Given her background and curiosity, Helen Mayberg seems to have been destined from girlhood to do what she is doing now--even though her current work was inconceivable then. Her father practiced family medicine in Los Angeles County. Her uncle used x-rays and nuclear medicine machines to research biochemistry. Today Mayberg peers into brains to examine mood networks--and with one startling experiment has transformed the treatment of depression. At the same time, by combining her father's bedside dedication with her uncle's technical sophistication, she is changing the leading theories of how thought and mood interact.

Like many researchers, Mayberg began her career hoping to advance her discipline. She expected to do so in the usual way, by slowly accruing results that would eventually alter the landscape. Now based in Atlanta at Emory University as a professor of psychiatry and neurology, she has indeed achieved such an effect. But last year she also created a big peak all at once, when she and two collaborators described how they cured eight of 12 spectacularly depressed people--individuals virtually catatonic with depression despite years of talk therapy, drugs, even shock therapy. They did so by inserting pacemakerlike electrodes into a spot deep in the cortex known as area 25. A decade earlier Mayberg had identified area 25 as a key conduit of neural traffic between the "thinking" frontal cortex and the central limbic region that gives rise to emotion, which appeared earlier in our evolutionary development. She subsequently found that area 25 runs hot in depressed and sad people--"like a gate left open," as she puts it--allowing negative emotions to overwhelm thinking and mood. Inserting the electrodes closed this gate and rapidly alleviated the depression of two thirds of the trial's patients.

The study won her instant renown. "Mayberg is beginning to do for depression what we did 25 years ago for cancer," says Thomas Insel, director of the National Institute of Mental Health. "It's early yet. But we can safely say that Mayberg's work shows us whole new avenues into understanding and treating depression."

Mayberg's success stems from a certain irony. She thinks she is probably the only board-certified neurologist whose main title is professor of psychiatry, which she says is "sort of strange" considering that she rejected psychiatry, her original choice of study, as too nebulous a discipline. "I didn't like the tool kit," she explains. Even though she says she is "all about the wiring diagram" of the brain, she has produced one of the most significant findings in years about depression, psychiatry's most common and elusive patient problem. And her discovery could redefine our understanding of the relation between reasoned thought and unreasoned emotion.

The Grail: Area 25
Sit down for dinner with Mayberg, as I did at Mayhene's in Washington, D.C., where she had come for a conference, and you are treated not just to a good meal but to intellectual excitement. Lively, with big eyes and a ready smile, Mayberg exudes the enthusiasm of a freshly inspired grad student combined with a 50-year-old veteran's appreciation of history.

"I was always a tinkerer," she recounts. "Summers I used to spend hours in my uncle's lab [at the University of California] at Berkeley. He did early work mapping out thyroxine dynamics in the brain. Wed talk mapping, which Ive always found fascinating, and hed give me little lab tasks to do. I loved the lab--the logic of it, the gadgets and Geiger counters. Measuring things to solve puzzles."

She entered medical school at the University of California, Los Angeles, figuring she would be a psychiatrist. Yet when she advanced to her psychiatry rotations in the late 1970s she found few gadgets and little quantitative measurement. "There were no CT scans available then," she recalls, "much less PET imaging or fMRIs. And most psychiatrists didn't fully accept the biology underlying psychiatric disorders." For instance, the profession viewed schizophrenia--which today is seen to rise from genetic and neural underpinnings--as primarily a reaction to maternal neglect or abuse.

In 1980 Mayberg did a senior-year clerkship with neurologist Norman Geschwind at Harvard University's Beth Israel Hospital. Geschwind had spent four decades pushing the notion that the brain works as a system of coordinated functions that arise from different regions, rather than as a single unit. Dysfunction results from breakdowns in the coordination between regions.

Geschwind's vision, buttressed by his research and brilliant readings of earlier cases from neurological literature, led the profession's move from the view of a monolithic brain, which dominated the first half of the 20th century. When Mayberg began studying with Geschwind, the emerging network model was being confirmed by an explosion of discoveries about how hormones and neurotransmitters carry messages between various brain areas. Mayberg, watching Geschwind apply these models to patients on Beth Israel's neurology wards, found a far more appealing theory of mental function than psychiatry offered.

After graduating, she took up a neurology residency at Columbia University, where she investigated depression in stroke patients. She hoped to localize the neural networks involved. But the stroke patients lesions varied so much in location and severity that she could not find consistent patterns.

Still, the project honed her interest, and when she finished the residency and moved to a postdoctoral program at Johns Hopkins University, she began studying depression in Parkinson's patients. Parkinson's offered more promise for isolating neural networks, because it results from damage to a well-defined, deep-brain structure crucial to movement, the globus pallidus. At the time, Johns Hopkins led the world in neurotransmitter research, breaking new ground almost monthly on dopamine and serotonin function, so Mayberg naturally started by trying to find anomalies in the patients neurochemistry. But focusing on chemicals suited her little better than psychiatry did.

