---

Psychiatrists are ridiculed for calling every quirk a
mental illness, but new research on genes and the
brain suggests they might be right.

-------------
   He was young for a stroke victim -- only 48. But that
wasn't what most puzzled neurologist Theodor Landis
and neuropsychologist Marianne Regard about the
political journalist recuperating at University Hospital in
Zurich. Although a lesion in the right frontal part of his
brain had made his left side so weak he couldn't walk,
the patient didn't complain about being bedridden. He
griped instead about the lousy hospital food. In a diary
that the researchers asked him to keep, he wrote, " . . .
sex I start to really miss, and it is time for a real hearty
dinner, e.g. a good sausage with hash browns or some
spaghetti bolognese, or risotto and a breaded cutlet,
nicely decorated. " After the patient recovered, he
returned to work. As a dining columnist.

Of 36 other patients newly preoccupied with fine food,
Regard and Landis found 34 with a brain injury exactly
where the journalist turned food writer's was.
"Gourmand syndrome, " they reported last year, can be
a sign of neurological damage.

 The first edition of "The Diagnostic and
Statistical Manual of Mental Disorders " (DSM),
published in 1952, listed 60; the second, in 1968, had
145; the fourth and latest version, in 1994, lists 410.
Until recently it was easy to blame this psychiatric
bracket creep on therapists trying to expand the
population of paying clients. But two recent
developments make it harder to dismiss. The first is
brain imaging. MRI, CT and PET scans that peer into
the structure and activity of the brain are turning up real,
physical correlates of eccentric behaviors. The second is
genetics. Researchers are finding genes that seem to
increase the risk of particular mental illnesses.
Because virtually all such illnesses are thought to involve
several genes, it is tempting to label people who have
only one or two of them "a touch " schizophrenic, or
"just slightly " paranoid. And since the genes and brain
quirks seem pretty common, "ultimately, " says Dean
Hamer, a leading behavioral geneticist at the National
Cancer Institute who is best known for discovering the
so-called gay gene, "it might mean that we're all a little
bit crazy. "

MENTAL HEALTH, in this new view, is a continuum.
At one extreme might be a Ted Kaczynski, the
Unabomber suspect described by his brother's lawyers
as obsessive-compulsive, out of touch with reality,
delusional, antisocial and paranoid. At the other end of
the spectrum lie what are usually considered normal,
even wonderful, human differences. The computer whiz
who hasn't clue how to engage in small talk is, according
to the new theory, not merely socially awkward; he
suffers from a mild form of autism. The emotionally
needy person you can't get off the telephone has a
frontal-lobe abnormality. And the originators of religious
dietary rules and hand-washing rituals? They had mild
obsessive-compulsive disorder.

In their 1997 book "Shadow Syndromes, " psychiatrist
John Ratey of Harvard Medical School and Catherine
Johnson of the National Alliance for Autism Research
argue that all sorts of quirky behaviors are actually mild
mental illnesses.

The debate might have remained a standoff. Except that
psychiatrists who believe in shadow mental illnesses
are, to even their own surprise, getting support from
science. "For years clinicians have been seeing people
who don't fit the DSM criteria, and realizing that these
syndromes don't just cut off abruptly, " says Catherine
Johnson. "They've gotten accused of empire-building, of
drumming up patients. But now geneticists and
neuroscientists are finding the exact same things. " Or
close to it. "It's absolutely going to be the case that
geneticits will come to the aid of psychiatrists in this
debate, " says Stanford University neuroscientist Robert
Sapolsky. "The idea of a continuum represents a major
cognitive breakthrough for genetics. It suggests that a
middling genetic load [of mental-illness genes] gives
you a personality disorder, a lighter one gives you a
personality quirk and a still lighter one gives you
mainstream America. "

Researchers found the first hints that mental illness
comes in mild forms when they examined relatives of
seriously ill people. "So-called schizoid personalities,
who are extremely withdrawn, are commoner in families
of schizophrenics, " says Dr. Jonathan Benjamin of Ben
Gurion University in Israel. "And awkward social
behavior is more frequent in the biological parents of
autistic children. " That suggests that while the patient
has many mental-illness genes, the relatives have only
a few, and thus have "shadow syndromes. "

