睡眠大师课

很好，谢谢埃里克邀请我。

Great, thanks Eric for inviting me.

我非常兴奋。

I'm super excited.

是的。

Yeah.

那我们直接进入主题吧，睡眠与神经退行性疾病，特别是阿尔茨海默病之间的联系。

So let's get right into the topic, the connection between sleep and neurodegenerative disease, particularly Alzheimer's.

你对它们如何相互关联的整体看法是什么？

What's your overall perspective about how they come together?

嗯，我认为至少我所了解的，睡眠与神经退化在两个大领域存在交集。

Well, I think there's two broad areas, at least that I'm aware of, in which sleep and neurodegeneration overlap.

一个是阿尔茨海默病，以及睡眠或昼夜节律紊乱如何可能与早期阿尔茨海默病病理形成双向关系——我们当然知道，一旦人们患上阿尔茨海默病痴呆，就会出现非常高的睡眠问题发生率。

One is with Alzheimer's disease and how sleep or circadian disruption, may, have a two way, direction with early Alzheimer disease pathology, where we know obviously once people get Alzheimer's dementia, they have a very high prevalence of sleep problems.

但我们现在知道，即使在临床前期，也就是尚未出现任何认知症状时，人们也可能通过多种方式检测到睡眠障碍。

But we now know that even in the preclinical stage, meaning prior to any cognitive symptoms, people may have sleep disturbances that are detectable through a variety of means.

此外，有一些证据表明，睡眠紊乱可能会促进或加速阿尔茨海默病相关蛋白（如淀粉样斑块和tau蛋白缠结）的积累。

Also, there's some evidence to suggest that having sleep disruption may promote or speed up the buildup of Alzheimer disease related proteins like amyloid plaques and tau tangles.

因此，在过去十五到二十年左右，大量研究数据开始出现，尤其是霍尔茨曼实验室在华盛顿大学进行的小鼠研究，深入探讨了睡眠与阿尔茨海默病相关蛋白之间的相互作用。

So in the past, say, fifteen, twenty years or so, there's been a lot of data, starting with mice in the Holzman lab here at WashU, that have really looked at the, interaction between sleep and, Alzheimer disease pro proteins.

随着时光推移，以及阿尔茨海默病生物标志物领域的发展，我们如今也在人类身上获得了越来越多的类似数据。

And, I think, as time has passed and as the biomarker field, in Alzheimer's disease has, advanced, we're getting more and more of these data in humans as well.

因此，这是我认为我们许多人非常关注的一个重要领域。

So, so that's one, large area that's I think of concern to many of us.

另一个睡眠与神经退行性疾病高度重叠的领域是突触核蛋白病，这是一组包括帕金森病、路易体痴呆和多系统萎缩的疾病。

The other area in which, sleep and neurodegeneration overlap a lot is in synucleinopathies, and this is a group of disorders that includes Parkinson's, dementia with Lewy bodies, multiple system atrophy.

我们知道有一种特定的睡眠障碍叫做快速眼动睡眠行为障碍，患有这种睡眠障碍的人在未来五到十年内被诊断为这些突触核蛋白病的风险会显著升高。

We know that there's a specific sleep disorder called REM sleep behavior disorder that, people who have that sleep disorder are at heightened risk of being diagnosed with one of those synucleinopathies, within five, ten years.

因此，我们知道睡眠可以作为一种信号，有时甚至是非常具体的信号，提示大脑中可能正在发生神经退行性过程，而这些过程在症状出现之前就已经存在。

So we know that sleep can be a signal and sometimes a very specific signal as to neurodegenerative disease processes that may be ongoing in the brain well before symptoms occur.

好的。

All right.

那么，你把两种最重要的神经退行性疾病——阿尔茨海默病和帕金森病——联系了起来。

Well, so you made the link between the two most important neurodegenerative diseases, Alzheimer's and Parkinson's.

但就机制而言，这真的与深度睡眠、睡眠的慢波阶段有关，还是与其他睡眠阶段也有关系呢？

But regarding the mechanism, is this really related to the primacy of deep sleep, the slow wave portion of sleep, or is it really other phases as well?

我接受过睡眠医学的训练。

So I'm a sleep doctor by training.

我认为非快速眼动睡眠和快速眼动睡眠都很重要。

I think that non REM sleep and REM sleep are both important.

你知道的吧？

You know?

它们就像我的孩子一样。

They're like my children.

对吧？

Right?

这些都很重要。

These are important.

但就淀粉样蛋白和tau蛋白而言，我们认为重要的是慢波睡眠，也就是非快速眼动睡眠的深层部分。

But, when it comes to at least amyloid, and tau, we think that it is the slow wave sleep, which is, the kind of the deep part of non REM sleep that's important.

我们实验室做过一个实验，专门探究睡眠的哪个具体阶段与淀粉样蛋白有关：我们让受试者在至少一个月间隔的两个晚上前来实验室。

One, experiment, that we did in my lab to really drill down into which specific part of sleep is linked to amyloid is, we did a study where people came in and spent two nights at least a month apart.

我们设置了一个闭环系统，当他们入睡后，我们会监测他们的脑电波，一旦他们进入深层慢波睡眠，系统就会通过耳机发出轻微的‘哔’声。

And we set up a closed loop system where, you know, after they fell asleep, we were reading their brain waves, and there was an automated system where once they started getting into deep, slow wave sleep, they would get a little beep through headphones.

这个‘哔’声每十秒会逐渐变大，直到将他们从深层睡眠轻轻推入较浅的睡眠状态，但不会完全唤醒他们。

And this beep would get louder and louder and louder every ten seconds until it nudged them out of deep sleep into lighter sleep, not waking them up fully.

我们在一个晚上进行了这种干预。

And, we did that one night.

而在另一个晚上，我们进行了对照实验，没有干扰他们的慢波睡眠。

And then on a different night, we did a sham condition where we did not, deprive their full weight sleep.

在这项研究中，我们发现，通过次日早晨的腰椎穿刺测量脑脊液中的淀粉样蛋白水平时，我们抑制慢波睡眠的程度与淀粉样β蛋白的增加量之间存在明确的相关性。

And what we found out, found out in that study is that when we look at the spinal fluid levels of amyloid, right, which we measure through lumbar punctures the next morning, there's a very specific correlation between how much we're able to suppress slow wave sleep and how much amyloid beta increases.