"With psychiatry," she explains, "the resolution was the whole brain. That was too low resolution for me. I discovered that the chemistry"--neurotransmitter action at the cellular level--"was too fine a resolution. I wanted to see how the parts worked together."

So Mayberg, applying her uncle's discipline of nuclear medicine, developed a new project in the early 1990s. She and some collaborators scanned 60 Parkinson's patients, some depressed and some not, with positron-emission tomography (PET). They were looking for differences in activity in the frontal and paralimbic regions--the "thinking" frontal cortex behind the forehead and the "older," more interior paralimbic cortex surrounding the limbic centers for emotion, memory and learning. They found that the depressed patients showed far less activity in both cortex regions. Over the next few years Mayberg performed similar studies comparing depressed and nondepressed patients who experienced stroke or who had Huntington's, epilepsy or Alzheimer's. The depressed patients in every study had the same reduced frontal and paralimbic activity.

Mayberg also found something else: the depressed people had one particular segment of evolutionarily older cortex, just over the roof of the mouth, that was especially busy. It was the region called area 25. Another researcher working independently--Wayne Drevets of Washington University (now at the National Institute of Mental Health)--also noticed this hyperactivity. The notion seemed odd; in depression, characterized by underactivity in the brain, one localized network was overactive. Area 25 proved to have strong connections between the limbic system's emotional and memory centers and the frontal cortex's thinking centers. Exactly how area 25 modulated traffic between these districts was not clear, but the region was clearly hyperactive in cases of severe depression. Perhaps it was working overtime as it tried to temper a depressive loop set up between emotional and thinking centers. Or perhaps it actually caused the problem by kicking into overdrive and letting depressive loops take over. In any case, Mayberg says, "we were seeing area 25 as important." It suggested a pattern, something fundamental about depression.

In 1997 Mayberg wrote a long theoretical review paper describing the findings supporting this pattern. Few psychiatrists took notice. "Quite frankly," she says, "no one was particularly interested. I was asking them to look at a lot of brain regions and think of depression in a new way. People weren't ready for it. So I got put in a box." Because most of her studies had been on people suffering some other neurological problem, such as Parkinson's or epilepsy, her colleagues branded the patients as having "secondary depression" rather than ordinary "primary depression." Their symptoms were an inevitable--and essentially unimportant--side effect of the main condition.

"So they'd say, 'Oh, you do that neurological depression stuff,'" Mayberg recalls. "'Very nice.' And I'm saying, 'No, no, no! This is about all depression.' But it just seemed to annoy people."

Annoyance changed to attention at the century's turn, however, as Mayberg tested her assertions with increasingly revealing studies. She asked healthy subjects to think sad thoughts and scanned them when the tears were flowing. The images showed depressed frontal activity and a hyperactive area 25. Yet as the sadness passed, the frontal area revived and area 25 calmed. She scanned depressed patients undergoing treatment with Paxil or with placebos. In both groups, individuals who recovered showed a rise in frontal activity and a calming in area 25. It seemed that, no matter what the cause, depression dampened frontal activity and either caused or rose from hyperactivity in area 25. And for all afflicted, curing the depression reversed these effects.

Then, in early 2004, Mayberg published a study that drew wide notice, and her own results threw her for a loop. She scanned two groups of depressed patients undergoing treatment--one with Paxil and the other with cognitive behavioral therapy (CBT), which aims to cure through counseling. The Paxil patients showed the same pattern as the earlier studies had found. The CBT patients displayed a new and confounding dynamic, however: when CBT treatment worked, area 25 slowed down, as expected, but the frontal areas showed less activity. They went from heightened to lower activity, instead of low to high, as had occurred in every other group.

"Oh, man," Mayberg says. "I was stumped. For a while I had to just set it aside." Why did the CBT patients frontal activity drop instead of rising as they got better? After discussions and contemplation, she finally realized the answer. The successful CBT patients, almost by definition, had to show this pattern. In CBT, patients learn to recognize and change thought patterns that would otherwise depress them. An active frontal area was virtually required to make CBT work. The patients who responded to CBT did so either because they were busier thinkers by nature (and therefore more amenable to CBT) or because they entered the study already trying to think their way out of their depression. The scans showing initial high levels of frontal activity, Mayberg explains, "were pictures of the tug-of-war between the depression and the patients attempts to self-correct." When the attempt succeeded, the frontal areas could relax, and the scans showed the reduced activity.

