>> From the Library of
Congress in Washington, DC.
[ Pause ]
>> Good morning and welcome
to our conference on stress.
The title of my lecture
is Physiologic
and Molecular Characterization
of the Stress System
in Health and Disease.
I will try to be as simple as
possible without being simplistic.
And I will start with a saying
by Epictitus or Epictetus
who was historic philosopher.
So what he had said is be equanimous
and remember not to believe easily.
So, I hope that everything we say
here is evidence-based and solid.
My lecture is divided into
four parts and I will go
over the first three
parts only today.
Stress concepts, stress mechanism,
effects of stress on the organism,
and finally, this is a part
of a lecture that's going
to really be used tomorrow
on coping with stress.
Stress Concepts.
Let's begin with a
saying by Antisthenes,
that's another historic philosopher.
He said that the beginning of
science is the visit of names.
So, let's visit the name "stress,"
the etymology, is an Indo-pean--
Indo-European root which is "str."
It exist Athens [phonetic]
and in Modern Greek
as "strangalizein"
which means to strangle.
Strangle also, English is coming
from the same root and then Latin
"strigere," which means to
press tight and it's used
in modern Italian as well.
Now, one of the western
philosophers that started thinking
of complex systems and now, we
are in the era of systems biology
or systems medicine was Pythagoras,
who lived in the 6th century BC.
And Pythagorus suggested
that the universe is
in a certain harmonious balance
and he called it harmony,
which is balance is frequently
disturbed by disturbing forces
and reestablished by adaptive
forces within the system.
His student, Alcmaeon, called
this phenomenon "isonomia"
which means equal division,
equal parts.
But then, in the end
of the 19th century,
Walter Cannon a famous American
physiologist, extremely intuitive,
called this "homeostasis" or a
steady state also from Greek roots.
So now, we have a certain
balance in us, human beings,
human societies called
"homeostasis," steady state
which is threatened stressors,
which can be physical or emotional,
and is being returned to the usual
balance by the adaptive response.
So, when we say stress, at
least in medicine and I think--
I hope everywhere, is the state
of threatened and in humans,
perceived-- even perceived
as threatened homeostasis.
Okay, so somebody feels
that his homeostasis,
her homeostasis is threatened by
definition he or she is stressed.
Let me just very quickly
go over the development
of the concepts of stress.
As I said, we started
with Pythagoras,
the harmony of the cosmos.
We continue with Alcmeaeon which
said that health is the equipoise
of opposing forces or isonomia.
Em-pedoclis who talked about the
elements and qualities of life,
of the universe which
are harmonious, and then,
Hippocrates himself, who
said that this harmony,
this homeostasis is health
and disease is disturbance
of this homeostasis.
And he was absolutely right.
And he also suggested that
nature heals a disease,
so there is an adaptive response
that will bring the balance back.
The Stoics talk very, you know,
extensively about "ataraxia,"
and ataraxia is the state
of imperturbability
of mind or equanimity.
So, the ideal for a Stoic
was to reach a state
where nothing would really
bother them as much as possible.
Epicurus, who was one of the best
philosophers of the ancient world,
also used ataraxia as the
imperturbability of mind.
But he also talked about "aponia"
which means absence
of pain and hedonic.
And in hedonic, he
didn't mean, you know,
eating or having sex
or anything else.
He meant this state of pleasure,
of bliss that one has
when is equanimous.
He also talked "eustatia" which
means eustasis, good state,
and the Greek name "Eusta--
Eustathius," very common,
which means somebody
who is in good balance.
Thomas Sydenham, the English
Hippocrates in the 17th century,
suggested that symptoms are
signs of a disease arise also
from the reaction of
the patient's system.
And indeed, as you will
see, this is what happens
when somebody is stressed.
They're reaction, which is the
hormonal and other mediators
of the stress response,
are causing the damage.
Claude Bernard, of course, talked
about the "milieu interieur,"
so the homeostasis of
our internal environment.
Walter Cannon talked about
homeostasis and stress.
He also talked about
bodily responses to emotions
and coined the term
"fight or flight reaction."
Now, we know there's
a third reaction
which is a freeze reaction
during stress.
Either way, you either
have to fight or flight
or just pretend you're dead.
Hans Selye, the last of the
great figures in this area,
described the general adaptation
syndrome or stress syndrome.
He said that it doesn't matter
what kind of stress you are in,
if it's chronic enough, it produces
the same manifestations regardless
of the original stressor.
And he also talked about disease
or adaptation, and Phil Gold
and I believed that a lot of
human pathology are disease
or adaptation, stress disorders.
And he also talked about bad stress,
distress and good stress, eustress.
And that's also correct, there is
bad stress and there is good stress.
Now, the fact that
there is a balance
in our body was mentioned
initially by Epicurus.
I just did not go over that
because I already mentioned it.
But there was another physician,
Asclepiades of Bithynia,
who suggested and I think I have
find this amazing, the human consist
of a molecules that are made
of atoms and void spaces.
That's exactly what we are.
And diseases are caused by
alterations of form, position,
or free flow of a patient's
molecules.
Okay, so he predicted
molecular disease,
genetic disease, and so forth.
Now, since we're talking
about complex systems
and stress is a concept that's
currently linked to complex systems,
let me mention that humans are the
most complex system we know of.
And the reason we are so complex is
because we have not only 23,000
zincs and 3 billion bases
in our DNA, but also, we have a 100
billion neurons in our cortex and 10
to the 18th power synapses
in our brains.
So if you calculate the complexity,
it is something amazing
more than the galaxy.
Now, we consist of units
which can be molecules,
gene, cells, et cetera.
Networks because these
units can form networks
and the stress system is
such a network basically.
We have programs and we have in
our body hardwired several programs
and the stress program
is one of them.
And finally, we have
systems within systems
and within systems
and it goes like this.
So what are complex systems?
They're self-organizing.
They have multiple interactions.
They adapt through feedback loops.
They are resilient to
perturbations up to a certain point,
and they have emergent properties.
So, as to say, for example, from
the planetary system emerged the
biosphere on earth.
And from the biosphere
emerged life and life--
from life, man and from man,
intellect or civilizations.
So, there's a series
of emergent properties
that basically talk
about complexity.
And here is such a complex system.
And what humans are, are systems
with in this complex system.
So, we are small complex systems
within a larger complex
system which is the biosphere.
And our own complex systems
interact with each other.
And that's what-- this
is called empathy.
[ Pause ]
Interestingly and that's
mostly for physicist,
we are open thermodynamically
as a system.
We have, however, an
organization of closure.
Oops, excuse me.
We have-- we generate and
sustain a relation and identity
under precarious conditions
and bring forth a meaningful
environment.
And some basic stuff in us
is the will for survival
of both the individual
and the species
and that's an end on its own.
Now, we also form a very complex
system as human societies.
And here, I mention the mirror
neurons and the spinning
or Von Economo neurons
that are responsible
for the feeling of empathy.
In other words, understand how
somebody else feels emotionally.
And Charles Darwin was the first
to talk about the beginnings
of empathy, which he
considered the love of a mother
to a child and vice versa.
That's the beginning of empathy.
You start caring about an
individual and that is extended
to their partners, to the
siblings, cousins, society overall.
So what he had said is that animal--
any animal, whatever and that
would well mark social instincts,
the parental infelio, affections
here included would inevitably
acquire a moral sense of cons--
or conscience as soon as its
intellectual powers had become
as well or nearly as
well developed as in man.
[ Pause ]
So, Frans de Waal in
a beautiful article
in the Annual Review
Psychology 2008 suggested
that moral instincts had
their beginnings in circuits
of emotional contagion or empathy.
And indeed, that's the
way it seems it's worked.
Now, another scientist from
Harvard, Sezon [phonetic],
has an evolutionary idea about
the cosmos and how we move
into ever increasing
power densities.
And just remember the concept
that as we-- as we develop--
oops, I'm doing something wrong.
[ Pause ]
No, unfortunately, it doesn't work.
But it's okay, I can explain it.
The power density is on
the left, and time in years
to several powers is the axis side.
And what you see is
that as they work,
the world becomes more
and more complex.
And as the power density increases,
things are happening much,
much faster in lesser time.
And right now, with societies,
we are at the highest possible
level of power density.
Now, both Walter Cannon and
Hans Selye used the Hooke's Law
of Elasticity to make people
understand what is meant by stress.
And what is that?
If you take a metal rod and press
it in the middle, the rod will bend,
and the more power you
put, the more it bends.
So if you express that as a-- an
equation here, you'll find that up
to certain point, it's
straight line.
So, you take the weight again or the
power and it goes back to normal.
So that's homeostasis, nothing
bad is happening to you.
But beyond a certain point
which is called the yield point
or tipping point, the
system starts breaking down.
And it never goes back
to where it was before.
And that is a state which
corresponds to human chronic disease
and has been called
"allostasis" or more correctly,
it should called "cacostasis."
It's a bad state, dynamic
state that the results
in earlier death for the individual.
And of course, there is a fracture
point at the top where its,
you know, the organisms
broken down completely, death.
Now, let's say somebody is in
an abnormal basal homeostasis
and something happened
to that somebody.
So, the straight line,
where in our homeostasis
and then a stressor occurs,
which can distressed or eustress.
And then, the adaptive
response kicks in
and the individual goes back
into its normal homeostasis,
in the middle, so that's eustasis.
Now, some individuals will never
go back to their normal state.
Example, PTSD, posttraumatic
stress disorder,
they are not the same
people afterwards.
So, this is deteriorated
homeostasis or cacostasis.
And of course, there
are people who benefit
from stresses especially
eustress such as exercise.
And their curve goes even higher and
we call this hyperstasis, you know,
a state that's well above, you
know, somebody's homoeostasis.
And then as we really
don't understand,
don't realize all the stressors
that are around us such as noise,
daily hassles, and so forth, we
don't realize that we're stressed.
But some people are negatively
affected for long times,
so the line goes down, and some
people are affected positive
for a long time and
the line goes up.
There is and so a beautiful
study comparing New Yorkers
to people in a smaller town.
And basically, New Yorkers
had high cortisol levels.
And I can understand that.
They're line was above the
usual homeostatic line.
Then another important
concept, one deals with all
of these complex systems
especially the homeostatic mechanism
of a complex system, is
everything in moderation.
And that's how this system's work.
They work best somewhere
in the middle,
you see an inverse U-shaped curve.
So, while we're in the
middle, we operate the best.
When it's too long, it's in
cacostasis, at deficiency.
When it's too much, it's
in axis, also cacostasis.
So we have to be somewhere
in the middle
and I'll give you the
example of arousal.
If you're under aroused,
you don't feel well
and you don't function well.
If you're properly
aroused, you do your best.
And if you are extremely
aroused, you have anxiety
and you don't operate well.
And that's true for all the
homeostatic systems in our body.
Now, human stressors can be anything
that will disturb our homeostasis.
And I'll start from daily
hassles, life transitions,
the life of a woman for example with
its various transitions, natural
and unnatural catastrophes,
starvations, excessive nutrition,
deficient exercise, excessive
exercise, obesity, job lost,
downsizing, loss of control,
bereavement if you lose somebody you
love, taking care of sick patients,
and here, we have patho--
we can pathologic empathy which is
quite stressful for an individual
or unprincipled compassion.
We'll say a few words about that.
Then addiction, use
of toxic substances,
all kinds of inflammations,
traumatic infections
or immune allergic, anxiety
depression and personality disorder
from a psychiatric point of view,
and even sleep deficiency nowadays
as our society sleeps two hours less
a day than these people in the '70s.
What is empathy and I
mentioned it several time.
Empathy means feeling
inside somebody else.
"Em" means "in" pathy.
And there is also sympathy which we
use when we feel bad about somebody
and we sympathize, and apathy,
where we don't feel anything.
Compassion is sympathy plus action.
And principal compassion is
beneficial or at least harmless
for both the caring and the cared.
Okay? So, on principal
compassion is very stressful.
And for physicians, nurses
and other people who take care
of people, that's very important.
So you have to be compassionate
but you shouldn't damage yourself
or the patient in this context.
And the other thing that's important
is that all of these stressors
when they occur together,
they are synergistic.
They produce a lot of
disturbance if you add them up.
And let me just say that there are
critical periods of life with such
as the prenatal life,
childhood, puberty,
and remember that the human
brain ontogeny is complete
at 25 to 27 years.
So the final connections of
the prefrontal and frontal lobe
to the rest of the brain are
complete at 26, 27 years.
So, during these critical periods,
hormones can have organizational
effect.
That means effects
that are there forever.
And such hormones are the stress
hormones such CRH which comes
from corticotropin-releasing
hormone, glucocorticoids
such as cortisone as
well as sex steroids
and cytokines of the immune system.
These hormones can have
permanent organizational effects
on the-- in the body.
And it's interesting that Leo
Tolstoy in the 19th century wrote
and he's absolutely
right, from the child
of five to myself is but a step.
But from a new born
baby to the child
of five is in a falling distance.
And why is that?
Because at three years of life,
we have the maximum number
of synapses in our brain.
And after that they,
start going down.
The circuits that remain present and
alive are the ones that are used.
The ones that are not used
are pruned, taken away.
So, depending on the environment
of a child that is important age,
zero to five years of life, will be
there for that individual forever.
Now, what are the homeostatic
systems that we have in our body?
Well, we have amygdala which
control fear and anger,
the mesocortical limbic system,
MCLC, which is the reward
and punishment system, feeling
well when you do good things,
feeling bad when you do bad things.
The stress system where I'm going to
concentrate, the metabolic system,
the immune, the fatigue and pain
system, wakefulness and sleep,
very important and the clock system.
And in fact, the stress
system influences everything.
And at this point, I'd like to
mention again, the prefrontal
and frontal lobe which serves
higher functions for us
such as interpretation of
the environment, social cues,
problem solving, planning
for the future,
and proper control of impulses.
So, this is really
what makes us human.
And in fact, the prefrontal
and frontal lobe, the logus
or the logic are our
best homeostatic system
that has allowed us to survive
and prevail on this planet.
Now, let me go to stress mechanisms.
The stress system that I'm talking
about is a heuristic concept.
In the brain and the
hypothalamus, we have two nuclei
that produce CRH and vasopressin.
These are the two central
stress hormones.
Those go to the pituitary, the
co-secretion of ACTH, corticotropin,
and [inaudible], it
goes to the adrenals
and causes secretion of cortisol.
The other part of the stress
system is the locus coeruleus,
that's in the brainstem,
the back of our brain.
And the norepinephrine system
and the locus coeruleus
in our nervous system are
responsible for arousal
and for sympathetic and
parasympathetic activity.
So, the peripheral component of the
LC immune system is the sympathetic
and parasympathetic
system, and of course.
the adrenal medulla that
produces epinephrine.
Now, are these central systems
communicating with each other?
And the answer is yes.
They innervate each other.
So you have fibers--
nerve fibers from the CRH
and the hypothalamus going to
all the way back to the brainstem
to stimulate the brainstem neurons
that secrete norepinephrine
and vice versa.
Norepinephrine stimulates CRH so
we have a positive feedback loop.
And in our organs, there aren't
many positive feedback loops,
but then once we have,
are extremely important
for survival, and that's
one of them.
Now, if you-- you don't need to
remember this, just to remember
that [inaudible] complex system,
it interacts with other
systems in the brain.
And it has its own feedback loops.
There are negative feedback
loops that control it.
And one of the most
important feedback loops is
from the GABA-based diazepam system.
If you give Valium, that
system is suppressed.
And that's because GABA
regulates the system negatively.
Also, there are interactions
with the cholinergic system,
the serotonergic system,
with oxytocin, and of course,
within mesocortical,
mesolimbic system
and the amygdala and hippocampus.
So, the stress system sits
in the middle in the body
and affects development,
behavior, growth, immune system,
the clock system, and
work [inaudible]
and sleep very important, the
reproductive system and finally,
participates in our aging.
So it's a very central system which
helps us but also can damage us.
And if I put it again in a
simpler way here, I'll just mention
that here on the left
is the HPA axis,
hypothalamic-pituitary-adrenal axis
and on the right is
the sympathetic system.
And you'll see that in the amygdala,
that center for fear and anger,
the neurotransmitter is CRH,
it's the same one that's
in the hypothalamus.
And actually, there is second
positive feedback loop there,
where the amygdala stimulates the
[inaudible] system and vice versa,
also feedback important
and also something
that needs to be controlled.
In the periphery, we'll
produce not only cortisol,
we also release oxidized
cortisol whenever we're stressed,
but they also produce
norepinephrine and epinephrine.
And also produce from the same
peripheral nervous system CRH,
the same one that's
in the hypothalamus.
And in the periphery,
CRH is proinflammatory--
acutely proinflammatory
causes inflammation.
And then both norepinephrine
and epinephrine stimulate
during stress a hormone
of the immune system which
is called interleukin-6
which is proinflammatory hormone.
So you realize that
when you're stressed,
you produce not only hormones
that you know that are stressful
but also others yet
that you don't suspect.
Now, I have this-- again,
it's for me to just explain
to you the general principle.
The stress system interacts
with these four other
systems in the brain.
Now all together they
form a circuit.
So if you affect one part of this
circuit, you affect the others.
And here, I have the example, the
stress system is at the bottom.
So it's secretion of cortisol,
catecholamines in IL-6.
And then there is the
positive feedback loop
with the amygdala stimulating
each other.
There is positive stimulation
by stress
of the reward system,
the MCLS, reward system.
So whenever we're stressed,
we stimulate the reward
because otherwise,
we won't do anything.
We'll abandon any effort.
Okay, so we need to stimulate
the reward in stress.
And then, we have the
hippocampus which is important
for intermediate memory which is
also the break of a stress system.
So the hippocampus sends this
GABAergic inhibitory effect
on the stress system.
So you can see that if you
damage any of these four parts
of the system, you will damage
the others because they're
so highly interlinked
with each other.
And here, too much to see
but I'll just tell you this,
we know exactly what stress
is doing to our reproduction.
It causes hypogonadism.
In other words, it decreases
our reproductive capacity
from libido all the way to
the levels of the hormones.
It inhibits growth,
so it's stress child
for as long as stress stops growing.
It affects the thyroid
system which is responsible
for the bearing of fuel in our body.
So, it suppresses that.
And finally, has a very complex
interaction with the immune system.
So, when we have an immune response,
the stress seems activated whereas
when the stress is deactivated, the
overall effect is antiinflammatory.
So, when we're stressed, our immune
system doesn't work very well
because innate immunity and adaptive
immunity part of it are suppressed.
And I'm coming back to
inflammation stress.
Inflammation is extremely
important as you see soon.
We have recognition
receptors in our cells--
all of our cells which actually,
when they recognize a foreign
substance or a substance
that is injurious, it activates
special proteins inside the nucleus
that cause the cell to be inflamed.
And acutely, this is
an adaptive response.
Chronically, it's not adaptive
chronic inflammation in our cell,
and it's actually carcinogenic.
Now we know that chronic
inflammation also is important
for oncogenesis, cancerogenesis.
Now, these are the various
inflammatory injurious agents
from microbial products,
to intracellular molecules,
to denatured molecules.
For example, oxidized molecules
produce inflammation in our cells,
add toxins, it doesn't matter,
and either that's injurious
will activate the system.
And here, I have the example of
larval polysaccharide which is part
of the wall of a gram-negative
bacterium, which actually,
for specific receptors,
patho-recognition receptors
activates inflammation in the cell.
And once that happens then you start
producing inflammatory cytokines.
And the first one that's
produce is TNF-alpha,
tumor necrosis factor-alpha,
the second IL-1, IL-6.
It's a cascade of events and the
end result is the cytokine circulate
in the blood.
And what they do is that they
activate the entire immune response
in the nucleus.
So this transition
factor [inaudible]--
you can see it very well.
It doesn't matter.
It grows in the nucleus
when activated
and activates all the genes that
are responsible for inflammation.
And in fact, some of this--
the products are the inflammatory
cytokines that come back
and activate the cell again.
So this is a third important
positive feedback loop
and there is one more
in the reproduction
for extremely important positive
feedback loops in our body.
Now, whenever we are inflamed,
there are four programs
that are activated in
our body and brain.
The first program is called sickness
syndrome or sickness behavior.
This is how we feel
when we have a flu.
The second is the acute
phase reaction.
You recognize physicians look
at-- see the active protein.
That's an acute phase reactor.
The pain and fatigue
neuro [inaudible] program,
and finally, the stress program.
So, you get the first three
and once the cytokines go
above a certain level then you
activate the entire stress program,
which is responsible for
helping inflammation on one side
but also blocking inflammation
on the other.
Absence of cortisol means
increased inflammatory responses,
causes you to be just right
to prevent inflammation
from overshooting.
So, this is four different networks
and four different
programs that are activated.
There is overlap among
themselves, however,
one should see them
as highly interlinked.
Now, we know that in sickness
syndrome, when the program
of sickness is activated, in our
brain, cytokines are either crossing
in the brain or produce
locally in the brain or both,
and the end result is to
have this sickness behavior.
We know exactly what happens
to the various neurotransmitter
systems and support.
It's an adaptive response of when
we are stress by inflammation,
you have to stay in bed and
wait until you get better.
You don't want to waste
the resources anywhere else
and that's exactly this program.
So let me now go to effects
of stress on the organism.
And let me mention that time is
extremely important when it occurs,
okay, especially, if it occurs
during the critical periods of life,
prenatal first five
years and adolescence.
Second, acuity, acute stress can
trigger some pathologic responses
and chronicity.
And unfortunately, this didn't
come out but it doesn't matter.
During critical periods of life when
you're stressed, let's say in utero
or the first years of life but in
entire life, but here is more--
the early one here,
much more sensitive.
You get the so called
epigenetic changes.
In other words, you change
forever the activity of genes
by methylating the regulatory areas
or the structural areas
and so forth.
So, somebody who is exposed to
stress early in life is bound
to have changes that will be
there for the rest of their life.
That's called epigenetic
and it's base--
it's a basis of all these changes.
So now-- so let's go to acute
stress and then chronic stress.
Acute stress and acute stress
response can cause asthma--
precipitate the asthma, eczema
in the skin or urticaria.
It can precipitate migraine
headaches or tension headaches.
It can precipitate gastrointestinal
pain and actually, in children
and in women, this is the most
common psychosomatic complain.
That they go to the
doctor, they're anxious,
and anxieties somatisized
as abdominal pain.
It's basically the stress
system stimulating the GI system
in the abdomen.
You can have a hypertension episode.
And if a host is compromised
and by the atherosclerosis were
examine all the race and so forth,
one can have a cerebrovascular
accident or even die during stress.
Also, one can have a panic
attack during stress.
Also, we have-- we can have
cardiac ischemia, an MI, arrhythmia,
death again in a compromised cause.
And finally, people who
have the right genetics,
you can precipitate
a psychotic episode.
Now, this is what stress
is doing to inflammation.
Nerve cells from our peripheral
nervous system produce CRH
which is the dark area.
So if you look an inflammatory
site, it's just full of CRH.
And what does CRH do there?
It degranulates mass cells.
These are cells that have
sit local in our tissues,
and when they're activated by CRH,
they secrete cytokines, histamine,
et cetera, and influence
local inflammation.
So, the key factor in the way
acute stress influences the
inflammatory response.
And it is how stress
influences the GI tract.
On one hand, CRH inhibits
the vagus nerve
and we have a decreased gastric
motility and indigestion.
Typically, you know, you feel full
if you're stressed,
you don't digest.
And then, on the other side,
CRH activates through the LC
and the neuron, the second
of parasympathetic system
to increase colonic motility,
and that's irritable bowel
syndrome is within that context.
Now, what are the chronic effects
of stress system malfunction?
Let me go first to behavior and
say that early effects hit right
at the locus and at the
self-regulatory system.
People who are stressed early in
life frequently are not able then
to regulate their impulses.
So they're impulsive, they don't
realize the long-term consequences
of their acts, and
do negative things
and that gets them into trouble.
Fear and anger is activated
at that system and the reward
and punishment is activated.
Also, the cardiovascular system, the
metabolic system, the immune system,
pain and fatigue system and sleep,
they're all affected by stress.
And let me hear I mention
what are the chronic effects
of stress system activation.
It causes anxiety, depression,
addiction, antisocial behavior,
psychosomatic disorders,
fatigue and pain.
It causes loss of weight and
poor growth or it causes obesity
and a metabolic syndrome, and
I'll say a few words about this.
It's also associated
with smoldering,
low grade systemic inflammation,
immune dysfunction, atherosclerosis,
cardiovascular disease then
osteoporosis, chronic stress
through cortisol and IL-6 causes
osteoporosis in our bones.
It also causes premature aging
of all valuable organs
including the brain,
that's neurodegeneration,
and the skin.
And finally, increases vulnerability
to infections and cancer.
So, if you look at these
disorders, you can see that most
of them are the so called
chronic non-communicable diseases.
These are the diseases that
curtail our life expectancy.
This is the problem
of the world now.
It's not the infectious disease
that is the worst in the world,
it's the chronic non-communicable
disorders
and they're all influenced
by stress.
And again, I'm going back to this
circuit that I showed you earlier
and would believe that somebody
when they're stress hyperresponsive,
they have a large stress system
that's activated robustly.
They have a large amygdala
so fear, anger, et cetera.
They have decrease hippocampus and
actually, you can see that on MRI.
You can measure the size and
its decrease, stress people,
and a decrease mesocortical and
mesolimbic system, reward system.
So this is a perfect combination for
somebody who is stressed, anxious,
doesn't feel well, and not control
their impulses and so forth.
Now, what happens during
chronic stress?
During chronic stress, if you
measure cortisol and IL-6,
et cetera, you'll find
that's elevated.
And for cortisol, we missed the
boat for many years because we saw
that somebody-- when
somebody is stressed,
they produce not much more cortisol,
a little more than normal, okay?
Everyday though for years, but they
produce it during the evening, okay?
So if you look into the top curve,
the interrupted line is somebody
who's chronically stressed.
Cortisol is high in
the evening at the time
when it should be undetectable
in somebody
who is chronically stressed.
And when that happens, it's
recently found unpublished.
It is when the sensitivity of
our tissues to cortisol are--
is elevated in the evening.
This was known by physicians
who treat with low corticoids.
But now, we know exactly why
that happens is the receptor
is diacetylated in the evening
and it's much more sensitive.
So even small elevation of
cortisol over time in many years,
it will cause the effects of
hypercortisolism, which is--
you may refer to it
as Cushing's Syndrome.
And also, the other thing
we need to remember is
that various stressed will
produce cytokines such as IL-6.
So, non-inflammatory stress is
associated with hypercytokinemia,
high immune function proteins,
cytokines which stimulate
inflammation.
And then I'm going
to say a few words
about obesities especially
visceral obesity and aging.
If you put somebody's body
mass index, okay, and--
against levels of Interleukin-6
or TNF-alpha,
these are two very powerful
inflammatory cytokines,
you get a positive response, and
[inaudible]-- positive correlation.
So the more busy you are, the more
cytokines you produce, therefore,
the more systemic low level
inflammation you have.
And that goes together
with the elevations of IL-6
that occur during chronic stress.
So, if you're obese and you're
chronic, it's about combination.
Now, in this slide, I'm just
summarizing everything I said.
Basically, based on our-- dependent
on our genetic variation, our genes
and our developmental history, how
much stress we are exposed earlier
in life and how much stress we
are exposed to now, currently,
and it does not need to be a real
stress, can be perceived stress,
and on the base of what we
eat, nutrition and on the base
of our age, we hypersecrete
cortisol, norepinephrine,
epinephrine, and interleukin-6.
We hyposecrete other
important hormones for growth
and the end the result is
to collect visceral fat,
fat inside of our abdomen.
Why is that?
Because cortisol stimulates glucose
and glucose stimulates insulin.
And insulin together with cortisol
are very potent growth factors
for the fat in the abdomen.
This is the fat that causes the
damage, okay, the visceral fat.
You may have heard the words also,
insulin resistance, the same thing.
And also, somebody who's
chronically stress, loss muscle
and bone, lean body mass.
So the under result is to have
insulin resistance, dyslipidemia,
dysregulation of our blood.