因此，可溶性淀粉样β蛋白与慢波睡眠之间似乎存在非常特定的关联。

So there seems to be this very specific link between soluble amyloid beta and slow wave sleep.

这并不是说其他睡眠阶段不重要。

That's not to say other stages of sleep are important.

它们确实重要，比如快速眼动睡眠对记忆形成和情绪调节等非常关键。

They are, you know, REM sleep is very important for memory formation, for emotional regulation, and so on.

但当涉及到实际的淀粉样蛋白β水平时，似乎慢波睡眠是我们最应该关注的睡眠阶段。

But when it comes to the actual amyloid beta levels, it seems like, slow wave sleep is the is the main part of sleep we should be concerned about.

是的。

Yeah.

所以你已经证实了这一点，这是一组非常棒的实验。

So you've confirmed that, and that's a great set of experiments.

这非常独特。

It's quite unique.

这些参与者参加了两次睡眠研究，还接受了腰椎穿刺，我必须给他们很大的赞誉。

These people that went to two sleep studies and then had their lumbar puncture, mean, well, I give them a lot of credit.

现在，这显然引起了广泛关注，还有其他神经炎症标志物，是否有数据表明血浆中的P2 17水平会直接受到深度睡眠的影响？

Now, which obviously has attracted lots of attention, as well as these other neuroinflammation markers, are there any data to show that the plasma blood level of P2 17 is affected directly by deep sleep?

我不知道是否有人做过针对慢波睡眠的特定干扰实验。

I don't know if anyone has done the specific slow wave sleep disruption.

是的。

Yeah.

很好。

Great.

Tau蛋白磷酸化会受到某些药物的影响，比如使用DORA这种双食欲素受体拮抗剂来促进睡眠，虽然不一定是专门增加慢波睡眠。

There are, Tau phosphorylation is affected, by, for example, giving a drug to increase sleep, not necessarily slow wave sleep, but DORA, which is a dual orexin receptor antagonist.

布伦丹·卢西亚及其同事在这里进行了一项人体研究，他们给受试者服用这种药物，结果发现血浆中的Tau蛋白磷酸化水平发生了可测量的变化。

There was a human study here done by Brendan Lucia and colleagues where they gave people, that drug, and that seemed to alter the phosphorylation of tau measurable in the plasma.

在慢波睡眠剥夺实验中，我们当然有来自下一阶段的血浆和脑脊液样本，但我们尚未检测不同的血浆衰老生物标志物。

In the slowly sleep, deprivation experiment, do have plasma and CSF, obviously, from the next state, but we have not, tested the different, plasma aging biomarkers.

那会很有趣。

Well, that'll be interesting.

我们下个月将启动一项阿尔茨海默病预防试验，涉及1200名高风险人群，这些人具有高水平的p-tau217及其他相关因素。

We're starting a prevention of Alzheimer's trial next month with twelve hundred people, very high risk, with high p tau, two seventeen, and other factors.

我们将观察睡眠对您一年内p-tau217水平的影响。

And we're gonna look at the effects of sleep on your p tau two seventeen over the course of a year.

因此，我们将获得一些与您所得数据互补的信息，但这会非常有趣。

So we'll have some complementary data to what you get at, but it'd be really interesting.

我稍后想再谈谈食欲素药物。

I wanna get back to the Orexin drugs in a minute.

但关于睡眠的这个故事，其意义远不止于神经退行性疾病和健康。

But this story about sleep is much bigger than just neurodegenerative disease and health.

因为例如，我们已经看到睡眠规律性指标与心血管疾病、癌症和神经退行性疾病这三大与年龄相关的疾病之间存在显著关联。

Because what we've seen, for example, the remarkable relationship of sleep regularity, the index, and across the board, cardiovascular, cancer, and neurodegenerative, the three big age related diseases.

这种显著的睡眠关联——无论您称之为关联，还是考虑其可能的因果关系——为何能贯穿所有这些不同的疾病？

How does this remarkable sleep connection, if you wanna call it association or even if you wanna consider possible cause and effect, how does it cut across all these different diseases?

我想，我还可以把死亡率也加进去。

Well, I guess I would add mortality to that as well.

因此，全因死亡率也与睡眠的规律性和持续时间相关。

So all cause mortality is linked with, sleep regularity and duration as well.

你知道，睡眠是健康的基础，如果睡眠不足或不规律，我们就打乱了本应每天进行的清理、休息和恢复身体与大脑的过程，而这些本应占我们每天30%的时间。

You know, sleep is a is a foundation of health and I getting insufficient sleep or irregular sleep, We're throwing off what we're supposed to be doing to clean up from the day and to rest and restore our bodies and our brains that we're supposed to be doing for 30% of our time.

因此，我认为睡眠不良会导致健康状况恶化，这并不令人意外。

So it's not surprising to me that there's poor health outcomes associated with that.

我必须指出，尤其是在神经退行性疾病方面，很难区分是睡眠质量差导致了这些不良后果，还是这些疾病本身已经以轻微形式存在，并表现为睡眠问题。

I will say, especially for neurodegenerative diseases, is that it can be hard to tease apart whether it's poor sleep that contributes to those poor outcomes or whether those problems are present to a small degree and if that is manifesting as poor sleep.

所以，我认为现在越来越清楚的是，阿尔茨海默病、帕金森病以及所有类型的神经退行性疾病都有一个非常漫长的临床前期阶段。

So, you know, I think, you know, it's becoming very clear that there is a very long preclinical phase of Alzheimer's, of Parkinson's, of all types of neurodegenerative diseases.

因此，我认为一些没有长期追踪受试者的研究，当它们进行横断面分析或仅追踪几年时，可能会发现有睡眠问题的人其实已经处于疾病前期阶段。

So I think it's possible that some of these studies that have not followed people for that long, that when they are doing cross sectional analysis or following them for just a couple years, that they might be finding that people who have sleep problems, perhaps they already have preclinical disease.

所以，当我们审视这些研究时，重要的是要意识到这种关系也可能是相反的。

So I think it's important when we look at those studies that we keep in mind the possibility that the relationship goes the other way.

