Sleep and Aging: The State of the Art. Podcast with Bryce Mander

Do we really need less sleep when we get older? We know that as people age, they tend to get less sleep. But interestingly, older people also seem to suffer less than young adults when subjected to sleep deprivation. They don’t feel as sleepy and don’t experience as much impairment when performing tests of vigilance after sleep loss. Such findings have led some to conclude that older people get less sleep simply because they do not need as much. But does all research on sleep and aging show this?

Sleep and Aging: Senescence Reduces the Ability to Generate Deep Sleep

Recent studies have revealed that the aging brain changes in ways that make sleep less restorative. As we get older, we typically experience less “deep sleep,” which is characterized by more slow waves, as well as bursts of faster waves (sleep spindles). Among other things, this type of brain activity is important for learning and consolidating memories. Research has shown that both older and younger people benefit when they get more of these slow oscillations that stimulate memory consolidation.

This suggests that the real reason older adults sleep less than their younger counterparts (even when allowed prolonged periods in bed) and experience less decline in performance subsequent to that sleep reduction, is because they are less capable of generating the type of sleep that they need. And it is likely that their health suffers for that loss.

Guest

In this episode of humanOS Radio, I talk with Bryce Mander. Bryce is a postdoctoral fellow in the Matthew Walker Sleep and Neuroimaging Lab at UC Berkeley. Bryce and colleagues recently wrote a review in the journal Neuron that comprehensively explores the subject of sleep and aging. Research has shown that a lack of deep sleep is associated with higher levels of amyloid beta, those misfolded proteins that accumulate in the brains of people afflicted with Alzheimer’s. Thus, it appears that sleep disturbance is not just a symptom of Alzheimer’s disease but may also play a key role in its progression.

This raises a number of interesting questions. If we could routinely test for signs of less robust sleep, could we determine who is susceptible to developing Alzheimer’s disease soon enough to intervene?

And can we find ways to enhance slow wave sleep oscillations as people grow older, so that we can enjoy high-quality restorative sleep our whole lives? (Note that I explored a novel way to enhance sleep in this episode of humanOS Radio.)

The answer appears to be yes and the technology to facilitate this might soon be available.

Tune in below to learn more about sleep and aging!

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Transcript

Dan Pardi - 00:03: Today's guest is Bryce Mander, a postdoctoral fellow in the Matthew Walker Sleep and Neuroimaging Lab at UC Berkeley. Recently, Bryce and his colleagues published a paper called Sleep and Aging in the journal Neuron, and this paper is the cross-section of two of my big scientific interests, so I'm thrilled to have Bryce join me on the show.

Bryce Mander - 00:22: Thank you. Thank you for having me on, Dan.

Dan Pardi - 00:23: I always like to start off and ask people about how they got involved with sleep research if they're a sleep researcher and, in particular, how did you become interested in the topic of sleep and aging?

Bryce Mander - 00:35: My interest in aging and sleep started a long time ago. I had always had an interest in sleep. When I was in high school, I was interested in sleep and dreams. When I was in college, I started working for Eve Van Cauter and learned about sleep [inaudible 00:00:55] metabolism. But in that time, that's when a lot of my burgeoning interests grew, because I became aware of how sleep universally impacts so many different processes in the body and in the brain. And it just blew me away how many different organ systems, how many different processes were functionally effected by sleep loss and chronic sleep restriction and all of that.

01:20: Through that work, I started working with them in an aging study where they were looking at how sleep impacts metabolism in older adults, because they had all that famous work they put out in younger adults. That's when I got to work with older people. It's just really fun working with those volunteers, the subjects, because they've got all these stories to tell. It's really fun, but where I really got into aging research was when I ended up in graduate school working with Phyllis Zee, and she's very big in aging and sleep — how sleep disorders and exercise habits and circadian rhythm changes can impact aging, and its relationship to metabolism, and relationship to responsiveness, to light, relationship to cognitive functions.

02:10: She let me play around with my own dissertation study and do neuroimaging, and we were very interested in this very bizarre literature showing that older adults respond very differently to sleep deprivation on tasks of common performance than young adults do. And it just led to this ongoing debate that's always been fascinating to me, about- so, older adults don't show as much of a drop after sleep deprivation on a lot of different tasks than young adults do, and so there are some people that think that older adults slowly just need less sleep, and there are some people that think that there's actually something changing in the brain that may impact the ability of the older adult brain to respond to sleepiness, to have a deep, consolidated sleep period, and to express sleep that was rich in the brain rhythms that are necessary to promote all of these [inaudible 00:03:02] body and brain functions.

03:05: That's where I really started getting into that, and it became my passion, and that passion really solidified in my postdoc working with Matt Walker, because there was this huge literature on sleep and memory, and at the time that I started, there wasn't really that much work on sleep and memory and aging. Since then, I think that field has exploded, and there's a lot of really exciting work in that area. It just became my passion, but my passion is sleep, more broadly, and how it's related to brain functions, and aging's just a great focus for that work, I think. A really necessary one.