For people who are
genetically sensitive
to polycystic ovary syndrome,
women that they can develop PCOS
and osteoporosis, of
course, sleep apnea.
And the key thing is that why
we live briefer life if we're
in chronically stress
is because our cytokines
and other hormonal mediators
influence our endothelium,
the layer inside are vessels.
So if you activate endothelium then
that attracts white cells there
and the start formation
of plagues and so forth.
That means atherosclerosis
and perivascular disease.
In the United States and
the rest of the world now,
we know that the curve
of body mass index
of Americans has moved to the right.
So, we're now much more
obese than we used to be
which is the red curve is moved to
the right over a period of 30 years.
And now, we know that one third
of the Americans at the age
of 55 have metabolic syndrome--
a full metabolic syndrome,
dyslipidemia, hypertension,
et cetera, diabetes type 2.
And one third have
possible metabolic syndrome
and only one third are healthy.
And I believed that
to a great extent,
this is due to chronic stress
that has not been managed
well for a long time.
Sleep apnea, that's also--
depends on the amount of
visceral fat in the abdomen.
These are the formation of plaques
through activation
of the endothelium.
And finally, let me say
a few words about stress
of our cells, cellular stress.
Every cell when we're stress,
our body is stress as well.
And there are three types of
stress that are pertinent to this.
One is mutational stress, if
you eat too much or too little,
so too much food, too little
food, inflammatory stress,
injurious agents, and
oxidative stress,
production of oxidant radicals
in our cells by the mitochondria.
So, in fact, nutritional
nowadays, it's insulin resistance,
what I mentioned before,
inflammatory [inaudible]
specific agents inside the nucleus
of the cell and oxidative
through the mitochondria.
When our-- at the colon [inaudible],
epinephrine, norepinephrine,
they stimulate mitochondrial
functions,
sugar produce oxygen radicals.
And chronic cortisol
elevations cause
by genesis of the mitochondrial.
So you have more mitochondria,
somebody who is stressed
and produces more oxygen radicals.
Now, how about our telomeres, do
they-- are they affected by stress?
Telomeres are little pieces of DNA
repetitive that sit at the edge
of our chromosomes and
protect our chromosomes.
And in somatic cells, there's a
limited number of duplications
of cells that can occur up
to about 30 duplications.
And every time the cell duplicates,
it loses some of the
telomere length.
Now, look at this study.
It shows that the more
obese you are,
the more metabolic
problems you have,
the smaller your telomeres become.
So, in fact, now we know
and Dr. Wadhwa will say more
about this later on that stress
decreases telomere length
and therefore, directly
influences our age-- our aging.
And I've been impressed
of how quickly people
who have chronic stress
age such as parents
of children with autism for example.
I've seen it my department where
you see them a few years later
and they look much older.
And that's because day and night,
they have a chronic stressor
to damage their body.
So, stress metabolic syndrome
and depression, Dr. Gold is going
to talk about that, are
tightly linked to each other.
They go together very frequently.
And inflammation sleep
disturbances and fatigue is part
of all three of these conditions.
And we know why, we know the
mediators that are affected.
And actually, I just mention
it as an interest thing,
drugs that improved our
life expectancy belong
to either anti-stress drugs such
as antidepressants, beta blockers,
converting enzyme inhibitors,
angiotensin II blockers,
anti-inflammatory agents
such as omega-3 fatty acids,
unsaturated fatty acids,
[inaudible] agonist,
and anti-oxidation molecules such as
fiber astringents and sulforaphane
and insulin as digestion
agents, [inaudible], exercise,
use of metformin, et cetera,
and finally anticoagulation,
antiplatelet agents.
So, we can now prolong the life of
an individual by using these drugs
and we know that is happening in
the United States and elsewhere.
So let me finish here and
open the floor for discussion
and we have enough time for that
with something that Aristotle wrote.
He wrote that the soul suffers
when the body is diseased
or traumatized while the body
suffers when the soul is ailing.
And indeed, this is true.
Thank you very much.
[ Applause ]
[ Inaudible Remark ]
>> Do we have any problems
or questions?
>> I have a question.
>> Sure. [Inaudible Remark]
Hereditary side of stress?
Yes. [Inaudible Remark] I heard it.
So, you're interested in the
hereditary side of stress.
[Inaudible Remark] The question is
how hereditary is a stress response?
>> Yes.
>> Yes. And the answer is to a
great extent, it's hereditary.
You know, there are some people
who have the right genome,
right combination of genes
that make them more responsive
to stress than others.
This doesn't mean that
it doesn't change.
It's irreversible.
It changes depending
on our early life.
So you can take, Dr. Jerome
Kagan had done these studies.
You can take a child
who is very stress,
the so called inhibited child,
put them in the right environment
and they become outgoing
and productive and so forth.
So, now, we tend to think
that heredity is important,
but environment appears to be
more important than heredity.
[Inaudible Remark] Dr. Rosenthal.
[ Inaudible Remark ]
>>Yeah, of stress, are
they hereditary themselves?
Is there any evidence that
the epigenetic changes can
be transmitted?
>> Let me tell you
that both genetics
and epigenetics are influenced
in a major fashion by stress.
So, our species went
through stressors
and we are who we are genetically.
We have the tendency
to get obese, you know,
to get anxious and so forth.
This is because we went through
those bottlenecks of genetics.
But in epigenetics, the majority
of epigenetic effects are
not transmissible, there--
for the ontogenies, for the
life time of an individual.
However, some of them
do get transmitted.
For example, you may have heard
the famine of Holland where now
for three generations
that they found
that children are more
prone to metabolic syndrome.
Three generations, which means they
obtain this epigenetic vulnerability
that lasted long.
So the answer is that some
of the epigenetic effects
do get transmitted
for generations, but very few.
>> A second question was that a
sort of correlations between stress
and telomere, if-- oh no,
sorry, the telomere effects,
I think it was a body
mass index or some--
>> Yeah, body mass index or about--
[Simultaneous Talking] Yeah, yeah.
>> The graphs you had up there.
>> Right.
>> Since you show about a 0.3
correlation which would suggest
like a 10 percent variance
accounted for,
now that's not trivial
but it's not huge so.
>> Thank God, yeah.
>> Thanks so much.
>> So let's used what is there.
And of course, it depends
on the amount of stress
that somebody is exposed.
This is a general population
that you would so.
[ Noise ]
[ Inaudible Remark ]
>> I think we're interested in
the implications of what you said
for circadian rhythm dysregulation.
That was implicit but I want
if you could say a little more,
we're use to thinking of
stress equal in cortisol
and which you point out is cort
elevations may not be all that high,
but when they occur,
it's very important.
So the deacetylation of receptors,
the increase in the evening but I--
you mention sleep apnea, but I
want if you could say a little more
about the effects of stress on
dysregulation of circadian systems.
>> Stress doesn't really change
the phase of the circadian rhythm
but it leads to production
of hormones such as cortisol
that are slightly elevated
in the evening hours.
Now, the glucocorticoid receptor
is high acetylated by clock.
This is the transition factor that
regulates the circadian rhythm
which we have in all of ourselves,
not just in the brain, everywhere.
So in the morning, he's
acetylated and doesn't feel--
sense cortisol very well.
In the evening, he's
deacetylated most likely
by an enzyme called serotonin.
I don't refer of it-- that's
where risperidone will presume
of the act from red wine.
So serotonin deacylates
the receptor,
and in the evening,
he's very sensitive.
So, if you have chronic
stress or if you travel
across time zones frequently or if
you work shifts alternating between,
you know, three or four weeks
and so forth, the end result is
that your tissues are
exposed to too much cortisol.
And you develop everything I said
from that including
visceral fat accumulation
and with all that it entails.
[ Pause ]
[Inaudible Remark]
>> I feel but it isn't.
So this maybe a naïve question.
But I'm getting the idea that a
lot of stress is not very good.
Is there that corollary where amid
to a little stress is also not good
and what does that imply
for the middle, the mean?
>> I'm glad you mention that.
Now and it's very recent, we
find that not having stress
at all is not good, yeah.
So eustress that Hans Selye
talked about is what we need.
So, some stress, not excessive to go
beyond our capacity to deal with it,
but not missing on the other side.
So again, we're back in
everything in moderation.
We need some stress to survive,
too much is bad, too little is bad.
[ Inaudible Question ]
Unfortunately, everyone
is different.
Each one of us is different.
So we'll have to define ourselves.
Generally, if you-- if you'd
excessive stress, you know it.
You become dysphoric.
If you say I feel stress,
you are stress by definition.
So your own reward
system will tell you
that you're doing something
bad that you need to change.
>> It seems like every month we're
having new findings on the impact
of the microbiota,
everything colonizing,
everything from the gut to the skin.
What do we know about the impact
of stress upon this
systems [inaudible] sort
of the feedback loops there?
>> I don't know that we
know anything about it.
And I-- as you probably mentioned
that microbiome is
still important for us.
You know, it's a symbiotic and
helps us more than damages us.
And I'm sure in chronic
stress, there will be changes
because they got functions
affected, you know,
glucose function is affected.
There are several functions
that will be in interaction
with the microbiome in
the gut or the skin.
So, I believe there's going
to be a lot effect but nobody
to my knowledge has studied it yet.
Dr. Smith [phonetic].
>> Yes. Well, very nice
presentation and very complete.
I just want to comment a little
bit about the role of diet
because there is no
question that account diet.
Particularly, in Western
cultures is extremely high
in omega-6 fatty acids
that are pro-inflammatory.
And there is very good evidence
that the omega-6 fatty acids
for example, shorten telomeres.
And that the telomeres are
definitely shorter in patients
who have coronary heart disease.
But if they have a balanced amount
of omega-6 and omega-3 fatty acids,
they have less severe disease, and
the telomeres are not as shortened.
Now, the-- since the current diet
is very high in omega-6 fatty acids,
in essence, it is a
pro-inflammatory diet.
And it showed very clearly
the role of inflammation in--
and the effect on the stress system.
So that from the studies that
are being done, it seems to me,
it will make a difference.
There is part of the
individuals or populations
on their background diet.
Because there is very
good evidence in humans
that as you lower the
omega-6 and raise the omega-3
and balance the ratio that you
have lower interleukin, lower TNF,
lower-- you suppress nuclear factor
kappa B, so that this whole concept
of studying stress, I
think it's very important
to consider the population,
the diet of the population,
and maybe somehow, you need to
find a way to evaluate the state
of inflammation of the
individuals of populations
because the results
would be very different.
>> Yes. As you-- you probably
saw I had omega in this layer?
>> Yes.
>> And diet.
>> I did notice that but
and exercise of course.
>> So exercise and proper
diet are key, you know, in--
>> Yeah, I just want to make
a comment in microbiome,
because this is a whole
new field of metagenomic
and there is very evidence that
the population of bacteria varies
with the type of diet that we have.
And then they go through the mucosa
and they influence the inflammatory
response in individuals.
No question about that.
>> Dr. Rosenthal.
>> I just want to mention that
Dr. Robert Schneider over here
and I are going to be talking
tomorrow about the effects of trends
in dental meditation and
not to sort of, you know,
give too much of the game away.
I think it's relevant to this
particular point over here
because what you're saying is
that stress is triggering
a tremendous amount
of physical and mental trouble.
And that we want to try to modulate
that stress in every way possible.
And what we will be showing, Dr.
Schneider on the physical level
and me, on the psychological
level, is that this form
of meditation is well-documented
to be a modulator of that stress
and the actual end results,
the toxic end results have actually
been documented to be decreased.
Thanks.
>> I've seen those studies
and I'm convinced basically
about how it works.
>> Now, I'm just going to mention--
I actually going to present
some brain imaging data
on mindfulness meditation
in a moment.
But, Elissa Epel in UC, San
Francisco following up on telomeres
and aging and stress has actually
demonstrated that even as little
as two months of daily meditation,
which is actually very little,
reduces the aging effect probably,
mediated by reducing stress
as indicated by telomeres
shrinking more slowly.
So, there's clearly
actually empirical evidence
that what we chose to
do, i.e. mental training,
influences our level of anxiety
and reduces the speed of aging even
in telomeres, and telomerase
the enzyme, yeah.
>> Good.
>> So there's lot of rich story.
>> Well, I think if
we're very interesting
to see what Fabrizio Benedetti has
to say later on because it seems
that placebo and nocebo work
partly through the stress system.
So, some of you expect to be good
is associated with better mind
of the HPA axis or
cortisol production.
And when it's something bad
like nocebo, it's the opposite.
So-- and of course,
there are other things
like the reward system
is affected, et cetera.
However, I'm looking forward
to listen to that talk
because we're going to get
a lot of good explanations
about what's happening
just on the basis
of what we expect that happens.
>> Actually, I was very impressed
to a number of years of ago
that someone did a study with a-- on
cortisol, that real time measurement
of cortisol, University of
Michigan, forgetting his name,
but were they'd had continuous
sampling for three hours.
And they simply ask the person
to modulate their moment
to moment cortisol
response every three hours
by shifting how they were
thinking and interpreting.
And a very clear demonstration that
how we think and how we modify,
how-- what we're thinking about,
literally, modulates the increase
and decrease of cortisol
over three hours.
And that was a very
clear demonstration
of thought to adrenal gland.
>> Dr. Chrousos.
>> Yeah?
>> Just to response to that case
[inaudible] effects of stress
on cardiovascular system and
there's one very interesting graph
that they gave the
subject isoproterenol,
which as many people here will
know raises blood pressure,
and everybody's blood
pressure went up.
And one woman's blood pressure
went down, and they asked--
while she was getting
the isoproterenol
and they asked her what
she was doing after this?
"Oh, I just, I took
my usual meditation."
So, it actually counteracted
the effect
of a potent blood pressure
increaser.
>> Yeah.
[ Pause ]
>> Any other comments or questions?
[ Pause ]
>> Is there any correlation
to as too much
or too little according to culture?
In other words, can
you make a general--
this is a really amateur question
but about somebody who's
not very well-informed
about the technical medical side.
But it raises the question, is
there-- quite apart from technics--
individual technics or
individual medical treatments,
are there any broad correlations
in terms of the world's cultures
or the principle national
or linguistic
or however you wanted to find it.
Is there any at all
correlation [inaudible]
who has too much and
too little stress?
>> The answer is we expect
that there is a correlation,
and I can give you, since we have
time, the data from a long term
of study that was done in Italy
by Professor Tiniore [phonetic].
He followed women from a certain
town in Italy for 30 years.
And at the same time, he followed
women from the same community
that went into a monastery
convent and became nuns.
And it's fascinating to
see how quickly women
in town developed not only obesity
but also cardiovascular disease,
hypertension, and many of them
by the end of 30 years had died.
Whereas, the nuns had
just gotten some obesity,
a little bit of metabolic syndrome,
no hypertension, and almost all
of them survived for
a very long time.
So just the atmosphere,
the environment
of the monastery was enough
to change the life expectancy
of these people and
how they manifest it.
So I believe, countries now like
Greece, where there is a lot
of stress, were start
seeing many problems related
to the stress response from a
doubling of suicides to a doubling
of admissions to the
psychiatric hospitals.
And I'm sure, within the next two
or three years, we'll be see more--
we'll be seeing more as far as, you
know, metabolic problems, et cetera.
So the answer is the
environment is key.
And to deal with stress, you
either change the environment
or you change yourself if you
can't change the environment
so that you can cope
or whatever there is.
And that's-- that's
the secret I think.
And we'll discuss tomorrow.
[ Pause ]
>> I'm interested if there have
been any studies on crying?
>> Not that I know
of but there may be.
>> Crying?
Crying-- crying as-- I mean that
there are studies that use crying
as a dependent variables so you show
like sad film clips and you share
to people who are-- who've never
been depressed, people who are--
have recovered from
major depression,
and you look at the rates of crime.
But I think, what do you
ask-- actually, asking crying?
>> Actually in our society, it seems
that women are more
allowed to cry than men.
And I just think it's interesting
to think about how that--
how that's handled and what
the effects of that are?
>> It's an expression of
sadness I guess, yeah.
>> Yeah, I think that this is to me,
one of the most fascinating
unstudied questions
because as a clinician,
we know there's the
phenomenon of having a good cry.
Why don't you have a good cry
and get it out of your system.
It's a very, very well [inaudible]--
I mean, most of us
have had the experience
of crying and then feeling better.
And I think it would
be fairly obvious
that there must be some
neuroendocrine function going
on when we cry that relieves
stress and tension that is
to my knowledge, never been studied.
And I know oftentimes when people
are depressed, one of their most--
the biggest complains
is that they cannot cry.
And I remember having one of
my patients who was depressed
on antidepressant and she
went to her father's funeral,
and her biggest complaint was
that she had been unable to cry.
So I think that this is a sort
of unstudied phenomenon
whereby obviously,
there is sort of exocrine function
of crying is probably correlated
with some endocrine or
neurological functions
that have homeostatic effects
that to my knowledge,
have never been studied.
Thanks.
>> Let me also mention that it's
an opportunity to discuss the fact
that men and women have
different responses to stress.
Generally, women are more sensitive.
Estrogen stimulates both
the CRH gene and the--
stimulates anabolism
of catecholamines.
So, women have a better
stress system
which apparently is very helpful.
But also, women develop diseases
of the stress system more commonly,
more often such as
depression, eating disorders.
And the same is true
for the immune system.
Women have a better immune
system which is less affected
by glucocorticoids
than the system of man.
But again, this-- which is--
this is so good to protect them
from infections and et cetera.
At the same time, it causes the
so called autoimmune disorders,
which is again higher as
presented in women than in men.
>> Hi.
[ Inaudible Remark ]
>> Yes? [Inaudible Remark]
>> Tears are full of
neurohormones said Dr. Gold.
And opiates for example.
>> Is it more than let's say other
fluids such as sweat or saliva?
Because you'll find those hormones
in all the circulating fluids.
[Inaudible Remark]
>> I taught stress management at
American University for number
of years and I had my students bring
in studies as part of the course.
All the effects of stress on
each of the six areas of health
that we study globally
and I'm positive that one
of the studies students
brought in study tears
and the chemical make-up tears
that were released during stressful
environments as well as happy tears,
sad tears, and there was
a chemical difference.
So, I wish I could tell you
exactly the study but I mean,
we're talking thousands that
I've reviewed over the years.
So-- but I do remember that very
specifically because we were looking
at the emotional versus the physical
versus environmental
and the community's--
>> So I'm wondering tears of
joy versus tears of sadness--
>> Yes.
>> -- different hormonal--
>> Different chemical, yes.
>> -- profile?
>> Yes, yes.
It was, yes.
It was a fascinating
study yet, I'm sorry
but I can't recall
exactly which one it was.
>> Wow.
[ Pause ]
>> I'll be men-- I'll be
mentioning tomorrow in our study
of support groups for breast
cancer patients that one
of the things we're--
many cancer patients try
to suppress their fear and/or
sadness about the disease
as though somehow feeling sad
about it will make it happen
more our groups to the opposite.
And we're actually able to show
that we reduce their tendency
to suppress their anger and sadness
and fear and that that was related
to long term less depression
and anxiety.
And the intervention seems to
also have an effect in survival,
I'll be talking about that.
But clearly, it's very
consistent with what you've heard
that helping people directly
express his emotions is helpful.
It's a good stress management tool.
It's not a bad thing.
>> To know-- sorry, I'm curious to
know how the knowledge of stress
and its effect on the disease
being actually practiced
in clinical medicine?
For example, do you
see in the near future
that maybe there will be
bioindicators that can be used
to actually diagnose somebody
that if you have hypothyroidism
which is due to stress
and so that, you know,
the management can
be accordingly done.
>> Well I'm sure that
we will be able to be--
to have sensitive measures
toward the stress response
in the next few years.
Right now, what we
measure is rather crewed
and it's not well individualized.
It's good to study populations
but not an individual subject.
However knowing the level of stress
of somebody will be extremely
helpful on how to deal.
>> Yeah, I will suggest
both the biological
but also the psychological
because in many cases.
As you already mentioned in your
talk, the same exact stress--
external stressor for one person
can cause incredible reactivity.
And for another person who
has a lot of equanimity
or flexibility, it's benign.
So, there's a lot that has to do
with our psychological filters
through which we actually label
something as fear-inducing or not.
No?
>> It's neither.
>> I think there's clinical
applications and you talked
about children, there are many
school systems now in the US
and South America around the world
that are now using meditation
programs as part of their education.
Transcendental meditation
and other programs
and this really affects
the children's development
as you theorized on the stress side
that on the positive
stress management side,
there was improved academic
performance and behavior
and even health parameter.
So, this anti-- this stress
knowledge can be use institutionally
and for health policy development.
>> I totally agree.
[Laughter]
>> It's 10:30, so we have
a break for 15 minutes
for a coffee and continue.
>> Thank you.
[ Applause ]
First of all, just to thank
you very much for inviting me
and I think I hope that this
is really useful, interesting
and provocative to make us all
think and reduce our stress.
Okay, very simply put,
very simply put.
And at first, I wanted to say thank
you to George for laying the ground
on top of which this talk can sit
and making my job a lot easier.
So I thank you very much.
So very simply put and I should
as a disclaimer, I'm trained both
as a clinical psychologist and
also as a cognitive neuroscientist
and I do both and more which you'll
see towards the end of this talk.
Psychological stress, right?
So, it's this ubiquitous problem
that we all experience
and have to deal with.
We have no choice.
And my work really goes across
looking at stress, anxiety, forms--
different forms of suffering,
looking at the brain systems.
The brain systems in which
psychological abilities
like emotion awareness, emotion
regulation are instantiated,
i.e. cognitive neuroscience.
And for today's talk, I study
of many things, cognitive
and behavioral therapy,
the passion or compassion.
But for today, I'm going
to talk about mindfulness,
and all with the clear
intention of reducing suffering,
understanding mechanisms
and optimizing performance
interpersonally, intrapersonally.
So the motivation is the
reality that there's stress.
But more importantly, stress
reactivity and that each
of us have our own unique profiles
and how we respond to stressors.
And the question is how do
we get from stress reactivity
that constrains us, makes
us less able to function?
To the other side of the screen
which is really about resilience,
psychological flexibility,
biological flexibility.
And how do we actually take
responsibility in ourselves
to train ourselves in skills
that make this happen,
make us much more optimal
human beings?
As it's already been
pointed out, stress--
the word stress as opposed to
stressors, Hans Selye in 1936,
Western scientist, the non-specific
response of the body to any demand
for change, any demand for change.
It's a special significance that we,
our minds project and
attach to something.
And that's very a key and then of
course, it causes anxiety, burden,
tension, et cetera, et cetera.
But in response, the other side
of it is it's really the stressor.
Stressors are anything that
cause wear and tear specially
in the hippocampus, but
in the whole person,
on the body's physical
and mental resources.
As it was elegantly pointed out,
disturbs our homeostasis, hence,
I love that you use
the word equilibrium,
the ability to dynamically know
when I am not in a balanced state
and the skillfulness
to bring myself back.
It can be acute or chronic,
external or internal.
So what are the top ten stressors
according to large surveys?
As you can see, childhood trauma,
death of a love one, divorce,
finances, job, health, personal
relationships, chronically ill,
child, pregnancy, danger and
the list goes on and on and on.
So this is simply to motivate
us to get our acting gear
and learn specific skills to be
able to deal with the stressors.
So as this point out, there are
incredibly clear gender differences.
Shelley Taylor, psychologist UCLA
and not many others have clearly
defined that men in contrast
to women relatively have much more
of a fight or flight response.
Think of the amygdala.
So that's a profile for protecting
or defending or saving yourself.
In contrast, women and again,
these are generalizations,
tend to have a very
different response.
Tend and be friend, attend,
pay attention, approach,
connect are very different
mode than most males.
So, we now have something
to learn in--
from women, given up that the
contexts have really changed.
It's no longer lions,
tigers, and bears.
But intrapersonal and intrapersonal
things that causes fear and stress.
So my-- I have-- my day job is that
I worked at Stanford and run a lab
and do lots of research with
incredibly wonderful people.
My night job is that I
teach and work at Google,
which is really refreshing to
have feet, one foot in academe,
one foot in biotech business.
So, I teach there regularly
and here's some data
from 80 Google engineers in Mountain
View, just south of Stanford.
So I'm going to propose, again
this is going back to my team
as a phycologist, perceived stress.
How we react to the
things that are stressors?
A very powerfully influence,
a whole matrix
of other phycological
abilities or qualities.
So look at this.
So people or these engineers
who report high levels
of perceived stress
report much reduce ability
to regulate their emotions,
lower mindfulness scales,
lower social support,
self-esteem, satisfaction with life,
emotional intelligence,
self-compassion, empathy,
are you getting depress
yet [laughs]?
Or an increase rumination, worry,
social anxiety and loneliness.
So this is actually-- think
about it, these are the 20
to 30-year-old super, hyper
intelligent, creative,
innovative people who make
everything on internet happen,
and they're very stress in one
of the best places on
the planet to work.
It's a fantastic place to work.
People are incredibly,
internally stressed to be creative.
So this is-- for this
reason actually,
you'll see that we
developed everything I'm
about to say has been transformed
into a program to help Goolgers.
And now, it's actually
going beyond Google.
So what's actually happening
when we're in the moment,
so I'm really into mechanisms?
Well, there's something
called amygdala highjack.
When the amygdala,
shown here in red,
within milliseconds perceive
something as threatening,
real or imagined, within
milliseconds, it kicks in
and becomes activated, emotion
detection, this is important to me.
This is personally
salient, kept in gear,
it immediately pings other areas.
The idea of highjack is that
the amygdala which is one
of the most interconnected brains
regions in the human animal, us.
Actually, within milliseconds,
influences all
of the higher order
cognitive abilities,
the higher functions is
the word that George used.
So within milliseconds, our ability
to focus our attention can be
highjack, disturbed, interrupted,
redirected, the ability
to think clearly.
Cognitive perspective
taking the key to empathy,
compassion for social
behaviors can be unended
or undermine within milliseconds.
Decision making, completely
influenced by activity
in the amygdala within milliseconds.
So the amygdala, wall
street on the floor,
people who have been driven their
emotions making decisions to sell
or buy or to take advantage
or to be honest.
So the amygdala within milliseconds
is really influencing every part
of our education, every part
of our prefrontal cortex,
our ability from attention
to higher abstract thinking.
So, as it's already been pointed
out, especially, a new focusing
in the amygdala and hippocampus
today and you'll see why.
Within milliseconds, the amygdala
is important for increasing
or decreasing arousal,
for activation
of sympathetic nervous system,
gearing up and getting ready,
behavioral freezing,
which is one to deal
with very acute stress--
stressful situation.
Stress hormones as was elegantly
explained already by George
through the HPA access, and
inactivation of the parasympathetic,
which actually helps
us put on the brakes.
So you lose the ability
to put on the brakes.
So this is obviously a very complex
and as already been pointed out,
one pathway is the HPA through
which our thinking, feeling,
decision making, influences
our releases of glucocorticoids
and specifically, in
humans, cortisol.
And we know that cortisol feeds
back right into the hippocampus
and other parts of the brain.
But especially, the hippocampus,
and I mention that because
that section here in the
beautiful little orange or red,
is that elegant research has
shown that chronic stress leads
to chronically elevated
hypercortisol
and damages specifically
the CA3 field within humans.
And this is important
because it's been related
to impaired memory encoding.
Some people in acute
stress, what cannot encode
and thus cannot retrieve
memories, right?
So you think of trauma, be it here
or in East Palo Alto or in the field
of war, faster cell atrophy,
that's been documented
and impaired long term
memory retrieval
and many other kinds of problems.
But we actually know where this is
happening in human animals in us.
So, one of the questions
is interventions.
Given everything that you've
referred already, what can we do?
So there are many ways to work.
One idea is stress management.
So, can you do the following?
I have so much less stress since
I removed the phone in the inbox,
the computer, the e-mail, the
text messaging, et cetera.
Well, we actually directly
address this,
there's such a thing
as mindful e-mail.
We can or cannot talk
about that later.
But this, of course, is unrealistic.
We have to live in the world and
we have to develop our abilities.
So here is another key point.
