Stanford’s Sean Mackey, MD, PhD on “Pain and the Brain”


SEAN MACKEY: We’re
going to focus now on my favorite organ, the brain,
this 3-pound, squishy mass that sits at the top of
your neck that is just an absolutely miraculous organ. It’s what makes us
all uniquely human and something that
we often think is just a passive receptacle
for everything coming in from our body, and just
magically, these experiences appear, particularly
around the aspect of pain. And what I’m hoping
to get across to you is that, in fact,
it’s anything but, that you have a lot of control
over these signals coming in from your body and what
they actually represent. But first, let’s take
a step through history and let’s talk briefly
about Rene Descartes, who set the stage for us
about our view of pain up until the contemporary times. He’s a 17th century
French philosopher. He was a brilliant mathematician
who gave us Cartesian geometry. And he also gave us a lot
about modern philosophy. But when it came to pain, I’ll
tell you, folks, he really screwed it up. He viewed pain as this
very linear direct link between the body and
the brain and the mind, illustrated by this little
boy with his foot in the fire, pulling on a delicate
string, leading up into what was thought
to be the common sense center in the brain, the
pineal gland, which was thought to make humans uniquely human,
opening up pores, ringing a bell, and causing the
child to withdraw his foot, showing a direct one-to-one
link between the stimulus and the response. And this model has been with
us for hundreds of years until the present
day, when we’ve learned that, in fact,
again, it was all wrong, that in fact, pain
is an incredibly subjective experience. It is one defined as
an unpleasant sensory and emotional experience. And as such, it is
whatever you say it is. We don’t yet have a well
validated pain-o-meter where we can objectify pain. I’ll tell you that our
research group here is working on developing that,
but we’ve got a long way to go. And it will never replace
the self-report of pain. And so everybody’s
individual unique experiences belongs to them. And we’re going to
talk more about that. But first, let’s
give you a little bit about pain processing
101 that will set the stage for the
remainder of the talks today. So we know that pain all
starts with the stimulus. It could be a
mechanical stimulus. It could be a temperature
stimulus– cold. It all has a common thread. It activates something we
call primary nociceptors. Now, primary nociceptors
is a fancy term, but think of it as
just a transducer, just like this microphone is
a transducer that converts sound energy into
electrical energy, except here, in our bodies,
in your hands, in your back, what you have are
transducers that take that mechanical energy,
that temperature, and convert it into a little electrical
signal, which heads up into your spinal cord,
crosses over the other side, heads up to the brain, the
synapses in the thalamus. Think of the thalamus
as Grand Central Station for your brain– all the
signals from your body coming in and then
heading off to other areas where then, the
perception of pain occurs. That’s when it becomes pain. What’s going on out here, this
is just electrical impulses. So once it hits the
brain, it starts to be shaped by all of these
other aspects I’ll talk with you about momentarily. But before then, what we
see is it gets filtered. And we need to have some way
of filtering this information. Because if we didn’t, if
we were paying attention, if we were experiencing
every signal that came to our awareness,
our brains would explode. And so what we’ve
developed over the years, these descending
inhibitory pathways. These are the blue ones that
come down from the brain. They synapse again
in the spinal cord. And what they do is they
act as a nice closed loop feedback that turn down
the signals heading up. And what we’re going to
talk with you about today, we hope to convince you, is you
have control over that feedback loop. One of the first things
our fellows learn when they come in and
train in our clinic is that the amount
of injury is not equal to the amount of
pain that is perceived; that, in fact, it
works like this– that you have these signals
coming in from the body. And these signals are important. Don’t get me wrong. They’re very important. But they’re then amplified. They’re turned up. They’re turned down. And as Beth said,
my prior training is as an electrical engineer. So I tend to think in
circuits and in amplifiers. And we’ve got all these little
amplifiers in the brain. We’ve got cognitive
amplifiers, such as attention and distraction. We have contextual
ones, like your beliefs. Expectation– if you
expect to have more pain, it turns up an amplifier in your
