"The Odds Ratio Product as a Marker of Sleep Depth" Magdy Younes (10/13/2021)

October 29, 2021

ID7096

To CiteDCA Citation Guide

00:00This.
00:21Here we go. I think we have a
00:24lot of folks have joined.
00:26So hello everyone,
00:27my name is Andres and Chuck.
00:29I'm an assistant professor here at
00:31Yale School of Medicine and I want to
00:33welcome you to our another edition of
00:35Joint Sleep Seminar this afternoon and
00:38our inaugural session for the year.
00:40And then since our inception in 2018,
00:42we have grown quite a bit and now include
00:45many of the hospitals in Massachusetts.
00:47As you can see on this PowerPoint slide,
00:49Beth Israel mass general Tufts.
00:51Brigham Boston Medical Center
00:53and of course, Yale.
00:55So I just wanted to thank all of
00:57my colleagues at each of these
00:59participating institutions for
01:00helping make this conference reality,
01:02and they wanted to just say a couple of
01:06announcements for today before before.
01:08I'll have Eric introduce our
01:10speaker for the day first.
01:12Please take a moment to
01:14ensure that you're muted.
01:15And also this is a CME related conference,
01:19so if you wanted to get credit for it,
01:21please see the chat room for instructions
01:23and you can text the unique ID for the
01:25conference anytime between 1:45 and 3:15.
01:29If you do have questions and
01:30I hope that you do,
01:31I encourage you to make use of the
01:33chat room during the hour and then
01:35lastly the recorded versions of these
01:37talks will be available for a couple
01:39of weeks in the link provided in the chat,
01:41so please let's welcome Doctor.
01:44Eric Heckman and Doctor Magne
01:47units for our conference today.
01:49Go ahead,
01:50Eric.
01:51Good afternoon everyone.
01:52I have the distinct pleasure of
01:55introducing Dr Eunice this afternoon.
01:57He has a long track record in
02:00the sleep and pulmonary fields.
02:04He does medical training and
02:06public health training at the
02:07University of Alexandria in Egypt
02:09before coming over to Canada.
02:11There he did his clinical training
02:14at Montreal General Hospital
02:16as well as his PhD in pulmonary
02:18Physiology at McGill and after that.
02:21Advance steadily through
02:22the ranks of academia,
02:24holding titles of professor at
02:26both the University of Manitoba
02:29and University of Calgary.
02:30Uhm, he also has been the director
02:34of Sleep Laboratories in Winnipeg
02:37and has had a very profound research
02:40career covering many research topics
02:43ranging from respiratory mechanics
02:45and controlled breathing to exercise
02:48Physiology and pathogenesis of
02:50respiratory failure is what as
02:52well as many sleep related issues
02:54like treatment of sleep apnea and
02:57technology and sleep evaluations.
02:59He's had a.
03:00A mind boggling 185 public
03:03publications and holds multiple
03:06patents in multiple countries.
03:08Notably for things like
03:10proportional assist ventilation.
03:12He's also been on the editorial
03:14boards of many different,
03:15well respected publications,
03:17including the Blue Journal and
03:19currently is a distinguished
03:21professor and senior scholar.
03:22Excuse me, a distinguished professor,
03:24Meritous and a senior scholar at
03:28University of Manitoba and so.
03:30Uh,
03:31I give a warm welcome to doctor
03:34Eunice and very much I'm looking
03:35forward to this presentation today.
03:43Andre, I think you're muted. OK.
03:53Wow.
04:13Per. Like maybe it looks good.
04:15No, I'm just trying to get the.
04:20OK. Here. Can you see it now?
04:27Yes, we can see we
04:29can. Yes we we have it in the presenter mode,
04:31so so it will show your notes as well.
04:34Alright, so I'm supposed to let you
04:36know about this new thing called or
04:40Pi like three letter abbreviations.
04:43And So what this what RP is,
04:48is a continuous index of sleep depth,
04:51and the first I need to show you
04:54the slide that was given to me
04:56by Yale so that you can read it.
04:58So I'll give you a few seconds to read it.
05:02Uh, it's basically to tell you that all my.
05:07Uh, activities have been mitigated.
05:10And you can. You can ask.
05:14You can send a text if
05:15you have any questions.
05:16OK, so let's go.
05:19The ERP is basically a continuous
05:23index that ranges from zero to 25 to 2.5.
05:28Sorry it is measured every three seconds,
05:32so it gives a number every three seconds.
05:35Seeing your sleep depth is somewhere
05:37between zero and 2.5,
05:39and so you can have an idea about.
05:41With these numbers mean of course you can
05:43get any number within any range you know.
05:46You can have .12 point 17.28,
05:49but just to give you an idea about what what
05:52we associate with very deep sleep and so on.
05:55So the lowest decile is 0.25,
06:00which is really very deep sleep point 252.5
06:03is deep sleep point between zero and one.
06:07It's really sleep like everybody would
06:09agree is sleep, but it is graded.
06:12From zero to one and then there is that
06:16middle section between one and 1.75,
06:18which is transitional sleep that
06:20you have a mix in the app of between
06:24sleep and and wake patterns.
06:26But generally the text will call it sleep.
06:301.7 to two is very drowsy awake.
06:342 to 2.5 is drowsie week and
06:36this is the important one.
06:38Fully week is the highest
06:41decile of this range.
06:43So why do we need a continuous measure of?
06:47Why do we need a continuous
06:49new index of sleep depth?
06:50Three reasons.
06:51First,
06:51there is a lot of a lot of work is
06:55being done to show that there are
06:57negative consequences to health in
06:59every in nearly every organ in the body
07:03and risk factors to many common disorders.
07:07Uhm,
07:07the impact of sleep duration,
07:10which is total sleep time and timing of
07:13sleep relative to the circadian rhythm.
07:16The impact of these two factors
07:18on health have been studied
07:20extensively and well documented,
07:22but there is very little information about
07:24the impact of sleep depth on health.
07:27And of course,
07:28you can imagine that we want to know
07:31whether if your sleep is deeper,
07:33your health is better,
07:34but there is no information about this.
07:38And the third reason why we need an index is
07:41that the conventional metrics of sleep depth,
07:44which are typically sleep efficiency,
07:47percent of time in any one and three,
07:50and the arousal awakening index this for
07:53indices which were typically used in in the
07:56clinic as indices of how deeply sleep is,
07:59more N3 means more deep sleep more,
08:02and one means more light sleep and so on.
08:05These are seriously flawed.