How do we shift from
compulsion to choice?
To what extent am I aware
that I have a choice?
To what extent do I
not take the time
to actually see what my impulsivity,
compulsion drives me towards?
So one of the key ideas is how
much does a person need to pause
to be able to become
aware more clearly
of what are the compulsive
behaviors, emotions,
thinking patterns, what
are the actual choices?
And this I would suggest
is directly trainable.
In fact, everything that
we're talking about here,
even modifying cortisol,
even modifying many levels
of the immune system,
the hormonal system,
you can actually modulate
it willfully.
There's more and more evidence.
It's-- and one way is
duh, of course, why?
'Cause this is all interconnected.
So, resilience is one word that
we might consider the ability
to recover quickly,
skillfully from an illness,
from a change, from misfortune.
This can be important
in terms of obviously,
in terms of relationships,
it can be important in terms
of just your e-mail system
changing at work increases cortisol
in everybody, right, for
the next several months
if not weeks-- weeks or months.
But on the other side, what does
it mean, and this is a challenge,
this is more at the provocative
side, to develop equanimity,
buoyancy, elasticity,
psychological flexibility.
And again, I'm going to drive
this point that this is trainable.
And does our culture, does our
current educational system,
mindfulness at schools,
meditation at schools,
actually support the cultivation
of these qualities which will last
and have effects lifelong.
My experience with Google engineers,
computer scientists, MDs, PhDs,
they're incredible high IQ, but
when they show up the class,
they're like, "I have
never been trained in any
of these things that really matter."
The highest level of leadership?
Greater emotional intelligence,
not part of anybody's education.
Not even PhD psychologists.
That's not part of our education,
big lacuna, missing point.
So, but this is nothing new
and George loves this slide.
One of our great, great heroes two
millennia ago, Marcus Aurelius,
Greek historic philosopher,
wonderful book if you don't--
haven't read it, get
it, Meditations.
And really, the point is
that there's nothing new.
If you are distressed by anything,
external or internal, the pain,
physical or emotional or spiritual
is not due to the thing itself,
but to your own estimate of it.
That's the key.
And this, you have the power
to revoke at any moment.
This is called skillfulness,
cognitive reappraisal, reframing,
cognitive perspective taking,
there's a lot of jargon in language
and many, many more
terms but this is--
but the point is, here we are 2012,
everything that we need
already existed 2,000 years ago,
in terms of psychological
health, skillfulness,
mastery of the real research
laboratory, which I was pointing
out as our own body and mind.
You don't need a grant to study it.
In fact, this is the most
important research laboratory.
And the extent to which we
miss that, we're suffering,
and we're stressed, and we
cause other people stress.
That's even more important.
We cause other people stress,
because of our own
lack of doing research.
Hence, when I give
talks, I ask everyone,
please be a scientist of this.
So, if Marcus Aurelius put this out
2,000 years ago, how do we get it?
Well, I worked with James Gross
at Stanford, a psychologist
who is Mr. Emotion Regulation.
So, emotion regulation refers
to many different types
of skills or strategies.
One simple definition
is the alteration
of ongoing emotional
responses through the action
of regulatory processes, blah, blah,
blah, blah, blah, lots of words.
The ability to willfully,
automatically entrain effortful
and non-effortfully
implements strategies that begin
to modify our emotions,
intensity, duration, valence,
amount of arousal, and to be
an expression or suppression.
So it's a whole set of skills
and that this is very important
because I think this is
directly related to the ability
to identify stressors,
stress response
or reactivity, and
then to act on it.
So, there are many stages.
So, the red arrow here refers
to something that happens.
Somebody, say your partner, you come
home tonight, your partner looks
at you with a grimace or an
angry, or a contemptuous face.
Within milliseconds, your amygdala
is firing, your prefrontal cortex
and other areas are
going, "Oh, my gosh,
it's going to be a horrible
night," and how do you begin
to implement different
emotion regulation skills?
Where are the opportunities or the
windows in which from the moment
that red arrow happens, that
event, where there are--
as you can see, there's a whole
range from attention regulation
to cognitive thinking
regulation strategies.
So even on a preconscious
level, we have evidence
that if you train yourself in
certain emotion regulation skills,
they can begin to be implemented
automatically even before willful
or the volitional activation.
That's exciting, but not
happening in most of us.
The next level is attention
allocation.
Where do I place my attention?
How do I regulate my attention?
We have beautiful research showing
that there are clear neural circuits
in which are instantiated
different types
of attention regulation abilities.
But maybe I missed that opportunity,
and then later is emotion appraisal.
My partner is freaked
out so you get used--
you appraise and you evaluate what
is the emotion that's occurring.
I'm scared.
The next level which requires
more skill and we already have all
of these but the whole idea
is how do you refine it?
Cognitive reappraisal,
reframing, changing the meaning
of a specific situation in
order to reduce the toxicity.
My partner had a bad
day, she's upset.
It'll be all right.
I can handle this.
Cognitive reappraisal, changing
the meaning, it's not about me.
Using thinking, language, logic,
different parts of the brain,
mostly the mediodorolateral
prefrontal cortex.
Then there's another
aspect which is suppressing.
Actively, willfully
suppressing, showing your emotion.
In some contexts, that
can be very effective.
If I show my fear, I might cause my
four-year-old to become more scared.
So I will willfully suppress
showing on my face what I'm feeling
in this context for the benefit
of the four-year-old child.
Long-term suppression of showing
emotions, as was already pointed
out in discussion, is not--
it leads to more mental
and physical illnesses as
opposed to cognitive reappraisal
which is a more adaptive
health-promoting form
of emotion regulation.
And then finally, and more
interestingly, more complex
but also more simple, both are
metacognitive strategies for working
with your emotions, and with
stress inducing stimuli.
So there's a whole range of
skills that one can work with.
Very simple model of how this
is happening in the brain.
There's a stimulus.
It can actually be a real
threatening situation.
You get an e-mail that says,
from your boss that says,
"I'd like you to show up in
five minutes in my office."
It might be completely neutral.
It might be real or
imagined and we imbue it
with the power to cause
stress in us.
Within milliseconds, thank goodness,
human animals, us, have been--
have evolved through evolution to
have our brain sculpted in a way
to respond to things that
are personally salient
within milliseconds.
So there's a whole limbic system
that supports emotion reactivity,
emotion detection,
emotion generation.
The amygdala, the insula
et cetera, and we all know
that within milliseconds or seconds,
we can-- our emotions can shift,
our emotional state can
shift to joy, bliss,
happiness, fear, anxiety.
This sends a bottom up signal
to recruit help from other parts
of the brain, shown here in
blue, regulatory systems.
Can I shift my attention?
Can I apply my attention in a way
that might modulate the
ongoing emotional response?
Can I do, can I engage
cognitive regulation areas
that change the meaning or that
give me cognitive perspective taking
and see the situation from
another point of view?
When-- the blue, cognitive and
attention regulatory systems
which are trained through
education and experience,
when they're functioning well,
they exert top-down regulation
to help modify ongoing
emotion reactivity.
When this system is working well,
I suggest that this induces a sense
of confidence, self-esteem,
reassurance to handle any emotion
and I would go even further that
you actually enjoy all emotions
and use it as a source
of information
without being afraid of feeling.
When this system is not working
well, hyperemotional reactivity,
deficient top-down emotion
regulation, this is the basis
for anxiety disorders,
major depression,
suicidality, stress et cetera.
But in human animals,
there are two more bubbles
that really make us
different from other animals.
The notion itself, how we
represent, relate, use language,
and view our self which is
really clearly instantiated
in brain systems that we can
see with brain imaging FMRI,
and also language, how
we-- the kind of type
of self-talk that we engage in.
Now, as a clinical psychologist,
this is of course apparent
in psychotherapy, everyone's
way of thinking, narrative,
how they describe themselves.
From a neuroscience perspective,
there are clear circuits
that show us when a person
is engaged in language,
cognitive regulation,
conceptual self-thinking.
The brain actually, in many
cases, is much more clear
than people's first person report.
In some cases, it's
not, that's a caveat.
So this is one of the
main tools that I use--
that we use in our group MRI,
magnetic resonance imaging,
a beautiful, beautiful
tool, the math
and the physics behind it are one
of the most incredible expressions
of the prefrontal cortex in
humans, it's an incredible machine
that allows us, it's like being
able to get under the hood of a car
and right into the engine.
Getting beyond first person
speech which has so many filters,
letting the brain speak for itself
and show us what it's doing.
So one slide primer of, well,
how do you get a functional magnetic
resonance imaging dependent variable
'cause most people don't know.
So you're lying in the scanner,
not always a comfortable p lace
but you're lying on your back,
and I show you your own
core negative self-beliefs
about yourself.
I'm not okay the way I am, something
is fundamentally wrong with me,
I'm unlovable, et cetera,
et cetera, et cetera,
people's own negative
self-beliefs, and of course,
that gets neurons firing,
circuits firing
and then those neurons are
consuming fuel, glucose, oxygen,
sends a signal downstream
to astrocytes saying "Hey,
open up the arteries, the arterials,
deliver more cerebral blood flow,
blood volume, glucose,
oxygenated hemoglobin to the sites
where neurons are firing."
That's the basis for what's called
blood-oxygen-level-dependent signal
which is the basis
for much of the kind
of functional brain
imaging that we do.
Lots of signal processing and then
you get these cute color maps,
color-coded maps of activity which
you see in Newsweek, Time magazine,
in blah blah blah, and-- but
our work begins at that point.
Now, we become functional
neuroanatomical detectives.
How does the brain activity,
the pattern of brain activity
across multiple regions relate to
the experimental design that relates
to the psychology of the experiment
that relates to the healthy
or clinical sample that relates to
the therapy or meditation training
or aerobic exercise training?
So it's a huge amount of
bringing together multiple streams
at multiple levels and it's very
challenging but it's really fun.
So this is, now, you all know
the dependent variable in FMRI.
So attention, we always begin with
attention because it's the gateway
to all other higher
order capacities,
and I was thinking back here,
the back of my brain has
a little gateway or a door
that allows signals to migrate
to the pre frontal cortex
where thinking, analysis, logic,
perspective taking can happen.
It has many components,
multiple components,
we'll speak about just a couple of
them, it's a very limited capacity,
it's happening in the brain.
And here, I would suggest
that the quality
of our attention is the basis
for prosocial behaviors,
noticing compassionate behavior.
In fact, I'm working on an
empirical data going all the way
from attention, emotion, emotion
regulation, empathy to compassion,
and suggesting that the quality of
attention is the basis for the glue
of social interaction, empathy
and even compassionate behavior.
So Tang and Posner, Posner is the
guru of attention, an amazing,
amazing example of a researcher
spanning from basic to clinical,
to social et cetera, educational.
And the question here is, if you
look at this green bar, cylindrical,
the idea that they post is is there
a quality of attention in each of us
that is the basis for
optimal performance?
And how do I know when my mind
is actually gravitating towards
nonoptimal, to a wandering mind.
And this empirical research is
showing that most of us spend most
of our waking hours in wandering
mind, which is associated
with more negative emotions.
On the other side, effortful
training where we're trying
to harness and focus our attention
in a very intense way
leading to mental fatigue.
And the challenge is, to
each of us, as you mentioned,
towards individual
differences is huge.
Am I familiar with what it feels
like when I'm an optimally,
attentionally balanced
dynamic state.
And if I don't know what that is,
I need to learn it, because that's
where you have optimal performance
if you are driving a car,
a therapist paying
attention to a client,
reading a scientific article,
meditating in a monastery,
sitting right here
and paying attention.
So this is essentially
a challenge for us.
How do you get there?
Well, I would say that
about a decade ago,
until about a decade ago, no
respectable scientist, maybe more,
would stand up at an
international conference and talk
about contemplation, meditation, or
even different ways of trainings,
specific aspects of attention
to ancient practices.
And again, nothing is new,
these are already here.
But Antoine Lutz is a
fantastic researcher
at University Wisconsin-Madison,
works with Richard Davidson.
He's done much of the seminal
work in looking at the effects
of different training programs
in both healthy adults
and trained masters.
And really, this is a
very conservative journal
and that they put a statue
of Buddha on the front,
it is really quite interesting,
but there are many ways
of training attention.
And I'm actually going to guide
you through that right now
because in a moment, I'm going
to show you the differential
brain patterns
that you literally are
training like a muscle
through these two different
practices.
So you can actually
sit just as you are.
You might want to just sit up,
and this will be very short.
But I want you in your
own research lab right now
to experience something
so you can help interpret
and understand the
brain imaging results.
So you can have your eyes
or close, but I'd like to--
if your eyes are open,
just bring your gaze down.
Very simply, bring your
attention to the sensations
of your own breath perhaps
at the tip of the nose,
inside the nostrils, simply
harnessing and focusing
with gentle intensity your
attention to notice the subtle
and gross sensations as we
breathe in, and as you breathe out.
[ Pause ]
You might notice the coolness
of the breath as you breathe in,
and the warmth of the
breath as you breathe out.
Notice the quality of your
attention, sustained, focused.
If anyone in mind becomes
distracted, note it
and bring it back to the sensation
of your breathe inside the nostrils.
[ Pause ]
Now, I'd like you to shift to
another form of attention training
which simply is like
opening the lens of a camera,
expanding the field of view,
no specific object to focus on,
simply noticing in the stream of
experience from moment to moment
to moment any thought, sounds,
image, sensation, memory, anything
and everything that moves through
to your awareness, your attention,
from moment to moment to moment.
No agenda, nothing to push
away, nothing to hold on to.
There's no right or wrong at all.
Simply noticing what is
moving through your field
of view, your mindstream.
[ Pause ]
Okay. Now, please take a deep,
deep breath, open your eyes,
look back at me, how many
people felt more distracted
when you're doing the focused
attention on the breath?
Okay, show of hands, a few.
How many people felt more distracted
when you're doing this
open monitoring open field
of view, more people.
Individual differences, in fact,
that varies throughout the day.
These are just two specific forms
of training, which we actually used
in a couple of our studies.
So not only science, but also
journalists, and even magazines
like Time, Newsweek, are now
putting meditation practices
on the front cover,
and I would suggest
that this is a direct response
to the level and intensity
of stressors that we experience.
People are hungry for tools, and
I would suggest that the word
for meditation "bhavana"
means to cultivate,
as you were just doing a moment
ago, insight into the quality
of your attention,
and then even further,
the processes of how this works.
It's a tool for examining,
that's essentially science
but intrapersonally.
So, one program to work on stress
that was developed 33 years ago
by Jon Kabat-Zinn,
UMass Medical Center,
Mindfulness-Based Stress Reduction,
a hodgepodge of practices to deal
with chronic patients with
chronic pain, physical
and emotional, 35 years ago.
And essentially, what's happened
now is that mental analysis
of this one program, there
are many kinds of programs,
clearly demonstrate reductions and
symptoms of stress, depression,
anxiety, increases any indicators
of well-being, social connectedness,
quality of life, satisfaction
with life,
just teaching some basic skills.
So the program is a hodgepodge,
and just as full exposure,
we study many forms of
psychotherapy, aerobic exercise,
[inaudible] meditation,
compassion practices, mindfulness.
Mindfulness is only
one kind of practice.
There's formal meditation-- sitting,
guided, there's informal practices--
taking pauses, and there's
Hatha Yoga, which in
and of itself is super
powerful in changing physiology,
helping to reduce stress
symptoms, et cetera,
so that's why I used
the word hodgepodge.
Jon Kabat-Zinn here, one word,
and some Buddhist scholars have
actually suggested we don't use the
word mindfulness anymore because
it no longer means anything.
The word itself sati or
suttee, Pali and Sanskrit,
literally means to adhere attention.
In some cases, it means to
recollect or to remember,
to stay in the present moment,
and you'll see how Jon Kabat-Zinn
has defined this, paying attention
in a particular way on purpose,
volitionally in the present moment,
not past or future
tripping, but in the present.
And the most difficult
for westerners,
doing this in a none judgmental,
nonself-deprecating way,
I'm really no good at this, I suck,
I'm never going to be skillful,
I can't read my mind,
it's hopeless, give up.
That's one way to think,
that's the opposite of this.
So, some brain imaging.
Here, there are many ways to
probe emotional reactivity,
and we've tried many different ways
from shock, pictures, video clips,
actors saying things to you.
But one of the most powerful
is your own negative distorted,
self-beliefs.
It's the most personally salient.
And what can you see here shown
in the red circles are greater
neural response in a set
of brain regions that have to
do with conceptual self-view.
So indeed, it totally makes sense.
When you're spinning on
your own negative thoughts,
you're activating a conceptual
self-referential circuit shown here.
What's nice is that, when
a person drops out of
that self-conceptual self-circuit,
we can see when they stop.
That's what so nice about
having a brain system
because first person report
might not be fast enough
or accurate enough, but the
brain is speaking milliseconds.
Also, in the other side, in the
black circle is the amygdala
and parahippocampal gyrus,
part of the hippocampus.
This is also super important
because this is indicating
that when you're spinning on
your own negative self-beliefs,
there's more arousal,
perhaps negative emotion,
and even recollection.
So this is how we setup the
pattern emotion reactivity.
And then the next question
is what can we do to that?
Well, as shown in the black
circle, the right dorsal amygdala,
one brain region, super important,
that has been pointed out,
in terms of fear, anger,
emotion, arousal,
activating the entire immune
system of the entire body.
How much can we actually modulate
its pattern of activity over time
through specific training?
So the Mindfulness-Based Stress
Reduction training is only two
months, every day at least half
an hour, that's very little.
And the question is, if
you look at the solid mind,
what you is when asked to react
to your own negative self-beliefs,
the black line takes a little
time without showing activity
in the right dorsal amygdala
increasing when you're spinning
on your negative beliefs,
and then a queue comes
on to shift your attention
to your breath
with your eyes open
inside the MRI magnet.
In the context of a
powerful negative stimulus,
shifting attention to
an object, your breath,
brings the amygdala
down at baseline.
Now, you look at the dotted line
and that represents three
months later after feeding.
And a couple of key points, the
first point is that the red circle.
There's a punctate increase
in amygdala response
to your own negative beliefs.
This has been replicated in
other labs suggesting that one
of the psychologically flexible
shifts that occurs in the brain,
mind, person is that become more
emotionally resonant-- responsive.
But the second red circle
is also very important,
you come back down
to baseline faster.
There's tons of evidence showing
that when you use emotional stimuli
with people with current or
even past major depression,
the amygdala goes on
and it stays elevated,
which is a clear indication of
being stuck, ruminating, spinning,
inability to attentionally
disengage.
One of the key things that we see
with mindfulness in other forms
of meditation training or other
kinds of training is the ability
to have greater psychological
flexibility,
but it doesn't mean numbing or
avoidance, destruction or lack
of experience or emotional
experience.
So this is really promising
and that's one--
this is focused attention to
the breath, so notice that.
Now, clinically, why
is this important?
The red areas here that
you see represent from pre
to post two months of mindfulness
training increased ability
to recruit sets of regions
in the brain that have to do
with visual engagement
with an external stimulus.
Most people with anxiety
disorders, the number one form
of the emotion regulation
is destruction or avoidance.
In fact, there's empirical data
now in just healthy adults,
the one form of emotion
regulation used-- most of--
more than anything
else is avoidance.
So I would suggest that most of
us are avoiding most of the day.
It's functional most of the
time, except when you come home
and you see your partner and
they need your full attention.
And if you avoid in that moment,
you're going to be
in much more trouble.
Hence, the red areas here
are suggesting that even
in people diagnosed
with anxiety disorders,
they can mount greater attentional
engagement even in the context
of something that is toxic,
their own negative self-beliefs,
as opposed to turning
off, shifting off.
The amount that they recruit
brain activity is directly related
to pre-post reduction in anxiety.
A brain-emotion-anxiety
relationship,
that's now when it
gets more exciting.
Again, Michael Posner and Jin Fan
have done a fantastic work, again,
standing on the shoulders
of great heroes,
delineating different
aspects of attention
and which neural circuits they're
instantiated in in the brain,
the ability to alert or place
your attention and be vigilant,
the ability to shift
attention, reorient as needed.
And then blue, top-down
executive control.
Okay. I get home, I see my partner's
face, I want to pay attention,
I want to implement attention
regulation for my benefit,
for her benefit, top-down
goal-oriented regulation
of attention.
The brain is showing us.
There are many other aspects of
attention, but those are just three.
Oops, sorry-- just
showing that, in fact,
from pre to post mindfulness
training, two months,
we actually see an increase in
brain activity in areas that load
on attention regulation ability.
Again, just a little piece
of evidence that you can--
attention regulation
and the application
implementation is trainable.
And you'll see why in a
moment this is so important
and we actually do this
at Google and now beyond.
So here's the latest [inaudible],
this is related to the second form
of practice you did, which
was the open monitoring
or it's often called
receptive awareness,
where there's no specific
object to focus on.
You're simply noticing
your experience
from moment to moment to moment.
That is very different kind
of practice than object-based.
And so, here is recent data,
analysis I did just last week,
brain imaging results are
showing that increases from pre
to post mindfulness training for two
months, increases in the top panel,
which is the insula and
specifically the anterior part.
The more you are able to
recruit the anterior insula,
which is an area that's
very important in emotion,
in awareness of visceral bodily
experience or somatic processing,
actually awareness
of bodily sensations.
The more that that increased in
patients with anxiety from pre
to post was associated at three
months followup, three months later,
with decreased use of suppression.
And I think as George
mentioned or someone,
suppression of emotional
expression is related
to a much more negative
emotional and physical profile.
So interesting that
the area that has to do
with greater visceral
awareness of what I am feeling
in my body is related to less use
of an automatic suppression emotion
regulation, that's really good.
What you see below is the
amygdala and the hippocampus.
Again, amygdala-- arousal, emotional
awareness, directing attention.
Hippocampus, if you go back to
the definition of the word sati,
mindfulness, means to
remember, to recollect,
to adhere the mind to
the present moment.
Hippocampus does many, many things,
but it's also involved
with memory encoding.
And here, what we find is increases
in activity in the amygdala
and in the hippocampus from pre
to post mindfulness training
at three months later followup
was related to increased use,
both use of and self-efficacy
metacognitive attention,
metacognitive ability of cognitive
reappraisal, amore adaptive form
of emotion regulation that has
long lasting beneficial effects.
Different brain regions changing
pre-post training related
to decrease in maladaptive
suppression,
increase in adaptive cognitive
reappraisal in patients
who normally do just the opposite,
they suppress and distract,
they are not skillful in
thinking or reframing.
So, what I'm going to
show is super important.
So we started with how do you get
from the state of stress anxiety,
angst, insecurity, on
the left to resilience,
phycological flexibility,
innovativeness?
I would suggest that the effects
of different meditation
practices is WD-40.
Is there anybody here who
does not know what WD-40 is?
Okay. Simply put, right, the grit,
the dirt, the automatic thinking,
emotional, even biological patterns
that we have developed
over time become sticky.
They block the ability for
the key to go into the lock.
WD-40 loosens up the grit,
these automatic mostly not
conscious behavioral, emotional,
even biological patterns.
So that is my metaphor for loosening
up even the neural circuits
that allows any form of training
to become more effective.
In fact, there's been
some suggestion
that mindfulness meditation
before you go
into cognitive behavioral
therapy for depression, anxiety,
eating disorders et cetera, et
cetera might enhance the skills
that are learned in cognitive
therapy, which are in some way easy,
but in some ways very
difficult to do.
So that's one key thing.
But now here comes the next thing.
So what? Everything I've said so
far, so what, cute, scientist, nice,
fun brain imaging colors, so what?
The social impact, which is
the third word in the phrase
of this conference, so what?
What's the actual relationship
to social impact?
Practical application,
here it is, ready?
There are many ways, here's
one way I'm involved with.
My second job is Google.
So four and a half, five
years ago, four years ago,
I was brought in to develop emotion,
mindfulness-based emotional
intelligence leadership training
for Googlers for the reasons
that I mentioned earlier.
Huge stress, emotional reactivity
and lack of education in emotion,
emotion regulation and clear
evidence, both within Google
and outside that the people who
are the top managers, leaders,
VPs are people who manifest
emotional intelligent skills,
and it was not part of
anybody's education.
So when the Googlers
come to the class,
they're hungry 'cause they know
this is the only way to really,
really advance unless they're going
to be an individual contributor
and not work with anybody
which is allowable
in Google, not other places.
So, this is the book
that's coming out April 24th
that actually most of the content.
We are making the entire
program open source free ware
with everything, books,
slides, teaching [noise],
because the explicit goal is to
actually enhance people's ability,
optimize their performance,
their well-being,
not only in the work place
but any organization.
And even beyond that, it's-- I would
actually say the goal is world peace
because this is already been taught
all over the world in Google offices
and the lawyers just
gave us permission
to take it outside the
Google, thank you lawyers.
So, that's coming.
Lots of people helped
me, I have my mentors,
you always thank your mentors.
At Rutgers, San Diego staff, thank
you for your attention and funding
and let's go back to thank
you for your attention.
[ Applause ]
>> Thank you very much Philip.
>> Yeah.
>> We don't have much time for
a discussion, but we'll going
to have plenty of time
at recapping at the end.
So, I will invite our next speaker.
Our next speaker is
Professor Pathik Wadhwa,
from the University of
California at Irvine.
His lecture is on early life
stress, infancy and childhood
and its impact on society.
Pathik?
[ Pause ]
>> Great. Thank you, George for the
invitation and for this opportunity.
So, I'm going to try to follow the
talks of this morning particularly,
the talk by Dr. Chrousos and then by
Dr. Romero, and speak to the issue
of some of the effects in utero
stress exposure on long term health
and disease risk outcomes.
And this talk will be representing
effort by some of my collaborators,
and me and so I want to acknowledge
Claudia who's here in the audience
and another of our collaborators
in putting this together.
We run a program at UC Irvine
called Development Health
and Disease Research Program.
And in the nutshell, the
goal of this program is
to study the interplay
between biological, behavioral
and psychosocial processes
in the early life.
And when I say Development Health
and Disease Research Program,
what am I referring to
when I use the term health?
So, I just put this up to tell you
that these conditions
represent the major burden
of disease in society today.
So, you're familiar with these
conditions in adult life,
it's heart disease, type
2 diabetes, cancers.
In early life, it's premature
birth, childhood obesity, asthma,
neurodevelopmental disorders.
For the first time, last
year in human history,
these noncommunicable disorders
represented the major global burden
of disease in the world.
So this actually last
year's change positions
with infectious diseases
according to a WHO report.
So, for these particular conditions,
these are all complex
common disorders,
common because they're common,
complex because they have
a multifactorial etiology.
And if you ask the
question generically,
what represents the likelihood
of an individual developing one
of these complex common disorders.
It would probably be a joint
function of exposure to risk factors
for that specific condition,
but we also know that a group
of individuals exposed to the same
amount of risk the differences,
individual differences and who
develops a disorder and who doesn't,
and that's subsumed by the terms
susceptibility or vulnerability.
So, it's a joint function
or exposure to risk
and the individual's vulnerability.
The traditional model has
been that this vulnerability
of predisposition has been
equated to genetic make-up.
So they say there's a
genetic susceptibility
and then there's exposure
to risk factors.
And the new thinking now is that
yes genetic make-up made us,
but it's really a combination of the
genetic make-up and the environment
in early life, that together
defines the structural
and functional integrity of systems.
So in a nutshell, you
have something that works.
It-- it's exposed to wear and
tear all the time depending
on the conditions in
which its operating.
And so one factor that goes into
disorder is the amount of wear
and tear that the systems exposed
to and the other factors how well,
how robustly, how strongly that
system was built in the first place.
And what I'm saying is that
the building of construction
of a living system in the first
place is not nearly a function
of the genetic make-up at
the time of conception,
but it's the interplay of those
genes with early environment,
the emphasis being on at early, so.
So, in this presentation, I'm
hoping to spend some time talking
about why one would consider
a role for maternal stress
and stress biology in the context
of long term implications for health
and disease risk, then share with
you some summaries of some the work
that we've been doing
related to this question.
