Greetings and welcome to the
National Heart,
Lung and Blood Institute NHLBI
Workshop on Neurodevelopmental
Disorders and Sleep.
I'm Doctor Lawrence Bazer,
a program Officer in the
National Center
on Sleep Disorders Research
Branch of NHLBI,
and I'm the organizer
of this event.
Over the next couple of days,
we look forward to hearing from
our panel
of experts about the current
state of the science in this
rapidly developing field
and important issues for further
investigation.
This slide charts the the the
the continuing development of
and brought
interest in this research area
and chose the approximately 4
fold increase in
publications in this area over
the past 20 years in Pub Med.
Also,
the significance significant
increase in
application grant applications
to NIH on neurodevelopment
disorders and their
symptoms over the past
20 years over that.
That same period of time.
Additional indications of
interest include the some 480
people registered
for this workshop.
I really appreciate your
participation, everybody who's
joining,
and the fact that several
different NIH institutes and
centers were involved in
this workshop,
either in its development and
its
conception, actually
carrying it out.
So National Institute of
Environmental Health Sciences,
Child Health Institute,
Human Genome Research Institute,
NINDS and Neurological Sciences
Institute,
as well as National Institutes
of Mental Health.
Many thanks to my Co chair is
Doctor Jared Salton from Brown
University in the
EP Bradley Hospital Sleep
Research Laboratory at Brown and
Lucia Pesciotto
from Washington State University
along with my NIH program
officer colleagues.
And special thanks to our
workshop support team who have
done a wonderful
job in getting this workshop
together and are helping support
it today.
So thanks everybody involved in
the conception and development
and execution
of this workshop.
A few meeting logistics to start
off, attendees will be muted and
your cameras
will be off.
The chat functionality in
Microsoft Teams has actually
been disabled.
You can't use that,
but participants can post
questions in
the Q&
A function in Microsoft Teams
and we're
going to try and leave a minute
or two at the end of the
speaker's talks so we can
maybe answer one question in
that period of time.
If your question is directed to
a particular speaker,
maybe you can include their
name, the name of that speaker
in your question.
Questions can also be answered
online by the speakers after
their talk is over.
They can respond to those
questions and there will
actually be also a 30 minute
discussion session at the end of
the day to address any remaining
or additional
questions that might come up
throughout the course of the
presentation.
Stay the workshop support time
will will again provide a
warning at about 17 or 18
minutes after the speakers start
their talk to try and leave some
time at the
end of the talk for a question
or two the workshop is being
recorded.
To enable closed captioning,
click the CC icon located at the
bottom
of your team screen.
Thanks again to
everybody participating.
And I'll turn to my Co chair,
Jared Sal and from Brown
University for a
few introductory remarks about
the goals and objectives of this
workshop.
Thanks, Jared.
Thank you Larry, and,
and thank you Lucia for for
going with us,
with me,
and thank you for everyone for
being here.
This is going to be a really
exciting couple of days and I
just wanted to
overview a couple of goals for
our workshop.
What Lucy and I really were
hoping to accomplish over the
next day or two is to
survey what we know about sleep
in nerve developmental
disorders,
but really what we don't know.
And so hopefully we're going to
be be filling in some gaps for
you,
but also revealing a number of
gaps that are apparent.
This includes both across the
the type and presentation of
nerve developmental
disorders,
how they progress on across the
human
lifespan,
but also how they translate to
animal
models so that we can better
identify preclinical targets
that might be
applicable to clinical studies.
We want to promote a better
understanding of the development
of sleeping circadian
regulation across typical
development and how that
developmental process helps us
understand the trajectories of
neurodevelopmental disorders.
We hope that we can identify
some factors that might
distinguish vulnerability and
resilience to differences in
sleep and sleep loss that might
occur across the
lifespan and how individuals
with neurodevelopmental
disorders might be
differentially responsive to
these factors.
And then more broadly,
we hope to establish a dialogue
and
collaboration both between the
sleep and circadian field and
then the
neurodevelopmental field so that
the 2 fields can come together
to really move
the science forward and address
new and unanswered questions in
this area.
We have an amazing slate of
speakers from both of these
fields, again,
focusing both on human work,
but also on animal models that
might
underlie some of the conditions
that we're going to speak about.
And I don't want to
hold up any more time.
So I'm going to turn it back to
Larry to introduce our first
speaker.
And thank you everyone
for for being here.
Thanks, Jared.
And let's keep those objectives
in mind when we go through the
talks in the
workshop today and and think
about how the talks are kind of
addressing those
objectives.
So introducing the first speaker
to considerable honor, then to
introduce.
Beth Mallow is the keynote
speaker for this workshop.
And she's clearly a widely
recognized expert in this field.
She's professor of neurology and
Pediatrics,
the director of the Vanderbilt
Sleep Division,
holds the Brewery Endowed Chair
and Child and Cognitive
Childhood development,
and serves as the vice chair for
clinical research in the
Department of Neurology
at Vanderbilt University
Medical School.
Her research focuses on the
interface of sleep and epilepsy,
autism and related or just
orders of neurodevelopment and
improving health and
quality of life for individuals
with intellectual and
developmental
disabilities across
the lifespan.
And she's going to provide us an
overview that will set kind of
the framework and
the context for the rest of the
talks we're going to hear in the
next couple of
days.
Thanks, Beth.
Thank you.
I really appreciate having this
honor to set the stage for our
workshop the next
two days, next, next slide.
I just wanted to quickly go
through my disclosures and
acknowledgments.
I consult for Neuron
Pharmaceuticals.
I am gonna briefly mention some
off label uses of medications
for sleep in the
conditions that we're gonna be
covering or some of the
conditions we're gonna be
covering.
There's there's very little as
you can imagine that has been
approved by FDA in
this area and I know I'm greatly
appreciative of my grant support
from
multiple sources.
Next,
what I'm gonna try to do in the
next few
minutes is set the tone,
set the stage for what we're
going to be
hearing about in much more
detail over the next two days.
I'd like to characterize the
types of and causes of sleep
problems common in
individuals with ND,
DS neurodevelopmental
conditions.
I put this photo in deliberately
because I say individuals, not
children,
because children grow up.
And this is one of my young
adult patients with autism and
intellectual
disability.
He also has sleep apnea,
and that's his mom as well with
us.
And this is something that is
really important to recognize
that it is a
trajectory,
it is a developmental continuum
between
children and adults and also
young adults and teens.
And so we'll do that.
We'll talk about the impact of
improving sleep on
neurodevelopment and also on
aspects related to well-being in
the individual and their family
members.
And then I'll highlight
treatments as well as gaps for
further study.
Next.
Lots of things happen in our
first year of life and we see
that in the EEG.
We see that in progression of
the different sleep stages and
going more
from R.E.M.
to non R.E.M.
And all different changes that
we see that reflect brain
activity.
And I just want to point out
that sleep is critical for
development,
especially for
memory and learning.
And that's what we'll be
focusing on a lot in this
workshop.
For example,
we know that when there's higher
sleep
efficiency in the first few
years of life, where there's
more advanced executive
function later on,
we know that when there are
frequent
night wakings,
it translates into poorer
cognitive
function,
while fewer night wakings have
resulted
in better performance
on memory tasks.
Next slide across the spectrum
of developmental conditions,
there are prominent sleep
disturbances and these can vary
somewhat according to
the condition I've just listed 5
conditions here we'll also hear
about
ADHD, we'll hear about epilepsy,
we'll hear about Rett syndrome.
So this is not an
exhaustive chart I.
I put it up to show you that,
for example, in Smith McGinnis,
there's more insomnia and also
daytime sleepiness,
while in Down syndrome there's
more obstructive sleep apnea.
So the more plus signs,
the more that problem exists.
And there's just a lot of
overlap in terms of the sleep
problems that we see
in these conditions.
But each condition has its own
unique signature.
Next slide,
I also wanted to emphasize the
impact of
sleep on emotional regulation,
core symptoms and daytime
behavior.
And this isn't really important
because we know that sleeping
better in and of
itself reflects
in better health.
We can control
our weight better.
It helps with
cardiovascular outcomes.
It prevents or it ameliorates
the development of diabetes.
If we're if we're sleeping
better, we know all that.
However, in this population,
NDD's, neurodevelopmental
disorders,
there's a huge impact that sleep
can make on emotional
regulation.
So I think of it as as sleep is
a great reset.
We all know, right,
what it's like when we don't
sleep well,
when we're sleep deprived for
whatever reason.
Maybe we're doing too much with
work or family or whatever,
burning the candle at both ends,
so to speak.
And we're grumpy, we're grouchy.
We're more apt to send that
snarky e-mail that we'll regret
later.
And this is where we see it even
more in the NDDS.
The kids, the adults with NDDS,
they really have a lot of issues
with
emotional regulation when
they're sleep deprived.
And we see this actually borne
out by functional MRI studies
that show that
when people are sleep deprived
and they're looking, for
example,
at aversive stimuli like bugs,
crawling or whatever,
they have increased activation
of their amygdala.
They also have decreased
connectivity between the
prefrontal cortex,
which keeps centers like the
amygdala in check when they're
sleep deprived.
So that's one area.
The other is core symptoms.
And this is work that one of my
postdocs, Olivia Veitch, did at
Vanderbilt with us.
She looked at more than 2000
children with autism in the
genetic Simon Simplex
collection and found that
severity scores for core
symptoms like repetitive
behavior restricted interest.
Social interactions were
increased when when children
were sleeping less than or
equal to hours per night and
then the other area is daytime
behavior and we
find that when we improve sleep
either with supplemental
melatonin.
Behavioral sleep education this
results, this is our work
results in decreased
core symptoms, improved mood,
improved parenting stress.
Parents feel more confident as
parents and children have
greater quality of life
when you improve sleep.
So,
so think of it like all these
drugs that
we use to treat irritability and
aggression in these populations.
They all have side effects,
but if we can improve someone's
sleep,
that can not only impact their
health, but all of these issues.
And I,
I think that's really huge and
that's why
I'm so excited.
We're doing this
workshop right now.
Next slide.
There's many different
contributors to sleep problems.
And I'll just say that often
times we emphasize what I put in
here,
read some of these biological,
not that they're not important,
and we're going to hear a lot
about animal models, genetics,
various other areas
in the talks to come.
I just want to make a plug for
the holistic nature of sleep.
And remember that, for example,
a lot of individuals with NDD
have
coexisting medical conditions,
whether it be sleep apnea or
seizures or
reflux or eczema,
or the psychiatric conditions,
anxiety,
depression, ADHD,
all that can contribute to
disordered
sleep.
And then you throw on the
medicines that we use to treat
these conditions,
like the stimulating
antidepressants and the
stimulants for ADHD and seizure
meds,
and you can see where sleep can
definitely take a toll.
So that's one area I wanted to
make sure we kept in mind over
the next two days.
The other is the
behavioral environmental.
A lot of people feel that that
NDDS, individuals with NDD are
not going to do
well with behavioral
interventions.
They need something stronger,
they need a drug.
But actually some of these
individuals do really well,
almost better than typically
developing individuals because
they love routines.
So we see that in autism, for
example, and these strategies
for a sleep habits,
sleep hygiene,
sleep interventions can be very
successful.
Limited, being light too late in
the day, but getting it early in
the day,
limiting those screens, limiting
caffeine, all those things can
be very,
very important.
Increasing exercise.
And then there is that
biological component.
And I'm not going to dwell on
that too much here because I
know you're going to
hear about it in
the talks to come.
I do want to emphasize on the
importance of genetics,
not just the clock genes that
share both impact in NDDS and in
sleep,
but also arousal dysregulation
and melatonin processing.
We can go to the next slide in
arousal dysregulation.
We know that the HPA axis is
dysregulated in both insomnia
and neurodevelopmental
conditions,
and this is an association with
increased
daytime stressors.
So if there are more stressors
on the individual and they
they're starting to
have more irritability and
aggression and meltdowns during
the day,
that can translate into higher
cortisol levels at night,
which interferes with sleep.
And then if you're not sleeping
well, you wake up already
dysregulated.
And you can see there's like a
wheel that we put together off
one of our papers
showing this vicious circle of
becoming more and more
dysregulated related as the
day and evening goes on.
And then in autonomic function,
we see additional evidence for
over
arousal or hyper arousal with
this was work.
We did it at Vanderbilt with one
of our PhD students.
Even when you go to sleep,
kids with autism had higher
resting heart
rates than kids who are
typically developing.
Even when they went to sleep and
those daytime stressors
disappeared,
they still showed evidence for
over arousal.
And we also see this with heart
rate variability and other
studies.
Next,
I want to talk a moment about
melatonin.
It's a hypnotic as well as a
stabilizer of the circadian
rhythm.
So hypnotic is MT1 receptors,
Chronobiotic or stabilizing of
circadian
rhythms is MT2 receptors.
This is the melatonin we make in
our bodies,
not the ones that we buy at
stores, which I'll talk about
next.
And there's a lot of variability
in melatonin in these NDDS and
they,
the levels may be normal,
they may be decreased inverted
in Smith
McGinnis, for example,
where you get more melatonin
during the
day and not as much at night,
which is backwards and can in
contribute
to their insomnia and
daytime sleepiness.
I wanted to emphasize a lot of
people say, well, if melatonin
levels are normal,
the child is
sleeping fine, right?
And it, it actually isn't there.
There are kids with normal
melatonin levels who still have
a lot of insomnia.
And the reason that is,
is that it's not just replacing
a
deficiency,
but we we are seeing impacts on
those
receptors even with normal
endogenous levels.
And then when we treat kids
where we give them the
supplemental melatonin,
we see improvements in sleep.
I think one of the things
driving this is a small
literature on how melatonin may
also act as an anxiolytic and
mitigate that hyper arousal and
anxiety and hyper
arousal are two
different things.
And,
and this may explain why
melatonin works
better in ND DS because we know
that our our individuals with ND
DS have anxiety
often times and they often times
have that inability to shut
their brain down
that over arousal.
Next,
and Speaking of supplemental
melatonin,
this is the number one,
I'm going to call it a drug
because it
really is a drug.
It needs to be regulated by the
FDA in my opinion,
but I do acknowledge that it is
the most studied medication that
we have and this
is in case series randomized
trials, reviews.
Improved sleep latency,
time to fall asleep with minimal
side
effects.
Not surprisingly,
supplemental melatonin when
combined with
behavioral interventions is the
most effective and one of the
most common
types of melatonin is the
immediate release.
But there are prolonged release
perhaps including the one that I
consult with
Neuron,
which they make a tiny micro
tablet.
And I just wanted to emphasize
that that has these have shown
promise in improving
night Wakings in their
developmental conditions because
the the immediate
release only has a duration of
action of an hour,
but the prolonged release is
time released throughout the
night.
So I think that has promised in
night wakings as well.
Next,
I just wanted to also emphasize
before we
move away from melatonin that
there's a lot of controversy
about melatonin right
now because of overdoses and
mixing it with CBD, baking it
into brownies.
Mixing it with Benadryl and the,
the issue here I think is not
the
melatonin as much as the fact
that it's not regulated.
So it's,
it's kind of like the Wild West
and
others like Judy Owens have
spoken about this.
I think the concerns
are very real.
My biggest concern is I don't
want to throw the proverbial
baby out with the
bathwater because melatonin
really works very well in a lot
of individuals with
NDDS for the reasons I mentioned
and I as part of a science
communication project I
did through the Allen Aldis
Center for Communicating
Science,
I was getting a
graduate studies there.
I designed a safety video and
blogs to help families figure
out on their own if
melatonin was right for their
child with autism.
And I think it extends to all
ADDNDDS and maybe even typically
developing kits.
But I want to make
these available to you.
The QR code takes you to the
video and the posts on Medium.
And I think there's a build if
you can go to those next, next,
right?
So a typical scenario,
you can do one more families
will come to
me in clinic, right?
And they will say,
Johnny is sleeping great.
He takes melatonin.
He's doing wonderfully.
And I'm, I'm like,
and why are you here?
Why are you in my clinic?
What's going on?
And oh,
his pediatrician said we had to
stop
melatonin because
it was dangerous.
So I owe,
I spend most of the time
educating them
on the safety of melatonin.
I try to make sure that the
family is using AUS P designated
brand because this
means it's the next best thing
to being FDA approved.
They, the company,
the dietary supplement company
submits
their data to the FDA to get
this designation and it looks at
purity,
it looks at bioavailability.
Because you may have read
there's all these different
melatonin brands that are
all over the map in terms of
bioavailability.
So you know that you're getting
a reputable product,
you know you're getting what the
label says.
Natural and Nature Made are the
two companies with the USP
designation.
So I recommend them.
Next slide and I did want to
touch on other medicines have a
very small
database.
So the only medicine that's been
approved by the FDA that I'm
aware of for sleep in
children is Tasmeltian which is
a melatonin agonist.
It was approved in Smith
McGinnis syndrome and also a non
24 hour sleep
wake cycle.
The other ones that are bold
have some studies but they're
sparse.
We studied gabapentin
at Vanderbilt.
We like it a lot.
It doesn't interact
with other meds.
It it also may work so well
because it it treats restless
legs and restless sleep
and the alpha
adrenergic agonist.
And also there's a recent study
of Doxepin have all shown
promise.
But these are all case series,
20 to 30 kids total,
so very small numbers.
We need more studies.
CBD has been studied.
It was shown not to work in a
randomized trial of 150, did not
show improvement.
And then these other drugs that
we use a lot like Trazodone,
have not been studied.
They need to be studied getting
studies in these about drugs
that are generic and
that have been out there a while
are you know not oftentimes
fundable by by anyone
industry isn't interested.
So that's a challenge
we can talk about.
And then I will mention the
benzodiazepines are very helpful
in
sleepwalking sleep terrors,
but not in the typical night
wakings that
we normally see.
So you want to keep that in mind
next slide.
And I wanted to just mention the
practice pathways very quickly.
We can really encourage people
to screen for sleep problems,
identify these are
pediatricians, identify medical
Co occurring conditions.
Start with behavioral
strategies.
If a family is willing and able,
and I do want to put a plug in,
we're doing a study sponsored by
our sleep foundation.
It does work to do these
behavioral strategies.
The challenge is how
to disseminate them.
For example,
we really lean on our therapists
and
community practices to work with
families, and we're having a lot
of success there,
like behavioral therapists
teaching families.
Sleep medicines should be used
sparingly, hopefully, to
facilitate these strategies.
And if someone has epilepsy or
ADHD, that's a good time to try
to choose a
medicine that can help sleep and
that condition.
And we have these wonderful tool
kits we developed at the Kennedy
Center for
things like sleep studies in
adults and kids.
Next slide.
I think this is my last slide.
Yeah, you have less time.
Yeah, 'cause I wanna wrap up.
So basically,
these are my future directions.
Sleep problems are common.
Take a holistic approach.
Remember the
developmental trajectory.
We'll be hearing more about
neurobiological underpinnings.
We need more research on how do
we implement behavioral
strategies and also
how do we combine medicines and
behavioral strategies with the
input of
individuals and families.
I think that's critical and I
hope we hear a lot about that
over the next two
days.
We need to hear from our
families what they need and
what's important to them.
Thank you very much for your
attention, and I'm excited to
hear the speakers that
follow.
Thanks so much, Beth.
I think this addresses a lot of
the questions that people on
this call
probably have about treatment,
both behavioral and
pharmacological.
So we need to,
we don't have time for questions
on now,
unfortunately.
Hopefully we can entertain
questions at the end of the day,
hopefully or put them in the in
the Q& A of anybody online and
maybe Beth can
answer them online afterwards.
So the next section is common
human disorders.
And it's wonderful to have Shu
Buckley from National Institutes
of Mental Health
serving as the moderator for
that that session.
So Shu, please
start the session.
Hi, hi, great to be here.
Thank you, Beth,
that was fantastic star to our
day.
I'm Shoe Buckley and been at the
NIMH studying sleep and
neurodevelopment for a
long time.
I'm very happy to be serving as
the moderator.
This next session session will
feature several common
neurodevelopmental
disorders.
They're likely polygenic in
origin and they're often they
present with a variety
of symptoms, including
sleep disorders.
So the first lecture you're
going to hear is from Heather
Joseph.
She is an assistant professor of
psychiatry and Pediatrics at the
University of Pittsburgh
Medical Center.
Her research focuses on early
detection of inattention in
neonates,
infants and toddlers at risk for
ADHD and identification of
protective and
resilience factors.
Her talk today is on treatments
for ADHD, including non
pharmacologic approaches.
All right.
So it's a pleasure to be here
today and to talk to you very
briefly about such a
broad topic of ADHD Co occurring
sleep problems and and try to
start to talk
about non pharmacological
treatments.
So I have no conflicts of
interest to disclose and I will
share a few findings
and ongoing studies that have
been funded by NIH and the
Klingenstein Third
Generation Foundation.
So my objectives for today is to
provide a very brief overview of
ADHD,
review common Co occurring sleep
problems with ADHD and introduce
the non
pharmacological interventions
for sleep and ADHD.
And I will focus primarily on
adolescents and children.
So ADHD is a common
neurodevelopmental disorder
affecting one in nine children
in the US and it's associated
with significant impairment
across multiple
domains, including health,
social functioning,
academic and occupational.
And importantly,
as many as 2/3 of individuals
that have
ADHD in childhood continue to
meet full diagnostic criteria
into adulthood.
And even those who don't don't
meet full diagnostic criteria
continue to have
significant impairment.
ADHD is associated with a
variety of genes, environmental
factors,
and differences in brain
structure and function.
But there is no single cause of
ADHD, and each factor that has
been found to be
associated really only accounts
for a small portion of the
variance.
However,
we do know that ADHD runs in
families and
is highly heritable.
So here I share with you the DSM
criteria for ADHD in childhood.
It's required that the children
have 6 symptoms of inattentive
or hyperactive,
impulsive,
and if they have a combined
presentation,
it's 6 symptoms in each category
and falling into the
neurodevelopmental
category.
These symptoms really are
onsetting in childhood,
so they must be present prior to
age 12 and that there are clear
symptoms in two
or more domains to more settings
of impairment and functioning.
When you enter adulthood,
the symptom criteria is lessened
to 5
instead of 6 symptoms.
And partly that's trying to
account for some of the
developmental changes and
maybe the appropriateness or
inappropriateness at times of
some of the
symptoms in the DSM for adults.
So for example,
these are the inattentive
symptoms.
If you look through some of
these easily distracted, loses
things,
doesn't listen when spoken to.
Some of that may be present in
childhood and into adulthood.
However,
when you're looking at the more
hyperactive, impulsive symptoms,
some of these things are a
little bit
more easy to see in children and
and by adulthood you've had a
lot more
compensation.
You might not be getting out of
your seat when it's
inappropriate.
So there's just a little bit
more wiggle room for adult
diagnosis here.
So the relation between sleep
and ADHD is multifaceted.
There are three,
there are potentially 3 separate
relations between them.
So just for example,
you might have ADHD symptoms
that are
impairing one's ability to
organize themselves around
bedtime and get into
bed on time.
That might be resulting in
shortened sleep duration, more
variable sleep onset,
or you may have sleep sleep
disorder primarily that is
resulting in poor sleep
and more inattentive or
cognitive impairments that may
present as ADHD
symptoms.
And then the third option is
perhaps that there's a common
underlying 'cause that
is linking both sleep and ADHD
symptoms, like for depression
might be one example.
So when we think about the sleep
problems presenting as ADHD
symptoms,
it's really important,
as the first talk kind of
alluded to,
that individuals who are
presenting for ADHD diagnosis
are evaluated for sleep
concerns,
and there should be
consideration of
whether there's an underlying
sleep problem that is actually
presenting and
confounding the diagnosis.
For example,
obstructive sleep apnea is
almost always
associated with inattention,
and restless leg syndrome is
present with
about 1/4 of the children with
restless leg syndrome having
symptoms that appear
like ADHD.
It's also true that individuals
with ADHD do have higher rates
of these sleep
disorders.
So it's not just One Direction.
There are also greater risk for
these symptoms,
even if it's not just the sleep
disorder presenting like ADHD.
So sleep problems are common
amongst individuals with ADHD
across the lifespan
and they really do
begin in childhood.
