[tt] When Worry Hijacks The Brain

[Eugen Leitl]

http://www.time.com/time/printout/0,8816,1649303,00.html

Thursday, Aug. 02, 2007

When Worry Hijacks The Brain

By Jeffrey Kluger

Even the most stable brain operates just a millimeter from madness. In such a
finely tuned cognitive engine, only a small part must start to sputter before
the whole machine comes crashing down. When that happens, reason and function
come undone, rarely as dramatically as in the neurochemical storm that is
obsessive-compulsive disorder.

Say you leave work at 6 p.m. for what should be a 12-minute drive home. Say
just as you're pulling onto the street, a child on a bicycle crosses in front
of you. A few feet later, you feel the thump of a pothole. But what if it
wasn't a pothole? Suppose you hit the child. You look in your rearview
mirror, and all is clear, but can you be sure? So you circle back around the
block. Still clear--except for a lumpy bag of leaves on the curb. But is it a
bag or a child? So you circle once more. Four hours later, you finally arrive
home, mutter something to your spouse about a late meeting and go to bed
spent and ashamed. Tomorrow you'll do it all over again.

Devoting an entire evening to a 12-minute drive is not the only way to know
you've got obsessive-compulsive disorder (OCD). You know it when you shrink
from the sight of a kitchen knife, worried that you'll inexplicably snatch it
up and hurt yourself or a family member. You know it when leaving the house
consumes hours of your day because the pillows on your bed must be placed
just right. You know it when you can't leave the house at all for fear of a
vast and vague contamination that you can't even name.

We all think we know what OCD is, and most of the time we're all wrong. It's
the nervous guy from Monk; it's cranky Jack Nicholson in As Good As It Gets.
In the end, though, things usually work out for them. They even get the girl,
who sees them as a kind of adorable emotional fixer-upper.

But OCD isn't adorable. About 7 million adults, teens and children in the
U.S. are now thought to have it in one form or another, and their pain is far
worse than you probably know. What's more, since one family member disabled
by the disorder can destabilize an entire household, a single diagnosed case
can mean several collateral victims. Worse, OCD is a condition that often
masquerades as other things. It is routinely labeled depression, bipolar
disorder, attention-deficit/hyperactivity disorder (ADHD), autism, even
schizophrenia. Victims often conceal their problem for years, ensuring that
no diagnosis--right or wrong--can begin to be made.

With the twin obstacles of secrecy and mislabeling, the average lag time
between the onset of the disorder and a proper diagnosis is now a shocking
nine years, according to surveys of doctors conducted by the Obsessive
Compulsive Foundation, a 21-year-old organization with headquarters in New
Haven, Conn. It takes an average of eight additional years before effective
treatment is prescribed. If the disorder strikes a young person, as it often
does, that can mean an entire childhood lost to illness. "OCD has had a slow
research start," says Gerald Nestadt, co-director of the OCD clinic at Johns
Hopkins University. "It's behind schizophrenia, bipolar disorder, autism and
ADHD."

But all that is changing. A burst of new genetics studies is turning up
insights into the causes of the disorder. Scanning technologies are
pinpointing the parts of the brain that trigger the symptoms. New treatments
are being developed. And refinements of old treatments, like talk and
behavioral therapy, are proving more effective than ever.

"Everyone has intrusive thoughts, but most people consider them meaningless
and can move on with their lives," says psychologist Sabine Wilhelm,
associate professor at the Harvard Medical School and director of the OCD
clinic at Massachusetts General Hospital. "For people with OCD, the thoughts
become their lives. We can give those lives back to them."

THE ROOTS OF OBSESSION

ON THE WHOLE, A LITTLE ANXIETY IS A VERY good thing. It was not enough for
humans in the state of nature to know there was no lion near the family cave;
they also had to be able to imagine all the other places a lion could lurk.
The same is true for other eccentricities of human behavior. Our anxiety
about all the ways harm may befall someone else keeps us mindful of the
safety of family and community. "There's a creative, what-if quality to this
thinking," says clinical psychologist Jonathan Grayson of the Anxiety and
Agoraphobia Treatment Center in Bala Cynwyd, Pa. "It's evolutionarily
valuable."

Something woven so tightly into the genome is not likely to be shaken loose
by a few thousand years of modern living. But that doesn't mean every person
with eccentric traits--the woman in the office next to yours who keeps her
desk impeccably neat and gets edgy if something is moved out of place, for
example--has OCD. "Having these OCD-like traits is a universal experience,"
says Judith Rapoport, author of the landmark book The Boy Who Couldn't Stop
Washing and chief of child psychiatry at the National Institute of Mental
Health. "I sometimes count on my fingers when I have nothing to count." The
key to diagnosing whether such behavior is authentic OCD is how great an
impact the behavior has on your life. "You have to show longstanding
interference with function, and that eliminates most people," Rapoport
explains.