Move to discussing some what
we believe are noble approaches
for the characterization of
psychobiological stress in pregnancy
and then end by briefly showing you
an overview of the current studies.
So, if one didn't have any empirical
data, would one even proposed
or hypothesize a role for
stress in early development.
And I would submit to you that one
word and this is based on concepts
and evolutionary biology,
developmental plasticity
and life history tell you.
So essentially, at the end of
the day, from the same genotype,
from the same fertilized egg, one
can get many different phenotypes.
You know, this animal breeders know
this well, botanists know this well
when they take the same seeds
in the different conditions;
they grow on that different
altitudes and so on.
The same is true with
mammals including humans.
So what is it about this journey
from genotype to phenotype
that determines what
specific phenotype
of particular genetic
make-up is going to acquire
as opposed to a different one.
It's really the process
of the interplay
with conditions during development
or environment during
development that defines this.
And I'm using the term environmental
conditions during development
and you might say well,
which condition?
That's a broad term.
What are you talking about?
And I would submit to you
that if one considers what the key
environmental considerations are
that have driven evolution
and natural selection,
then one good reasonably expect
that those same conditions would
probably influence the development
of an individual in early
life and intrauterine
and early postnatal life.
So what are those conditions?
The one absolute obligatory
factor that all life needs
from the outside is energy because
no life on this planet is capable
of the no synthesis of energy.
So, energy capture nutrition,
getting energy substrate,
anything that deals with how
much there is in the efficiency
of capture would be a key process
that drives not only evolution
but lifespan development.
And the second is once one gets
energy, how do you regulate
that energy, under what conditions
do you store, how much you use,
how much-- what place, what
organ systems do you supply more
to less to?
This whole thing is at the end
of the day driven by
the stress response.
That's the fundamental reason
for the stress responses,
is reallocation of energy
depending on circumstances.
And also, stress response
obviously comes into play
when there are threats
either actual or perceived
to either survival or
reproductive fitness.
So for these reasons, stress would
be something at least biologically
that developing organism considers
very carefully in terms of specifics
of how it's going to develop.
So again, two reasons.
One, because it represents
threat for mortality
and reproductive fitness; two,
because the stress responses
fundamentally the response
that regulates the allocation of
energy in terms of efficient capture
and where and how much to store
and use and keep changing this.
I'd submit that's the key.
There's another reason why one
would consider the effects of stress
which has to do with the
very large socioeconomic
and racial ethnic disparities,
and all the common complex
disorders I showed you starting
with reproductive and
birth outcomes and moving
on to the other conditions.
And we know that health related
behaviors only explain a proportion
on these social economic and
racial ethnic disparities
and there's been a hypothesis for a
long time that differential exposure
to stress may be playing some role
in explaining these disparities.
So, that's another reason
why one might consider a role
for prenatal stress.
So, in summary, I'm suggesting to
you that stress represents cues
or signals about certain
key environmental conditions
in the context of development.
The stress system represents
probably a very important
communication system between the
maternal and placental compartment.
So the same stress mediators
that represent cues also
communicate this information.
And then the same stress mediators,
glucocorticoids, cytokines,
actually act on various
targets of programing.
And so, it's a very
efficient way of collecting,
transmitting information, and then
producing effects based on this
and we're going to get
into a little bit of this.
So it's for all this reasons that
at least for me, the study of stress
and stress processes in early
life is very interesting.
So, moving to a little
bit of a summary of some
of the work we've been doing,
we started several years ago
with this question, does maternal
stress during pregnancy influence
fetal development and
subsequent outcomes?
We asked several specific questions
of which aspects of stress,
which outcomes does it influence?
Is this really a stress factor?
Is this an epiphenomenal?
Is it because these women are
experiencing obstetric complications
and are worried about that?
If there is an effect, what's the
magnitude in nature of the effect?
If there are effects, are they
critical of periods in gestations
when pregnancy and embryos
and fetuses are more
susceptible than other periods?
What are some of the mechanisms and
how are these signal transduced?
So, excuse me.
So essentially, we
started with studies
of psychosocial stress exposure
in pregnancy and we started
by considering the role
of the endocrine system
but these studies have evolved
overtime and we now in addition
to psychosocial stress are
interested in the effects
on nutrition and are doing
studies on that in the effects--
in infection and the
interplay of the three,
psychosocial stress,
infection and nutrition.
From the endocrine
work, we quickly move
to also including the immune
system and to studying some genetic
and epigenetic processes,
and from pregnancy
and birth outcomes such
as premature birth.
Now, we move to some of
the longer term effects
so I'll show you some of that.
If one look set the role of
maternal psychosocial stress
and adverse pregnancy outcomes
such as preterm birth or a small
for gestational age, if
you summarize the effects
across studies, you see what one
might describe as modest effects.
The pull averages,
most of the studies,
do suggest that there is an effect
such that women reporting
higher levels
of stress during pregnancy
tend to give birth sooner
and give birth to smaller babies.
This effect is pretty modest.
So, the two questions, one,
there's also in addition
to the modest effect, there's a
tremendous model hydrogenating these
studies in terms of the study
design, the conceptualization
and measurement of stress, of
outcomes themselves and so on.
So, the two possibilities are here.
One, that the effect
really is modest.
There is a real effects but it's
nothing to get to work up about, or,
that we are not perhaps
measuring this in terms
of whether there are
some specific individuals
under specific conditions other
that stress that go with stress,
at specific stages in gestations
who might be particularly vulnerable
to these detrimental effects.
So I'm going to come back to this
issue a little bit later and talk
about how we are trying
to address and study this.
In terms of biological
pathways, these are some
of the common pathways, endocrine,
immune, inflammatory and vascular
that are discussed in the
context of the mediation
of stress effects on
fetal development.
And I'll say couple of
words about each of these.
So, two things that are interesting
about endocrine processes
in mammalian and particularly
in primate pregnancy are that,
primates, humans and nonhuman
primates are the only mammals
that in the state of
pregnancy produce large amounts
of CRH in the placenta.
You've heard a bit about
CRH from Dr. Chrousos.
And this is the hormone
that organizes
and mediates the endocrine
stress response.
Now this is made by the placenta,
this hormone is "stress sensitive"
and that its production is regulated
by all the non-mediators of stress
such as cortisol, catecholamines,
neuropeptide Y,
inflammatory cytokines, and it's
non to produce important effects
on two sets of processes.
One is in regulating the length of
gestation determining the timing
of both, and the other is
regulating various aspects
of growth and maturation.
It's the combination of these two,
the synchronization of these that is
in important in mammalian
development.
So, we've published
several studies that suggest
that maternal psychosocial stress
is associated with this regulation
of the maternal HP axis,
which in turn correlates
with placental CRH production,
which in turn correlates
with birth outcomes such as preterm
birth and fetal growth restriction.
The next set of studies, we
began examining the interphase
between stress and
infection in pregnancy.
You heard a little from
Dr. Romero about the role
of intrauterine infection
in pregnancy.
And we have been pursuing
two hypotheses
and have published a little bit
on each of these two questions.
One, the idea that the maternal
stress, women reporting high level
of stress are more
susceptible or vulnerable
to developing reproductive
tract infections.
And the second is that among women
with established reproductive tract
to intrauterine infections,
those reporting high levels
of stress seemed to have-- it seems
to exacerbate the pathophysiological
consequences.
So in fact, we've shown, Dr.
Chrousos has mentioned this.
CRH is important agonist
of inflammation
when antigens are presented.
So, at-- in the noninfectious
state, we used maternal blood
in early gestation,
those no association
of CRH levels with cytokines.
But when we stimulated
the blood with LPS,
you saw a robust proinflammatory
response, individual variation
and this variation
in the proinflammatory response
was very nicely explained by levels
of CRH such that women with higher
CRH had a more robust stimulated
antigen, stimulated response.
And we did this both whole
blood and with PBNCs.
We're also pursuing the role
of stress related gene environment
interactions in pregnancy,
and we're considering several
stress related, HP related genes
in both the maternal
and fetal compartment.
And the approach is to look at
various combinations of maternal
as well as fetal genotypes
always in conjunction
with environmental
exposure such as stress
or other exposures of interest.
And so that's some of, you know,
that just a thorough brief summary
of some of the work looking
at adverse birth outcome.
Moving to some other longer
effects, we're interested
in exploring the long term effects
in the brain and in the periphery
of intrauterine conditions
with a focus on stress.
So, you've already been introduced
by-- a little bit by Dr. Chrousos
and then more by Dr. Romero to
this concept of the development
of fetal origins of
health and disease.
If one had to summarize this in one
slide, it would probably be this
that many, many epidemiologic
studies all
over the world have not established
a correlation between markers
of birth phenotypes such as
birthweight and risk for disease
in later life such as hypertension,
coronary artery disease,
diabetes, and so on.
The assumption here is that these
adverse birth phenotypes are markers
of adverse intrauterine conditions.
So, we've-- among the
questions we're interested
in is this question, are the effects
of prenatal stress exposure
necessarily mediated
by adverse birth outcomes?
So can you get subtle effects
that you can pick up later
in life despite having what
appeared to be normal pregnancies
and normal birth outcomes?
So, we-- again, you know, are
looking at brain development
and periphery and one of my
collaborators who is focusing
on the effects on brain development
is here, Dr. Claudia Buss.
She's published several studies.
She started her work looking
at adverse birth outcomes,
again as markers of adverse
intrauterine conditions and looked
at those and the interplay of those
with adverse postnatal conditions
on several measures of structural
and functional outcomes in brains,
in starting with adults and
then moving in to children.
And now this work has become a
prospect then I'll give you a couple
of examples.
So you heard again this
morning about the amygdala,
the importance the amygdala
in the regulation of emotions.
You heard some references too.
The circuits in the amygdala
and this I believe is one
of the first set of data.
It's unpublished as of now but
we believe in a couple of weeks,
it's going to be published in PNS.
This is one of the first
pieces of evidence that links
in utero stress exposure, in
this case, glucocorticoids.
With the size of the amygdala
in children and in turn links
that with emotion regulation
and affective processing,
so it's sort of completes this
structure function relationship
and ties it, correlates this
with prenatal stress exposure.
So as I've said, in about two weeks,
we should be seeing
this paper coming out.
Here's another finding that
Claudia has developed that speaks
to the importance, not
just of prenatal processes
but even characteristics that a
mother brings to her pregnancy.
And you've heard this morning about
obesity and the inflammatory milieu
that accompanies obesity.
And in this finding that
Claudia has developed,
she links prepregnancy BMI with
the cortical thickness in children
as analyzed with brain imaging.
So after controlling for child
age, child BMI, birth outcomes,
and so on, she found that
cortical areas particularly
in the prefrontal cortex
are reduced in women
with a higher prepregnancy
BMR controlling
for weight gain in pregnancy.
And we think that this
potentially is tied to a high risk
for higher impulsivity,
less inhibitory control
which we heard discussions about
in terms of the implications
for psychopathology, for
ADHD and possibly even
for obesity risk later in life.
Are other colleague,
Sonja Entringer,
has been asking this question in
terms of physical health phenotypes,
endocrine immune metabolic,
is there a direct relationship
between measures of exposure
to prenatal psychosocial stress
and some of these phenotypes that's
independent of birth outcomes?
And so, the first study she did
examined this using a retrospective
case control design.
You heard again this
morning about some lists
that represent very severe
stressors that most people would--
we all know that there's a lot
of variation in the middle range
of what we'd consider as stressful.
What I might consider as stressful,
he might find not only not stressful
but enjoyable and challenging.
But there are some extreme
conditions that most
of us would probably agree on and we
saw a list of those like the death
of a spouse and the loss of a job
and a severe illness of somebody.
So these were the sorts of stressors
that Sonia looked for in terms
of history of prenatal exposure.
She decided to focus in the study on
young adults, healthy young adults
where there was no evidence
right now of disease
because while psychological
state can produce disease,
disease itself alters
psychological state.
So she didn't want that
confounded in this study.
She made sure of from obtaining
the actual medical record
in the index pregnancy that there
were no major obstetric risk
conditions, no adverse birth
outcomes in this study.
She looked at the whole bunch
of metabolic, immune, endocrine,
cognitive outcomes that
I'll discuss in a minute.
And she used a lot of
challenged tests to look at these.
So these are healthy
25-year-old men and women,
half of them have a history
of exposure to prenatal stress
in the index pregnancy where
the mothers experienced
when they were pregnant with this
person who's now 25 years old,
the death of someone in the
family or the loss of a job
or severe illness, so
you follow the design.
Except for this, nothing untoward in
the pregnancy, no adverse outcomes,
these 25-year-old men and
women are perfectly healthy
on all measures right now and have
been healthy through childhood.
So we brought them into the lab
and performed various assessments,
physiological assessment.
She looked at a challenge test
because if you are interested
in knowing whether I'm at risk for
let's say, developing hypertension
and if you measure my blood pressure
at rest, it's not as informative
as if you make me exercise
and measure my blood pressure
in response to a challenge.
If you are interested in
knowing whether I'm at risk
for developing diabetes and you
measure my blood glucose at rest,
it's not as informative as if you
were to give me a glucose load
and then look at how I
regulate blood sugar.
So when you challenge your system
and you watch how the system
response to a challenge,
that's when you first see
signs of dysregulation
and you see those well,
well before years and years,
sometimes decades before
over disease sets in.
So these were the sorts of tests
she used in looking at endocrine,
immune, metabolic and
cognitive functioning.
Ongoing to the details
of those but I'll way
through quickly some of the results.
So she found that the
offspring of mothers
who had experienced a high level
of prenatal stress had a high BMI.
Already by 25 years of
age, insulin resistant,
although they were not diabetic.
And they had a lipid
profile that's consistent
with the metabolic
syndrome, low HDL, high VLDL.
In terms of the endocrine system,
they were producing in response
to a challenge more
ACTH and less cortisol.
This is something that has been
noted in the HP axis of people
who are particularly prone
for psychosomatic disorders.
She got blood samples from
these young men and women before
and after stress and noted a shift,
a Th2 shift in the Th1-Th2 ratio
suggesting an immune dysregulation
that places these folks at risk
for allergic and atopic disorders.
In terms of memory, he found
impairments under stress
so she looked memory both at basal
condition and then once again,
after administering cortisol and
found that the post cortisol memory,
the memory on the challenge
was impaired.
And then finally looked at
the marker of cellular aging
which I'll discuss a
little bit more [inaudible].
So, we tend to think of fetal life
in childhood and young adulthood
and then we think separately
of aging.
And we ask the question here, does
the rate of aging, cellular aging,
does that have anything to do with
conditions in intrauterine life
and does stress play a role
in determining how one ages?
So for this, we were interested and
we recently published this paper
and I know Dr. Chrousos
was one of the reviewers.
We-- you heard some mention
some about telomere biology.
And just to remind you
these are the ends of--
these are DNA sequences
that are at the ends
of chromosomes and how it loop.
They protect chromosomes from
damage to the DNA base pair regions.
They get shorter every time a cell
replicates, but they get elongated
when an enzyme called
telomeres is expressed.
So the ultimate shortening is
the shortening with replication
and the little bit of elongation
with telomeres when it's expressed.
So, in balance, there
is some shortening.
There are some recent studies
that many, many conditions
and Dr. Chrousos showed
you some of those
that telomere lens associated with,
people with shorter
telomeres die sooner,
more likely to have
heart disease, diabetes
or a bunch of other conditions.
In addition to these
now, in the last year,
there have been somewhat I consider
landmark papers that suggest
that telomeres and telomere
biology fundamentally regulates all
processes to do with
aging in the cells.
And it does this by
maintaining their tightness
with which DNA strands
are one together.
So, one hallmark often
all the cell is
that the DNA is not
as tightly configured.
And this is because of histone
production gets compromised
in old age.
These studies now show that histone
production through some signals
that are not yet identified
but that emerged from--
a telomeric region regulate histone
production that's responsible
for global second order
chromatin integrity.
And so, experiments have
demonstrated some of these--
have demonstrated in
terms of senescence cells
that if you just remove senescence
cells which again is a function
of a telomere lengthened telomerase,
you get a dramatic, if not reversed
or at least in the rest
of the aging process.
So we looked at telomere length in
these young men and women and lo
and behold found that
those who'd been subjected
to prenatal stress
had shorter telomeres.
Shortening was about
the equivalent of 3
and a half additional
years of aging.
So already by the age of 25, the
cells look 3 and a half years older
in those who'd been
exposed to prenatal stress.
So now moving to some of
the ongoing work, remember,
I said to you that the two
possibilities, one that the effect
of psychosocial stress on adverse
birth health outcomes are either
modest or there are some
women who have fetuses
under certain conditions at
particular stages in gestation
who might be particularly
vulnerable.
So, if one asks the question
well, what is the likelihood
of a stress related
adverse health outcome.
Again, using the same logic, it
would be a function of two things.
One, the amount of
exposure to stress,
but the second would be
individual differences
in the biological responsivity
to stress.
So if for instance, if
the fire alarm went off,
you saw some smoke coming in
to this room, if we all believe
that there's a fire, all of us would
experience some degree of stress,
mentally and physiologically.
But then, you know, few second go
by and someone comes in and says,
"That was a false alarm,
everything is okay."
We'd all settle down and get okay.
But that'd be quite a bit
of variation in this room
about who remains agitated for
how long and who gets calm quickly
and whose blood pressure and
catecholamines and cortisol come
down quickly versus state.
That's the psychobiological stress
response with the component.
This is something that hasn't been
looked at in studies of pregnancy
in terms of the response though.
So, what we're doing now is in the
most recent studies we're doing,
we're working very hard and
luckily, we have the cooperation
of our research subjects.
We're instrumenting
them with gadgets
such as what you see
in this picture.
They'd collect 24 hours a day,
they'd collect EKG respiration
with an accelerometer.
They collect physical activity
and posture the combination
of this-- asleep.
And then they complete
and electronic diary
about 15 times a day.
So we do this thing 4 days in each
of the 3 trimesters of pregnancy.
So they spend 6 days with-- it
has one day to train and one day
to come back and return
the equipment.
And they collect these data
for us for 4 whole days.
The only time they
don't collect these are
when they're taking a shower,
but otherwise, during sleep
and during natural
living conditions.
We get quite a bit of physiology
from the diaries, 15 times a day,
they tell us where they are, what
they're doing, how they're feeling,
what they've eaten
and drunk recently.
We also collect 8 samples
of cortisol a day.
So, I'm not going to
go into the details
of how we combine all these
data, but I'll tell you
that we get what we believe
are far better self-report data
about how they're doing than the
usual questionnaire interviews
that have you asked me to think
back over the past week of my life
and summarize on average
how I've been feeling.
This is in real time and then you
get data about physiological state.
You can combine this.
You can create averages for
what average stress levels are
and then combine these to look at
psychobiological stress reactivity.
And this approach looks
it's working.
We have published some
preliminary studies on this
with the first few subjects.
We now have projects that are doing
this protocol and then following
up the babies with in terms of
our interest in brain imaging
and in understanding
metabolic function.
So, instead of focusing on discrete
conditions like psychosocial stress
or infection on obstetric
complications, we're focusing
on looking at an array of
biological mediators of stress
such as cortisol, CRH,
IL-6 C-Reactive Protein,
because each of these biological
stress mediators is driven
by any of the antecedents.
And again, we've heard Dr.
Chrousos say a little bit
about some of these.
So we're measuring this
longitudinally all the cause
of pregnancy, all the
way till birth.
These are our markers of
prenatal stress exposure
and we'll be characterizing
the exposure,
specific stages of
gestation cumulative.
We'll be looking at trends
of change overtime as well.
And then in one of the projects
that Claudia is heading up,
she's looking at the
vulnerability hypothesis which says
that vulnerability
for neurodevelopmental disorders
is impart a function of alterations
in the brain which
are produced in part
by the influence of
prenatal conditions.
So she in this study is doing very
extensive brain imaging with MRIs,
with diffusion tensor imaging
that looks at fiber tracks.
Also now, she's using resting
state FMRI, you've heard some talk
about MRI-- FMRIs and
these are resting state,
these are in challenge.
Looking at these in infants
during natural sleep,
looking at several postnatal
conditions as modifiers,
and I've already shown you some
examples of the data she's produced.
Another of our colleagues is looking
at susceptibility for obesity.
So, no matter what,
one cannot become obese
if one doesn't consume more
energy than one expends.
That's the bottom line, you
just cannot become obese.
But, among people who consume the
same, more or less the same amount
of energy for body weight,
there's huge variation in who puts
on weight and who doesn't.
This susceptibility is something
that we believe may have something
to do with developmental
conditions in intrauterine life.
So it's not actually obesity but
it's the susceptibility for that
and the equivalent
conditions of energy balance.
And that's what we're looking
at in this other project
where we're doing-- using the DEXA
scans to do whole body imaging,
using blood samples to get
that insulin sensitivity,
and then doing measures of energy
expenditure using a procedure called
the doubly labeled water method.
Also, focusing on the role of
postnatal nutrition, breastfeeding
and the constituents of breast
feeding in this project, so.
So then, to wrap up, if
one talks about prevention
or stress-related disorders, I
think it's reasonable to suggest
that primary prevention would
begin in intrauterine life.
If one starts thinking about
doing something about stress,
even after birth, it-- you know,
may not capture the whole spectrum
of susceptibility that
stress produces.
I read this quote somewhere and I
liked it, and I think it's up here,
the wealth of a society
lies primarily in the health
and well-being of its girls
and women of reproductive age.
And that's certain
it couldn't be more--
more true in terms of susceptibility
both for males and females in life.
And I, at least hope
I suggested to you
that stress biology is interesting
in its own right and terms
of the effects of stress
but it's far more than that.
It has the potential of offering a
unifying framework in the context
of framing questions about
one million adaptations
to environmental variation because
it is the system that's used
to detect, to transmit
information, and the system
that produces effects based on this.
So, I think it's, a very good
modern system, in understanding,
the effects on environmental
variation.
So, all of us have different
ways of dealing with stress,
and these are my personal
stress buffers,
the dog is more than my wife.
But we won't tell her that, and I
have the fortune of collaborating
with many, many wonderful
people, at several institutions.
All of this work is, funded
very generously by grants
from the [inaudible], thank you.
[ Applause ]
I think we may have time
for one or two questions.
Dr. Schumaples [phonetic].
[ Pause ]
>> That was an excellent
presentation.
>> Thank you.
>> I wonder in the data that you are
collecting, whether you have data
on fatty acid intake, in terms
of arachidonic acid, EPA,
and DHA in the mother
at the cord blood,
and then during the first
two years of infancy.
>> So, I don't know exactly.
I'll tell you what we're collecting
and maybe the informations there.
So number one, we're using this
ND in our software to get 3,
24 hour diet recalls
in each trimester.
Are you familiar with
that methodology
that asks people to
list in great detail?
>> Yeah.
>> So, if these constituents
can be picked up there,
we'll get that, that's 0.1.
Then the second thing is
we're collecting plenty
of maternal biological
samples in each trimester.
So we have, starting with
maternal hair, maternal saliva,
plenty of maternal blood, and
maternal cervical vaginal fluid so,
not in the cervical
vaginal, but at least in,
some of the other [inaudible]
with blood.
We have plans for looking at
some nutritional biomarkers.
We are not funded to do that,
but we have an interest in them.
We do not, at the present time
have funding in these new set
of studies to collect cord blood.
But we've just applied
for some, we just applied
for a new grant on
supplemental project.
So if we get that, then
we will have cord blood,
but at the present time, we don't.
And then last in post natal,
early post natal life,
we're again administering
nutrition questionnaires
but also collecting breast milk
samples, both in the early-mid
and late part of a typical feed.
>> Yeah. Well you actually,
you actually need either.
Plasma, or red cell
membrane phospholipid levels.
To have, to know exactly how much
is getting across the placenta
to the baby, from the
cord blood, and later on,
because there are genetic
variants in the pathways
of the omega 6, and
omega 3-fatty acids.
So that a dietary history
is not adequate.
One and secondly, in
terms of epigenetics,
both the arachidonic
acid, in EPA, and DHA,
they can have enormous
influence on DNA methylation,
and histone modification.
And in terms of development
in cancer,
this area is expanding
by leaps and bounds.
And in fact it becomes terribly
important in terms of IQ.
[Inaudible] found out that certain
genetic variance make a difference
in the IQ.
So I think it's important to
know the genetic variation,
and the epigenetic
variation, which is much larger
than the genetic variation.
>> So we of course had DNA from
the kids, and from the parents.
The epigenetic, it's limited
as to what we can study but,
it's just maybe, it's my personal
bias, but I think the majority
of studies, associating
epigenetic changes with exposures,
and in this case, in early
life, are suspect because most
of the epigenetic changes, a large
proportion of them are not stable.
For instance, we heard this
morning from Dr. Chrousos that,
maybe you didn't show the slide--
Maybe you didn't show the slide
but you have a beautiful slide
that shows how circadian
variation changes about 15,
20 percent of the expressed
genomes somewhat these effects are
through glucocorticoid.
So depending on what time or day
one looks there will be changes,
these are all hundred
percent epigenetic.
And it's not as stable as it's
being sold right now to people
that this is a process
that is stable
and stays in this state forever.
Most of it doesn't, except--
except the epigenetic process
that actually differentiate cells
from undifferentiated into you
know, liver pancreas, muscle.
A lot of the other
stuff is not stable.
So I don't question the
importance of studying
and understanding epigenetic process
because that's one of two ways
by which you regulate
gene expression.
No question about the
importance of that.
I don't think that a lot
of the studies right now
that take one time samples and show
these differences between state A
and state B will replicate.
>> You could start in the method
along which is relatively stable.
>> Even that--
>> Acetylation, you said they are
not stable and change overtime
but methylation, you know--
>> No. So, I thought
that till a week ago.
Where was that?
We found the paper,
what was it, on full--
I'm trying to remember
the paper that looked
at Methylone, methylation--
>> Methylone.
>> That showed surprising
degree of change.
I would have argued to
exactly what you said.
>> We really should
look at children with--
>> Till a week ago.
>> With obesity and then
there are a lot of--
they wanted changes in the
Methylone with these children,
which may explain why they don't
respond very well to any treatment.
>> But I agree with you
on the importance of this.
I don't know--
>> Genetics and nutrigenomics
focuses on that.
>> Yes, yes.
Oh yeah.
>> Yeah. I think you
have the samples
and you could do great
things with the samples.
Just give them a [inaudible].
>>We certainly are
storing the samples,
yes, no question about that.
>> Any other questions?
>> Thank you very much Pathik.
>> Thanks.
>> Those are wonderful.
[ Applause ]
Our next speaker is Dr. Lorah Dorn
from the University
of Pittsburgh right?
Cincinnati, yeah.
Still my jet lag is--
it's not functioning.
Dr. Dorn would talk about stress
in puberty and adolescence.
[ Pause ]
>> Okay, first of all, thank you
very much to both Dr. Chrousos
and Gold for the invitation.
This is great.
I think the conference has
been really good and everyone
so far has set the
stage for the next talk.
So George, I think you
have the hardest job
because you were first, so.
Okay, I have 5 primary goals
today that I'm going to do.
First of all, I'm going to talk
about biological transitions
is the time of vulnerability.
Second, adolescence and
puberty and then specifically,
I'll talk about changes in
puberty both normal changes
as well as early changes.
Third, the health paradox
of adolescence.
And fourth, I'm going to give some
examples of the impact of stress
on various outcomes in
childhood and adolescence.
And then finally, I'll talk a
little bit about opportunities
for intervention for this.
Okay, what are biological
transitions?
Well, I had the good fortune
of working with George
on this paper several
years ago where we talked
about biological transitions
or times of vulnerability
of increased physical
or psychological vulnerability
for some.
Now we've already heard
some of that today
with just the most
recent presentation.
This vulnerability may
be related to changes
in reactivity of the stress system.
It may be genetic or constitutional
and the context may modulate
the effect of the transition.
So many of those terms
we've heard already today.
Biological transitions are processes
that primarily occurred
during reproductive phases
across the life span.
We heard about pregnancy
this morning for example.
They involved distinct
hormonal changes and they may
or may not be accompanied
by physical changes
that are external as well.
