Single-Cell Analysis Pinpoints Brain Malfunction in Tourette Syndrome

A detailed analysis of brain tissue from individuals with Tourette syndrome has uncovered specific cellular disruptions underlying the disorder. Published in Biological Psychiatry, the study  used advanced single-cell techniques to examine gene expression and regulatory elements in six individuals with severe Tourette syndrome and six controls. The researchers from Yale University identified three key abnormalities in the caudate-putamen, a brain region critical for movement control.

First, there were approximately 50% fewer interneurons—cells that regulate electrical activity—in the basal ganglia. This loss may impair the brain’s ability to suppress involuntary movements and vocalizations. Second, medium spiny neurons, responsible for long-range signaling, showed reduced activity in mitochondrial genes, indicating metabolic stress. Third, microglia (brain immune cells) exhibited heightened inflammation, which correlated with the metabolic stress in neurons. This unexpected link suggests previously unrecognized communication between immune and neuronal cells.

The findings challenge the notion that Tourette syndrome stems solely from genetic mutations. Instead, altered gene regulation—improper activation or silencing during development—appears to play a role. “We found evidence suggesting that these changes in gene activity may be caused by alterations in the regulatory elements that control gene expression,” said co-lead author Yifan Wang.

"What makes this research particularly compelling is that despite Tourette syndrome having one of the highest familial recurrence rates among complex neuropsychiatric disorders, large genetic studies have identified only a few risk genes. This suggested to us that we needed to look more deeply at the actual brain tissue to better understand what's happening at a cellular and molecular levels," noted co-lead author Liana Fasching.

While developmental origins remain unclear, the research offers a foundation for exploring immune-neuronal interactions and gene regulation in Tourette syndrome. Lead investigator Flora M. Vaccarino concluded, “We hope these findings will inspire new therapeutic trials for individuals affected by this condition.”