"Keeping Time in the Clinic - Understanding and Managing the Circadian Patient" Sabra Abbott (04/13/2022)

April 20, 2022

ID7740

To CiteDCA Citation Guide

00:00My name is Andrea Zentrack and I'm
00:03an assistant professor at Yale
00:05University School of Medicine.
00:07And welcome to yet another edition of
00:10the Joint Sleep Conference between
00:14our programs in the Northeast.
00:15I think we've grown from 2.
00:18Two programs to 6. And I don't know.
00:22Just say that we have an
00:24outstanding speaker today,
00:26and so during the talk I'll ask
00:28you that you mute yourselves.
00:30If you have a question or
00:32wanted to make him comment,
00:34please do so in the chat.
00:37In the chat is where also
00:40instructions for obtaining CME
00:42credit for today's talk will appear.
00:45And so if you are not
00:47registered with the LCM,
00:48you would have to do that first.
00:50And you can receive credit for
00:53attending the session 15 minutes
00:55prior to the end or 15 minutes
00:57after the end of the session.
01:01And so, without further ado,
01:03I wanted to introduce the
01:05very special speaker today.
01:08A friend of mine and a colleague
01:11of mine doctor Sabera Abbott,
01:13and so Doctor Abbott is an
01:16assistant professor of neurology
01:18at the Northwestern Medicine.
01:20And in Chicago, and I know Sabra,
01:23since our residency times and neurology
01:26back in Beth Israel Deaconess when
01:29I did my detour through neurology
01:30before I went to a pulmonary critical
01:32care and then eventually sleep,
01:33and so little,
01:34did we know we started in the same
01:36place and ended up in the same domain?
01:38And so I'm really excited to have
01:41her talk to us today because
01:43she is an outstanding physician,
01:46incredible scientist,
01:46and the and a a great clinician
01:50who cares about her patients.
01:52But aside from that,
01:54she started her academic career
01:56at Carleton College,
01:58where she received the BA in Psychology
02:01and then moved on to University
02:02of Illinois at Urbana Champaign,
02:04where she got her masters,
02:06followed by a PhD in Molecular
02:08and integrative Physiology,
02:10and then got her MD there before
02:12moving on to Beth Israel Deaconess
02:14Medical Center with Harvard,
02:16where she got her.
02:18Neurology residency,
02:19where she was also a chief resident,
02:21and.
02:22Completed her clinical sleep fellowship
02:25back in Chicago at Northwestern and
02:29so Sabra is a prolific academician.
02:35She does research and has ROI and
02:38program grants that she is a Co
02:41investigator on and she's old so
02:45published dozens of papers and.
02:49Chapters that are read throughout the
02:53world and are also appear in doctor
02:58Kriegers principles and practice,
03:00Sleep Medicine,
03:01and so just looking at her first publication,
03:04it sort of gives it away of
03:06what her passion is and her
03:08first publication back in 2003,
03:10and journal Neuroscience is
03:11circadian clock controlled
03:12regulation of cyclic GMP protein
03:14kinase G in an external domain,
03:16and so she is a.
03:21Aficionado of circadian clock.
03:23And that's what she's going to talk to us
03:26today about keeping time in the clinic.
03:28Understanding and managing the
03:30circadian patient from bedside
03:32to from bench to bedside. And so.
03:35I'm looking forward to the stock.
03:37Thank you so much for being with
03:39us Zebra and let's get to it.
03:42Great, well thank you Andre for
03:44that very very kind introduction
03:46and I too am very pleased that
03:49despite losing you as a neurologist,
03:51our paths continued across along the way so.
03:56It was in one of our discussions that
03:58Andre and I actually had about this
03:59talk where he made what I thought
04:01was a very insightful comment.
04:03Which and I don't know if you
04:04even remember this,
04:04but you said that circadian rhythms are
04:07like the neurology of Sleep Medicine,
04:09and I think that is very true
04:11in some respects.
04:12I think that circadian rhythms and
04:14neurology are both a little intimidating.
04:16When you first experience
04:18them and 1st approach them.
04:19But once you actually understand
04:21the logic behind them,
04:22they can be incredibly gratifying.
04:24And really a great field to be in.
04:27Granted,
04:27I have the bias that I am a neurologist
04:30who specializes in circadian rhythms,
04:32so maybe I am taking that
04:34a little personally,
04:34but my overall goal today is
04:36really to try to make circadian
04:38biology a little less intimidating
04:40for everybody in the audience,
04:42and I know we've got a wide range
04:44of experience just based on some of
04:46the names that I've seen coming in
04:47in terms of how comfortable people
04:49may be with circadian biology,
04:51but hopefully everybody will
04:52walk away just feeling a little
04:54bit better about the topic.
04:56I'm gonna start off.
04:57With just a general overview
04:59of circadian rhythms,
05:01just to make sure everybody is
05:02starting off on the same page and
05:04then gonna walk through a couple of
05:05case examples of patients who've
05:07come through the circadian clinic
05:08with me both going through them as an
05:11illustration of sort of how to manage
05:13the bread and butter circadian patient,
05:15but also some tips and tricks that
05:17we've taken from the research
05:18domain to try to help manage them.
05:20And then lastly,
05:21I'll wrap up with a summary of
05:23a research project we recently
05:26completed that was really based on.
05:28Some of the insights that we
05:29had from seeing these patients.
05:31So without further ado.
05:34First step is to get the slides to advance.
05:36There we go, so I have no disclosures.
05:39And as Andre said,
05:40the CME information is also gonna
05:42be in the chat for you,
05:43but it's on the screen here.
05:46So just to get things started,
05:47I always want to make sure that we
05:49kind of talk through the general
05:51concept of what do we even mean
05:53when we're talking about circadian
05:54rhythms and they're in general all
05:56of the physiological processes that
05:59we have that have a near 24 hour
06:02or about a day property to them.
06:05And I think it's easiest to understand
06:07these if we think about them from
06:09the idea of our sleep wake rhythms,
06:12because those definitely have a daily
06:14occurrence to them, and so I've.
06:17Plotted out here just a very idealized
06:20sleep wake schedule of somebody,
06:22and so we've got daytime over here.
06:23On the left.
06:24We've got night time here,
06:26and these black bars are the sleep
06:27periods for each of these individuals,
06:29or for this one individual.
06:31And you can see that in this 24 hour
06:34environment every day they go to bed at
06:35the same time wake up at the same time,
06:37and they're generally sleeping when
06:39it's dark out, but the question?
06:41The first one that comes up is,
06:43is this something that is simply
06:45a response to the environment?
06:47So the sun goes down.
06:48So we decide maybe we'll go to sleep.
06:50The sun comes up, we wake up.
06:51Or is this something that's
06:53actually intrinsic to your biology?
06:55Is this something that would
06:57happen even outside of that?
06:59Twenty that light,
07:01dark environment,
07:02and so several researchers set out
07:04to try to answer this question.
07:06One of them was the pair of
07:08Nathaniel Kleitman and his
07:10graduate student Bruce Richardson.