08:08And the. The next couple of
08:12slides will show you why I mean,
08:17because it is important that you
08:19know that the indices we are using
08:22now are not really that reliable.
08:24The first thing,
08:26sleep efficiency is really gives you the
08:30percent of time you are awake or asleep.
08:33But it doesn't tell you anything
08:35about the quality of the week state.
08:38The AG and epochs that are typically
08:41scored a week can range from patterns
08:43that are very similar to anyone,
08:46including periods of microsleep
08:48to patterns of full wakefulness.
08:50And here is a slide we published
08:54recently that shows you. And C3 and two.
08:58An airport that we would call fully awake,
09:01and then you start getting a little bit
09:04of theater in the second one and more
09:06theater in this and then in the last
09:08one you can see a period of microsleep.
09:10But all of these are scored
09:13awake according to RNC,
09:15because even when you have
09:17micro skip like that,
09:18it doesn't meet the 15 second criteria.
09:21And I just also want to make
09:23you aware of this phenomenon,
09:25which which is very important clinically.
09:28This again is an epic of full wakefulness
09:31or sorry I I should have shown you this.
09:34So the RP here the average for the
09:3610 numbers because we have 10 three
09:39second efforts here, so 10 or P values.
09:42The average here is 2.5 which is pretty
09:45close to the maximum range for RP.
09:48And then as the patient gets a little
09:51bit more of the sleep pattern.
09:53The RP goes down and here is still
09:571.69 because because,
09:58but it is very close to being asleep now.
10:03This this this this example here
10:06just illustrates something that
10:09we see commonly in.
10:10You know, in severe OSA patients.
10:14And can be misleading.
10:15So so this is the patient in a full
10:18wakefulness just before lights out.
10:20And then when he when he gets into the sleep,
10:24you can see that in the top one DRP is
10:27pretty close to 2.5 in every three seconds,
10:31and the average is 2.48.
10:34But in this one the same patient,
10:36now he's going to sleep,
10:38but and he still called awake.
10:40But you can see that in this
10:41airport these are two epochs.
10:43This is 30 seconds.
10:44And this is another 30 seconds
10:47and you can see that here.
10:48He was wide awake.
10:50And then he starts dozing off.
10:52You see the OR P coming down.
10:54He gets an apnea, wakes him up.
10:57Or P goes up again.
10:59Then he tries to go to sleep again.
11:01You see the OR P coming down,
11:03he gets another apnea and this is what what
11:05your patients are doing in the waiting room.
11:08While you're waiting for you.
11:09Is there a week they are awake,
11:11but they're really getting recurrent apnea,
11:14so I think you appreciate that
11:16there is a big difference between an
11:18awake epic like like the top one,
11:21and we kept looks like the bottom one here.
11:23Here the patient really has
11:25no sleep drive and he can't.
11:27Told us people he's not even
11:29trying to fall asleep,
11:30but in this in the lower one you you
11:32appreciate that the patients really
11:34very drowsy and wanting to sleep.
11:36But every time he falls off a bit,
11:40as evidenced by the RP,
11:42he gets an apnea which prevents
11:44him from going into deep sleep.
11:46So this one would score pretty
11:48high on your P,
11:50which means that sleep
11:51pressure is not high at all.
11:53It's very low,
11:54whereas these ones while
11:56also called the week.
11:58Would score quite low on
12:00the on the awake or P,
12:02which goes down to about 1.5
12:06minimum and so so that what means
12:09the patient just can't sleep
12:11because he's got a lot of drive.
12:14But this one says he doesn't have any drive,
12:16and these two obviously are very difficult.
12:19Different conditions in the same patient,
12:22and when we just use the
12:25conventional criteria,
12:25we cannot distinguish between these.
12:28But the RP will give you the OR P value in
12:31the weekend box and the lower they are,
12:34the more drowsy the patient is
12:36and the more there is something
12:38keeping him from falling asleep.
12:40The second reason the conventional.
12:44Criteria or fraud is that the
12:47ASM amazingly requires that you
12:49changed non REM sleep to stage one
12:53every time there's an arousal,
12:55so you still staying in one
12:57until there is a spindle,
12:59but they spend their can come
13:00in the next 5 seconds or it may
13:03not come for 545 apples,
13:05so every time there is an arousal
13:08you're adding and adding to end
13:10one pending the appearance of
13:12spindles and so so and one really.
13:15Doesn't add anything over over
13:17the arousal index.
13:19The more arousals you have
13:21with the current criteria,
13:22the the more and one will be,
13:25so that is a that is a problem.
13:27If you want to use N1 as
13:30an index of light sleep.
13:32The ability of technologies
13:34to estimate total duration of
13:37qualifying Delta DSM says the Delta
13:39Wave has to be 75 microvolt has
13:41to be between .5 and two second,
13:43and so on, and the text are supposed
13:46to identify every delta.
13:47Even then,
13:48add up their durations to see if they
13:50add up to six seconds before they get.
13:53They call it and three, well,
13:55I mean which which tech is going to do this?
13:57This is a study we published
13:59a few years ago that shows.
14:03Uh,
14:04seventy 7070 PSGS.
14:07Each one was scored by 10
14:09technicians and the number
14:10on the X here is the is the average
14:13N three times by the 10 technicians
14:15which we use as the gold standard.
14:18But you can see at any
14:20average like here is 11.
14:22One technician called 01 technician
14:24called 30 and and it's all over the
14:27place so that it's really like like
14:30tossing a coin to figure out which
14:32it all depends on which technician,
14:35Technologist has scored the file.
14:37So that ends three as an index
14:39of deep sleep is not really
14:41that reliable if you are in N3,
14:43you know you're in deep sleep,
14:45but you can't use that as an index.
14:47You can.
14:48You can be in deep sleep without having
14:50the required delta waves because.
14:53The easiest small or whatever,
14:55so so that takes care of N3.
14:59The other very important thing is
15:02that N1 and N3 usually occupies more
15:05fractions of the recording time and
15:08that represent the extremes of sleep depth.
15:10But most of the time we spend in
15:13end two and most of this range of
15:15sleep depth happens in end two as
15:18you go from one to deep sleep,
15:20you go through all the stage
15:22all the depth when you reach.
15:24And three are in very deep sleep,
15:26but you don't really know
15:28what's happening in end two.
15:30And here are five epochs in end.
15:32Two these top five year and you see
15:35this one is pretty close to anyone.
15:37But there is a spindle here,
15:39but then it gets.
15:45You cannot see the pointer.
15:47Oh, I see, but they cannot
15:49see this. Yeah, we can.