Here's puberty.
This is a lot of people's
vision of what puberty is.
It's a big time of change,
very stressful for some.
But the next slide actually shows
you what the adolescent prospective
of puberty is.
This was on a t-shirt
I saw actually.
Puberty is when parents
are difficult.
So maybe we're actually
studying the wrong thing,
we should be studying
parents during puberty.
Okay, I want you to keep
adolescence and puberty
as kind of two separate things.
Adolescence occurs basically
in the second decade of life
with psychosocial changes.
Puberty is a part of adolescence.
It occurs during adolescence.
More recently, we found out
that there is an increase
in stress-mediating
activity during puberty.
And that this increase probably
partially mediates the risk
of emotional pathology
in adolescence.
Okay, I mentioned there
are multiple changes
that occur during the
adolescence including puberty.
I'm going to talk a little
bit about puberty now.
First that includes as you
know, sexual maturation
and also physical growth.
Then during adolescence, you see
cognitive developmental changes,
changes in motivation in
emotion, maturation of judgment
and self-regulation skills, and then
brain changes are actually linked
to each of those components.
And then of course during the
adolescence there are various social
and role changes that
we're all familiar with.
In normal pubertal development,
there are really two components
that actually have some overlapped.
The first component people
don't hear about very much.
It's called adrenarche.
It means awaking of
the adrenal glands.
You get higher concentrations
of about three different
adrenal androgens.
Those hormones at least during
puberty tend to be responsible
for things like development
of body hair and pubic hair.
Gonadarche is the next component
that we've all heard about.
Nowadays, it happens as early as 7
or as late as 13 for the initiation
and you'd get the rise
of the distinct rise
in several gonadal
hormones during that time.
We think it's earlier in girls and
I'm going to show you a few slides
about that because that has
something to do with a lot
of the stress research that has been
going on at least in adolescence.
This slide on the left depicts sort
of normative order of
changes that occur.
There could be a lot
of variation here.
If you look at the left
which is for girls,
you can see the breast budding
which usually is the
first change of puberty.
It can be as early as eightish
or as late as thirteenish
for the initiation and then full
adult breast development might occur
as early as 11 or so all
the way up to 16 or 17.
Huge variations.
So if you're that girl,
it makes a big difference
where you fit in in terms of timing.
If you're the parent of that girl,
it also makes a very big difference.
You can see the first period is,
could be anywhere from 9, 10 or so,
maybe not until 15 or 16.
And I want you to notice that that
is not the initiation of puberty.
That's about a mid-process change
because puberty is a process.
For boys on the right hand side,
you can see that usually the
first change for boys is change
in testicular size, the
first part at the top there.
At about 10-1/2 could be that early
all the way up to 17 for completion.
And peak height velocity, you can
see is different for boys and girls
and boys tend to mature
physically about 1-1/2
to 2 years after girls do.
So is puberty in girls beginning
earlier than previous years?
I think the answer is probably yes.
For a number of years
we weren't sure
but now I'm fairly
convinced that that's true.
That aged onset is now about
age 7 to 8 in some girls
and I say some girls 'cause
it's not in all girls.
And the age at menarche has dropped
across the last decades
or even century.
This study was print,
published in 1997
and actually had a lot
of controversy with it.
Herman-Giddens did this
study with over 17,000 girls.
And you can see here, it's talking
about development at
tanner 2 or above.
Tanner 2 is the first stage
where you enter into puberty.
So in this study, at age 7 in the
dark bar, African-American girls
about 25 percent were already
at tanner 2 by age 7 compared
to about 5 or 6 percent
of Euro-American girls.
By 8, those percentages
really change dramatically.
Now, there have been several
other studies since this time
that corroborate these findings.
Early in puberty in girls, I
mentioned could be a stress
and there really is quite
a vast amount of literature
that does support this in terms
of girls being more at risk
for both physical and mental
health sorts of issues.
Girls can have shorter adult
stature if they early mature.
There's also some indication
for higher rates
of breast cancer as an adult.
Depression, substance use,
behavioral problems,
et cetera, et cetera.
There're many, many studies on this.
There's less literature
on boys in puberty.
Some studies do show that boys with
early maturation maybe more likely
to have higher rates
of testicular cancer.
Now, girls with one type of early
puberty called premature adrenarche.
Remember that's awakening
of the adrenal glands.
These girls are at risk
for physical disorders
in adulthood that I've listed there.
Now those probably
look familiar to you.
Dr. Wadhwa just described
some of the studies with girls
with the early birth--
small progestational age
and perhaps prematurity,
may be more at risk
for some of these.
Anecdotally, it seems like
a lot of parents with girls
with premature adrenarche mention
about all the behavioral problems
in that that come with that.
So we actually did a couple of
studies to focus on that, to see,
are they at risk for
those sorts of issues?
This study was published in 2008
and that had 40 premature
adrenarche girls in the light bars
and 36 healthy comparisons.
And what this is showing along
the horizontal axis is a behavior
problem checklist score that
parents rate their children on.
We took and figured
out who hit a 60 score
which was considered
clinically significant.
And to you and I, that if you
were the parent of that girl,
you would notice this behavior.
If you were the teacher, you
would notice this behavior.
And the PA girls had nearly 25
percent of these girls has hit
above the 60 mark for social
problems and total problems
on the far right and also
aggressive behavior compared
to the healthy comparisons.
Now, I also want you to remember
that there are brain changes
in adolescence and you've
heard some about this already.
It used to be several decades
ago and even maybe more recently.
We thought brain didn't
change much in adolescence.
I know when I did my training,
we thought 2 years old was kind
of the last development
of your brain.
Not true, but actually, brain
changes, some proceed pubertal
and hormone body changes.
Some maybe the consequence
of pubertal hormone changes
or they may be totally
independent of those processes.
Okay, this shows an imaging slide.
This one is just structural
imaging of the brain.
What I'd like you to focus on, it
shows the wide age range of kids
and young adults here
on the, vertical access,
it's showing percent
of total adult relative
to total adult brain volume.
And I just want you to focus
on the highlighted arrows there
that show you different structures
of the brain mature
at different ages.
Now notice it's age on the bottom.
Puberty isn't there and that
really is something lacking
in the literature that we really
don't know how puberty affects
those things.
People tend to look at age, so I
think the jury is kind of still
out where puberty affects
specific regions.
Now what about the health
paradox of adolescence?
Well adolescence really
is one of the healthiest
and most resilient
periods of the life span.
So, pretty lucky to be an
adolescence from that prospective.
They have enhanced strength, speed,
reaction time, reasoning ability.
They have increase resistance
to cold, to heat, to hunger,
dehydration, most types of
injury, yet the overall morbidity
and mortality rates
increased by 2 to 300 percent
from childhood to late adolescence.
I mean that is really kind of
an unacceptable percent change.
What are some of the
sources of these,
of the morbidity and mortality?
Well primarily, causes of death and
disability are related to problems
with control of behavior
and emotion.
You know, you see increasing rates
of accidents, of suicide homicide,
depressions, substance used.
There are also high rates of
risk-taking, sensation-seeking
and emotionally-influenced behavior.
So those are some of the things
happening in the adolescents.
Now, why might puberty
matter for taking some
of these risk behaviors to heart?
I particularly like this view
that Randall, one of my colleagues
when I was at Pittsburgh
[inaudible].
He likens puberty or early
puberty to starting the engines
without a skilled driver and I
think that's pretty accurate.
So earlier time in a puberty
results in several years
where an adolescent has
this totally mature body,
and sex-activated brain circuits,
yeah, they're really fairly immature
in terms of neurobehavioral
systems that are really necessary
to control those behaviors
and for affect regulation.
Remember those are the things
that we just talked about our key
with these risk-taking behaviors.
So what's likely to happen?
Well, perhaps increased risk
for disorders of self-control,
difficulties navigating complex
social emotional situations.
So how many people are stressed out?
Now thinking about their own
adolescents or the ones they have
at home, thinking oh my
gosh, oh a few hands, so.
Okay, let's think a
little bit about the impact
that stress may have in adolescents.
And children with adverse early
life histories have double the risk
of emotional disorders from
childhood to adolescence.
So we've heard some
about pregnancy risk,
some about prenatal, neonatal risks.
The second thing here is
that there is calibration
of stress-mediating systems.
The stress axis you've heard about
today that occur earlier in life.
Increase in activity of the stress
system with puberty may contribute
to this vulnerability that
I talked about earlier
and to negative outcomes
in adolescents.
Okay, in rodent models and much of
what we know for this is related
to different lower animal models.
We know that the period surrounding
puberty may be another period
when HPA axis is programmed.
We heard from Dr. Wadhwa in
terms of programing of HPA axis
that was in the neonatal period.
So, we're now thinking during
the biological transition
of puberty and adolescence.
So, improved conditions in
puberty can reduce the impact
of early life stress on emotion
and stress-reactive system.
So stressors encountered in
puberty have strong long-term
and negative impacts.
Again, we know more
in the animal model
that certainly your
studies are going
to shed a lot more light on that.
This is some work done
again in a rodent.
On the left hand side
for the vertical axis,
it's looking at corticosterone
in humans that would be cortisol.
A restraint stress with the black
horizontal bar and you can see
on the left block, prepubertal
and adult rodents have virtually
identical stress responses
to a restraint stress.
But if you look at a chronic stress
situation on the right block,
you can see tremendous
differences with the prepubertal,
not amounting as high
as stress response.
So there are developmental changes
in stress-sensitive brain regions
in puberty that may make an
individual more vulnerable
to some harm.
But here I think is a
great key to think of.
It also can allow for
opportunities or interventions
to diminish earlier,
emotional or physical trauma,
so the opportunity for intervention.
Now, Dr. Chrousos laid
out a great list
of how stress can impact
physical health.
Today, I'm focusing a little
bit more on mental health
and psychosocial problems but some
examples of physical health issues.
Dr. Chrousos, actually,
I thought you we're going
to show a modification of this
slide but this comes from Chrousos
and Gold work showing
different HPA axis responses.
And what I have highlighted
in red are the ones
that you see either initiated
or peak during adolescence.
Now certainly there are more we
could list here but for example,
depression and anorexia nervosa,
we know those occur more
during the adolescent period.
So the red means adolescent,
in this case.
Now what's the impact of
context on the stress system?
I'd like to give you a few
examples from the child
and adult research that's--
sorry child and adolescent
research that is out there.
And first I'd like you to keep
in mind what Selye has said
which is every stress leaves an
indelible scar and the organism pays
for its survival after
her stressful situation
by becoming a little older.
So hopefully, there's a
good side to this too.
Now what I'd like to show you today
is thinking about different context
that we've looked at
the HPA axis response in
or even basal conditions using
some child and adolescent examples.
For example, children from
orphanages, child maltreatment,
we heard that, that's one of
the highest ranked stressors
that I think we all
would agree with.
Kids with obesity,
also foster children.
I'm not going to be showing
anything about PTSD or depression
because I'm thinking that the people
tomorrow will be doing some of that.
But those could also
fit here as examples.
So thinking about kids
in orphanages,
this was an earlier
study from Megan Gunner.
On the bottom what you-- first
of all, on the vertical axis,
it's looking at daily
average cortisol done
across 3 days in children.
Romanian orphanage kids are on
the left, early adopted children
in the center, and then
Canadian-born children
that were just like your
healthy comparison group of kids.
You can see for their
average cortisol,
there are big differences here.
So the Romanian-born
children who then were adopted
but later have much
higher cortisol levels.
What about in the day-care
setting, this one I'm using mostly
to illustrate gender differences.
Dr. Chrousos mention gender,
at the end of his talk here
and there truly are a lot of gender
differences and stress research.
What we're looking at here are boys
and girls, boys in the solid line,
girls in the dashed, and
the top figure is focusing
on anxious and vigilant behavior.
So, you can see that girls on
this in the lower 25th percentile
at the left of anxious
or vigilant behavior,
and boys have essentially the
same cortisol concentrations.
This is during the stress paradigm.
You get huge differences when you're
at the high part 75th percentile
or greater of anxious
or vigilant behavior,
broad gender differences here.
And it essentially
flip-flops in the bottom slide.
The bottom slide is focusing on
angry and aggressive behavior
where boys, you see
the higher cortisol
with the higher aggressive behavior.
So big gender differences
in this area.
What about child maltreatment?
For maltreatment, I'm
talking about either physical,
emotional or sexual abuse.
So in some studies, they combined
those 3 things, some thought just
about sexually-abused
so it does vary.
This is a slide that Dr.
DeBellis and I were fellows
with Dr. Chrousos; it's
on the left we're looking
at plasma ACTH during a
physiological stressor.
And you can see in
the-- filled in circles,
those were the abused girls.
They have a much lower response
to this physiological stressor
than a healthy comparison group.
And also even before the
stressor, the CRH test,
there are differences here.
So already at a young age of these
girls were roughly 6 to 11 or 12.
You see some big HPA
axis differences.
Now, this was when girls were
younger but the next slide I'm going
to show you is from the
same group of girls,
but it's following
them longitudinally.
And this is really
quite a unique study.
The principal investigators
were Frank Putnam
and Penny Trickett, Jennie Noll.
In this slide across the horizontal
axis, it's showing years since CPS,
Child Protective Services
substantiation of abuse.
We're looking at nonstress cortisol
concentrations and you can see
at the early years which was
at the beginning of the study,
the sexually-abused girls
in the dashed line had a little
bit higher cortisol concentrations.
As you go out in time, their age,
you see differences in cortisol
where they have more of a blunting,
the longer out the abuse had,
from the situation of abuse.
So this is really a
very unique study.
Right now, these girls are
now young women in their 40s
and with a proposed
follow up of this.
So I would say stay tuned for
some more information on this.
This is the same sample but
it's looking at obesity.
Focused on the far right hand
part of this wherein red,
you see abused girls,
about 40 percent
of them meet obese criteria
compared to about 30
in the healthy comparison.
You don't see this significant
difference until young adulthood.
So some of the things that you
were mentioning, Dr. Wadhwa is,
they might not occur right at birth
but you're seeing longer
term changes here.
What about how might
marital function
of parenting impact
child stress responses?
On the left, we're looking at
wake up and bedtime cortisol.
Bedtime cortisol is always
lower and the solid line,
MF stands for parent maternal,
or parent marital functioning.
So the higher that score is,
the better the parent
marital functioning is.
So you can see that there is a
wider spread at bedtime for those
with higher maternal
marital functioning,
they have lower cortisol
and you want your cortisol
to be lower at night so that's good.
If you go to the right hand figure,
it's looking at adolescence
compared to those kindergartners.
And you do see some differences
but the lines really are not
that different depending
on if you have low
or high marital functioning.
Okay, how might early puberty
or in early adolescent girls,
impact the stress reactivity
and behavior problems?
Focused just on the left
hand side of this slide
and what we have is rule-breaking
behavior, and cortisol reactivity.
In the dark bar, you see boys
with early timing of puberty
who have low cortisol
reactivity, the far left bar,
have much higher rule-breaking
activity.
So here you have kind of a
difference with early timing
versus on time relate and the
cortisol reactivity variable.
So timing does matter.
In this study that was by Sasman
[phonetic] and her colleagues,
there were no effects for
girls similar to this.
So, I want to focus now on more
of a physical health outcome
where we look at the impact
of the stress axis on bone.
You've heard a little bit
about osteoporosis being one
of the later health issues
that we're concerned
with in terms of stress.
This figure is taken
from a study done
at the NIH a number of years ago.
It's looking at bone mineral
density in women on the X-axis
and it's showing two
groups, depressed women
versus normal healthy women.
And in each of the
six areas of the bone,
you can see that the depressed
women have lower bone density
in most of those.
Now, what we think this is
related to is the HPA axis.
In fact, these women,
if I'm remembering correctly had
higher urine cortisol levels.
So that would be an indicator
of the stress response.
Now, I was able to do a
study in adolescent girls.
In adolescence, girls gain
about, accrue about 50 percent
of their bone mineral density.
So it's really a crucial time.
So this is in 262 adolescents
where we looked at the impact
of depression and anxiety
symptoms on bone health,
as well as smoking effects for that.
And what we found is girls
with higher depressive
and anxiety symptoms, it was
associated with lower bone mass
in these girls at the
base line visit.
And how that relationship
varied depended on what kind
of a smoker you were, never
smoker or ever smoker.
So we were encouraged from
a scientific perspective
that we saw [coughs],
excuse me, something similar
to the adult literature
but it's really worrisome
from a health perspective
to think that this might,
that depressive symptoms
or substance use might
be impacting girls
at this really kind of risky period.
So, we found that 1 to 6-1/2 percent
difference in bone mass depending
on where you were on the
depression or anxiety scale.
And those percentages are equivalent
to what a menopausal woman would
lose annually to the 5 percent
or a woman on Depo-Provera which
is a hormone contraceptive.
So girls potentially, adolescent
girls are having a deficit
in their bone bank.
Could you?
I think I'm getting my water
rather than yours [laughter].
Now we haven't mentioned
intervention and what
that might look like with
changing the stress axis.
This is in foster children
who were 3 to 6 years of age
and in the top left, the RFC
stands for regular foster care.
The panel to the right is the same
type of children in foster care
but what is really fancy embellished
program, both for the parents,
the kids, and their
whole environment.
And the bottom left is just
a healthy comparison group
of matched kids.
Now, this is looking at
AMPM cortisol differences.
So it focuses more on
diurnal type concerns.
What you want to have is you'd like
to look like this bottom left figure
and the kids in the enriched
environment, cortisol across time,
across the 12 month period.
If the enriched environment is
very similar to healthy controls,
which is good news, but the
regular foster care kids do decline
in what their diurnal rhythm is.
Now-- or difference I should say.
Now these are kids who have
probably been in an average
of 5 foster care homes, so
certainly stressful, for that.
So intervention seems to change
the HPA axis for these kids.
I'm putting up the same biological
transition slide to remind you
about the vulnerability
for some individuals.
But that the context
may moderate how you do.
But there is this silver lining.
Even though you can be especially
vulnerable to harm at this time,
it also allows for the opportunities
or interventions that I mentioned,
then I'd like to elaborate
on that a little bit.
For example, we heard stress is a
part of everyday life but as parents
or educators or clinicians,
we need to think about things
like how does the negative context
impact the kid and cannot be changed
and then recognizing
emotional stress in these kids.
Not everybody can recognize that.
Can we intervene when necessary
and also promote successful
coping strategies?
Some of these do have
some policy implications
but let me elaborate
on this a little bit.
In the family setting, I think,
we could think about things
like safe home environment,
is that around?
How can you minimize parent discord
or enhance parent mental health
or their knowledge in
communication about child develop--
and communication with
their children?
For schools, thinking about the
education for teachers about stress,
education for safety issues
about bullying, not a day goes
by that we don't hear about
the impact of bullying
on children and adolescents.
Also in schools, are
there opportunities
for activities and relaxation?
You mentioned some of the studies
with relaxation in school systems,
which seems like a good idea.
In neighborhoods, are there safety
issues in certain neighborhoods?
Yes, we know that.
Is there opportunity for recreation?
All of these things could
potentially decrease stress.
And then I'd also like, do you think
about what I've called
the setting of technology?
All of the different technology
kids use from texting to Facebook,
all of those different things.
Do adults have the
understanding of this technology?
And can they monitor what's going
on because certainly those sorts
of things can be a stressor,
depending what kids are
texting to each other.
So, I don't think our work is done.
We need, in this area, we need
many more longitudinal studies
that tell us more about the
impact of these early stressors
or current stressors on
children and adolescents.
We're also really lacking
diverse samples by race, by SCS.
We know virtually nothing about kids
in third world countries,
in cortisol and stress.
We can only kind of surmise
from those sorts of things.
Collaborative studies where
disciplines are included,
behavior studies including
biology, biology including behavior,
and then culture and context
are included in that, as well.
That's it, perfect timing.
Sure, thank you.
[ Applause ]
>> We have time for a couple
of questions before our break.
>> Oh, there's one over there.
>> Dr. Brown.
[ Silence ]
>> As I'm listening
to all these factors
that impact stress--
let's take adolescents.
Is there any evidence that increase
the understanding on the part
of the adolescent as to
these various factors,
would facilitate their capacity
to deal with all of them?
I'm not even sure which of the
many things you've talked about,
but if they were 1 and
2 like I don't know,
expression of aggressiveness or
something, if you knew it was
in your brain or your, you
know, what's that relationship?
>> Yeah, I mean, I do think that's
kind of the 64,000 dollar question,
you know, like from a parent's
view or a clinician's view,
you might say, I told her that
that was really chancy to do.
But you know, if your friends
are all doing that and, you know,
they are encouraging you
in that sort of thing.
I don't think education only
is the answer, you know.
I think there are so many factors
that go into it, because they'll--
and also because of the brain
immaturity too, and the mismatch
between all those things.
But is--
>> Yeah, I'm listening.
>> Does that kind of answer or--
>> I wasn't thinking
parental admonition
because we know there are all
sorts of problems with that,
but just as you or
I during my study,
science in 7th grade or something.
We study machines, I remember that.
But suppose you would study
something about impulse control
and the elements that affect
that in your own physiology,
is there any studies
that would suggest those,
that kind of knowledge we'd have?
>> You know, I haven't seen any.
I don't know if anyone
in the audience has
but I think we could do better
job, a better job of exciting kids
about for example, about the
brain, and brain development.
You know, I don't know how
many health classes show,
some of the colorful
pictures that you showed.
You know, that's more
exciting to a kid or thinking
about imaging studies
and that kind of thing.
Like I do know, there are
classes in school about like,
relational aggression which
has some to do with bullying.
So how much of it sinks in, I
don't know and I'm not aware
that anybody has studied,
if that helps.
>> Is it true that the majority
of adolescents are doing well?
Well adapted to some--
>> I'm glad you brought
that up George 'cause
that is very important.
There are some studies that show
that it's really only 20 percent
or less of all the adolescents
that really have traumatic
times during adolescence.
So it's not all bad, there's a
lot of good adolescents out there
and some of these risky-type
behaviors are very short-lived,
you know, it's trying
it, it's experimenting.
So it's a small portion
that go on to be
in the more problematic
suicidal concerns.
So, good.
>> Great.
>> Good, thank you very much.
>> Thank you.
>> 15-- minute break.
[Applause] It's time to
continue with our next speaker,
Dr. Philip Gold from the National
Institute of Mental Health,
longtime collaborator
and a super expert
on depression, stress
and depression.
>> I was told to keep the
talk really quite accessible.
I thought to myself, you know
this stuff is very easy 'cause
when I was-- about 15 years
ago, there were, you know,
the New Yorker has little blurbs
of newspaper clippings
and they had this one.
Mr. Philip Gold was awarded
the [inaudible] prize
for the best Neuroendocrinology by
investigator under ten [laughter].
So, I went downhill
from there, I think.
So I'm going to talk
about depression
as a dysregulation of
the stress response.
And I'm going to cover part of this
stress response that really seems
to be most involved with depression,
although George very eloquently went
beyond this into multiple systems.
[ Pause ]
The World Health Organization has
named major depression the 4th
leading cause of disability
worldwide.
And, I think this is
for many reasons,
we now know that depression
is associated
with increased systemic
illness and a shortened life.
And also depression is a serious
illness that has a unique incidence
in children and adolescents.
And it's a lifetime disorder.
So there are many people out
there with this chronic illness
that begins even in
childhood and adolescents.
The mental anguish of depression
is only the tip of the iceberg
of a serious systemic illness
that doubles mortality in any age,
independent on suicide,
smoking and other risk factors
for poor health including
hypertension as well.
The excess mortality is equivalent
to approximately 9 or 10 years
and similar to that, I
mean, stopping smoking
and treating hypertension
effectively.
And patients with major depression
have premature coronary heart
disease, and premature osteoporosis.
And for coronary heart disease,
the incidence is doubled
and osteoporosis is found,
we reported that even
premenopausal women
with major depression develop
premature osteoporosis.
Now, I thought I started this,
you know, we talked about sort
of traditional stressors
with just sort of the concept
of existential things that
make life difficult even
if you live a very successful
and comfortable life.
You know, we all face, you
know, internal contradictions,
ambiguities and paradoxes.
There are elements of victory and
defeat, and defeat and victory.
There's loss of opportunity,
embedded in every choice,
you'd choose one and you give up all
the others, and after with clashes
between passion and duty,
the liability to change
in fortune no matter how worthy.
We sometimes must act in ignorance.
The renunciation is intermingled
with gratification and honor.
There's a possibility of suffering
about learning and changing
and sometimes suffering is
necessary to learn a change.
Coexistence of love and anger, the
unreachability of the ideal self,
the debilitating effects of
perfectionism, time is irrevocable.
We cannot recapture the past
and life is a continuous
progression towards death.
So there are many sort of,
to be alive, I think is to,
have to do internally
with many conflicts
that a few or any of us can escape.
The stress system, one
of the principal elements
of the stress system is anxiety.
Anxiety is essential for survival,
if of course if we're being,
like pursued by a bear,
certainly would require anxiety
to motivate and to find safety.
Now emotional memories, like,
those are associated with anxiety,
are exceptionally well-remembered.
They don't just occur for
a moment but they get--
they get encoded in a
number of brain regions,
but especially the amygdala.
And they are very difficult
to extinguish.
Now, there are actually very
good people who are working
with medications that
promote extinction
of aversive behavior,
of aversive memory.
That would be good for
posttraumatic stress disorder.
Emotional memory can be
retained even if other aspects
of memory remain unchecked.
Remain-- and for instance
the story of a woman
in a hospital had brain damage
to the part of the brain
that affected procedural memory
for objects and places and events,
and he came by and he gave her
a little pinprick every morning
and they-- in her palm and he came
by 6 or 7 times and each time,
she would withdraw her hand and
then on the 8th day, he pricked her
and she jumped back and he said,
by the way, do you know who I am.
She said, I've never
seen you before.
So, emotional memory can be
retained even if other forms
of memory are not intact--
remain intact rather.
Evolution has given us an abundant
circuitry to encode anxiety.
And there are many, many more
neurons that encode anxiety
and many more fibers that are
sent from the areas of the brain
that modulate-- that modulate
the thinking part of the brain.
So there is just not much
representation and in contrast,
there are not many fibers that go
down from the cortex to the areas
of the brain that generate anxiety.
And it's very difficult to
treat and I'm really pleased
to hear these methodologies that
the folks are developing to deal
with anxiety and similar problems.
[ Pause ]
During a stress response,
so you have anxiety,
the next is an innovation
of so-called the vegetative
functions whose activation would
impede adaptive responses
during threatening situation.
That would be sleep for instance,
you don't want to fall asleep
if you are being chased by there.
Feeding, you know where
to stop and eat.
Sexual activity, you wouldn't
want to stop for that.
And actually the capacity
to experience pleasure
is also somewhat clamped
because you wouldn't want an
individual who is just running
for his life to stop and
pause and see something
that gave some pleasure that
was very interesting him.
And programs of growth and
reproduction are also sacrificed
in a certain extent to
provide energy for other sites.
Now, stress hormone secretion.
Actually I'm just talking
now about in general.
There are two major stress hormones.
You heard a lot about cortisol
and also rather three, adrenaline
and noradrenaline is also important
and they're both secreted
during stressful situations,
noradrenaline first and
then cortisol follows.
And the cortisol has many positive
effects in normal concentrations
but it is very deleterious
when the levels are high.
It promotes the breakdown
of tissue, muscle.
It increases hypertension
as an immunosuppressant
and there are many things
that would be deleterious
with one had sustained
hypercortisolism.
Norepinephrine is the same.
It's secreted from the--
it's released from the sympathetic
nervous system and it's--
it promotes vasoconstriction, so
hyper-- blood pressure rate rises.
It promotes increase in heart
rate, increase in blood pressure
and increase in the
contractility of the heart.
But again, going on for a
relatively longer period of time,
and one that is usually experienced
during an ordinary stress response
would cause them many difficulties.
[ Pause ]
Now, the stress hormones do things
other than affect physiology
and of course they have
effects on behavior as well.
But they increase the
intensity and the duration
of emotional charged memories.