There you can see that across
childhood, adolescents and
adulthood,
the rates of sleep problems are
70 to 80% for individuals with
ADHD as compared to
20 to 45% in the
general population.
And adolescence is a period of
increased sleep difficulties
even amongst
individuals without ADHD.
And this is often due to more
transitions to independence with
less oversight on
sleep schedules,
shift in biological timing,
and competing demands for their
schedules, so after school
activities and early
school start times.
But adolescents with ADHD
experience even more sleep
problems than their peers,
including delayed onset of
sleep, shorter sleep duration,
poor sleep quality,
more variability in their sleep
timing
and greater daytime sleepiness.
There's also some evidence to
suggest that ADHD may be
associated with
disturbances and circadian
rhythms, such as greater
tendency for eveningness
later, which is, you know,
having later bedtimes, later
wait times,
and later peak arousal for
individuals with ADHD.
And a meta analysis of of So
when we think about children
with ADHD,
there's a meta analysis done to
kind of look at parent reported
sleep problems.
And there are several things
that were reported by parents of
children with ADHD
more frequently than children
than parents of children without
ADHD.
And the largest difference was
in bedtime resistance.
So insomnia is a common clinical
concern for individuals with
ADHD and their
parents of young children with
ADHD presenting to the clinic.
We hear a lot about sleep
problems, particularly insomnia.
And not only, you know, in the
first talk, we also mentioned
like insomnia is
associated with many things that
these sleep problems are
disrupting not just
the child,
but their family and the
parenting stress
and parenting functioning and
self competency.
So we also see that it's
associated with increased ADHD
symptom severity,
risk for other psychiatric
concerns, mental health
symptoms, anxiety,
depression or even ODD.
And it is related to poorer ADHD
treatment response and then
worse health
related quality of life for
children and their families.
So one example from my work is
that the we examined 2 cohorts
of individuals with
and without ADHD as new parents
and their infants.
And so really I'm looking at the
heritability of ADHD and how
family
factors might predict
differences in child outcomes
and trying to find early
signals of risk for ADHD.
But when we followed these
children longitudinally,
we were able to look at parents
and and what factors might be
different in
parents with and without ADHD.
So in our sample,
we found that parents with ADHD
and their
Co parents reported greater
parenting distress in the first
year postpartum.
And we wanted to examine what
factors might be predicting
parenting distress.
One of the largest things we saw
here was that in this sample,
parents with ADHD and their
partners had significantly worse
sleep quality in the
first year postpartum.
So not just the individual with
ADHD, but you could imagine that
if someone
with a sleep disorder or
difficulties is in and out of
the room or disrupting the
environment,
that their partner would also
have worse
sleep.
And so these parents and their
partners with ADHD had
significantly worse sleep
quality than parents
without ADHD.
And this is in the
postpartum period.
So as you can see,
the mean for the parents without
ADHD is
3, which is still not great.
It which is to kind of be
expected when you have a young
infant.
But what was interesting here is
that when we considered sleep in
the model,
it was associated with greater
parenting distress.
And interestingly,
the association between parent
ADHD and
parenting distress was no longer
significant.
So this cross-sectional
association supports the
possibility that sleep
quality may mediate the effect
of ADHD on parenting distress.
So to shift in the time that I
have left to talk about some non
pharmacological
interventions that have been
studied in adolescents and
children with ADHD.
For adolescents,
a large majority of the research
that is
starting to come online here is
focusing on cognitive behavioral
based
interventions,
which have been found to improve
sleep
and associated mental health
symptoms in individuals even
without ADHD.
So as you can see,
the there's two published
studies that
I'm highlighting here from 2022
and 2024, as well as a third one
that is ongoing
without results yet that are
really trying to take these
evidence based
interventions for adolescents
and move them into adolescence
with ADHD.
And these studies have been
finding promising results with
moderate to large
sleep improvements and
improvements in other mental
health symptoms and daily
functioning and decreased
nighttime wakefulness and
daytime sleepiness for
school aged children.
There are nearly a dozen
randomized controlled trials of
behavioral sleep
interventions for children with
ADHD that support improvements
in sleep and ADHD
symptoms.
The majority of these
interventions are focused around
sleep hygiene and
strategies for common sleep
interfering behaviors,
and they've been found to have
reduced sleep problems with
moderate to severe
sleep problems.
And the other group is really
focused on supporting parents in
how to reduce
bedtime resistance and other
sleep difficulties.
So this there's a parenting
piece to it, especially when the
children are probably
a little younger and have a
little more control over the
sleep environment.
There is one study that looked
at weighted blankets as another
option for
sleep interventions for children
with ADHD.
The mean age for
the sample was 9.
And the weighted blanket did
have a significant impact on
total sleep,
sleep efficiency,
and wake after sleep onset,
but it did not improve sleep
onset latency.
And there's some evidence that
perhaps it was more beneficial
for children that
were a little bit older, 11 to
14, and that children with the
inattentive
presentation might
have benefited more.
The one other study I wanted to
highlight here is ongoing,
and it's a novel intervention
called Power Down for Sleep,
which is a sensory based bedtime
intervention that teaches
parents a deep
pressure massage and guided
mantra to help settling for bed.
And this intervention is being
tested and developed by Doctor
Hartman at the
University of Pittsburgh.
And although the study is
ongoing, families have reported
that they like the
intervention,
that they feel that it's low
burden and
seem to be seeing aspects of
sleep and falling asleep
improving in just two
weeks.
So the last thing that I was
going to share with you today is
another ongoing
study.
So this is an NIH sponsored R34
and the goal of this is really
to see if we can
intervene early.
So ADHD symptoms and sleep
problems both present before
school entry and can lead
to a cascade of
negative consequences.
So our team wondered if early
preventative interventions for
preschool
aged children and their parents
could improve both sleep and
ADHD symptoms,
and possibly even before the
onset of an ADHD diagnosis.
So to do that we are combining 2
evidence based interventions.
So parent behavioral
interventions are gold standard
treatment for childhood
ADHD in the preschool age and
have been found to be effective
in reducing ADHD
symptoms,
parenting distress and improve
overall
parent child relationships.
And the sleep piece here we are
combining elements of the Sleep
Well intervention.
So I'll share a
little bit about that.
So Sleep Well is a brief
behavioral intervention for
toddlers and
preschoolers who have caregivers
reporting poor sleep problems
for the
child.
And this intervention has been
developed and tested by Ariel
Williamson and it was
really adapted with community
engagement, meant to be a
comprehensive model to
address poor sleep health
behaviors, insomnia and
insufficient sleep in
toddlers and preschoolers with
an emphasis on strategies that
are
accessible and acceptable to
individuals living in a
disadvantaged context.
So combining that with COPE,
which is coping with a DHDA
commonly used
parent behavioral intervention
that has been adapted for
several ADHD clinical
trials across preschool and
early childhood.
We are able to infuse the sleep
well content into the COPE
session format,
which includes success oriented
homework, some videotape
vignettes for the parents,
brainstorming with the therapist
around strategies for
implementing the skills
that were taught in that
session, and then assigning
specific homework.
So in this study,
we are implementing it in five
pediatric
practices by 6 behavioral health
specialists that are embedded in
each of
the primary care offices.
It will enroll 30,
it'll enroll 50 preschoolers and
their
parents and the ages
of the three to five.
And these children are at risk
for ADHD, meaning that they have
elevated ADHD
symptoms, so four or more,
but they do not have to have an
ADHD
diagnosis.
And the families are being
randomized either to coping
only.
So the the standard parent
behavioral intervention or sleep
focused parent
behavioral intervention,
the Oasis intervention and it's
6
sessions and it's
delivered virtually.
So some of the parenting
strategies that are used are the
praise and attending
planned ignoring transitional
warnings when then statements
and incentive
systems.
The parents that are enrolled in
the standard parent behavioral
training will
also receive time out,
but time out was removed from
our sleep
enhanced version for the sake of
time and to include the sleep
strategies.
So our sleep strategies,
everyone receives the bedtime
routine,
which is refined throughout the
intervention and then a second
and
sometimes third sleep strategy
is selected with the parents
based on the
child's presenting problems.
So the Oasis clinical trial is
ongoing with 34 families
enrolled and 50
anticipated.
So stay tuned for results.
And just to kind of conclude
here, sleep problems are common
amongst
individuals with ADHD.
Behavioral interventions improve
both sleep and ADHD symptoms.
And what's next?
How do we make these evidence
based interventions scalable and
accessible?
And one thing of interest to me
really is can we reduce ADHD
symptoms and
associated impairment before
school entry by intervening with
sleep early?
So thank you to NIH for inviting
me to speak here for grant
support.
And then a special thank you to
the Oasis team.
Thank you, doctor Joseph,
we do have one question in the
chat,
but in the interest of time to
stay on schedule,
I think I'll just note it and
maybe we'll get to it at the end
of the day,
if that's OK with you.
Our next speaker is, oh, forgive
me, Dan, is Renee Shellhouse.
Dr.
Shellhouse is the David T
Blasting game professor of
neurology at Washington
University in Saint Louis.
Her research interests include
sleep as a marker of brain
function in newborns,
neonatal seizures,
and early life epilepsy.
Her talk today is on pediatric
epilepsy and sleep doctor
Shellhouse.
Hello,
Thank you so much for inviting
me and get
our screen set up here.
Thank you so much for the,
this opportunity.
And I'm,
I'm really thrilled that we're
having
this workshop today because I
think, well, we're, I'm
preaching to the converted,
but this is a really important
topic of, of sleep and medical
disorders.
These are my disclosures.
My objectives for this of this
talk are to talk with you a
little bit about sleep
disorders among children and
adults with severe epilepsies.
And this is a kind of epilepsy
that we bucket into.
Developmental and epileptic
encephalopathies are the DES and
think
about the reasons that people
with DES may be at high risk for
sleep disorders
and talk about the potential
impacts of treating abnormal
sleep Physiology for
people with epilepsy.
Before I launch into all of
that, I want to make a shout out
to the
American Epilepsy Society that
has really fantastic resources
available to any of
us about sleep and epilepsy that
can be very helpful for a
patient.
I would encourage you
to check that out.
I'm a child neurologist and I'm
an epilepsy Dr.
by training and interested in
neonatal neurology.
So what am I doing in a in a
sleep symposium?
I really think that over the
years, as my career has
advanced,
I've become convinced that sleep
is really the next frontier in
child
neurology research.
Treating sleep disorders in
typical children improves
behavior and quality of
life, and it also helps their
parents, right?
Sleep problems are highly
prevalent in children with
neurologic disorders and
abnormal sleep patterns
even in newborns.
And then in some of the work
that my team has done predicts
developmental outcomes.
So even in the first days of
life, we have an opportunity to
to study,
understand and parents identify
sleep disturbance as high
priority for research.
I think it's high time that we
address sleep as a key strategy
to improve the
outcomes for our patients.
Why am I focusing on the
developmental and epileptic
encephalopathies today?
Simply because epilepsy is a is
a very large topic and people
with the DE ES are
people who have very
severe epilepsies.
They have frequent disabling
seizures and associated
significant neurodevelopmental
disabilities.
Our parents in our in our
clinics tell us that sleep
disorders are a serious
concern.
They're very common among these
individuals.
There's a very high caregiver
burden related to those
seizures,
the neurodevelopmental
disabilities and the sleep
problems.
And so I would,
I would submit to you that the
interplay
between sleep frequent seizures
and a very abnormal EEG along
with the
neurodevelopmental impairment
positions the DES as ideal
targets for proof of
principal sleep research.
We can make a difference here.
We can apply it into
broader communities.
One of the paradigms of
developmental and epileptic
encephalopathies is something
called Gervais syndrome.
These children appear to be
normal when they're first born,
but within the first year or so
of life, they begin to have very
frequent
disabling seizures,
and they go on to have
neurodevelopmental
disabilities.
Here's a parent survey of 76
families who had a child with
Gervais syndrome.
Median age of the child of 7.
5 years and 93% of those parents
monitor
their children during sleep,
with more than half by Co
sleeping with
that child.
The reasons for that are
manifold but include a high
incidence of something
called SUDEP or sudden
unexpected Death in epilepsy
patients for people with
Gervais syndrome.
So parents are concerned their
their children might die in
their sleep,
but also that there are a lot of
behavioral concerns around
sleeping in
people with Gervais syndrome.
Half of the parents reported
sleep disruptions due to
seizures at night.
But 3/4 of families also
reported non seizure related
nocturnal awakenings more
than three times per week.
That's a lot of sleep
disturbance for this patient
population.
In a hot off the presses paper
that just came out this week,
there are the study looked at 30
participants with Gervais
syndrome who
had a polysomnogram,
a mean age of just about 10
years.
And what this study showed was
that they also had activity.
It's an interesting study that
children who had tonic seizures,
they they stiffened during their
seizures had shorter REM sleep
duration.
Children who had convulsive
seizures, they had shaking with
their seizures had
shorter slow wave sleep and
three duration.
And even when the children were
not having seizures,
the abnormalities that show up
on their Eegs.
There's an example here on the
right with bursts of generalized
discharges are
associated with hypotenia.
So subtle respiratory events.
Interestingly,
over the last several years,
a new medication called
penfluoramine has become
available for dreadful syndrome
and it's very helpful in
controlling seizures.
It turns out that the hypotenuse
were much improved when a child
was treated
with lymphoma.
That's compared to not off that
medication.
That's interesting.
The overall apnea hypopnea index
or STB sleep disorder breathing
severity was not
reported in this paper.
So there's still
more work to do here.
There is a consensus guideline
on on how you manage people who
have Gervais
syndrome and one of the aspects
that is covered in that
guideline is sleep
related recommendations.
And in this and in the
development of this guidance,
there were physicians as well as
caregivers and people with
Gervais
syndrome.
Virtually all of them agreed
that sleep problems are seen in
a majority of
persons with Gervais syndrome.
100% of them agreed that
questions regarding sleep should
be routinely asked
as part of continuing care of a
person with this epilepsy type.
A formal sleep study should be
obtained if a clinical history
of a possible sleep
disorder is obtained.
They agreed on this.
Although I would say it's
interesting that it was not 100%
consensus that a
formal polysomnogram should be
obtained since that is the gold
standard for
diagnosing many sleep disorders.
So we need to think about that
and the accessibility of
polysomnography and the
acceptability of polysomnography
for people who have significant
neurodevelopmental disability.
Attention to sleep hygiene is,
is important to managing sleep
problems
associated Dravet,
just like we heard about for
ADHD.
I thought this was really
interesting that only 60% of
caregivers agree with
this statement,
hinting that that there's more,
more to this story that we need
to, we need to explore.
And melatonin we have heard
about already a couple of times,
certainly may be considered as
as one option for treatment for
sleep problems
with Dravet syndrome.
There are lots of other
kinds of epilepsy.
As I said at the very beginning,
the Rare Epilepsy Network funded
a
database where parents could go
in and provide a lot of
information about their
children with early
life epilepsies.
And parents reported a lot of
sleep problems in their in their
children.
So Geeta Gupta,
who was doing a postdoc with me
when she
wrote this paper,
looked at the number of parents
who
reported sleep concerns for
their children with early life
epilepsy.
And one of the things that was
interesting was that the the
number of of
kids who had sleep concerns
seemed to increase as children
got older,
which is opposite to typical
typically developing children
where as parents,
we are concerned about our our
baby's sleep when they don't
sleep through the
night when they're
young infants.
But it tends to get
better over time.
For these children,
they didn't get better over time
and
parents became
increasingly concerned.
We wondered whether it had
something to do with having
seizures at night,
and many of the children who
were included in this study did
have seizures
at night,
but that was not the primary
explanation
for the the increase the sleep
concerns over time.
There are a lot of reasons that
sleep seizures at night are bad
news,
but one of them is that seizures
can cause apnea.
Here's Here's simply an example
of a polysomnogram that happened
to capture a
tonic seizure.
The seizure is the dense spikes
that you can see in the middle
of the screen and
you see the apnea
indicated by the arrow.
Now OK, seizures
can cause apnea.
Does that mean that we don't
need to worry about other kinds
of apnea in these
children?
Of course not.
Absolutely does not mean we
should ignore concomitant sleep
disordered breathing.
Why do we pay so
much attention to it?
One one way to look at it is
that obstructive sleep apnea or
one form of
sleep disorder.
Breathing and epilepsy can
exacerbate each other make a
positive feedback loop.
We have intermittent arousals,
nocturnal seizures,
effects of anti seizure
medicines and behavior problems
that contribute to
sleep deprivation and contribute
to or have concomitant hypoxic
hypoxemic neuron
injury.
You get increase in neural
inflammation and what does that
do?
In a simplistic way,
it increases neuronal
excitability,
which is a problem for somebody
who already has epilepsy and has
neurons that
want to fire abnormal, right?
Then you have those abnormal
neuronal firing episodes in,
in epilepsy that causes more
seizures and can be associated
with central apnea and
with challenges with
airway muscle tone.
That airway muscle tone can be
from abnormality can be from the
underlying
epilepsy etiology, from the
seizures, from the medicines
that we that we give.
So lots of reasons to be
thinking about how can we break
this potential positive
feedback loop for somebody who
has both OSA and epilepsy.
The good news is that
obstructive sleep apnea is
treatable and that the treatment
might help seizures.
So in,
in this meta analysis that's now
from a
few years ago now,
they looked at people who were
had
epilepsy and were treated with C
pap or not treated with C pap
for their
obstructive sleep apnea.
And one of the outcomes was a
50% seizure reduction.
So that's a typical trial
endpoint for testing in medicine
is how many patients
have a 50% reduction in the
number of seizures that they
have.
What they found was for people
who were treated with C pap for
their OSA,
the odds ratio of reaching a 50%
seizure reduction was 6.12.
It did cross 1,
so not statistically
significant,
but really an interesting
tantalizing finding.
Additionally,
the odds of becoming seizure
free after
initiating C pap as compared
with not become not receiving C
pap,
that was an odds ratio of four
which was statistically
significant and I think
clinically very meaningful.
There are some additional
studies that have looked at
similar kinds of of
designs with outcomes of adults
with epilepsy who were treated
with C pap.
And here's one report where the
group that was treated with CPAP
had a 32 times
increased likelihood of
achieving a 50% seizure
reduction compared with those
who
did not receive CPAP.
So this is good news.
We know how to treat some people
who have OSA and happen to also
have epilepsy and
it can make a difference not
only in their general well-being
health and all
of the things that come with
obstructive sleep apnea, but
also with their seizures.
Why might that be?
Well,
lots of potential theories and I
showed
you that that initial diagram
about that feedback loop.
Another possibility is that the
the prevalence of EEG spikes may
be reduced
by Cpl.
So the the spikes on an EEG are
an indicator of a tendency to
make seizures.
So if you have fewer spikes,
you're probably less likely to
have
seizures.
So that that's one possibility.
Another option that we have for,
for research,
and I'm not going to dig deeply
into this, but just to give you
an idea,
is that for people who have
focal epilepsy,
who are being considered for
epilepsy surgery, where the, the
idea is to,
to surgically remove the area
that starts the vast majority of
their seizures.
Many of them have intracranial
EEG monitoring.
So long term monitoring whether
they're measuring EEG activity
directly from the
brain for many days on on end.
And what this group reported was
that the the rate of EEG spikes
was much higher in
non R.E.M.
than in wakefulness.
And this is something that we've
kind of known from from the
scalp EEG world as
well.
And that the spatial
distribution of the spikes,
so how much of the brain is
involved is larger in non R.E.M.
than in wakefulness.
On the other hand,
the spatial distribution of the
seizure
onset zone,
exactly where those seizures are
starting
in how far the seizure spreads,
there's not difference between
sleep and
wake state.
So I,
I present this just as one other
way that
we can evaluate in some detail
the impact of sleep Physiology
on brain function.
Then we think about how do we
treat people with epilepsy.
And just to state the absolute
obvious, epilepsy treatments can
cause or
exacerbate sleep disorders.
We know this, right?
We have lots and lots of anti
seizure medications and they can
cause somnolence.
Those are highlighted in blue
and they can cause insomnia.
So we need to pay close
attention to which medicines
we're prescribing and
what the side effects are for an
individual child.
Another option for treatment is
vagal nerve stimulation that can
be associated
with exacerbation of sleep
disordered breathing.
And about 1/3 of of people with
epilepsy treated with VNS have
SDB.
It doesn't matter if they're
children or adults, go true.
On the flip side,
VNS can also have positive
impact on the
spleen,
especially in situation and the
overall
distributions that break stages.
There's a nice systematic review
published in Epilepsy a few
years ago if
you're interested
in more details.
Treating epilepsy and curing the
seizures can improve sleep.
This shouldn't be a huge
surprise, but here's a a nice
study of 48 adults
who had temporal lobe epilepsy.
That they had the
temporal lobe removed.
The seizures got all better,
and every which way you survey
them about
their sleep,
things were better after their
their
epilepsy was cured.
If that's true for people with
temporal lobe epilepsy,
I would hypothesize it's also
true for others with epilepsy.
And I'll just leave you with one
other set of data to think about
is people who
are at risk for
developing epilepsy.
You know,
I study babies with neonatal
seizures and
follow them for the long run and
think a lot about the the impact
of having a
child with seizures on their
parents and their family.
And our our family partners have
asked us like,
are we ever going to sleep again
as parents?
Are these children going to be
able to sleep OK?
And I would say it's very clear
that we need to watch out
clinically for sleep
problems.
We had 116 parents of five year
old survival survivors of
neonatal seizures
who reported on their children's
sleep and their mean children's
sleep habits
questionnaire score was 45,
which is well above the healthy
cutoff of
41 and and LED to say us
concluding a nearly 2/3 of these
children's had
abnormal sleep at the age of 5.
About 1/4 of them screened
positive for sleep disorder
breathing on the the PS:
QSRBD subscale.
Interestingly,
children who have lower scores
on their
Vineland and their whipsy.
So children with lower IQ were
more likely to have symptoms of
sleep disorder
breathing.
And the question then I would
pose is could earlier diagnosis
and treatment of
the sleep problems have improved
their behavioral and
developmental outcomes?
And that's something that is a
tantalizing possibility and
something
that is is ripe for study.
So to conclude for you,
people with epilepsy,
just like people with ADHD,
as we just heard,
are at high risk
for sleep disorders.
Treatment of the sleep disorder
may improve seizure control and
vice versa,
seizure control helps with sleep
disorders.
Routine screening for and
treatment of sleep disorders
could make a real
difference for our patients and
their families.
And I think that the evidence
base has significant gaps.
But this is an area of research
that really holds important
promise to
generate actionable results,
which practice changing
implications in
the very near term.
So I think this is an exciting
place to be looking and we have
an awful lot of
work to do for those who are
interested in infants leave.
I'll just put on a quick plug to
to join us for an upcoming
conference where we're
going to be talking specifically
about Neil in Belgium.
Look at this year.
Thank you very much.
Thank you.
Thank you, Doctor Shellhouse.
That was really that
was a fabulous talk.
And I, I have a question.
I hadn't heard about C Pap
actually decreasing the spike
burden in any EGS.
And I wonder if you've thought
about potentially or if anybody
documented the
changes in maybe REM sleep and
did you end up with increasing
the REM sleep
ratio and you know, Rems to be
protected, right?
Because we know that REM sleep,
like wakefulness is protected
against
seizures.
And right, I don't know,
I don't know the answer from
that
particular study whether they
looked at the distribution of
sleeping stages.
But obviously the point of the
question and how are we
balancing out what are
what are sleep cycles look like
when we when we initiate
treatments?
It's something that
definitely should.
Yeah.
And also that you'd be more
likely to experience R.E.M.
for physiologic, I mean, apnea
during R.E. M., right, for
physiologic reasons.
So we'd be interrupting it.
So you you alleviate the OSA,
you end up with just naturally
more R.E.M.
and then sort of a
natural protectant.
So I think that would be an
interesting thing to look at.
Thank you.
Thank you so much for an
informative very as usual as
always and wonderful talk.
Now we have Doctor Pohm.
So thank you guys for
waiting patiently.
Dr.
Pohmes is an assistant professor
Pediatrics of Sleep Medicine at
the
University of Arizona Center for
Sleep, Circadian and
Neuroscience Research.