07:12And they did an experiment where
07:14they went into Mammoth Cave in
07:15Kentucky and monitored their sleep.
07:17Behaviors in the absence of
07:19those light dark time cues,
07:22and then similarly,
07:23you're going to ask off who is
07:25really considered kind of the
07:27father of human circadian biology,
07:29underwent a series of bunker experiments
07:31in Germany where he took subjects
07:33and put them into this bunker here
07:36and then monitored their behavior in
07:38the absence of those external time cues,
07:41I encourage you to go read
07:42these original papers,
07:44but I just took a small excerpt from
07:46them here and you can see he describes.
07:48There's a locked double door at the entrance
07:50in the small room between the two doors.
07:53An ice box serves for a first storage of
07:55urine samples through the same channel.
07:58We supply the subject with fresh
08:00food and other necessities such
08:01as one bottle of endex beer daily.
08:03So remember that when you're
08:05writing your Irbs include beer.
08:07If you're doing German research studies,
08:10but what I thought was really
08:12insightful about this was that
08:13he also participated in his own
08:15studies as a research participant,
08:17and so this is actually a plot of his own.
08:20Sleep wake rhythms when he was in
08:23that bunker and so you can see these
08:25black lines here are when he was
08:27going to bed and waking up each night
08:29as well as plotting the rhythms of
08:31his urine output during that time.
08:35He included in the paper this
08:37comment that from the knowledge
08:39of animal experiments,
08:41I was convinced that I had a
08:43period shorter than 24 hours,
08:44which had previously been seen
08:47in many nocturnal animals,
08:49such as mice for example.
08:51But he said when I was released on day 10,
08:53I was therefore highly surprised to be
08:55told that my last waking up time was 3:00 PM,
08:57and so again an example that even the
08:59best minds in the world sometimes are
09:01hypothesis are wrong and we have to
09:03sort of change our thinking about things.
09:05But I think also just a very interesting,
09:07interesting description of these first
09:10experiments trying to figure out
09:12what actually happens to humans
09:14in the absence of these time cues.
09:16So as you can see here,
09:17if we took our idealized human here,
09:20put them in an environment
09:22devoid of time cues each day,
09:24most humans get a little bit later
09:27and a little bit later each day.
09:30These behaviors are primarily regulated
09:32by the Super cosmetic nucleus,
09:34and so I have a cross section here.
09:36This is a coronal section through a human
09:40hypothalamus and you can see basically here.
09:42We've got our optic chiasm,
09:44the Super chiasmatic nucleus are these
09:46two little areas outlined in yellow here.
09:48They're directly above the optic
09:50chiasm and within the hypothalamus,
09:52so they can receive light
09:54information from the environment,
09:55and then they can also take that information
09:58and send signals to the hypothalamus.
10:00Where they can regulate things like sleep,
10:02wake behavior, feeding behavior,
10:04core body temperature,
10:06rhythmic hormone release,
10:07everything else that has
10:08that daily rhythm to it.
10:10Now we know that it's not just the SCN it
10:13seems to be sort of the primary pacemaker,
10:16but every other cell and tissue
10:18in our body also has a clock in
10:20it and the SCN we think serves
10:22to help coordinate and keep those
10:24clocks In Sync with each other.
10:27So I think one of the things that I
10:29find most fascinating about circadian
10:31biology is not only that we have this
10:34intrinsic time keeping mechanism,
10:36but it's also dynamic and it can be reset
10:40like a clock or a watch with time cues,
10:44and that resetting is both stimulus
10:47specific and time of day specific.
10:50So if we go back to our human example,
10:52so now we've put them in a cave,
10:54they have no light, dark exposure.
10:56Each day, they're going to bed.
10:57A little bit later and a little bit later,
10:59and if we come in at some point
11:02during their biological daytime,
11:04the time when they'd normally be
11:06awake normally be expecting to see
11:08light and expose them to light.
11:09You can see that the following day,
11:11it really doesn't change that daily rhythm,
11:14but if instead we came in shortly
11:17after the time that they fell asleep,
11:19so during a time when they normally
11:21wouldn't expect to be seen light
11:23and expose them to light,
11:24you can see that the following day
11:26that whole behavior gets later.
11:28And you can interpret that as
11:30almost an error signal.
11:32So perhaps the signal that day
11:34length is longer than expected,
11:37so we should push everything later.
11:38So again,
11:39we're sleeping when it's dark
11:41and we're awakening it's light.
11:42And then on the other end of the spectrum,
11:44if you take them and expose them
11:46to light in the early morning.
11:48So shortly before they were gonna wake
11:50up shortly before dawn would normally occur,
11:53you can see that the following
11:54day they actually get earlier,
11:55and so again a stimulus that daylight
11:58is showing up earlier than expected.
12:00We should move everything earlier,
12:01so again, we're appropriately aligned.
12:05In order to actually plot these results,
12:07we use something called a
12:08phase response curve and we'll
12:10show some more of these later.
12:11But basically this is just a 24
12:15hour plot here and our stimulus
12:18during the daytime has no effect,
12:20so it's not causing a phase shift,
12:22whereas our early evening
12:23stimulus is causing a delay
12:25or a negative deflection here,
12:27and our stimulus at the end of
12:29the night is causing an advance
12:30or a positive deflection here.
12:32Now that was a cartoon.
12:33This is what it actually looks
12:34like in real life.
12:35This is an example of a light phase
12:38response curve obtained from humans
12:39and one of the important things to
12:42keep in mind when you're managing
12:44circadian patients is the switch point,
12:46right here,
12:47and so we know that this occurs
12:49about the point of the core
12:52body temperature nature,
12:53which for most people occurs about 2
12:55hours before their natural wait time.
12:57So if you're trying to time light
12:59to appropriately shift a patient
13:01in One Direction or another,
13:03it's really important that your
13:04timing that light based on their.
13:06Biological time and not based
13:08on the external clock time just
13:10to give you an example,
13:11many of my patients don't fall asleep
13:14till 345 in the morning and so if I
13:15were to give them light in the quote,
13:17UN quote morning,
13:18so at 7:00 or 8:00 AM,
13:20I'd actually still be hitting
13:21them on the spades delay portion
13:23of the phase response curve and
13:25could potentially make them even
13:26worse by shifting them later.
13:28So making sure that you keep this in
13:30mind when you're trying to determine
13:33treatment timing for your patients.
13:35Now one of the other.
13:38Stimuli that we make use of in the clinic.
13:40Like I mentioned,
13:41each response is both time of
13:44day and stimulus dependent,
13:46and so one of the other tools
13:47we use is melatonin,
13:49so our bodies naturally produce melatonin,
13:52typically with levels rising a few hours
13:55before you naturally fall asleep at night.
13:57As you can see,
13:58indicated by the up arrow here
14:00and then dropping off as we fall
14:01asleep and the proposed sleep
14:03window is approximately here.
14:05With these, these upright lines here.
14:08And so with melatonin.
14:10Again, think of it like an error signal.
