NIMH Team Links Tourette's Severity with Supersensitive Receptors

In 1885, Georges Gilles de la Tourette, M.D., described in the Achives of Neurology  a neuropsychiatric disorder characterized by chronic motor and vocal tics that begin in childhood. During the next century, researchers demonstrated that the disorder, which came to be called Tourette's syndrome (TS), is probably inherited as a dominant gene that expresses with widely varying symptoms, even within monozygotic twin pairs.

Now, scientists have a neurobiological explanation for differences in the severity of TS symptoms. On Aug. 29, researchers at the National Institute of Mental Health (NIMH) released results of a study that traced symptom differences to possible "supersensitivity" of dopamine D2 receptors in the part of the brain responsible for carrying out automatic behaviors.

The findings, which were published in the Aug. 30 issue of Science, suggest that this dysfunction may underlie the compulsion to act out the sudden movements and vocalizations that characterize TS, which affects about 100,000 Americans with its full-blown form and up to 0.5% of the population with milder symptoms, plus is often accompanied with obsessive-compulsive disorder (OCD).

The new study, carried out by Steven Wolf, M.D., Daniel Weinberger, M.D., and colleagues in the NIMH Clinical Brain Disorders Branch, involved brain imaging of five pairs of identical twins differently affected by TS.

"Identical twins with differences in tic severity provided a unique and powerful statistical design that allowed us to focus upon environmental influences that affect the clinical expression of TS, since identical twins share a common genetic load," said Wolf, who led the research project. "We hypothesized that, if differences in dopamine function in the striatum, a region involved in planning and execution of behavior, in fact regulate clinical symptoms of TS, then the dopamine dysfunction should be more apparent in the more symptomatic twin."

Wolf explained that although previous studies comparing unrelated TS patients with unaffected persons had failed to show differences in dopamine system function, the NIMH team was led in that direction by the fact that symptoms do respond to drugs such as haloperidol [Haldol], that block the D2 dopamine receptors. Also, drugs that stimulate dopamine release often worsen symptoms of TS, he said.""It takes a far greater number of subjects to detect small differences between groups when the groups are only matched for age and sex, as in previous studies, whereas our study used identical twins who are matched in almost all respects except for their differences in symptoms. Therefore, earlier studies could easily have missed the subtle abnormality."

However, added Wolf, the NIMH study was not easy to perform."We had to scour the entire United States to find identical twins with TS," he said. "With the help of the Tourette Syndrome Association (TSA), we identified 100 identical twin pairs. Of these, only about 20 pairs differed significantly in their symptoms. And out of these, an even smaller number were free of medication, or willing to go off medication, and come to Washington, D.C., to participate in the study."Said Wolf: "Identical Tourette's twins with symptom discordance are not exactly common."

To image dopamine binding in the twin pairs, Wolf's team used a radioactive tracer drug, IBZM (iodobenzamide), which, like haloperidol, blocks D2 receptors, and a SPECT (single-photon emission computed topography) scanner. They found that binding to D2 dopamine receptors in the caudate nucleus was higher in the sibling with the more severe symptoms. "Strikingly, the degree to which the twins differed in this caudate D2 binding predicted almost absolutely their differences in tic severity," said Weinberger, who is chief of the NIMH Clinical Brain Disorders Branch. "This also likely explains the ebb and flow of tics experienced over the course of TS and its overlap with OCD."

Furthermore, in each case, the differences were seen only in the head of the caudate nucleus but not in the adjacent putamen.

"Previously, researchers had focused on motor aspects of tics, with corresponding focus on the putamen for clues into the disease," said Wolf.

Continued Wolf: "Our findings supported the hypothesis that dopamine D2 receptor supersensitivity explains the phenotypic variation in TS. Differences in clinical expression of tics between individuals may result from subtle changes in D2 receptor binding. Conceivably, the marked fluctuations seen over time within an individual may also be explained on the same basis."

Wolf added that his team's findings tie in with functional brain imaging studies of OCD that also implicate a brain circuit that includes the head of the caudate nucleus."Our findings certainly support the widely held suspicion that TS and OCD are overlapping neuropsychiatric disorders," he said. "We suspect that the caudate nucleus is part of the brain circuitry contributing to the compulsive aspect of tics, and that dopamine abnormalities there provide a biochemical link between the ideational and motor aspects of TS."Wolf said that while the team's findings offer treatment, "it has no immediate implications for that. However, with that caveat in mind, it should certainly focus therapeutic research efforts upon the dopamine system in this particular brain region."

Wolf also noted that although most psychiatrists and medical practitioners are aware of TS, the disorder is still frequently underdiagnosed. And failure to diagnose can lead to severe social isolation and psychosocial repercussions for sufferers, he said.Anne B. Young, M.D., Ph.D., chair of the Tourette Syndrome Association's Scientific Advisory Board, called the NIMH findings "intriguing."

"This is the first anatomical confirmation of brain activity occurring with the symptoms of TS," she said. "Also, sound research into TS may well provide valuable information about a host of more prevalent neurobehavioral disorders affecting millions of people."