Dan Pardi - 03:43: That's interesting. My interest parallels yours, Bryce. I can't say that I was interested in sleep since high school, but as soon as I started to work in the field, my interest grew rapidly. Sleep provides a window into how to understand the inner workings of the body, and by understanding sleep better, we understand how the body works in general. How do we develop and perform across the lifespan? I have a similar fascination with the subject, and thank you for sharing your story.

Bryce Mander - 04:10: Sure.

Dan Pardi - 04:11: I must admit my interest in aging science is more recent, but I'm feeling a similar degree of motivation to get to know the details of the subject fluently. There's just so much potential again to understand how the body works, and by understanding aging mechanisms, of course, we can better understand how to affect these mechanisms so that we can age better.

Bryce Mander - 04:33: Yeah, it's very exciting.

Dan Pardi - 04:35: What are some ways that sleep changes as we age?

Bryce Mander - 04:40: In just about every way you can measure sleep, there's some level of change with age. If you start at the most gross level, the amount of time that they spend asleep every night, that generally shrinks. If you think about its organization and its structure, the amount of time in any given sleep stage is changing. Usually the deep non-REM sleep, slow-wave sleep, is reduced as people get older, and I'm talking right now on a population level. We may spend more time in lighter non-REM sleep, and your sleep will become more fragmented. You'll have a lot more awakenings at night. You'll have slightly longer sleep latency. You'll have a harder time falling back asleep again.

05:27: And in addition to that is some very fascinating ... There are some papers that showed that the organization and the predictability of going from one sleep stage to the next also changes. So it's almost like this controlled and very stereotypic pattern of going through all of the different stages of non-REM up into REM, and non-REM up into REM, throughout the night. These cycles that we expect to see when we study sleep becomes harder to predict in older adults. You may go from two to stage three non-REM to back to two, maybe to one. Maybe go down back into two and three, and then maybe go back up to awake. And so, you're just going back and forth, and it's harder to predict, and it's more disorganized.

06:09: That, in a nutshell, is the gross measures of how sleep is changing, but if you look at the micro-features of sleep in the EEG, that also changes rather dramatically. You can get as much as a loss of 80% of the intensity of your deep slow-wave sleep. The number of these characteristic brain rhythms in sleep, slow-waves and sleep spindles, they'll disappear, but in a very topographic specific manner. There's these changes in the micro-features of the EEG. There's changes in how predictable and how consolidated that sleep is and changes in the amount, and one of the big mysteries has been why, and is there a unitary mechanism behind it or are there disparate, different mechanisms behind it? That's something we tried to tackle in our review, but there's just a lot more work that needs to be done in this area. That just became clear to me.

Dan Pardi - 07:12: Does it happen uniformly, at the same time, to the same degree, in all people?

Bryce Mander - 07:17: Yeah. Yeah, Well, that's great. I mean, for example, there's some ... Gender, I think, is a great example of that. You have these giant studies of thousands of PSG's recorded in people from ages 30's to their 70's. You look at men and they have 10-15% of their sleep is slow-wave sleep when they're in their 30's and then less than five in their 70's. In women, you have a pretty consolidated, stable 15-17% across the 30's to the 70's. That just blew me away reading about that, that there was such ... I mean, I always knew there was a gender difference in sleep that emerges with age, but I had no idea how massive it could be. And why? And what does that mean?

08:06: Maybe the answers to the question, "Is sleep relevant for your cognitive functions as you get older?" Maybe that depends on things like gender or individual variability or some of these other factors. And so, there's this huge variability between individuals, and I think some really great researchers have really tried to make that point that if you get older, sleep disruption and poor sleep quality is not inevitable, just like memory problems are not inevitable. There is a successful way to age. It's just figuring out scientifically what the path to that is. And that's really going to be the Holy Grail in this work, I think.

Dan Pardi - 08:50: It speaks to why we do these shows in the first place. The science is always interesting in and of itself. The tools and the techniques and the questions that are asked on how to get at finding answers, but ultimately it's to understand it well enough so that we can figure out ways to make more people have better sleep as they age, in this case. We know that there are super-agers, the people that tend to age well, sleep well. Tell us a little bit about the characteristics of sleep in this population.

Bryce Mander - 09:17: I don't think that that population's been characterized well enough. But what I do know is that if you tend to be someone who is cognitively with it and sustaining your mental functions, you tend to be the person who has higher intensity slow-wave sleep, has sleep more rich in spindles. You tend to have more consolidated sleep, and you tend to not have medical co-morbidities. That's another thing. You have to be generally healthy, because, really, one of the biggest factors that predicts or explains sleep disturbances and sleep disorders is the presence of other medical conditions that can also impact it, which then are impacted by it as well. It becomes a vicious cycle.

