New experimental types of brain implants are offering hopeful possibilities for the millions of people diagnosed with the most severe cases of depression.

According to the National Institute of Mental Health , a unit of the National Institutes of Health , nearly 18 million American adults are affected by depression, and millions suffer from a disabling form of the disorder known as treatment-resistant depression (TRD). For them, neither antidepressant drugs nor psychotherapy — not even shock therapy — have worked.

But researchers are now experimenting with deep brain stimulation (DBS), targeting a region of the brain known as Brodmann Area 25 — or just Area 25 — in hopes of being able to treat major depression.

Area 25 recently was put in the spotlight in a "60 Minutes" segment, providing Sunday evening introduction to millions of Americans, most of whom had never known they had such a region, or knew of its importance.

Currently targeting Area 25 is a DBS technology called Activa. Developed by Medtronic (Minneapolis), Activa is a pacemaker-like device that delivers electrical stimulation to Area 25, Joe McGrath, a spokesman for the company, told Medical Device Daily.

McGrath described Activa as being made up of three implantable components — the lead, extension, and neurostimulator.

The lead includes four thinly coiled insulated wires with four electrodes at the lead tip, implanted in the brain. It is connected to an extension consisting of four insulated coiled wires. The extension is threaded under the skin from the head, down the neck and into the upper chest and is connected to the neurostimulator.

The neurostimulator, or "brain pacemaker" is the battery pack, McGrath said, a small, sealed device that contains a battery and electronics and is implanted beneath the skin in the chest below the collarbone. It produces electrical pulses delivered through the extension and through the lead to the targeted areas in the brain, he said.

Medtronic plans a full-scale clinical trial of Activa in the U.S. as a treatment for depression. Activa has already been used in smaller studies at independent centers, including one last year at the University of Toronto (Toronto, Canada), led by Helen Mayberg, MD, now a professor of psychiatry and neurology at Emory University (Atlanta). The Toronto study was the focus of the 60 Minutes segment "Changing Minds: Area 25" that aired earlier this month.

In the Toronto study, six patients diagnosed with major depression that did not respond to any other type of treatment, including medication, psychotherapy and electroconvulsive therapy, participated. Guided by MRI, researchers implanted the thin wire electrodes in each patient's brain adjacent to Brodmann Area 25 — more technically the subgenual cingulate region (Cg25).

Located in a band that runs deep within the frontal lobes, down the midline, the area plays a critical role in modulating sadness and negative mood states in both healthy and depressed people, according to Mayberg's abstract about the trial published in March 2005 in Neuron.

Mayberg is continuing her research at Emory Medical Center (Atlanta) with a study to evaluate the safety, feasibility and efficacy of chronic, high frequency stimulation of Area 25 using another DBS device, this one made by Advanced Neuromodulation Systems (ANS; Plano, Texas), acquired last year by St. Jude (Medical Device Daily, Nov. 30, 2005).

The trial is now enrolling patients and will include 10 unipolar and 10 bipolar patients, Andrea Barrocas, research coordinator for the study, told MDD. The study is scheduled to begin after the first of the year.

Rohan Hoare, PhD, vice president of strategy and emerging therapies at ANS, told MDD that the company is also involved in four different pivotal trials with the device — two in the U.S. focused on treating Parkinson's disease and Essential Tremor, and two outside the U.S. focused on treating depression and obsessive compulsive disorder. Those trials are in the early stages, Hoare said, and are expected to take three to four years to complete.

ANS has named its DBS device Libra, after the zodiac sign considered to symbolize the concept of balance, because the device is intended to help restore balance, he said.

The ANS Libra Deep Brain Stimulation System operates similarly to Medtronic's device, sending pulses of electricity into particular areas of the brain, such as Area 25, for the treatment of depression.

"Brodmann Area 25 is being viewed as a very interesting target for depression," Hoare said.

If and when DBS is approved as a depression treatment, Hoare said, it would most likely be used with other strategies, including drugs, to treat the disorder.

"I don't think that neurostimulation will be a stand-alone treatment," Hoare said.

Studies have also been done at Cleveland Clinic (Cleveland, Clinic), and Butler Hospital of Brown University (Providence, Rhode Island), on the use of deep brain stimulation to treat severe depression.

John Grohol, PsyD, publisher/CEO of PsychCentral, an online portal targeting mental health and mental health therapies, said the studies that have been done on DBS as a treatment for depression are part of a good "first-result" program.

"Anything that helps treat people for depression, especially people who are drug-resistant or psychotherapy-resistant, is beneficial," Grohol told MDD.

But because previous studies have been so small-scale, Grohol said it would be too soon to start recommending the procedure to patients from a clinical standpoint.

"Very little can be conclusively said about such a small-scale study of only six people, where two of them did not receive benefits from the treatment," Grohol said in an article he wrote for PyschCentral about the study done at Cleveland Clinic and Butler Hospital. "Put into context, if one more person hadn't received any benefit from the DBS treatment, the treatment would have no better than 50/50 chance in helping someone with depression."

While the use of DBS to treat depression has just recently emerged in the experimental stage, neurostimulation is hardly a new concept.

Medtronic has been using DBS to treat patients with the most severe and disabling forms of neurological movement disorders such as Parkinson's disease, Essential Tremor, and Dystonia, for the past decade, McGrath said.

The FDA approved its Activa therapy for the treatment of tremor in 1997 and for treatment of advanced Parkinson's disease in 2002. Similarly, ANS has been using neurostimulation for about 20 years, Hoare said, to treat chronic pain.

Cyberonics (Houston), another company pursuing deep brain stimulation — in this case stimulating the vagus nerve — received FDA approval in July 2005 for its implantable device as an adjunctive treatment for adult patients with TRD. The device is approved for patients with unipolar or bipolar depression in a major depressive episode.

However, Cyberonics' Vagus Nerve Stimulation (VNS) system has not been widely accepted by doctors or insurance companies (MDD, Sept. 8, 2006), and the company faces an uphill road in this sector.

Similar to other DBS devices VNS Therapy consists of an implanted device, roughly the size of a pocket watch, that delivers mild, intermittent electric pulses to the patient's left vagus nerve, which then activates areas of the brain.

Cyberonics's first target was commercialization of the system for reducing seizures from epilepsy in the U.S., winning FDA approval for that indication in 1997.

PsychCentral's Grohol said larger-scale clinical trials will demonstrate the effectiveness — or lack thereof — for the various DBS treatments for depression. He also said the risks of neurosurgery shouldn't be underestimated.

But that, of course, is the major drawback of much device therapy – especially that which is invasive – when it is first unveiled, a major example being "flap and zap" surgery, now commonly called LASIK, when it first emerged for vision correction.

"With greater use and greater amounts of doctors learning the procedure and doing it, certainly there's the possibility of it becoming as common place as something like laser eye surgery," Grohol said.