So that's a problem if you have a
very significant emotionally charged
memory and you're likely
to be secreting cortisol
and norepinephrine.
A clear study show that if
you can prevent their rise
to very substantial levels, then the
aversively charged memory is more
easy to extinguish.
And it seems to inhibit excess
of positively charge memory.
Now later on in depression, it seems
that-- and I thought this years ago,
the depression seemed to
be a continuous access
to negatively charged memories
that were without the content
which were influencing or
producing the psychological pain.
There's adaptive redirection
of energy.
I've mentioned that breakdown in
proteins and muscle has broken down
and the amino acids are incorporated
into new proteins that can be served
as fuel, and there's mobilization
of glucose for the brain,
so your blood sugar goes
up when you're stressed.
I might stop for a moment to talk
a little bit about the mechanism
of that because it's interesting,
'cause everybody hear so much
about insulin resistance
and may not--
it's very simple really that when
you're stressed cortisol causes a
block in the doorway from the
blood into the cell for insulin.
So ordinarily insulin will excite
the receptor and enter the cell
and exert regulatory
properties and lower blood sugar.
And what happens during stress
is cortisol is secreted,
so more insulin has to knock on that
door, higher levels have to knock
on that door to get through it
because the door is now more
resistant to being open.
And insulin has many deleterious
properties that I'm talking
about that later, but it increases
the sympathetic nerve system
and it promotes inflammation.
It promotes a bad lipid
profile and so forth.
Now there are other events that most
of us don't associate
with a stress response.
And by the way, by stress response,
I talk about running from a bear
but the same apparatus
is called into play
if someone hurts our
feelings or if there's a loss
and we happen to adapt into it.
So, to psychological stressor
or to a physical stressor,
inflammation is produced and
we've become slightly or pro--
in a proinflammatory
state, and kids for instance
who are not massively
obese but who are heavy,
they've done a study
on 12-year-olds.
They are all in a proinflammatory
state.
They all have increased
levels of hormones that work
on the immune system to
[inaudible] its function
and these are called cytokines.
One other new development is
that new neurons are produced.
The brain was not thought to divide.
We thought it retained a
stable number of neurons
and it didn't change so that
one would not lose sight
of one's personal history,
memories throughout a lifetime.
But we now know that
new neurons are created.
There is something called
neurogenesis and they are helpful
in modulating the stress system.
If you take an experimental
animal rat
and stress the rat very strongly,
the level of these compounds follows
and they are restored by the
administration of antidepressants.
And so one figure now is the
antidepressants may work on--
had been helping then
to produce new neurons.
As I'll show later, depression
is not only a sort of physiology,
but there is neurotoxicity, loss of
tissue in many parts of the brain
that are involved in a total
symptom complex of major depression.
But we never would have thought
of that maybe 20 years ago.
And nerve growth factors
must be secreted also
to promote the system
to respond to stress.
They are trophic to specific
systems and they coordinate repair.
Also rapid changes are required
and we call this neuroplasticity.
If you stress an animal, if you
imagine a neuron, you've seen them
with the little strings
that come out of them or--
it will grow pushy outgrowths,
and it will occupy more room.
But it's actual morph-- shape
changes and its function changes.
It is much more able to influence
home or a lot more nerves and genes
than the neuron was
able to do before.
Now animal models of depression
show that this neuroplasticity,
this should-- it's sort of--
it's like a tree kind of
blooming and opening its limbs.
It-- so that if animal
models of depression show
that these nerve growth factors fall
and that if you give animals anti--
standard antidepressants,
the nerve factors return
so that treating an established
depression even experimentally,
it's not really depression in a rat
but it's a model and it makes sense,
it's a stress model that you
can promote the regulation
of the stress response.
And one of the things that
happens pathologically is
that it doesn't turn off.
It's all right.
It's good for us for the short
term but it gets to be a problem
when it remains turned on.
Same thing for autoimmune
disorders, if you--
we need immunity but
patients who are--
have increased immunity
are not healthier.
These immunologic factors
attack tissues and destroy them
and cause disease like
rheumatoid arthritis.
[ Pause ]
Now let me talk about
major depression.
I have here that it's both
a disorder of mood as well
as a serious CNS driven
systemic disorder associated
with premature cardiovascular
disease
to help pathologic
bone growth and death.
I brought that out.
I won't stop with [inaudible] now
because I don't think I
have enough time, excuse me.
Now what is the composite stress
response that I've told you about?
They're fear related
behaviors and anxiety.
There's an inflexible mood
and cognition you don't want
if an organism is in danger
or if we're in danger,
we don't want to be having
our ideas and thoughts jump
around from one place to
the other or even working
on complex associated--
associated programs because there--
that could have been time
to execute them in a context
of a life threatening situation.
So the mood gets clamped
and the stress mode--
you see they get stress
hormone production
and they get [inaudible]
they get blood which is a--
rather sugar or blood sugar which is
the [inaudible] and not going in--
coming-- going into
the cells efficiently
because the door is fairly locked.
Therefore you get, I'm
sorry, glucose for the brain
for the nutrients that the brain
needs in order to function properly.
There is an innervation of
nerve vegetative programs
as I've mentioned, sleep,
feeding, sexual behavior, pleasure.
Now this rate-- the depression I'm
presenting here is a dysregulation
of that stress system.
As I mentioned, the stress system
is fine if it turns on momentarily
or for a few hours
or even a few days.
But it stays activated in one
way or the other over months,
then tissue damage and
illness results just
as the illness responds
to autoimmune disorder.
[ Pause ]
Now here's a phenotype of-- a
phenotype is a form of depression.
We generally think that there are
many different forms of depression
with their-- at least there are
two that are recognized formally
and one, this one called melancholic
depression is really the one
that holds true.
It's very similar from one
patient to the other rather,
and in other situations,
the depression seem
to be a heterogenous.
So this form of depression
belies the term depression
because it's a state of
activation, arousal, rumination.
It's often associated
with the anxiety
and as I mentioned before that,
anxiety is attached to itself
and the cruelest manifestation
of this particular form
of depression is that people
lose their regard for themselves
and regard for the-- what
they were in the past
and their past achievements,
what they are in the present
and what their prospects are
for future gratification,
essentially in theory itself.
[ Pause ]
There are physiologic and
disease of hyperarousal,
stress hormones were elevated
but they're inflammatory
mediated to elevated.
Also one other thing
I didn't mention,
there's also more blood clotting.
The reason I think, by the way,
going back to inflammation,
that there is inflammation
during stress.
This is a premonitory rise in
a fight or flight situation
in case there's an injury.
They are inflammatory mediated
around to repair the damage.
And the reason that-- pardon,
back-- back on here, okay.
Now the depressed mood and
melancholy are described actually
in several different ways.
It intrudes upon elements
that define our humanity.
The [inaudible] manifestation
of the melancholy is a
pronounced sense of worthlessness.
The anxiety is an important part
of melancholia and it is directed
against the self, it really
is an anxiety about the self.
I'm worthless, no one
will care about me.
There's intense [inaudible]
rumination
and this is an intriguing
feature which is present
in almost all patients
with melancholia.
The mood is significant-- is
more severe in the morning
and the evening, and they just
for the most part getting
only slightly less severe
but that pattern holds true, and
the mood is clamped like it is
in a stress response
but in a pathologic way.
There are cognitive deficits in
patients with depression also.
There is a sort of a switch from
sequence associational type learning
and executions
to more well-rehearsed
almost instinctive programs
that the organism or
the person can put
into play rapidly in
order to survive.
But in a sense, these two forms
of cognition hold true in a person
who becomes-- sustain depression and
one of the issues, disturbing issues
in patients with major
depression is that memory
and intellectual acuity somewhat
influenced by the depression
and is completely [inaudible]--
is completely reversible.
And melancholic depression, also
I've mentioned earlier seems
like an almost continuous
bombardment
of emotional memory
that had been laid down.
And this emotional memory by the
way comes back without the content.
You feel the feeling but don't
necessarily you're not able
to put your finger on
the fact that this is
because someone had insulted
me terribly 25 years ago.
Now there are newer vegetative
features in depression,
in melancholic depression.
Instead of inhibition of sleep,
there is a sleep disturbance
and that sleep is almost always
in early morning awakening.
If I see someone who is
depressed and they wake up early
in the morning, I think the
diagnosis is fundamentally made.
There's a loss of appetite,
there's reduced sexual activity.
There are decreased endocrine
programs of growth and reproduction.
So it's similar to this
vegetative picture in a stress
but it's a-- is regulated.
There's a maladaptive
direction of energy
and that [inaudible] is an
excessive breakdown of protein
and there are high blood sugar
levels because of insulin resistance
which occurs early
on in the depression.
There's excessive cortisol secretion
and excessive norepinephrine
secretion.
Here's data taken in our laboratory
a long time ago and if you look over
and saw the left panel
which is at night,
that's what those dark
columns represent.
The levels in red in the depressed
patients are significantly higher
than they are in the controls
and that is usually at night
which is intriguing
because it suggests
that these high cortisol levels
are not necessarily related
to the stress of the
illness during the day time.
And norepinephrine
secretion is also increased.
This is an interesting
kind of study.
We had patients and we measure
their baseline norepinephrine.
This was spillover over in the
arteries and we follow them early on
and the blip you see is when the
control subject was playing a simple
video game, but norepinephrine
went way up and it remained high.
The lower panel that the-- the
black curve is the baseline level
and it's interesting that if you
noticed an increased baseline level,
you could still jack the system up.
Usually if you have a system that's
activated, it's a little harder
to further jack it up because
the mediators that influenced it
or because it raised it
become less sensitive.
And I mentioned that the
effect of stress hormones,
encoding emotional
memories and in depression,
it's excessive inflammation
and it's-- in excessive.
Actually, I didn't mention
this very successive increase
in blood clotting also just as
the inflammation is premonitory
to perhaps the protecting-- person
if there's a possible injury.
The increased coagulation
is there as a help or stay
against potential hemorrhage.
And here is a study we did
where we put in a little canula
and took bloods out at regular
intervals for something called IL-6.
IL-6 is a cytokine.
It's really one of the
most important mediators
that stimulates the immune system
and it also stimulates what
is something called an acute
phase response.
We see it, it is elevated throughout
the night and is-- becomes a--
rather in the daytime
and it falls at night.
The-- well, there are certain
mathematical formula you can play
with this kind of curves and
see if they show a regularity
or if they show a sort
of an irregularity
that is dictated though
by a physiologic system.
And that was [inaudible] high
for this form of secretion.
The pattern of it was also abnormal.
[ Pause ]
Now the fibrinogen plasma,
fibrinogen, fibrinogen is one
of the principal clotting
factors and just a few measures
of depressed patient at baseline,
you'll see that the
fibrinogen levels are elevated.
And again, if this was stressed
and they're elevated during stress
as well, this would be premonitory,
perhaps to stay against hemorrhage.
Now a little bit about
the circuitry there,
much more is known
about the circuitry now.
There are 7 or 8 areas of the
brain where there is a notable loss
of tissue that impairs
the functions of elements
that are involved in depression.
Now at the top, the
green arrow is pointing
to the medial prefrontal cortex.
And the medial prefrontal cortex
is a very important function.
It restrains the amygdala
fear system.
It promotes intellectual
like thinking.
It restrains the stress hormones,
and perhaps its most
important function is
as I mentioned is restraining
the amygdala.
So in this, this break
on the amygdala,
it has diminished function.
Amygdala function increases
and there is increased anxiety.
And I think when that
happens over the long haul,
that's what produces the depression.
The amygdala by the way, I'll show
you next, is the area of the brain
that is essential both for the
conscious experience of fear
but also it prints memories that
are not necessarily connected
with the specific sources and stores
them for long periods of time.
So there is the amygdala.
It is essential for fear,
condition fear responses,
inhibition of the medial prefrontal
cortex, and activation of the CRH
and local [inaudible] system.
So by the way there's a positive
feedback response going on.
You want the amygdala to be calm so
that it-- so there is an anxiety.
And I think sometimes,
I think depression is an
organized native anxiety.
But it's attached to the self.
So you want to restrain
the amygdala.
Now the medial prefrontal
cortex sustains it.
But when its low, the
amygdala function increases
and then the amygdala
function then goes
on to stimulate the medial
prefrontal cortex more and it goes
on to you know, if it's a--
it sets into motion a
positive feedback loop.
And these systems are the systems
that control norepinephrine
and CRH secretion.
And they also influence the
medial prefrontal cortex
in a positive feedback loop,
amygdala with a positive
feedback loop.
So this system is really whirring
around once it gets started.
It's very hard to stop it because
each element is not only doing its--
playing its old rule, but it's
influencing the functional activity
of the other.
Here is a graph of the
tissue volume which is taken
from a medial prefrontal cortex
and I've rather this one--
now this was taken during a PET
scan and what we see is the volume
of the medial prefrontal cortex
is rather high in the control,
it's reduced in both the bipolar
and the unipolar patients.
And in bipolar and
unipolar patients,
they decrease in the volume of the--
it's called the subgenual
prefrontal cortex,
is as much as 40 percent,
which is enormous.
Now there's some suggestion that
antidepressants can reverse this
or mood stabilizers
can reverse this,
and the data will be coming for--
I think it looks like they--
they do reverse the loss
so it's not irrevocable.
So another important reason to treat
depression I think is medication
because the medication
can restore some
of these pernicious processes back
to their homeostatic state
as George described it.
And there have been some
imaging studies in depression
that sort of-- they're interesting.
I'll just show you 3 that suggest
that the medial prefrontal cortex
activity is not functioning as well,
and that the amygdala is overactive.
One study which was
very interesting,
faces with distinct features were
flashed in a very rapid function
and went from a very
smiling expression
down to a neutral expression and
down to a frowning expression.
Now, the pictures were being
presented too quickly to be seen
by the naked eye, but
these folks were hooked
up to the imaging machine
and what we saw is
that the depressed patients
started to increase the activity
of their amygdala just before
they got down to neutral.
They didn't have to go
down into the frown,
and the controllers have the--
are far down to see the frown
so that the pregenual cortex
function was not proper By the way,
one of the important
functions of the pregenual--
of the pregenual prefrontal cortex
is estimating the likelihood
of punishment or reward
in a particular session
which I think you would see as very
important in a depressive disorder.
Now, when patients with major
depression anticipate a negative
event, the circumstances
often described is dread.
There's a subgenual
prefrontal cortex dysfunction,
will lead to an abnormal persistent
negative affective response,
even if the dreaded
response doesn't occur.
So the depressed patient can be
told something terrible is going
to happen.
And when it doesn't happen
in two or three hours,
the controls are back to normal.
The depressed patients
are still functioning
as if they are expecting
a punishment rather
than reward or a neutral situation.
When depressed patients reflect on
their internal state or in words
that apply on themselves,
the subgenual prefrontal cortex
activity changes indicating
significantly more
negativity than controlled.
And patients with major depression
have a significantly lower response
in the nucleus accumbens to
a pleasure from stimulus.
The nucleus accumbens
is a dopamine-rich area
that plays a great
role and is translucent
in pleasurable experiences.
So, if you give a pleasurable
picture, say,
or a series of pleasurable
pictures, to control,
their nucleus accumbens
will significantly increase
in metabolic activity and
in the depressed patients,
it's much less evident.
So there is this antidote
or difficulty
in the experience pleasure.
There's another form of depression.
I'm not going to spend a
great deal of time in it.
But remember in here, you
have melancholic depression
with this kind of hypo,
you know, it's arousal.
The atypical depression
is associated
with a pathological hypoactivity.
It's associated with
profound [inaudible] fatigue,
patients feel much less alive
than usual rather than anxious.
They have like the
melancholics a decreased capacity
to experience pleasure.
They have an increased appetite.
They have an increased sleep,
have a deep sense of loneliness
as a part of this disorder.
I think because one of the things
that happens is it whereas maybe
the depressed patients have too much
of a capacity to get-- to retrieve
negatively charged emotions,
these patients seem to be attached
with themselves and they can't seem
to retrieve memories, emotional
memories and they feel empty
and alone 'cause all the figures in
their life sort of figuratively--
and they should remember
are not accessible to--
this is an instance of
they lost their past.
This very good depression here is
the antithesis of that melancholia.
It is less in the morning and
more severe in the evening.
And as I mentioned
often, there's the state
of loneliness and isolation.
We've done studies
in these patients.
I will show the data.
But these patients actually have
evidence of hypoaction, HPA axis.
Their baseline cortisols are low.
We use certain stimulation
tests that give us information
about the relative roles of
the brain, the pituitary,
and the adrenal glands in
regulated cortisol secretion.
And it seems that at the level
of the brain, the nature stimulus
which is an activating
compound is significantly lower
in these patients than in control.
We have other sets of data by
the way where their response
to other stimuli are
also hypoactive.
You get a big cortisol and ACTH rise
with a greater treadmill exercise.
And this doesn't occur as
randomly in the patient.
And like the pattern by
the way which is comparable
with essential rather
than a peripheral defect.
It's a little harder to
treat the melancholia.
Now melancholia has
probably the highest rate
of response among the depressions.
It responds to a range
of depressions.
This struggle is not
used very often,
although it still has its place.
But imipramine is a-- which is a
tricyclic antidepressant is great
for melancholic depression.
But atypicals don't respond to
it all, they respond to less
than [inaudible] to placebo.
So it probably has an
immersive effect on them.
Perhaps it turns down
the axis even further.
[ Pause ]
I mentioned this before that a
melancholic patient seems to be
in a continuous contact
with the past,
diverse in the past of the memory.
And the atypical depression
seems to have lost his past self.
Now, I mentioned that medical
complications of major depression,
that major depressed patients have
an increased risk of mortality twice
that of [inaudible] control,
increased premature coronary
artery disease and osteoporosis.
[ Pause ]
So here, osteoporosis, I don't think
you can see this slide very well.
On the bottom, if you
see that dotted line,
it intersects that normal
range right at that level
that would denote osteoporosis.
Well, I didn't get a
good figure for that.
We've actually done some
bone biopsies in women
with osteoporosis and here's one.
We have the normal bone on the left
and the abnormal bone on the right.
This is in a 38-year old woman.
And what you see over there, you
see these canals as they were
and a continuous connection between
these, the structural components
so it adds stability to them.
But here, that structural
component is lowest.
And young women don't tend to
get fractures in their 30s or 40s
because they're young and that
bone strength is still strong.
But when they are 50 or
55 rather than 65 or 70,
they're very prone to osteoporosis.
It's important to recognize that,
and I think many doctors will think
about bone health in patients
with major depression 'cause
it can be so readily treated.
Coronary artery disease, I'll
flip this by very quickly.
These are studies on norepinephrine
secretion and epinephrine secretion
in patients with major depression.
These were very severely
depressed patients.
As you see, it's elevated just
in the cerebral spinal fluid.
We actually had a lumbar
drain in several patients
that we can excuse CSF,
cerebral spinal fluid.
For 24 hours, it's a
virtually painless procedure
and perfectly safe.
So you see in red, the depressed
patients are significantly elevated
above the controls in black.
The next [inaudible] thing on
the top is plasma norepinephrine.
And one thing I would note here that
the levels still go down at night
but they reach their peak at around
9 or 10 o'clock both in controls
and in patients, and it's a very
cardiotoxic compound and that
that may be one reason
that the time--
the greatest risk for
an acute heart attack
or sudden death is
around 9 or 10 o'clock.
And the next one shows again
elevation of the norepinephrine
in the patients versus the controls,
and the last is epinephrine.
And epinephrine doesn't
show the same--
their own variation but it's
much higher than in depression
and it's a cardiotoxic compound too.
And we also show that cortisol
follows these same patterns.
And a cortisol and adrenaline
and noradrenaline were
not quite synergistically
in being cardiotoxic.
And they are simultaneously elevated
at the same time and it's so--
turns out that the highest levels of
adrenaline are at that time as well.
These patients were
very severely depressed,
although there are some suggestions
that depressed patients do
have high blood pressure.
But their control blood
pressure is on--
is in yellow and in men it's
again that there's in the patients
and then after these patients were
so severely depressed
that they got an ECG.
But after ECG, the systolic tension
fell back again to normal levels.
And here we have the diastolic
pressure, that's the lower number.
It's also prior to the
ECG that comes down.
Now they're elevating fasting
insulin and glucose levels
in patients with major depression
and we've matched these
people very tightly,
the BMI match controls
and we had 32 patients.
They were thin so that obesity
was not a compounding factor.
And what you see is that they
have increased levels of glucose,
and increased levels of-- rather of
insulin increased levels of glucose.
These levels do not
meet the criteria
for insulin resistance
or type 2 diabetes.
You need to get the
fasting blood sugar.
Now it's up to 100 rather than 120.
But they are significantly
higher, and there are data
that there is sort of a
continuous risk with these
with respect to the levels.
So if the levels rise even
5 points over 10 years,
and that's carefully documented,
there's a doubling in the incidence
of type 2 diabetes, and patients
who have type 2 diabetes 2
or 3 times more frequently
than controls.
And again, that high
insulin levels are pernicious
and the insulin causing increased
sympathetic activation raising
cortisone causes increased
[inaudible]--
pardon me, I'll skip that.
A couple more.
Can you get this to go back?
Okay, here's an interesting slide.
These two women are
the exact same weight.
They have the same BMI.
Let's say it's probably
right at 125 or 30 pounds.
But this patient who's a depressed
patient has a much large mass
of what is called abdominal
fat, intra-abdominal fat,
which is different than
the subcutaneous fat.
And as you see this intra-abdominal
fat is producing all kinds
of inflammatory mediators.
All of these are compounds
that generally activate
their cytokine receptor.
Now with so much activity and
increased inflammatory activity,
these inflammatory mediators
also raise insulin secretion,
and insulin produces insulin--
rather an insulin stimulates
the secretion of cytokines.
So we have another positive feedback
between metabolism and insulin.
The reason this may be so, and
this is a system-- I guess it's--
because it was not really
very clear why that insulin--
inflammation should be so
wrapped up with blood sugar.
But the thought is that with
the increased-- that the--
with the increased levels of--
that cytokines do is to
affect norepinephrine levels
that will further increase the
insulin resistance which you need.
So there's a very tight
relationship.
Another thing that-- the
things do that is possible is
that when one gains weight
and you have more sympathetic
nervous system activity,
that also can be soluble.
Now here are some good and positive
stress responses of the controls,
patients with depression, and
then the epinephrine findings.
So the controls-- the
positive stress response,
you had these elements that are
all changed with depression.
Fear-related behaviors and anxiety,
inflexible moods and cognition,
stress hormone production,
redirection of fuel
to the blood stream, premonitory
inflammation and coagulation,
inhibition of neurovegetative
functions
which were the ones we talked
about sleep and so forth.
And also there is nerve
cell growth--
nerve cell growth factors and
increased neuroplasticity,
and there is effective
termination of the response,
and I didn't mention here that
neurogenesis with production
of neurons, new neurons also occurs
as part of the stress response.
And in stressed individuals,
or at least in stressed animals
as I mentioned, that the increased
generation of neurons that commit--
submit growth factors, that help--
that means that the kind of the--
sorry, the volume of the brain
and especially the subgenual
prefrontal cortex would
be protected.
Sorry about this.
That was at most [inaudible].
Now melancholic depression
looks very, very similar.
You have increased and prolonged
fear-related behaviors and anxiety,
inflexible mood and
cognition, increased
and prolonged stress hormone
production, increased redirection
of fuel to the bloodstream
and brain, increased
and prolonged premonitory
inflammation and coagulation,
increased and prolonged inhibition
of neurovegetative function,
and decreased [inaudible]
growth cell factor
with decreased neuroplasticity
and insufficient termination
of response.
The last is atypical depression,
and again is the antithesis
of major depression.
Oh, actually see I told you before.
It's characterized by profound
[inaudible] and fatigue.
Patients feel less alive.
A decreased capacity to experience
pleasure is likely melancholic,
increased appetite and sleep,
a deep sense of loneliness.
The severity of the depression
is less in the morning
than in the evening, and often a
state of isolation and loneliness.
Means I'll stop here.
[ Applause ]
[ Inaudible Remark ]
[ Noise ]
>> Any questions?
>> Then down there.
>> Yes please.
>> [Inaudible] and I'm wondering
if that-- what the relationship is,
is the stress triggering and
already existing bipolar--
[Inaudible Remark] -- syndrome?
>> Stress does precipitate bipolar
disorder but we understand less
about the actual biology of--
the physiology and the
biology of bipolar disorder.
That's one of the reasons you didn't
see many slides on bipolar disorder.
The hormones and CSF compounds have
not in the-- examined as readily.
It might be in part because
of the relative [inaudible]
bipolar patients.
But also, it's very difficult to
study them when they're manic.
I personally feel that they
are part of the same illness,
that there's a continuum on from
depression and it gets more severe
and perhaps they can be a
development of bipolar disorder.
And it seems that many patients
who do have bipolar disorder had
unipolar depression before they
developed the bipolar depression.
The good news about
bipolar depression is
that there have been treatments
now with the anticonvulsants
like lamotrigine and so forth.
>> Dr. Rosenthal.
>> Yeah, thanks very much
for the comprehensive
description and discussion.
One thing that really
intrigued as I--
we've both been dealing with
depression for many decades now
which is completely new and
unexpected is the extreme loneliness
that you described in the
atypical depressed people.
Are there any lonelier than
any other depressed people?
I mean where is-- where is the data?
>> No, I have no data.
It's my clinical observation
that I've seen that kind
of malignant loneliness more
frequently in the patients.
>> But you sort of described how--
and sort of how they
would express it
or how it would emerge
in a clinical interview?
>> Actually simply say they have--
you know, it's often very difficult
for them to interact with
other people and some say--
and they seem burdened even the
slightest task, and many tell me
that they feel so depressed
in a way that even carrying
on a conversation seems like, you
know, tremendous work out of your--
>> And certainly very familiar
to me because of course one
of the areas of-- that I've
researched is the seasonal affective
disorder and most of those
people are atypically depressed.
>> Right.
>> And I think it's the effort
of interpersonal engagement
that is overwhelming and
that they can't bear it.
And I've seen many people just
let go of a relationship because--
>> Right
>> -- it's just too much work.
>> They do it, yeah.
>> So I've never sort of seen
that as loneliness but rather
as just this is more work than I can
muster and more work than it's worth
and if the partner or
lover or friend has to go,
then that's just what's
going to have to happen
because it's all I can manage.
>> You know, I think that's right.
But I do think, you know, and
this is just metaphorical.
They do seem less alive, flatter,
and I don't hear much talk from them
about their past as I do say
for the melancholic patients
who are equally depressed.
They may be disconnected from it.
>> No, that's interesting
and I think
that the melancholic
depressives are more agitated--
>> Yes, they are more [inaudible]--
>> -- and more activated.
And that goes along with
the HPA axis activation
and these people are
just flat [inaudible].
>> Yeah. Yes, and activated
[inaudible].
>> Thank you
>> Continuous anxiety.
Any other question?
>> Dr. Romero.
>> Yes. Phil.
Phil, can I ask you, thank you
very much for the presentation.
I have three questions, very brief.
One, you show a study in which
interleukin-6 was elevated
in the morning and I saw that
you had samples taken throughout
the day.
Does that represent a change in the
circadian rhythm of interleukin-6?
>> Yes.
>> And how often did
you sample the patients?
>> I think we were every 15
minutes on every patient.
>> 15 minutes.
>> Yeah,
>> The second question is, you
know, forgive me for asking this,
it's an obstetrical question.
Most women have a changing mood
and then we have the
extreme postpartum depression
that can end in suicide.
And I wonder, one, are there
studies about what imaging,
neuroimaging in postpartum
depression?
>> I don't believe so.
George and I have studied that,
you know, endocrinologically
and it seems like they're very
hot core, so that was they have--
causes the third trimester
plasma CRH levels.
When that's removed, then they have
an activation of the immune system.
>> It's in a typical form.
In other words, cortisol
goes down for three
or four months after the delivery.
>> Yes, right.
>> David.
>> Hi Phil, thanks, you've
really pioneered this area.
I appreciate your work.
Two questions, so is the elevated
IL-6 in the morning related
to the elevated cort at night.