是的。

Yeah.

这其实很有趣，因为关于你的昼夜节律，我以前在开始监测睡眠之前，是个特别深沉的睡客。

Well, it's really interesting because this whole idea of your circadian rhythm, And that before, I was a terrible deep sleeper when I started to get it monitored.

我说，我得好好解决这个问题。

I said, I got to work on this.

那会儿我每晚平均睡眠还不到十五分钟。

It was averaging less than fifteen minutes a night.

而我做出的最重要的改变就是保持规律性，睡眠时间也因此大幅提升。

And then the one biggest change I made was this regularity, and it really jumped up from that.

当然，坚持规律作息并不容易，但它确实带来了巨大改变。

And of course, it's not easy to keep on a schedule, but it sure has made a big difference.

这和遵循我们各自独特的昼夜节律有关吗？

Is that related to keeping on our unique individual circadian rhythm?

我们的昼夜节律和睡眠系统是分开的，但它们关系非常密切。

So our circadian rhythms are separate from our sleep systems, but they have a very close relationship.

我认为昼夜节律就像是为最佳睡眠设定一个时间窗口。

And I and I think of the circadian rhythm as the thing that sets the window for your best sleep.

我们都曾飞过几个时区，对吧？

So we've all, you know, flown a couple time zones.

我们要去睡觉了。

We're going to bed.

我们感到疲倦，却无法进入良好的睡眠。

We feel tired, yet we can't get into good sleep.

这是因为我们在时差状态下没有与自己的生物钟同步睡眠。

And that is because we're not sleeping aligned with our circadian rhythms when we have jet lag.

如果我们坚持自己的生物钟，你知道，大多数人其实并没有做到，通常都是在夜间睡觉。

So if we are sticking to our own circadian rhythms and, you know, I I the majority of people aren't, you know, that off of, you know, typically sleeping at at nighttime.

如果我们每天在固定时间上床和起床，并且与我们的生物钟保持一致，这可能是我们能做的最重要的一件事，以获得良好睡眠的机会。

If we go to bed and get up at a regular time that aligns with our circadian rhythm, that's probably like the number one thing we can do to give ourselves the opportunity to get good sleep.

我要指出，通过不同可穿戴设备测量的慢波睡眠或深度睡眠，可能并不是最佳的衡量指标，而且这可能会让人感到沮丧，因为这些算法在不同设备间会变化，算法差异可能导致结果不同。

I will note that, you know, the getting slow wave sleep or deep sleep as measured by different wearables, that may not be the best metric to shoot for, and it can get frustrating because those algorithms can change device to device, differences in algorithms might, you know, might, end up showing different results.

人们其实对自身睡眠质量非常敏感。

You know, people are actually very sensitive to, the quality of sleep that they got.

所以我鼓励我的患者，或者那些来找我询问的人，当他们问：我怎么知道我睡得好不好？

So, you know, I encourage my patients or people who, you know, come up and ask me when they say, how do I know if I'm getting good sleep?

我会说，如果你早上醒来，最好是不用闹钟，而且感觉睡眠很提神，那很可能你睡得很好。

And I say, well, if you're, you know, waking up in the morning and preferably without an alarm clock, and you feel like your sleep was refreshing, you probably had good sleep.

你知道吗？

You know?

所以我认为，如果我们过度依赖可穿戴设备或其他测量方式，可能会失去感知睡眠质量的能力。

So I think that sometimes we lose the ability to sense that and to sense the quality of our sleep if we rely too much on wearables or other ways of measurement.

说到可穿戴设备，显然这里有好几种类型。

Well, while we're on the wearables, obviously there's several types here.

比如Rings，特别是Aura，非常受欢迎。

There's the Rings, particularly Aura that's got a lot of popularity.

还有各种智能手表以及床垫传感器。

There's the various smartwatches and then mattress sensors.

我的意思是，种类非常多。

I mean, there's a lot of different ones.

这些设备是否经过与睡眠实验室金标准的验证，以评估睡眠的不同阶段和其他指标？

Have they been validated against the gold standard sleep lab for the different metrics of phases of sleep and whatnot?

有些设备已经验证过，但我不确定他们在升级算法时是否每次都重新验证。

Some have, but I don't know if they revalidate every time they upgrade their algorithms.

我明白了。

I see.

是的。

Yeah.

我明白了。

I see.

总的来说，在我的研究中，我们大量使用加速度计，也就是运动传感器，我们使用的是经过多导睡眠图或睡眠研究数据同步验证的研究级设备。

In general, for my research where we use actigraphs a lot, which are motion sensors, we use research grade ones that do have concurrent polysomnography or sleep study data.

我们通常不会使用那些市面上可以买到的设备，因为根本无法确定，自原始验证数据采集以来，其算法是否发生过变化，或者在研究过程中是否会改变。

We generally don't use, you know, ones that are available over the counter, shall we say, just because we simply do not know whether that algorithm has changed, since, you know, they gathered the original validation data or if it will change during the study.

所以，我认为如果人们使用这些设备来帮助自己保持自律，比如按时上床睡觉，或者按时起床，那是非常好的。

So, you know, I I I think it's great if people use those devices to help be accountable to themselves, you know, to get into bed on time or to, you know, to get up at a regular time.

这很好。

That's great.

但我认为，人们应该意识到使用这些设备的局限性。

But I think, you know, people should be aware of the limitations of of using these devices.

是的。

Yeah.

过去几年，我一直比较环形设备、手表和床垫传感器。

I've been comparing for now a couple of years a Ring versus a watch, an Apple Watch and a mattress sensor.

只有环形设备似乎与我的感受相符，这真的很有趣。

The Ring is the only one that seems to correlate with how I feel, which is really interesting.

苹果最近才推出了睡眠评分，但它们还很初级。

And only recently did Apple introduce scores, and they were pretty primitive.

因此，正如你所指出的，评分可能并不是可靠的依据，因为算法和不同设备都会发生变化。

So the scores perhaps are not the best to rely on, as you point out, the changes in algorithms and different devices.

我现在想稍后再回到这个问题，但有人问到了睡眠评分，我觉得这是个重要的问题。

Now I want to get in come back to that in a bit, but one of the people asked about sleep scores, I think it's an important question.

