Researchers are trying to target specific areas of the brain. But how do we know which ones? Where does depression exist in the brain? Helen Mayberg is the director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai's Icahn School of Medicine in New York, and that's where she joins us now. Hello Helen, how are you today? I'm just fine. Good to be with you. All right, so you have pioneered some of the work in mapping depression in the brain. I got to know, if I was to put up two different brain scans, one of a depressed brain and one of a non-depressed brain, can you tell me the difference? Not exactly, but in theory, yes, because we study groups of people to get an average map of depression, but then we can get into the individual. So where does depression exist in the brain? Everywhere. Except that, think of depression like the transit system in a city. It's not the whole city itself. It's not every building, every person, but the infrastructure of a city is dependent on the interaction of a communication system and a transport system. And depression basically is when something goes wrong in how various parts of a city work together.

When you say something goes wrong, I am curious, on a scan, what does that actually look like? So again, let's define some terms. Scans can be done to give you the actual structure of the brain, but the kind of scans we're talking about is your brain in action. Because the problem with depression, it isn't as though it's not a stroke where you area of the brain is damaged and then you can't move your arm, you can't speak, or your balance is off. Depression is almost pervasive, um insidious, but profoundly disabling, just like if you take out a transformer in a city. It doesn't impact everything, but it impacts not just where the transformer is, but all the things the transformer communicates with. So, when we do scans that measure brain function, we literally can get a picture of the brain in action. And it's a dynamic picture, not a static picture. And you can just, you know, the problem with depression is when you're depressed, it's pervasive. It's not just when you go outside or just when you sleep. It's all the time, 24/7. So you can take a picture of a person at rest and actually look for how do people with depression look different from people who don't have depression. And that was the early days of mapping. Is there an activity problem in the brain and where is it? It turns out your frontal lobes are really important. And when they are underactive, it commonly goes with people being depressed. But that's just kind of part one, because the frontal lobes talk to many other areas of the brain. And when their communication with some of the deep areas of the brain that control our mood, our drives, our thinking go wrong, you can get to where the signal can go in and it can't get anywhere, just like in a city communication system. So one has to think about mapping depression as mapping a layer in a complex brain. And it turns out that there are some key areas in the brain that when they stop functioning normally, they impact everything and you get the syndrome of depression.

One spot in the brain that I want to talk about is area 25. You were able to locate that. How did you find it and what did that tell you about depression? So, years ago, when we were using these positron emission tomography scans, they're called PET scans for short, that we can measure brain glucose metabolism, the primary energy source of the brain. We can get a measure of whole brain glucose metabolism, the activity. We noticed that the frontal lobes were down. And so we did the obvious next experiment. We said, "We're going to treat people and we'll see what happens when they get better and we'll show that the frontal lobes is the source of depression cuz we'll correct it." Mhm. Well, what we discovered was, yeah, the frontal lobe corrected, but an area we didn't even know about, that I had to look up in an atlas, actually didn't increase its activity, it decreased its activity. And then in trying to understand it more, we tried to figure out what can we do to activate it. And we, like others, basically took healthy people, put them in a scanner, and had them think of something profoundly sad. Mhm. And sadness is very different from the negative feeling in depression, but we just went with that. And when you think about a loss, or something that can often cause depression in vulnerable people, even just for a short period of time, and you can take a picture of that with the brain in action. The area of the brain that activated the most was area 25. And it turned the frontal lobe off. So the relationship of treatment is the opposite, if you will, of what happens even when you get transiently negative. And that was the start of investigating area 25.

Well, let's talk about that relationship and what it could mean for for treatments. Can you now look at someone's brain scan and predict how they will respond to different types of depression treatments? We actually can. And let me just make the caveat that we don't do this routinely. Should we, should we not? You know, scans are expensive, people have to learn how to do it. But with those caveats, the answer is for many years, that was the next set of our experiments, including when I was working at um in Toronto. If actually area 25 changes only when you get better and doesn't change in people getting the treatment who don't, maybe we can start to study why some people respond to one treatment over another. And we started to realize that if you look at the relationship of area 25 to other areas of the brain in people who can get better on therapy or who can get better on drug versus those that you shouldn't have bothered, it turns out area 25's communication with areas in the frontal lobe and areas in the brainstem can actually predict which treatment you're going to respond to. And we've done this with drug and therapy in different um different labs. And we and others have been really searching for what we really need in the field, which is not just to have treatments that work and are durable and prevent relapse, but we need to match people to the treatment that is best for them. And further, avoid things that are unlikely to work.