15:51OK can you see my pointer now?
15:55Can you see my pointer?
15:56Yes, yes, maybe yeah.
15:58OK, so you can see that the top one.
16:03Is it's pretty much like anyone except
16:05for a spender here and then it gets you
16:09got more and more theater and delta waves,
16:12but they don't make the end 3 criterion
16:14because they don't add up to six seconds,
16:17so you can see that the RP is going from 1.8
16:20all the way down to .6 with in stage two.
16:24And you know once you get into stage
16:26three or already in very deep sleep,
16:29but you don't really know when when the
16:31patient was an end to how deep it is. Was.
16:35The other reason is that conventional
16:38metrics of sleep debt there is many of them.
16:41There are several of them,
16:43and sometimes when you do an intervention
16:45like taking a drug or putting
16:48a patient on CPAP.
16:49One of them goes in the right direction.
16:51Other ones go in the wrong direction.
16:53So so for example,
16:55arousal index may get better with C PAP,
16:58but N 3 is lower.
17:00So is it sleep better or worse?
17:02We don't really know,
17:04whereas lower P is a single metric and you
17:07know there is no problem with interpretation.
17:10Finally,
17:10there are other index which is
17:12often used as a measure of sleep.
17:15Continuity is simply an account
17:18at count of sporadic events.
17:21That does not consider their
17:23duration or intensity,
17:24and we know that the duration can
17:26be up to 15 seconds or down to
17:29three seconds and the intensity.
17:30We have papers Ali,
17:32who as he is is here has published
17:34a paper about how arousers can be of
17:38different intensities and how these
17:41intensities affect the physiologic responses.
17:44So so I hope I've convinced you
17:46not to look anymore about the sleep
17:49stages that you get on the report.
17:51I know it's difficult,
17:52but this is this is true.
17:54How is it measured?
17:57So it's the it's measure is it's
18:00describing great detail in this paper,
18:03and so I don't really want to
18:04take much time going through this.
18:06If you can read it.
18:09There is a brief version version which
18:11I'm going to describe to you now,
18:13so you start with a 3 second airport
18:16and you do all kinds of manipulations.
18:19You end up giving it a four digit
18:23number 8410.
18:24The eight is the relative power,
18:26eight out of nine,
18:28the eight is the relative power
18:30of delta waves.
18:31The four is the relative power
18:34of Theta waves.
18:35The one is the relative power of alpha waves.
18:40And the zero is the relative power
18:41of beta so that that number.
18:43Actually, if you think about it,
18:45gives you a very good idea about
18:48the shape of the EG.
18:50The trick is how to get from
18:52this pattern to this number.
18:53But once we get to this number
18:55then there is a look up table says.
18:58How often does this number happen
19:01in epochs that are scored awake
19:04or during arousals?
19:05So it gives us a percent of zero to
19:08100%. So if the if the number
19:10for example is one way.
19:12It will say the probability of it
19:15happening in a week epochs is zero,
19:17or it could be 100%.
19:19And then just to be a
19:21difficult and different,
19:22we don't want to be so ordinary.
19:24We divide this zero to 100
19:27probability by 40 to make it zero to 2.5.
19:30But it's just the OR P is.
19:32Basically it's basically the the
19:35probability divided by 4G that direct.
19:39So this is the short version.
19:41I have the wrong version,
19:42but I'm not going to go through it
19:45if there is time at the end then
19:48someone wants to go through the method.
19:52Uh. And that gives you this some examples.
19:55This one would be 0000 and
19:59the probability is 37%.
20:01This one will be 9843 and the probability
20:05of it being awake is zero and so on.
20:08OK the validation again.
20:10I'm not going to go through
20:12there several studies.
20:14Some of them by arms length
20:17investigators to show that it really
20:19does reflect the depth of sleep.
20:22In addition to these validation studies,
20:25there are numerous studies.
20:26I don't know how many,
20:27again,
20:28by independent investigators using
20:30or P to show association with
20:34different outcomes like future
20:36occurrence of my cognitive impairment
20:39or driving accidents or whatever,
20:43and all of them are quite.
20:44Positive,
20:44but I want to get into the meat now.
20:47The most compelling validation
20:49is the relation between what RP
20:52is right now and the probability
20:55of an arousal or awakening or
20:57caring in the next 30 seconds.
21:00Not right now, but in the next.
21:02So that shows you how close you are
21:05to being spontaneously aroused.
21:08Uhm?
21:10The this this relation is is amazingly good,
21:14so it shows.
21:16Again these are 5282 hundred apples
21:20with OR P in the first decile and
21:25you can see the probability of
21:27arousal occurring in the next step.
21:29AC is very low,
21:31but as the current over P
21:33gets higher and higher,
21:35the probability of arousal goes up and
21:38up so that by by the time or current or.
21:42PS2 there you know it's almost certain
21:45you will wake up or get an arousal.
21:47So this is this is the main
21:49evidence now that there is a
21:51linear relation between current,
21:53what we measure as current or P,
21:55and the likelihood of an arousal which
21:59translates into the arousal index.
22:01So what are the potential applications of RP?
22:06The first one which is a
22:09new index I came up with.
22:12Using the ORP is to measure sleep adequacy.
22:16Like you know the the ASM says you
22:19need seven or eight hours of sleep.
22:21But what kind of sleep?
22:22I mean, if your sleep is poor,
22:24you need more than seven or
22:26eight hours or some people.
22:28Not everybody needs 7 or 8 hours.
22:30There are short sleepers and long sleepers,
22:32not for any disease,
22:34but because of the bell
22:35shaped curve of sleep,
22:37sleep needs.
22:38So one of the nice things about RP
22:41is that you can tell.
22:42Whether the patient sleep
22:44is adequate for him.
22:45In other words, this is a a good way.
22:49To two to figure out how much
22:53sleep the patient needs. Uh,
22:56this is 11 histogram that you are used to.
23:00And of course it looks perfectly normal
23:02and you see what the 32nd over P,
23:06so this would be about 800 or 900
23:08epochs and this is the time course.
23:11So this is the first cycle and you see
23:13sleep going progressively down with
23:15in stage two when it hits stage three.
23:18It's very low down and in REM
23:20sleep in many patients will get to
23:23that later of quite interesting.
23:25In many patients,
23:27the RP during REM sleep is much
23:30higher than RP during non REM sleep.
23:34You can see it here, all of them.
23:36But another important thing is
23:38is that you see that there is a
23:41trend upwards in the RP despite the
23:43oscillations up and down that there
23:45is a trend upwards which gives us an
23:48idea about how restorative sleep is.