What causes some people to suffer that interference and most not? Why does
their internal alarm keep shouting "Lion!" long after they've checked every
place a lion could plausibly be? The answer has always been thought to lie
principally in a small, almond-shaped structure in the brain called the
amygdala--the place where danger is processed and evaluated. It stands to
reason that if this risk center is overactive, it would keep on alerting you
to peril even after you've attended to the problem.

As it turns out, the amygdala is indeed a big player in the pathological
process of OCD but only one of several players. Functional magnetic resonance
imaging (fMRI) and other scanning technologies have allowed researchers to
peer deeper than ever into the OCD-tossed brain. In addition to the amygdala,
there are three other anatomical hot spots involved in the disorder: the
orbital frontal cortex, the caudate nucleus and the thalamus--the first two
seated high in the brain, the third lying deeper within.

"Those areas are linked along a circuit," says Dr. Sanjaya Saxena, director
of the OCD program at the University of California at San Diego. It's the job
of that wiring to regulate your response to the stimuli around you, including
how anxious you are in the face of threatening or frustrating things. "That
circuit," says Saxena, "is abnormally active in people with OCD."

Saxena, who has conducted extensive scanning research, has even come to
recognize the neural fingerprint that distinguishes one less common type of
OCD behavior--hoarding--from better-known ones. Hoarders who live alone have
been known to crowd themselves into small areas of their home, with clear
paths left from sofa to kitchen to bathroom, and the rest piled high with
debris. When Saxena scanned the brains of these highly particular people, he
found that they had equally particular abnormalities. Instead of
hyperactivity in any area, they had reduced activity in the anterior
cingulate gyrus, the part of the brain that helps you focus your attention
and make decisions. "Those are things that compulsive hoarders have a lot of
trouble with," he says.

GENES AND GERMS

ALTHOUGH SCANS CAN TELL YOU THE landscape of the obsessive-compulsive brain,
they can't tell you how it got to be that way. As with many other
psychological disorders, research is revealing that ocd has a powerful
genetic component. Having any blood relative with ocd puts your risk of the
disorder at 12%, and while that seems low, it's still more than four times as
high as that of the U.S. population as a whole.

If the disorder comes to you through the genes, the next job is to determine
which ones. A team of investigators at Johns Hopkins University last summer
discovered half a dozen areas in the human genome that appear to be linked to
the development of OCD. Analyzing 1,008 blood samples from 219 families in
which at least two siblings had the disorder, they discovered gene markers at
six sites on five chromosomes that appear more frequently in those kids than
in family members and other people without OCD. That study did not tease out
how those genes do their damage, but another group has identified a seventh
gene whose mechanism is clearer.

Located on the ninth chromosome, that gene--discovered in two studies by
researchers at several universities including the University of Michigan and
the University of Toronto--appears to regulate a brain chemical known as
glutamate. One of a number of substances that stimulate signaling among
neurons, glutamate works fine unless you've got too much on hand. Then the
signals just keep coming. In the case of the alarm centers in the brain, that
means the warning bell just keeps on ringing. "Glutamate has to be taken up
quickly because otherwise it becomes toxic to the brain cells," says Vladimir
Coric, director of OCD research at Yale University and a leader in studies of
the chemical.

What makes the glutamate-related gene especially suspect is the particular
people it affects the most. OCD strikes males and females about evenly, but
early-onset forms tend to target boys more than girls. This is particularly
true in cases in which the boys also exhibit the involuntary tics or
vocalizations often associated with Tourette's syndrome. Interacting with the
glutamate gene are three genes related to androgens, or masculinizing
hormones. Interacting with those is another gene that has been implicated in
Tourette's. Gather all these together in the same chromosomal neighborhood,
and they can make trouble. "Kids who start early tend to be boys, tend to
have tic disorders and, in genetic analyses, tend to have parents with tic
disorders too," says John March, chief of child psychiatry at Duke
University.

Other compelling, if controversial, research has long pursued an entirely
different cause of OCD: streptococcal infection. As long ago as the 17th
century, British physician Thomas Sydenham first noticed a link between
childhood strep and the later onset of a tic condition that became known as
Sydenham's chorea. Modern researchers who saw a link between tics and OCD
began wondering if, in some cases, strep might be involved with both.