His research interests include
the cognitive and quality of
life effects of
sleep disorders in children with
special healthcare needs,
as well as identifying new
treatments to mitigate the
effects of sleep disorders
in this population.
So this talk is going to focus
on Down syndrome.
Doctor Combs.
OK, thank you very
much for having me.
You scared being you started
introducing me the first time,
but so yeah.
So I am excited to talk about
sleep problems in people with
Down syndrome.
I could talk about this all day,
but I've got 20 minutes,
which is probably a fortunate
for everyone here.
There we go.
So my disclosures,
I have research funding related
to Down
syndrome and sleep apnea from
NIH, NT Cory and then we're at
clinical trial
site for Eidorcia.
That's not particularly related
to this talk, but I disclosed
it.
So common sleep disorders.
So there are lots
of sleep disorders.
I'm going to focus on two of
them, but just to kind of paint
the broader
picture, obstructive sleep
apnea, probably everyone on this
call,
if you hear Down syndrome,
you should probably take
obstructive
sleep apnea.
In terms of sleep disorders,
restless leg syndrome,
parasomnias,
circadian rhythm disorders,
insufficient sleep are all
potential
issues are mostly either not
very well studied in people Down
syndrome.
And so in the interest I'm I'm
kind of glossing over them,
but that's not to say they're
not important.
And then insomnia,
I'm going to touch on very
briefly at the
end.
So obstructive sleep apnea in
people with Down syndrome, why,
why do we think
about this so much?
As early as infancy,
about one in three infants with
Down
syndrome have obstructive sleep
apnea that more or less steadily
progresses
over the course of your life.
So by childhood about half to 3
/4 have obstructive sleep apnea
and by adulthood
this is pushing essentially
almost everyone will have sleep
apnea.
So it's incredibly common and is
obviously a very important
issue.
Importantly,
many children with Down syndrome
and OSA
don't have typical OSA symptoms.
So loud snoring, gasping,
choking, all of those things
would clue you in.
Many parents don't report those
symptoms despite their child
having OSAOSA in kids
with Down syndrome tends to be
more severe,
so it's during about half of
cases, which is much higher than
typically
developing children.
Because of the lack of symptoms
and the incredibly high
prevalence,
universal screening with
polysynography is recommended by
age 4.
Unfortunately, we are
not great at this.
So in one study looking at this,
only 25% of kids had actually
had a sleep
study by age 4.
And from a clinical experience,
I would say that's probably
probably
accurate.
Maybe ideally we make it half by
age 5 or 6.
So there are many children with
Down syndrome who are hanging
out who are
undiagnosed.
Why is it so common in people
with Down syndrome?
I broadly think of it kind of in
two areas.
So the first,
anatomic structure.
So people with Down syndrome
tend to have a relatively small
airway.
So mid face hypoplasia means
kind of your airway is a little
bit set back and
smaller.
From that perspective,
people tend to have a relatively
large
tongue compared to the size of
their mouth.
And so that can lead to
obstruction from their tongue at
the tongue base.
And then adenotongs or
hypertrophy is also fairly
common in children with Down
syndrome.
The other big area in the area
that we focus our research on is
hypatonia.
So airway hypatonia is a known
thing in people with Down
syndrome.
So we all have decreased muscle
tone during sleep.
If you start off hypatonic and
go to more hypatonic,
that's when you see that that
spontaneous airway collapse,
which is obstructive sleep
apnea, effects of I was saying
in people with
Down syndrome,
these are really all of the kind
of
typical things that we've seen
in everyone.
This tends to be more of an
issue because it's kind of a
second additional decrease.
So for example, verbal IQ,
my collaborator Jamie showed
about a six
point.
So children of Down syndrome
without sleep apnea versus with
sleep apnea,
the children with sleep apnea
had a six point lower verbal IQ.
If your baseline OQ is 110,
that six points is not going to
be huge,
huge deal.
Obviously, it'd be better not
to, but when you're going from
45 to 39,
you can see really dramatic
effects in terms of your
adaptive function.
Like are you, are you staying in
a, in a group home?
Are you living with your parents
versus how, how independent you
can be.
So we know decreased adaptive
function if you have sleep
apnea,
decreased verbal fluency.
Interestingly, in adulthood,
Alzheimer's disease is
incredibly
prevalent for people
with Down syndrome.
There are some studies in adults
without Down syndrome showing
that there's
increased amyloid,
suggesting obstructed sleep
apnea can
complete can contribute to
Alzheimer's Alzheimer's disease
development.
This is not an area that's been
very well studied so far in,
in people Down syndrome.
We know quality of life goes
down as this common sleep
disorders,
your quality of life takes a
fairly big hit.
And there's also some a little
bit of data showing that even
cardiovascular
effects.
So you,
you have decreased left
ventricular
function.
So what can we do about
obstructive sleep apnea?
So all of the kind of common
treatments that I'm gonna touch
on.
So the alternative treatments,
so standard Endoton selectomy,
CPAP,
most people are typically
familiar with these alternative
therapies.
So myofunctional therapy is
essentially speech therapy
exercises that try to
increase your airway muscle tone
during the daytime,
with the idea being that if your
airway muscle tone is stronger
in the day,
at night it will hopefully be
stronger too.
There is one study of this doing
one week of myofunctional
therapy for a group of
kids with Down syndrome.
The baseline HI and follow up HI
were essentially the same so no
difference.
anti-inflammatory medication.
There's some evidence
Montelukast and and Flonase can
help,
especially for mild
OSA in children.
There are two retrospective
studies looking at these
specific to kids with
Down syndrome.
That too had no benefits.
GLP one medications tirzepatide
was recently approved for
obstructive sleep
apnea in in adults.
There is no data for people with
Down syndrome.
I think this is
fairly promising.
I've actually had a handful of
patients in clinic,
my adult patients who are
already taking it.
So we will see what
happens with that.
So that I think
that's very promising.
There's no data for it at all in
Down syndrome in the more of it
this time and
dental approaches.
So things like palate expansion
in younger kids where you use a
bar to
expand the the palate increases
your your airway dimensions.
For teens with most of their
adult teeth, you can use
mandibular advancement
devices,
which is essentially a device
that pulls
you lower drop forward to open
up your airway more.
There are no studies specific to
this in people with Down
syndrome.
If you are not obese and have
mild OSA, it's probably a
reasonable option,
but again,
it's it's unstudied so I'm
willing to
mention it,
but there's no doubt either way.
Hypoglossal nerve simulation is
in the green.
So it is studied and then auto
oxy is something that we're
studying so I'm
gonna touch on that as well.
So adeno tonsillectomy is your
typical first line approach.
Unfortunately,
it's not especially effective
for kids
with Down syndrome.
So about half to 3/4 will have
residual objective sleep apnea
after tonsillectomy.
It does at least
decrease OSA severity.
And so,
and there's been many studies of
this at
this point,
but about half of children will
show
about a 50% reduction in their
OSA severity.
That tends to be a
fairly wide range.
So some kids do get completely
better, but some kids get no
benefits.
Unfortunately,
there's no way to predict who's
going to
be a great responder
that I'm aware of.
In terms of published data.
There are some other ENT
procedures that can be
considered.
I'm gonna gloss over those.
CPAP works great if you use it,
and I think everyone is aware of
that.
The big issue with this is
therapy adherence.
One study showed about 46%
adherence in kids with Down
syndrome.
This was people who are followed
in clinics.
There might be a selection bias
where these are kids who are
showing up to
clinic because
they're using CPAP.
One study in clinical trial
showed an average of two hours
per night.
If you're thinking they're
sleeping 8 to 10 hours per
night,
they're only treated about 20%
of the time.
So CPAP is fantastic if you use
it, but unfortunately for the
majority of
children who children and adults
who don't use it,
CPAP next to you does not do any
benefit for OSA hyperglobulin
nerve simulation.
So currently on the market is
the Inspire device.
So this is essentially A
pacemaker battery implanted in
your chest with a
wire that goes up to an
implanted lead right here that
uses electricity,
uses voltage to essentially push
your tongue forward to keep it
out of your
airway.
This has been FDA approved in
adults for a while at this
point.
This was approved
I believe 2023.
That's when the
clinical trial was done.
So there is a study that looked
at a 42 adolescent, so age 10 to
21,
baseline obstructive HI was 22,
which is severe OSA for kids.
Treatment got a little bit more
than 50% improved adherence was
excellent and they
did find quality of life from
approved significantly.
This is now on the market.
It's FDA approved to age 13 plus
I know there are ENT's out there
who are
implanting in younger patients,
but the FDA approval is age 13
and then
adoxy.
So this is a clinical
trial that we did.
So we did a smaller study
initially in 12 children.
So,
so adamoxydine is FDA approved
to age 6
for ADHD.
It's, it's generic,
fairly inexpensive increase of
norepinephrine,
which also happens to increase
airway
tone in non R.E.M.
oxybutynin the FDA approved down
to age 6 for overactive bladder,
it decreases muscarinic receptor
activity, which also happens to
increase airway
tone in REM sleep.
So we looked at the
combination of this.
There was a study in 2019 in
adults without Down syndrome
that showed about
an 80% improvement.
So we thought this might be
particularly effective for
children with Down syndrome
because airway hypatonia is such
such a critical issue for
obstructive sleep
apnea for them.
Interestingly enough,
we found about a 50% reduction
in OSA
severity.
This was 12 kids aged 6 to 17.
And you can see that the
individual participant level
data here.
So you can see that some people
responded fantastically,
so participant in the orange and
then some did not have nearly as
much benefits,
but on average,
it's about a 50% improvement.
We have an ongoing larger study
that will look at about 36 kids
over six months to
look to see if we improve
quality of life as well as
cognition.
That study's ongoing that will
hopefully conclude next year.
So we'll hopefully have results
of that to present next year.
So this is a promising therapy.
There is a somewhat similar
medication called 81 O nine that
is in clinical
trials in adults without Down
syndrome that uses a different
version of of
oxybutynin essentially.
And so this is, this is
promising, but further studies
need to be done.
Does OSA treatment improve OSA
associated adverse effects in
people Down syndrome?
This is the important question.
There is a little bit of data
that suggests that the answer is
probably,
unfortunately,
they're both very small studies.
So one was a a study of of CPAP
that happened to include six
kids that had
Down syndrome.
Parent reported quality of life
and their behavioral outcomes
were improved.
There is one study that included
children with
mucopolysaccharidesis or Down
syndrome,
which did to improve quality of
life.
There was a pilot study of
hypoglossal nerve simulation
that also showed really,
really promising results that if
you can effectively treat OSA,
you do improve all of those
associated adverse issues.
So it works.
Quality of life and beared
cognition, all of those seem
like it probably gets
better.
Again, this is a study of nine.
One of the historic issues has
been that if CPAP is the only
effective therapy,
it's very hard to do a trial
where you know that at least
half your participants
are not going to use your study,
your intervention to show
efficacy.
So as we get more effective
therapies, I'm optimistic that
we're going to start
seeing larger improvements.
So obstructive sleep Ave.
take home points.
OSA is common in people.
Down syndrome is associated with
a lot of worse outcomes,
cognition,
quality of life,
cardiovascular behavior.
Current OSA treatments are
effective for some people Down
syndrome,
but not not all.
And we have multiple new
treatments that are under
development that may be more
effective for people
with Down syndrome.
So I think this is a really
promising area and I'm really
optimistic that in
the next 5 to 10 years we'll see
a lot of dramatic improvement in
OSA treatment.
Turning briefly towards
insomnia, insomnia related
complaints are extremely
common in children and adults
with Down syndrome.
The big issue with this
literature is most of these
studies tend to kind of
focus on sleep problems, sleep
complaints, and don't tend to
use strict diagnostic
criteria.
This gets challenging to
interpret because obstructive
sleep apnea can
simply cause sleep complaints,
whereas a more rigorous kind of
insomnia
diagnosis would probably be a
lot more helpful.
So in sum,
if you talk to parents of
children with
Down syndrome, this
is a common complaint.
This is a very open area that I
think really needs to be studied
kind of
briefly to highlight this.
So my general approach to
insomnia in clinic is really
someone comes in with a
complaint about insomnia,
they can't sleep,
You need to figure out what's
causing that says that a medical
condition.
So sleep apnea,
restless legs or kidney rhythm
disorders
and just asthma, untreated
reflux, things like that and
treating the
underlying disorder might make
that insomnia complaint go away.
Conversely, more of
the primary insomnia.
So insomnia where nothing else
is causing it kind of splits
broadly in the sleep
association insomnia limit
setting disorder in kids and
then primary or
psycho physiologic
insomnia in adults.
And behavioral therapy,
as it's been mentioned,
can be extremely
effective for these.
And so I'm going to gloss over
to sleep onset association.
So parent rocking childlessly,
the classic of this limit
setting
insomnia is really just children
testing boundaries.
And this is far too broad a
topic to talk about treatment in
detail.
I'm going to touch a little bit.
So older children,
so teens and adults tend to have
more of
the, in some,
we have adults experienced where
it's,
I want to sleep and
I can't fall asleep.
Maybe I'm stressed,
I'm worried about something.
And so treatment for that is
really focused on perpetuating
factors.
And so predisposing factors,
your risk for insomnia.
So you might have underlying
genetic risk, family risk,
precipitating factors,
you're worried about it and
things like that.
These tend to go away.
And then the reason people have
chronic insomnia is usually not
active coping
strategies that
make things worse.
The classic is
people don't sleep.
They try to go to bed super
early and then they're not
sleepy so they can't
fall asleep.
That's probably the most common
one that people tend to do
cognitive behavioral
therapy for.
Insomnia is the gold
standard for this.
This is a package of a bunch of
interventions.
Importantly,
a lot of these things are things
like
sleep restriction.
These are really effective for
people with a broad level of of
cognitive
function.
And so I think could probably be
adapted for many adults with
Down syndrome.
There's no research on this.
And so I'm mentioning it in
hopes that someone is feeling
inspired to begin
doing it.
And so I'll end with kind of
future research directions.
Insomnia,
really rigorous studies are
lacking a lot
of, again,
they tend to be focused on sleep
complaints, kind of vague,
not specific diagnostic
criteria.
And so even doing studies trying
to window down, is this primary
insomnia,
this is insomnia due to sleep
apnea or needed Cbti or other
behavioral
interventions are probably
adaptable to individuals across
a wide range of
cognitive abilities.
This is completely unstudied as
far as I'm aware for Down
syndrome.
And then as it's been touched on
by other speakers,
medications are really commonly
prescribed.
There's really minimal data for
safety or FX advocacy specific
to Down syndrome,
obstructive sleep apnea.
So we, we need, we
need better therapies.
I think there's studies ongoing.
So maybe there's a role for
position medicine to identify
the right OSA
treatment for the
right patients.
We got a recent PECORI grant
that is starting this year that
will attempt to
do exactly that.
So we'll see if we can predict
if people are going to be better
responders to auto
oxy versus oxygen as therapies
based on their sleep studies,
their based on sleep studies.
And then broadly long term,
does treatment improve cognition
importantly lower Alzheimer risk
as individuals with Down
syndrome age,
the Alzheimer risk is very,
very important concern for
families.
So I will stop right there.
Thank you.
Thank you so much.
That was a great overview and
and pretty comprehensive.
We do have a question in the
chat and then if we have time, I
have one.
The question is,
can you please comment on the
feasibility
of PSG in the
pediatric population?
How often are valid PSG
assessments just not attainable
and is this greater or
lesser problem in NDD patients
recognizing that there are lots
of
different types of NDDS?
That's a great question.
I actually had a slide on that
and I took it out 'cause I
didn't get time to talk
about it.
So,
So the answer is from a clinic
perspective,
we do about 500 sleep studies a
year at
our clinic.
I would say we have less than 1%
get cancelled for propeeds so
they can be
done.
Some of my collaborators,
so Ignacio Tapia,
Chris Cello have looked at home
sleep tests for,
for children and adults with
Down syndrome depending on the
device you use.
Those were actually
very promising.
And so the kind of traditional
home sleep apnea tests that look
at airflow at home,
they,
they had fairly good success
with that.
And so I think there
are other options.
We would love to have an in lab
TST for children,
but also some it's not going to
happen for everyone.
I think looking at the home
sleep test is an entirely
reasonable option clinically.
We will do that sometimes.
Some of the other devices like
the more ring types,
devices that look at
cardiovascular, cardio,
pulmonary coupling,
I'm hesitant to recommend
because I don't know that
there's a lot of data to
support them and I think there's
a high risk of inaccurate
studies.
But anything that that looks at
airflow I think is entirely
reasonable and it's
probably relatively useful.
So thank you.
Yeah, it's a very
comprehensive answer.
Thank you.
So I do have this time for I I
am The auto oxy stuff is just so
exciting and
it's so great that you're doing
that Super promising.
I didn't catch whether or not
the kids who are enrolled in in
those trials are
the people with Down syndrome
who are enrolled if they had to
have a prior TNA.
So have you done the standard
sort of for them or are they
sort of folks who didn't
want to have the surgery or how
did how does that get?
That is a great question.
So for that study,
children with three plus
tonsils,
so like essentially very large
tonsils are not eligible unless
they get a
tonsillectomy first.
In that pilot study,
everyone had a tonsillectomy
before the
study anyways.
So they just all happened to
have had tonsillectomy,
which I think is
generally the case.
In our larger study,
I think we have maybe 10% that
haven't
had a tonsillectomy.
So I think we've just,
the reality is that they've
almost all
had a tonsillectomy before they
do the study.
And so,
and then how many of those sort
of had
resolution or I guess that's in
the paper, like where they were,
how well they responded before
they started the Idoloxy.
So we don't because we didn't
look at their tonsillectomy
beforehand.
So we, we do a baseline study.
So we,
we know what their status is
post
tonsillectomy, but we don't
really, we don't collect the
data on pre tons
like me,
just because a lot of them don't
necessarily have it.
Thank you.
Thank you so much.
Awesome work.
OK, we're gonna,
we are right on time and we are.
Oh,
we might have one more if we if
it's a
62nd question.
Oh,
this is just a comment about the
attoxy
slide looking like they're a
bunch of subjects who did a bit
worse with the
higher dose.
Was that reflecting
intolerability issue?
So they were less adherent with
the higher dose.
Is that something
you'd comment on?
I don't know that I can
officially answer that question
because it's such a small
study.
For the larger study we're using
the low dose.
So I think that there probably
is some we saw more side effects
with the higher
dose.
And so there's
probably some of that.
But because it essentially works
nightly, as long as they took
the medication the
night of the study,
they should have had advocacy.
I think there was one or two
that needed to take it like in a
liquid.
And so maybe they didn't finish
their whole dose.
But we based on that data,
that data we used the the lower
dose for
our larger study.
OK, OK, thank you very much.
We are gonna turn now
to our next speaker.
Demetrius Milonas is an
assistant professor of
psychology in the Department
of Psychiatry at Massachusetts
General Hospital.
His research interests include
the development and
implementation of new
analysis methods to neuroimaging
data, EE, GMEG and MRI.
His presentation will focus on
autism spectrum disorder.
So thank you so much for
inviting me today that So today
I'm going to speak
about sleep ET biomarkers in
autism and I don't have any
disclosures.
So we focus on sleep ET in our
work and we're trying to
establish links between
the underlying secretary and
manifestations
neurodevelopmental
disorder.
So today I'm going to speak how
we can study non sleep
oscillations to inform us
about the thermocortical
circuitry and how this is linked
to impaired sleep.
You notice,
and there is probably no need
for that
because the previous speakers
talked a lot about that,
but sleep is a
important problem.
You notice up to 80% of children
and adolescents report sleep
problems,
including difficulties falling
asleep or waking after sleep.
Oncids and importantly as Doctor
Malo mentioned,
these were sleep problems
actually are associated with
more severe core symptoms
and worse day day functioning.
So it's very important to
understand the neural
underpinnings of impaired
sleeping
autism and to develop novel
interventions, and also for the
existing interventions
to actually understand, like
melatonin, for example, to
understand how they act.
So I will go very briefly.
I will give a very brief
overview of sleep.
Just want to say that sleep is
not a monolithic phenomenon.
There are different stages
states of sleep and by using EG
actually.
So what you see on top is the
typical hypnogram of sleep with
a different sleep
stages and at the bottom is the
window in the brain activity
that EG can offer.
On the X axis is the time,
the 9 hours of sleep and the Y
axis are
the frequencies.
So using EG,
we can actually see that the
different
sleep stages are characterized
by different by different brain
activities.
So slow wave sleep here,
stage sleep is characterized by
this
increase in low
frequency oscillations.
You can see it here, even here.
And knowing about of sleep,
stage 2 and stage stay sleep are
aligned
very well with this increased of
increased power in Sigma
frequency.
This 12 to 15 Hertz activity,
you can see it very clearly.
And this is important because
this increases in power actually
reflect brain
oscillatory
oscillatory activity.
So this increases in low
frequency reflect slow waves,
slow oscillations.
And this increases in Sigma band
actually reflect spindles such
spindles.
And since this will be my main
characters, the main characters
of my talk today,
I will spend one more slide to
go over them.
So slow waves or slow psilations
are cortical,
cortical waves that are
generated in the cortex, in the
pyramidal cells,
in the cortex.
Spindles,
which are the hallmark of stage
2 slip
are generated in the salami
reticular nucleus.
And then we have sharp wave
rippers generated in the
hippocampus.
And these are the three non REM
sleep oscillations.
Importantly,
these oscillations are actually
synchronized, synchronized
altogether, so they don't act in
isolation.
So during non REM sleep,
this secretary is in a constant
dialogue
and I will spend one more slide
to focus on the thalamic
thalamocortical circuitry
because and explain why we think
that thalamic reticular nucleus
dysfunction
may contribute to both sleep and
wake symptoms in autism.
So this is this red structure.
Here is the thalamic reticular
nucleus which is a thin shell of
gabytic neurosis,
completely inhibitory and it
wraps around the lateral and
ventral thalamus.
So due to its strategic
location, TRN is actually
modulates thalamocortical
communication.
So during the day TRN actually
inhibits the incoming sensory
information or like
filters the incoming sensory
information leaving only the
salient the salient
stimuli to to come in and works
functions as a Searchlight of
attention.
So dysfunction of this inhibitor
reaction can actually lead to an
overflow of
sensory stimuli to the cortex
and over stimulation,
sensory sensitivities etcetera.
So during night the same
structure generates sleep
spindles by inhibiting
this thalamocortical neurons.
And there is a large large body
of literature showing that sleep
spindles
play a protective role in sleep
with the same idea that during
the sleep spindle
the cortical response to
external auditors stimuli is
quite suppressed.
So again,
this inhibition or dysfunction
of
thalamocortical circuitry might
leads to impaired sleep,
more awakenings both over
stimulation, sensor
sensitivities and impaired
sleep,
very common
phenotypes in autism.
So a main research test of mine
is developing methods to detect
spindles,
low waves and their coupling.
And I won't go into the details
here of these methods, although
I would love to,
but will take us a long time.
But these are examples of this
is an example of a spindle and
how we can
characterize it.
You know, the, the, the, the
duration, the features in
general,
these are slow waves detected
slow waves during sleep.
And this is what I talked about
the coordination of spindles and
slow waves.
So this is a spindle here riding
on top of of a on the upstate of
a slow wave.
And this is a cartoon now of the
same concept.
But we can actually quantify
this synchronization of slow
waves with
spindles.
If we do that,
like if we find spindles that
are
synchronized across the night,
we can actually calculate the
preferential coupling phase with
spindles peak during the phase
of the slow wave,
and we can actually evaluate how
consistent this synchronization
is.
And my point of this slide is
that we have all these
measurements that can
actually index the function of
thalamocortical security.
They can show us,
they can offer a glimpse of how
this
secretary works.
So we did the study.
We analysed data in 2022 from a
sleep study run by Masquita 2015
in boys with
autism from 9 to 17 years old.
That was an at home sleep study
using the sparse EGRE in 19
typically developing
children and adolescents and 18
children with autism.
Not surprisingly,
we found that sleep overall was
worse in
autism.
Kids spend more time in bed,
they had more awakenings after
sleep
onset,
and they took them longer a
longer time
to fall asleep.