23:51So if or P goes up a lot by the
23:53end of the night,
23:55we know that the patient had
23:57a lot of restorative sleep.
23:59So and then I'll show you
24:01other other patients right now.
24:03So the.
24:04What is called cumulative sleep index
24:07or to measure sleep adequacy is.
24:11Is that we measure this the the
24:13the reduction in RP every airport?
24:16So in this case it's gone down from
24:19week to week level to maybe five.
24:22So the delta RP would be two.
24:24We can do that for every airport and
24:27add them all up during the study.
24:31So in this particular patient it was 818.
24:34Now that number doesn't mean anything
24:37until you can see the normal
24:40values than normal values are.
24:42Or between 570 to 700.
24:45These are normally on sleepers.
24:47Uh, so that gives you an idea that
24:50this patient needs a lot of sleep.
24:52But he's got good sleep,
24:54normal sleep.
24:55The second patient you see.
24:58He also has fairly normal sleep,
25:00maybe a little bit more weight time,
25:03but you can see his OR P now.
25:05You can still see the cycles,
25:07but but now his average or P is quite low.
25:11And when you multiply it by total
25:14sleep time we get and and total of 482,
25:18which is, which is much less than this.
25:21And and then here is another.
25:22Patient with insomnia and
25:25short sleep duration,
25:27and again he's got now a lot of awake time,
25:31but still a lot of end too.
25:33And some entry,
25:35and yet his his integrated amount of
25:38sleep is is maybe 1/3 of this patient.
25:42Now how do we know like if if you?
25:46If you take this patient number
25:48one and stop the study here,
25:50because this is 7 hours or six hours,
25:52he has to go to work.
25:54You you will see that he had deep sleep.
25:58And you say this is a normal sleep study,
26:00but in reality is orpa didn't go
26:04up very much during the study.
26:07So this patient, you can suspect
26:09that he didn't get enough sleep.
26:11We don't yet know what is eight.
26:14180 may have 500 here by
26:16this time instead of 800.
26:19So in patients like this that
26:21have a high number like this or
26:23or the over P doesn't change
26:25very much during a regular time.
26:286-7 hours.
26:29It would be nice to actually let let
26:32the patient sleep without any restriction,
26:35so you can, for example ask the patient.
26:37On the long weekend to do a home study
26:41of EG and and and let him sleep.
26:44You know the first two days of
26:46the weekend you can sleep as much
26:48as you want it to be,
26:49to to lose any sleep loss that
26:51he had and measured this number
26:54that that you know if he can sleep
26:56818 units in a study that means
27:00he needs a lot of sleep.
27:03So if the patient has symptoms and this
27:05is the social social problem that.
27:08We have now if the patient has
27:10symptoms and during the regular
27:12sleep study had only 500,
27:14but on the long weekend on Monday he had 18.
27:17You know this patient needs more
27:19sleep and maybe the advice would
27:21be remember everything I'm going
27:23to say from now on is speculative.
27:26These are only my interpretations,
27:28but they make a lot of sense
27:30and therefore they are,
27:32but they're worth testing in the clinic
27:34to see whether they are right or wrong.
27:36So if you have a patient like this.
27:38You you know that he needs.
27:41He needs a lot of sleep and
27:42maybe he can be advised that can
27:44be subject to a clinical trial.
27:46If you take a patient like that and
27:48tell him go to bed an hour earlier,
27:50two hours early or get up an hour,
27:52maybe his symptoms will disappear.
27:54That needs to be clinical testing
27:56this patient you know he's got a
27:59low amount of sleep but his his,
28:03his or P seems to creep up very nicely,
28:05so maybe that's all he needs and that
28:08would be there. Just fine, you know.
28:10We don't worry about his or P
28:12being too low because it because
28:13it is a response to the fact that
28:16he doesn't need much sleep.
28:17On the other hand,
28:18this one also is is his creeping up
28:21his or PS creeping up across the night.
28:24So this is a patient that we now
28:27identify as one with hyperarousal.
28:29These people are not sleepy at all,
28:31despite the fact that that they have
28:33a lot of their very little sleep.
28:36And again it is nice to be aware
28:38of the fact that.
28:39This patient sleep needs are very low,
28:42even though they don't have.
28:45They don't have OSA or anything
28:47because these people are probably
28:50sitting ducks for getting insomnia.
28:53If if they have any excessive
28:56arousal stimuli.
28:59OK, now the second, in the second
29:02use of this or P is investigation of
29:05mechanism of sleep fragmentation.
29:07So this is the linear relation between.
29:11Current or P?
29:14And the expected arouser index.
29:17And this is the.
29:2095 confidence interval in normal people.
29:24So now I'm going to plug three different
29:27patients against this background.
29:29This is the normal background.
29:31Now this patient has as
29:33an arousal index of 48.
29:35He's gotten each oil for 50,
29:39so he's got severe sleep apnea and his
29:42sleep apnea is associated with a lot
29:45of arousal and his older P is high.
29:48So because his or her peers high,
29:51we expect a lot of arousals.
29:53So in this case the high arousal
29:56index is because of his sleep apnea,
29:59but we don't know whether the high or P.
30:02In other words, the light sleep is because.
30:06Of the OSC or is because of a
30:09central problem like like a hyper
30:12arousal state or or poor sleep need.
30:15Uh, uh. Billion problem and so on.
30:23So this is one patient.
30:24Then we get a patient like this who has
30:28no hi, no problems and he's also got a
30:32high arousal awakening index relative
30:35to his ORP at an RP of .8 we expect
30:39only 20 with an upper limit of 30.
30:42So so, So what does that mean?
30:46That means to me anyway?
30:48Like I say all that needs
30:50to be confirmed it means.
30:52That this patient has something
30:54bothering his sleep that wakes him up.
30:57That is not hi and pilens under full.
31:00We're not seeing it in the sleep
31:02study in a patient like this,
31:04then high arousal index with
31:06a normal or P and nothing to
31:09see in the sleep in the sleep.
31:11Study what I would do.
31:13I don't do any clinical work anymore
31:16so I can pontificate what I would do
31:19is to go over the organ system what?
31:22We used to call functional inquiry
31:24to see if he has any GI problems.
31:27Colleagues, itching, pain in the joints,
31:30anything that might be a source
31:33of arousal stimuli that does not
31:35show itself in the sleep study.
31:37And here is a third pitch.
31:40A third patient who has.
31:42Severe sleep apnea and not
31:45as bad arousal index,
31:47but his or P is low and I'm
31:49sure some of you have seen this.