但每个觉得自己睡眠不足的人都希望改善睡眠。

But everyone wants to get better sleep who feels that they're sleep deprived.

我们还想谈谈一些补充剂。

And there are supplements we want to talk about.

有一些药物通常被使用，但可能会让情况变得更糟。

There's drugs that have been used characteristically that potentially make things worse.

还有你提到的勃起功能障碍药物，我们稍后再谈，先聊聊几种补充剂，比如褪黑素、镁和南非醉茄。

Then there's the erection drugs that you touched on, and we want to get back to Let's just talk about a few of these supplements like melatonin, magnesium, ashwagandha.

这些补充剂有没有数据支持它们的有效性？

Mean, do any of them have any data to support their use?

我想我先从褪黑素说起，因为这是使用最广泛的一种。

So I guess I'll start with melatonin because that one I think is used the most.

大量荟萃分析显示，褪黑素确实有一定帮助。

There is decent data to show, you know, in large meta analyses that they do help.

我认为它只对特定人群有效。

And I believe it's in a subset of people.

这些人群是那些昼夜节律延迟的人，也就是夜猫子，他们会在目标入睡时间前两小时服用，以调整生物钟。

And those are people who have delayed circadian rhythms, meaning they're night owls, who take it a couple hours before their desired bedtime to shift their internal clocks.

它确实对他们有帮助。

It does help them.

有一项关于褪黑素治疗失眠的荟萃分析，你知道，不是针对夜猫子类型的失眠，结果显示它对这类人群帮助不大。

There was a meta analysis for looking at melatonin in insomnia, you know, not related to, being a night owl, and, it probably doesn't help them very much.

我认为很多失眠研究、药物或相关疗法的问题在于，与其他疾病相比，失眠对安慰剂效应异常敏感，即使通过睡眠研究这种金标准来测量，安慰剂的效果也非常显著。

And I think a problem with a lot of insomnia studies or drugs or things tested for insomnia is that even compared to other conditions, insomnia is exquisitely sensitive to the placebo effect, meaning even when measured by sleep studies, the gold standard, placebo has an amazing effect.

它可能解释了睡眠药物临床试验中观察到的约三分之二的效果。

It's probably responsible for about two thirds of the effects seen in clinical trials for sleep drugs.

因此，在失眠治疗中，要超越安慰剂效果非常困难。

So it's hard to beat placebo in insomnia.

所以标准非常高。

So the bar is extremely high.

但总体而言，对于褪黑素来说，它确实对有睡眠相位延迟的人有帮助，或者说是夜猫子类型的人，尤其是那些在睡前两小时服用的人。对于那些因为入睡困难而想尝试褪黑素的人，我认为尝试一下是合理的，因为它的副作用普遍比较轻微。

But overall, when it comes to melatonin, it does help for people who have delayed sleep phase or, you know, if they're night owls, particularly have taken a couple hours before bedtime, For, people who wanna take it for, trouble sleeping, I think it's reasonable to try because it has a generally, you know, benign side effect profile.

但如果无效，人们就不应该继续服用，抱着它会随着时间累积起效的错误想法。

But if it doesn't help, then people should just, you know, they they shouldn't keep taking it with some belief that it'll like build up over time and help them.

没用。

It doesn't.

对。

Right.

你知道，我觉得如果它能起作用，那就会起作用。

You know, I think if it's gonna help, it'll help.

否则，人们就可以放弃了。

Otherwise, people can throw in the towel.

那镁呢？

What about magnesium?

镁有时候有帮助。

So magnesium helps sometimes.

我觉得有些失眠实际上是不宁腿综合征的一种症状。

I think some of this is related to, some insomnia, actually being a a symptom of restless legs.

所以有些人说，他们服用镁之后，不宁腿综合征改善了。

And so, some people report that their, restless legs is better with magnesium.

所以我认为在这些情况下可能会有帮助。

And so I think it may help in those cases.

我有很多病人会服用镁补充剂。

I, you know, I have a lot of patients who take magnesium.

他们也不太确定是否有效，但还是继续服用，你知道的。

They're not quite sure if it helps, but they still take it, you know?

我认为主要的潜在副作用是可能引起腹泻或胃部不适。

I think the main potential side effect is that can cause diarrhea or stomach upset.

所以，如果不会对他们造成伤害，我就建议他们服用。

So, if it doesn't hurt them, I say go ahead.

和所有补充剂一样，如果某种补充剂效果非常好，我认为它们早就被制成处方药了。

I have not been Similar to all supplements, if they worked really great, I think they would make them prescription.

是的，确实如此。

Yeah, yeah, really.

好吧，我们稍后再讨论处方药的问题。

Well, we'll talk about prescriptions in a moment.

那 Ashwagandha 呢？或者这个长长的潜在补充剂清单中还有其他值得提及的吗？

What about the ashwagandha or anything else that is worth mentioning about on this long list of putative supplements that help?

我认为这些补充剂中，没有一种有经过随机、双盲、对照的临床试验让我真正印象深刻到它能胜过安慰剂。

So I don't think any of those have randomized, double blind, controlled clinical trials where I have been really impressed that it beats placebo.

对。

Right.

另一方面，我知道确实有些人说它对他们帮助很大。

On the other hand, I do know that some people say it has really helped them.

所以我说，如果它对你有帮助且不会造成伤害，那就继续用吧。

So I say, if it helps you and it doesn't harm you, go ahead.

是的。

Yeah.

对。

Yeah.

这确实很有趣，但你提到了安慰剂效应，因为即使在研究中你告诉受试者这是安慰剂，它仍然有效。

Well, it's really interesting, but you mentioned about the placebo effect because even in studies when you tell the person it's a placebo, it still works.

是的，这对失眠尤其如此。

Yeah, and it is especially so for insomnia.

这很好，但也不太好；不过在失眠药物试验中，通过客观多导睡眠图观察到总睡眠时间增加半小时甚至四十分钟是非常常见的。

It's great, and it's also not great for But clinical seeing a half hour or even forty minutes of increased total sleep time on objective polysomnography is very common in insomnia drug trials.

现在有一篇关于安必恩的论文。

Now, there was a paper about Ambien.

