[Music]
I wanted to sort of pitch or present the
work today in the context of the effects
of stress because of the high burden
that mental illness has on young people
that is as many as 40% of young people
today experience a mental illness the
majority of these are related to anxiety
and stress and if we don't treat these
early they can go on to lead to chronic
illness both psychiatric as well as
physical illness so the questions that
we've been asking and our laboratory
over the years is how are these early
life experiences impacting emotional
well-being and the underlying brain
circuitry involved in that well-being
and ultimately what we need to do is to
use this information so that we can
facilitate and enhance healthy brain
development and also of course
well-being of young people which is then
going to be well-being of our society
but if we first take a just a simplistic
look at all the changes that are
happening in postnatal development what
you'll see is that there is dramatic
changes just in the number of synapses
throughout the brain that develop
regionally so we see a proliferation and
a subsequent pruning of these
connections simultaneously there changes
in nerve chemicals and neurotrophins
that are absolutely essential to
development and learning and with all
these regional changes it is
co-occurring with increased myelination
throughout the brain which is making the
connections stronger so we've been
focused on all these dynamic changes and
trying to understand with just one
picture using human imaging and focusing
on one circuitry that's really important
for our ability to process emotional
information so emotion regulatory and
emotional reactive processes and during
this time during childhood and
adolescence their major changes in the
circuitry and we think that they will
are one pathway for us to seeing how
early life experiences are reflected in
them and how this continued development
may also be a window of plasticity sorts
where we may have the biggest change now
in human studies one of the ways that we
try to look at this in these circuitries
and the behaving human brain
non-invasively is to use simple stimuli
or cues that we present so here or
here's an example of a cue of emotional
information we examine how these cues
impact both brain and behavior these
cues can be positive smiling faces or
negative or they can be neutral but what
we see is even if you were in the
laboratory performing this task if we
ask you just to press a button whenever
you saw one of these cues you would be
significantly longer in detecting a
threat cue a fearful cue then you would
be to a neutral happy as you see here so
we have a longer latency there it's
adaptive when we see cues that have some
uncertainty or ambiguity I don't think
for a minute when I present this cue to
you that you are threatened by that
however we learn over a lifetime and we
see cues like this that there might be
potential danger and what's very
important for us to understand is in
this context is it a threat so if a
bearer were to come into the room I
might have an emotional response but the
circuitry is important if I saw a bear
in a zoo to know that that bear in that
situation I would be safe because they
were hot behind a a cage or wire so now
if we look at these responses in this
change in our responses depending on the
potential threat of information in our
environment if we open up the brain and
look in
side the areas that tend to be related
to that delay and our approach behavior
in such situations involve the amygdala
and the prefrontal cortex and hopefully
what you note from this slide is that
the amygdala the more active it is the
slower you are to respond the amygdala
is very important in picking up the
emotional significance of information in
the environment and has been associated
with emotional reactivity in contrast
the prefrontal cortex which has direct
projections to the amygdala based on
elegant animal work and more recent
human work that area is less active when
you're really slow to respond and the
more active it is the quicker you are
that is you see a potential threat you
are able to understand in this
particular situation with repeated
presentations of it get over yourself
alright already
nothing's going to happen to you now
I've just made a sort of claim that over
time nothing's going to happen to you
well let's look at that in the brain and
what systems are absolutely essential
for that what's important when we look
at with those repeated presentations how
well you have bitchu 8 to these cues is
this inverse coupling between the
prefrontal cortex and the amygdala in
the circuitry and this inverse coupling
or negative connectivity seems to be
changing radically from childhood to
adolescence and it is when you are not
able to habituate that response that is
associated with heightened anxiety so I
just want you to focus on this quadrant
for a moment and basically if you look
over at the y-axis that's amygdala
situation and it's a negative score that
means not only was there not a change
and how active the amygdala was to these
cues but that was actually sensitized
and it was increasing over the course of
the experiment and that's related to the
highest level of self-reported trait
anxiety now some of these pictures had a
lot of data and I think data slides and
pictures are worth a hundred or thousand
words but movies my
tell a simpler story so this is an
example of an individual who reports low
anxiety and they're being presented with
these cues a potential threat so you'll
see there's bilateral activity in the
amygdala with repeated presentations but
then it's like the system begins to
return to baseline and it turns blue
that represents from the increase going
back down to baseline in contrast when
we look at an individual with high
anxiety we basically see a similar
pattern at first with this bilateral
activation of the amygdala but then it
stays up and it stays up and it stays up
and it doesn't return to baseline so
it's that vigilant state of anticipation
of threat and an uncertainty of what
these cues potentially me so two
different paths that we've taken in
trying to understand these two very
different neural signatures here is to
look at differences in genetic factors
that may explain this but in the
interest of the symposium today also and
the environment or experiences that we
have so how does early life stress
impact the development of the circuitry
and we have used really an extreme
example of early life stress it is an
unfortunate but a natural occurring one
and that is children who grow up in the
orphanage now in the orphanage
experience all that Worthen ajiz vary
but there's always going to be some
fragmented caregiving because of the
high ratio of so many children to a
single caregiver so what we've been
interested in is as these children are
adopted to families in the United States
we've been trying to understand how this
dysregulation of their needs not being
met how there's not a tune Minh and the
child's needs with what the caregiver
can actually provide to them how that
impacts their ability to regulate itself
but particularly today I'll talk about
how to regulate emotion so again we use
these simple cues and we ask children
who have been adopted from the
orphanages as well as comparison group
who have not been adopted who live in
the United State
they all have moved the adoptive