31:51Sometimes people with even
31:53in in stage three sleep.
31:56They have sleep apnea,
31:57but it doesn't wake them up that much.
31:59And this now is a patient who has
32:04severe severe sleep apnea that wakes
32:06him up or even without waking up that
32:10causes oscillations in breathing.
32:13Uh, even though he sleep is very deep
32:15and we do have lots of examples of all these.
32:18So that's how if you plot the patients
32:22arousal index and hi on this graph,
32:25you can sort of say,
32:26well this patient has has a low
32:30arousal threshold, high or P.
32:33This patient has a high arousal threshold,
32:36so this is the kind of patient
32:39that underwhelming now would say.
32:41You know,
32:41if we can make you sleep deeper,
32:43his sleep apnea will go away,
32:45whereas this one is sleep apnea will not
32:47go away if you make you sleep deeper
32:49because they sleep is already very
32:50deep and this is someone who sleep.
32:52Fragmentation is coming from
32:54somewhere else in the body.
32:56Again,
32:56these are all hypothesis that
32:58you guys need to confirm.
33:01The third use of or P because it
33:04is calculated every three seconds,
33:07is that it gives you an idea about
33:10the dynamics of sleep regression.
33:12Uh, so here are two patients.
33:16This is published also,
33:19so here is an arousal.
33:21Up to the up to the vertical line and
33:24we can see the order here is very high,
33:28so the work this is 3 second or pH
33:31very high full almost full wakefulness,
33:35and then he goes to sleep here
33:37at the vertical line.
33:38This is visually I drew it.
33:40And you can see now that he's
33:43changing to sleep.
33:44His over P goes down quickly,
33:47but only to about 11.2
33:49and then it lingers there.
33:51If you wait 10 minutes it will
33:54go down without arousals.
33:55It will go down to very low level,
33:58but of course he gives getting
34:00arousals because of the lower P,
34:02so that becomes very difficult.
34:03So this is we measure the RP in
34:06this in the 9 seconds immediately
34:09following the arousal and we call
34:12that over P9 and you can see that.
34:14In this patient,
34:15he's stuck with stuck at 1.5.
34:19Which is one of those transitional
34:22transitional states where
34:23anything can wake you up.
34:25On the other hand,
34:26this patients same arousal also
34:28caused caused very high or P.
34:31Here is the end of the arousal,
34:33and you can see the door P within
34:369 seconds went down to almost 0.
34:39And now he becomes very resistant
34:42to arousals,
34:43so if he gets another hypopyon
34:46here right after this arousal,
34:48he's not likely to wake up,
34:49and Mila may may just actually stabilized,
34:53whereas this patient is stuck there.
34:56And for for several minutes,
34:58he would stay there unless he,
35:00unless he doesn't get an arousal.
35:02If he gets an arousal at any time,
35:04this would go up again and
35:07then come down again and.
35:09That's why you see the yeah,
35:12no, it's not here.
35:14OK,
35:14so I hope this is clear.
35:16So or P9 is a measure of how quickly
35:20the patient goes into deep sleep.
35:23If it's high,
35:24it means he lingers in in a in a in
35:26a light sleep for a long time and is
35:29more susceptible to getting arousals.
35:31And it's very hard to find a patient
35:35with very severe OSA or severe
35:37purlins with arousals that has the fasten RP.
35:41That is, that is not not that high,
35:44so this is.
35:46This is a very big risk,
35:49very big risk for recurrent arousal,
35:53and this guy.
35:54Then you know if he gets OSC,
35:56chances are he will get much fewer arousals
35:59then just like I showed you before.
36:01So this is the other way we can
36:04understand the what's underlying
36:06the patients problem.
36:07Uh.
36:10Oh, this is just this is just
36:12this is just showing you that even
36:14the one with the high or P9 will
36:17ultimately go down to deep sleep.
36:19If he's not aroused.
36:22Now this is the fun part and and what a.
36:26What what I'm deep into now and and I
36:30would like to spend the rest of the
36:33of the talk with you know before that.
36:37OK, so here is a section of a sleep study.
36:41Oxygen saturation the histogram.
36:44And this is our PC with you.
36:48See during stage two how much it goes down.
36:51Most of the range of RP happens here.
36:54But when he goes into RAM,
36:56the RP goes up.
36:58This patient has fairly severe sleep
37:01apnea and you can argue that that it is
37:05the sleep apnea that's fragmenting his ram.
37:09Here is another one.
37:11Very different, you know,
37:13gets into very deep sleep and you see he gets
37:17into stage three when he is way down there.
37:20But we don't see anything
37:22happening before that.
37:23Again, not again this patient.
37:26Now he goes into them,
37:28but his RAM or P is very
37:31close to another MRP,
37:32so you know in until now we've never
37:37really distinguished RAM RAM as being
37:39multiple stages different stages,
37:41whereas in reality RAM can
37:44be very close to awake.
37:46Like this patient,
37:47you see two which is very close to a week,
37:50whereas here is about .5 which
37:52is very deep sleep.
37:53And and you know,
37:55we didn't appreciate that
37:56until we got the RPC here.
37:58He's sleeping deep and he's
38:01getting seriously saturation,
38:02whereas here he doesn't
38:04because he wakes up right away.
38:08So so, but you can argue that that
38:10the reason this one is obvious
38:12because he has severe sleep apnea,
38:14so we put both patients on C PAP and
38:18we eliminate the sleep apnea again.
38:22You see, this patient still has a high
38:25RPM ramp even though he has no sleep
38:28apnea and this one has low or P and RAM,
38:32even though he doesn't have sleep apnea,
38:34so so that tells you that this is a trade.
38:37For the patient and before I get into that,
38:42we just confirmed in a recent study
38:44that this is actually a treat.
38:47We compared the Orpen and RAM in 2600.
38:51People who had sleep heart health
38:54one and two,
38:56and this is the correlation between oh RPM.
39:01One and two,
39:02which are separated by five years.
39:04So it shows that it shows that
39:07oh RPM is a trait is really.
39:10I mean this is intraclass correlation of .79,
39:13which is which is very high.
39:15Now going back here along with the
39:18yoga masotti a colleague of mine,
39:20we looked at the characteristics of
39:22REM sleep as a function of Rambo RP.
39:25So here are people with lower
39:28MMORPG just like this one.
39:30And here are people.
39:32Like this fellow, so again,
39:35these are the sleeper cell study people,
39:38so we're talking about.
