Images of depression adorn the office of neurologist and AAAS Fellow Helen Mayberg.
Framed on the wall and floating on a white background are wispy red strokes, like the projecting ornamental feathers of a male bird of paradise in full courtship display. The image is art, but it’s also science. This strange, beautiful bird, seemingly untethered by gravity, is in reality a three-dimensional rendering—a map—of a neurological network inside the human brain. The red wisps are the network’s tendrils, its roads, a skull-obscured highway of electrical pulses and metabolic activity played out in gray and white matter. Just don’t let the beauty fool you.
The image’s weightless grace and intricate details hide a terrible burden: this is what clinical depression looks like as it blazes its path through the human brain. It’s also an insight into how Mayberg has learned to understand depression and how it rewires the brain. The neurology of depression is Mayberg’s longtime object of study and she knows it intimately, even aesthetically.
“I see them [brain networks] as three-dimensional objects,” Mayberg said. “When I look at the maps, I find there is beauty in their shape and their direction.”
This particular map results from a collaboration with two mathematicians, but there are others.
Mayberg currently works at Emory University in Atlanta, Georgia, where she is a professor of psychiatry, neurology, and radiology. Her office walls are covered in images from her years of research. In January of next year, she will head to New York’s Mount Sinai to direct the research hospital’s new Center for Advanced Circuit Therapeutics.
Over the decades via various types of brain scans and clever experimentation, she has mapped how depression disrupts the brain’s normal information processing, creating its own unique neurological networks. Charting depression’s map has led her to new ways to diagnose and treat the disease, even finding ways to break the seemingly monolithic force that is depression into subtypes based on treatments.
By analyzing the brain networks of depressed individuals, Mayberg has been able to identify who among her patients are most likely to respond to conventional anti-depressants, who might need talk therapy, and who might need a more extreme intervention to treat their malady. As Mayberg has discovered, when it comes to treating depression, one size doesn’t fit all.
The image here is a functional connectivity map of the depression network in the human brain. | The image is the result of a collaboration between neurologist Helen Mayberg and mathematicians Joachim Böttger and Daniel S. Margulies of the Max Planck Research Group for Neuroanatomy & Connectivity, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
“It’s clear that the status quo is really inadequate,” Mayberg said. “We know how to take care of [depressed] patients, but when you think about it, no, we really don’t. Some treatments work on average, but we don’t always know how to get people the treatments that are the best fit for them.”
What Mayberg is referring to is what is sometimes called the shotgun approach to treating depression. Patients suffering from the disease typically endure a period of trial and error as they wait to see if their prescribed therapies work for them...or not. If they don’t, then something else is tried until the disease is eventually hit…hopefully.
Mayberg’s research seeks to take much of the guesswork out of treating depression. The key to her success lies not only in her aesthetic appreciation of the forms depression can take, but also in how she has designed her experiments over the years.
Very early on, Mayberg decided to use treatments for depression—antidepressants and talk therapy, among them—as research probes. Essentially, Mayberg determined, that if she knew how to identify who responded well to certain treatments she could then look for patterns in her scans that pointed to connections. Knowing the pattern, she could then use the therapy again to refine her understanding of the scans and the networks they were revealing and on and on.
Mayberg’s first research using treatment as a probe began in the late 1990s during the heyday of the popular antidepressant Prozac. The drug, like similar antidepressants, seemed to work for some people but not for others. Some shots hit. Others missed. What’s more, no one really knew how the drug worked. Prozac was well known to affect serotonin levels in the brain, but Mayberg suspected that there was a larger network story going on as well. She suspected the brain was being rewired. So she decided to do her own research.
Using PET scans, Mayberg examined the brains of depressed patients both before and after they received a treatment of antidepressants. She then looked for differences in the brains of patients who responded to treatment and those who didn’t. From the resulting before and after images, Mayberg was able to determine that a particular brain pattern seemed to determine who responded to the drug and who did not. This work would evolve into the mapping of depression subtypes based on whether or not patients were likely to respond to a given therapy.
