Deep Brain Stimulation

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.

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.

Mayo Clinic Study Finds Anemia Might be Associated With Development of Parkinson's Disease

Mayo Clinic Study Finds Anemia Might be Associated With Development of Parkinson's Disease


ROCHESTER, Minn. — Results of a new Mayo Clinic study support an association between anemia experienced early in life and the development of Parkinson's disease many years later. The findings will be presented at the American Academy of Neurology Annual Meeting in Seattle on April 30, 2009.

"We were surprised to discover that chronic anemia or low levels of hemoglobin were linked to the risk of Parkinson's disease 20-30 years later," says Walter Rocca, M.D. an author of the study and a neurologist at Mayo Clinic.

Hemoglobin is the protein that transports oxygen in the blood, an essential element for life. "We looked at both anemia as diagnosed by a physician and low hemoglobin values," Dr. Rocca says. "Both were associated with an increased risk of Parkinson's disease. This might indicate that Parkinson's disease actually starts 20--30 years before we see any motor changes in the body."

The case-control study included 196 people who developed Parkinson's disease in Olmsted County, Minn., from 1976 through 1995. Each case was matched by age and sex to a general population control subject who was not affected by Parkinson's disease. The medical records of cases and controls were reviewed using the resources of the Rochester Epidemiology Project to determine if there was a link between anemia or low hemoglobin levels and the risk of developing Parkinson's disease many years later. Anemia was significantly more common in the history of cases than in the history of controls.

Dr. Rocca and his team hope to replicate these results in another population group. "We first need to confirm the study results. If the findings are replicated, we will try to understand what are the underlying mechanisms. Understanding the mechanisms may lead to new ways to prevent or treat Parkinson's disease," Dr. Rocca says.

Other members of the Mayo Clinic research team included Rodolfo Savica, M.D.; Justin Carlin; Brandon Grossardt; James Bower, M.D.; and Demetrius Maraganore, M.D.

Parkinson's Disease: More Than Shaking Going On Researchers discovering non-motor symptoms may happen first

Parkinson's Disease: More Than Shaking Going On Researchers discovering non-motor symptoms may happen first

(live-PR.com) - TORONTO, ONTARIO -- (Marketwire) -- 04/21/09 -- Parkinson's is much more than a tremor. That's a message Parkinson Society Canada hopes to drive home this April during Parkinson's Awareness Month.



In Parkinson's, the most common symptoms are movement-related: tremor, slowness, muscle stiffness and balance problems. However, by the time Parkinson's is diagnosed, people have already lost 60 to 70 percent of the dopamine-producing cells. Now researchers are discovering that non-motor symptoms such as sleep problems, depression and smell loss may represent the earliest signs of Parkinson's, for some people, and may appear years before the diagnosis.



In research at Montreal's Sacre-Coeur Hospital, Dr. Ronald Postuma, assistant professor of neurology at McGill University found that people with a rare sleep disorder where they physically acted out their dreams had a 50% risk of developing Parkinson's disease or dementia within 12 years. The patients had REM-sleep behaviour disorder, which Postuma describes as "punching and yelling or kicking out while asleep. It mostly affects people in their 60s and 70s, almost always men." Not all will develop a neurodegenerative disease but Postuma says, "Patients with true REM-sleep behaviour disorder have a considerable risk of developing Parkinson's disease."



Depression and anxiety can surface early in Parkinson's. "Many people, as they're starting to lose their dopamine, may not yet have developed a tremor, slowness or trouble walking, but may feel anxious and depressed," says Dr. Susan Fox, assistant professor of neurology at University of Toronto. "Depression is also part of Parkinson's disease itself and not just a reaction to having a chronic neurological disorder." Fox notes untreated depression can reduce quality of life.



Smell loss is a common occurrence. "The general consensus is that the changes in olfaction (sense of smell) occur about five years before the Parkinson's diagnosis." says Dr. Harold Robertson, a professor in the Brain Repair Centre and Department of Pharmacology at Dalhousie University in Halifax. "That could give us enough lead time to try to stop the process."



Joyce Gordon, Parkinson Society Canada President and CEO says "The more dollars we can put towards Parkinson's research, the sooner we may be able to establish if there is a definite link to Parkinson's when a person has sleep problems, depression or loss of smell. This would lay the groundwork for developing treatments to delay or stop this debilitating disease in its tracks. The answers can't come soon enough for the 100,000 Canadians who have Parkinson's disease and those who are unknowingly at risk."



In the meantime, the first step for anyone experiencing difficulties with sleep or mood is to see a doctor for a proper diagnosis. REM sleep behaviour disorder and depression are treatable. Smell loss is not currently treatable but is worth mentioning to the doctor, during a routine visit, as it may be due to a variety of causes.



Parkinson's is a progressive neurological disease for which there is no known cause or cure. When cells in the brain that normally produce a chemical called "dopamine" die, symptoms of Parkinson's appear. The most common symptoms are: tremor (shaking), slowness in movements, muscle stiffness and problems with balance. Other symptoms that may also occur for some people include fatigue, difficulties with speech and writing, sleep disorders, depression and cognitive changes.



For over 40 years, Parkinson Society Canada (PSC) has been the national voice of people living with Parkinson's disease. PSC has over 230 chapters and support groups. PSC's mission is to fund research, support services, advocacy and education.



For more information on Parkinson's disease and Parkinson Society Canada, visit the PSC website at www.parkinson.ca : www.parkinson.ca or call 1-800-565-3000.

Contacts:
Parkinson Society Canada
John Provenzano
416-227-3399 or 1-800-565-3000 ext 3399
John.provenzano@parkinson.ca : John.provenzano@parkinson.ca