当然，这是在实验模型中，但它显示，与脑内有毒代谢物的清除相反，安必恩导致了反向流动。

Of course, was in the experimental model, but it showed that instead of the washout of toxic metabolites from the brain, Ambien led to a backflow.

也就是说，它让情况变得更糟。

That is, it made things worse.

现在大家是否普遍接受不要服用安必恩的观点？我本来就不觉得这药有多好，但它真的会让睡眠质量变得更差吗？

Is that accepted now that don't take Ambien, which I never thought was a very good drug anyway, but that it actually can make your sleep worse, quality worse?

所以我认为，总体上我们应该谨慎对待让人服用药物来增加睡眠的做法。

So I think that in general, we should be cautious in having people take drugs to increase their sleep.

因为我认为最好的睡眠是人们自己能够获得的睡眠。

Because I think the best sleep is the kind that, people can get on their own.

对。

Right.

对吧？

Right?

所以大多数人的大脑都有能力每晚入睡。

So most people's brains have the ability to fall asleep every night.

对吧？

Right?

所以如果人们有睡眠问题，需要药物帮助入睡，我认为在医疗实践中，我们有时会直接开药，而没有去探究人们为什么会有睡眠问题。

So if people are having problems sleeping where they need to they're asking for a medication to help with their sleep, I think sometimes we kind of, or in medical practice, we can jump to giving the drug without maybe looking for why people are having problems sleeping.

睡眠障碍非常普遍。

Sleep disorders are extremely common.

例如，睡眠呼吸暂停，可能你知道，百分之二十到三十的美国中老年人有睡眠呼吸暂停。

For example, sleep apnea, probably, you know, twenty, thirty percent of the American, population, Malaysia or older has sleep apnea.

但大多数开阿普唑仑或任何安眠药的医生，在开药前可能并没有筛查或检测睡眠呼吸暂停或其他睡眠障碍。

But, know, most peep most doctors who prescribe, say, Ambien or any of the sleep drugs probably are not screening for and testing for sleep apnea or other sleep disorders before they prescribe them.

所以我认为我们需要谨慎思考，这些服用药物的人究竟是谁，对吧？

So I think we do need to be cautious about, well, who are these people who are taking medications, right?

那么他们是否有睡眠障碍？

So do they have a sleep disorder?

他们是否还有其他原因导致最初出现睡眠问题？

Do they have some other reason to be having the sleep problems in the first place?

所以问题可能并不一定出在药物本身。

So it may not necessarily be the drug.

问题可能是他们最初需要或想要服用安眠药的根本原因。

It could be whatever is going on that is causing them to want or need the sleep drug in the first place.

我不认为NBB RA类药物，也就是唑吡坦所属的这类药，就一定是坏的。

I don't think necessarily, the NBB RAs, you know, the class of drugs, that, zolpidem is in, I don't think that they're necessarily bad.

你知道，如果情况合适，我会在少数患者身上开这种药。

You know, I prescribe it in, you know, in a small number of patients if it's appropriate.

但事实上，对于任何安眠药，我们都希望患者只在短期内、尽可能短的时间内使用。

But really for any sleep drug, we want people to be taking it for a on a temporary basis as short as possible.

我认为，长期或持续每天使用药物来改善睡眠，这并不健康。

I think that permanent, or never ending daily use of a drug to improve sleep, I don't think that's healthy.

好的，接下来，医疗界还没有充分意识到，尽管这类药物已经上市一段时间了，那就是食欲素类药物，如果要开药帮助睡眠，它们理论上是最理想的。

Okay, so next, the medical community isn't yet really aware, even though it's been available for some time now, on the Orexin group of drugs, which are supposedly ideally suited if you're gonna prescribe a medicine to help sleep.

你能谈谈这些药物吗？

Can you talk about those?

当然可以。

Sure.

DORAs，即双重食欲素受体拮抗剂，几年前上市了。

So DORAs, which stands for dual orexin receptor antagonist, they came on the market a few years ago.

目前有三种，分别是苏沃雷生、雷美尔通和多瑞雷克坦。

There's now three of them, suvorexant, lemborexant, and doritorexant.

它们都是通过阻断食欲素的作用来发挥作用的。

And these all work by blocking the action of orexin.

食欲素也被称为下丘脑泌素。

Orexin is also called hypocretin.

当食欲素水平低下时，就会导致发作性睡病。

When that's, when hypocretin is low, that's what causes narcolepsy.

所以，食欲素是一种促进清醒的通路。

So, Orexin is a wake promoting, pathway.

因此，这类药物属于新型助眠药，因为此前所有的药物基本上都是增强睡眠通路，而这是第一种通过抑制清醒促进通路来发挥作用的药物。

So it's a new class of sleep drug in that all the prior ones, basically, increase sleep, pathways, whereas this was the first one to tamp down a wake promoting pathway.

所以，在过去几年里，它属于一种新型药物。

So, it's a it's a new class of drug in the past few years.

你知道，与安慰剂相比，它在总睡眠时间和睡眠效率方面都有客观测量到的改善。

You know, it does have objectively measured, improvements in, total sleep time and, sleep efficiency compared to placebo.

而且，你知道，这些药物已经上市了。

And, you know, they've been available.

我认为它们的普及率不高，主要是因为价格昂贵。

I think the uptake has been kind of sold because they are expensive.

而且，在美国，我们的保险覆盖范围非常有限。

And, you know, in The US, we are very limited by what insurance covers.

很遗憾的是，当药物还在专利期内时，即使是有良好保险的人也可能负担不起这些药物。

And it is unfortunate that, you know, while drugs are on patent, it's, the drugs can be out of reach even for people with good insurance.

这些药物已经上市了，我认为这很大程度上取决于个人，有些人可能对它们的反应更好，或者与其他助眠药物或其他失眠治疗方法相比更有效。

So they've been on the market, and, you know, I think, it really kinda depends on the person, whether they respond better, or compare it to, you know, any of the other sleep drugs or other insomnia treatment methods.

但我注意到，它们通常能帮助那些说‘我就是停不下来脑子里的想法’的人。

But I have noticed that, you know, it tends to help people kind of say, can't turn my mind off, you know?