39:40C, 5000 or 4000 is a very nice
39:44correlation between Remo RP and how much
39:47wake interruptions you have during RAM.
39:50You see here.
39:52This is interrupted here,
39:53whereas here he's solid solid REM sleep so so
39:58as well as there is less REM sleep we don't.
40:03I don't have the figure if MORP is
40:06high you get less less REM sleep
40:08and more fragmented than sleep.
40:10And we I think we all know the sort
40:13of the the link between REM sleep,
40:17fragmentation and say psychological
40:20anxiety disorders and depression
40:23and PTSD and all that.
40:25So that's another use of sleep deaths.
40:28Which of RP which we haven't been aware of,
40:31and that could explain some of the.
40:35Mental well,
40:36well anxiety disorders and so on.
40:39Finally,
40:40nowadays we haven't published this yet,
40:43but I'm about to submit the paper
40:45this is using or P to describe
40:49sleep architecture in addition to or
40:52instead of the conventional system.
40:55So you have seen this in broken
40:57and broken graphs before.
40:59So these are three awake epochs,
41:01again showing the different or P levels.
41:05These are four or five and two.
41:09Oh, this is N1. And it's here.
41:15And then four non REM RP again showing
41:19degradation of RAM and this is N 3 so
41:23this particular person is this is his
41:28conventional architecture normal normal?
41:30You know.
41:30In other words,
41:31sleep efficiency of 86% a little
41:34bit of anyone quite a bit of N3
41:36and RAM and a lot of north two.
41:39I mean everyone knows that but here.
41:41Then I got the idea.
41:42Well,
41:42why don't we,
41:44instead of breaking it into
41:46five stages like this,
41:48we break it into 10 so so I divided the
41:52total range of RP into 10
41:54deciles and now I plot instead of
41:58percent percent in a week time.
42:00I plot percent of the recording
42:03time in this very deep sleep.
42:05Deep sleep oops.
42:10How?
42:14These two are or. This is deep sleep.
42:17This is sort of average.
42:18This is light sleep and then it in normal
42:21people it trickles down quickly as you
42:24get into the very lights not sleep.
42:26I mean transitional States
42:28and these are the three ranges
42:30that are usually called awake.
42:33This is drowsy awake.
42:34This is drowsy. This is very drowsy,
42:37drowsy and this is full wakefulness.
42:39So this patient didn't have much
42:42full wakefulness of this kind.
42:44So that is the the new the what I'm
42:47proposing to use as a new architecture,
42:50and what I'm hoping to convince
42:52you that this is a good way to go.
42:57So these are two normal people,
42:59so now of course with this new
43:02gadget or gizmo I started looking
43:05at all kinds of people and I
43:08have 10s of thousands of of PSGS.
43:13And so I started looking and a lot of
43:16people of course look normal like this.
43:18These are two normal people and but
43:21then you see this these patterns.
43:24OK, so this is this is a pattern.
43:27This is another pattern you see.
43:29This one picks the peak.
43:31The people currents of air boxes in
43:34the in the transitional very very
43:37very light sleep if sleep at all.
43:41By contrast to this,
43:42this one has really no peak
43:44in the sleep range,
43:45and he has plenty of wakefulness.
43:48This this fellow has a lot of deep
43:51sleep just like normal people,
43:53with very little full wakefulness.
43:56And this one has both both ways.
43:59A lot of deep sleep,
44:00but also a lot of full wakefulness.
44:02So it struck me that this this
44:06four different patterns represent
44:08different pathophysiology.
44:10Uh, in that this patient.
44:14This patient has very little deep sleep.
44:18What can that be?
44:21That could be because the patient
44:23has very low sleep pressure.
44:25Or it could be because there is
44:27something we can keep waking the
44:29patient up every time he falls
44:31asleep and preventing him from
44:33progressing into deep sleep.
44:35So these are the two possibilities
44:37for a very low amount in deep in
44:40very deep sleep in deep sleep.
44:43But if it was a low sleep pressure,
44:45why is he having very little
44:47full wakefulness?
44:48You know,
44:49we know that if you have a lot of if
44:51you have very low sleep pressure,
44:53you would get a lot of full wakefulness.
44:55If you have a lot of drowsiness,
44:58which would happen here,
44:59you can have a lot of a lot in
45:01eight and nine, but not in 10.
45:03So this pattern would suggest,
45:05then,
45:05that this is a patient who has
45:08pathology that is preventing him
45:10from getting into deep sleep,
45:12and as a consequence.
45:14He's sleep deprived, so this is.
45:17This is subject one.
45:19This one also has very low amounts.
45:22Remember this is 5 and zero is 5.
45:24By comparison this is 20 and
45:27seven and this is 22 and eight so
45:30very very little in deep sleep.
45:33But unlike this guy, look at that.
45:35He has 2527% in full wakefulness,
45:39so that's a different pathophysiology.
45:41The low,
45:42the low amount of deep sleep here
45:44could very well be because of low
45:47sleep pressure, such as people say, uh.
45:51In in with a hyperarousal state or or
45:54you know they they sleep too much,
45:56they nap all day and you know they
45:59have no sleep pressure at night.
46:01This is the third.
46:03Type you know,
46:04like lots of deep sleep,
46:06but he doesn't manage to get some
46:09full wakefulness like the normal people.
46:12In other words,
46:13he didn't really completely restore himself,
46:17and so,
46:18but so the both here are low.
46:23One low and one high, one high and one low.
46:26And here both of them are high,
46:29so this suggests again speculation
46:32that this patient is his deep sleep.
46:36At some point in the night completely
46:39satisfies his sleep needs and he
46:41spends the rest of the night a week.
46:43Now this is very different from this,
46:45although both of them have
46:48excessive full wakefulness,
46:49so I decided then to make a schemata to
46:53break break these patterns into discrete
46:56phenotypes that we can use to then
47:00compare patients outcomes and disease.
47:05And before I get into that,
47:06I just want to show you the relation
47:09between the the metrics we used to
47:12indicate levels of sleep and and so here.
47:19This is what we call transitional sleeper
47:22or virtually light sleep one and 111.7.
47:24This is north one.
47:26You can see there is very little correlation.
47:29Again, this is what we called
47:31deep sleep less than .5.
47:33Here is not percent of time in stage three.
47:35Again, very significant, but we have
47:385000 people so but it's very poor here.
47:41Is there wake epochs in full
47:45wakefulness versus Epoc scored a week?
47:47And what is important?
47:49Here is that you can have someone who
47:51has virtually no deep sleep by the RP,
47:54but he can have 30% awake time.
