Examining Depression Through The Lens of The Brain: Dr. Helen Mayberg (Transcript)

Here is the full transcript of Dr. Helen Mayberg’s talk titled “Examining Depression Through The Lens of The Brain” at TEDxEmory conference.

Listen to the audio version here:

TRANSCRIPT:

Understanding Depression

So, what I’d like everyone to do is just close their eyes because I think this morning, inspired by all the other speakers, I’d like to actually put us all in a first-person perspective on the topic that I’m going to be discussing, which is depression. And I want to start by having you just listen to depression.

[Video clip: I was pretty convinced that I was going to die, that there was nothing left for me. My life had completely closed in. I had no other choices, really, clinically. My own psychiatrist said basically there was nothing left to do.]

So, just imagine that that’s the sound of a malignant depression. If you’ve ever been depressed, you might think that, well, that doesn’t sound any different from the state that any depressed person gets in, except you usually come out of it. That’s the sound of a 37-year-old man, a son, a partner, a valuable employee, a cyclist, a competitive cyclist, who actually had become depressed. Not the first, not the second episode he’d ever had, but he got stuck and he couldn’t get out.

He had stopped responding to multiple medications. Psychotherapy was essentially worthless. He had even failed multiple courses of electroconvulsive shock therapy. So the question is what happens when you are so low, so stuck, so unable to get out of the hole that basically nothing is left for you? Think about it. The question is what is the neurologist standing here in front of you telling you about it?

The Neurological Perspective on Depression

What’s the point of a neurologist in this story?

Well, what you heard is when the brain fails to be able to adapt to circumstance, to the situation, when it breaks. And the question is that’s what neurologists study. That’s what I’ve been trying to figure out. And I’m going to tell you the story of how we look at depression through the lens of the brain, but from and listening to the first-person perspective of those patients to understand what goes wrong and how do we fix it.

So I need to put you back a number of years where actually this story is about imaging and the mapping of circuits in the brain. And these are extremely old pictures, probably older than many of you in the audience. But at the very beginning, it was simply a matter of can you map depression in the brain? If you’re measuring the brain in action, does it have a signature?

And it turned out if you studied patients with stroke or Parkinson’s or Huntington’s or unipolar or bipolar depression, when people were ill, there was a pattern. There was a signature. And it wasn’t one area of the brain that wasn’t functioning normally. It was a whole constellation of brain areas, which turned out to be a circuit.

And the question was, how could we map that circuit? The approach was to do what neurologists always do: deconstruct, compartmentalize. Different areas of the brain serve different functions. In the old days, we were very simplistic, lesion, deficit, an area does a particular function.

Mapping Depression in the Brain

It turns out it’s an orchestration, a symphony, with different regions across the brain working together to choreograph complex function. But in depression, a big issue is that it’s always about negative mood, but it’s also about change in drive, whether it’s appetite, libido, sleep. But in the setting of your thinking is off, you’re slow, you’re inattentive, you’re guilty, you can’t feel pleasure. And your movements get slow.

Your will to act becomes impoverished. And it’s the combination of these various symptoms is what we map. And through a series of experiments, we tried to understand what regions, what combination of regions did what. We treated people. We took advantage of every treatment known, whether it was therapy or drug or shock or magnets, to actually understand how do you change the brain, what symptoms change.

And actually, what’s the state of going from sick to well, to understand what in the brain isn’t working. And we had a very classical view, because we followed what psychiatry told us. When you’re sick, you’re in state A. When you’re well, you’re in state B. There’s a linear transfer of going from a low state to a high state. We have rules that apply these linear principles. I’m trying to pretend like I’m talking math here.

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But in fact, we have a threshold where we say when you’re 50% less bad, we call it a win. Any combination of those symptoms, if you’re 50% better, it’s a win. And that was all fine and good, except there was something that started to really gnaw at me about, again, as a neurologist thinking about depression, it was easy to look at the cognition, easy to measure motor speed, easy to measure immune or inflammatory markers.

