How deep brain stimulation is helping people with severe depression

Jean Mary Zarate: 00:04

Hello and welcome to Tales From the Synapse, a podcast brought to you by Nature Careers in partnership with Nature Neuroscience. I’m Jean Mary Zarate, a senior editor at the journal Nature Neuroscience.

And in this series, we speak to brain scientists all over the world about their life, their research, their collaborations, and the impact of their work.

In episode ten, we meet a researcher who uses deep brain stimulation to help patients who suffer from severe depression.

Helen Mayberg 00:38

My name is Helen Mayberg. I’m a neurologist and neuroscientist, and working as director of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai in New York City.

So my lab studies depression, and we study treatment-resistant depression. And we work with a technology called deep brain stimulation. So it’s an experimental treatment strategy that tunes a circuit in the brain with an implanted device. And we’re using this to test and understand treatment recovery in patients with severe depression.

As a neurologist, I see the combination of intense, unrelenting, negative mood, to the point that you want to be dead. That basically arrests, makes you virtually paralyzed. And that distorts your thinking, and that you cannot escape from it.

That is intrinsically a problem with your brain. And it ought to be mappable dissectable, put into a systems neuroscience structure, no different from mapping Parkinson’s, mapping the visual system, mapping Alzheimer’s disease, mapping any disorder that we see as neurologists or psychiatrists.

And that’s a strategy to look at signs and symptoms in a syndrome, and look for patterns that one can attribute to a map in the brain. And that’s actually all I’ve been doing my entire career.

Helen Mayberg 02:31

So deep brain stimulation research, deep brain stimulation as a neurosurgical specialty, (and I’m not a neurosurgeon) requires a multidisciplinary team. And our experimental DBS group is no different.

This work involves me as a neurologist and the principal investigator, but a functional neurosurgeon who’s an expert in doing these implants, a psychiatrist who needs to be an expert on treatment-resistant depression. Our team also involves a full-time psychologist who can do psychological rehabilitation of various kinds with these patients after they’ve been implanted.

And then, importantly, a team of neuroscientists that provide the imaging expertise to precisely map the brain, so the surgeon can properly implant in individual patients, can track and have expertise in different kinds of post-implant brain imaging to track what happens over time, electrophysiologists to do both EEG recordings, so extracranial, electrophysiology recordings to track recovery over time, as well as PET scan over time, as well as now engineers and computer scientists to build and leverage advances in the devices themselves, to basically make measurements of changes in intracranial recordings that we can measure off the device itself over time.

Helen Mayberg 04:32

So we have a fairly rarefied set of patients with depression. They’re categorized as treatment-resistant, which means that while they may have responded in past episodes of depression, which for most people is an episodic disorder, they’ve reached a point where no available treatment works.

So our patients have been in their current depressive episode generally a minimum of a couple of years, they have failed at least four medications. They have had TMS, transcranial magnetic stimulation, (often ketamine now, a very commonly used new treatment for patients in the state). But all of our patients have also stopped responding to electroconvulsive therapy, which is the best and most aggressive treatment that we’ve got, and generally works.

So even if they can get well, they don’t stay well, so this is end-of-the-line depression. And all of our patients need to meet this criteria. This is an experimental treatment. So if something else can get you, well, then we use that. This is for when patients stop responding. All the patients meet that strict criteria. And Brandy, who you’ll hear from, is really one of our typical patients.

Brandy: 06:01

For me, it’s like a stickiness. It kind of holds me down, and it takes so much effort to do anything, or to experience anything, and there’s always that cost of, kind of reminds me of like scar tissue, like every time you stretch, it comes back and it holds you even tighter.

Helen Mayberg: 06:30

So what’s really interesting, as you listen to the narrative of a patient with depression, is look, there are a classical, agreed-upon set of signs and symptoms that a psychiatrist or any medical doctor can follow to make the diagnosis.

People with depression have sad mood, low interest in pleasure. And then some combination of problems with sleep and appetite, libido, interest, guilt.

Many people feel like they want to be dead. And there’s a list of symptoms that are required for the diagnosis, that by the time you reach a place where you are stuck ill, the individual symptoms stop mattering. And what really dominates all of the patients that we’ve operated over all of this time, (Toronto, Atlanta, New York), is this pervasive, unsettling negativity that you can’t escape. You can’t think your way out of it, you can’t move, and that it’s really no longer about all the rest of the symptoms. It’s negative. It’s psychic pain, and immobility.

And patients develop their own shorthand for what that feels like. And it’s all different. It’s on no psychiatric list of symptoms. But every patient has it if you ask. And Brandy’s description is lyrical, and everyone that hears it can feel it. Even if you have never been sick, nobody wants to be there.

