Mice With OCD Can Mean New Hope for Humans

A new study of mouse brains leads to new insights — and perhaps new treatments — for a common disorder

By Jeffrey Kluger

0786-000103

There may be no torment quite like the sublime looniness that is obsessive-compulsive disorder (OCD). Your hands are clean, the door is locked, you didn’t insult a colleague at work or drive over someone on the way home or mishear the 17 doctors you’ve seen in the past month who told you that no, you really, truly don’t have whatever disease you think you’ve got. And yet you keep washing or locking or checking or worrying.

Most people think they understand OCD — and most people are wrong. It’s not just tidiness, it’s not just fretfulness, and it’s not a glib adjective (“You should see how neat my desk is. I’m so OCD!”). It is, instead, a profound malfunction in various regions of the brain — principally the amygdala, which processes fear, anxiety and other primal emotions — and the mere fact that it is exceedingly treatable with cognitive-behavioral therapy, medication or both does not make it any less awful if you’ve got a real case of it. Now, thanks to a new study just published in Science, people suffering with OCD have at least a little more hope of recovery than they did before — and people studying the disorder have a lot more insight into what causes it in the first place.

The fact that OCD can be expressed in so many different ways has always suggested that it is caused by idiosyncratic interactions among several different brain regions. The amygdala likely plays a role in all of them, but the best-known forms of OCD — contamination anxiety and the excessive washing that can follow — are thought to be governed by the orbital frontal cortex (OFC) and the ventromedial striatum (VMS). The OFC governs decisionmaking and volitional activity; the VMS governs how we experience fear and risk. It’s not hard to see how an alarm set off by the VMS can lead to a decision to wash by the OFC — even if that decision defies reason.

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To explore that circuitry — and the way it goes haywire — a team of researchers led by Dr. Susanne Ahmari, assistant professor of clinical psychiatry at Columbia University, turned to a new technology called optogenetics. The researchers first engineered a common adenovirus — usually associated with upper-respiratory infections — to carry the genetic coding for a light-sensitive pigment known as rhodopsin. They then injected the virus into the OFC of lab mice, where it could enter brain cells carrying its rhodopsin payload with it. That caused the otherwise normal cells to become light sensitive. Finally, the scientists inserted fiber optic strands into the mice’s brains and stimulated them with pulses of light. What they expected to see was an increase in grooming behavior, which is common among mice — and in their species-specific way is similar to hand washing in humans. But when they flicked the light on in the mice’s brains what they got was pretty much nothing — at least at first.

“When we hyperstimulated this specific circuit, we thought we were going to see an increase in abnormal behaviors,” Ahmari said in a video released along with the Science paper. “That stimulation did not lead directly to repetitive behavior, but if we repeatedly stimulated for several days in a row for just five minutes a day, what we got was the progressive evolution of grooming behavior.”

The mice, in effect, had been neurologically nudged to a full-blown case of OCD, and even when the researchers quit the stimulation, the behavior stuck around for at least a week. In some of the mice, small doses of fluoxetine — the generic form of Prozac and other selective serotonin reuptake inhibitors — hastened the disappearance of the behavior.

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All that reveals a lot. For one thing, it may help explain why some OCD patients can go for years or decades without the disorder and then experience a single traumatic event — a near accident on a highway, a legitimate disease scare that turns out to be nothing — and shortly after, develop OCD symptoms related to the experience. They may have been born with a predisposition to the disorder (the genetic roots of OCD are still not completely understood), but the triggering event, like the few days of light stimulation in the mice, tips them fully into it.

More important, the research maps the underlying neural wiring behind the disorder and could help in the development of better, more precisely targeted drugs. For people with intractable cases of OCD that resist both behavioral and pharmacological therapy, other researchers have looked at deep-brain stimulation (DBS), using fine wires to activate or deactivate trouble spots. This is already being used successfully to treat the tremors associated with Parkinson’s disease. What science learns from studying mice could eventually lead to improved DBS.

None of this fully explains the mysteries of OCD, and drilling into the heads of human patients to insert wires is clearly a last therapeutic resort, especially since the large majority of cases do respond so well to less invasive treatment. Still, for sufferers who long castigated themselves as weak-willed or otherwise responsible for their own suffering, it can be a relief to know that OCD is just a sickness like any other — and as with so many sicknesses, relief is increasingly possible.

 

http://science.time.com/2013/06/07/mice-with-ocd-can-mean-new-hope-for-humans/