14:12So if you give someone melatonin before
14:15they would naturally be producing it,
14:18you end up pulling them
14:20earlier or advancing them.
14:21Whereas if you give them melatonin
14:23after they stop producing it,
14:25you end up delaying them
14:26or pulling them later.
14:27And so again,
14:28tools that we can make use of in the
14:31clinic to try to help shift people
14:33in One Direction or the other.
14:35But keeping in mind that if
14:37you give somebody melatonin.
14:38You want to make sure that if
14:40you're giving them melatonin
14:41with the goal of advancing them,
14:43you wanna make sure that you're
14:46having the melatonin present here,
14:47but no longer having it present here,
14:50which is why we care so much
14:52about dosing of
14:53melatonin, because we want to make
14:55sure we don't give them a really
14:56high dose of melatonin here,
14:58so it may help advance.
15:00But then it's still sitting
15:01around in the system out here,
15:03where then it's delaying and
15:05then working against us.
15:10So with that as the introduction,
15:13I now want to move on to talking
15:15about how we actually put this
15:17into practice in the clinic,
15:19and we think of primarily these four main
15:22intrinsic circadian rhythm sleep disorders,
15:24advanced delayed non 24 in your
15:27regular sleep wake rhythm disorder.
15:29We also do see some shift work disorder.
15:33Excuse me and then very rarely some jet lag.
15:37Starting to come back now,
15:38but had a two year hiatus from that.
15:40With the Payam pandemic certainly,
15:43but for today what I really wanna
15:45focus on are the two disorders
15:46I tend to see most in clinic.
15:48Specifically, delayed sleep,
15:50wake phase disorder and non 24 and
15:53we're going to start off with the case.
15:58So we have a patient who is a 34 year old
16:01woman and she comes into clinic and says,
16:04you know I used to be a quote
16:05UN quote normal sleeper.
16:06I'd go to bed around 11.
16:08I'd have no trouble falling asleep
16:10sleep through the night. I was fine.
16:12She got into a car accident,
16:14had a whiplash injury.
16:15And really since that point,
16:17her bedtime moved around to the point
16:19where by the time she came to see me,
16:22she was often not falling asleep till 3:30.
16:24Sometimes as late as nine.
16:25AM. And so as a first step,
16:28when evaluating these patients really
16:29what we want to do is get a sense of
16:32what are their patterns really like,
16:34and to do that,
16:35we use something called actigraphy.
16:37So this is just an example of one of
16:39the actigraphy watches we use in clinic,
16:42and an example of what the
16:43data might look like.
16:44This is not from this patient,
16:45as you'll quickly figure out,
16:48but basically general activity.
16:50Again, we plot in 24 hours,
16:52so we're going from noon to noon.
16:54Activity is indicated by
16:56these black bars here.
16:58Light exposure by the yellow
17:00line that's running through
17:01here and then we've highlighted
17:03the sleep window here in blue,
17:05and so this is actually for myself.
17:07When I was testing.
17:08One of these watches,
17:09and you'll see why I didn't use
17:11the patient as an example here,
17:13because it gets much messier
17:15in the clinical environment.
17:17And so these dark blue bars here are
17:20actually when the patient took the watch off.
17:23So you can see the first problem is
17:26simply getting patients to wear the
17:27watch for the full one to two or three
17:30weeks that you're having them wear them.
17:32But the other thing is that you can
17:34see from this recording are one.
17:36The overall activity thresholds
17:37were sent the set the same on
17:39both of those actor grams,
17:41but you can see this patient
17:43is quite inactive overall.
17:44And then you can also see overall
17:46her sleep patterns are quite
17:48irregular in terms of wait time.
17:50Often this is set by other obligations,
17:53for example like having to
17:54get to work on time,
17:55but on average she's typically
17:57falling asleep somewhere on one to
17:59two in the morning during this time
18:01frame and getting up anywhere from
18:048 to noon depending on the day.
18:07So one of the other tools that we
18:09can make use of to try to get a
18:11sense of whether a patient has a
18:13circadian disorder and what exactly it is,
18:15is to get a sense of what time
18:17they're naturally producing.
18:19Melatonin.
18:19Like I said,
18:20for most people that typically starts
18:22an hour or about two to three hours
18:24before their natural sleep time.
18:26And so in clinic we've set up these
18:29kits where we can actually collect
18:31melatonin from an individual saliva.
18:33So over here we've got these tubes.
18:35They have a little cotton swabs in them.
18:37They can go through these in
18:39order every half hour to hour.
18:41During that time point before bedtime,
18:43we have them wear these blue blocking
18:45glasses and dim the lights during
18:47that time and using that we can
18:49then obtain a profile of what their
18:51normal melatonin profiles look like.
18:53So in this particular patient you
18:55can see her saliva melatonin here,
18:58so she started collecting around
18:597:30 and you can see that the point
19:02at which your melatonin started
19:04to rise is just after midnight,
19:06and so this fits with her report when
19:08she came in of often not falling
19:10asleep till 2-3 in the morning,
19:12and so all of this data together.
19:15Really supports the diagnosis of delayed
19:18sleep wake phase disorder and I've
19:21included here the ICCSD 3 criteria.
19:23Basically,
19:24you need a significant delay in the
19:25phase of the major sleep episode in
19:27relation to the desired or required
19:29sleep time and wake up time.
19:31Symptoms have to be present for
19:32at least three months,
19:33but if they're allowed to
19:35choose their own schedule,
19:36they actually sleep better.
19:39It look like to diagnose this with either
19:42a sleep log or actigraphy for at least 7,
19:45preferably 14 days.
19:46To show this delay in the
19:48timing of their sleep period,
19:49and then obviously you want
19:51to make sure that you rule out
19:54other sleep disorders that could
19:56be explaining this better.
19:57In terms of what causes delayed
19:59sleep wake phase disorder,
20:00there are many potential theories,
20:02so there are familial cases of this,
20:05and so there's been a description
20:07of a cryptochrome 1 mutation
20:09in some families with this.
20:10This is one of the core clock genes,
20:12and I didn't go into this
20:14in the introduction,
20:14but we have within each of ourselves
20:17a core set of clock genes and that
20:21transcription translation feedback loop
20:23typically takes about 24 hours to complete,
20:26but mutations?
20:27Could be their speed that up or slow
20:29that down can either make you advanced
20:31in the case of speeding it up or
20:34delay in the case of slowing it down.
20:36So you can think of these patients
20:38as simply just persistently running
20:40a little bit behind everybody else.
20:43And that goes along with demonstrations
20:45from several labs that these patients
20:47tend to have a longer circadian period.
20:50So left to their own devices they
20:52get later and later each day much
20:55later than the average person.
20:57And there have been several reported
20:58cases of people with head injuries,
21:00and we think that this may be due to
21:03either a delay and or decrease in the
21:05amplitude of melatonin production.
21:07And then we'll get into this a
21:09little bit more later,
21:10but there does also seem to be a role
21:12for both timing of exposure as well
21:14as responsiveness to bright light.
21:18So we've made the diagnosis.