这正是问题所在，对吧？

That's the issue, you know?

没错。

Right.

但它的效果并不是百分之百的。

But, know, it's not a 100%.

和所有药物一样，它们可能会有不同的副作用。

And like all drugs, you know, they may have they have different side effects.

不过，它们确实进行了良好的临床试验。

And, but but they, they did have good clinical trials.

我很想知道，随着这些药物更广泛地使用，长期数据会是什么样子。

And I'm curious to see what the long term data look like as there's more widespread usage.

到目前为止，我认为安全性数据看起来相当不错。

So far, I think the safety data look pretty good.

但佐匹克隆和其他非苯二氮䓬类受体激动剂刚上市时，数据也看起来很不错。

But zolpidem and the other NBV RAs also looked pretty good when they came out.

这些数据的积累花了一些时间。

It took some time for that data to accumulate.

所以我很期待在未来五到十年，随着我们对这些药物的经验增加，会发生什么。

So I am curious to see what happens in the next five, ten years as we get more experienced with these drugs.

是的。

Yeah.

不，我认为这正是很多人不了解这类药物的原因之一。

No, this is, I think, one of the reasons that I think a lot of people are not aware of this class of drugs.

你提到它们价格昂贵，且不被保险覆盖。

You point out they're expensive, not covered by insurance.

你之前提到降低p-tau217这一点非常引人深思。

The one thing you mentioned earlier about lowering p tau two seventeen, that's really provocative.

我假设它们比安慰剂更能促进更高水平的慢波深度睡眠。

I assume they do promote a higher level of slow wave deep sleep than placebo.

它们还被宣传为不会成瘾或上瘾。

They also are touted not to be habit forming or addictive.

我不确定这是否属实。

I don't know if that's true.

我也不确定这是否属实。

I don't know if that's true either.

是的。

Yeah.

无论如何，人们至少应该了解它们，因为它们可能很有帮助。

Anyway, people should at least know about them because it could be helpful.

现在，睡眠困难有两个方面，不是睡眠呼吸暂停——我们稍后会讨论这个——而是入睡和维持睡眠。

Now, there's two parts to the sleep difficulty, not sleep apnea, which we'll talk about in a moment, but getting to sleep and staying asleep.

它们看起来非常不同。

They seem to be very different.

当然，你刚才提到的，Yo-El，关于思维游离和思绪飞驰的问题，这可能与两者都有关。

Of course, you just mentioned, Yo- El, about the mind wandering racing issue, which could be related to both.

你因为某些干扰醒来，然后你的思维高速运转，再也无法入睡。

You wake up for some interruption, and then you just your mind's moving at a high velocity, and you can't get back to sleep.

作为一名睡眠医学医生，你在应对这两类问题时，看法上有何不同？

Are there differences the way you look at as a sleep medicine physician about how you deal with those two categories?

是的。

Yes.

很多时候，那些入睡困难的人，可能是他们的生物钟出了问题。

So a lot of times people who have problems falling asleep, it may be their circadian rhythm.

我是个夜猫子，我非常理解并同情其他夜猫子，你们很难入睡，但一旦睡着了，就能睡得还不错。

So I'm a night owl, I have great sympathy and empathy for other night owls out there where, you you have trouble falling asleep, but once you got to sleep, you can stay asleep okay.

尤其是在年轻人中，这可能是他们难以入睡的最常见原因。

Especially among younger individuals, that's probably the most common reason why they can't fall asleep.

当人们在半夜醒来时，比如凌晨两三点或四点，那是一个非常难熬的时刻。

When people are coming in with awakenings in the middle of the night, you know, that two, three, four AM is a is a very difficult time.

这可能是每个人醒着时最焦虑的时段。

That's probably like the most anxious time, for everyone, when they're awake.

而且，如果人们已经耗尽了帮助他们在夜间入睡的睡眠驱动力，重新入睡也会变得困难。

And it can also be hard for people to get back to sleep, especially if they've used up that sleep drive that helps put them to sleep at the beginning of the night.

因此，治疗起来可能更棘手，尤其是使用药物时，因为显然你不希望患者出现残留的嗜睡反应，毕竟他们几个小时后就要起床去上班、上学等等。

So, when, and it can be trickier to treat, especially with medication, because, you know, you obviously don't want any hangover sedation because people are going to have to get up in a couple hours, drive to work, you know, be at school or, and so on.

所以，如果我们决定使用药物治疗，我们会采用不同的用药策略。

So, we, we, have kind of different medication strategies if we decide to go with medication.

但无论人们在什么时间段出现睡眠问题，我都会尝试找出究竟是什么导致他们难以入睡或导致他们醒来，以便对症处理。

But regardless of the time that people are having problems sleeping, I try to identify, well, what is actually causing you to have problems sleeping or what's waking you up to try to address that.

而我们治疗失眠的首选方法，应该是认知行为疗法（CBTI）。

And then, also our first line treatment for insomnia, it should be, CBTI, which is cognitive behavioral therapy for insomnia.

因此，失眠发生的时间其实并不那么重要。

So, it kind of doesn't matter when the insomnia is.

我们确实会尝试识别那些影响睡眠卫生的习惯，比如在一天中较晚的时候喝咖啡或摄入咖啡因。

We do try to identify, you know, the, you know, the sleep hygiene things that can improve, any bad habits people are engaging in, like having coffee or caffeine late in the day.

或者，我们会尝试找出真正导致失眠的原因，因为失眠的表现是不同的。

Or, you know, we try to identify what's actually causing insomnia because it is different.

没有一种方法适合所有人。

There's no one size fits all.

是的。

Right.

对。

Right.

这是一个重要的区别，你需要深入挖掘，才能找出潜在的关联因素。

Now that's an important distinction and how you got to dig deep to potentially figure out what is linked.

最近有一种观点认为，可以通过外部设备刺激迷走神经，从而帮助你入睡。

Recently, there was the idea that you could stimulate the vagal nerve, these external devices, and that would just help you sleep.

这有道理吗？

Is there anything to that?

嗯，我认为有很多设备和方法，可以说，旨在帮助人们改善睡眠，获得更好的睡眠评分或增加慢波睡眠。

Well, I mean, I think there's a lot of devices and strategies, shall we say, to try to help people sleep and, you know, to get a better sleep score or to increase their slow wave sleep.