The Uncharted Territory of Emotional Pain

The issue was, where’s that sad part? There’s something about the pain of a major depression that’s unlike anything. I’ve never been ill. But even to take the third person perspective, to be empathetic, compassionate with a patient who is ill, is to experience a true black hole, even in third person. And what is that state to suffer yourself that must be like?

That, to me, has always been the part that’s hardest to explain, hardest to localize. And at the end of the day, the only thing that’s really most important to try to understand as a starting point. Because in many ways, everything else is a derivative of what happens when you have that negative experience. So if you think about, this is something that has been known for a very long time.

William James described his own depression not by, “I can’t think straight, I can’t go to class, and I don’t feel pleasure,” but by the mental pain. Something that is so indescribable that a person who has an experience can’t know what it is. And our patients, if one listens, actually describe the same thing. Annoying agony.

How can pain cause you to be self-loathing? What an amazingly cruel state, a twisted state to be in. That not only do you feel bad, but you actually think it’s somehow your fault. If ever there was a state where you said there was a loose wire in the brain, a miscommunication of what something should be functional was not, I think it would be hard to argue that this is it.

I particularly like this because it really shows how the negative state starts to invade every part of everyday life. Every action, every thought, to do anything that one wants to do, gets hung up on that loop of hesitation. And it ends up feeling like you can’t move at all. But actually most critically, and again thinking about why does sadness, why does pain, why does, and why do we use empathy and compassion to deal with both our own pain and pain of others, even in the non-pathological state?

What happens when you can’t get outside of yourself and literally can’t connect to anybody else around you that also might be able to help? So the question is, where is that? Where is that? And really in the early experiments, we could model that with a really kind of poor approximation of the clinical state. But to ask, even if a healthy person experiences an intense recollection of a personal loss, what happens in the brain? In real time, you can map that areas of the brain change. Some areas go up, some areas go down. And it turns out that that pattern is incredibly important.

Discovering the Brain’s Role in Depression

The pattern helped us to identify that limbic areas, core drive state areas, and dominated by a region called the subcallosal cingulate, or Brodmann Area 25, led the charge. When it activated, it shut down the cortex. Areas that drive thinking, planning, moving, are offline when these emotional centers are activated. But importantly, if one maps how patients responded clinically as they got well, there was a flip of the pattern.

That Area 25 down-regulated its activity, and in concert, cortical areas came back online. It’s what we all know. There’s a natural toggle between our emotion and our action. When we really get inside ourselves because something happens, we actually turn our attention to other things away from outside to inside.

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So the question becomes, what happens if that natural toggling can no longer happen? And I think that that is the point that we reached now more than 10 years ago. And again, we were mapping all in third person what happens if you treat with X or Y, what happens when you get better, when you don’t, even to actually start to discriminate that people before you actually offer them a treatment might be in different states, where you could actually treat people to match a brain type so that people who need therapy should have therapy and should never see a drug. Or alternatively, if you need a drug, you get a drug, and therapy or rehabilitation can always help you.

But again, in science and in medicine, the question is, what do you do when you don’t have an alternative? How do you use where you are at the present point in time to appreciate or to test out what some people might think is a radical idea or where, in fact, the data is telling you this is actually the next step? And this is really the switch where from the problem of people who are in a depressed state and can’t get out, who really are off the grid, to actually just think about their brain and realize that maybe we can change the balance by directly intervening.

The Innovation of Deep Brain Stimulation

If we know the map that we can go directly to what we think might be the source, and you might say a tad audacious perhaps, but not so much, because back in 2001, 2002, we were in the heyday of deep brain stimulation, the implantation of small leads that can electrically tune specific neural circuits to treat Parkinson’s disease. They had taken the strategy of map the motor system, understand the nodes in the circuit, and target a node in patients who no longer respond, where the science itself informed where in the network one should go.

And we took that same strategy knowing that Area 25 seemed to be very important. It was a node in a much more distributed network, and maybe we should implant and see if it can have effect in patients who have no other options. This is the point where you go from mapping in third person to actually listening to the patient. And what we did is you can see the electrodes, two, one on each side, implanted deep in the brain through small burr holes in the skull. Patients are implanted. They’re awake in the operating room.