21:20Now what do we do as far
21:22as treating this patient?
21:24And I've put up two things.
21:26We'll get to the next one,
21:27so I've included here.
21:29The current published 2015
21:31ASM treatment guidelines,
21:33which basically say that in
21:34both adults and children,
21:36we recommend using
21:38strategically timed melatonin.
21:40Now I will say that I don't actually
21:42follow what's currently in the guidelines,
21:44so the one reference that they cite
21:47actually was a study that used 5
21:50milligrams between 7:00 and 9:00 PM.
21:52And So what I've put here is actually
21:54what I tend to do clinically,
21:56and we're starting to work together
21:57with several other circadian clinics
21:59on some consensus guidelines.
22:00And I think we're all in agreement
22:03that we typically now tend to go lower
22:05and have changed the timing slightly.
22:07So if I'm managing a patient with
22:10delayed sleep wake phase disorder.
22:12I will typically give them
22:13half a milligram of melatonin.
22:15Again,
22:15with that idea of keeping that
22:17dose low so it's that strategic
22:19pulse that's there when you
22:21need it and gone when you don't.
22:23And based on that phase response
22:24curve that I showed you earlier,
22:26it's about five hours prior
22:27to their current bedtime,
22:29so if they biologically were allowed
22:31to sleep when they prefer to,
22:34or if they're not that delayed,
22:36we're just trying to shift
22:37them an hour or two.
22:38I will sometimes just give it an
22:40hour prior to their desired bedtime,
22:42and we'll go through some of that.
22:43Data for that in the next slide.
22:46It's key for all of these patients to
22:48avoid bright light prior to bedtime,
22:50we'll talk about some of the
22:52data supporting that later.
22:53And then we also make sure that they
22:56get bright light after their wake
22:58time and that can be anywhere from 30
23:00minutes to two hours of light total.
23:02I usually spread that out over
23:044 hours and again,
23:05like I emphasized if they're having to
23:07get up earlier than they naturally would,
23:10I actually have them wear dark
23:11glasses until that time when they
23:13would be waking up so they're not
23:15inadvertently getting bright light
23:16during the phase delay portion of the
23:18phase response curve instead of the
23:20phase advanced portion where we want it.
23:23So I told you I'd go through the rationale
23:26for the one hour prior to desired bedtime.
23:28So after the ASM guidelines came
23:30out this this study was published,
23:32which basically was looking at the
23:35use of melatonin in the treatment of
23:38delayed sleep wake phase disorder.
23:39They took 116 participants with
23:42delayed sleep wake phase disorder.
23:44They define that as the delmo had to either
23:46occur less than 30 minutes before or at
23:48some point after their desired bedtime.
23:51So there was a mismatch
23:52between their biological.
23:54Timing and when they wanted to sleep.
23:57In, on average, these patients
23:59had a sleep onset of about 1:30.
24:02Their sleep offset was at about 9:00 AM.
24:05And they were randomized to either
24:07four weeks of placebo or half
24:09a milligram of melatonin,
24:10and they were told to take it one
24:12hour prior to their desired bedtime
24:14and then to get into bed at that
24:16desired bedtime and on average for
24:17the study population they wanted
24:19to go to bed at about 10:30.
24:23After that four weeks,
24:24they found that the melatonin group
24:26had an onset sleep onset time that
24:28moved about half an hour earlier.
24:29Their sleep efficiency also improved.
24:31They did do a subgroup analysis
24:33where they didn't actually find
24:35a significant change in Dino,
24:37and to go back to the point
24:39that I made earlier that I do
24:41differentiate between the milder and
24:43the more severe delayed patients.
24:46This tends to work pretty well,
24:47for example, if it's a patient
24:50who's falling asleep at 12:31.
24:52They wanna fall asleep at 1111 thirty.
24:55It tends to help them shift at that point,
24:57and they're not spending a tremendous
25:00amount of time in bed not able to sleep.
25:03But take for example if I have one of
25:05my patients who doesn't fall asleep
25:07till 3-4 or five in the morning,
25:09but they'd like to fall asleep at 11.
25:12Now I'm telling them take this
25:14melatonin at 10:00 PM. Get into bed 11.
25:17And lay there for five hours.
25:20Obviously that's just going to feed
25:22into some of their frustrations
25:24that they've been dealing with for
25:26most of their life, and we do see.
25:29A lot of comorbid insomnia in these patients,
25:32and so that's why if we're trying
25:34to make larger moves,
25:35there's a larger mismatch.
25:36We tend to do this more targeted
25:38treatment where we really inch
25:40their rhythm earlier instead.
25:44So going back to case one so we treated
25:46her with that timed melatonin timed light.
25:48She responded really well and
25:50she actually was able to shift
25:52her bedtime to about 10:00 PM.
25:53Her sleep latency decreased about 10 minutes,
25:56which was great and she actually
25:58did really well for about two years.
26:00But then she started having several
26:02days per week where she started drifting
26:04later so she was falling asleep and
26:07waking up later and ended up having to
26:09miss or be late to several days of work.
26:11She was at the point where she was about to.
26:13Trust or sick days.
26:14She was potentially gonna lose
26:16her job and so we really needed to
26:18figure out something to do.
26:20And it was actually right around this
26:22time that Ken writes group published
26:24this study and so another one.
26:26If you haven't read it,
26:27definitely take a look at this,
26:28but this was his infamous camping study
26:31where he took a group of individuals
26:33and you could see indicated over here
26:36under electrical lighting conditions.
26:38Their melatonin onset was
26:40occurring sometime after sunset.
26:42They're offset was occurring.
26:43After sunrise,
26:44so they were delayed with
26:46respect to the environment.
26:48He took them camping in Colorado
26:50for a week and with that natural
26:53light exposure he managed to shift
26:55everybody earlier and better in,
26:57train them with the environment.
26:59You can see melatonin onset and
27:02offset are now better matched with
27:04sunset and sunrise and so this
27:07made it into the general public.
27:10News had a lot of publicity
27:12around it and so my patient.
27:14All this and her question for me at
27:16first was should I go to Colorado
27:19and go camping and it turns out that
27:22she is somebody who likes to camp.
27:24She will often go camping in the
27:26area in Illinois and Wisconsin
27:27and we sort of talked through the
27:29rationale behind the study.
27:30And so there's really nothing magical
27:32about the Rockies as far as we know.
27:34It's really just that elimination of
27:36electrical lighting that made the difference,
27:39and so she actually was able to
27:40set up a tent in her backyard.
27:42This is not her tent,
27:43it's a Google image of tent.
27:45Backyard,
27:46but she was able to set up a
27:48tent in her backyard.
27:50Really could follow that schedule for a week.
27:52She turned off all electrical lights,
27:54all lights in her yard.
27:56The only thing that kind of failed
27:58us along the way is one night a
28:00skunk did come in sprayer tent,
28:01but because we had talked
28:03through what the principle was,
28:04that one night she went into her house
28:06trying to make sure she turned on.
28:07No lights,
28:08washed her tent the next day and
28:10went back to it and it actually
28:12worked really well.