对于所有这些方法，我觉得有时候人们就像在没有地基的情况下试图建造一座摩天大楼。

And for all of these, I think that it's it it it kind of feels sometimes like people are trying to, like, build a big skyscraper, but they don't have a foundation.

你知道吗？

You know?

我的意思是，基础的东西其实能起到很大作用。

Like, you know, the the basics actually do a lot.

比如，保持规律的起床和睡觉时间，避免晚上接触强光——这会抑制你体内自身的褪黑素，还有锻炼，这对睡眠尤其是慢波睡眠有巨大益处。

You know, keeping a a regular wake time and sleep time, you know, avoiding bright lights in the evening, which will suppress your own endogenous melatonin, exercise, which has enormous benefits on sleep and specifically slow wave sleep.

实际上，我们可以做很多事情来改善睡眠，所以我有时会想，如果我们基础打好了，那些我们经常谈论的花哨方法，真的有人需要吗？

You know, there there's just so many things that we can do to actually improve our sleep that I sometimes I wonder whether some of these fancy things that that we talk about, I I don't know if anyone would actually ever need them if they had the foundations in place.

而且你提到了一个关键话题，即睡眠与体力活动、饮食之间的相互关联，这包括饮品，也包括你进食的时间和内容。

Well, and you're bringing up this critical topic of the interdependence of sleep with physical activity and with diet, and and that includes beverages, but also when you eat, what you eat.

我的意思是，当然，这不仅仅是睡眠问题。

I mean, it's not just sleep, of course.

这是一组复杂的多变量方程在共同作用。

It's a multivariate equation that's coming together.

最近有一篇非常有趣的论文指出，当人们白天出现紧张间隙时，实际上会清除大脑中的代谢废物。

Now recently, there was a really interesting paper that when people have a tension lapse during the day, actually that they're getting some washout of these waste products from their brain.

是这样吗

Is that

我觉得这相当酷。

So I thought it was pretty cool.

我的意思是，他们的研究方法非常精密

I mean, they it was a very sophisticated

对。

Yep.

是的。

Yeah.

他们的实验方案中使用了功能性磁共振成像。

Protocol in that they used fMRI.

他们进行了心理运动警觉性测试，以观察注意力的短暂缺失。

They did, psychomotor vigilance testing to look for attentional lapses.

他们还使用了脑电图。

They had EEG.

你知道，这真的很酷。

You know, It was very cool.

我认为我们在将睡眠仅仅视为清除毒素的时间时需要保持一点谨慎，因为星形胶质淋巴系统——这是一个涉及胶质细胞、血管周围间隙以及细胞外液中溶质清除的系统——与那项研究中所观察到的脑脊液通过第四脑室的流动是完全不同的。

I think we need to be a little bit cautious in thinking of sleep as just like a time when we wash away toxins because, the glymphatic system, right, which is a system that was described involving glia and the perivascular spaces and the clearance of solutes in the interstitial fluid, that's very different from, for example, what was studied in that study, which is the movement of cerebrospinal fluid across the fourth ventricle.

所以，这两种模型中空间的规模差异非常大。

So, you know, just the scales of the size of spaces are very different, in those two models.

对我来说，想象睡眠时就像一台巨大的洗碗机，把体内所有东西都清理干净，这种想法非常吸引人。

And it is very appealing for me to think of, oh, when I'm sleeping, it's like a big old dishwasher and I'm getting everything cleaned out.

如果这样想能帮助人们保持规律的睡眠作息并重视睡眠健康，我觉得非常好。

And, you know, if if thinking of it that way helps people, you know, maintain regular sleep schedules and to prioritize their sleep health, I say great.

但我也认为我们应该记住，大脑中的细胞会不断将物质释放到细胞外间隙中。

But I think we should also remember that there's The cells in the brain are putting stuff into the interstitial space.

对吧？

Right?

所以会产生溶质，你知道，淀粉样蛋白β和其他所有废物都需要以某种方式进入这个空间。

So there's the creation of solutes and putting, you know, the amyloid beta and all the other waste products need to get into that space somehow.

对吧？

Right?

这发生在人们清醒的时候。

And that happens when people are awake.

所以我认为，在睡眠期间，这些物质的产生或释放以及清除都会发生变化。

So I think that there is both a change in production or release of those things as well as a change in clearance, during sleep.

因此，我认为我们在思考睡眠时，需要避免过于简单化。

So I think we need to be careful about not being too simplistic about how we think about sleep.

是的，没错，我觉得那篇论文非常有趣。

Yeah, no, I think it's I found that paper fascinating.

我们在发布帖子时会附上这篇论文的链接。

We'll link to it when we put the post up.

但事实上，正如你所指出的，这是一种不同的液体波动，即脑脊液。

But the fact that And it's a different wave of fluid, as you point out, phaddics, it's the cerebrospinal fluid.

当你感到注意力涣散时，那是因为你的大脑在试图补偿前一晚睡眠不足或质量不佳的问题。

That time when you feel that you lose your attention span, and then your brain is trying to compensate for the poor or inadequate sleep the night prior.

最近，《纽约客》刊登了一篇关于短睡眠者的文章。

Now, another recent piece appeared in The New Yorker about the short sleepers.

我们已经讨论过这个问题很多年了。

And we've talked about this for a number of years.

我认为，最早是加州大学旧金山分校发现了这些人，他们携带某种罕见基因变异，每天只睡三到四个小时，但表现却和睡足八小时、拥有充足深度睡眠和快速眼动睡眠的人一样出色。

I think it was UCSF first case with these people that have these rare variants, that they can sleep three or four hours and they have just perfect performance as if they slept eight hours with lots of deep sleep and REM sleep and whatnot.

我们能从这些人身上学到什么，让所有人都能只睡四小时，却依然像那些拥有罕见基因变异的人一样思维敏锐？

Is there anything we can learn from these people that everybody could only have to have four hours of sleep and be just as sharp as the people with the rare endowed gene variants?

首先，这些人极其罕见。

Well, one, they're extremely rare.

很多人希望自己能来自这样的家庭。

Think a lot of people wish that they came from one of these families.

