She Found the Spot
Helen Mayberg spent 40 years looking for where depression lives in the brain. Then she stuck an electrode in it.
I spent the early part of this week at the Brain Stimulation as a Subspecialty Symposium. As I’ve written before, Josh Brown wrote about the coming of Brain Medicine, and he’s really on to something. Just a few years back, Drs. Nolan Williams and Shan Siddiqi saw the need for a new intersectional discipline in medicine. They decided to make it happen. I was proud to be in the room this time around, and I want to tell you about one of the speakers today. Dr. Helen Mayberg is a giant in the field that isn’t even officially a field yet.
She trained as a neurologist, but has spent her career investigating depression—and caring deeply about the patients who suffer with that illness. What do we do when patients aren’t well yet is a fire animating her like few others. She is a driving force around DBS for neuropsychiatric disorders, and in the process, her work has illuminated much of my day-to-day work. It turns out brain circuits may be closer to ground truth for my patients than “chemical imbalances” ever were.
And now, my reporting on the talk she gave.
If you need to brush up on Deep Brain Stimulation, here is an instructive blog post at Radial.
There’s a moment in every great scientific talk when you realize the person at the podium has been playing a completely different game than the rest of their field.
For Dr. Helen Mayberg, that moment came about ten minutes in, when she said, almost offhandedly, that she never planned to be an interventionalist. That she was a watcher. Other people brought her the science, and she just looked at it.
And then she stuck wires into people’s brains and fixed their depression.
Ok, not wires. VERY FANCY probes that could measure and stimulate specific brain circuits. Some of those people are patients. Others? Friends. A brief aside for one such friend’s story—living a life that is good thanks to Dr. Mayberg’s determination.
Mayberg spoke at the BRaSSS meeting -- the Brain Stimulation Subspecialty Summits, which are exactly what they sound like: an annual gathering of international leaders in brain stimulation trying to turn the field into a formally recognized, accredited clinical subspecialty. The first meeting was at Brigham and Women’s Hospital and Harvard in 2023. The second was at Stanford in 2024. The third, this year, is at the MGB hospital building across from Assembly Row in Somerville, which is both charming and a commentary on the Marriott Autograph Collection hotels, which I will save for another time.
The basic project is ambitious: take a field that currently trains people through apprenticeships, disease-specific fellowships, and self-teaching, and build a real accreditation pathway. The fellowship would cover TMS, DBS, ECT, VNS, eCOT-AS, eTNS, PRISM, and other modalities, and it would be open to psychiatrists, neurologists, and neurosurgeons alike. They’ve already voted on the name (brain stimulation, chosen democratically), launched a nonprofit to run the accreditation process, and are certifying existing programs.
There is a grandparenting provision for people already in practice. There is a concern that insurers will use board certification as an excuse to restrict reimbursement. There is, as in all fields, the problem of who gets invited to the meetings that decide what the field is.
Mayberg was asked by Siddiqi to “bear her soul a bit.” To tell people how a neurologist ends up as the person who figured out where to put a deep-brain stimulator to treat refractory depression.
She started with Hippocrates.
The actual quote she cited was from a book called Art and Fear, which, if you haven’t read it, is ostensibly about making art but is actually about the terror of committing to something. Life is short. Before you do something, figure out if it’s worth it.
This is not complicated advice. It is, however, advice that most people in academic medicine are constitutionally incapable of following. Academic medicine often selects for people who would rather run one more experiment than make a call.
Mayberg is of another ilk.
Her Parents, Which Is Relevant
Her mother’s thing was: dream big. Her last words to Mayberg were “please don’t stop working so hard” -- wait, no, the opposite of that -- “please don’t work so hard.”
Her mother’s brother was a physician-scientist who had to choose, at a fork in the road, between the Manhattan Project and medical school. He had a single mother and a sister to support. He made the responsible choice not to blow up the world, as it wouldn’t provide for his family.
Her father was a pragmatist. Private practice, entrepreneurial, and when she complained about things (as children do), he would say: "Life isn’t fair, figure out a workaround.”
His last piece of advice to her?
You can’t just let it happen. You have to make it happen.
This, it turns out, is the entire scientific method.
How You End Up Studying Depression When You’re a Neurologist
It starts, as many things do, with a pivot you didn’t entirely choose.
Mayberg was going to do behavioral neurology. She was going to train in Boston with Norman Geschwind, the behavioral neurologist’s behavioral neurologist, a man who examined eye movements on everyone and made it seem like a very cool game.
Then Geschwind died. With his passing, she was left bereft of a mentor and “the plan.”
A neurosurgery resident, rotating with her in the middle of the night as neurosurgery residents do, started talking about his PhD work on opioid receptors. At Hopkins. On a PET scanner.
Mayberg had read Saul Snyder’s work on D2 dopamine receptor binding. The elegant finding that antipsychotic potency correlated with how tightly a drug bound to its receptor. The idea that you could map neurochemistry. Hopkins had a machine that could do that in living human brains.
As a brief aside, I’m a psychiarist because of my experience as a study subject in one of Ramin Parsey, Maria Oquendo, and J. John Mann’s PET studies many years later.
She called Henry Wagner the next morning. Or close to it.
“That was a total pivot,” she said. “Absolute total pivot.”
She went to Hopkins. She learned PET. She met Bob Robinson and Sergio Starkstein, who were studying post-stroke depression, who needed a scanner, and who were doing exactly the thing she should have been doing.