28:12So after a week of camping
28:15we got our schedule.
28:16Advanced and then she will sometimes
28:18now go back and re entrain with these
28:20electricity free weekends to kind
28:21of get herself back on schedule.
28:23And I think from a logistics
28:25standpoint probably the thing I'm
28:27most satisfied about is we could get.
28:29We got her a week of short term
28:31disability to do this camping as well.
28:34So we got our employer to cover
28:36it as part of her treatment.
28:37So that was just a nice insight
28:39into both how to manage the basic
28:42circadian disorder as well as
28:43how we make use of some of the
28:46published data that's out there.
28:47And now I'd like to move on to my
28:50second case so this is another one of
28:53my favorite patients who I've been
28:55following pretty much from the bright after.
28:58I think he may have been one of the first
28:59patients I had as a brand new attending,
29:01and I've been following him ever since.
29:03At the time I first saw him,
29:06he was 35.
29:07He was somebody who like many of my patients,
29:10said he's always been a night owl,
29:12but he came in because at some point
29:14things got worse and he could no
29:16longer follow a 24 hour schedule
29:18I've dubbed in the Martian because
29:19a lot of my patients with this
29:21disorder will refer to themselves
29:23as that because the Mars day is a
29:25little bit longer than the Earth Day.
29:28So, like many of my patients,
29:30he had kept meticulously blogs
29:32before he came to see me,
29:34and this is just an example of
29:36what his sleep looked like before
29:38things started to get even worse.
29:41What I have here is a double plot,
29:43and so we've got this sleep period.
29:45Up here is replatted down here.
29:47This is 48 hours and you'll see why
29:49in the next slides it's a little
29:51easier to plot things this way,
29:52but if you wanted to just focus
29:53on the right side to begin with.
29:55What we have is kind of what we
29:56typically see with these delayed.
29:58Emotions that they sort of force
30:00themselves into a midnight to 8:00 AM
30:03scheduled during the week they delayed
30:05to their preferred schedule on the weekend,
30:07and then they go back and
30:09forth and back and forth.
30:10It's not great, but they can live with it.
30:14He saw a very well meaning sleep
30:17provider who was trying to treat
30:18him initially by giving him some
30:20bright light in the morning,
30:22which you can see here and then he was
30:25instructed to follow Chronotherapy.
30:27So that idea of gradually delaying
30:29your sleep wake period until you reach
30:32the point where you're going to sleep
30:34and waking up when you prefer to.
30:36And at that point you're supposed
30:38to try to put the brakes on it
30:40and keep things from delaying.
30:42And with that he was supposed
30:44to start taking melatonin.
30:45As indicated in green and using bright light.
30:49Unfortunately,
30:50he started drifting and just kept going,
30:54and so by the time he came
30:55to see me in the office,
30:57this is what his actigraphy looked like,
30:59and you can barely make out his activity.
31:02He overall tends to be a fairly
31:04inactive person, but if you kind
31:06of lean back and squint a little,
31:08you can see that his onset of activity
31:10every day gets a little later and
31:12a little later, and a little later.
31:14This is an outlier here because
31:15he had a doctor's appointment.
31:17The other thing that's noteworthy about him,
31:19and we'll get to this later.
31:21He really doesn't have a lot of light
31:23exposure and so you can see that that
31:26yellow line here has very low amplitude
31:27to it and if you talk to him about this,
31:30he really prefers to spend
31:32his time in dimly lit rooms.
31:34He finds bright light,
31:36kind of irritating and just
31:38really doesn't like it.
31:40So he fits the criteria for non 24
31:42hour sleep break rhythm disorder
31:43and if I didn't mention this before,
31:45he does have normal image forming vision.
31:47So this is not a blind patient.
31:51So for non 24 they can come in
31:53with lots of different complaints.
31:55They can either have insomnia,
31:57excessive daytime sleepiness or maybe
31:59both depending on where you hit them
32:01within that constant delay and cycle.
32:03Some of them have figured out
32:04what's going on,
32:05but it's something to keep in mind
32:06if you have somebody who just cannot
32:08describe their sleep wake schedule to you.
32:10Investigating a little bit
32:11further with that trigger.
32:13Fear sleep logs to really get a sense of
32:16what the pattern is can be very helpful.
32:19In terms of what causes this,
32:20so this was first described
32:22in blind individuals.
32:23We're going to get into this
32:25a little bit more later,
32:26but really it makes sense if
32:28you lose that photic input.
32:30If you lose that light signal to the SDN,
32:32telling the SDN when it's
32:34night and when it's daytime,
32:36you're then going to follow that
32:38intrinsic rhythm and get later and
32:39later and so in blind individuals.
32:41This has been previously described,
32:43although not everybody who's
32:44blind has this disorder.
32:45To keep that in mind.
32:47And then in our patient here we do see
32:49a lot of these in sighted patients.
32:52It's likely multifactorial.
32:53A combination of minimal social cues,
32:56potentially a prolonged
32:57intrinsic circadian period,
32:59and what I most often see is that
33:01these individuals will start as what
33:03we call sort of the extreme delayed,
33:06and then eventually they just sort
33:07of fall off and become non 24,
33:09and they may alternate and go back
33:12and forth between the semi stable
33:14and trainment and being non 24.
33:17So going through the task force
33:19guidelines on basically there
33:20is a recommendation for the use
33:22of timed melatonin.
33:23Clinically, what we tend to do in blind,
33:26we'll still follow that,
33:27so typically using half a
33:29milligram to 3 milligrams,
33:31taking an hour before desired bedtime,
33:33they're also is the approved
33:35medication tasimelteon,
33:36which we'll talk about in the next slide.
33:39In sighted individuals,
33:39it tends to get a little more complicated,
33:42and so we have a number of
33:45different protocols we've
33:46been trying. We will often do half a
33:49milligram of melatonin, about five
33:52hours before their desired bedtime,
33:54as more of the phase shifting dose,
33:57and then an additional 1 milligram of
33:59melatonin an hour before their desired
34:00bedtime is more of a hypnotic dose.
34:02Once they're close to their desired
34:04bedtime to try to anchor them there,
34:07we'll use very strict sleep schedules,
34:09timed light exposure when they wake up,
34:11and then we'll talk a little bit more
34:13about some of these other things we've
34:15used feeding and activity as well.
34:17Just to go through has a meltdown,
34:19so this is a melatonin agonist.
34:21This is the data from the set and reset
34:24trial indicating its effectiveness,
34:26and in this trial they were just
34:28looking at blind individuals and they
34:30found that 20% of the patients in the
34:32tasimelteon group met their criteria
34:34for in treatment at one month compared
34:36to only 3% in the placebo group.
34:38So this is approved.
34:40Technically,
34:40the FDA indications do not specify
34:43that you have to be blind or sighted,
34:46just that you're not.
34:4724 although sometimes you will
34:49run into issues with insurance,
34:51trying to say that oh, they're not blind,
34:52we're not gonna cover this.
