An analysis of PET scan of patients with Tourette syndrome (TS) revealed that the different clinical manifestations of the disorder are associated with the expression of two distinct metabolic brain networks, which may prove useful as biomarkers for assessing responses to new therapies for TS and related comorbidities.
THIS PATTERN (A), identified by spatial covariance analysis of FDG PET scans from 12 patients with Tourette syndrome (TS), was characterized by metabolic reductions in the cingulate and dorsolateral prefrontal cortex (DLPFC) covarying with relative metabolic increases in the precuneus and primary motor cortex. (B) The expression of this pattern correlated with Yale-Brown Obsessive Compulsive Scale (YBOCS) scores (p< 0.005) and discriminated between the patients with TS with (closed triangles) and without OCD+ (open triangles) (p< 0.05). (C) Relative to normal controls (gray), pattern expression was elevated in the TS OCD subgroup (green,p<0.05), but not in the OCD+ subgroup (white,p=0.55).
A new imaging study identified an abnormal metabolic network in the brains of Tourette syndrome (TS) patients and revealed another distinct network of activity in a subset of patients who also had obsessive-compulsive disorder (OCD).
The study, which used PET scans and a sophisticated method of analysis to map brain activity, underscored the fact that TS is not a one-size-fits-all disorder.
“These findings suggest that the different clinical manifestations of TS are associated with the expression of two distinct metabolic brain networks,” the researchers wrote in the paper, which was published online Feb. 9 before the print edition of Neurology. “These, and potentially other disease-related spatial covariance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related comorbidities.”
According to backgraound information in the study, about 50 to 70 percent of Tourette patients have OCD, and the two disorders have been linked in genetic studies. Attention deficit hyperactivity disorder also often accompanies TS.
“The neurophysiology underlying TS remains poorly understood with varying and inconsistent neuropathological and neuroimaging findings, attributable perhaps to the clinical heterogeneity of the disorder,” wrote the researchers, who were based at the Feinstein Institute for Medical Research, which is part of North Shore-Long Island Jewish Health System.
“Many common symptoms of TS can be viewed as a failure of neural mechanisms to suppress unwanted or abnormal behaviors, including obsessions, compulsions, hyperactivity, impulsivity, aggressivity and rage, and others,” they wrote. But pinpointing the root of the problem using imaging techniques has been difficult “given that the symptoms of this condition are likely to emerge from abnormal activity of one or more spatially distributed brain networks.”
In this study, the researchers performed F-fluorodeoxyglucose (FDG) PET imaging on 12 adult patients with TS and 12 age-matched healthy controls. The TS patients (on average, 32.6 years old and all men except for one) had been evaluated using the Yale Global Tics Severity Scale and the Yale-Brown Obsessive Compulsive Scale, and six of them had clinically significant OCD symptoms. All of the TS patients had been off TS-related medication for at least two years. The controls included five men and seven women. All study participants were scanned for 20 minutes at North Shore University Hospital and the TS patients were instructed not to suppress their tics during the imaging session.
The researchers then used special computer software to map networks of metabolic activity — seeing, in essence, what was happening in multiple regions of the brain at the same time, and how these regions interact.
“We were able to see how regions of the brain ‘co-vary’ with each other — for example, one is going up as another is going down,” Andrew Feigin, MD, associate professor of neurology at the Feinstein Institute and a member of the research team, told Neurology Today.
“Spatial covariance analysis revealed a metabolic pattern that discriminated the TS from the healthy subjects,” the researchers wrote. TS patients had increased metabolic activity bilaterally in the premotor cortex and cerebellum, along with decreased metabolism in the caudate/putamen and orbitofrontal cortex.
“The involvement of these regions may reflect the interaction between the defining core motor features of TS (i.e., tics), driven primarily by the striatum and cerebellum, and related behavioral features mediated by front and prefrontal involvement,” the study authors noted.
DR. ANDREW FEIGIN: “We were able to see how regions of the brain ‘co-vary’ with each other — for example, one is going up as another is going down.”
“You end up with a pattern that involves both motor and behavioral regions of the brain,” Dr. Feigin told Neurology Today. He said the pattern shows that TS “really is a functional disorder that has to do with how different regions interact with each other.”
The researchers also looked at brain activity in the 12 TS patients — comparing the six who had OCD to the six who did not.
“Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients,” the researchers reported. “This OCD-related metabolic covariance pattern was characterized by reduced activity in the anterior cingulate and dorsolateral prefrontal regions, associated with relative increases in the precuneus and primary motor cortex.”
That pattern of activity was more pronounced in patients with more severe OCD.“There are diverse hypotheses to explain the involvement of these particular regions in OCD,” they wrote. “The involvement of the precuneus, for example, may relate to its role in self-awareness,” and may “reflect the patients' efforts to resist the obsessive thoughts.”
“Similarly, the anterior cingulate, which connects with the precuneus, may play a role in both attention and in actions with exclusively internal motivations, with overactivity leading to OCD behaviors via erroneous interpretations of internally perceived errors or conflicts.”
In an editorial accompanying the study, Katie Kompoliti, MD, associate professor of neurological sciences at Rush University Medical Center in Chicago, noted several shortcomings of the study.
“One of the limitations of this study is the lack of quantification of the tics during the experimental procedure,” she wrote. “As a result, we cannot be sure to what degree increased activity in the motor areas is a reflection of active tics.”
Another problem, she said, was that the subjects were all adults. “Adults with persisting clinically significant tics have a more severe and, perhaps, atypical form of the disorder.” The TS patients and controls, as noted in the study, were also not matched for gender in very case.
DR. JOSEPH JANKOVIC: “This is an important study, but it may be difficult to generalize the results to the public at large,” Dr. Jankovic said, adding, in part, because the TS study subjects were all adults, mostly all men and “mild, as they did not require treatment with medication.”
THIS PATTERN (A), identified by spatial covariance analysis of FDG PET scans from 12 patients with Tourette syndrome (TS) and 12 healthy controls, was characterized by metabolic increases in bilateral premotor cortices and cerebellum covarying with metabolic decreases in caudate/putamen and orbitofrontal cortices. (B) The expression of this pattern discriminated the patients (triangles) from healthy controls (squares;p<0.001), but did not discriminate between the patients with TS with (closed triangles) and without obsessive-compulsive disorder (open triangles;p=0.80).
Still, she said, the study was illuminating.
“Neuroimaging studies have consistently demonstrated the involvement of specific brain regions in TS. The present study attempts to capture the dynamic covariance of all these regions in real time. Like the story of the blind men, who can only feel a small part of the elephant, and thus think that the elephant is more like a snake (trunk), a rope (tail), a wall (body), etc., this study is a step in the right direction towards identifying TS-related abnormal network patterns that encompass multiple interacting nuclei instead of isolated regions — a view of the whole ‘elephant.’”
Roger L. Albin, MD, professor of neurology at the University of Michigan and chief of Neuroscience Research at the VA in Ann Arbor — told Neurology Today that he thought the most interesting aspect of the study “is that they seem to be parsing out a subgroup, and that may turn out to be a very useful result.”
“This technology might be useful for clinical research, to try to define subtypes and target therapies,” he said.
Joseph Jankovic, MD, professor of neurology at Baylor College of Medicine, said TS is a very difficult disorder to study because imaging studies involving radiation cannot be done in children. Also, patients tend to move a lot, making it hard to do imaging studies.
“This is an important study, but it may be difficult to generalize the results to the public at large,” Dr. Jankovic said, in part because the TS study subjects were all adults, mostly all men and “mild, as they did not require treatment with medication.”
DR. ROGER L. ALBIN said that he thought the most interesting aspect of the study “is that they seem to be parsing out a subgroup, and that may turn out to be a very useful result. This technology might be useful for clinical research, to try to define subtypes and target therapies.”
Because of those limitations, Dr. Jankovic said he thought it was unlikely that the metabolic patterns identified in the study could serve as biomarkers — something the researchers said they hoped would be possible.
“I don't think these findings are sensitive enough to be used as biomarkers to measure a response to therapy,” Dr. Jankovic said. “I think that is overreaching the conclusion.”
Dr. Feigin said he and his colleagues hope to use the same imaging technique to study whether the brain activity of patients with OCD alone looks different from that found in TS patients with OCD. “Whether or not the OCD in TS is fundamentally different from OCD without TS has been a matter of debate,” his team wrote. •
Pourfar M, Feigin A, Eidelberg D, et al. Abnormal brain metabolic networks in Tourette syndrome. 2011; E-pub 2011 Feb. 9.