News Releases

ADVANCES IN UNDERSTANDING BRAIN CIRCUITS RESPONSIBLE FOR TICS IN
TOURETTE'S SHED LIGHT ON DISORDER

Recent advances are producing a much greater understanding of the
brain circuits responsible for the tics and problem behaviors seen
in Tourette's syndrome.

In one groundbreaking study, investigators have for the first time
measured the number of neurons in a particular area of the basal
ganglia-the brain area involved in Tourette's-in patients with the
disorder. Other studies suggest an imbalance in the basal ganglia's
inhibitory function could interfere with its ability to suppress
unwanted movements and vocalizations and thus lead to Tourette's
syndrome.

One of the least understood brain disorders, Tourette's syndrome
affects about one in 200 children. Symptoms usually appear between
the ages of four and eight and include repetitive involuntary
movements and utterances, or "tics." Tics vary according to where,
how often, and how strongly they are expressed. They are often
preceded by a sensory cue or "urge to tic" that can besiege the
individual's consciousness. Tics wax and wane in severity and are
typically worse during periods of emotional stress or fatigue.

Although many children experience their worst symptoms around the
age of 10 or 11 and then improve, some patients show their worst
symptoms as adults. In its most extreme form, the tics can be
virtually nonstop and include "purposive"-appearing repetitive
behaviors including obscene or socially inappropriate speech and
more rarely self-injurious behaviors. In addition to tics,
individuals with Tourette's also often have obsessions, compulsions,
and attentional deficits.

Scientists now know that symptoms of Tourette's syndrome likely
arise from dysfunction in a region deep within the brain called the
basal ganglia. Neurons in the basal ganglia inhibit or initiate
action plans by processing the information they receive from
the "executive centers" in the brain's prefrontal cortex and sending
it back to motor and sensory areas of the cortex through the
thalamus, new studies suggest.

"Recent imaging and postmortem studies now implicate the ventral
striatum and caudate nucleus—two regions of the basal ganglia—as
areas associated with the brain dysfunction seen in Tourette's,"
says Neal Swerdlow, MD, PhD, of the University of California-San
Diego department of psychiatry, co-chair of a symposium at this
meeting titled "Tourette's: The Self Under Seige."

"Although there is general agreement that the basal ganglia are
implicated in Tourette's syndrome, we know relatively few details.
For example, we know that increased activation in the caudate and
prefrontal cortex is associated with better tic control," says James
Leckman, MD, of the Yale University School of Medicine Child Study
Center and co-chair of the symposium. "There is also evidence that
the actual size of the caudate nucleus is reduced in many
individuals with Tourette's. But we don't know how these findings
are linked to the clinical features of Tourette's including its
waxing and waning course and why the tic symptoms usually peak in
early adolescence."

Knowing that dopamine antagonist drugs reduce the tics associated
with Tourette's and that selective serotonin reuptake inhibitors
reduce the symptoms of obsession and compulsions, Roger Albin, MD,
and colleagues at the University of Michigan department of neurology
investigated the idea that the ventral striatum—a brain region where
both dopamine and serotonin have important functions—could be
involved in Tourette's syndrome.

Noninvasive imaging studies show that the ventral striatum of
Tourette's patients has an excessive amount of dopamine-containing
nerve terminals. Other studies suggest that in normal brain
development, dopamine-containing nerve terminals are overproduced in
the years leading up to adolescence, and that these nerve terminals
are pruned back during adolescence.

"This raises the possibility that Tourette's syndrome is due partly
to abnormal persistence of excessive dopamine terminals in the
ventral striatum due to subtle changes in the timing of brain
development," Albin says.

The ventral striatum is known to be involved in the formation of
habits and is also involved in repetitive, stereotyped movements of
the face and limbs, some of which may be socially significant, Albin
says. "The tics of Tourette's syndrome may disrupt the unconscious
social communication normally mediated by these facial movements,
head position, and other stereotyped movements," he says. "This
could be the basis for the perception of tics as disruptive."
In other work, Flora Vaccarino, MD, also of the Yale University
School of Medicine Child Study Center, shows that patients with
Tourette's have an increased number of neurons that normally silence
brain activity in the internal segment of the globules pallidus and
a decrease in neurons in the caudate nucleus.

Using postmortem brain tissue, Vaccarino and her colleagues found
that Tourette's syndrome patients had about twice as many inhibitory
neurons in the globus pallidus, a part of the basal ganglia that
connects to the thalamus and inhibits its function. Inhibitory
neurons were decreased in other areas of the basal ganglia,
including the caudate nucleus, says Vaccarino.

Vaccarino suggests that the imbalance in inhibitory neurons could
change the timing of activity in the basal ganglia and thus lead to
the tics and other compulsive symptoms of Tourette's syndrome.
"The next step is to increase the number of brains studied, which
may allow us to relate severity of symptoms and anatomical
findings," Vaccarino says.

Leckman and his colleagues at Yale and Columbia University studied
patients who had had brain images taken during childhood to
determine if the size of any basal ganglia structures measured
before the age of 14 predicted their outcome years later as they
entered adulthood. Based on the earlier studies, they predicted that
caudate volumes would influence the course of the disorder.

"We found that the volume of the caudate nucleus and adjacent
structures in the subgenual region, which includes areas of the
ventral striatum and the limbic cortex, could account for nearly a
third of the variance of tic severity at follow-up," says Leckman.
These striatal and limbic regions are involved in the processing of
motivational and affective cues, which in turn may contribute to the
well-known sensitivity of Tourette's patients to emotionally laden
stimuli.

One of the challenges facing a complex nervous system with the
capability for many different behaviors is the need to prevent
potentially competing behaviors from interfering with desired
behaviors, says Jonathan Mink, MD, PhD, of the University of
Rochester Medical School department of child neurology. Mink
hypothesizes that a central role of the basal ganglia is to
facilitate desired behaviors and inhibit those that might compete
with the desired behavior. In Tourette's syndrome, clusters of
neurons in the ventral striatum of the basal ganglia may become
abnormally active, leading to inhibition of neurons in the globus
pallidus and substantia nigra (the basal ganglia's output centers).

"Neurons in these areas normally act to suppress unwanted
movements," says Mink. "But when the neurons themselves are
inhibited, they can no longer act to suppress unwanted movements,
leading to tics."

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