Benjamin Greenberg, psychiatrist

Some people with severe obsessive-compulsive disorder (OCD) respond to their intrusive, distressing thoughts with senseless compulsions that consume most of their waking hours. When drugs and therapy don't help, these patients can't hold jobs or maintain healthy relationships.

Now, psychiatrist Benjamin Greenberg of Butler Hospital and Brown University thinks technology may provide a solution. His team is conducting a 30-patient trial to test whether electrical devices implanted deep in the brain can ease the suffering of patients with intractable OCD.

Doctors have used deep brain stimulation (DBS) to treat patients with movement disorders, like the tremors of Parkinson's Disease, since the 1990s. Nearly 70,000 people around the world have received a deep brain implant.

In Greenberg's ongoing trial, nearly 75% of DBS-treated patients have fewer OCD symptoms. If the stimulation is stopped, their symptoms worsen again. He presented these results at the February 2011 meeting of the American Association for the Advancement of Science in Washington, D.C. Following the meeting, Greenberg spoke SciCom's Susan Young about OCD and the risks and benefits of his experimental therapy.

We seem to have a current fascination in this country with OCD-type diseases, given shows like Obsessed and Hoarders. Why do you think that is?

I'm not sure I'm enough of a social critic to answer that question, but I do know a lot of people have very mild symptoms of OCD or traits of perfectionism. Maybe one-third of the population has detectable versions of those, so a lot of people may see pieces of this in themselves. They also might know people who are real sufferers. Having patients in reality-style TV shows can sometimes be exploitative, but I'm glad people are interested.

Could you describe the range of OCD?

OCD has two kinds of symptoms. One set of symptoms are obsessions—intrusive, distressing thoughts or images, for example an image that something terrible is going to happen to a loved one. The other set of symptoms are compulsions—things you do, usually in response to those obsessive thoughts. They can be the familiar ones like washing, checking, counting, arranging, but they can also be unobservable, such as mental rituals that nobody can see.

In its more severe form, these patients avoid any circumstance that might trigger these compulsions. They can become housebound as a result.

What causes OCD?

We don't know. It runs in families. We think there is a genetic influence, and that children are not just modeling their behavior on that of their parents.

Since the early 1990s, brain imaging has shown that when people have OCD symptoms, they have abnormal activity in brain circuits that include parts of the prefrontal cortex [which regulates cognitive and social behaviors], and deeper nuclei in the brain like the thalamus [a major node in brain circuits, key to behavior] and the basal ganglia [involved in movement, habits, thinking and emotion].

What do you mean here by brain circuits?

[Brain circuits are built from] anatomical connections between different brain regions. You might call those the "wires" that connect one region of the brain to another. There are lots of circuits where information is flying around the brain at a furious rate. They have to do with all kinds of behaviors and mental activities, even unconscious ones.

So in OCD, something goes awry in the circuit.

We know the circuit looks abnormal when people have symptoms. If you make their symptoms worse in the brain scanner temporarily by exposing them to a trigger, like a glove that is "contaminated," that activity in these regions is further off. [Brain scanners can monitor blood flow or metabolism in the brain, which correlate with neural activity.] And when people improve, these circuits look more normal. It doesn't mean we exactly know what the cause is, but we know something about how the illness plays out in terms of the brain.

What is deep brain stimulation?

It involves putting a device called a brain "lead" with electrode contacts on it deep into the brain. The devices are thin, about 1.3 millimeters in diameter, and they are surgically implanted into deep points.

What is the surgery like? How long does it take?

The surgery has two different stages. In the first part, which typically takes a couple of hours, the people are actually awake. They have what's called a frame attached to their head to make sure we know exactly where we are putting the devices. Then the surgeon makes holes in the skull and inserts the wires into the brain using a stereotactic technique—precisely controlling where they go. Then the devices are tested to see if there are side effects, which we try to avoid, or effects that might indicate that the electrodes are in a good spot. The patients are sedated and have local anaesthesia, but they need to be awake for the testing so they can report to us how they are feeling and thinking.

After that, the patients get a CT scan to check for bleeding. Then you bring them back, either on the same day or within several days, to go under general anaesthesia to implant the rest of the devices. The surgeon makes tunnels under the skin to connect the wires [to a battery pack, usually implanted in chest like a cardiac pacer].

What kind of side effects can arise during or after the surgery?