This anomalous result held ripe suggestions about what kind of patients might best respond to CBT versus drug therapy. It also highlighted the central finding uniting all the various studies: even the CBT responders had an initially hyperactive area 25 that settled down as therapy worked and mood improved. Area 25 was overly busy in all types of depressions and was calmed by any successful therapy.

Instant Relief
Mayberg now possessed strong, replicated evidence that area 25 played a fundamental role in depression. This insight fit well with what others had discovered about the dynamics of fear, anxiety, stress and mood. Researchers such as New York University neuroscientist Joseph E. LeDoux [see "Mastery of Emotion," by David Dobbs; SCIENTIFIC AMERICAN MIND, February/March] and Bruce McEwen, a neuroendocrinologist at the Rockefeller University, had shown that mood disorders often develop because extreme or continuous stress, whether from a trauma or a difficult ongoing environment, kick fear and anxiety centers into long-term overdrive. The survival systems that have long served us well--a heightened neural and hormonal response to acute threat--turn corrosive when such memories and persistent thoughts trigger them continuously. The evidence for this dynamic was robust. But the crucial switches in the circuit remained elusive. Maybe, Mayberg started to think, area 25 was such a switch, and tweaking it could trip the circuit out of alarm mode and back to normal.

At about this time, Mayberg took a professorship at the University of Toronto, where she met fellow faculty members Sidney Kennedy, a psychiatrist, and Andres Lozano, a neurosurgeon. Kennedy liked to explore neurological models of depression, and Lozano had gained notoriety modulating another neural network gone awry--the one responsible for Parkinson's. In the 1980s it became common for surgeons to treat severe Parkinson's by removing the globus pallidus. The cluster of neurons is a gateway in circuits that control movement, and its hyperactivity somehow threw the neurology of movement off balance, causing the tremors and rigidity that afflict Parkinson's patients. Removing the globus pallidus seemed to reduce these complications. Lozano, on the other hand, had become one of several neurosurgeons who treated the same problem not by removing the globus pallidus but by inserting next to it a tiny, low-voltage electrode. The technique, called deep-brain stimulation, seemed to regulate the activity of the globus pallidus, restoring movement to near normal.

Might inserting such electrodes alongside area 25 calm it down? Mayberg, Lozano and Kennedy decided to try it. Beginning in 2003, the team implanted electrodes in area 25 in a dozen severely depressed patients. Lozano drilled a pair of nickel-size holes in the top of the skull, slid a pair of electrodes and slender leads to area 25, attached the leads to a small pacemaker sewn in under the collarbone, and turned it on. The pacemaker sent a continuous four-volt current to area 25.

The results were stunning. Some patients felt profound relief as soon as Lozano turned on the electrodes, and two thirds returned to essentially normal mood and function within months. They saw better, thought better, felt better. They talked of feeling like they were walking amid flowers, of the "noise stopping," of a horrid weight lifting. Side effects were almost negligible.

"We still don't really understand why calming area 25 has such an effect," Mayberg says. "That comes next. But it's clear that it causes depression when it's hyperactive and that calming it can bring relief." Indeed, the results shattered doubts. Mayberg's body of work, and this latest experiment in particular, had shown that in the emerging circuit model of mood, one could identify and modulate key switches. The results emphatically confirmed the network model of the brain as well as a long history of thought and metaphor. Reason and passion, thought and emotion, were indeed linked in a loop rather than stacked in a hierarchy. Neither stood as the other's slave. They engaged in a conversation that, to be healthy, had to be rich and balanced.

Figuring Out Why
The deep-brain-stimulation trial brought Mayberg fame. The renown she doesnt mind; the affirmation she likes. "It's nice," she says, "after years of writing papers people didnt finish reading, to have people pay attention. And as a scientist, this is what you really hope for: to feel like youve gripped the wheel of a really big ship and changed its direction, even a little bit."

Yet Mayberg hardly thinks she has solved the big questions of mood and mental health. She hopes to find new tools and new working models to track and treat the complex network that links thought and mood--the cortex and limbic regions--and sends us spiraling into depression when it malfunctions. Most immediately, this search means detailing how area 25 plays so crucial a role.

"I may spend the next 10 years trying to figure out what we did," she muses. "We really did this mostly by eye. I want to figure out how to better work this area. Id like to better define the neural network--the actual wiring, if you will. Id like to map the neurochemistry more finely. I want the genetic layout. What will all that tell us about the nature of depression? Can we find more reliable differences among different types of depression? Why do some people respond to drugs and some to CBT?"

Many people would flinch at so many questions. Helen Mayberg lights up. "You know what cracks me up?" she remarks. "When people ask, 'So where are you going to look next?' I tell them, 'What do you mean, where am I going to look next? Im going to look more closely here.'"