Deep Brain Stimulation: A Technique for Mood, Too?
A Technique for Mood, Too?


by Ann MacDonald

September, 2005

Deep brain stimulation (DBS) devices have been implanted in at least 30,000 people in the eight years since the Food and Drug Administration (FDA) approved them for the treatment of movement disorders in people with severe tremor or Parkinson’s disease. Now, as interest in using the technique for other neurological disorders has increased, so too has concern about proper training, patient screening, and avoidable complications.

DBS devices resemble cardiac pacemakers in many ways. A small stimulator, known as an impulse generator, is implanted in the chest, usually just under the collarbone, and connected to electrodes which are implanted in specific areas of the brain pinpointed before surgery by computerized tomography or magnetic resonance imaging scans. When the impulse generator is activated, it sends a series of high-frequency signals into specific areas of the brain (the exact target depends on disease and symptoms).

bw1005_1
Deep brain stimulation involves the implantation of electrodes, left center, as in this patient with Parkinson’s disease.© ZEPHYR / Science Photo Library

The technique is under investigation for use in neurological disorders such as epilepsy and multiple sclerosis, and even in psychiatric conditions. In March, the FDA approved use of DBS as a last-ditch treatment for people with obsessive compulsive disorder (OCD). The same month, researchers published a paper in Neuron about a small pilot study showing that DBS may provide a new option for treatment-resistant depression.

However, some concerns about deep brain stimulation have arisen. A study published electronically in the August 2005 issue of the Archives of Neurology analyzed the experiences of 41 people with movement disorders who sought additional help after DBS treatment failed, and found problems with both patient screening and surgical techniques. In 19 patients, surgeons had improperly implanted electrodes, so the DBS device was stimulating the wrong part of the brain. Thirty patients had been evaluated by a movement specialist prior to surgery. When the researchers reexamined all the patients, they changed several diagnoses and found that five patients who underwent surgery actually suffered from disorders not known to respond to DBS.

Other researchers have reported unexpected complications, including dramatic, though reversible, changes in mood or affect during DBS treatment. As a result, some physicians and researchers—including some who have pioneered DBS for different uses—are urging caution as researchers further investigate and refine the technique. For example, the OCD-DBS Collaborative Group—which consists of researchers from Brown University,

Columbia University, and the Cleveland Clinic in the United States, and colleagues in Belgium and Sweden— has recommended that certain minimal requirements be met before DBS is used to treat anyone with a psychiatric condition. These recommendations include careful patient selection and treatment only as part of an investigational study approved by an institutional review board. Yet as word about DBS success for various conditions gets out, the phones start ringing.

bw1005_2

In deep brain stimulation, or DBS, a stimulator in the chest connects with the elec-trodes in the brain. Approved for use with movement disorders, DBS is being studied as a possible therapy in other disorders. Reprinted from the Harvard Health Letter (September 2004) © 2004, President and Fellows of Harvard College. www.health.harvard.edu

“We’re being inundated with requests for treatment,” says Helen Mayberg of Emory University, the lead author of the pilot study on depression published in Neuron in March.  But Mayberg cautions that DBS is not appropriate for everyone with depression—or with other psychiatric conditions, for that matter.

“Not everyone with chest pain gets a stent,” she says, referring to an artery-opening technique cardiologists use. “If we see brain illnesses as disturbances in specific neural circuits, then we need to know how a particular circuit works, and which nodes are important, before we mess with them.”

Tracing a Brain Circuit

In an effort to better understand the neural basis of depression, and why some patients do not respond to conventional treatments, Mayberg and colleagues spent years tracing the circuit that connects the so-called thinking part of the brain (the cortex) with the feeling part (the limbic area) to try to determine what might underlie both the cognitive and emotional changes in depression. In doing so, Mayberg’s team identified a part of the brain not previously thought to play a role in depression: the subgenual cingulate (Cg25), located deep along the midline of the brain, just under the cortex.

Imaging techniques revealed that Cg25 functions somewhat like a toggle switch in a larger brain circuit. When Cg25 becomes overactive and lights up on the scans—as it does when people are sad or depressed—the frontal lobes of the cortex dim.