Helen Mayberg 08:49

You know, I came to neuroscience, I think through the back door. As a kid, I kind of liked everything. I was pretty precocious and sort of voracious to kind of learn about anything and everything.

My family background, my father was a physician with a busy general practice. So I had that exposure. I wanted nothing to do with the lifestyle of my father, who was very busy. I hated blood. My mother was pretty stunned with the idea that I would become a doctor.

What did I like to do? I like to sing. I played the piano. I got into photography. And I think the photography link probably forecasted my interest in maps.

I love music, but I really like visual arts, but more as a voyeur. I like patterns. I wasn’t a painter but when I found photography I could generally see things through the lens that were not just documenting what was there. I didn’t do realistic photography at all.

And I think that might have foretold that the idea of looking for maps or patterns in the brain would be something that I might do. But there were no ways to map the brain. I didn’t realize it at the time, that actually I was laying the foundation for things that I would do 20, 30 years later.

I struggled in college to find the scientific approach. I tried different kinds of labs. I love technology, I always gravitated to tools. If I think I’d had role models of engineers I would have been an engineer. I think that would have been a better fit.

Neurology became the closest to an engineering approach to behaviour. Psychiatry, in medical school, the problems were the most interesting, the most demanding, the most misunderstood, had the worst language. I hated the language, I loved the problem.

Neurology was second choice, because it had a better language. It had maps. It didn’t have maps of what I cared about. But it had tools to learn how to build maps, and to develop a language that could be applied to the problems I cared about.

And then the problems just presented themselves. And the tools became more sophisticated. And I was on the train.

So the research really entails, and the first experiments were really designed to say, “Can you, with the current tools, map depression in the brain?”

And what we wanted to do was really look at if we can see depression in the brain, what happens when you treat it? So again, having a signal for diagnosis needs to be followed up by “How do we fix it?” Does the abnormality go away? Do you have adaptation in another way?

And so we set up really simple experiments to map how brain metabolism with PET scanning changes when people with depression are treated with Prozac, are treated with placebo.

We had people in placebo-controlled design and we learned that the signal that changes in the brain, when you get better with drug or placebo, has some shared features.

We also learned that if you don’t get better, those signal changes don’t occur. And that was where we first identified that it wasn’t just that low frontal lobe activity, which was the reigning finding, corrected, like low frontal activity normalizes.

We actually saw for the first time that when people got better, not only did the frontal lobe change, but this area that hadn’t been associated with any depressant effects, Area 25, the subcallosal cingulate, decreased this activity.

So we had two issues that were surprising. We always thought that brain activity is low in depression. Here, we were getting that an area of the brain was high and was decreasing its activity. And if it didn’t turn down its activity you didn’t get well.

Area 25 needed to change with every kind of treatment that we or other people did. Its connections when people started doing fMRI, it was front and centre.

It’s a hard area of the brain to get at in animals. It’s deep, a lot of vessels, you have to have a reason to get there. It’s hidden. So that led to “If you can’t talk it, drug it, shock it into the right activity level.”

Deep Brain Stimulation was already active in Parkinson’s disease, that everything we knew about DBS at that time for Parkinson’s disease is that wherever you stimulated you blocked activity.

Turned out that was wildly over simplified and probably wrong. But if we could put an electrode in a place that I needed to turn down, it ought to work in people where no other treatment could get that brain region to behave as it should.

Because when it went wrong, it impacted everything it was connected to, including the frontal lobe

Helen Mayburg: 14:52

This is Brandy two years later, having basically had the DBS implanted, being on a stable dose and having continued stimulation, stimulation for this entire period.

Brandy: 15:06

What happened was incremental changes. Things got a little bit easier. And even in the smallest things, it got a little bit easier to brush your teeth, it got a little bit easier to get out of bed, it got a little bit easier to have hope. That just started a cascade of positive instead of the cascade of negative. And that was the difference. DBS didn’t make me happy. DBS, it didn’t solve all of my problems with how I was thinking or how I was behaving or my lack of boundaries in relationships.

It didn’t solve any of those things that needed to be worked on. All it did was make it possible for me to not have this huge burden, preventing me from being able to solve all.

Helen Mayburg: 16:01

What I find really interesting about re-listening to her review of her trajectory over two years, which is really the right period of time to really appreciate the arc in patients, is that it goes through different stages. And she describes them perfectly.

There is that initial fast reset, dramatic, a total unlocking of the door, ability to move. But when you really put it into context, what does it mean to have the parking brake come off?

That just means now you’re in the position to decide what you’re going to do. And she describes what she had to do.

