Findings published in Biological Psychiatry provide insights into gene expression and their regulation in all cell types in the basal ganglia of individuals with Tourette syndrome

Philadelphia, April 8, 2025 – In the first comprehensive, cell-by-cell analysis of brain tissue from individuals with Tourette syndrome, researchers have pinpointed exactly which cells are perturbed and how they malfunction, revealing how different types of brain cells are affected by the condition. Findings from this groundbreaking study in Biological Psychiatry, published by Elsevier, provide unprecedented insights into the interplay of different brain cell types in Tourette syndrome, suggesting new therapeutic directions.

What makes this study particularly groundbreaking is that it not only confirms previous findings about the loss of interneurons and inflammatory brain changes in Tourette syndrome but also provides new understanding about how different cell types in the brain interact and influence each other in this disorder.

Lead investigator Flora M. Vaccarino, MD, Child Study Center and Department of Neuroscience, Yale University, Yale Stem Cell Center, and Yale Kavli Institute for Neuroscience, explains, "While previous research using brain imaging has shown that the deep brain nuclei, the caudate-putamen, that are primarily involved in the control of movement programs, are smaller in people with Tourette syndrome, and our prior studies have found a decrease in interneurons in the basal ganglia region, we lacked a comprehensive understanding of exactly how different cell types in these brain regions are affected by the condition.”

In the current investigation the research team analyzed brain tissue samples from six individuals who had severe Tourette syndrome and six matched control subjects without the condition. Using cutting-edge technology that enables the study of individual brain cells, they examined the genes that were expressed in each cell type and the regulatory elements that control gene activity.

Advanced single-cell analysis techniques revealed three key changes in the brains of individuals with Tourette syndrome:

1. There were about 50% fewer interneurons (specialized brain cells that help regulate the pace of brain electrical activity) in the caudate-putamen region within the basal ganglia, which is crucial for controlling movement. These interneurons normally help down-regulate neuronal activity, and their loss may explain why individuals with Tourette syndrome experience difficulty controlling movements and vocalizations.
2. The medium spiny neurons, which are the main long-range projection neurons in this brain region, showed signs of metabolic stress, with decreased activity in mitochondrial genes that control cellular energy production.
3. The immune cells of the brain (microglia) showed increased inflammatory activity, and this inflammatory response was directly correlated with the metabolic stress in the medium spiny neurons. This unexpected relationship suggests these cells are communicating in ways that have not been previously recognized in Tourette syndrome.

Together, these findings create a pattern that may explain why individuals with Tourette syndrome experience involuntary movements and vocalizations.

Co-lead author Yifan Wang, PhD, Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, notes, "We found evidence suggesting that these changes in gene activity may be caused by alterations in the regulatory elements that control gene expression, providing new insights into how Tourette syndrome develops and new directions for future research. These findings suggest that the disease may not be caused by defective genes, but rather by improperly switching them on or off during development and lifetime."

Tourette syndrome affects as many as 1 in 150 children. Its primary symptoms are motor and vocal tics, such as eye-blinking or throat clearing that are performed out-of-context and in a repetitive fashion.

Co-lead author Liana Fasching, PhD, Child Study Center, Yale University, remarks, "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."

John Krystal, MD, Editor of Biological Psychiatry, says, “Current treatments for Tourette syndrome do not address the underlying causes of the condition. This study is particularly timely as it provides new insights into the disorder's biology that point to inhibitory interneuron neuronal and synaptic loss as a key contributing factor to the basal ganglia hyperactivity associated symptoms of Tourette syndrome.”

Dr. Vaccarino concludes: “Our first paper on basal ganglia interneurons of Tourette syndrome was published in 2005, exactly 20 years ago. While there is still much to be learned about the developmental causes of Tourette syndrome, we hope that these findings will inspire new therapeutic trials for individuals affected by this condition.”