All these reflected in poorer
sleep efficiency.
Again, not surprisingly,
based on what I mentioned
before,
we found that higher spindle
density actually predicted less
wake after sleep
onset.
So consistent to this protective
role of spindles against the
awakenings,
we found that more spindles were
associated with less wazzle.
We also found that in noticing
boys with autism had reduced
spindles in states
three sleep in slow wave sleep
in both frontal central
electrodes and when we
looked at the synchronization of
spindles with slow waves,
we found that in autism here
spindles speak later in the slow
wave phase.
This is a schematic
representation of the slow wave
of frontal and central
electrodes and with thread is
the autism group.
You can see that spindles
overall on average speak later
compared to the
typically developing peers and
the coordination was less
consistent.
So there was high variability at
the central electrodes in ASD in
autism.
And this is a small interim
summary of the study that we
found disrupted sleep
in autism a late this indices of
thalamocortical circuitry where
a typical
in autism and spindle density
was related as we expected with
less Guazo.
But the main caveat of or
limitation of the study was that
the sample size was
quite small.
And this is a common theme in
autism because I believe people
here can
appreciate how challenging sleep
studies are and sleep studies in
clinical
population are with you know
sensory sensitivities with
bedtime things with
sleep problems etcetera can be
even more challenging.
So this is a common theme notice
like small sample sizes in
sleep,
in sleep studies and if you
combine it with inherent
heterogeneity of the
disorder,
this is the perfect recipe for
how to put
it like mixed results
in the literature.
And this is what what we see a
lot in autism.
So our next step was to actually
try to use to turn to
wearability devices to
upscale our sleep studies.
And with the funding from the
Sandwich Foundation,
we started trying
wearable devices.
This is just an example of two
wearable devices sleep upon top.
This is developing this in
Switzerland And then three,
the device that's the device
that we opted using in in the
study.
We validated devices in the lab
and we embarked in a nationwide
study.
Before I go to that,
I want to say that they the
landscape of
wearable devices is emerging,
is growing and there is a lot
more
devices and very interesting
studies validating these devices
nowadays
actually.
So we embarked in this
nationwide study page.
Nicole and Tory are leading this
study where we ship this,
we ship these devices
all across the US.
We train,
they train families to use the
device at
night and we record 3 nights
from children to 12 to 19 years
old.
The first night is
an adaptation night.
The other two nights,
you know are the experimental
nights.
And we had quite a success here
with 76 children without these
men,
47 typically
developing children.
I have to say here,
I have to note that we had
support from
the Autism Science Foundation
and the QSONG to actually expand
this protocol is
to profound autism and Philan
McDermott syndrome syndrome and
also from the
Simons Foundation to expand our
protocol to include monogenetic
autism as well
like fragile legs and
the 16B11 deletion.
And as you can imagine,
we have a lot of influx of data
every day.
So we're using an open software
Luna and open software developed
by some percent
to actually do quality control.
And I give this out out because
it's important to use some
standardized
methods when we go like to these
larger data sets, these large
data sets.
And I want to show some
preliminary results on that.
Again, non not surprisingly,
we've found that kids with
autism spend
more time in bed.
They have reduced sleep
efficiency and increased wake
after sleep onset.
We didn't find any differences
in sleep onset latency,
but it's quite tricky actually
to measure this at home with
these devices.
I can get back to that later.
Again,
we found that lower spindle
density
predicted were sleep consistent
to this idea,
to this notion of spindles that
are protecting sleep from
awakenings.
And we found that either
measured by wake after sleep
onset or by sleep
fragmentation index,
this is an index showing that so
how many
transitions to lighter
sleep you have.
So again,
lower spindle density predicted
more
transitions to lighter slim.
And when we looked at the
spindle spindle density
initially we did not find any
differences typically developing
versus ASD children.
But when we broke it down by 6,
we found that maize in autism
have
reduced spindle density.
And I have to remind you here
that our initial study was in
boys with autism.
So that's a, that's
a replication here.
And there is a very interesting
interaction with sex,
sex effect that we need to wrap
our head around.
And finally,
I want to say that our goal is
to
actually target
these oscillations.
And last September,
I was funded by the American
Academy of
Sleep Medicine to use closed
loop auditory stimulation during
sleep class.
This is work led by my colleague
Brian Baxter.
What we do during class is
actually we monitor ongoing
brain activity.
You can sit here with the black
line and we're trying to target.
We were trying to target the
upstate of the slow waves with a
very short mild
auditory stimulus, pink noise.
And this here in this example
evokes a new cortical, a new
response,
slow wave response
and a spindle.
And this is working by Brian
showing that by targeting the
upstate of the slow
waves,
we're actually can elicit slow
waves
evokes the ways which is the
hallmark of slow way sleep of of
deeper sleep.
And we can also elicit increase
evoked Sigma power.
So we are developing our, our,
our algorithms right now
actually to, to,
to start to embark into this
study to try close repository
stimulation in children
with the autism.
And with that, I hope,
I want to summarize to say,
I hope I've convinced you that
by interrogating Sleepy G,
we can understand better the
circuitry that might contribute
to impaired sleep
in autism.
And importantly,
this can offer new biomarkers
that we can
target to we can target and to
improve sleep and weight
function in autism.
And I think I have maybe one
more minute I want to have a
teaser to speak a little
bit about the future directions.
We I talked mostly about the
slow waves and spindles,
but there is emerging literature
showing that there is an other
important rhythm
during non dream sleep,
the infra slow rhythm that lasts
around a
minute a period and is generated
by locus cellulose,
the source of
noradrenaline in the brain.
So during the high noradrenaline
in the in the thalamus,
this rhythm actually divides
sleep in periods of vigilance
that the brain is
more vigilant to the
environment, more prone to wake
up and periods of
consolidation where you find
abundance of these oscillations
that are linked to
memory consolidation.
Absolutely.
And I think this is a this is a
study showing that how this
intra slow rhythm
coordinates neural and cardiac
autonomic autonomic system as
well in audience and
humans.
This is quite understudy
understudied in humans and I
think by studying,
understanding this secretary
having a more fuller picture of
that and help us
understand why sleeping
impaired, you know this.
Yeah.
And with that,
I wanted to thank my Pi Diamond.
Not everybody in the lab,
the Lewis Centre and and our
sponsors and
of course our our participants.
Thank you.
Thank you for listening.
Oh, thank you Doctor Milan.
So we are right at
time, which is too bad.
I'll have to hold my questions
to the end because I have to
admit to being partial
when the main
character is Spindles.
OK,
we're going to move on to our
last talk
for this session,
and we'll just have to remember
all the
things we want to ask the other
speakers to the end of the day.
We're going to hear
from Jennifer Accardo.
She's an associate professor of
Pediatrics and director of
Virginia
Leadership Education in
Neurodevelopmental Disabilities,
or VA,
Lent or violent at Virginia
Commonwealth University.
Her research interests focus on
sleep problems in children with
neurodevelopmental disabilities,
autism, and ADHD.
Her talk today is on the effects
of medications on sleep and
symptoms of
neurodevelopmental disorders,
which is relevant to everything
we've
been talking about this morning.
Doctor Ricardo.
Thank you, Doctor Buckley,
and I very much appreciate being
asked to
speak at this very
interesting symposium.
All right,
no conflicts of interest and
basically
this entire talk is basically
off label with the exception of
the medication that
Doctor Mallow
referenced earlier.
I'm primarily A clinician and
that is the perspective I'm
going to bring to this
talk.
I wanted to start with this is
actually an citation from the
first issue of the
Journal of Clinical Sleep
Medicine in 2005,
the profile of the ideal
medication for sleep and
Pediatrics.
You'll notice ideally it would
take effect quickly, be very
bioavailable,
have both a long duration of
action so that it would
substantiate throughout the
night and also not
produce a hangover.
Minimal side effects,
no effects on sleep
architecture,
any palatable format.
Because one thing I've learned
from families of children with
autism over the
years is if a child does not
want to put something in their
mouth,
they truly will not.
This medication unfortunately
does not exist.
So many of my patients in sleep
and development lack the season
of All
Nature's Sleep,
and initially I was being a
little silly
putting this up in a reread
Macbeth recently.
But this this picture reminds me
of a resident's comment that I
had earlier
this week where someone told me
about medications I was using.
These medications are
dirty, and they are.
This is a somewhat dirty
business, the medication of
sleep in children.
My other disclaimer is some
years ago I was having a
conversation with another
pediatric sleep colleague more
about children with
disabilities.
We had a very nice conversation
and I thought we were wrapping
up and then he
took me aside and said, well,
what do you really do?
What is what is the I?
I think a lot of people are
looking for that break glass in
case of emergency
medication that unfortunately I
am not able to disclose because
I have not
figured it out yet.
So let's look at what some
people are actually doing And
Judy Owens and her
group had a couple of articles.
This was the more recent one.
There was also a 2003 looking at
primary care pediatrician
surveyed on medication
treatment and for insomnia.
This may not say specifically
children with neurodevelopmental
disabilities,
but realistically when she
looked at the characteristics of
the children who were
being prescribed medication,
many of them had autism,
intellectual disability, some
other, you know, ADHD, some
other condition.
So 28% over all of those child
psychiatry patients getting
medication treatment,
most commonly the
over the counters.
And at that time it was
antihistamine, melatonin and
various herbals.
And I believe some of those
percentages have flipped,
especially based on that more
recent IPSA International
Pediatric Sleep Association
review of melatonin,
that melatonin is now #1 for
better or
for worse.
I did find it very interesting
thinking about reasons why
prescribers used
medication and reasons why they
decided not to.
Can you get both
at kind of a first?
Then we tried other things.
They didn't help.
We get at family can't or won't
do other do other things.
We get at the behavioral changes
that I think Doctor Joseph
alluded to.
And some of the some of the
interventions can be hard.
Reasons not to use medication
for insomnia in children were
also pretty
robust.
I don't understand the second
one here, but control concern
about shorter long,
long term side effects may come
from a clinician,
may come from parents concerns
about giving the wrong message.
I don't know how many times I've
counseled parents about
behavioral
interventions and said, well,
and let's let's also try,
let's also try this other thing
to help you through the hard
part.
And at the follow up,
I hear the medication didn't
work well.
What about the changes that we
talked about?
Unsure of the best or most
appropriate medication to choose
is a real challenge
because there's frankly, spoiler
alert, not a lot of information.
Doctor Mallow,
I used to always put up the
Autism
Treatment Network insomnia
protocol, and I wanted to mix it
up a little bit
with something more recent.
But ultimately there's several
kind of expert consensus
protocols for what do
you do with the child with sleep
disturbance.
This particular 1 is out of
Lurie, so hello to my previous
presenter and
Mass General.
And all of these
protocols start with.
Are there other factors?
What else is going on?
Is there something physical that
is preventing sleep that is
irritating sleep?
Are there other
sleep conditions?
Is there adequate sleep hygiene,
which is not necessarily an easy
thing to
address?
I think the interesting twist in
the autism treatment network
protocol is
assessed parent willingness to
use these behavioral strategies
as well.
I think this gives us fairly
standard picture of what many of
us do in the real
world,
which is melatonin is often
first
Clonidine,
maybe Trazodone or hydroxyzine
or second
line.
I really do like gabapentin as
published by Doctor Robinson out
of Vanderbilt
those years ago,
and I don't know why that's not
more
widely showing up in these
protocols, but there we are.
I don't love seeing zolpidem at
the bottom of this,
but that's a different slide.
When do you want to think about
medication?
This kind of tracks back to some
sleep disorders.
I want to think about is this a
child who's getting enough
sleep?
Are they getting adequate
quality of sleep?
Quality is very quality can be
very difficult to measure and a
standard sleep
study isn't going to get at all
of all of my previous colleagues
kind of different
parameters in terms of spindle
density etcetera.
But like like in real estate,
location, location, location,
we can work with duration,
duration, duration,
appropriate timing of sleep in
terms of circadian, just like
with the DSM,
we don't just want
a sleep difference.
We want evidence that something
with sleep is interfering with
the reducing
the quality of function.
In order to be concerned about
this, I've in my developmental
practice,
I've run across plenty of
children who have odd sleep
schedules that are for
whatever reason not currently
bothering anyone.
They're homeschooling and it's
not an issue.
Other factors including families
and patients and shared decision
making.
Some families are seeking
medication actively.
Other families wanted on no
conditions whatsoever.
And I saw a young man earlier
this week who was using
melatonin whose goal was to
fall asleep without it.
But I think medication is a non
starter without addressing
significantly
interfering issues.
And my reminder slide here is
this is a picture of a Japanese
hikikomori,
a teenager or young adult who
has basically self-imposed A
hermit situation
where they are not leaving their
rooms, are often engaging in a
great deal of
screen time.
I would like to say we don't
have anything that extreme in
the US,
but I think we very much do.
And some of the people
experiencing this are not
neurotypical and fall under the
heading of this
of the symposium.
There is no I CD10 code for
hikikomori and this young man
actually seems to be
getting some sunlight which many
of my patients don't.
My point being,
there is no medication on earth
which is
going to moderate or improve
your sleep if you don't leave
your room and you're
in constant dim
light situations.
It is very challenging to use a
medication to improve sleep when
you have
almost unlimited screen time,
which applies to many of my
patients who
are not constantly
in their rooms.
Sorry about the soapbox
categories of sleep disorders.
The International Classification
of Sleep Disorders Third
addition gives us several
categories and I'm not going to
focus on all of them,
but I am going to hit insomnia a
little bit on sleep related
movement disorders
and a little bit with a nod to
Doctor Combs on sleep related
breathing
disorders with insomnia.
Again,
the first line often is
melatonin at this
point,
and part of the challenge there
is that
by the time I see somebody in a
sleep clinic tried melatonin and
it's more,
what exactly did you do?
How much did you take?
When did you take it?
What kind did you take?
Antihistamines are a bit less
popular, but if you don't ask
specifically,
you might miss that somebody's
using that to supplement the
effect of something
else or alternating
with something else.
Hydroxyzine is a
reasonable anxiolytic.
I'm increasingly using that for
my many anxious patients so that
that may have a
few different benefits
prescription wise.
We'll come to Clonidine in a
moment, Gabapentin and some of
the atypical
antidepressants.
I swiped this image from a
chapter that Roberta Lou did on
melatonin.
But again,
the darkness hormone you need to
not be
constantly exposed to bright
light in order to secrete this
mediated by the
retinal retinothalamic tract
heading to the Super chaosmatic
nuclei.
Coming back to the International
Pediatric Sleep Association
recommendations,
which were relatively recent,
you want to use this one caution
with children under 2.
The suggestion maybe a little
bit Contra we heard before,
not come to the sleep doctor
because you had to stop
melatonin.
It was working well.
But the idea to supervise use in
children with ND DS and
periodically reassess
whether children still need it.
I think that one of the great
needs and lacks in this field is
not just how to
put people on medication,
but how to take them off,
when to take them off.
Maximum dose 10 milligrams.
I think that this particular
paper suggested a range of two
to 10.
I've usually started kids on 0.
5 milligrams and I had a young
man
earlier this week who fessed up
to his mother to taking 40
milligrams because
the 10 wasn't quite doing it.
So he popped a few timing,
lack of long term safety data.
Doctor Mallow,
thank you for one of the follow
-ups to
try to address some of the
concerns about delay of puberty
and effects on HPA axis
with the follow up of children
treated with the pediatric
prolonged release and
the knowledge that at least in
that two year term,
the pubertal status and growth
were not really affected.
This is some information from
AUK review of Clonidine practice
prescribing
practices.
This one is pretty reasonable in
terms of onset of action.
In terms of duration of action,
for some of my patients it does
seem to
help not only with sleep
initiation but with sleep
maintenance.
It does tend to be R.E.M.
Suppressing and you can see what
the range is.
One of the things that we run
into with this medication as
well as others in the
world of sleep is that it seems
to be more effective initially
and over time
maybe not as much.
Many prescribers had concerns
about tolerance.
This being an alpha adrenergic
agonist, we also have effects on
hyper arousal
states which may be very helpful
for people with autism,
people who are chronically there
And I am short on time due to my
technical
difficulties.
So moving forward to
some side effects.
Constipation is not necessarily
minor, though it was in the
sample in children
with NDD.
In Doctor Robinson's paper on
gabapentin, this has been, I'd
say,
one of the more helpful ones in
terms of sleep maintenance.
Insomnia.
You can see some
irritability here.
You can see some changes in
sleep parameters.
One of the challenges here is
yes, it comes in a solution.
Yes, the solution
tastes terrible.
Restless leg syndrome
recommendations melatonin rides
again gabapentin at least
the ASM most recent practice
parameter recommended in adults
iron
supplementation low serum
ferritin is not diagnostic of
restless leg syndrome.
But for children who have
restless leg syndrome or more
commonly in the world of
developmental disabilities are
kind of restless and maybe
could.
And we want to try something.
Probably worth a try with
monitoring, with counseling
about side effects.
I was ready to go into a short
tirade about dopamine agonist
and the challenges
of disinhibition in children.
But now AASM is suggesting
against use for adults
routinely.
Interesting times.
Magnesium has been blowing up
right and left.
A small open label pilot study
in adults showed something,
but a recent ish systematic
review really didn't have a lot
of evidence.
And yet this is absolutely out
there for sleep.
Obstructive sleep apnea.
Nasal steroid sprays in the mix.
Again,
it's a little unclear when you
can
discontinue these.
Montelukast.
If you listen to the
otolaryngology consensus,
probably safe and affected for
mild to moderate OSA.
However,
there's a black box statement
about
neuropsychiatric effects.
There's fairly conflicting
evidence out in the world
whether they are a risk.
And if you counsel parents about
this, which you should because
they're going to
read about it anyway,
I find that many of them refuse
this.
I see Doctor Buckley is up.
Doctor Combs,
thank you so much for your work
in auto
oxy.
I am very intrigued and want to
investigate this further in some
of my
patients.
And I want to point out
following Doctor Mallows
mentioned that there is one FDA
approved medication for children
with sleep problems and it is
tassimilty on
specifically for Smith magenis.
A lot of times we get hung up on
side effects of medications.
I will say there are side
effects to sleep problems not
being treated and they
are often significant and
include familial sleep
deprivation,
safety risks for children who
are wandering and exploring at
night and
generally less pleasant behavior
by children.
I'm going to skip past some of
this quickly to say looking at
ADHD
medications,
thinking about medications that
are used
in kids with NDD.
Not specifically for sleep but
with potential side effects.
Yes,
stimulants can sometimes cause
sleep
difficulties, more
with long acting.
I don't think that's a reason
not to use them,
but is a reason to monitor with
seizure medications.
Shout out to doctor Schellhaas.
The thing I find fascinating is
the same medications can have
the opposite effect
depending on the child's
somnolence or insomnia.
SSRIs can trigger restless leg
syndrome symptoms,
which is important to know
should you be using those, which
many of us do.
And atypical antipsychotics come
with significant weight gain,
potential for obstructive sleep
apnea and sidebar potential kind
of metabolic
syndrome and directions.
There are more questions than
answers in the world of
medication for pediatric
sleep.
How do we integrate medication
use and behavioral sleep
strategies into an
effective and holistic
treatment plan?
We're we have expert guidance,
Is there kind of additional
evidence base
for rational
medication selection?
Where is our precision medicine
in the world of sleep for
Pediatrics?
What are acceptable formats?
Because some of my patients are
not going to swallow a pill or a
capsule and if
that tastes funny,
it is a no go.
Protocols for cessation,
issues of long term effects of
use,
measures of
effectiveness and Dr.
Combs Will medication for sleep
related breathing disorders
emerge as a treatment
option?
That would be wonderful.
Thank you so much for having me
and I very much appreciate all
the speakers and
I'm learning a lot.
Thank you.
Thank you so much,
Doctor Ricardo.
So we are about 90 seconds or
maybe even 120 seconds overtime.
So I think we're going to close
and go to break,
but I do have the questions in
the chat that we can revisit.
And I just think that was a
really fantastic way to round
out this morning.
So I think it's break time now.
It is to 130.
Thanks, you and
all the speakers.
OK,
welcome back to the
Neurodevelopmental
Disorders and Sleep workshop.
We're going into our third
session, which is population,
environmental and
other influences.
I'm Cindy Lawler.
I'm the Program Officer and the
Chief of Gene's Environment and
Health Branch at
the National Institute of
Environmental Health Sciences,
where I manage a portfolio of
grants seeking to understand
environmental
influences on autism.
I'm your moderator
for this session.
Our speakers will describe
challenges with sleep assessment
in people with
neurodevelopmental disorders,
the relationship of sleep to
developmental progression in
autism, and we'll also hear
about the use of
cohort studies for identifying a
variety of influences on how
these disorders are
manifest.
Our first speaker
is Jared Fallington.
He's one of the Co
chairs of this meeting.
He's an assistant professor in
the Department of Psychiatry and
Human
Behavior,
Ed Brown and Associate director
of the EP
Bradley Hospital Sleep Research
Laboratory,
A cognitive neuroscientist who
is studying sleep dependent
brain function
in typical and
atypical development.
His talk today is on sleep
assessments in challenging
populations.
Thank you so much and thank you
everyone for for attending.
Wonderful.
So again,
my name is Jared Salt and I'm
it's such a
privilege to share this this
incredible workshop and I'm
grateful for all the
speakers this morning.
My talk is not going to be a
data-driven talk,
although I'll try and hint at a
couple of things.
I'm really going to speak from
the lens of methodology and some
of the
difficulties that we face when
studying sleep in these
contexts.
As mentioned,
I'm a cognitive neuroscientist
who
studies how sleep and sleep loss
affect brain function in
neuropsychiatric and
neurodevelopmental conditions.
I'm incredibly grateful for the
NI HS support in this effort,
including an RO one that's
ongoing from NICHD as well as
funding from NIMHNIGMS
as well as as non federal
foundation funding.
And I think this is a great sort
of stepping to remind us the
scale of the
problem.
So I do a little bit of work in
neuropsychiatric conditions as
well as
neurodevelopmental disorders.
And when you look at the, the,
the amount of citations of of
studying
sleep in these conditions,
neurodevelopmental disorders
really lags
behind the psychiatry literature
for sleep research.
And I think some of this is, is,
you know, sort of trends and
interest in these
topics,
but I think some of this is also
about
the difficulty of studying sleep
this this very intimate
biological process in
individuals with some
of these conditions.
We've already heard pieces of
that in some of the talks that
were that were
presented this morning.
And I'm going to expound a
little bit on that in my talk.
So this is a framework that I
like to think in,
in terms of challenges for
studying sleep in this scenario,
if we take neurodevelopmental
disorders and break it down to
studying sleep in
circadian rhythms,
what are the assessments that
we're
really talking about?
And I,
and I'll use the word assessment
for this
talk to really talk about
research sign research
methodologies for probing these
processes.
We can think of sleep as both
the behavior, something that we
do,
something that we perceive and
has quality components to it.
And you've heard little bits
today already about the
neurophysiological
media,
the psychobiology of sleep in
terms of
its regulation at the brain
level and in the periphery.
So first we have to think about
what it is we are actually
measuring.
Once we come to that answer,
we see that we have a number of
different
ways in which we
can probe sleep.
They range from self
or part or recall.
These are things that might be
done at the bedside as well as
in research
studies.
They can scale from one question
to multiple questions.
Daily Diaries.
We talk about actigraphy as a
way to look at sleep, wake
behavior.
And then of course,
we have the physiological tool,
some of which you've heard of
already, EEG being different in
neurodevelopment
disorders and of course the EEG
milieu of sleep.
But we also have the periphery,
melatonin, biomarkers of the
circadian rhythms and
other aspects.
So measurement of sleeping
circadian rhythms is not
monolithic as as Demetrius
mentioned earlier,
it really is a complex state to
measure.
Understanding the domain of
measurement, then we have a
number of options.
We have gold standards that that
emerge from the sleep research
field.
And then we have all the way up
to novel technologies of folks
trying to get at
the problem in different ways.
We can do this at home,
in the laboratory and in the
field.
And then we have this incredible
complexity that comes to bear on
the
question development
across the lifespan.