Helen Mayberg started studying depression.
The Advice She Got at Lunch
Somewhere along the way, she was at Hopkins doing PET imaging, studying everything: epilepsy, receptors, depression, whatever crossed her path. She went back to visit the chair of neurology at her medical school.
He listened to everything she was working on.
Then he said: You’re not a radio chemist. You’re not a PET scan developer. You’re not a receptor pharmacologist. You’re a neurologist. What problem do you study? Pick one.
She went back and asked a bunch of senior people in PET imaging what they thought she was working on.
They all said depression.
She had been studying depression.
This is, incidentally, a very useful career data point. Ask other people what you work on. They may know before you do.
Area 25
Here is the actual science, briefly, because it matters:
Mayberg spent years imaging people with depression -- people with depression from strokes, from Parkinson’s, from Huntington’s, from plain old major depressive disorder. The idea was that if you could find a consistent neural signal for depression across all these different neurological contexts, you’d have something real. Something that wasn’t just an artifact of one disease.
She found it.
The subgenual anterior cingulate cortex. Brodmann Area 25. A small region tucked underneath the genu of the corpus callosum, hypermetabolic in depression, normalizing with effective treatment.
Every effective treatment. Antidepressants. CBT. ECT. TMS. VNS. Didn’t matter. If treatment worked, Area 25 quieted down.
If you’re doing imaging and you’re not a responder? Area 25 stayed “hot.
The brain, it turned out, had an address for depression. It had been there the whole time. This is the same brain region we are addressing in SAINT, as it happens.
The Part Where She Stops Watching
She had the map. The target was identified. Neurosurgery had tools. DBS was already being used in movement disorders; the technique was established, and its safety profile was understood.
Then she met Andres Lozano in Toronto.
She moved to the Rotman Research Institute. She had, on hand, a psychiatrist, a neurosurgeon, an imaging platform, and a question that had been building for twenty years:
If you knew the circuit was broken, where it was broken, and you had a tool that could fix it, what are you waiting for?
The answer, she says, was that it didn’t seem radical. Because they could see where they wanted to go. The plan was explicit: go in, stimulate, and measure. If high frequency didn’t work, try low frequency. If nothing worked, turn it off, take it out, call it a day.
“When you have a partner who basically says ‘I can do that safely,’” she said, “and you have an idea and a logic, you can execute.”
The 2005 Neuron paper came out of that. Six patients with severe, chronic, treatment-resistant depression. Subcallosal cingulate DBS. Results that were, by any reasonable measure, remarkable.
Then The Wheels Came Off
This is the part of the talk that nobody puts in journal articles.
The BROADEN trial, the industry-sponsored multicenter RCT, was halted partway through. No explanation. No public communication. Mayberg was an advisor; she knew what was happening internally. She watched people publicly attribute the failure to the treatment, while the actual explanation was more about M&A than data.
Grants dried up. She couldn’t get papers published. Every review came back with some version of: everybody knows this doesn’t work.
What she wanted to say, clearly, was that a failed trial is not the same as a failed treatment. The open-label data from BROADEN, from Toronto, from Atlanta, consistently showed roughly 50% remission at two years. In patients for whom nothing else had worked. In patients whose expected trajectory was chronic, intractable illness. Patients like Jon Nelson.
The problem wasn’t the treatment. The problem was the targeting. Patients whose electrodes missed specific white matter tracts connecting the SCC to prefrontal and limbic structures didn’t respond. You can find that on the MR tractography.
“You have to learn the difference between persevering and being foolhardy,” she said.
She put her head down, followed the data, and figured out the correctable failures.
The People Who Have Been Well for 20 Years
Some of the patients from the original Toronto series, people who had severe, chronic, refractory depression, people who had failed everything, have been in remission continuously for more than twenty years.
With the implant running.
Twenty years.
This is not a “treatment effect.” This is a life. This is the kind of friends I get to have, as your author, because of Mayberg’s relentlessness.
What She Built at Sinai
When Eric Nestler asked her what it would take to come to Mount Sinai, she had a list. The lab had to be embedded in neurosurgery. The psychiatrist, neurologist, and scientist had to be in adjacent offices, physically co-located, so that the collisions happen automatically.
She got Brian Kopell.
She got Martina Zagi and Martijn Figee. She built the Nash Family Center for Advanced Circuit Therapeutics, which is apparently the kind of place where the neurosurgeons and psychiatrists not only work together but know each other’s names and gladly talk to each other in the hallway. Heck, outsiders (me) are welcome to support their patients through a scary-sounding process.
This is a culture hard at work. Inclusion, collaboration, and humanity as cultural bedrock to allow science and healing to blossom.
The center now applies the same circuit-mapping logic to OCD, PTSD, and other conditions where neuromodulation is being pursued. TMS sits alongside DBS. The philosophy is the same: map it, target it precisely, measure everything, figure out who responds and why, and figure out what to do for the people who don’t.
“Nobody gets 100% market share,” she said. “What do you do with the people you didn’t help?”
The Thing That Will Stick With You
Near the end, someone asked her what structures could have made it easier, given that she said if she’d known how hard it was going to be, she might never have started.
Research paths are not linear. You have a method. The method limits the question. The question changes. The method has to change.
Mayberg spent forty years following the signal. She wasn’t wrong.
Now, I have both jovial friends and favorite patients doing well because of it.
Great article about a remarkably inspiring woman. Thank you.