Mind my pun here, but it seems like a no-brainer. Do you think that this type of brain imaging and the information that we know should be guiding how we move forward with treating depression? Well, you know, I'm obviously biased. I've been doing this a really long time and it's kind of like um Don Quixote and windmills. You can know it's true. You can have partners scientifically and clinically that know it's true. We can have grants and money to look at it and know it works. Knowing something and scaling something is hard. So, yes, mean, why shouldn't we do this to a problem where people die by their own hands if they don't get help? We do this in cancer. We do this in infectious disease. We even do it in deciding if we do heart surgery. We do a test to know the nature of the problem and to treat accordingly, whether it's right antibiotic, the right chemotherapy, the right surgery. So precision and kind of the subtyping, the brain typing, is very important. We do it in all aspects of medicine and we also do it in neurology. So, the answer, the long answer, the short answer is yes. And how do we get from the scan to maybe something that's easier? A blood test, maybe. A way you analyze um symptoms doesn't seem to work well. The genetics may help, but that the bottom line is the brain produces the disorder and the symptoms, so we ought to go to the brain to know what to do. We do this for treatments, for precision treatments that are electrical, you know, like TMS. You know, a transcranial magnetic stimulation. You have to be in the right part of the circuit, but it's also true that TMS may not work in people where the circuit that you're targeting is damaged. That's why deep brain stimulation which involves more invasive surgical tuning of the circuit may bypass what may be a broken roadway in our transportation system. You know, you always are trying to If you're trying to get from point A to point B, you have the most direct way. But sometimes you have to take a detour. What do you do when all the roads are blocked? That's how we have to think about the brain and we need to have strategies to get to where we're going and to have a brain working in a healthy way.

As we know, you know, depression is not a singular thing. It can be very different uh for for people. Um and I am curious, do we know how depression looks like uh sort of across the range of people uh in their actual brains and what it looks like? We do, you know, people have tried to study what may be different um as a function of men and women because men and women have depression at different rates, starting at different times in their lives. We know that symptom [snorts] profiles are different in different people. I might propose a different way to think about it. Individual people are different. Individual people have different temperaments, styles as humans. You know, everybody isn't the same personality. Everybody doesn't have the same early life experience. We know that early abuse is very bad for your brain and it puts you at risk for depression. Your brain is an adaptive machine. Its job is to solve problems, get you from A to B, help you to survive. And just like we know in life, you need to take creative measures sometime because plan A doesn't work. Same thing in your brain. It adapts even to bad things. So, consider that maybe what can go wrong, you know, you can take out a different transformer in the brain or block a different roadway or affect one region over the other's chemistry. But it's on top of individual differences that aren't about depression being different. The same thing will look different on different people because they are different, not because the depression is different. And that is I think intuitive, but when we set up to study people, it's easier to try to look at the symptom variation and say, "Oh, it's different kinds of depression." It's more that different brains can respond to the same insult in different ways. So, it has to kind of alter our thinking and the scanning has helped us is helping us to understand that, including by studying people who don't have depression.

Helen, as you as you mentioned, you have been studying this for quite a long time. So, I I I am curious, um how excited are you about where the future is heading for this type of technology when it comes to being able to personalize treatment? I'm well, I remain an optimist cuz that's my personality despite the fact that I study and watch suffering, it just makes me want to do more. I'm very optimistic and I'm optimistic because by knowing these maps is how we identified area 25 as a central hub and how we learned that you could tune and pace and change the activity in this very small, very deep area of the brain and change the pattern in the rest of the brain and not just affect somebody relatively quickly but actually have it be sustained, that they could learn to use their brain and not expect it to relapse. And when we are able to do that, we can learn that you can repair these wires in the brain, these communication roadways. So, I'm more optimistic now as we move very slowly through all of these new treatments and try to work to get people the best treatment at every stage of their illness. But we can work backwards from the most severely affected patients where we have to take the most aggressive treatments and work backwards to really kind of deconstruct this circuit in many ways. So, I remain optimistic. People that are sick for the first time need to be hopeful that there are things that can work for them. And that if one thing doesn't work, there are other options. And similarly, when people have developed very resistant depression, there are new things coming online, not just the kind of things we're doing. And that the future is bright and people need to have hope and people are working on the problem. And treatments now are available and talk to your doctor and get help.