Any surgery to put anything in the brain can cause bleeding or irritate the brain, and potentially cause a seizure. Because you are opening up the skull and the brain to the outside, you can get an infection. These things are relatively rare, but they do happen. The risk is a few percent each—the same risks you see for DBS for Parkinson's Disease.

Are the changes as obvious and instant as in the case of using DBS to treat Parkinson's Disease [in which a patient's tremors will suddenly cease during surgical testing]?

They can be more subtle, but we can usually pick them up. We try to avoid producing large changes. You may notice that the patients' facial expressions change: they become more spontaneous, they start talking to you, they'll make eye contact. They will tell you that their anxiety is less, their mood is better. Sometimes they'll say it's like a weight has been lifted from them. Sometimes they'll say they feel happy or they are smiling for the first time in a long time. So far, we think that's an indication that we've got the electrode in the right place.

Therapeutically, we want a certain degree of improvement in mood and anxiety in OCD patients, most of whom also have depression and non-OCD-related anxiety. But you can also overshoot that and produce excess energy, less need for sleep, or impulsive behavior, something we call hypomania [literally, "a little mania"]. You have to watch very carefully for those things, and may need to intervene rapidly to change the stimulation to stop hypomania.

Could you tell me about your role?

I'm the head of the overall project. Since these are psychiatric patients, it is important that a psychiatrist leads this work. You need to have a real sense of patients who are extremely ill with intractable OCD to make sure they are selected correctly, and to perform the follow-up care. Selecting the patients is a very detailed and exacting process. You need to make certain they are disabled by OCD and not something else, and that all reasonable conventional behavioral and medication treatments have been tried. Few patients referred to us meet our strict selection criteria.

We develop the anatomical targeting along with multiple colleagues in anatomy and surgery. I am in the operating room as the targeting is happening, or a psychiatrist colleague at one of our other study sites, working with the surgeon on where exactly to put the lead in the brain. We also do the testing and make sure the lead is intact and not broken.

How many patients have participated in your trial?

We are about to implant our tenth patient, so we're about one-third of the way done. Less than one out of every ten patients is appropriate, usually because they haven't had enough conventional treatment.

The other surgeries for OCD are actually lesion procedures. Instead of stimulating some of the circuitry we've talked about, you actually make precisely located holes in that circuitry. What's interesting is that after we've screened people who we think are appropriate for surgery and we tell them everything we know about DBS and lesion procedures, about half of them prefer to have lesion procedures.

Why do you think that is?

Because they won't have a device that they have to maintain forever. They also are not tied to having close links to an expert treatment center, which as far as we can tell has to be forever. Of course, if you don't make the lesion well, it can create side effects, which can be permanent. There are also potential side effects even when lesions are made correctly.

What percentage of OCD patients are appropriate for this treatment?

Very small. About 1% of the adult population in any given year has OCD, and the vast majority of them will not be appropriate for surgery.

How do you test the efficacy of DBS as a treatment of OCD without a large controlled trial?

We do a small controlled trial [laughs]. By virtue of how few patients you can enroll in such a study, a large controlled trial is just not going to happen. So you have to do the best you can and generate the best evidence you can. We are very grateful to have [National Institute of Mental Health] support for our clinical trial. But our study has much less funding than an industry trial would, which makes it harder to enroll people who don't have the right kind of insurance coverage. We're hoping to enroll 30 people. It's taken the leading centers in the U.S. two-and-a-half years to enroll ten patients. It's going to be a slow process.

But we will learn about the changes in brain circuitry and specific behaviors that change when people get better. That is the tremendous promise of this for the larger population. We will be able to focus our attention on developing other treatments that are less invasive, less expensive, less cumbersome, and based on better knowledge of brain circuitry and physiology.

The other thing that DBS can do is reinforce the idea that [OCD] is a brain problem. You put wires into somebody's brain and you turn on the electricity, and these behaviors change. That's pretty good evidence that it really isn't any different fundamentally than Parkinson's Disease. They are brain disorders in exactly the same way.

Susan Young, a 2011 graduate of the Science Communication Program at UC Santa Cruz, earned her bachelor's degree from the University of Texas at Austin and her Ph.D. from the UC Berkeley, both in molecular biology. She worked as an intern at the Stanford University news office, the Salinas Californian, the Multiple Sclerosis Discovery Forum, the Stanford University Medical Center, and Nature. She is now the online biology reporter for Technology Review.

© 2011 Susan Young