10:01: But, say, for example you take people that were the quiz show memory people. The people that have the memory that they can remember 30 years ago all the ingredients on a package of a burrito they microwaved. Those kind of people, their sleep is probably special too. I haven't looked at that much. I was able to collaborate a little bit with Ken Paller, and I think that was part of a study that Craig Stark was doing, actually, at Irvine. I looked at a few records of those that they had worked up and tried to compare that to some of our subjects, and it looked like they had a lot of spindles, more than young adults.

Dan Pardi - 10:42: Oh, wow.

Bryce Mander - 10:43: I don't know where that research is going to go. It was only a couple of people, but if that holds up, that would be fascinating. There might be something genetically different or developmentally or epigenetically different about certain individuals. But one thing it really hammered home to me is how connected these functions are. These functions of memory and sleep, that you would see profound changes in memory and that that would go with corresponding sleep changes, it's just incredible. But, to really answer your question, I'm not sure we know enough about it, but it seems to be stable, healthy sleep is one of the key components.

Dan Pardi - 11:19: Before we get into different ways in which we can manipulate sleep in order to facilitate healthy sleep across the lifespan and to enhance functional sleep components at any stage of life, let's first talk about the connection between sleep and neurodegenerative pathologies like Alzheimer's disease. To start, what is Alzheimer's disease?

Bryce Mander - 11:43: Alzheimer's disease, it is the most common form of dementia or neurodegenerative disease in the population. As we've increased the lifespan over the last 100 years, it has become much more prominent, particularly its late onset form, which is much more common than the early onset. It is very, very much predicted by age. The older you are, the more likely you are to get it. It's tied to two key signature pathologies but, of course, the disease itself is much more complicated than that. The two defining pathologies are something called neurofibrillary tangles and amyloid plaques. These are very specific proteins. One, which builds up extracellularly, is a transmembrane protein, which is clipped in a very specific way and forms little groups, and they can become very neurotoxic. That's amyloid. The tangle is intercellularly, it's a axonal filament that can get all twisted up and cause a neuron to not be able to communicate. It's very tied into neuro-degeneration.

12:55: These two proteins are thought to collude, and as they build up in the brain, they're thought to really just erode the brain, particularly in posterior and temporal regions of the brain, and then later spreading through the entire brain, ravaging the entire brain, leading to all kinds of the impairments that we see in movies like Still Alice. You know, where you see the loss of the ability to form new memories followed by the loss ability to remember older ones and recognize people you've known for years. It's a very tragic and debilitating disease, and I think it's probably one of the biggest public health, personal, and economic challenges of the 21st century is figuring out how to deal with this, because we have a healthy aging population that's getting bigger and bigger. You know, it's one of the biggest diseases that's still there, and we've made, unfortunately, relatively little progress on it, in terms of treatment.

13:53: There's been a lot of clinical trials, a lot of failed clinical trials, and there's been a lot of anxiety and unease in the pharmaceutical industry, I think, to how much more money we're gonna drop into this sinkhole. Because it is kind of like a lottery. You get the drug, and then you're gonna make a lot of money, and you're going to help a lot of people, but it's hard to figure that out. It's a complex disease involving a lot of different processes.

Dan Pardi - 14:22: Yeah, I've been following Dale Bredesen's work, former CEO of the Buck Institute. He talks about, there's probably 30 different paths in order to get Alzheimer's disease. It's not one condition, and there probably will never be a single drug that will be the silver bullet, if you will, to solve it because there's a lot of different entry points. I hope that we will make some advances from the pharmaceutical front, but I think that the lifestyle approach holds more promise to me, in my opinion, at this point.

14:47: The prevalence of Alzheimer's disease has risen, and that is partly due to the increase in population size along with increases in mean life span. So, we have more older people, but do we know if the occurrence of Alzheimer's disease is happening at an earlier age also?

Bryce Mander - 15:05: You know I don't know, actually, if it's getting younger, per se. If you look at the short-term scale, the incidence of Alzheimer's disease is actually going down slightly, and part of that is because there's been a huge push for improvements in cardiovascular health in the population public health perspective. There are some recent papers showing that, actually, if you control for just the size of the population, then the incidence is actually going down. And, you know, there's fewer people smoking than there used to be. There's fewer people engaging in as unhealthy behaviors. A lot of people care about their heart health now more than they used to. And so, one thing we know is that cardiovascular problems and strokes and white matter generation from strokes all interact with the pathology of Alzheimer's disease to make their symptoms more severe and make it more likely to emerge. So, that is one of the factors that's having a play on it.

