it so um they're powerful powerful painkillers but can also alter your entire brain and rewire it. Yeah. Well um all the more reason why I and many others are grateful that you're doing this work to figure out ways that people can recover um more quickly and more thoroughly.
I must say you've taught us a tremendous amount in um in a relatively short amount of time uh about the architecture of sleep the different phases the relationship between sleep and dreaming and this incredible structure locus coeruleus and I'm so happy we also got into the pons that just delights me because uh we rarely talk about the pons on this podcast but it's such an interesting structure. Um sex differences um that are important in creativity and problem solving and um and trauma sleep spindles just such a wealth of information and much of it for people. So first of all I want to say thank you for taking the time to sit down and have this conversation that so many people are sure to benefit from. I also want to thank you for doing the work you do even though I'm a fellow neurobiologist I think that um it's not often that um we take a step back and realize that it's really the the of um hard thinking, hard um, strongly motivated uh, PIs, stands for principal investigator by the way. PIs like yourself, you graduate students and post docs that really drive the discovery forward and that lead to these new therapeutics. Um, physicians are wonderful, clinicians are absolutely wonderful, but clinicians don't develop new treatments. They they only implement the ones that researchers discover. So, thank you for being a brain explorer with um, with a focus on um, growing the good in the world. Um, I know I speak for everybody when I say thank you so much. Thank you so much, Andrew. Thank you for being an amazing interviewer. You brought a lot out of me in a coherent fashion that normally I can't do when I'm speaking in public. I don't know about [laughter] that. I've heard your lectures and they're superb.
We'll direct people to some of the other ones, but Well, thank you. And I also want to put a plug in for graduate students in general and the key and amazing role that they play in research.
Um, I I'm a PI as you said. I used to be a graduate student and a post doc trainee myself doing all of this on the ground hands-on experimentation. It's so hard to do. It's so hard to do right.
It's so hard to think through all of that. Now I'm a PI, I get to be an idea person and just say, "Hey, why don't you do this?" and "Hey, you know, what do you think about that?" and they of course intellectually contribute so much to these um, these planned experiments, but they also do the really hard work. And so, I just want to say thank you graduate students. Thank you to my graduate students and all graduate students out there. Thank you post docs.
>> and and and listen and to the major institutions, Stanford, UCLA and all other major institutions, pay them more, please. We need them and they need to to have a standard of living. I'm not I'm not afraid to say that despite my primary employer. Pay them more. They need it. They deserve it.
>> They deserve it, absolutely.
Great. Well, we will absolutely have you back again if you'll if you'll be willing. And um, meanwhile we will direct people to where they can learn more about you and your exciting work.
And once again, thanks so much.
>> Thank you so much.
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