Deep brain stimulation: Expanding its reach to new patients

Electrical therapy, used for years to treat Parkinson's and other movement disorders, may soon tackle depression and more.
By Andreas von Bubnoff

June 1, 2009

Under the skin, a battery is surgically implanted -- generally within the upper chest. From the battery, wires snake up to the head, to tickle different targets deep inside the brain.

Such is the hardware for deep brain stimulation -- the equivalent of a cardiac pacemaker for the mind.

Until recently, deep brain stimulation was approved in the U.S. only to treat certain movement disorders, primarily those of Parkinson's disease, for which it diminishes tremors and rigidity and improves mobility. To date, more than 60,000 patients worldwide have had the devices implanted.

But now use of the technique seems set to mushroom.

This year, the Food and Drug Administration granted a so-called humanitarian device exemption for the treatment to be used in severe cases of obsessive-compulsive disorder -- the first approval of deep brain stimulation therapy for any psychiatric condition.

Large clinical trials are also in the works for use of deep brain stimulation for epilepsy and depression, and experimental studies in the U.S. and elsewhere -- still in their early stages -- are exploring the treatment for obesity, traumatic brain injury, severe chronic pain, Alzheimer's disease, anorexia, tinnitus and addiction.

There are discussions too on the possible use of deep brain stimulation to treat hypertension.

"The field is taking off," says Dr. Ali Rezai, director of functional neurosurgery at the Cleveland Clinic, who has been involved in research on movement disorders, traumatic brain injury, obsessive-compulsive disorder and severe depression, among others.

Some researchers warn, however, that with all this activity -- pushed in part by the industry that makes the brain-stimulation devices -- the field may be moving too fast.

"There is so much progress that's been made and so much potential -- you would hate to lose that potential," says Dr. Joseph Fins, chief of the division of medical ethics and a professor at Weill Cornell Medical College in New York.

Here's a look at deep brain stimulation as it moves beyond Parkinson's disease. (See the related story about reservations scientists have about the growth of the field, and go online at latimes.com/health for a look at less-explored applications such as traumatic brain injury and obesity.)

Obsessive- compulsive disorder

In studies with a total of 26 patients with severe obsessive-compulsive disorder, 60% of those whose device was turned on demonstrated "very much improved" symptoms after months of deep brain stimulation as measured by interviews and questionnaires, says Dr. Benjamin Greenberg, an associate professor at Brown University Medical School and Butler Hospital in Providence, R.I., who was one of the study researchers.

The patients had previously failed on medicines as well as behavioral cognitive therapy.

Yet the data, published last year in Molecular Psychiatry, can't really nail the effect of the treatment, Greenberg says, because the patients for the most part knew whether their devices were turned on or off. Thus, researchers can't rule out that some of the observed improvements were due to a placebo effect.

Patients were stimulated in an area called ventral capsule/ventral striatum, chosen, in part, because removal of nerve fibers in that area is known to cause improvement in obsessive-compulsive symptoms.

Based largely on these findings, the FDA recently granted a limited humanitarian device exemption that permits the device to be used in as many as 4,000 of the country's most severe cases of obsessive compulsive disorder per year.

To get this kind of exemption, Medtronic -- makers of the only deep brain stimulation device that is FDA-approved -- needed only to show its safety and probable benefit.

Greenberg is now doing a randomized, double-blinded trial with 30 patients, some of whom have devices turned on right away and some who have them turned on after a delay. No one will know whose device is turned on for the first several months of the trial.

Epilepsy

Medtronic has conducted a large-scale randomized trial for deep brain stimulation on epilepsy. Data will be submitted to the FDA this year, says Paul Stypulkowski, senior director of therapy research of Medtronic.

The device was turned on, for three months, in half of the 110 volunteers, stimulating -- and thereby, paradoxically, inhibiting-- an area called the anterior nucleus of the thalamus. That area is believed to influence a circuit involved in seizures.

The data, presented in December at a meeting in Seattle, show that deep brain stimulation reduced the number of seizures by 38% compared with what was seen before implanting the device.

That is slightly better than improvement seen with vagus nerve stimulation, another FDA-approved electrical stimulation treatment, which reduces seizures by about 25%.

The control group whose device was kept turned off, also improved, by 14.5%. That could be due to a placebo effect. Or it might be because people who join trials are usually at their worst -- and often tend to improve somewhat on their own, says trial researcher Dr. Douglas Labar, of the Weill Cornell Medical College in New York.

If deep brain stimulation is approved, Labar says, patients will have the choice between a more efficient but also more risky treatment and the slightly less efficient but also less risky vagus nerve stimulation.

Depression

Medtronic and a second company, St. Paul, Minn.-based St. Jude Medical, have two large-scale randomized trials underway for severe, treatment-resistant depression. (St. Jude Medical recently received approval to sell its device for the treatment of Parkinson's disease in Europe and is now completing studies aimed at securing FDA approval for treating Parkinson's and another movement disorder in the U.S.)

Medtronic's depression trial will follow about 200 patients stimulated in an area called the anterior limb of the internal capsule for at least one year.

This brain target for depression was identified by accident: When obsessive-compulsive disorder patients who also had depression were stimulated in this area, their depression also improved.

In one case, a patient produced a one-sided smile when stimulated on one side of the brain and also expressed feelings of happiness, says study researcher Dr. Wayne Goodman of the National Institute of Mental Health.

In a recently published unblinded study, about half of 15 patients showed at least a 50% improvement in severe depression symptoms a year or more after surgery when the anterior limb of the internal capsule was stimulated, says Rezai, who was involved in the study.

St. Jude Medical chose a different brain target, area 25, for its depression trial, which will enroll more than 100 patients. Brain imaging studies have shown that area 25 is more active in depressed people.

In a study of 20 patients, 55% still responded to treatment as late as one year after surgery, says study author Dr. Helen Mayberg, professor of psychiatry and neurology at Emory University. That is an "unheard-of response rate" given that these patients had tried and failed every other treatment, including several medications and electroconvulsive therapy, Mayberg says.

By comparison, Mayberg says, stimulation of the vagus nerve in the neck, approved by the FDA for depression, has only a 15% response rate at 10 weeks in similarly severely depressed patients.

Dr. Thomas Schlaepfer, vice chairman of the department of psychiatry of the University of Bonn in Germany, has been treating severely depressed patients by stimulating yet a third brain target, the nucleus accumbens.

The nucleus accumbens doesn't show normal activity in depressed patients, which could explain why they are less able to experience pleasure.

Last year, Schlaepfer showed that deep brain stimulation in this area led to acute improvements in three severely depressed patients. He says he has extended the work to 10 patients, half of whom showed an improvement when examined a year later.

With deep brain stimulation now being tried in at least three brain areas for depression, the question is, which target is the best? All agree that it's too early to tell.