16:10: And my understanding is not that it's necessarily been getting younger — you're more likely to get it younger and younger — but, it's certainly there's a lot more people getting it, just because you know the population makeup is not a pyramid, really, anymore. It's moving to the shape of a pillar. And so, you're just getting more and more old people, because we're living longer and longer.

Dan Pardi - 16:33: If the mean age of Alzheimer's disease is occurring earlier, and poor sleep is causative to its pathogenesis, then that would signal that our sleep is degrading as a society. Maybe due to increases in artificial light at night, poor sleep hygiene, etc.

Bryce Mander - 16:49: Yeah, well, maybe in 10 years we'll find evidence of that. It's just not enough time has passed, I think, and one thing we always need to remember is someone in their 30's may use a lot of time on the computer late at night, but at least I know my grandmother doesn't tweet out at two in the morning. Of course, some older people do.

Dan Pardi - 17:14: She's more a fan of Instagram. Is that right?

Bryce Mander - 17:16: Yeah, that's right.

Dan Pardi - 17:17: Yeah, right, exactly. Okay, so let's talk a little more specifically about the connection between Alzheimer's disease and sleep because that has been made, and that's a lot of the work that you guys are doing. What do we know about people that have Alzheimer's disease? Do they have sleep disturbance?

Bryce Mander - 17:33: Oh, yes. Oh, do they. We've known that for a long time. Back from the classic studies by Prinz, we've known that their sleep, in many ways, in some ways is a more exaggerated form of the sleep disturbance you see in older adults. Their non-REM sleep is even more disrupted than a cognitively healthy older adult. But they also have other sleep disturbances that aren't common in aging.

17:59: One example of that is REM sleep, is something that typically you see changes in non-REM sleep starting to emerge in the 30's and the 40's and 50's. REM sleep, duration changes at least, you don't really see in the healthy populations until their late 60's, 70's, 80's maybe. But, what if you have mild cognitive impairment? If you have Alzheimer's disease, if you have some other form of dementia, we typically can see changes or alterations in REM sleep, and it becomes profound, and that's one way in which people are trying to separate groups and say, "Hey, look, you can look at abnormalities in REM sleep and predict who's got mild cognitive impairment versus not; who's got Alzheimer's disease, who's not; who's at risk for developing, say, Parkinson's disease or at risk for developing Lewy Body Dementia or even Alzheimer's disease.

19:03: So, there are different ways that people have looked at that and, traditionally, the view had been these dementias, and the pathologies associated with them, are ravaging the brain, and it just happens to hit these sleep centers and is destructing their sleep, and it emerges as the disease progresses, and it's more of a symptom rather than any sort of causal part of the picture. But, a lot of work just kept showing over and over again that these relationships between sleep staging or spectral intensity measures of sleep, or just general markers of sleep stability and consolidation were actually padded to the pathologies even before you get mild cognitive impairment, even before into to dementia stage in terms of diagnosis. And so, it's happening really early.

19:52: In fact, in our one of our recent studies, we showed that just the burden of amyloid pathology in healthy people, they had no gross neuro-psych cognitive impairment. They were just going about their days doing their normal things, that the burden of that was linked to very specific changes in non-REM sleep quality itself. So, it's happening at the very initial stages, I think. A lot of the animal work coming out of David Holtzman's group at Wash U, for example, is showing in these animal models that sleep disturbance is associated with the increase in the propagation and production of these proteins, which is tied to an increased amount of time awake and a more active brain, essentially. And then in another group, [inaudible 00:20:43]'s group, showing that sleep, [inaudible 00:20:45] sleep specifically is associated with the clearance of some of those proteins to get it out of your brain. It shows that sleep is not just a symptom. It's not just an output, that it's tied to pathophysiology of the disease itself.

20:58: [inaudible 00:21:00] looked at all the processes that are associated with the production of the proteins themselves, so that has been a new picture that's emerged over the last, I'd say, 10 years. We're still characterizing all the relationships, and we still know very little about tau pathology and sleep, but there seems to be some kind of link. Whether it's a different link than amyloid or not is something that remains to be seen, but it's an exciting story, I think.

Dan Pardi - 21:26: Tell us about the glymphatic system.

Bryce Mander - 21:29: So, the glymphatic system was recently discovered, and this system is, the researchers that were looking into this were trying to solve the problem, "How does the brain clear waste?" Because it doesn't have the same lymphatic system as the rest of the body does and its structure, the original theories were, "Oh, it just diffuses." But that's so inefficient going through tissue, so they actually looked at these animal models, and they found that during certain states — not to give away too much — during sleep, the size of these glial cells shrinks, and then the veins to the arteries ... There's these smooth muscles start rhythmically, essentially, pumping and flushing CSF through that space, kind of like you're power-washing the brain, and it takes with it all kinds of toxins, which then are then cleared. It's thought that this is a way to keep the brain from having too many neurotoxins or too much waste built up, which can then ultimately impact the brain. So, it's the waste clearance system. And it turns out that it's most active when the brain is in deep non-REM sleep.