They’re available to talk to us and let us know what’s happening. Our goal was to, maybe we would change negative mood, but we were going to move that whole system. These people weren’t sleeping. Their appetite was bad.

The Impact of Stimulation on Depression

They had really little movement, little thought, and this intense, pervasive, negative, empty state that they were in that we could apply a small amount of current just like they did in Parkinson’s and see what happened. Our first concern was let’s just see if we can do this safely. Depression obviously takes a long time to get well. Why should this be any different?

And so what we did is we turned it on, and what we found is that as we applied the stimulation, first patient, as we crossed our fingers that nothing went wrong, first site of stimulation, nothing, second site of stimulation, nothing, and third site of stimulation, suddenly the woman expressing that she suddenly felt calm. And as she tried to explore and find the words to describe it, what she was really describing is a lifting, a clearing of this void, of this intense negativity that had just been part of her life incessantly for the last five years.

We turned it off, and suddenly all she could say was, well, maybe I was just imagining it. So these first effects in the operating room, totally unexpected, and it wasn’t even clear if it was even important. And so we proceeded to implant, test, use chronic stimulation to actually see if the depression syndrome would go away. But what we found in patient after patient, not always predictably, but that as you would hit the switch, that patients would say things like this, “The tension is gone, the vortex is gone.”

You can ask yourself, what is a vortex? Every patient had some odd idiosyncratic way in which they characterized this state, that they were no longer drowning, they were out of a hole. They felt lighter, less heavy, less resistant. The fact that they felt that they could breathe. People even started to describe the room being brighter, feeling more connected, to suddenly feel more optimistic, to feel more connected to us in the room. And even wanting to do stuff.

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The New Frontier in Depression Treatment

We all started cracking up when one guy on the table bolted into the operating device said, well, I know I’m kind of locked in right now, but if I was home right now, I’d really like to clean my garage. So suddenly, we were seeing that there was a consistent, although kind of not the routine pattern that you’d expect from a neurology examination. So personal, but so profound.

And so the question went back to not the gee whiz, oh, this is interesting, but what did we do to move from the amazement back to the disimpassioned, passionate approach to the science to just figure out what it was? And it was actually through the neurological process to say, what are we actually doing when we stimulate in that location? We’re actually affecting an entire circuit in the brain to map what exactly.

We can use our models of connection to Area 25, and we can actually plan our surgery now to precisely predict where we can get that effect. And when we can lift that acute change in mood, patients get well. So we have two phases now of recovery. This early, rapid change, the lifting, the reset. But then we have a delayed process, where actually patients have to relearn how to have a bad day. You don’t get better overnight.

All your new habits need to be reshaped. And we actually have to totally revise our linear way of thinking about depression to a nonlinear way of recovery. Regular depression is off to the left. You can go up and down along a continuum, less or more.

A New Understanding of Treatment and Recovery

We don’t understand what happens when you fall into that pit. But what we’re learning is that something about stimulating in this location can help you to jump out. And it’s then that the chronic stimulation, which is still required, combined with therapy, psychiatric care, and all of the other things that go on to recovery and rehabilitation can go on. So I just want to end with a last quote, because what’s happened now is an appreciation as scientists, is that it’s no longer about third person as a medical researcher.

It’s about using the first person perspective, to use the patient’s story, to let a patient tell us what’s happening to them. Because in fact, they know better what we’re doing to them than we think we know what we’re doing to them. And I think that what we’ve learned and what I’d like to help you to understand as I finish my talk, and I’m over time, is the fact that it’s about listening to the patient, but then disimpassionately moving in a direction to test the new hypothesis. We do it with the team, but the patient is our collaborator, not our guinea pig.

And that it’s only through this process that I think that we’ll really understand the nature of how emotion and reason interacts in our brain, and we’ll understand how to actually provide alleviation from suffering from patients in this situation. Thank you.