I'm going to focus mostly on
applications to youth, children
to adolescents,
but these lessons apply to
adults and to little infants as
well.
Then of course environmental
factors, social media of the
family,
medical complexity, cognitive
ability, sensory differences and
sensitivities and
Co occurring conditions all add
to the complexity of
measurement.
So I like to think of assessment
of sleep is really this lost in
translation
component here,
where the tools of traditional
sleep in
circadian science might be
useful in some scenarios and
might not be as useful in
others.
And so how do we go about
choosing which measurements and
assessments we want to
use in PDD?
Again,
I'm going to focus mostly on
tools and
approaches for scientific
research and mechanistic
methodologies,
but I think similar principles
apply to clinical assessments.
We've already heard little bits
about sort of the difficulty of
traditional
polystynography, for example,
in certain neurodevelopmental
disorders.
I'd like to start with this
paper, which is relatively
recent.
This is from Matt Jones's group
at the University of Bristol in
the UK looking
at sleep spindles,
and you heard a talk about that
earlier
in this context.
22 Q 11.2 deletion syndrome.
This was I think a really
amazing study because they did
have an incredibly
exhaustive examination of the
sleep EEG in less than 50
participants in A22Q11
group.
And I highlight that because the
sample size is still quite small
given the
heterogeneity and presentations
that we know are in their
development.
And what were they able to see?
Well,
they they were able to show this
incredible topography of
differences across the scalp for
spindle features and
slow wave features in the
coupling thereof.
This incredibly rich mechanistic
approach, but also one that's
not scalable to
routine measurement in the
clinic or even in a research
laboratory.
The talk on on sleep spindles we
heard earlier talked about the
need to to scale
this up to larger studies and
bringing a high density
polysomnographic array to
those larger studies
is really hard to do.
Even traditional
polysomnography, the gold
standard of sleep research as
well as Sleep Medicine might be
burdensome,
more intolerable to some
individuals with
neurodevelopmental conditions
due to both
the intrusional component of the
wires and the sense of being
monitored.
The requirement to potentially
sleep in an unknown environment
such as a lab,
or even just the sensory
complexity of having these
sensors on your head and on
your body.
And that goes for both low
resolution EEG montages and PSG,
as well as state of the science
high density EEG montages.
So wow,
these tools are incredibly
meaningful for
parsing sleep Physiology.
They are both difficult,
burdensome, and in some cases
intolerable for
individuals.
So where does that leave us?
Well,
if we want to look at sleep
Physiology,
we actually have a
number of options.
On the left here we have that
traditional polysomnogram.
Then we can move out of the lab
into ambulatory polysonography.
And one step beyond that,
home sleep apnea testing and
other non
full PSG paradigms are beginning
to be explored again,
more so in adults than in kids.
Although comments were made
earlier about Ignacio Tapios and
Christiello's work
trying to look at this in kids.
On the right side of the graph
we have what I call these novel
new technologies.
In the intermediate we have a
slew of different EEG wearables.
These are all headbands.
I just highlighted 3 of them.
As Demetrius commented,
the the state of this field is
really
changing dynamically.
There's new instruments coming
out every day.
Here are three of of what I
think are are among the most
used.
The Dream Headband, the
Hypnodyne Z Max, and the Muse,
all of which are headbands.
All of which requires something
sort of relatively constricting
on the head.
And then in the far right is a,
is a instrument that's that's
just
emerging that actually takes it
one step further, gets rid of
the headband,
but still you have a sensory
sticker on the head.
And some individuals, you know,
can respond to that in different
ways.
So we've gone from full scale
polysonography where we can
measure both
brain and peripheral signals to
some of these instruments that
maybe only measure
one or two channels
all together.
It might be great for looking at
things like sleep spindles or
slow waves that
are a function of the brain,
but ignore pulse ox.
We're not going to be able to
look at sleep apnea.
We're not going to be able to
look at restless leg syndrome,
periodic leg movements or other
peripheral signals.
So just switching to these, you
know, modern wearables,
it gets us one step further.
We can do those large scale
studies where we can scale up
who is able to
participate in maybe crossover
some of the sensory barriers or
the other
limitations of environment,
but it hinders us in other ways.
And so I want to think, you
know, just one comment about the
clinical
applicability of some of this,
you know, this is that work by
Chris that was
mentioned earlier about the
feasibility of home sleep apnea
testing and Down
syndrome.
You know, we need to be thinking
about, OK,
even for an evaluation in the
sleep clinic,
how are we adopting these
procedures that are the bread
and butter of sleep
assessments in adults and in
kids without neurodevelopmental
conditions to these
unique populations?
And the solutions might be
different for different ND DS
that have different
collections of, of sensory
experiences, tolerances,
cognitive ability,
and the necessity for parental
environment caregiver
involvement.
So I want to switch gears and
talk a little bit about another
Ave.
of assessment.
That's again,
sort of the traditional measures
of
behavioral Sleep Medicine,
which is actigraphy.
We can learn a tremendous amount
about sleep from octographic
estimated sleep
and, and, and wake rhythms.
These tools are used in the lab
as well as the clinic every day.
And on the far left,
we have what I call the gold
standard
traditional sleep octographs.
The one here is the AMI micro
micro motion logger.
Phillips was in many individuals
labs up until a couple years
ago.
We take one step to
the right of that.
We have instruments that are
widely used in research, but not
in sleep research,
the actigraph being one of them.
That's that's,
that's only now developing sort
of their
tools for sleep and wake.
One step further,
we have these open source or
wearable
octagraphs that are bare bones
accelerometers or even a Garmin
type
device or Fitbit type device
that aren't even designed for
research grade
accelerometry but give us
interesting data.
And then in the far right of
this we have the novel wearables
and veneerables,
things that are in the room that
might help us differentially
capture aspects of
sleep.
All of this is an open box for
exploration,
particularly when we talk about
individuals with
neurodevelopmental
disorders.
I want to spend a couple of
minutes talking about the
difficulties of doing
traditional lactography,
which is the gold standard,
highly stable estimate of
sleeping wakefulness.
It's been around for decades.
It's highly predictive of
sleeping wake against
polystomography,
but it comes with some cons.
It is costly relative to some of
those novel wearables that we
have today.
The ergonomics, again,
some individuals can't tolerate
wearing a
watch for both
neurodevelopmental reasons as
well as a neuropsychiatric
conditions.
Individuals will will not
tolerate wearing the watch.
It needs to stay on.
Once it's off,
we don't have any more
measurement.
Traditional sleep wake
actigraphy is highly dependent
on sleep Diaries,
either by the individual or by a
caregiver,
and then the scoring decisions
that get made using those
Diaries to get a
reliable estimate.
When we say actigraphy is well
validated against
polysonography,
we assume all of these factors
are in order, the Diaries are
good,
and scoring rules are using
validated methods to do so.
If you break any one of those
things, the validity of the
instrument goes down.
Moreover,
actigraphy is an incredibly
limited
assessment.
It gives us activity.
From the activity,
we estimate sleep and wake.
We maybe have light in some
devices, we have body
temperature,
but we're relatively limited in
some of these other peripheral
signals.
So what do we get?
We get a beautiful octogram that
tells us a lot about sleep wake
rhythms when we
score it appropriately.
This is a child with ADHD from
one of my studies.
You can see a little bit of
irregularity in their sleep.
I want to highlight a discussion
that's going on and this is Lisa
Meltzer's work
to really evaluate the rules we
use for evaluating sleep
actigraphy in pediatric
samples.
It is not as simple as finding
sleep the way we find it on the
EEG.
We have assumptions that get
made from the activity.
One of the traditional rules
that are used is that we look
for unconsolidated
sleep to define the sleep out.
We could be looking for three
minutes, 10 minutes,
15 minutes of of low activity on
the actigraph rhythm to define
sleep.
Well,
there were consequences to these
rules
and I think they come to bear on
understanding neurodevelopmental
conditions where sleep is not a
stable phenomenon necessarily.
This is an example octogram from
a child with a psychiatric
condition that's
recorded in our center.
And I think, you know,
if you're looking at in in red
are areas
where our traditional algorithm
see sleep and you see this red
throughout the day
because the child is
relatively sedentary.
So if you were to just squint
and say where is sleep,
you would I think find
it reasonably well.
But how do we put that into an
algorithm's perspective?
Where do we begin the night and
end the night,
particularly for an individual
whose cognitive abilities and
psychiatric
comorbidities might be blocking
their ability to do accurate
recall on the
sleep diary, how do
we define the night?
And so our group has been
interested in this recently.
We've been re evaluating
the rules we use.
And this is just an example of
how we can alter the rules.
So if we go from three minutes
to set to onset sleep and 5
minutes to offset sleep
versus looking for 15 minutes of
consolidated sleep on either
side,
we actually can reduce the
amount of ambiguities by about
50%.
But in doing that,
we are also shrinking the sleep
periods
that we're scoring, right.
We're moving the sleep estimate
and that might be meaning that
might be meaningful
when we have to care about sleep
and make recommendations on a
one to one level.
The variance will hold the same
when we look at group
differences.
But how does this translate
clinically into your
recommendations for your
patients?
We have to think very carefully
about this.
Where do we decide
sleep begins and ends?
Even at traditional active graph
level, the scoring is highly
time consuming.
It relies on those Diaries that
I mentioned and whether or not
those
Diaries are filled out
every single night.
Are they filled out
by the participant?
By the caregiver?
How much can we ask, when do we
ask, and who do we ask?
And how do we judge the data
quality of those Diaries in
order to make accurate
scoring of our actigraphy?
All of this is usually a human
process and I want to make a a,
a a a plea that one of the
things that I think might help
us translate these
methods to places where the
sleep scoring of actigraphy is
not as cut and dry in
neurodevelopmental disorders are
these data-driven solutions?
And here are just two of them
that I think are taking some
traction,
GGIR and active sleep.
These are two
different R pipelines.
I did not write them, others
did, but they are solving a
similar problem.
How can we take device agnostic
data, feed them through unified
pipelines to
produce reproducible and
scalable analysis?
There's a lot of power to that.
The problem is they're not well
validated in kids,
they're not well validated in
neurodevelopmental disorders,
and they require working with,
you know, software coding to
make work.
They're not quite as plug and
play or clinically useful.
So what if we leave
actigraphy altogether?
There's been an incredible
proliferation of wearables and
narrables for sleep
measurement.
We have the Nanate over here.
It's a video stenography device.
On the left we
have mattress pads.
We have things that are ambient
in the room, measuring
temperature,
measuring sound,
measuring humidity in the room.
There's been some incredible
work using temperature and
humidity and sound to
look at sleep disordered
breathing as sort of the X,
the exhalation component
of the disorder.
And then we have our rings and
our wearable wrist monitors like
Fitbit.
These are highly innovative,
passive of data collection,
often no intervention from the
researcher, no diary, no
scoring.
And they often get us many other
things, cardiovascular function,
heart rate variability,
temperature, light, sound and so
forth.
But once again,
we're often dealing with black
boxes,
changing algorithms,
subscription services,
unclear ownership of data,
and very few of these
instruments have
been tested in kids or adults or
kids with nerve development
disorders.
So everything has a caveat and
that has really pushed the field
to I think be
much more proactive in saying,
OK, you can go out and use an
instrument that
appears attractive to your
context, but let's do some work
to validate.
And Luca Mangini and others have
recently put out this framework,
which I think is really a
beautiful step by step approach
to how we evaluate these
trackers that we might purchase
and how do we determine what is
and is not ready
for research.
That's been summarized in this
lovely paper in Sleep Health
last year by Ju Ong,
where they took actually a
number of different tractors and
came to some
recommendations.
One being that, yeah,
we actually can get some pretty
good
Physiology from these EEG
wearables where we require that
degree of stability.
On the other hand,
we can go to these consumer
grade
trackers and we can get a
reasonable balance of accuracy
and tolerance,
but maybe only for healthy
sleepers and their and their.
And this is all a quote from
their conclusions because I
think it really
sums it up.
Lovely healthy sleepers,
individuals without sleep
problems and
certainly individuals without
neurodevelopmental or
psychiatric
conditions.
And then they issue the low cost
trackers all together,
the very cheap accelerometers
that you can buy because the
algorithms are really
not there yet.
So there's a lot
of work to be done.
I've only talked about a couple
of these of these opportunities
for measurement,
but even if you're not going to
put an instrument on an
individual,
I want to make a case that a
simple self reporter recall is
equally informative of
some things.
You know, during the ADHD talk
earlier, we heard that a kid or
an adult with ADHD
needs to be evaluated for sleep.
That simple evaluation
can shed light.
And this was some work that we
did in autism in the Rhode
Island Consortium for
Autism.
We need to wrap it up.
I'm going to close
in just a second.
OK, I'm going to close
in just a second.
But just to make the point that
asking about sleep matters and
you can
distinguish A diagnosis.
So take homes.
These are all things
that everyone knows.
I apologize for going over time.
I added a couple of of slides as
we were going.
But basically ask critical
questions of what you want to
measure,
who you're measuring it in and
what the needs of your
measurement are.
Reach out and thank
you very much.
Thank you, Jared.
If you have questions for Jared,
you can put them in the Q&A.
We can perhaps get to them at
the end of the day today.
We have some time for a panel
discussion in Q&A.
Our next speaker today
is Annette Estes.
She's an adjunct Assistant
Research Professor in the
Department of Psychology
at the University of Washington.
She's director of the
Autism Center there.
She is especially interested in
the role of the family in
supporting positive
outcomes for children with
disabilities and improving the
lives of people with
ASD.
She will describe the use of
cohort studies that can improve
early
recognition of infants at risk
for autism and identify brain
mechanisms that may
need lead to new strategies to
prevent or ameliorate autism
symptoms.
Annette, thank you.
Just to clarify,
I'm actually a research
professor in
speech and hearing sciences,
but I am a psychologist, so, you
know,
these things are very
complicated sometimes.
Thank you.
I'm sorry for the mistake.
That's fine.
Great.
So we can move on.
I'm gonna be talking about sleep
and the developmental
progression of autism.
And I wanted to start by saying
I have no conflicts to declare,
but we did receive funding from
the National Institutes of
Health and Simon's
Foundation for
some of this work.
And thank you to the families
for all their all with
everything that they've
given to these
research projects.
So next slide, what we have,
what I want to go over is that
autism
spectrum disorders and
neurodevelopmental disorder,
but it's based on behavior that
starts before H3.
We all might have heard that the
US prevalence recently changed
to one in 31.
It's more common in boys than
girls, but found across all
racial,
ethnic and socio
economic groups.
Next slide, please.
It's a diagnostic term that
describes a group of complex
disorders.
The commonality is 2 domains of
functioning, social,
communication,
and restricted and repetitive
behaviors and sensory
alterations are are found in
autism and that's
how we diagnose it.
OK, next slide.
The development of autism is a
complex thing to talk about,
but it arises over the course of
early development due to the
interaction
between several factors,
largely genetic.
So the the vast majority of the
variability in autism is due to
genes.
There's a little bit of
influence by prenatal
environment as well.
These things lead to alterations
in brain structure and brain
function,
which then lead to very subtle
early behavioral deficits that,
in a kind of ***********
developmental process,
lead to what later becomes
diagnosable autism symptoms.
Next slide, please.
So we ask ourselves in some of
our research, when does autism
start?
We know it's possible in many of
our research protocols to
diagnose autism
between 12 and 36 months.
There's sort of the variety of
of onset times.
The average in the US is closer
to five years of age.
But if you look,
there are some very early
emerging
features that are able to be
recognized in the first year of
life.
Next slide, please.
So one of the questions that we
have is when do sleep problems
in autism start?
We wonder about whether sleep
problems are an emerging feature
of autism along
with some of these other core
alterations that we see and
whether they contribute
to the developmental cascade
that precedes autism onset and
sort of
contribute to the ongoing
development of autism over time.
Next slide please.
So most autistic children have
sleep problems.
Many estimates are over 80%.
We all know that sleep can
adversely affect health,
cognitive development,
behavior,
functioning and increased family
stress.
But another thing to consider is
that sleep disruptions might be
more
consequential at critical times
for brain development.
So the work of Marcos Frank
showing the visual system of
cats being very much
affected by sleep.
And so we know that early brain
development in the first several
years of
life is is rapid, super dynamic.
Same thing at adolescence and
perhaps also in older age.
OK, continue please.
Next one.
Yes.
So in autism insomnia is the
most frequent sleep disorder
that we see.
So problems initiating sleep,
maintaining sleep, waking up too
early.
Less frequent but also notable
in autism are circadian rhythm
sleep,
wake disorders,
sleep related movement disorders
and
sleep related
breathing disorders.
I think one thing we don't know
is whether these less frequent
challenges
that we've noted in autism are
over and above what you would
expect in the
general population or whether
they are increased in autism.
So that's a question to address.
Next slide, please.
So we'd love this graph from
this National Sleep Foundation.
It illustrates the very large
changes that occur over time in
sleep duration,
with the highest sleep duration
in newborns and then reducing
over time
through older age.
Sleep timing also changes.
Babies develop circadian rhythm
over the first six months and
then increasingly
consolidate sleep to occur in
the night time.
Sleep architecture also changes.
So babies having
more active or R.E.M.
like sleep and then shifting to
more deep or in R.E.M.
sleep over time.
Next slide.
So one of the questions that
we're gonna address here is what
the developmental
timing and progression of sleep
problems is in autism.
That's something that
we're interested in.
We need to know a lot more about
that and what the impact of
sleep problems is on
behavior and brain
development in autism.
So next slide please.
One of the ways that we can
address this question in early
development is using
infant sibling study design.
And what that is,
is where we recruit and follow
infants
who have older
autistic siblings.
We sort of label this group as
high likelihood for autism.
The reason that we have that
label is that autism recurrence
is over 20% in
infants who have older
autistic siblings.
These infants also have other
learning and developmental
challenges.
About 30% of infant siblings
will have some kind of learning
or developmental
challenge even if they don't
have an autism diagnosis.
So this is a very important
population to study and it also
clinically and it also
allows us to study the very
earliest development of autism
and other
developmental challenges
associated with autism by
assessing and monitoring
infants even before the
behaviors associated with autism
emerge.
So next slide, please.
One of the groups that is
studying this is the infant
brain imaging study and
this is a consortium that's been
ongoing for over 20 years now at
the University
of North Carolina,
Washington University Children's
Hospital
of Philadelphia and University
of Washington.
And we have a data coordinating
center at McGill.
Next slide please.
And the,
the study design in the Ibis
study is
assessing infants who have older
siblings and also infants who
have no family
history of autism at 6/12/24 and
36 months of age.
At each of the time points
infants undergo MRI,
sleeping MRI to measure brain
structure, connectivity and
function.
Also we conduct developmental
assessments to measure behavior
over time and then
clinical assessment for autism
at 24 and 36 months.
OK, next slide.
So our first cohort of infants,
we collected 450 infants and we
categorize them into 3 outcome
groups based on their 24 month
diagnosis.
So we had high likelihood
infants with the older siblings
who are autistic who
also had an autism diagnosis
themselves at 24 or 36 months.
Then we had a group of infants
who are high likelihood,
negative or non autistic.
Then there's the low likelihood
group who had older siblings who
are not autistic
and no first degree relatance.
Next slide, please.
So what about sleep
in this group?
Well, sadly,
no sleep measures were included
in this
original Ibis study design,
but I was concurrently
conducting
randomized clinical trials,
a very early autism
intervention.
And as we were concluding one of
our final trials,
I asked parents and clinicians
what we needed to study, what
did we miss?
And overwhelmingly,
they talked about sleep.
So one of the biggest challenges
that is not being addressed
right now in early
autism intervention is helping
families with sleep.
And that got me thinking, well,
what's going on in our siblings
in the
IVA study?
And next slide, please.
So what we found out I was
working with a wonderful
postdoctoral fellow,
Kate Mcduffie is that we did
have a questionnaire,
the infant behavior
questionnaire that measures
infant temperament and there are
five items that ask about sleep
onset, latency and night
wakings.
And so we took those five items.
Next slide please.
And luckily in this multi site
study, a subset of the IABUS
infants also were
given some questionnaire called
the brief infant sleep
questionnaire that has been
validated and we were able to
show a high concurrence between
scores on this ISOP
or infant sleep onset problem
score and the BIZ cube.
So next slide and we asked the
question of whether this new
ISOP score at six and
12 months of age-related to
diagnosis at 24 months of age.
And you can see here that in the
high likelihood,
non autism and green and low
likelihood groups there really
wasn't a statistical
difference.
Next slide please.
But the three groups did differ
overall statistically and that's
because the high
likelihood autism group had
higher parent reported sleep
onset problems at six and
12 months.
And it's important to think
about this because it's a a
natural experiment in
which the families who were
reporting did not know which
kids were going to go on
to develop autism at 24 months.
Adding a measure of that
prospective measure kind of adds
a little validity
that we often don't get with
retrospective reports.
OK, next slide, please.
Next we ask whether sleep during
infancy predicted brain volume
at 6 to 24 months.
So we use linear mixed models
looking at six brain regions
subcortical the caudate,
amygdala, hippocampus, thalamus,
glowus, pallidus and putainment.
We controlled for age,
sex and total brain volume and
scan site
because as I said,
we had four different sites.
So next slide please.
And what we found is the sleep
infant sleep onset problem score
only predicted
hippocampal volume,
not any of the other subcortical
nuclei.
And this was only for infants
who went on to develop autism.
So if you look at this graphic
representation here,
you can see in green the high
likelihood autism group and in
pink and blue the low
likelihood and high likelihood
non autism groups.
And this was a significant
interaction where worse sleep
onset problems was
related to higher actually rates
of increase of hippocampal
volume.
And so yeah,
I think longer sleep onset at 6
to 12
months associated with autism
diagnosis at 24 months and a
different hippocampal
growth trajectory.
Next slide, please.
So the next step was to look at
the same group of kids at school
age.
So we're doing longitudinal
follow up with these infants or
with formerly
infants,
infants that are siblings I
should say,
now that they're older and we
added measures of sleep at
school age.
So next slide please and ask the
question whether or how we're
hoping to ask the
question how to do sleep
problems progress from 24 months
of age to school
age and we're doing that through
actimetry.
So direct assessment, 10 days in
the home, online sleep Diaries
and also a home
environment sensor looking at
temperature, light and sound in
the bedroom,
parent report questionnaires.
And then of course,
we're leveraging the Ibis
longitudinal
brain and behavior data.
We just finished assessing this
cohort of school age kids.
Next slide, please.
And so this is sort of a cartoon
if you will of the patterns that
we're seeing in
this initial look at our data
and what we found on the left in
the children's sleep
habits questionnaire,
the parent report measure was a
pattern
that we expected.
This is our we hypothesized that
we'd see the lowest levels of
sleep problems in
the low likelihood group,
an intermediate level in the
high
likelihood non autism and the
highest level of sleep problems
in the high
likelihood group.
This could be indicating an
endophenotypic pattern that
relates to
the sort of genetic
liability for autism.
It also could be influenced by
the environmental kind of
similar or
challenges that come with having
an older sibling.
But when you see that increased
autism score there you,
you really think about it that
the disorder of autism is, you
know,
predictably related to increased
sleep problems.
Now the curious thing that I
would love to hear more about
from all these experts
in the room is that our
actimetry data, this objective
measure of sleep for 10
days in the home is not showing
our expected patterns.
This is just a a glimpse at the
total sleep time score.
This is similar though for sleep
efficiency and other kind of
measures
that come from actimetry where
there's not statistically
significant differences.
And if there is small
differences, it's that the high
likelihood negative
kids are having kind of more
problems than the high
likelihood positive or low
likelihood.
So this is really interesting
and we're thinking that about
some of the reasons
that this could be the case.
So first of all,
it could be that the sleep
problems that
parents are reporting in the
high likelihood autism group are
being treated.
So we're looking right now at
the very complicated messy of,
but seem to be analyzable
medication data that we have.
And there are a lot of
medications and we've heard a
lot about them today that
can influence sleep either for
for good or ill.
And so that could be one of the
things going on.
Another thing that I'm
interested in is this high
likelihood negative group,
we could have increased sleep
challenges as well because we
know that this group
is more likely to have ADHD and
anxiety, two things that we know
are disruptive of
sleep.
