A Depression Switch?

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A Depression Switch?

continued

Those caveats notwithstanding, many scientists following the trial say they believe it will change how psychiatrists define and treat mood disorders. Mayberg, who speaks of a "paradigm shift," notes that she developed the trial to evaluate not a treatment but a hypothesis. In that sense the trial succeeded. Mayberg's focus on Area 25 tests the emerging "network" model of mood disorders, a new way of looking at psychiatric conditions that isn't restricted by the neurochemical model of mood that has dominated over the past quarter century or so. Rather, it incorporates neurochemistry into the concept of the brain as a circuit board or wiring diagram. The network model carries profound implications for research and, ultimately, treatment. The Prozac revolution showed everyone that tweaking neurochemistry can dampen and sometimes extinguish depression — but only through a generalized approach, hitting the entire brain. ("Carpet-bombing," one neuroscientist calls it.) And the 50 percent success rate of antidepressant drugs suggests that they aren't hitting depression's central mechanism. The network approach, on the other hand, focuses on specific nodes, pathways and gateways that might be approached with various treatments — electrical, surgical or pharmacological. This small trial appears to confirm this model so emphatically that it's already changing the neuropsychiatric view of the brain and the direction of research.

"People often ask me about the significance of small first studies like this," says Dr. Thomas Insel, who as director of the National Institute of Mental Health enjoys an unparalleled view of the discipline. "I usually tell them: 'Don't bother. We don't know enough.' But this is different. Here we know enough to say this is something significant. I really do believe this is the beginning of a new way of understanding depression."

When she started her research in the late 1980's, Helen Mayberg, too, looked at neurochemistry. "That's where biological psychiatry was then," she told me. "It was about the brain as a bowl of soup. You whip up a chemical, add it and stir. An alchemist point of view. But I soon realized I wanted to find out where things were changing."

Lively, smart and quick-witted, Mayberg talks of brain science with contagious excitement. She possesses just the kind of presence someone having a hole drilled in his head would welcome — authoritative but warm. Mayberg originally considered becoming a psychiatrist, but she didn't like the discipline's resistance at the time (it was the 1970's) to neurological explanations of mood. So she became a behavioral neurologist, doing a residency at Columbia University and then moving to Johns Hopkins.

Setting aside the bowl-of-soup model did not mean deciding that neurochemicals weren't important. Rather it meant deciding that neurochemistry, and particularly the chemistry dictating how individual neurons communicate with one another, was probably driven by traffic between different brain areas, and that identifying the patterns in that traffic might yield new understanding. (Or, using another metaphor, if the brain is an orchestra, then the neurochemical approach focuses on how well individual players listen and respond to the players adjacent to them; the network approach, like a conductor, focuses on how the orchestra's sections — strings, winds, brass, etc. — coordinate and balance volume and tone. When both are working well, you've got music.)

Imaging tools for tracking these relationships, like PET scans and later functional magnetic resonance imagery, were just maturing as Mayberg pursued her work. Neuroscientists were soon using these tools to help identify networks involved in mental processes ranging from distinguishing facial expressions to experiencing alarm or pleasure. Each of these networks engages different brain areas in different combinations. The areas active in recognizing a fearful expression, for instance, won't match those for recalling old memories, though some areas might overlap. Defining the network involved in any given process requires figuring out not just which parts are involved but also which parts are most vital and how one affects another.

By the 1990's, Mayberg was trying to define the network that goes awry in depression. She and other researchers soon established that depression involved abnormal patterns of activity in a network that includes limbic areas (a cluster of evolutionarily older brain areas around the top of the brain stem), which control basic emotions and drives like fear, lust and hunger, and the newer cortex and subcortex responsible for thought, memory, motivation and reward.

Several researchers were working on this. But Mayberg, and, separately, Dr. Wayne Drevets, then at Washington University and now at the N.I.M.H., increasingly homed in on Area 25, which seemed crucial in both its behavior and its position in this network. They found that Area 25 was smaller in most depressed patients; that it lighted up in every form of depression and also in nondepressed people who intentionally pondered sad things; that it dimmed when depression was successfully treated; and that it was heavily wired to brain areas modulating fear, learning, memory, sleep, libido, motivation, reward and other functions that went fritzy in the depressed. It seemed to be a sort of junction box, in short, whose malfunction might be "necessary and sufficient," as Mayberg put it, to turn the world dim. Maybe it could provide a switch that would brighten the dark.

To work the switch, Mayberg needed a knife. In 1999 she moved from the University of Texas at San Antonio to the University of Toronto, where she met Lozano, who had become expert at using deep brain stimulation for treating Parkinson's, the neurological affliction that causes tremors and rigidity as well as cognitive and emotional declines. By the time he and Mayberg met, he'd slipped electrodes into the brains of almost 300 patients.

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Depression is more elusive than Parkinson's. But approaching Area 25 with D.B.S. allowed the researchers to use a known tool. Neurosurgeons found as early as the 1950's that they could treat Parkinson's by destroying a small portion of the hyperactive globus pallidus, a brain area that is crucial to movement. The treatment illustrated one of the brain's many oddities: some areas can cause more trouble when they are excessively active than when they have no activity at all. In the early 1990's, surgeons increasingly began to use D.B.S. to quiet the globus pallidus by sending it steady, rapid pulses of low voltage. Patients' tremors would instantly ease or cease; their rigidity and uncontrollable body movements would fade over a week or two. Killing the current revived the symptoms. Surgeons have now implanted D.B.S. electrodes in some 30,000 Parkinson's patients worldwide. The procedure is not a cure-all. It helps some patients less than others, does little to alleviate Parkinson's cognitive and emotional decay and occasionally creates complications including infection, bleeding and memory loss. Its biggest problem may be its success. So many medical centers now do it that some do it badly or on poorly qualified patients. But done well, it usually works.

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Last updated: 4/06

A Depression Switch?

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