brain and you have more pain. Your mood– if you’re
depressed or you’re anxious, it amplifies things. And then your
individual differences, some of which we can’t
control– the genes that your parents
handed down to you will determine your sensitivity
and your vulnerability to pain. All of that shapes
your pain experience. And we’ll be talking about more
of that throughout the day. And when pain goes bad, for
those of you who are spinal tap fans, it’s like those
amplifiers in your brain were cranked up to 11. That’s what’s going
on when pain goes bad. We’ve taken that
information and now we’ve taken those things
that we previously said were psychological, those
fuzzy psychological concepts, and we’re now mapping
those directly into circuits in the brain. So now we can tell
you where in the brain things like attention
and distraction and expectations and
placebo are working. We’ve mapped them out to
specific areas of the brain, such as the somatosensory cortex
which is involved with some of the location of pain. Where is it hurting
in your body? The anterior cingulate
cortex, which invokes more of an
emotional aspect to pain, how unpleasant the pain is. The insular cortex involved
with what we call introception of pain, a fancy term
for simply meaning you’re kind of your internal
awareness of your bodily state. How am I feeling at this moment? All of these areas shape
your experience of pain. And what we’re learning–
what we’re learning, if I can get this to go. Let me go back one. What we’re learning is that
many of these brain regions that are involved with shaping
your experience of pain also overlap with the
same circuits that are involved with your
emotions and your cognitions. And so what we find is
that when you’re stressed and when you’re angry,
when you’re tired, if you’ve had a fight with
your spouse or your boss, those same circuits
in the brain involved with that negative
emotion are directly connected and overlapping
with those in pain so that that stress, that
anger, that frustration, all simply amplifies your
overall experience of pain. Now I alluded to earlier that
it’s a subjective experience. Let’s dive into that in
just a little bit more detail with what I mean by that. We know that there are
huge individual differences in the amount of pain people
have to a certain injury. We know that there’s huge
individual differences in, for a given injury, how much
disability somebody will have. We know tremendous
individual variability for if you go in and have
surgery or have an injury, the likelihood of your
developing chronic pain varies across a population. And the thing that’s
probably most frustrating for many of you, as
well as, quite frankly, for us who care
for people in pain, is there’s such wide variability
in your response to treatment. And we often go through this
very laborious trial and error process of treatment after
treatment after treatment until we find
something that works. And if any of you feel
frustrated about it, trust us. We feel just as much
frustration for you because we’d love to be
able to pick that treatment that we know will work for you. So how have we characterized
these individual differences? How can we describe it to you? Well, this was a cool study,
done over 10 years ago. They took 500 people, about the
number of people that are here. And what they did is they
applied a 49-degrees Celsius stimulus– it’s about
121 degrees Fahrenheit– to their arm. And they simply asked them,
how much pain was that? How would you rate it? And then they rank ordered it. And what they found
is that, in fact, people down here on the low end,
they rate it as 0 out of 100. They said, it’s not
painful, not painful at all. Then you get people up here
that were saying around– there were about 20 out of 100. They said, mildly painful. And then some people
saying medium. And then all the way up
at the top– oh, my god. This is the most painful
thing imaginable. Get that off me, for
exactly the same stimulus. And we know that, despite
the same stimulus, there’s huge
variability in pain, and that this was
shaped ultimately, yes, and somewhat by genes
that play a role, but also, like many
of those amplifiers in the brain I showed you
before– anxiety, depression, catastrophizing, personality,
temperament– all shape this. And just in case you were
wondering, docs are human, too. I teach the pain classes
here at Stanford. And I run a demonstration on
the medical students in one of the lectures. Yeah, it’s true. I have them come in, and we have
a circulating ice water bath. They stick their arm in
there for 15 seconds. They pull their
arm out, and they whisper in a research
assistant’s ear how much pain they have. Doesn’t that curve
just look exactly like the one I