She learned that everything is easier. What does that mean? Okay, I can move. Now that I can move, I have to have a plan. I have to decide what I’m going to do. I’ve got to test it out, I’m going to have starts and stops. I’ve got to figure out what I’m going to do now that my brain works.

And that’s what every person does every day with a functioning brain. Good days, bad days, three steps forward, hopefully only two steps back.

For a patient to get past after two years, that they aren’t going back into that hole, into that paralysis, they have to have enough days of it going in the right direction to trust it. And only with time and looking back on your own trajectory can you actually appreciate where you’ve come because after a while, it’s just as one patient said, “Like, you don’t look every day in the mirror to see how much of your hair has grown. Three months later, you realize you need a haircut. But every day you don’t think about ‘Is it today?’”

And that’s a phenomena that we see with all treatments for depression. You take a drug, it takes about three weeks, six weeks to kick in, you keep waiting every day “When am I going to be better?” One day you wake up and you’re just different.

Ketamine, you feel better the next day. ECT suddenly, after X number of treatments, you just click into a new state. Once you click into the new state, you’re now rejoining the rest of us with the ups and downs of everyday life, on top of retraining your new brain.

And I think that process of rehabilitation is its own new thing we have to study

Helen Mayburg: 18:58

You know, if you have been in that state for a while and you suddenly change, not only is it dramatic, it is disorienting.

You are like in a Star Trek episode, “Scotty beam us outta here.” And you beam out and then you go, “Where are we?” That’s what happens to these patients at the beginning. They are definitely out of a bad place, and they don’t know where they are.

And when you break your leg, if you have a really bad break, the healing process, the first effect is really different than if you have a small linear fracture. But everybody goes into a cast and everybody’s immobilized. And the question is, when do you know that it’s time to come out of the cast and start the hard work of rehabilitation?

Nobody has a problem with the idea that an open fracture where you’re in traction in the hospital for a month is going to be a different recovery course than a sprain.

But if you’re a marathon runner, where you want to be is very different from if you just want to be able to walk to the kitchen and get a cup of coffee, because you work at your desk.

Everybody needs to have a rehab plan that considers both the starting state of the abnormality, the initial repair process, and then the rehabilitative procedures.

And it is a process. And I think this is where neuroscience-informed rehab is going to take us.

I often have a nightmare with my tombstone that kind of reads like, “What did she think she was doing?”

Um, because all of us have to reckon with the fact that with what we know, at the present time, the future will look back on us with new tools and a new framing, and kind of see this as misinformed.

I would like to think that as we learn from history, I look at psychosurgery and I see well intentioned people that didn’t look at their data.

If we look at data, we will always be able to justify what we do if we keep the patient’s safety in mind, and that benefit will always outway risk.

In this process, we are using crude devices, we’re sticking a wire into the brain. People now are developing nanoparticles, smart, smart whatever, that can go right where we want them to go with things that will hopefully not hurt people. A lot of details to work out. I consider that we have a roadmap. We can get to it now safely. We have durability. I hope I live long enough to see that people won’t require a hole in their brain and a device implanted in this way.

But for right now, it’s safe, it works. And it has durability. But we ought to be able to take what we know, not throw it away, start from scratch and say I got a better mousetrap.

We gotta take what we know, just like we used what we learned from imaging, informed by what we knew from even people now that we hold in great disregard. They had the right idea, they didn’t have the right tools. And they got ahead of themselves.

That we just follow the data. People are building new tools that will get us into these circuits in safer and non-invasive ways. But we can’t go backwards, that if it’s non-invasive and not durable, because it won’t be scalable, it won’t be affordable, and it won’t be generalizable.

And we will be limiting what we do to the people who can pay for it. Or when NIH or some other funding agency wants to let us play for a while with our research grants. We have to be thinking about the future of taking what we know and getting to it so it can impact as many people as possible.

I have no grand delusion that people are going to walk around with a device and a battery pack. These are a pain, they have upkeep, they have batteries that need to be replaced. Things can break, have to have repeated surgeries. You do not want that. Nobody should want anybody going into their brain unnecessarily. But if that’s what we have to do, that’s what we have to do now, to return people to being able to be like Brandy, to function in the world like all the rest of us on an even playing field with a brain that works.

But I like to imagine that technology is way smarter than we are in neuroscience, or at least it’s faster. And partnering will get us into a new place where we can take what we’ve learned and push the envelope to be safer and more accessible.

Jean Mary Zarate: 24:29

Now that’s it for this episode of Tales from the Synapse. I’m Jean Mary Zarate, a senior editor at Nature Neuroscience. The producer was Don Byrne. Thanks again to Professor Helen Mayberg, and thank you for listening.