So something that we're going to
be looking more into.
OK, next slide.
So to wrap up,
sleep alterations might be
present prior
to the diagnosis of autism.
We know they're related to brain
and behavioral developmental
changes in
autism and that inter
relationship between sleep
behavior and brain
development may be
particularly relevant.
So next slide,
what we don't know is what are
these
longitudinal relationships?
Do sleep problems in the first
two years of life predict school
age sleep or
behavioral functioning?
Are sleep problems associated
with altered brain developmental
trajectories
in school age?
And that's to say nothing of
longitudinal relationships and
outcomes in adolescents
and older adults.
We have a real great need for
longitudinal studies to
understand this.
And finally,
all of this is in service of
developing
and testing approaches to
improve sleep and autism,
so we have to get
back to that as well.
Thank you very much.
Thank you, Annette.
You've kept us right on time.
If you have questions again,
you can put them in the Q&
A and we'll try to get to them,
some of those at the end of the
day today.
Our next speaker
is Natasha Morris.
She's a child and adolescent
psychiatrist and associate
professor at Washington
University School of Medicine in
Saint Louis.
Our clinical practice is
centered on early childhood
evaluations for autism
spectrum disorder,
as well as school consultations
for
students with autism and
associated psychiatric
conditions for research
interests.
Simply new approaches for
assessing autism phenotypes,
neurocircuitry and risk factors.
And our talk today will describe
progress in some of these areas.
So, Natasha, all right.
So here are disclosures or here
are my disclosures.
A lot of these relate to the
infant brain imaging study
funding from the NMANIACHD
and NIMH.
And I will talk about some of
these cohort results mostly
related to Down
syndrome.
So in terms of the relevance of
cohort studies of sleep and
neurodevelopmental
disorders,
cohort studies are a form of
observational analytic studies
that provide a temporal
framework to assess
causal factors.
And they do that through, you
know, some of that, again, you
know,
looking at things over time,
they're, you know,
part of the speed of
observational studies, you know,
some of which can be
more cross-sectional.
And for most of the descriptions
today, I'm really,
really tried to focus on ones
that had a longitudinal
component in terms of what
this can allow when thinking
about sleep and
neurodevelopmental disorders.
It can help to figure out what
the nature of sleep problems is
and issues with the
timing, the emergence,
as Doctor Estes just talked
about in
Persistence,
taking a look at contributory
factors to
these sleep conditions as well
as the impacts on health and
general functions,
and also looking at the
effectiveness of certain
interventions.
And when used in a
developmentally informed way to
examine the development
of sleep problems over time in
different developmental stages.
It can also allow for potential
insights into mechanisms which
can then in term
and form assessments and
treatments over the life course.
I will focus today on cohort
studies of sleep and Down
syndrome,
which is an area that I have
been able to become involved in
as part of working
with the infant brain imaging
study and following an infant
cohort of children
with Down syndrome and Down
syndrome is as has been
discussed,
is a multi system neuro
genetic condition.
This this recent review article
shows it quite well.
Multiple medical comorbidities
are associated with Down
syndrome.
It is the most common genetic
cause of intellectual
developmental disorder,
which is one of its most
penetrant phenotypes.
But when thinking about sleep in
this particular condition,
there's just also the issue of
realizing that there's many
comorbidities and that
these can all have
reinforcing impacts.
Sleep problems are common and
persistent as has been
discussed,
and when looking at the
literature on cohort studies in
Down syndrome,
many of the studies have been
retrospective,
involving clinically
referred samples.
This has been very helpful for
looking again at associations
with Co occurring
conditions as well as following
when at different points in the
life stage the
sleep problems in
Down syndrome emerge.
There are also prospective
studies which generally have
looked at treatment
response and the beginning of
predictive modeling to try to
understand what's what
predicts who will go on to have
sleep problems like obstructive
sleep apnea,
you know,
and what might be factors that
could help
determine which type of
treatment would be most
appropriate.
And one other thing is that a
lot of the work has been done in
childhood.
There is work in adults work in
infancy is pretty rare when when
good piece of
news when thinking about some of
the literature on Down syndrome
in the field
I deal with,
which is often brain development
is that
there does seem to be a range of
sample sizes, you know,
and it does seem like this has
been helped, you know, depending
on, you know,
sometimes access to large
databases or large clinical
centers.
So in terms of, you know,
just key findings of what has
have been
learned across some of these
cohort studies I had mentioned,
you know,
that one one thing to think
about is the nature of sleep
problems.
And as has been discussed,
there is a high prevalence of
obstructive
sleep apnea at multiple ages.
You know,
we heard how it is identifiable
in
infants.
Currently,
pediatric guidelines recommend
testing or
assessment for that at age 4,
but it does look to be starting
earlier.
But again, as mentioned,
infant studies are much less
common than
studies in childhood
or even in adulthood.
Increasing work has been done to
show that parasomnias,
insomnias and
daytime sleepiness.
So non respiratory issues
associated with sleep problems
are also very common,
as well as emerging evidence for
a movement disorder related
issues during
sleep such as periodic
limb movements.
And the sleep problems are also
very persistent.
And this is even true when
getting surgical treatments.
But also just in, in general,
they, they do, they do tend to
last.
I'm in looking at cohort
studies, observation of sleep
trouble or sleep
problems or using a milder non,
non surgical treatments in some
cases
often seems to
have mixed effect.
And then in terms of factors in
predictive modeling,
there is evidence that obesity
and as well as Tonsiller and
adenoid hypertrophy
are factors that increase the
risk of obstructive sleep apnea.
Other issues include early
feeding problems or periods of
long NICU stay,
you know, during early life.
And there have been the
beginnings of some models that
take a variety of
clinical and demographic
features that have identified
good negative predictive
value in terms of children who
you know were are unlikely to go
on to have
obstructive sleep apnea with
Down syndrome.
But models have been less
effective looking for positive
predictive value.
Other areas that have been
assessed with these cohort
studies are related to
practice patterns,
treatment effects and then
relationship
to function overall.
And so guidelines that have been
developed in the past decade and
1/2 or
so appear to have benefit and
children getting assessed and
referred to
treatment more often.
Although treatment effects as
have been mentioned have been
mixed, you know,
even those surgical treatments
are very commonly done.
The resolution of OHOSA symptoms
tends to be only partial,
although in many cases
it's been helpful.
There are newer treatments that
have been tried in terms of
hypoglossal stimulation
to increase tone and in that
upper airway and evidence in
adolescence through
adults as well as the beginning
of evidence in children.
And as I mentioned earlier,
while there are a variety of
treatments
that have been discussed that
have been tried and such as non
invasive
ventilation support and
medication, these often times do
not appear to have
the, you know,
even the relative consistency of
effects
that has been seen with more
surgical treatments and even
those are somewhat
mixed.
So there's a need to improve
treatments, you know, and
treatment targeting.
And then in terms of
relationships to function,
there has been a lot of work and
already discussed that, you
know,
aspects of cognition or
psychiatric symptoms.
These things are likely to be
affected when sleep is poor.
Although cohort studies in
general have not always found
these effects to be
consistent, you know,
which suggests that more work
should be
or needs to be done in terms of
measuring these things and
parsing some of the
sleep conditions that
are being looked at.
You know, more more precisely in
terms of, for example,
respiratory and non respiratory
sleep issues.
So just as a big broad, you
know, summary of kind of what
what the field
you know has has shown in terms
of looking at cohorts over time
of
individuals with Down syndrome.
There really has been, you know,
a lot of characterization of
respiratory
sleep problems primarily
relative to obstructive sleep
apnea,
with more work needing to be
done in the non respiratory
sleep problems.
You know, things like daytime
sleepiness, for example,
or parasomnias or insomnias that
also are thought to affect
function.
The representation across the
lifespan seems to be skewed a
lot towards
childhood and beyond,
less so in early development.
And as was discussed in the last
talk, you know,
there can be work to be done in
these areas when thinking about
neurodevelopmental conditions.
And some work needing to be done
on the consistency of
relationships of sleep
problems to outcomes and the
need to have treatments that
allow better resolution
of symptoms and ongoing interest
in evaluating the impact of
treatments on
health and function.
And that seemed to be an area
that was not particularly or not
as well addressed
as some of the others.
So in terms of additional work
that can be done on using cohort
studies, you know,
for for infant infancy, as I
mentioned, you heard a bit about
the infant brain
imaging study.
So I will be
somewhat brief here.
Multi site study.
We focus on developmental
neuroimaging.
We've been funded for over a
decade originally starting
looking at children
who have an increased familial
likelihood of autism,
but we've also done work in Down
syndrome and fragile X syndrome.
And this timeline of the Infant
Brain Imaging Study Network
shows the variety
of cohorts that we have been
able to explore,
which does in the future allow
for some opportunities for cross
cohort comparison
with neurodevelopmental
conditions.
More recently,
we have taken up more work with
Down
syndrome, which is the, the,
the reason I've been focusing on
that on
that here.
However, at the same time, our,
our work, you know, looking at
the, you know,
children,
you have increased likelihood of
Down
syndrome has been helpful in our
ability to begin to establish
relationships of
behavioral differences in terms
of sleep issues and the brain.
And so I just wanted to briefly
allude to some of the work that
doctor Estes,
you know, had mentioned.
This basically showed that with
parent report information on
sleep,
our team was able to show under
her leadership that children
that the
children who went on to have ASD
did show strong associations of
their sleep
problems with
hippocampal volume.
This was also true with other
groups, but especially true in
that group,
and it was specific to the
hippocampus relative to other
brain structures.
Currently what we are are are
have been able to do and again
acknowledging Dr.
Estes with this work is to look
at our current new infant
samples and to look at
a cohort of infants with Down
syndrome as well as a new cohort
of infants that
increase familial likelihood for
ASD at six and 12 months of age
are too early
time points the study.
The study is continuing to have
data collected through the 24
month outcome
and to begin to ask what kinds
of sleep characteristics by
parent report do we
see in these two cohorts when
followed across these ages.
And so this table here shows our
current sample sizes about, you
know,
close to 60 kids in the Down
syndrome Group,
A large group of children with
increased family likelihood for
autism and you know,
173.
And then also a group of
children without a family
history of autism are most
likely to be our typically
developing controls.
And parent reported sleep
concerns were obtained using the
Brief Infant Sleep
Questionnaire.
And we began by taking a look
at, you know,
what was the level of parent
reported sleep problems reported
in these two
groups and comparing across the
the Down syndrome group as well
as the group that
has that increased
neurodevelopmental liability
related to increased likelihood
for autism.
And at six months,
parents of infants with Down
syndrome
reported fewer concerns than the
high likelihood and low
likelihood groups here.
So again,
that group with increased chance
of
autism and then
our control group.
So an interesting finding there,
especially given how many sleep
problems
there are in Down syndrome later
in the in the life course.
However,
in infants with longitudinal
data,
what we did find when comparing
6 and 12 month scores was that
the group with Down
syndrome showed the greatest or
should increased parent reported
sleep concerns.
And so that can be seen by the
increased size in the darker
Gray bars in the
beginning of a little black bar
showing up in the Down syndrome
group and
compared between
6 and 12 months.
So suggesting here that some
advancement of development is
beginning to have,
you know,
some some change in the ease of
sleep
that parents are
able to pick up on.
And looking at the the bisque
questions on day sleep, night
sleep,
night wakefulness,
night wakefulness and sleep
onset.
And we were able to compare the
change in sleep characteristics
from 6 to 12 months.
And looking at the groups,
we could see that both the Down
syndrome
and children at increased
likelihood of autism did not
increase in night sleep as
much as the low
likelihood group.
So this would be an expected
part of development that seems
to be not
proceeding at the same pace as
it is, you know,
for the for the control
children, the Down syndrome and
high likelihood
groups also increased relatively
in night wakefulness.
So again,
in terms of what's happening
during the
typical development or in the
typically developing group,
this is also a different.
And the Down syndrome group also
showed increased sleep onset
latency versus the
low likelihood group.
So something between 6 and 12
months is beginning to change in
the in the
children with Down syndrome and
is looking in many cases even
more
significant than what is being
seen in the high likelihood
group,
at least when looking grossly at
these percentages.
So what we do see then is signs
of emergence of sleep problems.
And this is something, you know,
again that the Down syndrome
group stood
out in in certain respects.
And this suggests that when
thinking about the relationship
of sleep
differences and and mechanisms
of biology that can contribute
to these sleep
differences,
there may be some specific
profiles that
could be compared between Down
syndrome and the high likelihood
group,
which could again provide some
helpful information about the
differences than
brain development
that are contributing.
There is parental awareness of
these sleep problems that does
appear to change
with age,
although correlation with
objective
metrics would be helpful.
And there's the implication then
that earlier sleep targeted
interventions
could be helpful for outcomes
and in this population.
So I will, you know, so that is
a, you know, using a parent
report measure,
a very interesting, you know,
way to get at, you know,
the issues with sleep that are
being reported in this cohort.
But through the include project
and NIH wide research initiative
to expand
research in Down syndrome,
our Ibis network team will also
have the
opportunity to participate in
another study,
which will allow a more lifespan
cohort approach.
And so as part of include,
there's a goal to investigate Co
occurring conditions that affect
individuals with Down syndrome
and the
general population and to
increase the number of
investigators and trainees
studying Down syndrome and to
engage a wide range of those
with DS and their
families.
And this this cohort project is
1 one way to do that.
And so this this research effort
is known as the include
collaboration for Down
syndrome progress.
And the goal is to study the
Natural History of Down syndrome
in a deeper way.
That's been done before with a
multi site cohort through data
collection and this
lifespan cohort,
which will involve 5 study sites
evaluating children, children,
adults and infants, you know,
all across different ages.
We'll be able to examine Co
occurring medical conditions
that will also allow
us to understand the range of
individual differences in Down
syndrome.
A lot of data will be collected
that allow identifying the
impact of
experience as an environment on
development and the hope will be
to
provide a foundation for future
therapeutic approaches.
And at the same time,
this program will also strive to
keep the
community engaged in creating an
inclusive research program.
So I'll show the structure of
the study and then briefly talk
about some of the
sleep metrics that
we will be obtaining.
These five boxes here describe
the different projects that are
involved in
the in the include cohort
development program.
So the Infant Down syndrome baby
Brain study is an extension of
the Ibis network
that will continue to look at
infants at six, 1224 months of
age.
But we have several other
groups, you know,
collaborating from institutions
around the country that are
looking at quality
of life factors, you know,
related to quality of life
factors in
health and youth and young
adults with Down syndrome,
aspects of metabolic health.
Yes, one minute left.
OK, thank you.
Metabolic health,
lifestyle and risk.
A Latin American project and a
study looking at omics.
These groups will do a common
protocol of measures that
persisted or that cover
various domains
across the lifespan.
And we will have work with the
data Coordinating center,
clinical Coordinating center,
a biorepository,
and a community Advisory Board.
These are the common protocol
domains that we are collecting a
vast array of
neuropsychological data that
will focus on cognition,
adaptive function,
attention, memory,
medical data that will include
deep
medical history and extraction
from the EHR,
biospecimens that will allow
Monti omics, neuroimaging and
physical activity
measures with actigraphy.
For sleep,
we will be doing two or two
different
kinds of home sleep
study measures.
There will be a portable
polysonography system,
the Knox A 1S that will be done
at several ages as well as the
watch pad,
a device used for diagnosing
sleep apnea at home.
We'll also have actigraphy as
mentioned as another sleep
measure and sleep diary
and activity logs,
sleep quality questionnaires
which have
been helpful for us before and
medical record record
extraction.
And overall these,
the population will be around
2000.
So there will be well,
while some of these sleep
studies will be
done as sub samples,
there will be opportunities to
track
sleep problems at different
stages of the lifespan.
And the project will have
longitudinal assessments.
So we'll be able to look at the
association of sleep issues with
both,
you know,
contributory medical factors or
associated medical
factors and outcomes.
We'll have very deep
characterization in early life
with our infant cohort and be
able to study early brain
development is related to sleep
outcomes.
So in conclusion,
cohort studies of sleep and
neurodevelopment token
conditions can clarify a variety
of features and
contributory factors,
impact and elements of
treatment.
They can influence practice.
Developmentally informed cohorts
and lifespan cohorts can really
enhance our
ability to study these more
thoroughly, especially when
using multimodal measures.
And multidisciplinary cohort
studies as well can be important
in quantifying
factors and outcomes
across domains.
And we're very excited to be
able to use a variety of sleep
measures to study this.
And for acknowledgements,
I'd like to thank again our
funders.
P is of the infant brain imaging
study, especially a Doctor Estes
who is a
champion sleep moving forward
and our include cohort
development program.
The P is of the sites,
the infrastructure and also the
remote
studies work group.
Doctor Tapia who's been
mentioned several times has
helped advise on the sleep
measures being used.
Thank you.
Thank you, Natasha.
We're going to move on to the
last speaker in the session
today,
and that's Kristen Lyle.
He's an associate professor and
chair of the Department of
Epidemiology and
Biostatistics at Drexel.
She has experience in
environmental, nutritional,
perinatal, reproductive,
and psychiatric epidemiology.
Her current research examines
environmental factors in
relationship to
neurodevelopmental outcomes,
has a strong focus on autism.
Your talk today will describe
how you can use data from ECHO
and other cohorts to
characterize the influence of
these factors.
Thank you for the opportunity to
come despite my technical
challenges.
So I'm going to in some ways
kind of build on the prior
speaker and thinking
about cohort studies and
specifically with the lens
towards looking at autism
and environmental risk factors.
So if you go into the next slide
and just a,
a brief outline in terms of
thinking about the context of
autism etiology and
and sort of the role of cohorts
and advancing or understanding
of that.
I think it's helpful if in
thinking about consortium
efforts to also kind of think
about the steps along the way to
get there.
But I am going to be focusing my
talk mainly on the ECHO
consortium,
which I'll I'll define as we go
forward and thinking about some
future
opportunities.
So if we advance to the next
slide, you know, autism is,
is a condition which I think is
has been reviewed in this
session.
So won't spend too much time on,
on diagnostic criteria.
But given the heightened focus
on autism and continued focus,
I think it's important to also
review if you advance.
There's some slide
animations here.
The what we know and what we
don't know about the etiology of
autism.
So in terms of what is known,
we do know that autism has a
complex
etiology.
There's no one single 'cause it
is complex and multiple factors
likely
contribute.
In addition,
there are likely different
causal sets in
different case groups.
So that's on the known side.
On the unknown side,
I would say the etiology is not
well
defined for all cases and we're
still learning more about
different causal
mechanisms.
We know there's a strong role of
genetics as well as evidence for
environmental
factors,
but we have a long way to go in
terms of
better understanding that
background susceptibility and
thinking about
interactions.
In addition,
and when we're thinking about
environmental risk factors,
there is evidence for
susceptibility
windows and very early
development and, and even in
utero as as a critical window.
But we're in terms of specific
risk factors and,
and when they exert their
strongest effects,
we we don't have that fully
understood for all risk factors.
There's also evidence shared
pathways for for multiple
different neurodevelopmental
disorders,
but less known about specificity
of risk
factors to different disorder
pathways and contributions to
variability and
functioning.
So if we go on to the next slide
and I'm not going to spend too
much time here
given our,
our prior speaker did a really
wonderful
job of of kind of summarizing
the benefits of cohort studies
and thinking
about the opportunities to have
that longitudinal and
prospective follow up.
So if you advance,
there are also some challenges
of course
with the cohort design and and
the overall relatively low
prevalence of
autism despite an increasing
prevalence for a general cohort
approach and of
course the sort of practical
implications here as well.
So if we advance to the next
slide, before I get got into
talking about ECHO,
I also wanted to touch base on a
couple of cohort studies that
I've been involved
in that I do think have have
helped advance understanding and
also
contributed in some ways to the
the path of of why studies like
ECHO are needed.
So very similar to the Ibis
cohort that our prior speaker
went through early,
which stands for Early Autism
risk longitudinal investigation
is a high
likelihood autism cohort design,
which really capitalizes on the
fact that
we know that younger siblings of
children with autism have a much
higher likelihood
of developing autism themselves.
So by enrolling pregnant women
who already have at least one
child with
autism and following that
younger sibling through their
early development,
it really enables this efficient
design to be able to
prospectively study risk
factors.
And so yeah,
of course there's a a wealth of
exposure
data that can be collected
prospectively under this design
enabling bio specimens
to be collected and what we
suspect to be critical windows
and also paired with
really rigorous clinical outcome
assessments.
The challenge of course with a
design like this is,
is some small sample sizes in in
trying to and especially if
we're trying to look
at rarer exposures as well.
If we advance to the next slide
in comparison population based
cohorts,
so thinking about capitalizing
on large cohorts that have been
drawn from the
general population.
Some work I've done includes
using the nurses health studies
and and there are
different cohorts of these.
So nurses Health Study 2 was
initiated in 1989 following sort
of a mailed
questionnaire structure
including over 100,000 US
nurses.
There have been sleep sub
studies within the Nurses Health
Study two which have
included sleep diary data and in
addition we conducted A nested
case control study
of autism within the context of
Nurses 2 and there's a more
detailed study
following children of
this cohort as well.
Currently we're collecting some
quantitative trait data and
Nurses Health
Study 3 related to autism and
there's maternal health sub
studies which really
focus on pregnancy and a wide
range of exposures.
And I think, you know,
thinking about what are the key
strengths
of this study population is
really rich maternal data,
including information on dietary
factors, reproductive factors,
medical conditions,
pregnancy conditions.
What's more limited when we're
outside the context of some of
these sub studies,
it is detailed
information on the child.
So if we go on to the next
slide, this then kind of leads
us to thinking
about consortium efforts.
So I've been really excited to
be involved in the ECHO program.
So ECHO stands for environmental
influences on child health
outcomes.
The sample includes
over 50,000 children.
ECHO was first initiated in 2016
with 69 pediatric and pregnancy
cohorts that
already existed in this country
and were already collecting data
on their own
study populations and then came
together to pool and harmonize
existing data,
but then also collect new data
under a common protocol.
ECHO is now in its second seven
-year cycle,
which includes a set of
continuing pediatric cohorts.
So really having a very unique
opportunity to follow children
from birth
into adulthood as well as new
pregnancy cohorts and a novel
interconception
follow up.
And the goals of ECHO are really
to better understand
environmental
contributions to child health
across 5 primary outcomes and to
find solutions to
advance child health.
So those outcomes include pre
peri and post Natal outcomes,
obesity, Airways,
positive health and
neurodevelopment.
And as an autism researcher,
I can say this presents really
exciting
opportunities for autism when we
pool data across all these
different cohorts
to be able to have sample sizes
to address some really novel
questions.
There is also a public use data
set available within ECHO and in
my updated
slides I had added some other
figures, but I'll just kind of
talk through those.
So there are, you know, over 50,
000 children.
In addition,
we have mother data on the
mothers and,
and some father data as well.
There's also a clinical trials
arm, a public use data set and a
scientific
dissemination webinar series and
various different efforts to to
communicate
science as well.
So when we think about using
ECHO data, you know,
there's challenges with any
longitudinal study in, in terms
of missing data.
With extant data,
we have to consider things like
cross
site variability
and harmonization.
But I think these are all
addressable problems and we have
methods to account
for them in different ways that
we can consider these factors.
So if we advance to the next
slide in terms of autism data,
so we have parent report of
clinician diagnosis and then we
can also think
about the the existing data that
cohorts came in to ECHO with and
some cohorts
including detailed
clinical assessments.
Along those lines ECHO as a
compilation of multiple
different cohorts includes
different different
cohort types.
So that early study the high
likelihood of autism.
There were also a couple Ibis
and BSRC sites included in the
initial cycle of
ECHO.
So there is also the opportunity
to do some of those interesting
cross cohort
type comparisons.
We have preterm,
both birth cohorts as well and a
case
control study in addition to
parent report of clinician
diagnosis.
There are screening data
collected via the NCHAT and then
sort of broader
measures and dimensional trait
measures, including the SRS,
the Child Behavior Checklist and
NH Toolbox, as well as some
other measures,
which I'll talk a bit more about
on the next slide if we advance.