showed you before? And it’s an incredibly
important demonstration for those medical students
because it shows them that they need to take
care and not projecting their own perception of what
is painful onto other people, that even docs are humans too,
that we all experience pain in a wide variability to
the same exact stimulus. Where is this all coming from? Well, I love this study over
10 years ago by Bob Coghill. This is a real seminal study. It was simple in design
but incredibly elegant. And what he did is
he did the same study I showed you before
with the heat, but he took the low and the
high sensitivity people, put him into a brain
imaging scanner, and then subtracted the
difference to find out where are these differences. And what he found is that the
individual differences were explained by the areas I
was pointing out to you in that other brain slice
before– the anterior cingulate cortex, the primary
somatosensory cortex, the somatosensory cortex. What was I thought
most cool about this was that when you looked at the
differences in the thalamus, Grand Central Station, the
big relay center taking in all the information from a
body, there was no differences. It was no differences. It suggests that maybe we,
as humans, all transduce. We all conduct that information
from our bodies much the same way, but it’s not until
it gets to our higher brain centers that our
individual differences get shaped by all those little
amplifiers in the brain I was telling you about. I’ve had a particular
interest in fear. I’m just going to
give you one taste of some of these amplifiers. And so what we did
is we characterized how much fear you have to pain
using some questionnaires, and we applied a
similar heat stimulus. And what we found
is that we can map how much fear you have to pain
and the individual differences of it directly to
this area called the right lateral
orbital frontal cortex, an area involved
with your evaluation of incoming
information, whether it be physical,
painful, emotional– evaluating it and
making decisions about what to do with it. And it shows a huge variability. Those who have more
fear of pain– much, much higher brain activity. We’ve also learned that the
pain that you have fundamentally alters your brain structure. So this is not a
brain activation scan that you see up here. This is a brain
structural scan in which we’re showing changes
in gray matter– either increases in gray matter
or decreases in gray matter compared to healthy
people who have no pain. And what we find is
that pain fundamentally is associated with
alterations in this area. We’re just starting now to be
able to use this information to get a more objective
biomarker of pain and to ultimately
use this information. Where we’re going
with it is to predict what type of treatment
response you’ll have to a particular therapy. Let me close out
on one last study that we did that
was kind of fun. And this one involved love. I’ll share with you that
as a neuroscience geek, I often go to the
Society for Neurosciences and hang out there to see
all the latest and greatest science. I was there with
a guy, Art Aron, who studies passionate love. And the wine was flowing. And he was talking about
the neural circuits and passionate love,
and I was talking about the neural
circuits and pain. We had some more wine. What he said is, has
anybody ever studied this center, this connection,
between these two? And the answer was, no. So we had some
more wine, and then we ultimately came
back to Stanford. And we did what we do here,
and that is we studied it. And so Jarred Younger,
who was a post-doc in the lab at the time– he’s
now an associate professor at UAB– led this. And we decided to take
on the early phase of a romantic relationship, that
period when you’re intensely focused with the one
that you’re in love with, you think about
them all the time, you crave being with
them, you feel terrible when you’re not with them. Doesn’t that just sound
like an addiction? And it’s because it has
the same neural circuits as an addiction. Passionate love is
just like an addiction. And it engages
specific brain centers involved with dopamine, which
is our feel-good chemical in the brain. So what we did is
we ran this study, and we put up flyers
on Stanford’s campus, right around here. And we just simply
said, are you in love? And within a couple hours,
we had over a dozen couples banging on our doors,
raising their hands, saying, we’re in love. We’re in love. Study us. And I should have done
this study years ago. It was the easiest one we’ve
ever recruited in our career. And so we said, bring in
pictures of your beloved and bring in pictures
of an equally attractive acquaintance. This is a control condition–
and by the way, clothed. So get your minds