Dan Pardi - 22:46: Let's talk a little bit more about that stage of sleep. Characterize it for us.

Bryce Mander - 22:50: Okay, so, deep non-REM sleep. This is a state where your brain functions very, very differently than it does when you're awake. Normally when you're awake, your neurons are firing in very organized fashion in circuits that are tightly controlled. If you measure the brain in its activity, it looks like it's very low-voltage mixed frequencies. In other words, the wave forms are really short, and they're really, really fast, and they're modulated based on what your brain is cognitively or emotionally focusing on.

23:28: In non-REM sleep, it looks very, very different. You have, essentially, this controlled state of post neuronal activity and neuronal silence, and so, you get these lazy slow brain waves called slow waves, which is on a scale of slow seconds, you see periods of neuronal silence and then periods of synchrony of firing, and it's thought that these up states where they all fire together can be associated with things like neural plasticity or down-scaling or secretion of certain hormones, a lot of different things. But this is a very, very different brain state, and in this brain state is one where if you wake someone up from it, it's so different from a waking brain state that you can feel groggy and not awake as your brain transitions to a normal brain wave state. It's called sleep inertia.

24:27: David Dinges, who is one of the biggest psychometric and neuro behavioral performance specialists in the world in relation to sleep and sleep loss, has said that sleep inertia's impairment in cognition could be greater than, or as great, as 88 hours of sleep deprivation. It's just profound. It just shows that it's such a different brain state, it's just such a different brain state.

Dan Pardi - 24:51: What else is happening in that state that is important for our discussion on Alzheimer's disease?

Bryce Mander - 24:59: That's a good question. During that state is when we think that the glymphatic system is most conducive to clearing these proteins. So, that's that's one other thing particularly relevant to Alzheimer's disease. The other thing that might be relevant too is that there is this whole other literature trying to link epileptic activity to the machinery of slow waves themselves and how epilepsy can hijack that, and facilitate the expression of abnormal rhythms in propagated waves. It's thought that these waves actually kind of propagate and release things like calcium waves and change, essentially, the function of neurons around them. One of the things that's a new emerging idea is that Alzheimer's diseases, and particularly that related to amyloid itself, is associated with the increase of epileptic-like spiking.

26:02: And one thing that's interesting is you sleep-deprive flies, for example ... This is all from the Woo lab, which has done great work on Alzheimer's disease in flies. If you sleep-deprive these flies, they're more likely to have these epileptic spikes and more likely to build up more pathology. That's something that I think needs more focus on it, is how those two are tied to sleep and slow wave sleep in general. There's a recent paper that came out showing that if you have childhood epilepsy, you're actually more likely to get amyloid pathology later in life. So, there is some interesting connection there. But, the main focus right now in non-REM sleep has been how it's related to the glymphatic system itself.

Dan Pardi - 26:48: The vicious cycle, let's discuss that as well. So, the medial prefrontal cortex is partly responsible for generating this certain type of slow wave sleep, and it seems like that part of the brain is particularly susceptible to accumulate these protein aggregates?

Bryce Mander - 27:05: Yeah, it turns out that it seems that there are essentially medial parts of the brain, in the frontal part of the brain and then back in the posterior part, called the posterior cingulates and the precuneus, are amongst the earliest cortical regions to develop these amyloid plaques. And it's thought that the amyloid in the medial prefrontal cortex is particularly early in the process, and so that happens to be where a lot, or most, of the slow waves in the brain are generated, particularly the really slow ones.

27:36: It seems like a collusion of unluckiness. You know? You have this pathology, but then there's probably a reason for it, structurally. I mean, slow waves tend to be generated in areas that are highly interconnected with other parts of the brain, and it kind of make sense that it has to do with synchrony and firing. Right? You'll want something that's connected to a lot of things to fire in time. And it turns out that also happens to be where you get these amyloid plaques building up.

28:06: And, there's this idea, this theory called local sleep, where the more that you work certain neurons — and I personally think particularly if that involves plasticity — you're going to be more susceptible, your neural system that's really being driven hard, is gonna be clinically tired. And so someone, Tononi at Wisconsin, has been talking about this local sleep idea and how it's relating to the function of these neurons, and there's new ideas relating to how that might be explaining, at a local neuronal level, whether or not your neurons just kind of collapse into this micro-sleep state relative to the tissue around them.

28:48: And so, there's this idea that sleep is not always global. It's not always the entire brain that sleeps together, but there are certain parts that might be islands where they're asleep or wake at any given time. If you're driving these neurons really hard, they're going to need more of this deep sleep to be restorative. Like you were saying earlier, there's the whole cellular restitution hypothesis that these cells need slow wave sleep to restore themselves, to repair themselves, to repair the damaged DNA that goes on with oxidative stress in a very active neuron or cell. By having a more intense sleep, you're better able to restore that. You might be the place that's really generating a lot of these rhythms might be the place that's really challenged and stressed and active all the time.

