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Neurology Now:
Feature: Depression

Shortcircuiting Darkness

CLANCY, FRANK

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Frank Clancy is a medical and science writer whose articles have appeared in Health magazine and Consumer Reports on Health.

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Abstract

By implanting electrodes in patients' brains, researchers shed new light on treating severe depression–and defining mental illness

Depression enveloped them like a dark cloud, disrupting every aspect of their lives–their ability to sleep, to work, to experience pleasure, to carry on relationships with family and friends. One man had been depressed for 10 years. One woman had suffered 12 episodes of depression over three decades. All six of them had tried a variety of treatments, including medication and psychotherapy. Five had received electroconvulsive therapy. Nothing worked.

So when they heard about an experimental study recruiting patients who were suffering from the most serious and intractable type of depression, all six volunteered. Never mind that it was a radical and risky experiment that some of the researchers themselves thought unlikely to succeed.

“The severity of the patients' illness, the number of medicine trials and the impact on their families were all extraordinary,” recalls Valerie Voon, M.D., a psychiatrist on the University of Toronto research team for this study. “Given all that we know about severe depression, the likelihood of their improving [in this clinical trial] was very low.”

The experiment was the first to try a surgical intervention known as deep brain stimulation (DBS), which is used most commonly for advanced Parkinson's disease, to treat depression. Two wire leads, guided by MRI, were threaded into a pea-sized area deep inside the brain known as the subgenual cingulate, or Brodmann Area 25. Even the neurosurgeon who drilled holes into patients' skulls and inserted the wire leads, which were connected to a generator that produced low-voltage electricity, expected “nothing” to happen.

Instead, change occurred almost as soon as the electricity was turned on. The patients, as reported last year in the journal Neuron, spontaneously described feeling: “sudden calmness or lightness,” “disappearance of the void,” “connectedness,” “sudden brightening of the room,” “sharpening of visual details,” “intensification of colors.”

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Figure. The SwitchTo...
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At home, with the electricity turned steadily on, most patients began to sleep better. They had more energy. Over several weeks, they began showing renewed interest in family and social activities. Apathy dissipated; pleasure returned. Patients showed improved ability to plan, and to complete tasks they'd found impossible to attempt before the surgery.

After six months, four of the six patients had improved significantly. Three experienced near or complete remission of their depression.

“Given that it was a pilot study,” says Dr. Voon, now a research fellow at the National Institute of Neurological Disorders and Stroke, “the results were very dramatic.”

However dramatic those results might be, renowned neurologist Helen Mayberg, M.D., lead author of the Neuron study, is wary about their being misinterpreted. “It is really hard to deal with hundreds of calls from depressed patients asking for DBS,” she says. DBS, she cautions, remains an experimental, unapproved treatment. These preliminary results must be replicated, ideally in placebo-controlled studies. And the surgery is an expensive, invasive procedure–with risks. No matter how effective it proves to be, it's unlikely to be used for any but the most toxic and treatment-resistant forms of depression.

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Rather, the significance of the study, suggests Dr. Mayberg, is that it builds upon almost two decades of research identifying specific areas of the brain involved in depression.

This research has led to a new view of depression: as a disease that results from flawed or inadequate communication between regions of the brain that are linked in a network or circuit.

Problems in a dispersed network would explain why depression often affects many aspects of a person's life–not only mood, but sleep and sex drive and the ability to think clearly, among others. Similarly, though Dr. Mayberg and her colleagues stimulated a tiny area of the brain, several other areas changed measurably in those patients whose depression lifted. Dr. Mayberg, now professor of neurology and psychiatry at Emory University in Atlanta, calls Area 25 “a critical junction box,” and adds, “When its activity is affected, it has consequences on a number of other critical targets that together are responsible for mediating healthy emotional responses.”

This still-emerging conceptualization of depression is known as the “network” or “systems” model. It contrasts with older views of depression, which focus on neurotransmitters like norepinephrine, noradrenaline and especially serotonin and their effects on individual cells. That “chemical” model got boiled down in ads for modern antidepressants to an oversimplified equation: If you were depressed, you were low on serotonin–and antidepressants filled the tank.