47:57In other words, sleep efficiency of 70.
47:59Or you can have equal amount,
48:01meaning all the airports are
48:04in full wakefulness.
48:05So here now are the nine.
48:07The nine patterns.
48:08This is the one I showed you before type,
48:11So what I did is.
48:13Measure the percent of time in deep
48:16sleep and the percent of time in full
48:18wakefulness and put them on a scale,
48:20each one on a scale of one to three,
48:22one being in the lowest
48:25quartile of the 5000 patients,
48:28and three being in the highest quartile.
48:30So when we have one one,
48:32it means one refers to the amount
48:35relative amount in deep sleep and
48:37the 2nd digit refers to the relative
48:40SO11 means is low in both of them.
48:441/2 he's in low low end and deep sleep,
48:47but has his in the interquartile
48:49range in in full wakefulness.
48:52This is in the highest quartile in
48:54full wakefulness, but also in one,
48:57and it goes like this,
48:58so this is 3/1 a lot of deep sleep
49:00and very little full wakefulness.
49:03This is 3/3 a lot of both.
49:05So so when you see the number,
49:07you can actually visualize the histogram,
49:10and you can actually visualize
49:12the quality of sleep.
49:13In this patient was happening to him.
49:16So this is the second last slide,
49:18but it's going to take some time.
49:20This is now how often these
49:23different nine patterns occur in
49:26different clinical disorders, so.
49:30So don't look at all the numbers.
49:32I you know the significant values
49:35are indicated by by these digits.
49:38Mild OSA doesn't differ from no disease,
49:41no disease, meaning noisy or PLM.
49:44So by analysis of variance,
49:46mild OSA, the distribution of patterns is
49:49very similar to people with no disease,
49:51hence probably needed.
49:53We shouldn't be treating them moderate
49:55is also very little different or
49:59those significant from no disease.
50:01Now we get into severe and very severe,
50:04and these are the significant
50:07differences from the people with no AC
50:11and these are 1/2 and 1112 and 1/3 zip.
50:14Adding them up here in the very
50:17severe very severe means more than 50.
50:19Hi, we have 4060 more than 60%
50:23of the of the patients have this
50:27pattern with 112 and 1/3.
50:31So these patterns are are are
50:33the characteristic of severe's
50:35of severe sleep apnea.
50:37Insomnia with normal sleep duration.
50:39There is nothing significantly different.
50:42A short sleep duration.
50:45There are two dominant patterns.
50:47One is 1/3.
50:49Which is the one in the top
50:51right corner and one is 2/3,
50:54which is the one below it.
50:56The difference is that this one
50:58has very little deep sleep.
51:00This one has an average amount of deep sleep,
51:03so there are two types of of
51:06our patterns and insomnia and
51:08insomnia with obstructive sleep
51:11apnea is significant only in 1/3,
51:13so now here are the patterns is
51:17just to remind you this is this
51:19is one one this is 1/2.
51:22This is 1/3 and this is 3,
51:25three or two three.
51:28Now, in some ways also looked at
51:31quality of life and DSS, so type 11.
51:34It's primarily seen in severe OSA,
51:38but sometimes it occurs in in people
51:41with noisy.
51:42It has the highest ESS and the
51:45lowest quality of life scores SF 36.
51:48And it has a high or pee.
51:51I told you you don't get into very
51:53high hiz unless unless you have high or pee.
51:57In other words, you have a central
52:00problem in keeping sleep tight.
52:03This second one, one in two,
52:05also primarily seen in OSA.
52:07You don't see well.
52:09You see quite a bit in normal people,
52:11but this is 25% mostly seen in severe
52:14OSA is also associated with high SS
52:17and low quality quality of life,
52:20but not as bad as this.
52:21And it also has high RPM.
52:25The third one, which is 1/3 this one.
52:30Primarily seen in severe OSA
52:33insomnia with short sleep duration
52:36and insomnia with OSA.
52:38So these are the three times
52:41that they happen and.
52:43It's at,
52:43there's asociated with very low quality
52:46of life scores, high risk of blood,
52:49high blood pressure, and low survival.
52:51In addition to these are not,
52:54but this one is. And very high.
52:57This is the highest or P9.
52:59In other words,
53:00the highest highest slowness of
53:03progression to deep sleep and more
53:06likelihood of sleep fragmentation.
53:09But they are not sleepy, they are.
53:11They are among the lowest sleepy.
53:13And finally,
53:13this one is primarily seen in
53:16insomnia with short sleep duration
53:18with source liberation.
53:20It also has low ESS and we would expect
53:23that from the excessive amount of.
53:26Of a full wakefulness.
53:28But it says normal quality of
53:32life scores. No increased risk
53:34of blood pressure or reduced
53:36survival and has a normal RP.
53:38So clearly these two are different
53:40phenotypes even though they are lumped
53:43to get both of them would be called
53:45because they have this have insomnia
53:47symptoms that meet the criteria
53:49and they have short sleep duration
53:51so they get all lumped in this.
53:54But we realized that there
53:55are two patterns here.
53:56One of them is terrible and the
53:58other one looks pretty good,
54:00so that maybe maybe we can start looking at.
54:03These two types within ISD and see whether
54:07they respond to different treatments
54:10or they have different outcomes.
54:12Finally.
54:13Uh, as I mentioned before,
54:17even people with noisy or or or or or
54:23anything that we can see on the PSU
54:26takes 10% have 1/2 and 8% have 1/3.
54:30So what do we do?
54:32Is this?
54:32I mean these are probably the patients we
54:35get sometimes complaining of excessive
54:37somnolence or non restorative sleep,
54:39and we do a sleep study and it's
54:41normal and we tell them go home.
54:43You know it's just all in your head.
54:45But in reality,
54:46now we actually know the
54:48explanation of these patterns.
54:49We when we get people like this with with
54:52these three types and they have symptoms,
54:55then we should really consider that
54:58they have something that's either
55:00interrupting their sleep that we don't
55:03see on the PSG from other organs,
55:06or that they have a hyper arousal state.
55:08But they're not complaining about insomnia,
55:10and we should pursue them
55:13a little more vigorously.
55:14Finally, I just want to show you that.
55:16These are four.
55:17The four patients for subjects I
55:19sold you from at the very beginning
55:22that they're all coming from
55:25people with no AC or or insomnia
55:28and it just shows you that these
55:30people happen in people with with
55:32with no complaints but not not.
55:35They may have excessive sleepiness,
55:36but with nothing on the PSG showing
55:40an that we should pursue them.
55:43And this is just to confirm
55:45to you these people.