29:37: There's a lot of evidence that these medial prefrontal areas, one node amongst many in this network called the default mode network, which tends to be active a lot because ... And it's called the default mode network because if you have someone in an MRI scanner, you're looking at brain activity, you don't [inaudible 00:29:57]. These are the areas that keep coming up as being active again and again and again. A lot of people have theorized that those brain regions are associated with rumination or internal thoughts or internally-generated processing. People spend a lot of their time thinking about their memories, or the past, or how something affects them personally and all that, so they're very active, and they're very plastic and adaptable, so they may need more sleep, but because they're more active, they may also build up more amyloid. Because that's the idea is that more the neurons are active, and I think particularly if they are plastic, the more likely they are to be building up these proteins. And so, they kind of collude together.

30:40: It's almost like the neurons are saying, "I'm really taxing myself. I'm really pushing myself here, guys," and one of the negative byproducts of that is the pathology is building up. The brain's response is, "Let's just really make that part of the brain sleep really, really deeply." So, they're kind of working against each other.

Dan Pardi - 31:00: So, for the listener, as Bryce said, the default mode network is this interacting group of brain regions whose activity highly correlates with each other, and is distinct from the activity of other brain regions like attentional networks that help you focus on something specific.

31:18: The best way for me to grasp what the default mode network does, or facilitates, is that this is the network that is active when you daydream or when your mind wanders. And interestingly, I'm thinking about this for the first time, but there are a few things that have shown to deactivate it, like acupuncture and, specifically, meditation. In fact, Karen Fox of the University of British Columbia did a meta analysis that found reduced activation and reduced functional connectivity of the default mode network in long-term meditation practitioners. My thought is, if you are reducing activity of the default mode network through regular meditation and are thereby reducing the buildup of usage-dependent substances, are you reducing the risk of acquiring Alzheimer's disease via two ways? Reduce pressure to produce an accumulate amyloid beta, and secondarily improve sleep by better stress regulation and via reduced amyloid burden in this sensitive area that is generating slow wave sleep.

Bryce Mander - 32:19: That's a great idea. I think that there's indications of that. I think we need work on that. I think we need studies on that. What I do know is that there is evidence that forms of meditation can profoundly help people with insomnia, whether they're old or not, and they tend to have a dramatic change in their subjective ratings about how restorative they feel their sleep is. That's an example. Well, maybe. Because we know that insomnia is a risk factor for dementia. Right? And so, if you're able to target and improve insomnia, then you're theoretically going to be able to decrease your risk for dementia. I think that would be a great grant. I think that would be a great study to do, a great series of studies to do, definitely.

Dan Pardi - 33:15: I remember Eric Noffsinger came and gave a presentation to the Stanford grand rounds, probably in 2004. This was a long time ago. But there, he talked about work he had done in insomniacs were he used FMRI to image brain activity, and he found that the people that had insomnia didn't often experience clinical changes in PSG, which is the common way sleep is measured, so polysomnography. But, when they use this other technique brain imaging, they found that there was this hyper-frontality during sleep. So there was a higher than usual activity in the frontal area, which is the area we're talking about, which accumulates protein because of its high usage. It's not resting during sleep as much as it should, you would think that would correlate with earlier occurrence of Alzheimer's disease, exacerbation of the condition, and the statistics say that it does.

Bryce Mander - 34:10: Noffsinger's data is so fascinating. And it really changed the game, I think, when we started putting out those data, because before that, people had that ... They have this term for it. They called it sleep state misperception. Right?

Dan Pardi - 34:27: Right.

Bryce Mander - 34:27: And it's this idea that people say, "I'm not sleeping well. I'm sleeping terribly. I'm up hours of the night," and then you bring him into the lab, and this gold standard for measuring sleep for decades and decades and the polysomnography shows, "Hey, look, your sleep looks pretty similar to some other average John Doe who has no problems, so you're just misperceiving your sleep." And we need to understand why that it is and what that means and target and focus on that.

34:59: But what we measure and how we measure depends on the tools we use. These data really convinced me that we were just not measuring everything. We were not measuring that, sure, they may be in slow wave sleep, but their slow wave sleep is not as deep and not as restorative. And there's even some people who said, "Well, if you look at the spectral quality of their slow wave sleep, overall it looks the same, but how it changes across the night might be different, and that may be another example of that." It's something we always have to do, I think, as researchers and clinicians, is really question our assumptions.