out of the gutter. This isn’t about sex. It’s not about lust. It’s about focused
passionate love. And we also gave them a
distraction task, which is, think about every sport
that doesn’t involve a ball. Think about every
vegetable that’s not green. It’s distracting. And then we caused them pain
at each of those conditions. And what we found–
yeah, it’s true. We have a lot of fun in the lab. And we pay these
students really, really well, let me tell you. And we don’t harm the students. We don’t harm the subjects
that come into the lab. Take-home message–
love works great, folks. Love works great. We lead to about a 44%
reduction in pain with love. And it turns out the
more in love you are, the more pain relief you got. Now, how do we know how
much in love you are? Well, it turns out
that psychologists have got scales for everything. So there’s a
passionate love scale. And one of those items
is how much of the time you spend thinking
about your beloved. And we had Stanford
students here thinking about their beloved
80% of the day– amazing. It’s amazing they
got any work done. But they’re really smart. So that other 20% of
the day, they obviously could pass the test. They had three
times the analgesia from viewing their beloved
than those who were spending time, less than half a day. We then repeated this study. We stuck them in the
scanner, did the same thing. And what we find is that we
get this great activation in the brain in the
nucleus accumbens, this area involved
with dopamine. It’s your rich feel-good
center in the brain. And it directly connects
with this area, the PAG– the periaqueductal gray. This is where your
own endogenous opioids are released. These are the
pain-relieving chemicals and a direct intersection there. So what does this mean? What this means is,
well, as a physician, I can’t write you
for a prescription for a passionate love
affair every year. That won’t fly,
not even in Vegas. But I can tell you, go
do something rewarding. Go do something fun. Go read a new book, like
maybe one of these books that you’re going to get today. Go for a walk on
a moonlit beach. Go listen to some music you
haven’t listened to before. Do something that’s
rewarding, and it will have a pain relieving effect. So in closure, we
know that chronic pain is a disease that causes changes
throughout the entire central nervous system. And it behaves much
like a disease. The key message here that I
want to leave you with here, it’s not just about the body. And let me be very clear. It’s also not just
about the brain. It’s about everything. It’s all interconnected. And so our message is, target
everything, and take back your life. Thank you. [APPLAUSE] So I think that we
have literally a moment for I think just a
couple of quick questions if people have any before we
get onto the next speaker. Any specific questions? And it may take them time to
be able to get a mic over, so raise your hand if
you have a question. Any? MODERATOR: There’s
one right there. SEAN MACKEY: All the way
in– right here, yes. AUDIENCE: Is this
presentation downloadable? SEAN MACKEY: We will make
PDFs of the presentation available for you,
yes– good housekeeping question we should have covered. Yes, in the back. AUDIENCE: Are we allowed
to take a stretch break? SEAN MACKEY: [LAUGH] Yeah. Listen, we only intentionally
cause pain in our lab, not here. The question was, can
you take a stretch break? And the answer is, absolutely. Did we mention where
the bathrooms are? MODERATOR: No, we didn’t. SEAN MACKEY: All right, we
have a number of staff here that can point you to the
bathrooms and do encourage, if needed– you know, stand up. Take a stretch break. If you’re in front of people,
try to step off to the side. But yes, thank you
for that question. Other questions? Yes? AUDIENCE: So I find
that distraction works to alleviate pain temporarily. But then the mechanical effects
of discs being compressed onto nerves, then, well,
that precedes regardless of whether I’m distracted or not. SEAN MACKEY: Yeah, distraction
can work effectively up to a certain level,
if you will, of pain. And then these other
systems kind of take over. The key I think here is each
of these little amplifiers, whether it be
distraction, or love, or reducing one’s anxiety,
or meditation, each of them in itself is not going
to eliminate pain. But the idea is if you’ve got a
lot of tools in your tool box, you can break out a number
of these, each one that’s taking a chunk out
of it, and that you know how to use the right tool
in the right circumstance. Again, I’m talking
like an engineer because I’m a recovering
engineer and I think about tools, and I want to
make sure that you guys have the right tools.

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