Schizophrenia offers the classic illustration.
Schizophrenics have less gray matter in the frontal
cortex, the seat of higher thought, says psychiatrist
Tyrone Cannon of the University of Pennsylvania. And
in the hippocampus, which helps run memory and
emotion, cells are out of place. People with mild
schizophrenia, whose symptoms are not severe enough
to keep them socially isolated, have mild versions of
these brain abnormalities. People with severe
schizophrenia, who are unable to distinguish fears and
fantasies from reality, have severe versions. "Our twins
study suggests that people with two genes out of a
hypothetical 10 might have only subtle changes in brain
structure and function, " says Cannon. "But as you
increase the number of genes you pass over the
threshold to clinical significance. "

One such subtle version is called schizotypal personality.
People with this diagnosis tend to be suspicious of
others; they prefer isolation and are overoccupied with
unusual ideas such as a belief in the paranormal. Their
speech is vague and digressive; their dress is eccentric.
Studies of families support the idea that milder forms of
mental illness result from having 1 or 2 rather than all 9
or 10 genes that contribute to the full- blown illness.
"The risk that a sibling of a schizophrenic will have the
[same] disease is doubled or tripled " compared with the
general population, says NCI's Hamer. "But for a
schizotypal personality, the risk to the sibling of a
schizophrenic of having this is 10-fold higher. That says
that a schizotypal sibling shares fewer of the disease
genes than a schizophrenic sibling. " Schizotypal
personalities may not believe that the CIA has implanted
a transmitter in their dental fillings, says Dr. Kenneth
Kendler of the Medical College of Virginia, "but they
are the ones who, when they walk into a bar, feel that
people are looking at and talking about them. "

LAST YEAR ADDICTION, A MENTAL illness,
was found to be on a continuum with a normal
personality trait. Researchers discovered an abnormally
long version, or allele, of a gene on chromosome 11
(humans have 23 pairs of rod-shaped chromosomes,
along which genes are strung like pearls). The allele was
found more often in heroin addicts than in nonaddicts.
The job of this gene is to produce a receptor -- a sort of
molecular docking site -- for the brain chemical
dopamine. Here's where the continuum comes in: the
long version of the gene is also common in mentally
healthy people who exhibit "novelty-seeking " behavior,
according to research groups in Israel and at the
National Institutes of Health in 1996. Such people tend
to be impulsive, fickle, excitable, quick-tempered and
extravagant; they seek thrills and feel exhilarated in novel
situations. They are the world's race-car drivers and its
explorers. This gene is only one of an estimated 10 or so
that determine novelty-seeking, explains Ben Gurion's
Benjamin. Someone with 2 or 3 of the 10 might be a
little impulsive. Someone with all 10 might be a risk
freak -- or a heroin addict.

In just the last two years, researchers have discovered
several genes that may account for personality quirks
and, in combination with other genes, trigger mild or
full-blown mental illness:

* In 1996 researchers led by NCI's Hamer identified a
gene on chromosome 17 that contributes to neuroticism.
This catchall term includes being anxious and sometimes
depressed, hostile and impulsive. The gene comes in
short and long forms, Hamer explains in "Living With
Our Genes, " a book due in March. It makes what is
called a transporter, a protein that sweeps away the
brain chemical serotonin from between neurons.
Serotonin, Hamer believes, causes anxiety and
depression. The short form of the gene makes less
transporter, which is less effective at removing serotonin.
One would therefore expect a connection: short gene,
more serotonin, more anxiety. That's what the
researchers found -- the short form of the gene is more
common in people who are neurotic (as determined by
questionnaires). But this gene accounts for only a tiny
amount of the differences in people's genetically
determined degree of neurotic behavior. Hamer
estimates it at 7 to 9 percent.