55:46All have normal sleep architecture
55:48by the by the regular stuff and it
55:52shows you the difference in their
55:54health outcomes and the last.
55:57The last thing we're looking at is
56:01whether these patterns can help
56:04us understand response to CPAP
56:08so so so this is type one.
56:10This is the last slide type one you see here.
56:13Type one very little here and
56:15very little here.
56:16And when we put them on CPAP you can see
56:19the left shift now getting towards normal.
56:23And the RP goes from one point.
56:26132.88.
56:27Sleep efficiency doesn't change, but.
56:32Because the sum of these three is
56:33the same as the sum of these three.
56:36But let's sleep depth improves.
56:39Here is type 1/2.
56:40Again, nothing here but modest amount here,
56:43and they also respond very nicely
56:45to see PAP if they have severe OSA.
56:48This is Type 3,
56:50the insomniac,
56:51or 36% of patients in this group
56:55of 200 patients
56:56had this type and when we put them on C.
56:59Pap, what you see happens is there is.
57:02Some improvement here 'cause you might be
57:04the OSA was just cutting or cutting short
57:07the amount of time in this and then when
57:10we put them on C PAP they went up a bit,
57:13but the insomnia didn't go away and
57:16these are people that have normal
57:18pattern before CPAP and nothing happens.
57:21Use either or P if anything actually
57:24went down. Sleep is less deep and
57:27their sleep efficiency went down.
57:29So we are now looking into whether.
57:32Improvement on sleep as identified
57:35by this pattern.
57:37Also, will predict compliance
57:38with C PAP and we're not done yet.
57:41But it looks very promising.
57:43Thank you very much.
57:45And any questions?
57:46I hope I didn't go too long.
57:50What do I do now?
57:52Oh, hi Maggie, that was wonderful talk.
57:54Thank you very much for giving us a look
57:59at this amazing work that you've done
58:01and there we are almost out of time.
58:04We have a couple of minutes for a few
58:06questions and so I'll just take some
58:07questions from the chat and Doctor Eric
58:09Heckman is asking whether you looked at
58:12or P and CSI in idiopathic hypersomnia
58:15patients and whether the numbers.
58:18In what patients idiopathic
58:20hypersomnia patients? No,
58:24no I have. I have several of
58:25them and but there's no question
58:27that they're going to be 31.
58:31Or even yeah, or even just
58:33continuously in deep sleep.
58:35I have I. I studied five of them
58:37in the original or the paper and
58:39they they were just like that.
58:41You know they had very
58:43low or peace throughout,
58:44but they didn't get enough
58:46time to recover completely.
58:50Uhm and Doctor Hilbert from Yale is
58:53asking whether or P is stable within a
58:56patient from 9 tonight. And so simple,
58:58yeah, well, you would expect
59:00that it would vary a bit,
59:02because because you know the amount
59:04of sleep pressure that you have at any
59:07given night can vary a lot by not a lot,
59:10but can vary depending on what you were
59:12doing the last few days or the last night.
59:15Alcohol and and all that.
59:17So it does vary and we do have Amy.
59:20Aimee Bender, who who works uh with us,
59:25not with me directly,
59:27but with the company. She just ran.
59:30They have this prodigy system and
59:33she restrained 20 normal subjects.
59:3720 consecutive nights.
59:38OK, each one ran 20 nights to look at
59:42this day-to-day variability in RP and we
59:45do have some earlier studies that also
59:47show that there is some variability,
59:50particularly in in,
59:52in in metrics that are that should
59:56be affected by sleep depth such
59:59as OR P in full wakefulness.
01:00:01And you know how much shift
01:00:03to the left or to the right,
01:00:05but you are there is in MORP,
01:00:08as I showed you.
01:00:09Doesn't change,
01:00:10it's very reproducible from night
01:00:12tonight and from one REM episode to
01:00:16another RAM episode during the night,
01:00:18but.
01:00:19I'm actually very glad to see
01:00:21Mary Krieger is the one who
01:00:24started me who started not know.
01:00:26He started me on this but when I
01:00:28moved to Winnipeg he showed me how to
01:00:30run a sleep lab and stuff like that.
01:00:32So thank you mayor and and.
01:00:39Any did I answer your question?
01:00:42I think so. What we'll do
01:00:45is we have to wait for the results of the
01:00:472020 to come up with the final answer
01:00:50on how much the ability you get, but you
01:00:52generally stay within the same pattern.
01:00:54It's just that you get a little bit
01:00:56of shift to the left or to the right.
01:01:00Suggesting that maybe a a characteristic
01:01:02or a trait for an individual.
01:01:05Yeah, alright, OK.
01:01:08And so I think I'll just ask one
01:01:10more question before we finish up.
01:01:12Make sure that we are mindful of the time
01:01:14and so one of the questions is that,
01:01:17like N3 decreases with aging,
01:01:19is there data that you looked at that
01:01:22shows any changes in RP with aging?
01:01:25Yeah, yeah, it's part of the same study
01:01:27we are going to be submitting and what
01:01:30happens actually with aging I I don't
01:01:32know if I have the slides right now,
01:01:36but. Uh, no, I don't.
01:01:40What happens with aging is the amount in
01:01:43deep sleep goes down progressively with age.
01:01:46We looked at them from 20 to 90,
01:01:49have a group of healthy young people
01:01:51from 20 to 4G, and then they sleep
01:01:54heart cells which covered 40 to 90.
01:01:57And yeah, it's a very very gradual
01:02:00drop in amount and deep sleep.
01:02:02That's that's the size one and two
01:02:06and progressive increase in decile 10.
01:02:09OK, so there is a progressive shift.
01:02:11To the right in and and the the.
01:02:16Epochs with yeah with high the the
01:02:19types with high full wakefulness are,
01:02:23you know,
01:02:23they they are quite frequently in old people,
01:02:26but they are very rare in young people.
01:02:29Wonderful, well thank you very much man.
01:02:31I did this was outstanding and I
01:02:33think for the sake of time I'm gonna
01:02:36hold off on asking more questions
01:02:37and hopefully folks can email you
01:02:39and connect with you if they have
01:02:40additional questions about you.
01:02:42Absolutely anytime. That's
01:02:43all I do is answer emails so.
01:02:48Alright, thank you very much for hosting me.
01:02:51You're looking forward to the
01:02:53next session that we will have in
01:02:55November on November 10th and so
01:02:57thank you kindly everyone and stay.
01:02:59Stay well and enjoy this fall weather.
01:03:03Thank you bye bye.