So one of the things that is
most exciting about ECHO is this
really this
breadth of data across
longitudinal time window
spanning early childhood and
middle childhood,
adolescence and now even into
early
adulthood.
There are data across medical,
social, psychosocial, lifestyle,
neighborhood,
all these different areas.
In addition,
there are biospecimen
collections,
so offering the ability to it to
look at genetic and epigenetic
factors to conduct
novel environmental chemical
assays and then think about
examining multiple
different types of outcomes in
addition to different diagnosis.
And one of the things that that
I'm particularly excited about
under Cycle 2
is continuing to follow our
cohort sites specifically for
these autism familial
cohorts into adolescence and
young adulthood.
And the table is just showing
sort of a snapshot of some of
the neurodevelopment
specific measures and ECHO and
these capture developmental
milestones,
temperament, social cognition,
emotional behavioral
functioning,
general cognition and perceive
stress if we go on to the next
slide.
So I have to address the caveat
here that I am not a sleep
researcher and my work
primarily focuses on
environmental risk factors.
And so I just wanted to touch
base and OfferUp some summaries
of,
of work that my team has been
doing within Echo,
which I think can also then be,
you know, considered in addition
to sleep.
And,
and there are opportunities to
consider
how various different risk
factors may impact sleep or
interact with sleep to
influence various different
outcomes across the life course.
So within ECHO,
we've been using a lot of the
outcome
data in some sort of
psychometric assessments to
think about measuring the
autism phenotype and, and how
can we, and can we validly
measure things in a
brief way.
We've also been looking at
demographic correlates of
diagnosis versus treats.
There's really novel
opportunities to study dietary
factors.
And so we've done some work
demonstrating inverse
associations between prenatal
fish intake and autism as well
as autism related traits as well
as sort of this
middle panel is looking at
mixture analysis,
but as applied to nutrients that
we know are really important in
neurodevelopment
and suggesting an inverse
association with broader autism
related traits.
And then also kind of doing some
work comparing across outcome
types, types and,
and looking at things like
maternal metabolic conditions
and showing
associations not only with the
diagnosis, but also with the
broader traits
suggesting sort of a shift in
the distribution of the traits
with certain
risk factors and ongoing work
planning on on looking at
interactions across factors.
So if we go to the next slide,
so there's a wealth of of sleep
data
being collected and already
collected in ECHO on the
prenatal and maternal side,
there are measures capturing
maternal sleep health in
pregnancy including sleep
disturbances and sleep related
impairment via promise measures.
There is also measured physical
activity and sleep via
accelerometer data and
sleep Diaries.
And in in terms of the child,
there are sort of parallel
measures
looking at sleep health across.
The age bands in children and
adolescents and even early
adulthood and infant sleep
ecology questionnaires and both
parent and and child report data
available.
So right now the participant
numbers across these various
different measures
sort of range from about 900 to
over 17, 000.
And with cycle 2 are the current
funding cycle of ECHO data
collections ongoing?
These numbers are only
going to increase.
So if we advance
to the next slide.
So what's been done in terms of
sleep and neurodevelopment and
ECHO.
So Sheffrey ET all examined
considerations of of trying to
incorporate sleep health
measures into autism screening
to look at the utility
of of whether screening could be
improved by capturing sleep
disturbances within
autism.
And while they did not find
improvement in screening with
incorporation of of
parent reported sleep problems
in this study, there were,
consistent with prior research,
high rates of sleep problems
found in in
ECHO children with autism.
In addition,
a a couple of papers have looked
at
children's sleep health in
relationship to other outcomes
and and other behaviors.
And so a paper examined looking
at children's executive
functioning and
sleep as well as other health
related behaviors.
That paper did not see an any
significant associations with
sleep,
but more in In addition,
another paper is looked at sleep
health
in relationship to offspring
ADHD symptomatology and did find
a significant
association between poor sleep
and pregnancy and ADHD symptoms
according to
the CBCL or child
behavior checklist.
So if we go into the next slide,
I think you know it,
we were actually just talking
about this in the
neurodevelopment working group
in
ECHO today.
There's really an opportunity to
utilize this sleep data.
Very few studies have have
looked at this yet and within
ECHO in terms of sleep and
autism.
And so there's an opportunity to
expand on,
on those existing studies and to
think also about using the
longitudinal data
that are available in novel
ways, which I know is a theme
that has has come
up in prior talks as well.
There's the ability to,
to start pairing these different
environmental factors with sleep
data and, and examine how how
multiple factors are,
are influencing various
different outcomes and to also
think about sleep as
a,
a moderator of certain
associations as
well.
And then sort of more broadly,
I think the wealth of data that
are
collected and ECHO offer
opportunities to think about
comparing across different
outcome types.
And that may be my last slide,
but just to to kind of broadly
comment
about lessons learned from ECHO
data harmonization and an
individual cohort
site variability can be a
challenge and, but we have
methods to kind of carefully
consider and,
and address that and within a
course in
consortium framework.
And ultimately,
I think these consortium data
offer
really novel opportunities to
address questions that are often
not possible for
outcomes like autism and
individual studies.
And, you know,
to think about trajectories and
multiple
help domains and exposures from
a broad range.
And just to acknowledge my
funding as well as no conflicts
of interest to
report.
So hopefully I I helped get us
back on time and,
and apologies again for the
initial technical problems you
did, Chris,
Kristen and great performance
under pressure as well.
I want to thank all of the
speakers in this session.
And I suspect you know what
we've heard will kind of enable
a really rich
discussion at the
end of the day today.
But I'm going to close this
session and go on to the next
since we are running
just a few minutes behind.
Thanks so much, Cindy.
So the next session is on
perspectives from parents and
caregivers and patient
advocates.
And Lucia Pesotto Pesciotto,
one of my Co chairs,
is moderating that session.
So Lucia, welcome everybody,
and it's an honor.
Can you hear me?
Yes, thank you.
Yes,
it's an honor to chair the last
session
of the day.
My name is Lucia Pesciotto.
I'm an associate professor at
the Department of Translational
Medicine and
Physiology and the Sleep and
Performance Research Center at
Washington State
University.
This session is focusing on the
perspectives from parents,
caregiving and
patient advocates.
Our first speaker is Doctor
Kathleen Nadeau.
She's a clinical psychologist
and the founder and director of
the Chesapeake
Center in Bethesda, MD,
one of the largest private
clinics in the
United States that specializes
in ADHD, autism spectrum
disorders,
and auto neurodelemental
disorders.
Doctor Nadeau has written over a
dozen books related to ADHD and
has long been
considered a thought
leader in the field.
It's a pleasure
to have you here.
Welcome Doctor Nadeau,
and to just introduce myself
again,
I have been an ADHD specialist
for more than the lifespan of
most of the people
that have been presenting here,
and I have a very personal
interest in
the topic of ADHD.
In fact,
I would wager that I am the only
person
giving a lecture today who has
the neurodevelopmental disorder
about which
I'm speaking.
I come from a family where I
have daughters, granddaughters,
sisters,
brothers,
all sorts of other relatives
with ADHD
and sleep in and of itself is
just a hugely important and
largely overlooked
topic.
I would wager even within my
clinic, and we have gathered
together probably
the largest private ADHD
speciality clinic in the
country.
We have almost 40
providers at this point.
And yet, even within our center,
I think we are not paying nearly
enough
attention to ADHD.
And interestingly,
we have continuing Ed
presentations
monthly.
I consulted a group of sleep
specialists in the Maryland area
and not one of them
was prepared to talk
about ADHD and sleep.
And yet ADHD is such a common
neurodevelopmental order
disorder and
sleep is such a common issue.
So it's a greatly neglected area
and I'm just delighted that I've
been invited to
talk about it.
So there are lots of differences
that need to be taken into
account.
And I'm very frustrated when I
hear, you know, use good sleep
hygiene.
What I would say about good
sleep hygiene and ADHD is it's
necessary but far from
sufficient to understand what's
going on in the ADHD brain and
how to help those
of us with ADHD to sleep better.
There's structural differences
in the ADHD brain that impacts
sleep.
We have a smaller pineal gland
which effects melatonin
production.
Prefrontal cortex, of
course, is impacted.
We're all familiar with that,
leading to the executive
functioning
issues that hugely impact sleep.
If we're very disorganized,
if we're time blind,
it's going to be very difficult
for us, more difficult than for
other people to
follow good sleep hygiene.
There are neurochemical
differences in our brain.
We have baseline lower dopamine.
We have lower melatonin
production, which of course
effects sleep onset.
And interestingly,
and I don't hear a lot of people
talking
about this,
we have neural network
differences.
Curiously, in the ADHD brain,
the default mode network does
not turn
off when the task
mode network turns on.
And we call that mind wandering.
I call it listening to multiple
channels in my brain at the same
time.
And you can imagine how that
impacts settling down and going
to sleep.
And our sleep architecture in
general is different.
It's fragmented.
There's reduced deep sleep
phases in the ADHD being and
diminished REM sleep.
And interestingly,
I'll talk a little bit about
this later,
I think this is
hugely important.
But we now know that the
glymphatic system of the brain,
which was just discovered a few
years ago, is the pulsating
system by which
cerebrospinal fluid goes in and
out of our brains,
cleansing our brains
of toxins, proteins.
And if we have less deep sleep,
then we have less cleansing of
the brain.
And I really think that
extremely important area of
research should be
linking that to the also
recently documented greater
likelihood of dementia
in those with ADHD.
So these,
there's so many incredibly
important
things for us to talk about.
Their long term consequences for
us with ADHD because of chronic
sleep problems,
they're much higher rates of
obesity and metabolic disorders.
Of course we all are familiar
with poor academic and poor work
performance,
executive functioning
difficulties, dysfunctional
family interactions and
relationships impacted by many
people in the same family having
chronically
inadequate sleep and non
restorative sleep.
And research that just came out
of the UKA few weeks ago
documenting that those
with ADHD on average have an
almost decade long shorter
lifespan.
Huge consequence.
And I think the chronic sleep
problems we experience have a
lot to do with that.
So what?
What are the primary sleep
problems associated with ADHD?
Certainly sleep deprivation.
I mean, it's ubiquitous.
It's ubiquitous in kids and
adolescents and adults.
We don't get enough sleep.
And that has to do with the
delayed sleep phase syndrome
that many of you may be
familiar with
associated with ADHD.
I sort of refer to
it as ADHD jet lag.
Our bodies may be on the East
Coast, our brains are on the
West Coast and not
nearly ready to go to bed.
Very common disordered sleep,
breathing in kids and in adults.
There are movement disorders.
We've talked about restless leg
syndrome and other movement
disorders and
disrupted sleep architecture.
So lots of things are going on
in the ADHD brain that get in
the way and think
specific to ADHD in the
environment that affects sleep
have to do with family
environment.
If you have kids with ADHD,
you almost certainly have adults
with
ADHD in the family and that
means that this recommendation
for good sleep
hygiene.
It sounds good,
but how in the world do you
achieve that
If you have a child with ADHD
and a parent with ADHD and
there's time
blindness, there's
disorganization.
How in the world do I get my
kids to bed at night and how do
I get myself to bed
at night?
There are all kinds of lifestyle
factors including.
Haven't heard a lot of talk
about digital devices,
but I think our national
international addicted addiction
to our digital devices
is even more ubiquitous and
powerful when ADHD comes into
the picture.
I know of so many teenagers that
leave their alerts on all night
long so that
they're constantly being
reawakened because they want to
be sure that they're
in the mix if one of their
friends text them during the
night.
And all kinds of time management
issues that impact our inability
to really
follow good sleep hygiene,
restless leg syndrome and ADHD.
It's the prevalence is between
10 and 40% among kids,
slightly lower 20 to 33% among
adults, but basically in general
twice the risk.
And there is a lot of emerging
research that talks about a
common physiological
pathway between restless leg
syndrome and ADHD that involves
sleep fragmentation
and dopaminergic
system impairment.
There's also a greater
likelihood of having periodic
limb movement disorder if
you have ADHD.
And interestingly,
fairly recent research shows
that
periodic limb movement disorder
is much more likely in those
with great symptoms.
Severity in ADHD, more
pronounced anxiety, worse
executive functioning deficits.
If you look at the circadian
rhythm, we talked about this a
little bit earlier
about delayed sleep phase
syndrome, the natural
progression is for people
with ADHD to become more and
more alert and able to focus and
function until
about 2:00 in the morning.
I've had so many adult clients
say that if the world left me
alone,
I would probably get much better
sleep and I would go to sleep
about 3:00 in the
morning and I would
sleep till 10.
And some people who are self
-employed actually arrange to be
able to conform to
their natural sleep schedule.
But as we all know,
we're raising kids.
They have to get to school,
we have to get to work.
And so we're sort of enforcing
chronic sleep deprivation on
those with ADHD.
The sleep issues differ
depending on the age.
We heard a little bit about
this, but bedtime resistance,
hyperactivity,
and difficulty with sleep on set
are very common in children with
ADHD.
For boys,
just motoric restlessness during
the
night is very common.
For girls,
anxiety is another contributor
to
difficulty falling asleep.
See,
that's something characteristic
of
females throughout the lifespan
and sadly it starts in early
childhood for many
girls.
Then with adolescents,
all adolescents as you're
probably
familiar with,
have a natural delayed sleep
phase
syndrome.
So it's only compounded when you
have ADHD.
On top of that,
there's a lot more stress
related
insomnia,
not necessarily the anxiety I
was talking
about in girls,
but just the stress that many,
if not most teenagers experience
with multiple demands being
placed on them and
not knowing how to juggle and
manage all of the things that
are impacting them in
their life.
So they struggle with daytime
sleepiness, falling asleep in
class.
And there's an impact that
fragmented sleep really disrupts
brain development
during adolescence.
By adulthood,
it's estimated that 50 to 70% of
adults
with ADHD experience
chronic insomnia.
The delayed sleep phase
syndrome, of course, continues.
And because there is a
connection between impulsivity
and overeating and weight
gain,
obstructive sleep apnea becomes
more
common as we get older.
So when we're talking about
basic sleep hygiene,
what I always say is it's
necessary, but it's not
sufficient.
We have to take all of these
other factors into account.
So what does help with a DHDI?
Call it we're
treating ADHD jet lag.
I have experienced this myself
all my life.
My parents used to joke that I
never wanted to go to bed.
They thought I just didn't want
to miss anything that was going
on because older
siblings and parents
were still up.
My mother used to joke,
when you are my age,
you'll be dying to go to bed,
but you won't be able to because
you'll
be the adult in charge.
And that never happened.
In fact, even today I really,
really struggled to get myself
to bed at
a reasonable hour.
Why is that?
Because our brains
are waking up.
And the other thing that needs
to be taken into account is that
late night
hours are the only hours when
the buzzing, booming world isn't
interrupting us,
distracting us,
and we can finally focus much
better.
So it's really a very rewarding
time of day to be awake and
we're paying for it
with with chronic
sleep deprivation.
So how do we treat ADHD jet lag?
Pretty much the same
way we treat jet lag.
Melatonin supplementation
really helps.
Morning light
therapy helps a lot.
There are artificial dawn lights
that I recommend to clients so
that they can set
especially in the winter months
when it's dark so much later
they can set an
artificial dawn to
begin to wake them up.
To expose themselves to very
bright light, the very same
lights that are used for
seasonal affective disorder.
I own one, my daughter owns 1.
Putting this super bright full
spectrum light on your kitchen
table as you're
having breakfast for 20 minutes
really wakes up our brain.
Exercise has a huge impact on
regulating our biological clocks
and improving the
quality of our sleep and
magnesium supplementation.
There's more research suggesting
that magnesium may help regulate
sleep and
also reduce anxiety.
I don't see these kinds of
recommendations being made,
but we really are treating
chronic jet lag, if you will.
Then there's all the issue about
how do we deal with digital
devices.
I set my phone so that the light
being emitted by my phone after
9:00 at night
is in the red range rather than
the blue range.
But Even so,
we're still stimulating our
brains and
we're dealing with really sort
of an almost addictive
propensity with an ADHD
brain that we're
seeking stimulation.
And digital devices and
algorithms on various platforms
are designed to addict
us to one more
time, one more time.
And So what I find sadly,
is that we're training our
children from
the earliest age that the iPad
has become the digital
babysitter.
We're training them that the
world is in this box,
is on the screen and not outside
in the real world.
So we're particularly vulnerable
to digital stimulation because
it's designed
for reward seeking it,
it really can become dangerously
addictive.
Anxiety is another huge impact
that I haven't heard a lot of
people talking
about,
but there are lots of ways that
we can
address anxiety to
help us get to sleep.
There's been earlier talk about
weighted blanket therapy.
I think that can
be very promising.
There's sound therapy.
There are all sorts of there's a
wealth of information on calming
sounds that you
can listen to.
Tibetan bowl sounds which are
just almost hypnotic and
relaxing.
There's been research on pink
noise and brown noise as being
more relaxing.
Magnesium supplementation,
which I mentioned before.
And also there's biofeedback
training that can literally
train us to relax.
Progressive relaxation
with biofeedback.
So there's something that I
haven't heard anyone else talk
about that I think is
really critical in helping
people with ADHD get to sleep.
And this goes back to what I
mentioned before about the
default mode network
never turning off.
And so the less that's going on
in your environment,
the more the default mode
network kicks in.
And except when you have ADHD,
it's a real hyperactive bouncing
around
from one thought to another.
And so it may sound
counterintuitive, but what helps
our brains get ready for
sleep is to have something to
focus on rather than allowing
that default mode
network to take us
in 1000 directions.
And so we need to carefully
select something that's going to
engage us just
enough that we have something to
focus on, but not too much.
Not TikTok, not social media,
not online shopping in the
middle of the
night.
And I sort of call
it the Goldilocks.
The just right stimulation.
Not too much, not too little.
Interestingly,
my youngest granddaughter with
ADHD
discovered that she could go to
sleep very well listening to Mr.
Rogers.
She found that online.
And you know, Mr.
Rogers was from certainly
generations before her.
And his calming voice, his
reassurance, you know,
the friendly magical
neighborhood of Mr.
Rogers allowed her to peacefully
fall asleep.
Kathleen,
maybe we can give you the wrap
up because
we want to give
Carol Dean some time.
You bet, Lucy.
I see.
I see that Geraldine is actually
online, so maybe we can get her
to give her talk
when Kathleen wraps up.
OK.
Sure.
So I'm right ready
to wrap up right now.
OK.
Thank you.
And just that I think there's an
enormous need for research on
pragmatic,
structured efforts to teach
people to get better sleep that
go far beyond the
standard sleep hygiene.
I talked a little bit about how
to deal with the circadian
rhythm disorder.
I think it's also important to
treat the entire family that we
heard a little bit.
I was very interested this
morning with Heather Joseph
talking about helping
parents to get
their preschoolers.
But I think the entire family
needs to work on it if it's
going to be workable.
And we tend to just work with
individuals in our offices and
we give them all these
recommendations that is very
hard for them to follow because
of the executive
functioning disorder.
And I think we also really need
as a nation,
but goodness knows within the
ADHD impacted families to deal
with familial
digital addiction.
I think that living in a digital
world is hugely worsening our
ability to get ADHD
brains to calm down
and go to sleep.
So I thank you so
much for inviting me.
I apologize for the technical
difficulties and I'll sign off
now and
listen to the next presentation
with interest.
Thank you, Kathleen,
and thanks everybody for bearing
with us
with our technical challenges.
At the end of the day,
it is a pleasure to reintroduce
Gerald
and Bliss.
She's the president and Co
founder of Kyrshank and I'm just
gonna let her go on
with her talk in the interest of
time that I am Geraldine Bliss
and I have a
son with Fallon
McDermott syndrome.
It is caused by the loss of a
gene called Shank 3.
Shank 3 is a gene that's
expressed in the brain at post
synaptic densities.
And yeah,
I have to close teams and able
to share
my my, my slides.
So we're going to
skip the slides.
Charles.
Oh, you can see now, can you?
OK, great.
Thanks.
We all put them up.
Thanks so much.
Charles is a sweetheart,
but family McDermott syndrome
has a
profound effect on individuals
who are affected by it.
Let's go to the next slide.
OK,
this is Charles when he was was
a baby,
we did not know
anything was wrong.
Generally his development was
grossly normal.
As you can see in the very first
picture, he's at two months
propped up,
looking very robust, healthy,
walking at 9 1/2 months.
And at 12 months,
you can see very socially
engaged,
just everything, you know,
a family hopes for.
But I will say he was
a terrible sleeper.
He never slept for more than two
to four hours at a time.
And even at, you know,
10 months was really not
sleeping through
the night at all.
He was very, very
frequently, frequently.
So when I look back
retrospectively, I wonder if
that really wasn't our first
tip off, that
something was amiss.
And next,
this is Charles now when he's 2
years old.
And by now we had some concerns.
We knew that his speech was not
keeping up with his peers.
He had a handful of words,
but his expressive communication
was far
behind that of
other two year olds.
We were beginning to see some
behaviors that were a little bit
concerning and we
were suspecting a
diagnosis of autism.
And indeed, at the age of four,
he was diagnosed with autism.
During this time,
we saw a very frequent awakening
at night
and he was unable to put himself
back to sleep.
Next, when Charles was six years
old, he was diagnosed with
Thaneland McDermott
syndrome.
And this was because we had been
treating him for ADHD and he's
having some weird
side effects,
and we wondered if maybe there
was
something going on,
like a metabolic problem in the
geneticist who saw us referred
him for chromosomal microarray.
Charles was one of the very
first patients ever, ever,
anywhere to be diagnosed through
chromosomal microarray.
And we were surprised to find
out that he was missing a small
piece of the 22nd
chromosome involving
the Shank 3 gene.
We connected quickly with the
family McDermott Syndrome
Foundation,
and we learned that sleep
problems indeed were very, very
common in the syndrome.
A couple years later,
he had his first generalized
tonic clonic
seizure.
And it was really a
turning point for us.
The next month he had another
one, and then another,
and then it just exploded.
Charles was having dozens of
seizures every single day,
tonic seizures during sleep and
a tonic drop seizures during the
day.
And certainly the emergence of
the nighttime nocturnal seizure
pattern
really made me start wondering,
is it possible that he was
previously
having epileptiform sort of
subclinical seizure activity at
night that we just
weren't identifying?
Could that have been
contributing to his sleep
disturbance?
I don't know that that's
necessarily the case.
We don't hear,
I mean many individuals with
only 40% of
individuals with Phala McDermott
syndrome actually have seizures.
So I'm not sure that that would
explain all of the sleep
problems that we see in
our syndrome next.
OK,
Now this is when Charles was
diagnosed
with Lennox Gusto.
This was about six months after
that first generalized tonic
clonic seizure.
And Charles,
we had a very difficult time
getting his
seizures under control.
We have tried every medication
out there, ketogenic diet,
cannabidiol, VNSRNS,
now corpus callosotomy.
But sitting bedside with him in
the hospital, you know,
I expressed such frustration
with kind of the poor choice of
treatments for
managing epilepsy and
individuals with Linux gusto.
And I really bemoan the fact
that, you know, hey, we've got
this gene,
we know what it is,
we know what it does in the
brain.
Why can't we have
precision medicines?
And that was really a turning
point for me when I became
involved as a patient
advocate and when I thought, you
know, we really need to start
thinking not just
in terms of epilepsy or autism,
but in terms of the underlying
by
genetics and the underlying
pathology of the disease.
If we really want good
treatments, that's where we need
to go.
So next slide.
So today Charles is he's going
to be 27 next week.
He has transitioned all of his
medical providers to adult
medicine.
He has transitioned into the
adults Medicaid waiver program.
He lives at home with us.
And that's how we
want it right now.
But thinking about the future,
one day we won't be here to take
care of
Charles.
Or maybe our health concerns or,
you know, our capacity to care
for Charles may
diminish over time and we need
to kind of think about like what
the future options
for him will be.
So we have explored some group
homes in Texas where we live and
we found
absolutely nothing that will
serve his needs well.
Why?
Because, one,
because of the severity of his
epilepsy
and the fact that he has very,
very frequent seizures,
but also because most of the
group homes don't provide
nursing care overnight.
To to my knowledge,
there are only two group homes
in the
state of Texas that do provide
nursing care.
