The Effects of Early Life Stress on Brain and Behavior

The Effects of Early Life Stress on Brain and Behavior


(upbeat 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 in 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 gonna be
well-being of our society. But if we first take just
a simplistic look at all the changes that are happening
in post-natal 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 are
changes in neurochemicals 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 emotional regulatory and emotional reactive processes. And during this time, during
childhood and adolescence, there are major changes in the circuitry and we think that they 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 of sorts where we may have the biggest change. Now, in human studies,
one of the way that we try to look at this in these
circuitries and the behaving human brain, non-invasively,
is to use simple stimulator cues that we present, so here’s an example of a cue with 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 asked you just to press a button whenever you saw one of these cues, you would be significantly
in detecting a threat cue, a fearful cue, than you would
be to a neutral or 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
when 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 bear 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 behind a cage or wire. So now if we look at these
responses and this change in our responses depending
on the potential threat of information in our environment,
if we open up the brain and look inside, 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’s 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
gonna happen to you. Now, I’ve just made a sort
of claim that over time, nothing’s gonna 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
habituate 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 habituation
and it’s a negative score. That means, not only was there
not a change in 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 100 or a 1000 words but movies might
tell a simpler story. So this is an example of
an individual who reports low anxiety and they’re being
presented with these cues of potential, so you 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 mean. So two different paths that
we have 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 in 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 naturally-occurring one and that is children who
grow up in the orphanage. Now, in the orphanage experience,
all the orphanages vary but there’s always gonna 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 disregulation of
their needs not being met, how there’s not attunement
in the child’s needs with what the caregiver can
actually provide to them, how that impacts their
ability to regulate self, 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
States, they all have moved, the adopted 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 of potential threat, but in the task, we
tell them, 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 more lower 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 in the amygdala, and that’s shown here on the left and the right side. But I think what’s important
about these findings is first, this is greater activity in
the children who were 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 eye contact they
had with the caregiver. Also, the less eye gaze they
actually held on the faces that they were presented in
the experiment, as well too. Now when we have
naturally-occurring experiments such as this, we don’t really
have control on pre-existing conditions that may be there,
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 had been developed by
individuals like Regina Sullivan at NYU and also Tallie Baram at UC Irvine to induce sort of a
fragmented caregiving of a dam to her pups, and so I wanna
just 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, she’s a little bit slower than that. So basically, I don’t even
know if you can see the control dam, so she has all the
nesting materials 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 a 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 pup. So then if we look at
their ability to regulate their emotions, not the
dam, but now her offspring who have been given this fragmented care, basically what we see,
a paradigm in which, we’ve trained them that a
nozzle will lead to them having access to condensed
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 a stressed dam relative
to the mice whose 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 C-Fos 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 in the
human data that I presented is not as much as 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
in these mice is somewhat reminiscent of work that Nim
Tottenham has done at Columbia in collaboration with Dylan
Gee, who’s now a colleague of mine at Yale University,
and she’s actually shown that if you look at this
frontal lymbic circuitry, that 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,
there are drastic, significant changes from coupling
between the prefrontal cortex and it becomes inverse or
negatively-related in adolescence, what we see in children who
have grown up in the orphanage is you’re already seeing
those changes early. And so now, Nim is trying to
follow and see just how rigid does that make the individual
when they go through adolescence, which is an even
more stressful time of life in meeting so many challenges,
and I just wanna 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 these 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 task and you can counter-balance that
with the 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, or 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, too,
this last bit of work, the importance of having
very early interventions and also the importance of the caregiver in 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 wanna 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 to also thank you for your attention. (gentle music)

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