Dan Pardi - 35:44: To summarize, we know that poor sleep is not only a symptom of people that have mild cognitive impairment and Alzheimer's disease, but it's now thought to be a potential cause, and the evidence is accumulating that that is in fact true. We also know that we lose slow wave sleep as we age, and there are some differences between men and women with how that occurs, but there's also new research that's looking at how to enhance slow wave sleep. And so, I have a particular interest in how to keep sleep healthy across the lifespan, but I'm also really interested in technology and how we can now utilize transcranial direct current stimulation, which you're seeing more and more of those devices come onto the marketplace, whether it's lifestyle hygiene — regular physical activity, circadian alignment, the right diet — but then also things like auditory stimulation, playing pink noise that's phase-locked with certain components of slow wave sleep, and maybe even aromas. Tell us about some of these technologies. What's some of the critical questions are that need to be solved, but what's the potential of this entire area?

Bryce Mander - 36:50: I think there's enormous potential in this area. The main real thing we really need to do though ... All those technologies you mentioned, I think, are really just fascinating avenues to pursue. In addition to the transcranial direct current stimulation, there's now transcranial alternating current stimulation for sleep spindles, which has been shown to be important for cognition and particularly motor memory. And so, there's a lot of different ways you can stimulate the brain. The big thing that's really missing from that field, I think, though is the positive results from a large, double-blind placebo-controlled studies.

37:36: That's what we really need because a lot of these are promising results from small-scale studies, where you can take, for example, transcranial direct current stimulation. That's the one that probably has the most data accumulating around it, outside of, of course, pharmacological studies, which is another avenue. That has shown a lot of ... There's been some failures to replicate in that literature, but there's been successful replications in a number of different patient populations, including epilepsy, actually, where you would basically enhance the quality of slow waves and make them deeper, taller, and more intense, particularly in the frontal part of the brain. Then it results in some memory benefit in these populations relative to when they don't get stimulation but they think they did ... So the Shane stimulation studies. There's been a number of these smaller studies that have shown that, and there's now at least two studies that have done that successfully in older adults.

38:45: This is another part of the literature, and I think is important, because not only is there this view that older adults need less sleep versus maybe their brain is less capable of producing sleep, there's also a debate, "Is sleep-dependent memory gone in older adults?" And a lot of that literature is tied to just an enormous number of studies that show a mixed mix literature.

39:10: There's a lot of studies that show negative associations, positive associations, or no associations with these neuro-psych variables of memory and gross sleep stage measures. This literature has been reviewed very well by this professor at Baylor now, Michael Scullin, who went through like five decades of research and then looked at this and said, "Well there's so many studies where we don't see in effect in the older adults, or they're just not associated, but we see it consistently associated in young adults." And his interpretation of the literature was a reasonable one, was that, "Well, maybe older adults, their sleep dependent mechanisms are eroded away, and they're gone." But, there's a lot of other possible explanations for that too.

39:57: There's the possibility that that's true in some older adults but not others. There are certain factors, like structural changes in the brain, or functional changes in the brain, that may make some individuals lose that more than others. There's also, it depends on the test you're looking at. Is it declarative or procedural? Becky Spencer's work has shown that there's a profound impairment in motor procedural learning in older adults, but that there's still a lot of strong, robust relationship between declarative memory and sleep in older adults. Then there's also, are you measuring sleep stage, or are you measuring these actual brain rhythms themselves, the slow waves, their intensity, how many there are? Are you measuring the ones that are most tied to the memory, the really slow ones, slow slow waves for example, that are being stimulated with these technologies you're talking about.

40:55: I think it's really important that these technologies are showing that in older adults, at least in these smaller studies, are getting a memory benefit. So that to me argues that, well, it's not gone. It may be weaker. Its effect size may be smaller, but it still can work.

41:14: This effect has been replicated with that auditory stimulation, which I think is very exciting because it's completely non-invasive. The other thing that really hasn't been done, we don't really know the answer to, is what if you did this for a long time? Most of the studies are, you do it for a day and you show improvement in memory, but what you really care about is keeping an older adult to successfully healthily in terms of their memory and their cognition for years. Right?

41:43: It's kind of like the drug trials. You have them do a drug, maybe they'll show a short-term benefit, but we want to really know it's safe to use in the long-term. And it's hard to do studies past a couple of years just because it's so expensive and grants are usually short-term scale. So I think those types of questions still need to be answered, but I think that literature is very promising and it just needs you know bigger-scale reputation, longer term follow up ... I'm particularly excited about the acoustic stimulation. It seems to foster not only the intensity of these waves but also how they couple with spindles, and that's the coupling of the slow waves and spindles that's thought to be the true mechanism that promotes memory, not just one brain rhythm getting more intense, or another one getting more intense, but actually how they coordinate together to transform memories in the brain.

42:37: So I think that's exciting. I do want to just say real quickly, I think exercise is an exciting research area in this, and then there's been some great work showing that the exercise benefits of memory or specifically to sleep as a mediator that. [inaudible 00:42:57] And pursuing that more, I think it's going to be really critical.