* In 1997 researchers linked a gene on chromosome 22
to obsessive-compulsive disorder. OCD is marked by
intrusive, upsetting thoughts (the "O "), like not being
able to let go of the idea that you forgot to turn off the
oven, and repetitive behaviors that interfere with daily
life (the "C "), like constant hand-washing. The
purported OCD gene makes a sort of bio-vacuum
cleaner -- an enzyme that gets rid of brain chemicals
after they have carried a signal between neurons.
Everyone has this enzyme, but the OCD version makes
such a wimpy version of it that the brain chemicals keep
delivering the same infernal message over and over -- a
nagging "did you turn off the oven? " Again, several
genes are thought to cause OCD. Someone with all of
them might be so tied up in worries and obsessions as to
be dysfunctional. Someone with one or two might keep
a superneat desk.

New research suggests that milder forms of OCD arise
from milder brain abnormalities, too. PET scans, which
detect regions of high activity in the brain, have shown
that a circuit running from the orbital frontal cortex -- the
bottom front of the brain, which acts as a sort of
error-detection system -- is hyperactive in OCD
patients, finds Jeffrey Schwartz of UCLA. "It gives you
the feeling of being stuck in gear, " he says. In people
with depression but not OCD, just the outer rim of the
orbital frontal cortex is running full tilt. "These people
have problems getting ruminations out of their mind, "
says Schwartz. "It's not a true obsession, but a milder
thing " -- with a milder brain abnormality.

* In December, researchers at Johns Hopkins
University traced a gene for manic-depression to
chromosome 18. That makes at least five genes
associated with this disease. "It may be that if you have
only one gene, " says Dr. Francis McMahon, who led
the team, "you might be more susceptible to mood
elevations that let you meet deadlines through a burst of
activity, or lead your business team across the finish line.
The gene may be overrepresented among artists and
creative types. " Actor Robin Williams has described his
deep depressions; any fan can see his mania. But
someone with all five manic-depression genes might be
too buffeted by mood swings to function. Says
neuroscientist Dr. Samuel Barondes of UC, San
Francisco, "Maybe having one of these genes is really
good for you, but having all of them makes you crazy. "

Genes associated with mental illness might, in fact,
keep society supplied with the personality types it
needs. People with schizotypal personality disorder,
explains Stanford's Sapolsky, gravitate toward solitary
lives. They are lighthouse keepers and fire- tower
rangers. Those with a touch of OCD are the dogged
employees who don't let go of a task until it is complete.
Long ago, they may have been shamans and witch
doctors and, perhaps, the men who established religious
rituals. Who else could have thought up a Hindu ritual of
washing the left hand 10 times, the right one 7 and both
5 more at the beginning of the day? The visions of Joan
of Arc, the prophet Muhammad and Saint Paul are
suggestive of hallucinations produced by temporallobe
epilepsy.

EVEN IF NEUROSCIENTISTS FIND brain lesions
linked to holding grudges or spending too much time on
the Internet, and even if geneticists find stretches of
DNA linked to being aloof or persistent, that will not
prove that biology is destiny. For one thing, the structure
and activity patterns of the brain reflect experience, not
just the biology one is born with. The 40-year-old who
has no interest in his lover's feelings may indeed have
"bad brain chemistry. " But that chemistry could be the
product of a bad relationship with his father, social
pressures to be emotionally distant -- even a traumatic
first date. And Schwartz's work with OCD patients has
shown that they can overcome their "brain lock " by
"willfully activating healthy circuits to predominate over
the unhealthy ones, " he says. Even genes that affect
behavior by acting on the brain may determine our fate
only in part. In a recent study, biologists found that baby
rats whose mothers lick them have physically different
brain structures from those whose mothers don't. The
differences lie in regions that respond to stress. Licked
rats handle it better than deprived rats do, suggesting
that life's experience shapes the brain even when it
comes to a trait as basic as temperament.

So pundits will still get to poke fun at the notion that road rage,
gourmand syndrome and other nouveaux disorders are
real mental illnesses. But as genetic and neuroscience
discoveries add support to the idea that something real,
something physical, underlies these and other seemingly
trivial ills, it will be harder to laugh.