Mind Power

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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