34:53Usually that can be addressed
34:55in a peer to peer.
34:56The main reason I don't use this more though,
34:58is that if you look down here,
35:00the price of one month supply of
35:03tasimelteon is about $23,000 compared to
35:06$3.00 for one month supply of melatonin.
35:09I don't have anything personally
35:11against hazing Melton.
35:12I think I've gotten a reputation
35:13as somebody who doesn't like it.
35:14It does work.
35:15I just like to try the cheaper option.
35:171st and then move to tasimelteon.
35:19If I can't reach success with melatonin.
35:23So we started treating that individual
35:25and he got back to me after we got his
35:29sleep wake schedule on track and he said,
35:31well.
35:31I'm going to bed and waking
35:33up when I want to,
35:34but now it really feels like my
35:36body has three different schedules.
35:37My physical self now seems to
35:39follow a more normal schedule.
35:41My mental self seems to be highly
35:43nocturnal and my metabolism has
35:45changed to require only one small meal
35:47every 24 hours instead of 12 hours.
35:49And for me this was really
35:52interesting because this to me
35:54said we have desynchronized him,
35:57so I mentioned that we have clocks
35:59throughout our all throughout our body
36:01and it seemed like we had gotten.
36:03Sleep wake schedule on track.
36:05But for example, his peripheral clocks.
36:08His metabolism was not in line with that,
36:11so we got some sleep or some food
36:13logs from him and you can see just
36:15listed here his meals and I did some
36:18estimated calories and it really
36:19like you said he's just eating
36:22one meal encompassing most of his
36:24calories for the day at one time.
36:26And so we started to do some additional
36:29work with him on adjusting food timing.
36:31Really coming up with the skeleton.
36:33Eating period to be in alignment with his
36:36sleep wake timing and we managed to get
36:38him in trained and so now here he is.
36:41He's still diligently and if this is now
36:4310 years later I think almost he continues
36:45to send me these monthly sleep Diaries
36:47just to show me he's still on track.
36:50He's still in trained.
36:51We were able to get him back to work.
36:53He's on a flexible schedule now so he
36:55works more of like a second shift hour,
36:57but he's going to work everyday and
37:00is pretty happy with the schedule.
37:02So that leads to the final question,
37:04which is why do patients develop
37:06delayed sleep, wake phase disorder,
37:08and more importantly,
37:09why do sighted patients develop
37:12non 24 and we think about this
37:15first in terms of light exposure.
37:17So if we go back to that idea
37:19of in treatment,
37:20so how do the rest of us without
37:24circulating disorders sleep when it's
37:26dark and be awake during the daytime?
37:28And we think a lot of that comes from
37:30that daily exposure to sunshine.
37:32Giving us that morning advancing
37:34signal to keep us in line so that
37:37we're asleep when it's dark.
37:38So one theory for delayed sleep,
37:40wake phase disorders.
37:41Oh these are people who are just
37:43staying up later and waking up later,
37:45so maybe they're getting too much
37:46light at night and it's pushing
37:48them even later and they're getting
37:49less of that morning.
37:50Advancing signal because they're
37:52just not waking up in time.
37:54So we did one study trying to look at that,
37:56and there are several of these
37:57out there published,
37:58and certainly if you look on the
38:00left hand panel here at light
38:03exposure related to clock time,
38:05our delayed patients are here in blue
38:07and you can see that midnight is over
38:09here on the left and really anywhere
38:11from about 10:00 PM to about 4:00 AM.
38:13They're definitely getting more
38:15light exposure than our controls,
38:16getting much less light first thing
38:18in the morning up until about noon.
38:21But interestingly,
38:21if you align that based on their.
38:24Clock time so their internal time,
38:26so using dim light melatonin onset
38:29you can see that actually on this end.
38:33So in that region of fades delay
38:35there's really no difference in
38:38that first early morning region.
38:40There's really no difference.
38:41We're only seeing a bit of a
38:44difference in what we're terming
38:45the late phase advance window,
38:47so sort of later in the morning.
38:50The delayed are getting a little
38:52bit less light exposure than the.
38:54Controls are getting,
38:55and so we think they may be missing
38:57out on a little bit of that phase.
38:59Advancing signal,
39:00but maybe not necessarily enough
39:02to fully explain the phenotype
39:05that we're seeing.
39:06And So what are some other theories?
39:08So,
39:09another idea is that you get
39:11the same light exposure,
39:13but you have more of a response to it,
39:15so maybe you're overly sensitive
39:17to evening light or under
39:19sensitive to morning light.
39:21Sean Kane's group in Australia has done
39:24some work looking at this and they did
39:27find that with the exact same light
39:29pulse patients who were delayed had a
39:32larger phase delay and I don't like
39:34how this graph is because the delay is
39:37actually positive instead of negative,
39:39but they have a larger fades delay as
39:42well as greater suppression of melatonin
39:44in response to an evening light pulse.
39:47So there does seem to be some excess
39:49sensitivity in some of these individuals.
39:51But then what?
39:52About the other question,
39:53what about this morning light sensitivity?
39:57So getting back to what I was touching
39:59on before our eyes do a lot of things.
40:02We have what we most commonly
40:04think about this image,
40:05forming visions that we look at an apple.
40:07We see an apple,
40:08but there's also non image forming vision.
40:11So these are things like these
40:13circadian light response.
40:15The alerting effects of light
40:16and that sort of thing.
40:17So the image forming vision.
40:19This is a an image of the retina
40:21here image forming visions mediated
40:23primarily by our rods and cones here.
40:27That non image forming vision
40:29is primarily mediated by these
40:30intrinsically photosensitive retinal
40:32ganglion cells that contain a
40:35photo pigment called melanopsin,
40:36and the nice thing about these
40:39cells is that they not only project
40:41to the SCN where they can mediate
40:44the circadian signal of light,
40:47but there's also a projection from
40:49these cells into the brainstem to
40:52the olivary pretectal nucleus,
40:54which goes to the Edinger Westphal
40:56nucleus which controls pupil.
40:57Diameter so we can use that pathway
40:59as a way of measuring how well
41:02these cells are functioning.
41:04We can do that in the clinic using
41:06something called a pupillometer
41:08as we have pictured here,
41:09so there's a set of binoculars that
41:11the subject is going to look into,
41:13and then there's an infrared camera
41:15that actually outlines the pupil
41:17diameter as seen here and then you can
41:20provide different light stimuli and
41:22then measure the pupil response to light.
41:25When we're looking at melanopsin,
41:27these cells really give you a sense of
41:30the overall light tone of the environment,
41:34and so rather than being a second by
41:36second response to the light that's there,
41:39they hold sort of a static response,
41:41and this is illustrated here.
41:43If you look at the dotted blue line,
41:44so we've got pupil diameter here.
41:47If you provide a blue light stimulus,
41:49the people constrict.
41:50You turn off the stimulus,
41:52and if those melanopsin cells are
41:54functioning the way they're supposed to.
41:56That pupil will read dilate but not
41:59fully back to the baseline right away.