Does cort drive that or
is it independent of that?
>> [Inaudible] cort [inaudible]
suppresses IL-6 actually
for the most part but IL-6 does
stimulate cort to a great extent,
and that stimulation is probably
for a negative feedback response.
We have IL-6 which is
crossing information.
Yeah, and you have a-- it
promotes the secretion of cortisol
and cortisol restrains the access.
So that's one component
of cortisol--
corticals of negative effect
on, on the immune system.
>> Coincides with the catecholamine.
So when the catecholamines
are high, IL-6 is--
>> IL-6 is high.
>> But it's not [inaudible].
>> If everything is low.
>> It's not a [inaudible] why it
would happen given the elevation
of cort particularly at
night and depression.
>> Yeah. 'Cause IL-6 and cort
are probably, I say have--
they don't have similar, ordinarily
have similar circadian rhythms.
>> All right, thank you.
So the second question has to
do with medial prefrontal cortex
which you mentioned
inhibits amygdala.
Medial prefrontal cortex
is also involved
in social perception and cognition.
>> Right.
>> And so I wonder if you
have any comments about that,
the isolation of depression
and the [inaudible].
>> That's a good question.
I don't think people
have studied atypicals,
but it wouldn't surprise me
that they, they feel awkward.
They feel like they're not going
to present themselves effectively.
Yeah, it's a good question, I
don't know if there's a central--
a modulation of a central sort
of socializing component
which does exist.
>> [Inaudible] it's on.
Could you speak through the
long-term effects of living
in a constant state of vigilance?
>> Good question, it hasn't been
studied really as much as it should
and I think that there'll
be a vulnerable population
like everything else will
respond with the depression just
like they'll respond to-- with
depression to various other things,
but they're all going to
respond at the same thing.
That's not an answer
to your question.
I think people haven't really looked
[inaudible] a study to my knowledge.
It certainly should
have been done on--
what is the incidence of depression
of people who think [inaudible].
I'll bet, I'm sure it's
going to be higher.
[ Pause ]
>> Another question?
So thank you very much.
>> Thank you.
>> And time to go to our
last but not least speaker.
Thank you, Phil.
>> Thanks [inaudible].
[ Applause ]
[ Inaudible Remark ]
[ Noise ]
>> Next speaker is Dr. Daniel Clauw.
He's going to talk about pain
and fatigue states,
PTSD and war syndromes.
Dr. Clauw is professor of medicine
at the University of Michigan
in Ann Arbor, Michigan and
formerly of Georgetown University
and a collaborator and friend.
>> Thanks George.
[ Pause ]
The University of Michigan
makes us show these slides.
I'm not trying to show off a
drug company consulting, so.
So you've heard today about
the notion that there may be,
if you will, vulnerable
host that for one reason
or another have some
type of vulnerability
that when they're exposed to stress.
Phil and others talked a lot about
the development of mood disorders.
I was asked to talk about
posttraumatic stress disorder
but I don't consider
myself to be an expert
on posttraumatic stress
disorder, so I'm just going
to talk very briefly about that.
What I do know a lot about is pain
and so what I'm really going to talk
about now is the role that
stress has in triggering,
exacerbating a number of
different chronic pain states.
So, let me begin by being
a little bit provocative.
I'm a rheumatologist by
training, I'm not a psychiatrist.
I become a neurobiologist as
a result of studying pain.
But these are knee x-rays
from two different people.
For those of you who might not be
used to looking at knee x-rays,
the bone at the top is the
femur, the bone at the--
the big bone at the
bottom is the tibia.
You can see an outline of
the kneecap or the patella
and you see there the space between,
on the left between the femur
and the tibia is actually
made up of cartilage.
Cartilage does not
show up on an x-ray.
Bone does show up on an x-ray.
So, as a rheumatologist
or an orthopedist,
when we look at a bone x-ray,
especially a weightbearing x-ray,
we're looking for a joint space.
And when we see a joint space, that
indicates there's cartilage and the
under [inaudible] bones, and that
theoretically would be normal.
But the question I
have for you here is
which of these people has knee pain?
The person on the left with
the wide open joint space,
i.e. intact cartilage on both
sides of the bone or the person
on the right that one side
of their joint space has been
entirely obliterated.
That's the-- what the
answer is supposed to be.
But if the answer was the person
on the right, I could sit down
and you wouldn't-- I wouldn't
have to tell you anything
about pain and pain processing.
As it turns out, this is by far
the most common cause of arthritis
in humans, so-called osteoarthritis.
It's the type of arthritis that most
of us will get if we get old enough.
The rate of osteoarthritis
is going up exponentially
in the United States as we get
older and fatter as a country.
The estimates are now
that about 50 percent
of individuals will develop
osteoarthritis just of their knee,
that's not any other joints or
any other areas of the body,
just given our lifespan, obesity
and some of these other factors.
Now, as it turns out, the
person on the left is the one
that has severe pain and the person
on the right is the
one that has no pain.
And in fact, this is aligned
with population-based studies.
If you don't happen to be a pain
researcher or a rheumatologist,
you would not know that 30
to 40 percent of the people
in the general population that
have x-rays looking like the x-ray
on the right, bone and bone,
grade 4 radiographic evidence
of osteoarthritis have
absolutely no pain, so--
And 10 or 20 percent of people
that have severe knee pain have
entirely normal radiographs.
So, what has become increasingly
clear in the pain field is
that this inordinate focus on
the periphery and this attempt
to explain most if not
all pain on the basis
of peripheral nociceptive input.
And what I mean by peripheral
nociceptive input means
that there's a sensory nerve
out in the periphery or nerves
that are being irritated either by
chemicals, by mechanical pressure
or some other signals
to send an impulse
to the brain to be felt as pain.
The reality is there's actually
not any chronic pain condition
where anything we can measure out
in the periphery, an x-ray, an MIR,
a cystoscopy, a laparoscopy
accurately predicts who is going
to be experiencing pain or how
severe the pain is going to be.
The problem-- and I'm not
here to talk about this--
is that our diagnostic paradigms
even at present still assume
that if someone has pain in the knee
that the problem is in the knee.
If they have pain in the hip,
the problem is in the hip.
And they don't in any way account
for by far our most common
pain conditions, headache,
irritable bowel syndrome,
fibromyalgia.
We know there's no
problem in the periphery.
The headaches aren't because
there's brain tumor or are problems
out in the head, that they likewise
have central nervous syndrome
mechanisms as I'm going to talk
about in the next half hour
or so are contributing to
most chronic pain states,
and some of this in
fact can be triggered
by different types of stress.
Now, in the pain field, one of the
unfortunate things that happens
in general in medicine has certainly
happened in the pain field,
is when we see these individuals
where there is a disparity
between what we can see
in an x-ray or an MRI
and what they're experiencing,
we've had a historical tendency
to say there's something
wrong with the person.
It's psychological factors, they're
crazy, it's all in your head.
And a lot of times when I give
this talk to pain audiences now,
I say it really is all in
their head because the advent
of brain imaging has made it clear
that there are neurobiological
reasons
by which people develop
these chronic pain conditions
without any peripheral
nociceptive input in the periphery.
And these are not just operative
in conditions like migraine
and tension headache, irritable
bowel syndrome, fibromyalgia,
these very prevalent
conditions, but now,
what we're realizing is
these are playing a role
in any chronic pain
state, low back pain,
osteoarthritis, rheumatoid
arthritis.
At the end of the day what--
there are two systems that
are sensing pain in the body.
One of the systems in the
body is sensing peripheral
nociceptive input.
Is there damage or
inflammation out in the periphery?
But that information, once it
enters the central nervous system,
gets filtered by the spinal cord
in the brain and the spinal cord
in the brain can either turn down
the value of control in that.
So, those individuals that
have something really wrong
with their knee but don't have any
pain have very robust descending
analgesic activity in their brain
such that even though there's
something wrong in their knee,
that information is
not allowed to go
up to the brain to be felt as pain.
But at the other end of the bell
shaped curve are individuals
that have a very high volume
control setting in their brain
and their spinal cord, and they
don't have to have anything wrong
in order to have pain
diffusely throughout their body
as occurs again in
conditions like fibromyalgia.
So what I'm going to do is talk a
little bit about what we've learned
about the biology of
these conditions,
the treatment of these conditions
and then highlight the role
that stress may have in
leading to these conditions.
Now I want to emphasize that
these are non-psychological,
non-psychiatric factors that
seem to turn off and turn
down the volume control
setting, that these are somewhat
or largely independent of
constructs like depression, PTSD,
and other psychiatric disorders that
have been talked about more today.
So, the direction that we need
to go is instead of saying
that someone has osteoarthritis or
rheumatoid arthritis or cancer pain
or neuropathic pain or
fibromyalgia, what we instead need
to move towards is where we actually
identify the underlying mechanism
in each individual, because
what we know is that,
although most individuals with
osteoarthritis or cancer pain
or rheumatoid arthritis do have
ongoing peripheral nociceptive
input, i.e., there is something
wrong out in their joints,
out in their tissues, we know
that about 30 percent of people
with osteoarthritis or rheumatoid
arthritis or cancer pain have
so called centralized their pain,
and that the central nervous system
is playing a very active role
in their pain.
I can do what you would see
in someone with fibromyalgia
that doesn't necessarily
have anything at all wrong
out in the peripheral tissues.
So I'll talk about fibromyalgia
for just a second more
as a metaphor rather than
a standalone diagnosis
because fibromyalgia is
the first pain condition
that in general we realize must
be coming from the brain rather
than coming from peripheral tissues.
But every year or two,
there's a new pain condition
that where we realize the brain
is playing a more prominent role
than the peripheral tissues.
And, as that occurs, we
actually change the name
of this pain condition.
So, fibromyalgia used
to be called fibrositis
until we learned there was no -itis.
Itis means inflammation of the
tissues and we changed the name
to -algia which means
that there's pain.
Irritable bowel used to
be called spastic colitis.
I now lead an NIH network
studying interstitial cystitis,
a chronic pelvic pain condition.
And that, within the next
six months to a year,
will be renamed bladder
pain syndrome instead
of interstitial cystitis.
So what's happened overtime is
that the initial idea always
is peripherally focused
that there is inflammation
out in the periphery that's causing
these different pain conditions,
but the reality is, most pain,
until people start to get older
and develop wear and tear
conditions like osteoarthritis
or if they have an autoimmune
disease which only occurs
in about one percent
of the population,
like rheumatoid arthritis,
they can have pain on the basis
of peripheral nociceptive input.
But if you look at people before
they get to be age 50 or so, by far,
the most prevalent pain conditions
are these central pain conditions,
fibromyalgia, irritable bowel
syndrome, headache, endometriosis,
where we're learning with each
advancing year, we're learning
that these are more a brain
and a spinal cord pain amplification
problem rather than a problem
out in the periphery and where
the pain is actually experienced.
And so, our group had spent a
lot of time moving from thinking
if fibromyalgia as a discrete
or unique illness to more
of a final common pathway.
That all it really is,
is that these people,
that the central nervous system
is playing a very prominent role.
And in fact, the only
role in fibromyalgia,
but fibromyalgia patients have more
severe and more widespread pain
than any other rheumatologic
condition that we actually know
of even though the pain doesn't seem
to be coming from the periphery.
Now there's a lot of overlap between
these regional pain syndromes,
a widespread pain syndrome
and psychiatric disorder,
and we think that one of the big
reasons for this is they share some
of the same brain regions and share
some of the same neurotransmitters,
and I'll talk more about that.
But, in clinical practice, we're
learning that the simplest way
to identify whether people
have a more peripheral reason
for their pain or a
more central reason
for their pain is ask them
pretty simple questions.
Give them a body map and ask them to
mark in different areas of the body
where they have had chronic pain
over the course of their lifetime.
And the more X's that a
person has, the more likely
that they have a spinal
cord or a brain problem.
Because what will almost always
happen with people that end
up developing fibromyalgia
in say age 35 or 40,
they're finally diagnosed
as fibromyalgia.
Those people start
out in adolescence having
functional abdominal pain,
painful menstrual periods,
headaches.
And that's just the
start of their pain,
and then their pain
becomes more widespread
and more severe as they get older.
And then they finally get labeled
as having a condition
like fibromyalgia.
But you can almost always
track going into childhood
that these individuals are more
pain sensitive throughout their
entire lives.
And I'll show you some
data suggesting
that genetics is playing a very
strong role in pain sensitivity.
Just in the last five years or
so, five or six different sets
of genes have been identified
that are capable of turning
up the volume control setting
such that if you happen to be born
with one or two or
three of those genes,
you will have experienced more pain
for the same amount
of nociceptive input.
And if your volume control is really
high, it's like a radio that is set
to no station but just static,
is that this is what seems
to be happening in
conditions like fibromyalgia.
Is that there's no filtering that
that occurs in normal individuals
and people get barraged with pain
and other sensory information
because so many of the
filters that are present
in normal individuals are not
present in these individuals.
Now the way we can identify these
people is they don't just have pain
all over their body, they
have fatigue, memory problems
and sleep disturbances,
also, either at the same time
as they're experiencing
pain, or at any--
in other times during their lives.
And again by far, the
most plausible,
biological plausible reason
that this occurs is the same
neurotransmitters that are capable
of turning up or turning down the
volume control setting in pain
in the spinal cord,
control sleep, control mood,
control level of alertness, these
are things like glutamate, GABA,
substance P, norepinephrine,
serotonin.
So someone has low serotonin in one
area of their brain, that might turn
up their volume control
for pain processing.
In another area, their brain,
that may make them sensitive
to all sensory experiences
not just pain.
And in yet another area of the
brain, that might cause them
to sleep poorly or
develop a mood disturbance.
So what we're learning is that some
of these critical neurotransmitters
that, in neuroscience,
it's like real estate, that
what's most important is location,
location, location.
Is that the neurotransmitter
imbalance in one area
of the brain might lead
to one clinical phenotype
where that same neurotransmitter
imbalance in another area
of the brain leads to a
different clinical phenotype.
But there's only about six or eight
neurotransmitters that the body uses
to send signals between all neurons.
And at the end of the day,
some of these neurotransmitters
have systemic influences,
genes that will make serotonin
low everywhere in the body,
GABA low everywhere in the body,
glutamate high everywhere
in the body.
And this leads to a lot of this sort
of chronic somatic
symptoms and pain states.
But again, it's not just pain,
chronic fatigue syndrome is
another condition that's squarely
in this entire spectrum of
illness where people have pain,
has a more minor complaint,
but fatigue is their major
complaint rather than pain.
These illnesses cause--
occur about one and a half
to two times more common
in women than in men.
Again, there's very strong
familial and genetic underpinnings,
and the reason I'm here is
that these can be triggered
or exacerbated by a variety
of different types
of biological stress.
Now, I can't help myself,
I'm intermittently in lapse
into being a pain researcher
instead of a stress researcher
because that's sort
of what I've become.
But one of the exciting
things in the pain field is
that the exact same pain prone
phenotype predicts everything bad
in the pain field.
So we are always asked why, why does
such a small proportion of people
with acute low back pain
developed chronic low back pain?
Why does a small percentage
of people
that has any surgical procedure
develop new chronic pain at the site
of their surgical procedure?
But it turns out the exact same
phenotypic traits project everything
bad in the pain field,
the transition from acute
to chronic pain, new chronic
pain after a surgical procedure.
And so, where-- there's been
a lot of work looking at the
so called pain prone
phenotype as well as trying
to identify the genotypic correlates
of this pain prone phenotype.
Because what seems to happen is
the pain prone phenotype is female
genetic factors, early life
trauma, a family history
of chronic pain and mood disorders.
This-- it turns out
that chronic pain is one
of the most familial disorders
that we know of in medicine,
but this was only realized within
the last five to six years or so.
And then, cognitions
like catastrophizing,
I mean some of the
things that we can measure
on an experimental basis, brain
imaging, experimental pain testing.
But the people with this
phenotype, when they're exposed
to different types of stress or
acute peripheral nociceptive input,
this can be modulated
by psychological
and behavioral responses
to that pain or stressor.
These are the people that are at
highest risk of developing a new
or different region of chronic pain.
Now, the stressor that's
seen to be capable
of triggering these illnesses,
a couple of them I'll go
into much more detail,
our early life stressors.
Having a peripheral pain syndrome,
I alluded to this earlier.
But about 20 to 30 percent of
people with rheumatoid arthritis,
osteoarthritis or lupus are
classic rheumatic diseases developed
comorbid fibromyalgia or
comorbid centralized pain.
And when that occurs,
they stopped responding
to peripherally directed
orally administered analgesics
or peripherally directed therapies
like surgical procedures
or injections.
And we have to move more
towards treating those people
like they are fibromyalgia
patient rather
than an osteoarthritis patient.
Physical trauma can trigger this,
like motor vehicle accidents.
War can trigger this.
Our group spent a tremendous amount
of time studying post-deployment
syndromes,
the First Gulf War,
these current wars.
And in the First Gulf War, there
was an epidemic of fibromyalgia
and chronic fatigue like
illnesses after the First Gulf War.
After these two current wars, all
three of these things are occurring,
severe PTSD, mood disorders, and
these pain syndromes are occurring
in part because the amount of
stress that people are exposed
to in the current wars
is significantly greater
than it was in the First Gulf War.
If you-- there was almost no PTSD
after the First Gulf War because,
you seem to need to have very vivid
personally traumatic stressors
in order to get PTSD.
And the way we fought
the First Gulf War,
there was virtually none
of that and no PTSD.
So that the nature of the
conflict, most of you will know
that PTSD was invented
after the Vietnam War.
The nature of war will determine
the relative rates of PTSD
versus depression versus
these somatic syndromes.
And after the First Gulf War,
we saw almost entirely
the somatic syndromes
without depression or PTSD.
Infections can trigger this
in psychological stress
or just stress can trigger this.
Now, for those of you who may
not be familiar with conditions
like fibromyalgia, I will just
tell you as someone that spent much
of my life and my career
studying it is people--
no one used to believe that
fibromyalgia was a real illness.
They used to think that these were
just neurotic middle aged women.
There are still some people that
think that but those are people
that will never take their head
out of the sand and look at data
and look at evidence, so I
stopped talking to those people
in the last couple of years, 'cause
there's overwhelming evidence
and overwhelming data that
there's objective evidence
of pain amplification in these
conditions like fibromyalgia,
irritable bowel and across the
entire spectrum of pain disorders.
But it is-- it's sort of have
been dogma in the pain field
for a long time that conditions
like fibromyalgia were due
to stress were triggered by stress.
But I just want to point out that
that actually is largely wrong.
It seemed like the perfect story
because some of the early studies
in fibromyalgia done at the
NIH before I started working
with George, these were studies
that were done by Leslie Crofford
and Mark Demitrack in chronic
fatigue syndrome showed HPA
abnormalities in people
with fibromyalgia
and chronic fatigue syndrome.
But as those studies went
on longer and longer,
that there were inconsistencies
in the direction
of the abnormalities probably
because there were inconsistencies
in the rates of comorbid PTSD
and comorbid major depression
versus atypical depression in the
individuals who were being studied.
Also because in subsequent studies
that we did looking directly at CRH
in the spinal fluid, the
most potent driver of CRH
in the spinal fluid is how
much pain someone was in.
So pain is a driver of stress.
Anyone that takes care of
postoperative people know
that the most common
cause for hypertension
after a surgical procedure is pain.
Treat the pain and the blood
pressure will usually go down.
And so, a lot of those studies that
were done looking at the HPA access
in conditions like fibromyalgia
and in pain states were
probably tremendously confounded
by all the other things that
occur, the early life trauma,
the psychiatric comorbidities
and the other things
that occur very commonly
in the pain states.
There are a lot of-- there's a lot
of evidence that different types
of stress when people are exposed
to those stress, for example,
the terrorist attacks in 9/11,
we accidentally did a study
in Washington D.C. where we were
having fibromyalgia patients wear
PalmPilots that were
beeping five times a day
and tracking their symptoms, right--
and right in the middle
of this 12-week study,
the planes hit the
Pentagon, and the planes--
we were still at Georgetown then.
And the planes hit New York City.
And there were accidental studies
that were being done by our group
in Washington D.C. and by Karen
Raphael in New York City that showed
that after the stress of the 9/11
attacks, there was no increase
at all either in fibromyalgia
patients
or in the general population in
pain, fatigue, or in stress per se.
Perhaps because that the nature of
the stress, if any of you happened
to be living in Washington D.C.
or New York City at the time,
it was even more horrifying
than living in the rest
of the country 'cause there were
tanks going down the streets.
But the one thing that
occurred immediately
after those attacks is this
incredible sense of patriotism,
and it's coming together
of the country.
So people didn't experience that
type of stress alone on an island
like you do getting in rush
hour traffic, get in argument
with your spouse or your boss.
And then in the context of
stress, whether it's characterized
by a sense of control, a sense
of support, may have a lot to do
with whether it actually
triggers illnesses like this
or whether the stress is
actually sort of good stress,
that actually makes
people feel better.
But in the pain field, for a long
time there were retrospective
reports that early life trauma
was associated with chronic pain
in a number of different
chronic pain cohorts,
but it wasn't until
a couple of years ago
when UK researchers exploited what's
called the 1958 UK birth cohort.
This is an incredibly cool study
that the United Kingdom did in 1958,
that they decided 1958
that they wanted
to follow every single person
born in the UK in one week in 1958
for the rest of their life.
And they now are still
actively following 71 percent
of those people, some
50 years later,
or I guess it's 53 years later
'cause I'm-- I was born on 1958.
And what they found is that
they went back and they found
that at age 8, those-- that the
children's parents were sent a
survey asking about
different bad things
that might have happened
to the child.
Excuse me.
If the child had pain
at age 8, the likelihood
that they had fibromyalgia
42 years later was one
and a half times greater.
If the child was in a traffic
accident in age 8, the likelihood
that they were to have
fibromyalgia 42 years later was one
and a half times greater.
You can see all of those life
stressors increase the odds ratio
of developing fibromyalgia 42 years
later by 50 to a hundred percent.
And if you had a bunch of bad
stuff happen to you in that year,
your risk could have been two
and a half or threefold greater.
So this was-- is the only
prospective data showing
that early life trauma at age 8
is a very potent primer or trigger
of developing chronic
pain later in life.
And again this didn't at all need
to look at retrospective recall.
Now that's psychological stress.
The problem though is every
kind of biological stress seems
to be capable of triggering
the spectrum of illness.
A bunch of different
infections, Lyme disease,
urinary tract infections, infection
of the vagina are all known
in about 5 to 10 percent of people
to trigger a new regional
pain condition in individuals.
And the things that trigger
widespread pain are things
like an Epstein-Barr virus
infection or Lyme disease.
The things that will trigger
intersitial cystitis are repeated
urinary tract infections.
Vulvodynia or chronic vulvar
pain will be triggered
by sexually transmitted diseases.
So it seems like about 5
or 10 percent of people
that have an infection that causes
usually subacute pain in an area
of the body, that about
5 or 10 percent
of people will never
become pain free,
that they will develop chronic pain
as a result of that infection rather
than just have an acute
self-limited course.
And then the-- by far the best study
looking at this was a study funded
by the CDC in the [inaudible]
region of Australia.
What they did is they
followed people who were seen
by primary care physicians with
three totally different types
of viral infections,
Epstein-Barr virus,
acute fever, and Ross River virus.
Those cause totally different
acute and subacute manifestations,
but what they found is with
those three viral infections,
I guess they're-- one of them
is not really a virus per se.
That the same exact factors this
pain prone phenotype predicted who--
which of those people, the five
to ten percent of people would go
on to develop a chronic, chronic
fatigue like fibromyalgia picture,
and the exact same
proportion of all three
of those infections develop this
chronic fatigue like picture,
and it had nothing to do
with cytokine profile,
the acute infection with
clearance of the pathogen
with baseline psychological factors,
it was all this pain prone phenotype
that I showed you earlier that
predicted the five to ten percent
of individuals who were going to go
on and develop a chronic pain state
like fibromyalgia or chronic
fatigue syndrome rather
than having an acute
self-limited course.
So what we seem to be dealing
with here is that people are born
at different points in this bell
shaped curve of pain sensitivity.
I labeled this tenderness here, but
it's a synonym for pain sensitivity.
Where you're at on this
bell shaped curve is
about 50 percent the
genes you're born with
and then 50 percent environmental,
things that happened to you.
But early life trauma and
stress can clearly move people
to the right side of
that bell shaped curve.
As it turns out, not sleeping well
and not exercising regularly
also move you to the right side
of that bell shaped curves.
So, two of the most
effective treatments
for these central pain states beside
drugs are getting people sleeping
better and getting
them exercising well.
That probably sounds familiar
to some of the psychiatrists
to treat mood disorders or PTSD.
And again, we knew that these
conditions like fibromyalgia
and temporomandibular
disorder and irritable bowel
and headache were all characterized
by augmented pain processing
in the central nervous system, but
it's only been the last 3 or 4 years
that we've appreciated that
all chronic pain states,
that there is a proportion of people
that so called centralized
their pain
that look identical to fibromyalgia.
And then once that occurs, these
individuals have to be treated
with different drugs and different
nondrug therapies than people
with a purely peripheral
or neuropathic pain state.
I alluded to the fact
that genes are being shown
to play a very important role.
If you care, here are some of the
genes that have been identified.
And literally all of the genes that
have been identified seem to be--
it's either turning up or
turning down the levels
of these different
neurotransmitters,
and again the psychiatrist
that study mood will look
at these neurotransmitters and say,
I know these neurotransmitters,
these are the same ones
that I'm dealing with.
But the reality is that
the neurotransmitters
that increase pain sensitivity
are substance P, glutamate
and other excitatory amino
acids and their growth factor.
Serotonin is a little bit
schizophrenic depending
on what receptor it binds to.
It can either increase
pain sensitivity
or decrease pain sensitivity.
In general, we think of
norepinephrine, serotonin,
and dopamine as being
antinociceptive
or inhibiting pain, as we do GABA.
And even though we think
of the opioid system
as being an endogenous
analgesic system,
these arrows here are the
direction of the abnormality
in these neurotransmitter systems
in people with fibromyalgia,
and the only neurotransmitter
system that's been studied to date
in fibromyalgia that
is not been abnormal
in the direction we
would have anticipated,
we would have anticipated that a
bunch of these would be elevated
and a bunch of these would be low,
and that would shift people
towards being more pain sensitive.
But the endogenous opioid system
in fibromyalgia patient is
actually increased activity.
And PET imaging, we
using a mu-opioid tracer,
has shown that fibromyalgia patients
actually don't have hardly any
unoccupied mu-opioid
receptors in their brain.
So these helps explain why opioid
analgesics i.e. narcotics don't work
in the centralized pain states.
In fact, a lot of us think that
not only do the opioids not work
in conditions like fibromyalgia,
but the people with fibromyalgia are
at high risk for developing so
called opioid-induced hyperalgesia.
We're giving those people an opioid.
We'll actually turn their volume
control up higher and higher,
make them more pain sensitive
and actually make them
worse in front of your eyes.
And in those individuals, the way
to treat their pain is first get
them off of the opioid and then go
on and try to actually
manage the hyperalgesia
that might have occurred
for some other region.
There's a lot of evidence,
and this isn't just a problem
with pain processing.
People with fibromyalgia and
other pain states are sensitive
to the brightness of lights,
the loudness of noises, odors.
And Rick Harris and our group has
done really elegant studies honing
in on the anterior
and posterior insula.
The anterior insula is involved in
the affective regulation of pain,
whereas the posterior insula is more
of the sensory intensity of pain.
And what he's shown is that
the glutamate levels are high
in the anterior and
posterior insula.
The GABA levels are low.
So what we're doing is sort
of increasing the excitability
of these brain regions, and
it's shown that with drugs
like pregabalin, which
is a drug Lyrica,
there's very clear evidence
now from Rick's imaging studies
that Lyrica is working by reducing
glutamatergic activity in the insula
that reduces functional connectivity
between the insula and a number
of networks including
the default mode network.
And that-- and you can see which
people are going to respond
to the Lyrica at baseline
because it's the people
who have the highest levels
of glutamate in the insula
that are the ones that are most
likely to respond to a drug
that seems to be acting
on glutamatergic activity.