children have been here for at least two
years to make sure they get acclimated
to their new home and their new culture
and environment and what we do is we
present these cues a potential threat
but in the task we tell them you know
ignore these try not to pay attention to
them and you find in the situations in
which you have these cues relative to
situations where you present a smiling
face that the adopted children are much
slower in anticipation of one of them
occurring so even if it's a neutral face
on the screen if they know they're about
to see a threatening face they're really
hesitant to respond but if it's to a
happy face or smiling face you don't see
a difference between the two groups now
this is paralleled in the brain by
enhanced activity and the amygdala and
that's shown here on the left and the
right side though I think what's
important about these findings is first
this is greater activity and the
children who are adopted from orphanages
abroad relative to the comparison group
the area in blue is actually more active
in the comparison group this is a part
of the brain that's important for
attention regulation and emotion
regulation so one is being able to
regulate their emotions and ignore and
the other is quite reactive that group
but more importantly when you see images
like this and you have these neural
signatures it is how does that relate to
their actual behavior when you get them
outside of the scanner environment or
the laboratory and so we measured how
the behavior between caregivers and
their adopted children when they had
been separated briefly and then they
were reunited and we looked at the
amount of eye contact they had with
their caregiver when they were reunited
and basically we see that the more
active the amygdala was the less I
contact they had were the caregiver also
the left eye gaze they actually held on
the faces that they were presented in
the experiment as well - now when we
have natural occurring experiments such
as this
we don't really have control on
pre-existing conditions that may be
their genetic or environmental so we've
actually turned to use mouse models to
try to see if we can control for the
genetic and environmental confounds that
might otherwise explain what we're
seeing and so we borrowed paradigms that
have been developed by individuals like
Regina Sullivan NYU and also Talley
Barron at UC Irvine too and do sort of a
fragmented caregiving of a damn to her
pups and so I wanted to show you those
movies on the top is a dam where we've
taken away the nesting material she has
a little bit but not sufficient so she
is running around oh this is not in real
time a little bit slower than that so so
basically I don't even know if you can
see that control dam so she has all the
nesting material she needs and she's
spending the majority of her time
grooming and feeding nursing her pups
but you can see the mother above is
trying to pull together the nesting
material and sometimes her pups
over to her corner for the nest so
basically you're seeing this fragmented
care because she can't attend to her
pups when she's doing other things which
we thought might in the slightest way
mimic some of the fragmented care that
we see in the orphanages and if you look
within two hour period you see a
significant difference in the amount of
time that the dam is spending with her
litter relative to controls but quite
frankly if you look across a 24-hour
period they're spending almost as much
time with physical contact but it's very
fragmented in that contact so there's
not that attunement between the
caregiver and the and the pop so then if
we look at their ability to regulate
their emotions not the dam but now her
offspring who's been given this
fragmented care basically what we see in
a paradigm in which we've trained them
that a nozzle will lead to them having
says to condense milk and mice love
condensed milk and so we put that nozzle
in a novel cage with a bright light
where there's potential threat for mice
and we see that when we put it there
there's a difference between those mice
that grew up with the stress dam
relative to the mice who's a dam their
mother was not stressed and you don't
see any difference in terms of how
quickly they move to the nozzle and
their home cage and then if we look at
the brain using cephus activity as an
index we see heightened amygdala
activity in this group relative to the
controls and so this gives us a bit more
confidence that what we're seeing and
the human data that I presented it's not
as much associated with maybe
pre-existing conditions as it is with
the early life stress because these
parallel quite nicely
now with the mice unlike our human
children who are usually adopted by
super parents if you do nothing after
that you see that there is persistent
effects of that early life stress so
that they're still showing heightened
amygdala reactivity in adulthood even
though there's continued development of
the circuitry now this persistent effect
and these mice is somewhat reminiscent
of work that NIM Tottenham has done at
Columbia in collaboration with Dylan G
who's now a colleague of mine at Yale
University and she's actually shown that
if you look at this front Olympic
circuitry that there may there appears
to be something similar to a premature
closing of a sensitive period of neural
development of this circuit such that if
you just look at healthy children what I
described before their drastic
significant changes from coupling
between the prefrontal cortex and it
becomes inverse or negatively related in
adolescents what we see in children who
have grown up in the orphanage is you're
already seeing those changes early and
so now neem is trying to follow and see
just how rigid does that make the
individual when they go through
adolescence
which is even more stressful time of
life and meeting so many challenges I
just want to end with one more study an
area of work that dr. Tottenham is
following up on and that is showing how
important the caregiver is and so in his
experiments where we're showing these
very simple stimuli in the scanner while
we're taking pictures of the brain and
watching how they perform games if you
simply put a picture of the face of the
caregiver along the screen where they're
performing the tasks and you can
counterbalance that with a face of a
stranger she sees that that's associated
with decreased activity in the amygdala
so it's a decrease in that emotional
reactivity just by having that parental
cue present there and also there is an
increase in the inverse coupling with
the prefrontal cortex that is typical
more of adulthood but we're seeing the
parent has that ability to help regulate
so I hope what I've shown you or
Illustrated is just one small set of
experiments that are being performed
where we can show that early life stress
can lead to persistent changes in brain
and behavior particularly in terms of
emotional capacities and it highlights
to this last bit of work the importance
of having very early interventions and
also the importance of the caregiver and
helping to develop a healthy brain and
also in terms of enhancing emotional
well-being now and hopefully forward for
that individual so I just want to end by
thanking so many individuals who have
come through my laboratory over the
years the majority of them fellows who
are stellar stars now and it's also
thank you for your attention
[Music]