Multimodal Imaging Investigation of the Dentato‐Thalamo‐Cortical Pathway in Friedreich's Ataxia

BACKGROUND: Friedreich's ataxia (FRDA) is a spinocerebellar neurodegenerative disorder. The dentato-thalamo-cortical (DTC) pathway, an important cerebellar output involved in motor control, plays a crucial role in the neural mechanisms underlying ataxia symptoms in FRDA. OBJECTIVE: The aim was to quantify regional alterations in structure, connectivity, function, and neurometabolism along the DTC pathway in FRDA patients using multimodal magnetic resonance imaging (MRI). METHODS: Twenty-two individuals with FRDA and 22 healthy controls underwent a brain MRI. Volumetry, amplitude of low-frequency fluctuation of resting-state functional MRI data, and phosphorus MR spectroscopy were used to assess key regional changes along the DTC pathway. Diffusion tractography and dynamic causal model (DCM) were adopted to investigate microstructural integrity and effective connectivity of the DTC pathway, respectively. Associations with clinical parameters, including ataxia severity, were also tested. RESULTS: Compared to controls, FRDA patients exhibited reduced volumes and adenosine triphosphate levels in the bilateral dentate nuclei and right motor cortex, as well as elevated glycerophosphoethanolamine levels in thalami and the left motor cortex. In FRDA patients, fractional anisotropy was decreased in the dentatothalamic sections of the DTC tract and correlated negatively with ataxia severity. Additionally, DCM revealed elevated excitatory connectivity from the right thalamus to the left dentate nucleus in FRDA patients, showing a U-shaped association with ataxia scores. CONCLUSIONS: This study provides multimodal imaging evidence for comprehensive alterations along the DTC pathway in FRDA, including first insights into energy metabolism and effective connectivity. A better pathophysiological understanding of early metabolic and dynamic pathway disruptions might inform potential neuromodulatory interventions targeting this pathway. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.