So, functional imaging has
taught us a tremendous amount.
Much of what I'm talking about
today has been in the last 10 years,
since the advent of functional
neuroimaging and what we've learned
about pain processing, we've learned
that this increased volume control
is really seen in a broad variety
of chronic pain states, that this
is quite different than depression.
Some of the brain regions, anterior
cingulate, hippocampus, amygdala,
are co-activated in people
with pain plus depression
but those brain regions are
usually not anymore active in people
with pain without major depressive
disorder than in people without pain
or without major depressive
disorders.
So, it's when they
have that co-morbidity
that we see these brain regions
that are involved in affect start
to become more activated.
And then cognition is
how people can think
about their pain via the same
kinds of prefrontal regions
that people have talked about
today and being involved in mood.
These are all involved
in affect as well.
I mentioned this notion
of connectivity.
I know that this is a big
area in the depression field.
It's a big area in the pain field.
Our group and another group
at Harvard last year showed
that measures of connectivity
between brain regions are very
abnormal in chronic pain states
like fibromyalgia and that
what we've shown in a couple
of subsequent studies again done
by Rick Harris and Vitaly Napadow
at Harvard is showing that the
strength of the connectivity
between the insula and brain regions
that it's not normally connected
to is highly related to someone's
spontaneous ongoing pain.
So, in the pain field, the Holy
Grail has been a biomarker for pain.
Something that we could put someone
in a scanner and say, you know,
we want to really know how much
pain this person is experiencing
in case they're lying to us
or malingering or whatever.
And three or four studies now
suggests that the connectivity
between brain regions might be such
a biomarker, either measured by EEG
or measured by functional MRI.
And again, people like
Rick have done a lot
of work showing the
default mode net--
or the executive attention
network are very impacted
when people have chronic pain, and
that this seems to be driven in part
by glutamatergic activity
in different brain regions.
Same kinds of brain abnormalities
in with respect to the size
of the brain that have been
identified in depression
and mood disorders in PTSD have
also been involved in pain.
I don't know what this mean.
I don't think this really means
that this is neuroplasticity
'cause this changes
so rapidly in the pain field.
There have been studies showing
that this can change within weeks.
And so I don't think this is really
brain atrophy per se but I do think
that we are seeing neuroplasticity.
I just want to go back now to our
classic osteoarthritis of the knee,
this condition that until three
or four years ago we thought was the
classic peripheral pain syndrome.
That there was something
wrong in someone's knee,
that information was sent via the
sensory nerves up to the brain
and that's what osteoarthritis
of the knee was.
There was a lot of
evidence that should--
clued us into the fact
that that wasn't the case,
the fact that there's
such a big disparity
between structure and pain.
Also because some of
the drugs that we think
of as being peripherally
acting drug,
nonsteroidal antiinflammatory
drugs, acetaminophen, we don't--
opioids are probably working
both peripherally and centrally.
But these drugs don't work nearly
as well as we used to think they did
if you look at some of those
latest [inaudible] metaanalysis.
But now there's been an explosion
of knowledge in the last year
or two showing that all of
the same imaging findings
and experimental pain testing,
findings that have been identified
in conditions like
fibromyalgia, irritable bowel,
tension headaches are being
identified in osteoarthritis,
rheumatoid arthritis, low back
pain, at least subsets, this 30
or so percent of people
that seem to be at risk
of centralizing their pain because
they have this pain prone phenotype.
And one of the biggest things in
the pain field was the revelation
that Duloxetine or Cymbalta worked
well for chronic low back pain
and osteoarthritis of the knee.
So, it was approved by the FDA for
chronic muscular skeletal pain.
It doesn't matter one bit whether
people are depressed or not,
they are just as likely to
respond to Duloxetine or Cymbalta
which was originally
developed as an antidepressant
if they are nondepressed
as if they are depressed.
So, it really does not matter
whether they have comorbid
depression, and that's the case with
other drugs, like tricyclic drugs
that were originally
developed as antidepressants.
I did do this partly as a
joke, but our group does a lot
of collaboration with a lot
of people in different fields.
And whatever you want to
call this spectrum illness,
I don't use the word
fibromyalgia much anymore
because some people will
always view that as the F word
and hate the term fibromyalgia.
But whatever you want to call
this spectrum of illness,
it's everywhere, it's ubiquitous.
And if there was a
name for it, it would--
I think it would be by far the
most common medical problem
because these people have severe
pain, fatigue, memory problems,
sleep disturbances and each
medical subspecialty has one
or two names for these people.
They call them idiopathic.
They say there's nothing
wrong with them.
But when you start looking into
the brain and you start looking,
it's the same thing over and over
again, this pain prone phenotype,
the same set of people
that you really see in all
of these different conditions.
So, with the way, the direction that
we're going in the pain field is
to acknowledge that knowing
the disease someone has
like osteoarthritis or
rheumatoid arthritis,
doesn't really help us treat
their pain because all pain states
at some level are mixed
pain states with--
in an individual, peripheral
factors might be playing a role,
nerve factors might
be playing a role,
central nervous system
might be a role.
And depending on which of
these are playing a role,
markedly different drugs work.
Opioids and nonsteroidal
anti-inflammatory drugs don't work
at all for conditions like
fibromyalgia, irritable bowel,
somebody's other conditions.
They work pretty well when there
is peripheral nociceptive input
like in osteoarthritis
or rheumatoid arthritis.
Anti-inflammatory drugs work great
in rheumatoid arthritis or lupus,
but they won't work at all in
conditions like fibromyalgia
that are not characterized
by inflammation.
So this is where we are in the
pain field now is at the choice
of drugs is really driven more
by what category pain
people have rather
than by the disease
that people have.
And then finally I just want to say
that non drug therapies can be
extremely effective, normally
and when I have longer to talk about
pain, I go on and rant about this
because things like education,
exercise cognitive behavioral
therapy can be extremely effective
in treating chronic pain.
Our group led by Dave Williams
developed a website that we tested
and we show that this website alone
that gave people education, exercise
and cognitive behavioral therapy
was just as effective as any
of the approved drugs
for fibromyalgia.
And I'm not suggesting to people
to use this instead of the drugs,
I'm suggesting just
as, is recommended
in treating any chronic medical
illness, is that use drug
and non-drug therapies together
because these non-drug therapies
can be pretty effective.
So to summarize, a variety
of different types of stress,
but not just psychological
stress, seem to be capable
of triggering chronic
pain in fatigue states,
these called early life
trauma, physical trauma,
ongoing peripheral nociceptive input
like rheumatoid arthritis lupus,
infections, war, psychological
stress,
these central pain states
are extremely common
in the general population because
they are called different things
by different sub specialties.
So and the current thinking is that
some of these neurotransmitters,
these shared neurotransmitters
are driving the fact
that people have comorbid pain,
fatigue, sleep disturbance and mood.
The trial that was done in
the setting of fibromyalgia
that was most illustrative of this
is the drug gamma-hydroxybutyrate
which unfortunately is GHB
which is the date rape drug.
But it is a very potent GABA
agonist, it raises GABA levels.
That drug when administered
to fibromyalgic patients,
led to a simultaneous improvement
in pain, in sleep, and in fatigue
and those were not
related to each other.
It seemed to be independently
effecting those three domains
because GABA controls
your level of alertness,
your level of sleep
and your level of pain.
And we see this with
somebody of the other drugs.
The serotonin norepinephrine
reuptake inhibitors
when we use those to treat pain,
we make mood better, pain better,
fatigue better rather
than making pain better.
So one of the advantages,
if you will,
of treating these central
pain syndromes rather
than peripheral pain syndromes is
people usually have more than pain
as a symptom and whenever drugs
that are non-drug therapies work,
we'll usually see amelioration
of symptoms other than just pain,
in some of these other comorbid
symptoms that travel very closely.
Thank you.
[ Applause ]
>> Thank you very much Dan.
We'll have time for questions
and actually questions can also be
directed towards earlier speakers.
Yes?
>> I'm speaking strictly
as a lay person.
Why then is medical field really
pushing morphine for all types
of pain, if it's known that it
doesn't affect most types of pain?
>> How long do we have here?
There is a couple of issues.
Number one is that
narcotics were approved
for pain before the
FDA was in existence.
So the rules that apply to a
drug company that has a narcotic
on the market are different than
the rules that apply to a company
that has a new chemical entity
that began testing after 1962.
So most opioids that get on
the market get a broad label
for chronic pain because
that was what the labeling
for opioids were before the
FDA came into existence.
That's the first problem.
So, the pharmaceutical
companies are incredibly good
at convincing people of things.
That's why most of you know
about fibromyalgia because most
of you watched the lifetime
network or whatever.
When I was watch sports on TV,
like I watch the news and sports
and my wife watches
like [inaudible] TV.
I have never seen a Cymbalta
commercial, on the TV that I watch,
but if you-- when I sit down
and watch television with her,
all the fibromyalgic commercials,
all the Cymbalta commercials
are aimed appropriately at TV
that more females watch because the
women with chronic pain are the ones
that are more likely to have a
central nervous system component
of their pain and in
fact more likely
to respond to a drug like Cymbalta.
So the pharmaceutical
companies are pushing opioids,
most physicians have
become anti opioid,
but one of the other problems is,
starting about 10 years or so ago.
There was a very active movement
by JCAHO, the accreditation agency
for hospitals and clinics,
to start tracking pain
and to following pain more closely.
And people can even be fined if
they didn't interact and attend
to people's pain on
the inpatient setting.
So what happened is we
thought people they had to ask
about pain more and treat
it more aggressively,
but our drugs didn't get any better.
So that we still have
the same drugs out there
and people were always taught
that if the pain was bad enough
and refractory enough,
opioids would always work.
And that is simply isn't the case.
Again, there is a tremendous
number of pain states
for which opioids don't work at all
and in fact may actually
be making people worse.
The FDA knows that the FDA is
extremely concerned about that
in trying to get opioids controlled
a lot more than they are right now.
[ Pause ]
>> I agree with literally
everything you said.
And it's very important
for the treatment of people
with chronic and acute pain.
I was surprised by one thing though.
In the non-pharmacologic treatments,
you didn't mention hypnosis
which is the oldest and most
empirically-validated central
treatment for pain.
And I wonder if you
could comment on that.
>> Yeah, I think it was because
that wasn't really what I'm supposed
to talk as therapy.
I wasn't, so I-- I'm
a [inaudible] of--
a whole host of non-pharmacologic
therapies.
We've done a lot of work on
acupuncture, acupressure.
We have annual trials of CBT,
I think most of the
exposure I think, so.
Yeah I agree that there is
yoga, tai chi just a num--
so many non-pharmacologic therapy.
But the problem is,
I hate to say this,
but no one is making money
off of most of those things.
I'm sorry, okay [inaudible].
The market forces in the medical
field are the drug companies.
The large hospitals like the
ones that I work for, that maybe,
that you work for, they make
a lot of money on procedures.
And so there is no one, there is no
market force driving the adoption
of these non-pharmacologic
therapies that are not covered
by a third party, often people
are paying out of pockets for them
and that's why way too many people
are getting injections and blots
that cause a thousand
or 2,000 dollars
and have never been
shown to work very well.
And not enough people are getting
someone sitting down and talking
to them, listening to
them, or are using some
of these non-drug therapies.
>> Okay. Thanks.
>> Thank you very much.
[ Applause ]
>> What do you think
Carol, should we stop and--
[Inaudible Remark] Okay we're
available for general questions.
Dr. Gold, Dr. Clauw, if anybody
has any questions please?
[ Pause ]
Well it was a very exciting
and intensive day today,
and a lot of new knowledge.
Actually I'm-- I was very glad to
hear new things about fibromyalgia,
especially that it's not
called fibromyalgia anymore.
>> It's still called fibromyalgia.
>> How common is it, in the
general, in the community?
>>Using the old criteria to the
[inaudible] of the US population,
using new criteria that don't
require doing any tender point exam,
or like 60 percent
of the population.
[Inaudible Remark]
>> So 6 percent is a
very high percentage?
>> But, yeah.
>> There are many millions
of people, you know.
>> Yeah, yeah probably 15, 20
million Americans and the notion
that this is a disease
of industrialization is
been really blown apart.
The rates are at least as
high in developing countries.
Another you don't know about
since we last saw each other,
I spent a month in Kenya every year,
and in Kenya there are very
high rates of chronic pain.
So this notion that chronic pain is
a lot due to worrying and, you know,
again the notion that
fibromyalgia used to be yuppie flu.
It was middle aged women,
you know, affluent--
all that's really been blown
apart by the epidemiologic studies
in the spectrum of illness.
>> So in Kenya it's just
as frequent as it is here?
>> At least as frequent
as it is here.
And I don't know why but--
>> Dr. Romero.
>> Could I ask you, at
what percentage of the--
you referred to genetic markers
to identify the patient
that is prone to pain.
What proportion explains the
genetic component of the variance?
>> About 50 percent.
>> What are the candidate
genes for this?
>> The strongest one I
identified so far is COMT,
Catechol-O-methyltransferase which
is breaking down catecholamines.
As you probably know, that has been
looked at in psychiatric disorders
and it might responsible for some
of the sex differences and some
of the difference psychiatric
disorders, but it's not associated
with psychiatric, any single
psychiatric disorders per se.
But it's one of the attractive
genes 'cause it's an estrogen
inducible gene.
So it might help us explain why
women are more pain sensitive
and more sensory sensitive.
>> Yeah, it's also a gene
that is very highly expressed
in the placenta and it's a mechanism
by which catecholamines are
deactivated and don't cross
from the mother to the fetus.
So it's a very interesting
biological system.
>> Right. So there is--
and I, there's a KCNS gene
the potassium channel gene,
there is some sodium channel genes.
There are GHC1-- what
does that stand for?
I don't know I'm blacking out of it.
But there is about 6 genes but the--
for these candidate genes that
have been identified so far,
the odds ratios for developing
disease or causing people
to be more pain-sensitive are
in the range of two to four,
very strong individual genes.
So you know when you look
at for example genome-wide
association studies for something
like type 2 diabetes, where no
single gene had an odds ratio
of more than like 1.1
for causing disease.
And the pain field, we-- the pain
field hasn't historically been
very well-funded.
So there hasn't yet been an
appropriately-powered GWAS study
in pain.
But the candidate gene
studies the ones
that people guess would be
abnormal, some of the ones
that I have been talking
about, have all had, you know,
a hundred patients
versus a hundred controls,
replicated in several studies.
So they're fairly powerful
compared to the genes
that are playing roles
in other states.
And some of them are genes
that you would recognize
in like the serotonin
transporter gene, has been shown
to be a risk factor just as it
is for mood disorders, right so.
>> Dr. Schumaples?
>> I had actually, an
identical question,
I was particularly interested--
I had the identical question
where I was particularly
interested in the genetic variance.
How many there are?
I'm sure there are common genetic
variance who has very little effect.
Do you have any idea about
the frequency of genes
and do you have any idea in
terms of tissue cultures,
what silences these genes?
And then move on to cannabinoids
and what are the effect
of the cannabinoids?
>> We don't know much
about the first couple
of questions that you have asked.
Really the pain field is so--
this is so, all this is
so new in the pain field.
This is really less 5 to 10 years.
So in contrast to the depression
field where you've known
that the brain is the problem for a
long time, this all relatively new.
And the cannabinoids-- I
have to be careful here.
So I didn't have this
on my disclosure side,
but I went to the University of
Michigan in the 70s, so let me make
that clear before I say what I'm
going to say about cannabinoids.
But in most countries other
than the US, there are one
or more synthetic cannabinoids
approved for pain.
So as a pain researcher, there is
actually a lot of evidence and a lot
of data that cannabinoids
work for chronic pain states.
I think the biggest reason
that there is not a synthetic
cannabinoid approved for use
in the United States for pain,
is political not scientific.
That intermittently, there have
been entire four [inaudible] periods
where you can't do any research
on good effects of cannabinoids.
So that--
>> They make people fat?
>> Yeah, well, yeah, yeah but the--
but when cannabinoids
are given for pain
and they're given orally
rather than--
when people smoke cannabinoids, they
get the munchies and they get high.
But when they take them orally
and there is a stable level
of cannabinoids, they don't have
anywhere near the side effect
profile, if you will, that we think
of recreational use of cannabinoids.
And so in states that have
had medicinal marijuana laws,
there are a fair number of people
that are getting some relief
of their pain with cannabinoids.
Those of us who are physicians
and treaters would much rather
have a synthetic cannabinoid
that we could prescribe
whether we would know the dose
to give and things like that.
But the notion that
cannabinoids don't work
in chronic pain is not really
supported by scientific data.
[ Pause ]
>> Any other questions?
Yes sir?
[ Pause ]
>> Thanks, could you talk about
how the political aspects,
particularly the classification
of certain narcotics,
and other drugs says and
the restrictions they had.
I work to restrict research in
this area and have impeded them,
maybe making some progress.
>> I guess I started, didn't I, huh?
>> Yup.
>> I mean, I think the thing
that you need to understand
that as a scientist, there're
a number of different paths
that we can choose to go down
in our scientific career.
And why would we choose
to go down a path
that intermittently
could be totally blocked
by someone deciding politically
that they, that all of a sudden,
this type of research
can't be funded
or that there was another set of--
it's hard enough to get NIH funding,
but to worry then about, you know,
the political climate from year
to year in NIDA or in an institute
that might be funding
research along these lines.
So, I think that people just stay
out of it cause it's like, you know,
why do I need even more
aggravation than there is,
innately in being a
biomedical researcher
where the funding lines are now at 8
to 10 percent, you know, at the NIH
and so that you know, 9 out of
10 grants we write are not going
to get accepted.
Why would you, why would you ask
for an even higher bar to jump
over by devoting your life to
studying cannabinoids and pain?
So I'm going to hate
to say it but that's--
we all have options as
researchers and I think that it have
to somehow be personally
incredibly pro-cannabinoid,
maybe in a bad way [laughs],
than in a recreational way,
before I could imagine that deciding
that you're going to, you know,
say that that's what my career is
going to be and I'm going to be
at the whims of, you know,
politicians that every
so many years might decide that this
is not something worthy NIH funding.
>> Yes?
>> This is for Dr. Romero,
you're talking about the second
and third trimester and fetal pain.
Can you talk about it in
terms of the first trimester?
>> So that is a difficult area
because the concept of pain and I'm
in front of an expert, so please
take over at any moment, you know,
it requires not only
that there is a stimulant
but there is the awareness of pain.
And that is a very difficult
thing to prove in a patient
that you cannot talk to, and
cannot tell you whether he feels
or she feels pain or not.
So I, we don't have any evidence.
I am hesitant to say that there
is pain in first trimester.
I believe that the data that I show
suggest, provide indirect evidence
that that occurs in the second
and the third trimester.
We know from ultrasound observations
that when we place a needle
and the baby in the amniotic
cavity moves the arm over the leg
into the needle, immediately
there is a response,
but that maybe a reflex, you know,
whether the baby has pain or not,
in the first trimester,
we do not know.
[Inaudible Remark] No, second and
the third trimester and [inaudible].
>> Well, how soon is the
pain system developing
in the embryo, is that normal?
>> I totally agree.
[Inaudible Remark]
>> All right.
[Inaudible Remark]
>> In fact until a child is able to
talk, studying anyone before that is
like looking at an animal, not
where we say we're
measuring a pain behavior
which is what you are measuring a
pain behavior and you are inferring
that it's pain, just like
a tail flick test in a rat.
But that's all you can do until
the child can speak to you.
And that's-- all the best you can
do is measure a pain behavior,
as a surrogate.
>> Yes?
>> So, I had a question, am I
right to summarize your talk
as saying there is
maybe 2 kinds of pain.
One that's peripheral
and ones that's central
and having all these different
diagnoses of fibromyalgia
and other kinds of pain maybe
not, maybe counterproductive?
>> That's pretty close.
I say that there are 3 types,
there's peripheral nerve pain
which is relatively uncommon.
But if you have either damage
to a nerve or compression
of a nerve, that can cause pain.
So that was that middle category
that I didn't talk very much about.
[Inaudible Remark]
No, that'll be like sciatica.
You have a herniated disc in your
back, carpal tunnel syndrome,
when the median nerve
and your wrist is pinched
and you get numbness and tingling.
So those would be examples of nerve
pain where the nerve is involved.
But by far the more common causes
are either are peripheral or central
and yes, more and more we're
realizing that the name
that you apply isn't that important.
And in fact, it's often confusing
'cause people with fibromyalgia,
they're seeing a rheumatologist
for their fibromyalgia,
they're seeing a gastroenterologist
for their irritable bowel,
they're seeing a urologist for
their interstitial cystitis
and they're getting conflicting--
they have pain in all
different areas of the body
and different diagnoses for the
pain in different areas of the body.
And they don't get one person
telling them, this is one problem
for which these-- this
is the best treatment.
They'll often be going to all
these different subspecialists
that are giving conflicting
answers actually.
>> So is that's sort of theories in
the experts' opinion or is that--
is that pervading the medical field?
I mean-- I mean it makes
a lot of sense to me.
What I'm asking you
is how widely accepted
and known is that sort of view?
>> It's like any other
scientific knowledge.
It takes a fair amount
of time for it to diffuse
into the medical community.
And it's more difficult to make this
diffuse into the medical community
because we're talking about 25 or 30
different subspecialties that have
to get this information to them.
Because that's how we
usually learn, you know,
unless you're a generalist
and you're a general.
But most of us are
learning from subspecialists
of the same subspecialties.
So it turns out that we
do work with, you know,
gynecologists studying chronic
pelvic pain and urologist studying--
and they're the ones that
then have to go give the talks
at those meetings to convince
the gynecologist or urologist
that this is more of a brain problem
rather than a peripheral problem.
But it's going to take, you know,
10, 15 years before this knowledge--
'cause this is fairly new
information, fairly new knowledge.
There's no one in the pain
field that would disagree
with what I'm saying but there
is a fair number of people
in the general medical community
that might still be quite unaware
of this sort of paradigm shift.
>> Dr. Rosenthal.
[ Inaudible Remark ]
>> You said that 30 percent
of the people with bones right
against each other wouldn't have
pain and 20 percent of the people
with the bones not touching
each other would have pain.
It still is a big difference
between those two in that 70 percent
of the bones touching each other
will have pain and 80 percent
of the ones won't have
pain in the other one.
So it's still a value, it just
doesn't explain all the variance,
I guess, this is what
I'm understanding.
>> I totally agree, yeah.
So nociceptive input is playing
a role but in some individuals,
that nociceptive input seems
to be incredibly dampened
by the central nervous system
and they don't have pain
when it looks like they should.
And in other individuals, it's the
opposite where it's being augmented.
So it's just that-- it doesn't.
Focusing on that is the
only cause of the pain
which is often done,
is a misguided venture.
>> Thanks.
[ Pause ]
>> Dr. Brown?
>> Just quickly in that
context, do you know--
can you say anything about
why acupuncture works?
Acupuncture.
>> So we do a lot of
work on acupuncture.
And when I say we, Rich
Harris and our group,
who's a junior faculty
member does the work.
He has shown-- the reality is
in chronic pain conditions,
acupuncture has been
sort of iffy with respect
to whether it shows efficacy
or not, shows that it works.
Some chronic-- some study
showed that it does,
some study showed that it doesn't.
It works way better in acute pain.
So it's a much more-- the
studies are much more consistent
that you've heard about people
getting surgical procedures in China
with the acupuncture
as the analgesia.
So-- but again, I think that's
because chronic pain
conditions are more heterogenous
and a little bit more complicated.
The other problem with acupuncture
research has historically been what
is a credible sham procedure.
So some people say that
when you put the needles,
the acupuncturist will say
that if you put the needles,
but you don't put them
in the right location,
you're still doing acupuncture, it's
just not as good of acupuncture,
that there is no such thing as a
placebo or sham needle insertion,
that any needle insertion
would engender some type
of an acupuncture effect.
But if you put them
in the right location,
it would engender more of an effect.
So there's a big controversy
and it really,
it's about like being a Democrat
or a Republican if you'd like.
I mean, if the people
are too polarized,
they either say that
it, that it works.
And they don't, they don't look at
any of the data showing that it,
maybe doesn't work and another
people are saying, "well it's,
you know it's just all
the placebo effect."
I would have to say that as a pain
researcher, I think the placebo,
you're going to hear about
placebo tomorrow, in pain,
placebo is pretty powerful.
There is a lot of medical
condition where it's not powerful,
but just getting someone to
believe they're going to get better.
You know, I think that that's
what healers have been doing
for a millennia even before
we had effective drugs,
as we were talking you
know, people that used
to be called healers are
now called physicians.
We'd sit down with people, we'd
talk to them, we'd convince them
if they were going to get better and
we were using the art of medicine
and we were using the placebo
effect to our advantage.
When I think that a lot of
medicine now, there's no such thing
as a placebo affect 'cause
the doctors don't talk
to their patients.
They don't spend any time with them.
They don't-- and so a lot
of that is lost and where--
but where people do get
that is in the settings
where people are doing CAM
therapies, the acupunctures.
Those are the people who would sit
and talk to people for a long time
and develop a therapeutic
alliance with them the way
that physicians maybe 50
years or so years ago did,
all the family physicians did.
But now in the day of the 6 to
7 minute return office visit,
there's not a lot of that time
that's being spent with people.
And I think that does make all
of our therapies less effective,
if we're not engendering the
body's own analgesic properties
which are incredibly powerful,
then we're disadvantaging all
of our therapies if, if
that's how we're doing it.
So I don't know whether
acupuncture works for chronic pain.
I do know that if someone
believes it works, about 40 percent
of those people will get improvement
with acupuncture and it's very safe
and it doesn't cost very much.
>> I think we're going to hear it
tomorrow but I just recently read
that Dr. Bernadette is booked.
And apparently with acupuncture,
you would get emerging studies,
changes that, the same
that you get with placebo.
But there are some extra sides
in the brain that are affected,
so it's not just placebo.
There's something else.
And the same is true for
cognitive behavioral therapy
or other therapies.
In other words, the
placebo areas are involved
but some other areas are
involved as well, additional.
>> Exactly.
[ Pause ]
One more question,
the last question?
>> I was just curious if
your research indicated
that there was any kind of a
correlation with obesity in pain?
>> It's a good question
>> The current data are pretty clear
that obesity contributes to pain
of weight-bearing joints.
We've known that for a long time.
There's emerging data
that suggested obesity
in general might be associated with
this kind of more centralized pain.
The pro-inflammatory cytokines
that are, that are released
by the adipose tissue may
be driving a very mild sort
of generalized inflammatory state
that can lead to nociceptive input.
But that, that's still
more a hypothesis.
What we know for sure is, in the
context of arthritis for example,
of weight-bearing joints, that a
10-pound weight loss will lead to,
in most people, to a
clinically-meaningful improvement
in their pain, if their pain
is in the knee or the hip.
If it's in the joint that is not
weight bearing, that doesn't seem
to make as much of a difference.
But the question I think you're
asking is more of a general effect
of obesity and that question
is still unanswered, I think.
Again you're seeing a lot of
intriguing associations with BMI
over the course of the
day today and I bet
that in the next several years,
we're starting to see some
of that you know, seeping
into the pain field as well
>> Does pain cause obesity?
>> Does pain cause obesity?
>> Chronic pain patients
are much more obese
than non-chronic pain patients.
But the reasons for that are, so
I don't want to say it's just pain
but pain causes inactivity
and inactivity causes obesity.
A lot of the drugs we use cause
craving and cause weight gain.
So it would be the same
as asking the question,
does depression cause obesity?
I think the answer would
be just as yes but because
of all these different reasons.
>> Well yeah, I agree with you.
I think the people
who are in pain may,
it may be harder for
them to exercise.
The drugs that we use as you say,
I've seen 20, 30 pounds put on both
with Lyrica and Cymbalta
in selected cases.
And the other thing is that sweet
foods have like an opiate effect.
So it may be one's own
way of dosing oneself, so.
>> Right, thank you very
much, it's a wonderful day
[ Applause ]
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