Overnight he has apnea during
the night, he desaturates even
when he's not having
apnea for reasons we don't know.
He has frequent waking,
he has difficulty falling back
asleep,
and he has some
behavioral challenges.
And I will say his behavioral
challenges are much better than
they were when he
was younger,
but he still has an
impulsiveness.
He would easily walk out of the
house given the opportunity.
He just doesn't understand that
certain things are dangerous.
Next.
OK,
so now I'm going to kind of
change tracks
a little bit.
I'm going to tell you a little
bit about what we know about
sleep and Phala
McDermott syndrome.
And the truth is not
really that much.
We've had a little bit of
research on sleep and Phala
McDermott syndrome,
not a lot.
So this is generally
what we know.
There was a study but done by
Ruth O'Hara and her colleagues
at Stanford and they
conducted an interview
with parents.
So that was kind of the first
problem, right?
It's,
it relies on parent report and I
think
our parents are amazing and can
report a lot of a lot of really
valuable
information about our kids.
But sleep is one of those
things, you know,
it's hard to understand what is
going on during the night.
That study showed that 90% of
parents reported sleep problems,
40% had difficulty falling
asleep, requiring a parent to be
with them,
60% did not fall asleep within
20 minutes of going to bed.
And I'm my guess is that for
most of the families,
it's more like an
hour or two hours.
70% are restless during sleep,
67% are incontinent at night,
59% awake for more than 15
minutes in the night.
And again,
I think that's that most famous
will say
my kid was up for hours during
the night and and only 22% have
had a sleep study.
And I think that that number's a
little concerning to me knowing
how common sleep
problems are in our population.
But it is a really hard
population to do sleep studies
in.
Why?
Because the kids have to go to
an unfamiliar environment,
most of our patients do have a
diagnosis of autism and they
have sensory issues.
It doesn't feel good to them to
have a bunch of sticky things on
their head or
stuck under their nose or stuck
to their their body.
It is tough for for families to
do sleep studies.
Next slide.
So a couple years ago we
organized what's called an
externally LED patient focused
drug development meeting.
This is a meeting that
we do with the FDA.
We had over 300 parents that
participated and provided either
oral or written
testimony.
And I look through the curated,
all the curated quotes from the
families.
We had 66 quotes from families
that involved sleep.
So you can tell that's a very
high priority topic for
families.
One of the themes was about the
intractability of sleep
problems.
We've been through the gamut of
all sleep medication.
I think we've tried six
different ones and none of them
have fully helped.
Now that is a story we hear
again and again in Family
McDermott Syndrome.
Next,
where we got the most comments
of all was
on the impact on families.
Sleep,
exhaustion and disturbance has
made it
very hard for us to carry on a
normal life as a family.
We lack energy and patience to
take on normal daily activities,
let alone the extra and fun
activities that typical families
get to experience.
This is a comment that we heard
again and again and again from
families.
This is one of the top things we
see every every week on our
Facebook group,
families talking about their
exhaustion, sort of the degree
of isolation that
they're feeling.
It is the combination of the
child not sleeping and when
their child is awake,
having a lot of really severe
and challenging behaviors.
The parents have to be vigilant
all the time.
And then at night,
they really don't have an
opportunity to
rest because of their child's
sleep problems.
Next slide.
OK.
And finally,
I think because of that
behavioral
concern during, you know,
when a child awakes,
families really they're,
they're, they're taking a lot of
precautions.
In this example,
you'll see the family reports
that their
child's room only contains 2
beds and a removable curtain rod
rod for safety
reasons.
And we had a death in our
community at several years ago
where a little girl
woke up and she was
playing in her room.
She became entangled in her
curtains and she strangled.
And she was found the next
morning by her parents and she
had, she was dead.
So a lot of our families are
very vigilant and they know from
the moment
their child wakes up their day
has started.
Either my husband or I sleep in
his room to ensure he is safe as
he is at risk of
elopement and because he rarely
sleeps through the night.
And that's a very
common problem.
Next slide.
OK.
So in family McDermott syndrome,
the core features are autism,
which about 75 to 85% of our
individuals either have a strict
a diagnosis of
strict autism or autism
spectrum disorder.
Intellectual disability of
varying degrees occurs in 100%
of our patients.
Some are a little or moderately
affected, others most tend to be
more on the severe
to profound end of the spectrum.
And infant hypotonia.
Seizures occur in about 40% of
our patients and sleep problems
occur in 90%
of our patients.
Certainly there are a lot of
things that could potentially
influence sleep that
occur in family McDermott
syndrome, for instance,
seizures.
What is the contribution of
seizures to sleep disturbance?
What about other
health problems?
Gastroesophageal reflux and
Constipation are really common
in our community.
And you know,
we certainly wonder if sometimes
discomfort from GI problems can
contribute to sleep problems,
especially reflux.
There's just a restlessness that
our kids have day and night and
maybe that alone
is a contributing factor.
And there's just, I mean,
one of the just difficult things
a lot of
parents describe as a lack of
sleepiness at bedtime.
It's if you're a parent and
you've been through the two to
three-year old stage,
you, you,
you know that feeling like when
your
child is so amped up after a
long day that they can't fall
asleep.
Well,
that's how it is in felony
Dermot
syndrome all the time.
So,
and then we also know there are
some
things that could be influenced
by sleep as well.
For instance,
Charles has much worse seizures
following
those nights of
especially bad sleep.
We certainly wonder about the
role that the kind of the effect
of sleep, you know,
sleep deprivation on learning
and memory and attention
certainly behavior and mood
as well.
Next.
OK, so like that's a problem,
like it's sort of there's this
bi
directional relationship it
seems between sleep and some of
the other like
troubling aspects of phaliumic
Dermot syndrome.
And I should say we could
probably insert many other
neurodevelopmental disorders
instead of phaliumic
Dermot syndrome.
I know these are really common
problems among all of the other
kind of genetic
conditions that are associated
with, you know, autism,
intellectual disability
and epilepsy.
And while they may not share the
exact same phenotypes,
they do have sort of this.
They seem to have
this bi directional.
You know, relationship between
sleep and, and behaviors and,
and other phenotypes.
So how are we going
to get past that?
And you think 1 is, you know,
we need to be able to measure
sleep
quality and quantity with better
precision.
And secondly,
we need to be able to collect
behavioral
data in real time.
And certainly I
again, this is 1.
I do trust our parents to report
on a lot of things and I think
they can report on
behavior,
but I don't think it can be
like, I think,
you know, in my mind,
maybe it's an app Families
report on a
daily basis,
not like once every six months
when they
go in or, you know,
some kind of a clinic visit or
clinical
trial visit.
Next slide.
OK,
so I created some data from
Facebook just
to see like,
what are people doing to help
their their
children with sleep in the
Phalen McDermott syndrome
community?
I'll tell you what doesn't work.
Sleep hygiene maybe minimally
helps, but it doesn't help their
kids overcome
all their sleep issues,
doesn't help them go back to
sleep,
doesn't prevent the nighttime
awakenings, sleep training and
ASMR YouTube videos.
See, families have
tried everything.
On the opposite side is are the
things that all the things that
families are
trying and I'm not going to read
that list.
I'll just let you
take a look at it.
A lot of families do use
melatonin, but they try all
kinds of things,
some of which don't necessarily
have evidence like THC, for
instance, right,
or evidence in, in children.
I think there's a real need to,
to start like doing clinical
trial,
like comparative effectiveness
research, looking at these
different options.
What I want to get away from is
parents like me and others in
our community
having to do north of 1 clinical
trials on our own children to
figure out what's
going to work.
We really need better guidance
on how to manage our sleep
problems and which of
these medications
are really effective.
And this is probably something
that we're, we could break it
down by different kinds
of genetic disorders,
different types of diagnosis,
have huge studies that
enroll these kids.
But then really where we're
trying to identify what works
for different
diagnosis.
And in family McDermott
syndrome, we do have some
consensus guidelines,
but they're not evidence based,
They haven't been,
there's been no like comparative
effectiveness research to
compare these
things.
These are just guidelines based
on some of our expert
physicians.
Next page.
OK,
so I was asked to prepare a few
questions
for future research.
The 1st is really to consider
doing genotype by sleep
phenotype studies.
And I wonder if you know,
thinking about other genetic
disorders
associated with
neurodevelopmental problems,
if potentially there's data in
electronic health records
including sleep studies.
And if this might help us
generate some hypothesis about
how you know about like
the different kinds of sleep
problems that may present in
different
neurodevelopmental disorders.
The second idea is to start
doing interventional trials,
enrolling different cohorts of
patients, especially patients
with different
genetic conditions,
and start doing pragmatic
clinical trials
of things that are already in
widespread use.
As you can see from the previous
slide, families are already
trying a lot of
things, right?
Doctors are prescribing
a lot of things.
Why can't we just take that and
then organize that into the more
systemic
systematic process instead of us
each doing our own and of 1
informal trial.
And the last recommendation from
my parent perspective as a
parent is that we
need in home studies with
digital data collection.
I mean,
sleep studies done in clinics
are really,
really difficult for
a lot of families.
And now we have some wonderful
devices, Cure Shank, my
organization,
we are funding a pilot of the
Dream Headband with Doctor
Milonis.
But we need lots and lots of
these kinds of projects just to
figure out what is
actually going to be feasible to
do in in home settings.
So anyway,
I am so grateful for this
meeting being
organized.
Many,
Many thanks to NHLBI for
organizing this.
I hope that you'll have
sustained interest and funding
research on sleep
disorders and neurodevelopmental
disorders.
And thank you so much to Lucia,
Larry and the other organizers
of this
meeting.
Thank you, Caroline,
and you were fast on time.
And thank you,
everybody for bearing with us
with our
technical difficulties.
We're going to move on all the
questions to our Q&A at the end
of the day.
So a lot of our speakers are
going to stay on.
So I'm going to transition to
Jared, who is going to be
moderating the Q&A.
Thanks, Lucy.
Thanks for everybody for their
patience with the technical
challenges.
Thanks, Jared.
Yes, and thank you everyone.
It's been an incredible day and
and you and I hope everyone can
see the breadth
of,
of conditions that we're talking
about,
types of sleep phenotypes,
types of interventions that
we're talking
about and also
what we don't know.
So there's a number of questions
in the chat for speakers that
are still with us.
I encourage you take a look can
add some responses because you
can actually type
them in if you can see them in
the Q& A.
If you can't let us know.
But I,
I want to open up to a couple of
themes
that have emerged and some of
the questions we've received.
And one of them I think is about
Co occurring conditions and
parsing sort of
either, you know,
comorbidities in terms of
psychiatric
components.
There's been questions about
anxiety in ADHD,
insomnia and ADHD parsing Co
occurring autism in ADHD and,
and what's driving the sleep
issue and, and where do we
mechanistically parse
these?
So I was wondering if any
speakers could talk about how
they treat either in their
research or in their
clinical practice.
You know,
how do you start doing the
differential
between some of these Co
occurring neurodevelopmental
disorders,
some of the comorbidities that
come with them and then
ultimately what the routes
to to to sleep are and,
and what folks thoughts on that
are?
That touches on a few different
questions folks submitted.
Do you have a way
you'd like us to?
No,
please call out if you have an
answer to
that very broad question on a
number of topics.
I am not a clinical
psychologist, so I will refrain
from parsing that
clinically, but I, I, I do
think, you know, it's absolutely
critical from a,
you know, I do research
mostly in ADHD.
We do a little bit of work in
autism and we take primarily
dimensional approaches
for exactly this reason.
And we see kids with ADHD and
anxiety all the time.
In terms of kids who come into
our studies,
we see a lot of overlap and ADHD
and autism.
We don't, you know,
so we make actually very we go,
we do not exclude for a lot of
these Co occurring conditions
because it it it
fundamentally changes the sample
from what we see in the real
world of kids,
you know,
coming in with with these
presentations.
So wondering how folks treat
this clinically.
Beth, go ahead.
Doctor Mallow, I
think you're muted.
Beth,
I don't know if you are trying
to talk,
your hand is raised,
but you should go ahead and
unmute.
OK, Hold on.
I think this is great.
Yeah.
I was trying to figure out how I
could unmute.
So can you hear me now?
Oh, that's wonderful.
Yeah.
Thanks, Beth.
Yeah, thanks.
Yeah, I was going to say I,
I tend and I'll try to put my
camera on
if it's enabled right
now, it's blocked.
I I really try to address the
the sleep problem as best as I
can.
The,
the reason I think the Co
occurring
conditions are important is #1
if there is a Co occurring
condition and you treat
it,
that can in and of itself
improve the
sleep.
And then it can also help you
with trying to figure out the
best medication, right?
So that we're not trying to over
medicate people,
we're trying to use medications
that we might already be using
for their anxiety,
their ADHD,
depression, whatever.
So those are the two reasons I
focus on the Co occurring
conditions.
With that said though,
my approach like I still find
often times
behavioral approaches and
medications work regardless of
the Co occurring
condition.
So I I tend to view the Co
occurring condition as making
sure that you address
it so that it's not contributing
to the actual sleep problem.
I hope that is helpful.
Absolutely.
Yeah.
And if I could,
if you could get our cameras on,
that would be awesome.
Oh wait, maybe it now popped up.
Other people might have the same
problem, other speakers, a neck.
Go ahead.
Yeah, well,
I was going to approach it from
a
research perspective and just
mention that the prospective
infant sibling
studies really pull for a
complex kind of less severely
affected sample of kids.
There are kids that don't tend
to have the genetic syndromes
and maybe aren't
super representative of who we
see in our clinics,
but they are harder in the sense
of that diagnostic question that
you started with.
Because we see kids that are a
lot of times on that borderline
between ADHD,
anxiety and autism.
And I think really polls for
asking some of those deep
questions about well,
what is the difference between
these different
neurodevelopmental disabilities
and what are the similarities.
And I think the thing that I
find really compelling about
sleep is that it is
something you can identify,
cross developmental disabilities
and
treat like, well,
Geraldine's talk just now points
to the
fact that you can't lump
everybody together.
They're not the same necessarily
in terms of how we want to treat
the sleep
problems.
But it does give us sort of a
way in at least, you know,
in terms of that phenotypic
diagnostic question that you
raised.
So it's a great question.
Yeah.
And I,
and I think it speaks also to
the
question that just popped into
the Q& A, which is about, you
know,
autism is this heterogeneous,
very broad term and what can we
do to get
it more specific
characteristics, especially vis
A vis specific genetic
ideologies.
And so, you know,
I know that there's work being
done in,
you know,
22 Q and then 17 and then 16 and
then
these specific, you know,
genetics first approaches that
might
suggest, OK,
different paths to overlapping
phenomena
through specific genes and
specific circuits.
And I think, you know,
that's part of there was a
mentioned
earlier about when you have
small samples and a
heterogeneous population,
you have a number of studies
that go one way and another
studies that go the other
way.
And so we,
we can solve that both with
sample size,
but we can solve that with
better sort of models about what
we're actually studying
and which samples we're actually
recruiting.
And I and I think tomorrow's
talk session is going to be
largely about model work
where we can, you know,
be much more pinpointed to
mechanism.
So that's to the question that
just came in.
I want to,
I want to pivot to a different
set of
questions because the last
couple speakers, I think there
were,
there were overlap in this idea
that sleep hygiene is not enough
in the advice
that gets given.
And,
and we know that there was a
number of
questions put in about Cbti,
cognitive behavioral therapy for
insomnia
is more than just the behavioral
health components and the sleep
hygiene
components,
but there's also this sleep
restriction
and homeostatic regulation piece
that comes in.
And can anyone speak a little
bit about how well those aspects
are tolerated and
some of the populations that
that you serve, particularly the
sleep restriction?
There were a couple
questions about that.
I can tell you experimentally,
'cause we restrict sleep in kids
experimentally to try and model
what they do in the school week.
And we and I, I,
I think it might actually
structure their
sleep in some ways.
But clinically, Dr.
Mallow,
I don't want to dominate the
conversation.
So if anybody else wants to.
Yeah, Well, I,
I have not found it that easy to
do.
You know, the the limit,
the sleep restriction in this
population,
because a lot of them are
already getting limited sleep.
The parents are not really
wanting to tolerate it.
The adults don't want to do it.
But what I do find is delaying
bedtime is huge.
That's probably the number one
thing I do behaviorally that
makes a huge difference.
Maybe it's because a lot of
these kids with NDDS are
delayed.
You don't have
delayed sleep phase.
But in any case,
I find that just moving bedtime
by 30
minutes or an hour is so
effective because if they're in
their forbidden
zone for sleep and they can't
express it to their parents,
they're going to fidget.
They're, you know, they're going
to stem, they're going to do all
these things that
are going to interfere with
sleep even more.
So it's always funny though,
in the clinic because the
parent,
the kids are always like, yay,
I get to stay up later.
And the parents are like,
we're never going to see doctor
Malow
again, right?
But it really does work.
I think so instead of like
focusing on calculating out this
restriction of sleep,
I just try to move
sleep a little later.
And that oftentimes
is very effective.
Doctor Nadeau I I would say that
kids are already doing lifelong
sleep restriction
experiments.
I mean,
just by virtue of the fact that
they have
to get up in the morning,
no matter how tired they are.
And The thing is,
they can't stay awake.
They they go, they
fall asleep in class.
Mean I remember when my daughter
was in kindergarten, they talked
to me about,
they were concerned about how
long her naps were because she
had not had enough
sleep and then long nap.
And then that exacerbates it.
One of the things that I've
found that is tremendously
helpful with kids and
adolescents is vigorous exercise
that seems to hugely help them
go to sleep at
night, if you can get into this.
In fact,
I've worked with kids who almost
treated
their sleep disorder and their
ADHD in general because they
were on the track
team or they were
in the swim team.
And we're just involved in this
amazing intense aerobic exercise
every day.
And then everything came roaring
back if they didn't get on the
track team in
college or didn't get in the
track team, the swimming team.
So the sleep restriction,
I've had some adults just say I
just
can't do it.
And, you know,
I'm driving in my car and I'm
slapping my
face.
It's dangerous.
I'm so sleep deprived.
And so I,
I think a lot of it is just
experimenting.
I mean,
there's almost no such thing as
ADHD
without coexisting conditions.
It just almost doesn't exist.
And so we're always having to
fine tune it with how much is
their anxiety.
And therefore there are all
kinds of things we can do with
calming sounds and
weighted blankets.
This I find that pink and brown
noise can be incredibly
impactful if it's loud
enough so that it just it's a
blanket that blocks out the rest
of the world.
So there there are lots of
different techniques that we can
use depending on
the particular.
I've had kids develop calm down
spaces in their closet and sleep
on the floor in
their closet because that
confined, unstimulating space
really helped them
with the anxiety,
with the hyper alertness.
So they're just a lot of
different things that needs to
be customized by the child,
by the adult.
Yeah.
And if I could pick up on
something you said at the very
beginning,
which is that children are sort
of living out a sleep
restriction experiment
typically as a function of how
we structure their day.
And, and I think, you know,
one of the important factors for
us is
that underlying development of
sleep and circadian rhythms that
creates that
Malstrom or as Mary Karskaden
calls the perfect storm, right?
I mean,
the change in the circadian
rhythm
pushing later combined with a
homeostatic system more capable
to stay up later and
then hitting the wall of how we
schedule these kids sleep is
eroded night to night.
Now all of that work is it
results from experimental
studies and typically
developing kids and and whether
or not we know that you know,
that kids with ADHD,
kids with autism,
kids with some of these other
genetic
conditions or kids with some Co
occurring psychiatric symptoms
go through that same
developmental trajectory at the
same time, in the same way.
We don't know the
answer to that.
We don't know.
And I think that that's really
fundamental too to think about,
OK,
how are those individuals then
going to respond to the
environmental influences
of light sounds, early school
start times, all these other
things that we always
talk about?
Are they going to
respond the same way?
I think that's right for for
investigation.
I couldn't agree more.
And so we, we're closed on time,
but I want to, I want to,
I want to have a theme.
There's a theme that came in I
thought was a wonderful question
of what,
how do we educate the public
about the intersections that
we've been talking
about?
You know,
I think there's an open
conversation
about sleep
education in general.
And, and Doctor Mallow, you,
you, you've done some of that
scientific
communications work.
How do we bring stakeholders in,
in the public,
in child health organizations
and and in in neurodevelopmental
organizations so
that this can be an integrated
conversation both from the sleep
side as
well as the
neurodevelopmental side?
And anyone please chime in.
Beth, go ahead.
I apologize,
but I'm going to have to sign
off.
I'm so sorry.
I'll have to sign off.
Yeah, I'll thanks so much.
I think, I think there's,
I think there's a couple of ways
to
approach it.
I,
I think that certainly we've
done some
practice pathways and position
statements and autism that are
then made available
and I think others have too.
I think she,
Buckley did one as well for
American
Academy of Neurology.
So that,
that's clearly something that is
important.
I think reaching the families is
critical too.
Like I,
I exhibited with the melatonin
blogs and
melatonin safety
posts and videos.
I because parents,
the problem is a lot of
pediatricians and
pediatric nurse practitioners
don't know about sleep and other
areas like
melatonin and,
and certain ways to approach
medicine.
So they're,
they're just in the dark and our
sleep
centers have major
access issues.
So anything that we can do to
get to the families and give
them reputable evidence
based medicine.
Actually, I heard the term
recently, instead of saying
evidence based, it's,
it may be better to say
treatments that work.
So giving them treatments that
work that are, are effective.
I mean,
they're hungry for this
information.
And we can also say here are
some, you know,
here are some simple resources
you can look at for trying to
figure out what
might be best for your child and
then bring it to your
pediatrician.
Don't.
We're not cutting
the pediatrician out.
I think we're just acknowledging
that parents can do some of can
look on their
own.
And if,
if they go to the Internet and
they see
reputable stuff that's from us,
then they can go to their
pediatricians
and have that discussion about
medicines or melatonin.
Because I,
I really think that empowers the
public.
And it's,
it's just super important in
terms of the
sleep education.
We've tried a lot of things.
I wish I could have expanded on
this a little bit more today.
I know our time was limited.
You know,
we've tried pamphlets and we've
tried
online modules and we've tried,
I wrote a book with Terry Katz
that's on
Amazon.
I mean, for some parents,
that's effective.
I, I really keep coming back to,
they need to be coached,
they need to be supported.
So that's why we're now doing
this project with the American
Academy of
Sleep Medicine to train
therapists, behavioral
therapist, speech therapist,
OT in communities so that the
parents can, you know,
they're trusted messengers for
these parents.
The parents love the therapist,
the therapist have amazing
empathy with
these parents.
And you know,
I think it also helps with that
whole
access at the sleep center.
So just wanted to add those
thoughts, those are good
thoughts.
And I will just chime in with
one more and that is that there
are some superb
patient advocacy groups,
especially kind of like in the
developmental and epileptic
encephalopathies and
neurodevelopmental
disorders.
These represent mostly represent
single gene disorders, not all
some represent,
you know,
but they're kind of organized a
little
differently,
but they're they're really good
at
sharing information and they're
really good at sharing, like you
just said,
not to use evidence based math,
but they're really good at
sharing data
that comes from research, right?
These are really
trustworthy groups.
So I'm hope you guys will rely
on us to help disseminate to our
communities.
Geraldine, just to clarify,
I wasn't saying we shouldn't use
evidence
based.
I was just saying for the
public, they might understand
treatments that
work better than evidence based.
Like it just it's less jargony,
that's all.
So it's such an important point
to use language where people are
right?
So they, I, I think, you know,
we're, we're right up against
time,
but I want to thank everyone
for, you know, a great
discussion.
I think there's so much work to
be done and and there's just an
incredible
excitement to bring this
community together, discuss
these themes in a,
in a number of different ways.
Thank you to everyone who's on
the call for attending tomorrow.
We're going into systems work
and then hopefully bringing it
all together and
thinking about how we can do
some translational dialogue
between very much
the human and patient
perspectives today and the the
basic science perspectives
tomorrow.
So thank you everyone.
Yeah, thanks Jordan.
Thanks to all the moderators,
the speakers and especially my
Co chairs
and the support team.
Look forward to talks tomorrow.
Thanks everybody.