43:00: And lifestyle factors are important. And it seems to be that it's not just that all of these negative factors collude with sleep disturbance, but all these positive- like healthy diet, healthy sleep habits, healthy exercise habits collude together, I think, to improve cognitive health.

43:21: And I'd love to hear more about the diet-sleep connection too. I think that's another [inaudible 00:43:26] that needs more work.

Dan Pardi - 43:28: To give people a little bit more detail about some of the things that we are discussing here, Natalie Papalambro's study at [inaudible 00:43:36] lab where you worked, the recent one that came out in Frontiers of Human Neuroscience, they took 13 older adults that were 60 years or older, and they gave them this one night of acoustic stimulation, and one night of sham, as you're describing. And what they found is, when they were able to do this phase-lock, where they could play the acoustic stimulation at the right time, that they were able to triple memory retention in the morning compared to the control [inaudible 00:44:02] If I'm correct, I believe this sort of effect has also been shown in younger people as well, so it's not exclusive to people that might be suffering from some degree of memory impairment, but might be consistent across ages.

44:14: Tell us a little bit about the phase-locks. So, could you just play pink noise, let's say, from when you went to bed when you wake up. Would that have a benefit?

Bryce Mander - 44:23: I don't really know, because then you're talking about pink noise no matter what sleep stage you're in. People tried something similar to that in non-REM sleep, because there's this view of, "Can you entrain the brain's rhythms to your pink noise?" That's been the older technologies, the stuff coming out of [inaudible 00:44:41] group in Germany, has been largely designed around that idea. That they just have this one-hertz style, or point-eight hertz style pulse, you know, auditory hum, that just occurs during the deep stage of their sleep, of their slow wave sleep. And then sees, "Okay, well, the brain rhythms will just adapt to that, and then you'll get this enhancement." And they showed memory benefit from that.

45:07: What's really particularly exciting about the algorithm that [Zee Lab 00:45:11] is using is that it actually tracks the individual's slow wave profile, and stimulates based on that person's individual slow waves. And that, I think, seems to be a smarter, more robust algorithm this will probably- I mean, we would need to see the data directly comparing those outcomes I think. But ultimately, that seems to me to be a much smarter way to tackle the brain's rhythms, because then you're basically making it unique to that individual, and how their brain works and how it functions. And that allows for the acoustic simulation to fall at the rate bays of the wave of that individual.

45:50: So it turns out that the stimulation depends on what part of the slow wave you're hitting. And alongside that, in addition to that, there's evidence to suggest that when you see- you know slow waves, and sleep spindles are coupled together in time, and where the spindle shows up on the slow wave, what phase it's expressed at, usually on the rising phase to go toward the de-polarized upstate ... that's where you get the maximum memory benefit.

46:21: [Ken Paller 00:46:22] had a paper where he showed that some of his stimulation paradigms, where you're trying to trigger cues to reactivate memories to then promote retention ... the benefit of that technology depended on what phase of the slow wave [EQ 00:46:39] was hitting.

46:40: So there's a very specific time- there's a very specific relationship between these things, and it's not just enough to hit these slow waves, you've got to hit them at the right time the get the maximal benefit.

46:52: And that tells us something about how the brain functions too, just from a biological standpoint, which is fascinating.

Dan Pardi - 46:59: So listener, imagine this ... we now have quantified self-technologies where you can wear them on your body, and they can remind you to live in accordance with some of your own objectives that are informed by guidelines about how many steps to take, or what time to go to bed, and how much sleep you should aim to try to get. And in the future we're going to see more technologies that not only help you with your behaviors, but might actually enhance your physiology itself.

47:29: So you have now even the Hello device - Matt Walker's the CSO of that company. They're measuring the ambient temperature, and any sort of pollution that's in the air, along with sleep. The better you can actually detect physiological sleep stages from either a wrist-worn device, or something that sits on your bedside table, or something that lays on the mattress, then you might be able to then play these auditory signals that enhance slow wave sleep and keep it really deep and strong, which facilitates memory, which facilitates clearance of beta amyloid, potentially.

48:03: And so it really is an exciting time, and this idea that technology has interfered with our health and so many ways, but it also might very well be the solution, it's why I love what I do. Because when you see the potential here ... it's very believable to me that something like this is going to be available on the marketplace within several years.

Bryce Mander - 48:22: I think that's true, yeah. It's so human that we take an impediment and turn it into an advantage. That's really exciting. Technology is a great example of that.

Dan Pardi - 48:35: Brilliant work, life changing, world changing work. You did a great job articulating it to our audience, so thank you for taking the time, and we really appreciate you coming on to Human Noise Radio.

Bryce Mander - 48:47: Thank you, my pleasure.