42:02Compare that to somebody who doesn't
42:04have well functioning melanopsin cells.
42:07You can see the pupil diameter
42:09here in the solid blue line,
42:11they constrict,
42:11and then they radiate essentially
42:13back to where they were before,
42:16and so we can use a measurement
42:18called the PIPR,
42:19which is literally just that
42:21difference between the post
42:22stimulation and the pre stimulation.
42:24So the larger that is.
42:26The better the melanopsin cells
42:28are functioning, the smaller it is,
42:30the worse they're functioning.
42:32So our simple question was,
42:34is the PIR impaired in patients with
42:36delayed sleep wake phase disorder
42:38non 24 and part of this comes back
42:40to I mentioned before that patient
42:42with non 24 had minimal light
42:44exposure that tends to be a common
42:47phenotype with these individuals
42:48they tend to not like bright light.
42:50They've kind of like your migraine
42:52or they've turned down the
42:53lights in the clinic room.
42:54If they have the option to they
42:56tend to spend more time in dimly
42:59lit environments because the
43:00light is irritating to them.
43:02So these are our study participants.
43:04We broke this down so we have our
43:07control individuals here and then
43:08within our clinical population
43:09we had patients who came in
43:11with purely delayed sleep,
43:12wake phase disorder,
43:13and I say that they just had a
43:16problem based on ICSD 3 criteria that
43:18they're sleep like timing was late,
43:20but they never had a time period
43:21where it actually got later and
43:23later and went around the clock.
43:24We had twelve of those and then we had 12
43:27patients who had symptoms of delayed sleep,
43:30wake phase disorder.
43:31But if you asked them that.
43:32Question,
43:33have you ever actually gotten so late
43:34that you've gone around the clock?
43:36Do you go back and forth
43:37between those two states?
43:38We had 17 patients who had that phenotype.
43:42Overall, similar age.
43:43Obviously lower scores on the
43:46Horn osberg indicating more
43:48eveningness within this population.
43:51Worst scores on PSQI,
43:52which is previously been
43:54described in DSPD patients,
43:56but not any sleepier than our controls,
43:59and then the average sleep onset,
44:01offset and sleep midpoint,
44:02was significantly later in our delayed and
44:05even later in our non 24 overlap group,
44:08but total sleep time was the same
44:10across all groups and then lastly
44:12the people on the tree testing in
44:15relation to time since they woke up
44:18was slightly closer to wake time.
44:21And our delayed and non 24
44:23overlap compared to our controls.
44:25But we know that from previously
44:27published studies the PIPR only tends
44:29to change around the time of dim light,
44:32melatonin onset and otherwise remains
44:33fairly stable throughout the day,
44:35and so we were well away from the Duomo
44:38window for all of these individuals.
44:41This is data from one control
44:43and one delayed subject.
44:44Just showing an example of the tracing.
44:47And as you can see here,
44:49our delayed patient in the solid blue,
44:53there's their pupil diameter.
44:54You provide the light stimulus,
44:56the pupil constricts.
44:57They radiate almost to exactly
44:59where they were pre stimulus
45:01compared to our control,
45:03who constricts and then maintains
45:05that constriction post stimulus so you
45:09can see smaller pipr in our delayed
45:12patient compared to our control.
45:14This is just quantifying it here
45:16and so you can see controls.
45:18Overall have a larger Pi PR
45:21significantly greater than the
45:23non 24 hour overlap,
45:24and then there's kind of a range within
45:27that just delayed group which we think
45:29may come from the fact that there
45:31are several different phenotypes of delayed.
45:33There's sort of this.
45:35We're still working on terminology,
45:36but some of them have a mismatch between
45:38their demo timing and their preferred timing,
45:41and some of them are both their
45:42demo and their sleep wake.
45:44I mean it's delayed,
45:45so I think that we're capturing that with
45:47some of the variability that we see here.
45:49But essentially this is a first pass,
45:51telling us that we think that we
45:53may have found a subpopulation
45:55of individuals who have at least
45:58based on bedside and office exam,
46:00have normal image forming vision,
46:02but they're non image forming.
46:04Vision may have some impairment and
46:06this may be part of why they end up
46:09either delayed or developing this non
46:1124 hour phenotype because they're just
46:13simply not able to respond normally to
46:16that morning advancing light signal.
46:19And so with that,
46:20I'd just like to acknowledge the people
46:21who helped me out with this project
46:23and elsewhere within the clinic.
46:24Uh, the funding sources for this,
46:26as well as their clinical staff
46:27who conducted some of the people
46:29on the tree measures and have been
46:31phenomenal at helping to manage
46:32these circadian patients as well.
46:34And with that,
46:34I believe I did allow some
46:36extra time for questions.
46:41Fantastic thank you.
46:43Thank you very much Sabra.
46:46A great great journey from the basics to
46:49clinic and over to the field of research.
46:52And so the question the the
46:55pupil is a amazing thing.
46:59And So what happens to the people
47:02and people who may not have sort of?
47:08May not be healthy otherwise,
47:09so like it is our comorbidities
47:12such as you know, diabetes,
47:14hypertension, etcetera.
47:15Obesity, for example,
47:16affect people that are responses.
47:20Absolutely. And So what I left out in
47:22the abbreviated summary is that we took
47:25very otherwise healthy individuals,
47:27and so the pupil does so many
47:30different things. It gives you an
47:32insight into autonomic function,
47:34and so that's often where we
47:35tend to use pupillometry,
47:36particularly in the ICU,
47:37in the diabetes realm.
47:39And so it can give you a sense of
47:41parasympathetic sympathetic balance that
47:43tends to be that more immediate response.
47:46And we do see some differences in these
47:48patients in that autonomic realm.
47:50As well, and then the PIPR that we were
47:54looking at tends to do more of that
47:56retinal ganglion cell measurement,
47:58but you can see a loss of those
47:59and lots of other disorders besides
48:02delayed supplicates disorders,
48:03so it's been reported there's been
48:05impairment in seasonal affective disorder.
48:07We think that there may be some drop
48:09out of this in patients with Parkinson's,
48:10and so absolutely,
48:12I think you just examining the
48:14people alone could find you know
48:16problems in almost every disorder.
48:20Cool well if you into the soul all right.
48:25All right, so so we have some other
48:26questions and I have a couple more,
48:28but I want to make sure I address
48:29the the folks in the Chancellor.
48:31Doctor Cohen is asking does
48:32the use of chronic exogenous
48:34melatonin have any impact on ones
48:38endogenous melatonin secretion?
48:39So does it suppress it?
48:42As we know, and certainly not
48:44at the doses that we tend to
48:46use for our circadian patients,
48:47and so I will see a lot of patients
48:50who show up in clinic, and I think
48:52our typical response is always well.
48:54If something doesn't work,
48:55let me take more of it and so I think
48:57the record I've seen is somebody who
48:58came in by the time they came to see me.
49:00They were taking 80 milligrams
49:02of melatonin at night.
49:03I was surprised that they were actually
49:05still awake in time for their appointment,
49:07but in those doses I might be
49:11more concerned about this.