But experts, at least, knew depression was more complicated. One problem, clearly, is the relatively poor response rate to antidepressants, which typically help at best half of all people with major depression; treatments that touch the core problem should be more effective. Similarly, when drugs work, their benefits begin weeks after serotonin levels in the brain increase.

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“Treating depression is not as simple as raising the levels of one neurotransmitter and everything is better,” says John Dani, Ph.D., professor of neuroscience at Baylor College of Medicine in Houston. “The brain is far too complicated for that.”

With the new network hypothesis, researchers are now focusing on whole circuits rather than individual cells. Neuropsychiatry experts hypothesize that successful treatment works by enhancing the brain's ability to repair itself through the formation of new connections and the strengthening of existing ones.

The process is similar to what happens with stroke-induced brain damage: Depending on the extent of the harm, rehabilitation can sometimes help patients move a once-paralyzed limb as the brain learns to develop an alternate signaling path.

With depression, however, there are myriad complex “tasks” to learn. Radically simplified, a person must learn to be happy–or at least not to feel overwhelmingly sad.

“We have to be thinking about the brain as a dynamic organ,” Dr. Mayberg says. “It isn't just whack an area out and that's the end of it.”

What excites Dr. Mayberg about her trial's results, in part, is their validation of the scientific process that led her to try DBS on one very particular area of the brain. That journey began more than 15 years ago, with the observation that neurological disorders such as stroke, Alzheimer's and Parkinson's sometimes caused the symptoms of depression.

“Depression is part and parcel of many neurological disorders, not because anyone would be depressed if you had a brain disease but because the neurobiology of the primary brain disease affects aspects of mood regulation; certain diseases affect mood,” Dr. Mayberg explains. “We started to fill in a kind of picture of the brain circuitry of depression.”

Functional imaging studies, showing the brain at work, led her and others to focus on Area 25. PET scans showed increased blood flow to parts of the brain that govern emotion, including Area 25, in people with depression. Similarly, Area 25 was very active when healthy individuals experienced profound sadness. Healthy people, however, recover from that sadness and Area 25 returns to normal. With depression, Area 25 remains, as the Neuron paper puts it, “metabolically overactive.” Meanwhile, the flow of blood to the right hemisphere, the part of the brain responsible for logic and reasoning, decreases.

In contrast, when individuals recover from depression, Area 25 calms down no matter what treatment the patient is receiving. “If that area was not affected by treatment, you did not get better,” Dr. Mayberg explains.

Area 25 is also wired neurologically to brain areas that govern sleep, appetite and libido–functions often affected by depression. People suffering from depression also say they're often unable to think clearly; decreased blood flow to the right hemisphere would explain that symptom, too.

The final leap was to deep brain stimulation. Though poorly understood, DBS has been used for more than 10 years to treat Parkinson's by delivering low-voltage electricity to overactive brain circuits. When effective, DBS extends beyond just Area 25–it affects an entire network.

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Figure. Lights OnAs ...
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Which is exactly what it appears to have done in Dr. Mayberg's trial.

It appears to modulate the entire network like a light switch. When Dr. Mayberg describes the study participants' experiences with DBS, there's an appreciation of not only its effect but its suddenness: “Drop an electrode in and all of a sudden someone says, ‘It's gone.’”

The six volunteers in her DBS study, along with another six who subsequently underwent the same surgery, were among the 20 percent of patients who fail to respond to conventional treatments. Of the 12 volunteers, eight felt their depressions lift with minimal side effects.

Not that this means the person is well, Dr. Mayberg cautions. “We stop a core element of the disease–the ‘psychic pain,’ the ‘black cloud,’ however a patient describes that angst part–and it goes away,” she says. “But you have long-entrenched ways of thinking which involve that area of the brain.” With depression, she adds, part of the brain has functionally atrophied and must be rehabilitated in much the way the body must be from physical injury.

Unlike other treatments for depression, she notes, DBS has an almost immediate effect. Yet, paradoxically, it requires continuous treatment.

It's teaching us something fundamental about the brain, she suspects, and about depression. One possibility, she suggests, is that the brain, much like the heart, has a rhythm; perhaps DBS disrupts or reverses a chronically aberrant rhythm.

Unlikely? Perhaps. But so it once seemed that a few volts of electricity might reverse years of depression.

For more information about depression, see RESOURCE CENTRAL on page 46.

©2006 American Academy of Neurology

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