Tourette syndrome (TS) affects 1 in 200 children. Though long viewed as a movement disorder characterized by involuntary sounds and movements, clinicians and researchers have come to realize that it is much more complicated than that.
TS patients have physical, sensory, or psychic sensations that precede the tic, which some individuals describe as a discomfort or tension that is relieved only by making the tic. Additionally, half of the individuals with TS have attention deficits and two-thirds have obsessive-compulsive behaviors, with half of those meeting the full criteria for obsessive-compulsive disorder (OCD).
Along with an improved clinical understanding of the disorder, researchers have started to develop insight into what has gone awry in the brains of patients with TS. Unlike some neurological disorders that disrupt the function of a single cell type in the brain, “TS is one that affects a whole brain circuit,” says Neal Swerdlow, professor of psychiatry at the University of California, San Diego, and chair of the scientific advisory board for the Tourette Syndrome Association, an advocacy and research organization.
The first image that comes to mind for many people when they hear the phrase “Tourette syndrome” is that of a person spouting obscenities. In fact, fewer than 10 percent of patients with TS ever develop that particular tic. Tics range from simple, relatively nondisruptive movements, such as eye blinking or shoulder shrugging, to more complex ones that can even become damaging, including a head snapping motion. Additionally, for a diagnosis of TS, a person must have at least one vocal tic that has lasted more than a year, as well as more than one movement tic. Vocal tics can take the form of a hum, like an “mmmm” inserted within sentences or words; grunts; throat clearing; innocuous words or phrases; or, in rare cases, cursing.
The typical age of onset for TS is 7, and the symptoms are frequently the worst between ages 10 and 12. By the age of 20, nearly one-third of people who had TS as children no longer have tics, 46 percent continue to have symptoms but the symptoms are relatively mild, and 22 percent have moderate to severe tics, according to work by Michael Bloch and James Leckman of the Yale University School of Medicine.
Numerous studies over the years have suggested that TS results from dysregulation or malfunction in the basal ganglia, a region of the brain that is thought to facilitate desired actions while inhibiting undesired or inappropriate ones. Several new studies add credence to that theory. The basal ganglia encompass several interconnected regions of the brain, including the caudate and putamen in the striatum, a specialized portion of the ventral striatum called the nucleus accumbens, the globus pallidus, and the subthalamic nucleus.
Recently, Leckman and colleagues used magnetic resonance imaging (MRI) to look at different brain regions in patients with TS and controls to determine if there were any anatomical differences. They verified previous reports that the size of the basal ganglia is reduced in patients, with a 5 percent decrease in volume in the caudate nucleus. Although the change in size is relatively small, it is statistically significant.
Given that only some patients continue to have symptoms throughout life, researchers want to know if any of the anatomical differences they see can predict who is likely to remain symptomatic. To address this question, Bloch, Leckman, and Bradley Peterson of Columbia University used MRI to measure the size of different brain regions of patients with TS when they were 8 to 14 years old and then again seven to nine years later.
“The first thing you have to do before you can solve any major disorder is understand what it is.”
When they compared this anatomical data to the patients’ clinical progress, the team found that a reduced size of the caudate and the subgenual nucleus accounts for approximately 30 percent of the variation in TS outcome. “The caudate information begins to give us a clue as to which children will have persistent problems,” says Leckman, though it is clear that the size of these regions does not account for all of the variation.
In a related study, Flora Vaccarino, also of the Yale University School of Medicine, studied postmortem tissue of patients who had TS and found that the distribution of different neural types was altered in patients versus controls. Specifically, there were excess neurons in the globus pallidus and fewer in the caudate nucleus, which likely disrupts the output of the basal ganglia system as a whole. Vaccarino hypothesizes that during brain development, which continues until the early 20s, there is a miscue of some sort that tells neurons to move or form in one place rather than another.
This chart shows subregions of the brain’s basal ganglia, which researchers believe play a role in Tourette syndrome. Anatomical differences may help predict who will continue to experience symptoms throughout their lives.
Additionally, when Roger Albin’s group at the University of Michigan in Ann Arbor used positron emission tomography (PET) to look at the abundance and location of neurotransmitters in the brains of 19 patients, all of whom were over 18 years of age and had persistent tics, they saw an increased number of dopaminergic terminals in the ventral striatum, relative to healthy controls.
“It doesn’t say that this is the only potential abnormality in the brain of Tourette’s patients, but it does suggest that this one particular very important brain system is abnormal in TS subjects,” Albin says.
Combining these findings with previous data, Jonathan Mink of the University of Rochester in New York has developed a model of what he thinks is going wrong in TS.
“Imagine that you have an itch on the back of your neck but are holding a cup of hot coffee in your hand,” Mink says. “It would be very undesirable to scratch your neck.” It is the job of the basal ganglia to block inappropriate movements, such as scratching your neck, and to facilitate a desired motion, such as setting down the coffee cup. But the basal ganglia also are part of the reward pathway in the brain, and researchers think that one of the problems that patients with TS face is an inability to distinguish between important or salient stimuli and ones that should be disregarded as background noise.
To model what is happening, Mink divides the basal ganglia into three layers. The middle layer, the globus pallidus, blocks unwanted actions such as tics by inhibiting activity in the thalamus and the cortex, which form the layer that is the target of the system.
However, sometimes the globus pallidus itself is deactivated, allowing a tic to proceed unchecked. The globus pallidus receives input from two structures that compete for its attention, the striatum and the subthalamic nucleus. The striatum receives information, such as “you have a cup of coffee in your hand,” from the higher processing and sensory centers of the brain, including the cortex, and passes that information to the globus pallidus, telling it not to activate. At the same time, however, the subthalamic nucleus tries to do just the opposite: activate the globus pallidus neurons. Normally the two inputs work together. Signals from the subthalamic nucleus block unwanted movements and those from the striatum allow desired movement to proceed. When the balance is disrupted, as in TS, involuntary movements can occur.
That map, combined with the fact that repetitive stereotyped motions can be induced when researchers place a stimulatory electrode into the striatum in monkeys, leads Mink to suggest that the primary defect in the basal ganglia circuit in patients with TS occurs in the striatum. He thinks that if the inhibitory signals coming out of the striatum are exaggerated or constitutively turned on regardless of outside stimuli, then a particular movement or behavior would occur regularly. The patient would have an undesired movement or behavior—in other words, a tic.
Although the model is complex and perhaps seems esoteric, it provides researchers with a necessary place to start. It gives them specific predictions that they can begin to test, and perhaps also a basis from which to start looking for specific TS treatments that are currently unavailable.
“The first thing you have to do before you can solve any major disorder is understand what it is,” says Swerdlow. “In the last 10 to 15 years the most important thing we’ve done is begin to understand what Tourette syndrome is.”