我也是。

I do as well.

你知道，我不确定试图复制这种分子或免疫机制是否真的有用，因为首先，这些人数量极少，对吧？

You know, I don't know whether it would actually be that useful to try to copy whatever molecular or immunogenic mechanism is going on because, one, these are extremely small numbers of people, right?

他们都来自一两个家族。

They're all within one or two kindreds.

所以我不知道是否值得去模仿这种机制，还是我们不如直接去做那些我们知道效果更好的事情。

So I don't know if it's worth trying to copy that or whether we'd be better off just doing the things that we know help a lot more.

我想我说的是，如果这条生物通路被明确了，未来或许可以通过药物甚至基因编辑技术来复制它，毕竟我们大约三分之一的时间都花在睡眠上。

I guess what I'm saying is, if that pathway, the biologic pathway is known, you could replicate that with a pill or even a genome editing approach someday, and that we spend a third of our time approximately in sleep.

如果你能将睡眠时间大幅减少到六分之一，想想看生产力会提升多少。

And if you could only spend a much lesser proportion, a sixth of our time, look at the productivity.

你甚至不需要人工智能。

You don't even need AI.

你只需要有生产力的人类——总之，

You just get productive human- Anyway,

作为一位睡眠医学科学家，即使那种药片真的存在，我也不会使用

Sleep, speaking as a sleep physician scientist, even if that pill were available, I would not use

我不会。

it.

好的。

Okay.

我会——我认为睡眠非常宝贵，睡眠期间会发生很多神秘的事情，这些事情很可能无法简化为一颗药片，至少在我有生之年，我不愿意服用这样的药片。

I would- I think sleep is really valuable, and there's a lot of things that occur during sleep that are mysterious and probably can't be boiled out into a pill that, at least in my lifetime, I don't think I'd wanna take such a pill.

我喜欢你的回答。

Well, I like your answer.

我倾向于同意你的观点，但无论如何，这观点都很有启发性，因为它让我们开始想象接下来会发生什么。

I tend to agree with you, but I think it's provocative at any rate because now it's almost like use your imagination of what's gonna happen next.

现在回到一个更平凡但极其重要的话题，因为你提到至少百分之二十的人口患有睡眠呼吸暂停。

Now going back to a more mundane, but a very important topic, because you said at least twenty percent of the population has sleep apnea.

多年来，我们一直依赖CPAP或BiPAP机器。

And all these years we were relying on CPAP machines or BiPAP machines.

我们有没有摆脱过这种情况？

Have we ever gotten out of that?

我们有没有进步到不再需要人们旅行时随身携带、还发出很大噪音的这些机器？

Have we ever progressed from these machines that people have to carry around when they travel, and make a lot of noise?

有没有更好的睡眠呼吸暂停治疗方法？

Are there better solutions for sleep apnea?

当然，除了我们看到的一些显著效果的GLP-1药物带来的减重效果之外。

Besides, of course, lose loss of weight with GLP-one drugs that we've seen some real impressive results.

所以，第一个问题是，有没有更好的方法？

So one, is there a better approach?

第二个问题是，治疗睡眠呼吸暂停真的能改变一个人健康的自然病程吗？

And two, does fixing the apnea spells really change the natural history of a person's health?

还有其他治疗方法。

So there are other treatments.

我认为这取决于个人，他们是否会认为这些方法更好。

I think it depends on the individual, whether they would consider them better.

至少在我的病人中，我觉得他们在治疗方式上分歧很大。

At least among my patients, I feel like they really split on path.

他们要么非常喜欢，要么非常讨厌。

They either love it or they hate it.

对吧？

Right?

所以对于那些喜欢的人，我觉得很好。

So for the people who love it, I say great.

我认为在过去十五到二十年里，下颌前移装置持续得到了改进。

I think in the past fifteen, twenty years, there's been continued improvements in mandibular advancement devices.

这些就像人们佩戴的牙套，可以将下颌向前推。

So these are like mouth guards that people wear that push the lower jaw forward.

而最近，出现了舌下神经刺激器。

And, more recently, there's been, the emergence of hypoglossal nerve stimulators.

这些就像起搏器。

These are like pacemakers.

它们是植入体内的。

They're implanted.

它们刺激舌下神经或第十二对脑神经。

They stimulate, the hypoglossal or twelfth cranial nerve.

从而增加舌根部位的肌肉活动。

So it increases the muscle activity at the base of the tongue.

这有助于保持上呼吸道通畅，防止其塌陷。

And so that helps hold the, upper airway open and prevents it from collapse.

这相当酷。

So that's pretty cool.

它们配备了一种植入式刺激器，可以防止患者出现呼吸暂停。

Know, they have an implanted stimulator that prevents them from having apneas.

所以，这种设备已经上市几年了。

So, you know, that's been on the market for a few years now.

因此，现在我们有不少患者，至少在我们的睡眠中心，正在接受这种治疗。

So, you know, now we have a substantial number of people, at least at our sleep center, who are treated with that.

哦，但你知道，这并不完美。

Oh, But you know, it's not perfect.

这可不是像日间手术那样做完就完事了。

It's not like you walk in as a day surgery and you're done.

你知道，因为这些设备需要植入，然后睡眠时还需要调整参数，所以要让一个人真正通过这种方法得到妥善治疗，我觉得大概需要九到十二个月的时间。

You know, the because the devices have to be implanted, and then they need to be the settings need to be titrated during sleep, you know, it can take, I would say, a good nine to twelve months to get someone actually properly treated with that, with that method.

所以目前还没有治疗睡眠呼吸暂停的灵丹妙药。

So there's no, there's no magic pill yet for sleep apnea.

很高兴你提到GLP-1类药物。

I'm glad you mentioned GLP-1s.

在我的职业生涯中，第一次有相当多的患者通过减重自行治愈了睡眠呼吸暂停。

I think for the first time in my career, I've actually had a significant number of patients cure themselves of sleep apnea by losing weight.

以前，人们做胃旁路手术的情况极其罕见。

Previously, it was extremely rare where people were getting gastric bypass.

通过饮食和运动减重的人非常少，我一只手就能数得过来。

A very small number would actually lose through diet and exercise, but I mean, I can count them on one hand.