Last year investigators from the University of Chicago and the University of
Washington studied a group of 144 children-- 71% of whom were boys--who had
tics or OCD. All the kids, it turned out, were more than twice as likely as
others to have had a strep infection in the previous three months. For those
with Tourette's symptoms, the strep incidence was a whopping 13 times as
great.

The tics and OCD are probably the result of an autoimmune response, in which
the body begins attacking its own healthy tissue. Blood tests of kids with
strep-related tics and OCD have turned up antibodies hostile to neural
tissue, particularly in the brain's caudate nucleus and putamen, regions
associated with reinforcement learning. "There certainly seems to be an
epidemiological relationship there," says Dr. Cathy Budman, associate
professor of psychiatry and neurology at New York University, "but what it
means needs to be further investigated."

HOW TO FIX IT

NO MATTER HOW OR WHEN THE DISORDER hits, the first step in striking back is
usually comparatively short-term behavioral therapy, using a technique known
as exposure and response prevention (ERP), in which OCD sufferers don't try
to avoid their particular source of anxiety but actually seek it out.
Eventually, emotional nerve endings grow desensitized to the stimulus. The
point is to tough it out until that happens.

At the Obsessive Compulsive Foundation convention in Atlanta last summer,
Grayson, the Pennsylvania-based clinical psychologist, gave those in
attendance who had OCD a quick taste of ERP. Inviting the ones in the
audience with dirt and germ anxieties to come forward, he instructed them to
sit beside him on the ballroom carpet. Then he told them to touch the carpet
and bring their fingers to their lips. Left to themselves, most would have
refused or, if they went along, would have then found the nearest bathroom
and spent long minutes--perhaps long hours--scrubbing. Instead, they sat with
Grayson and the anxiety, learning a very early lesson that the pain does
subside. Extended ERP treatment involves a graduated series of such
exposures, each a bit more challenging than the one before it.

Such tactical jujitsu works for all manner of OCD, though it's not always
easy to find a doctor skilled at administering it. Patients obsessed about
their sexual orientation, who become intolerably anxious if they so much as
notice an attractive member of the same sex, are assigned to do just that:
flip through magazines for scantily clad same-sex models. People plagued by
what's known as relationship substantiation, who become consumed by
inconsequential defects in a partner, are encouraged to seek out those flaws
and even exaggerate them in their mind.

Medication helps too. Antidepressants such as Prozac and other selective
serotonin reuptake inhibitors (SSRIs) can help dial down the anxiety enough
that patients can get started with ERP and, significantly, stay with it. When
patients are children, practitioners are more reluctant to prescribe
medication, but they are careful not to stay too long with ERP alone if it's
not producing results. "The longer a child struggles with an illness, the
more impact it's going to have," says Dr. John Piacentini, director of UCLA's
child OCD clinic. Still, there are some people--kids and adults--whose OCD is
so acute that more extreme methods are needed, such as hospitalization, more
intensive exposure therapy and other medications.

Coric, of Yale, is among the growing group of investigators experimenting
with drugs targeting the glutamate problem. The best medication so far,
riluzole, was originally developed for Lou Gehrig's disease and works simply
by turning down the glutamate spigot, reducing the amount that's available in
the brain. In Coric's admittedly small studies and clinical observations,
half of about 50 subjects experienced at least a 35% remission, and almost
all the rest improved at least a little.

Much more invasively, investigators are looking into deep-brain stimulation
(DBS), in which electrodes are implanted in the brain and connected by wires
embedded in the skin to a pacemaker-like device in the chest. Low doses of
current can then be applied as needed to calm the turmoil in the regions of
the brain that cause OCD. The procedure sounds extreme--and it is--but it's
already been used in about 35,000 people worldwide to treat Parkinson's
disease, and FDA approval to use DBS for OCD as well is pending. "Many of our
OCD patients are able to re-engage in life rather than being stuck at home,"
says neurosurgeon Ali Rezai of the Cleveland Clinic, who performs DBS surgery
for Parkinson's and has researched it for OCD.

For the vast majority of people, the treatment never needs to go so far. OCD,
for all the suffering it inflicts, is nothing more than the brain doing
something it's supposed to do--warning you of danger--but doing it very
badly. Living in the world means living with risks: real ones, imagined ones,
exaggerated ones. That's not an easy lesson, but it's a powerful lesson--one
that, once learned, can offer a paradoxical state of peace.

with reporting by Dan Cray / Los Angeles, Rachel Pomerance / Atlanta