“The two areas are interrelated,” notes Mayberg. “This helps to explain why when you become depressed, you can’t think clearly.” Conversely, when antidepressant therapy works, Cg25 becomes less active, while the frontal lobes become more so. “You can think, and you feel less sad,” she says.

The more Mayberg and colleagues looked at Cg25, the more crucial it seemed in depression. “This is not necessarily the ‘sad’ part of the brain, but it comes online in response to sadness and in turn exerts a series of local and remote effects on the brain,” Mayberg notes.

Cg25 has neural connections not only to the cortex but also to the brainstem and hypothalamus, which might explain why sleep and appetite changes may occur in depression.

“Our hypothesis was that in treatment-resistant patients, Cg25 might be stuck in the on position,” Mayberg says. “If this area wasn’t responding to drugs, psychotherapy, or [electroconvulsive therapy], we thought it might be possible to regulate it more directly with DBS.”

The Electrical Connection

Brain cells communicate through a combination of chemical and electrical signals. Medications target chemical imbalances, while DBS and related techniques—such as repetitive transcranial magnetic stimulation, magnetic seizure therapy, and vagus nerve stimulation (FDA-approved in July for treatment-resistant depression)—seek to correct electrical abnormalities.

The effects of DBS are often immediate. Because the brain can’t feel pain, patients remain awake (though sedated) during the operation to implant the electrodes, and surgeons are able to adjust voltage, pulse width, and frequency based on feedback from the patient.

In the case of Parkinson’s and other motor disorders, the surgeon might ask the patient to operate a joystick in order to gauge improvement in motor abilities. In the pilot study on depression, Toronto neurosurgeon Andres Lozano made adjustments based on changes in a patient’s perceptions and energy level, which provided a way to gauge mood.

“During the operation, when we reached a certain frequency threshold, some patients became acutely calm or more aware,” Lozano says. “They would say things like ‘The room has turned from black and white to color.’”

As reported in Neuron, Mayberg, Lozano and colleagues at the University of Toronto recruited six patients suffering from severe treatment-resistant depression who had not responded to at least four previous antidepressant therapies, including medication, psychotherapy, or electroconvulsive therapy. About 20 percent of people with depression do not respond to these mainstays of antidepressant therapy, and the consequences can be deadly, as untreated depression may lead to suicide.

After one month of treatment with DBS, two of the six patients with previously treatment-resistant depression began to respond in a clinically significant way; by the second month, five were responding. At the end of the six-month study, four of six continued to respond.

Meanwhile, positron emission tomography scans taken at the start, midpoint, and end of the study showed that Cg25 activity decreased, as expected, in people who responded to DBS treatment. Mayberg calls the pilot study “proof of principle” that DBS may provide a new way to treat previously treatment-resistant depression, but further research will be necessary before the technique is available for clinical use.

Caution and Clues

Although DBS alleviated depression when directed at Cg25 in that study, the technique can induce depression when directed at other parts of the brain. This complication has most often been observed in people with Parkinson’s, but—to further muddy the waters—so has the opposite result.

“Stimulation of the subthalamic nucleus in patients with Parkinson’s disease can lead to or relieve depression,” depending on the patients, observes Yves Agid, a French doctor who helped pioneer the use of DBS in people with Parkinson’s and has written about mood changes in this population associated with the technique. “Depression can also be provoked or ameliorated when other brain areas are targeted” in Parkinson’s.

Other researchers have reported scattered cases in which dramatic, though reversible, changes in mood or behavior occur during DBS treatment in people with Parkinson’s.

What is going on? It is not clear, but further DBS research may help provide the answer.

Mahlon DeLong at Emory University, who has studied complications of DBS in Parkinson’s disease, says that changes in mood and affect are rare. It also is not clear in all situations exactly what part of the brain is being treated.

“Some of the electrodes may be a little off target,” DeLong says. “So medically I think these cases represent fascinating but unusual examples. And this tells us that there are neural substrates that exist that we really don’t understand.”

And, he says, DBS may be precisely the best type of tool to better define the various neural circuits underlying depression and other psychiatric illnesses.

“DBS can be turned on and off,” DeLong points out. “It is relatively noninvasive, nondestructive and reversible.” Used correctly and with the proper informed consent from patients, he says, DBS has the potential “to help us dissect the neural pathways underlying depression, all the pathways and substrates, as it has with movement disorders.”