Mayberg puts it this way: “The scans provide credence to the long held notion that while everyone could benefit from therapy with drugs, some people should only get therapy and should never see a drug.”
More interesting still, her late 1990s work led Mayberg to the discovery that antidepressants and other therapies worked not by returning the brain to something like a pre-depression state, but by rewiring it, creating novel networks in the process. This theme would return again and again in her work as her maps of depression become exceedingly more complex and nuanced.
Mayberg likens depression’s many neurological patterns to visual motifs in Japanese watercolors and woodblock prints and those in the work of Ralph Steadman, the psychedelic-inspired artist best known for illustrating the exploits of gonzo journalist Hunter S. Thompson. But Mayberg does something more than see depression, she hears it too.
“You need to understand by talking to patients what their personal metaphors [for depression] are. Everyone’s metaphor is different,” Mayberg said.
Sometimes they’re drowning. Sometimes it’s quicksand. One is stuck at the bottom of a pit, surrounded by slick, oil-covered walls that are impossible to climb. Still another of Mayberg’s patients has described her depression as a cloud that engulfs her, drawing cartoonish stink lines that orbit her body like those around the character Pig-Pen from Charles Schulz’s Peanuts. For these severely depressed patients, suffering from what’s called “treatment-resistant depression,” their brain maps demand something more than conventional therapies. They need a breakthrough.
That breakthrough first came for a small group of patients suffering from treatment-resistant depression in the early 2000s. Mayberg, then at the University of Toronto, knew what she was proposing was something of a gamble. The invasive therapy involved brain surgery during which electrodes would be placed in the brain and turned on at the right frequency and amplitude to act as a kind of pacemaker for mood in much the same way conventional pacemakers regulate heart rates.
The aptly named deep brain simulation was a risky proposition. It had been used successfully with Parkinson’s patients, but this was the first time anyone was going to use it to treat depression. Nonetheless, Mayberg knew where to start.
Mayberg’s previous research had identified a key node in depression’s network known as Brodmann area 25 (BA 25), a section of the subcallosal cingulate sitting in the center of the brain, below the higher functions of the frontal lobe and above the more primitive sections, including the hypothalamus and amygdala. Mayberg’s earlier research had revealed that BA 25 showed decreased activity when patients successfully recovered from depression and this pattern held true across multiple kinds of therapy, from antidepressants to talk therapy. What’s more BA 25 was often overactive in individuals who didn’t respond to traditional therapies, patients labeled as suffering from treatment-resistant depression.
The reason BA 25 was so important had to do with how it regulated both higher and lower brain functions. The region has connections running both to and from the lower and higher brain regions. Mayberg and others’ research had also shown that when activity in BA 25 went up, higher brain function went down—showing up as reduced attention spans, for example—and lower functions also suffered—including disrupted sleep patterns and lingering negative mood. This is how it acts as a node in the network, an important junction with many on and off ramps on depression’s highway. When it gets clogged with activity, gridlock below and above ensues.
The solution, it seemed, was to zap the node, disrupting activity between BA 25 and the other regions of the brain. And this is what the deep brain simulation therapy appeared to do for Mayberg’s patients. Following their surgeries, her patients have variously described deep brain stimulation treatment as “a lifting of the void” and returning them to “connectedness.”
Mayberg first published the results of this study in the journal Neuron in 2005. Since then she has continued to pioneer the use of deep brain simulation. It’s now clear, Mayberg said, that deep brain simulation, like antidepressants and other forms of therapy, works by not merely disrupting BA 25, but by reestablishing its connection to the rest of the brain. It’s the dynamics of the network, the connections between the tendrils of pulses and metabolism to and from the lower and higher brain regions, that’s ultimately the object of study and what the multiple pictures framed on her wall illustrate.
“Depression is in some ways totally ethereal, at least on the surface,” Mayberg said. “It is both profound in terms of how it impacts lives and certainly not subtle in what it does to people. But the brain doesn’t want to give up its secrets easily.”
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