49:12But using half a milligram,
49:14just trying to mimic physiological doses.
49:16We haven't noticed any.
49:17Inability to produce your own melatonin.
49:20Know sort of negative feedback loop.
49:21Anything like that,
49:23right? Cool? Yeah, because I think
49:24you know a lot of people use
49:27melatonin for induction of sleep,
49:28and some of them go up,
49:29you know, 1012 etcetera and so,
49:32and so that that always that's the cross.
49:35Our mind as we think about this.
49:37And so, doctor Ahn says,
49:39and have you found that there are any
49:42dietary effects on melatonin testing?
49:44So I have read that nuts,
49:47fruits, alcohol?
49:48Rice can increase melatonin levels,
49:50and you instruct patients to avoid
49:52these substances and the night when
49:53they do their military and testing.
49:55So we have a whole set of
49:57instructions that we give patients,
49:58so there's a bunch of things
50:00that can affect melatonin.
50:01I think one of the most important things
50:03to keep in mind is beta blockers actually
50:06inhibit melatonin production, so.
50:10Keeping that in mind when you're
50:11testing your patients bananas,
50:13ibuprofen other things can also influence it,
50:17and so we in general instruct
50:19patients do as much as possible,
50:21don't eat anything within 15 minutes
50:24of doing the saliva testing as well.
50:27But yeah, there's lots of things that
50:30can influence melatonin production,
50:31so we do try to instruct subjects
50:33to be careful with them.
50:37So from a practical standpoint.
50:41How do you order the milestone testing?
50:44Who passed for it? Is that a pocket?
50:46Because I I want to do it with
50:48my patience and so how do I?
50:49How do I? How do I do that?
50:51I mean, I've done it before,
50:52but it was, you know,
50:54it took a little legwork
50:55right now. Our kids are homegrown,
50:58so we put them together ourselves and
50:59had to go through a whole process of
51:01making our own epic order and everything
51:03else to be able to implement and
51:05them implement them in the clinic.
51:09There is at least one commercial testing
51:11group available that I've seen out there.
51:13Their prices tended to be a little bit higher
51:16and I would interpret the data yourself.
51:21But the right now I think the biggest
51:25downside to melatonin testing is
51:27it's not covered by insurance.
51:30We are working as a sort of consortium
51:32of people interested in circulating
51:34disorders on putting out a paper on
51:36melatonin testing and sort of the
51:38clinical benefits of it and continuing
51:40to work to try to get insurance
51:42companies to routinely reimburse
51:43for both demo testing and you didn't
51:46open the other can of worms,
51:47which is getting reimbursed
51:48for actigraphy testing,
51:50which we're also working on.
51:52Well, thank you and I'm
51:54doing it on both sides.
51:55That doctor Hilbert has a question.
51:57Given the variability and over
51:59the counter melatonin branch of
52:01brand or locked a lot even what
52:03do you recommend from melatonin
52:06prescription or or purchases?
52:08It has to be USB grade or.
52:11So I I wear two hats on this.
52:14UM, my clinical hat is really what I care
52:17about more is that they get a low dose
52:19and whatever they're able to track down,
52:22as long as it's half a milligram.
52:24I'm actually fine with that.
52:25We do have some specific melatonin that
52:28we use for research studies and tend to be
52:31a little bit more consistent with that,
52:33but it's you know it's the
52:36practicalities and medicine of trying
52:38to get patients what they need.
52:40One of my odd.
52:41Of odd hobbies Prepandemic was I
52:43would wander around drug stores in
52:45the area and start looking at their
52:47melatonin Isles and I would sort of
52:49keep my running list of where within
52:51walking area of the hospital you could
52:53actually find low dose melatonin so
52:54I could direct patients there too.
52:57Nice OK great. And and
53:01so I I think so. So the.
53:06I guess one of the other questions I had was.
53:12Do you use any other technology other than?
53:16Actigraphy is there anything else out
53:19there that is close enough to actigraphy to
53:23be used to understand activity patterns?
53:27So, are you referring to things like like a
53:30wearable personal wearables? Yeah,
53:32I will take whatever data I can get
53:34and I don't want to mess up my camera,
53:37but the bulletin board that I have
53:39right behind me in my office here
53:42actually has examples of many different
53:44types of sleep logs and reportable
53:47data that I've gotten from patients.
53:49Like I said, they tend to track
53:52their data before they come in,
53:54and so if all you have access to
53:55and I think we also got much more.
53:58Creative with this in the pandemic
53:59when we had times where we couldn't
54:01send out actigraphy,
54:02we couldn't get all the data on
54:04the way that we normally did.
54:06If they wanna send me Fitbit data with
54:08all the caveats of how accurate that is,
54:11whatever data they have available
54:12and can send me, that's great.
54:14The downside to those,
54:16and where I can get some insight
54:18with that tiger fee that I can't
54:20get from some of the consumer
54:21wearables is light exposure data and
54:23that is a tool that we often use,
54:25and so we'll often find,
54:27for example, in these delayed.
54:28Since we can get a sense of ohh
54:30you actually get a ton of light
54:31right before bedtime or you have
54:33horrible curtains in your bedroom
54:34and you're getting a bunch of morning
54:36light before you're waking up.
54:37And so that's some insight that I can't
54:39necessarily get from the consumer wearables.
54:42But if we're just getting a
54:43sense of overall patterns,
54:45we're trying to get a sense
54:46of treatment response.
54:47They're great and we've been trying to
54:49find ways to more easily get that data.
54:52Like not knowing the ends when
54:54you need to know the house, right?
54:57You gotta have both sides of the equation.
54:59OK wonderful, so so Sabra.
55:01This is really great and so if you
55:04were to give you know two bullets
55:07of advice for somebody who is
55:10managing a delayed phase patient,
55:13what would be the one thing you have to do?
55:15And one thing you should never do.
55:18Never give light at 8:00 AM unless that's
55:22their natural wake time and you have
55:25to. Why is that? Why don't you give let Adam
55:27why don't you give light at 8:00 AM?
55:28Because at that point you're
55:30probably gonna end up delaying
55:31them and making them even worse
55:33instead of making them better.
55:35And the one thing you should do
55:37is keep that melatonin dose low.
55:39So like I said, typically half
55:41a milligram no more than half a
55:43milligram to 3 milligrams don't
55:45get up into ten 2080 milligrams,
55:48OK? Perfect excellent,
55:49so early and low and then late
55:53and bright I guess is the.
55:57Cool awesome well great.
55:58Thank you very much.
56:00And so if anybody else has any other
56:02questions we could probably well.
56:04Actually, it's 259 so we're we're just
56:06out of time and so thank you so much, Sabra.
56:08This was wonderful and thank
56:10you everyone for attending yet
56:11another edition of our conference.
56:13Please if you wanted to have your
56:15credit for attending this conference,
56:17you can go ahead and use the CME
56:20code and we will see you guys in
56:22May in the second Wednesday of May.
56:24Thank you so much everybody.
56:28My favorite.
56:30For having me.