Fronto-cerebellar connectivity disruptions and functional reorganization in Friedreich’s Ataxia: A structural and resting-state fMRI study

NeuroImage, vol. 332, pp. 121872

Abstract

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disorder characterized by progressive ataxia and multisystem manifestations resulting from involvement of the peripheral and central nervous systems. While regional atrophy is known to be associated with symptoms, functional network alterations may represent a critical pathological mechanism; however, their specific contribution to motor and cognitive impairment remains unclear. We combined T1-weighted anatomical MRI and resting-state functional MRI (rs-fMRI) in 37 individuals with FRDA and 41 age- and sex-matched healthy controls and explored how functional connectivity differences are related to atrophy, clinical severity and cognitive performance. Regional volumes were quantified using morphometry analyses, spontaneous rs-fMRI activity was assessed via amplitudes of low-frequency fluctuations, and functional co-activation was evaluated among regions showing structural and neuronal activity alterations. Volume reductions were most pronounced in the brainstem, cerebellar white matter, hemisphere of lobules VI, X, and thalamus. Functionally, individuals with FRDA showed decreased fronto-cerebellar connectivity alongside increased intracerebellar, thalamo-striatal, and hippocampal-cerebellar coupling. Infratentorial and thalamic volume loss correlated strongly with clinical disease severity, whereas reduced frontal co-activation with cerebellar lobules VI, Crus I and II was moderately associated with poorer motor and cognitive performance. In contrast, increased intracerebellar and hippocampal-cerebellar coupling was observed particularly in individuals with more advanced disease and was partly associated with better cognitive outcomes. These findings indicate widespread disruptions of long-range cerebro-cerebellar connectivity together with increased intraregional coupling and potential network reorganization, underscoring the importance of network-level mechanisms for understanding clinical heterogeneity in FRDA and guiding future prognostic and therapeutic studies.

Authors 9

1. Ravi Dadsena Aachen Department of Neurology JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

   RWTH Aachen University · Jülich Aachen Research Alliance

   Affiliation as printed

   Department of Neurology, RWTH Aachen University 52074, Aachen, Germany; JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11), Research Centre Jülich and RWTH Aachen University 52056, Aachen, Germany

2. Sandro Romanzetti Aachen Department of Neurology JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

   RWTH Aachen University · Jülich Aachen Research Alliance

   Affiliation as printed

   Department of Neurology, RWTH Aachen University 52074, Aachen, Germany; JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11), Research Centre Jülich and RWTH Aachen University 52056, Aachen, Germany

3. Stella Andrea Lischewski Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, RWTH Aachen University 52074, Aachen, Germany

4. Yinghua Jing Aachen Department of Neurology

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, RWTH Aachen University 52074, Aachen, Germany

5. Dagmar Timmann

   Essen University Hospital · University of Duisburg-Essen

   Affiliation as printed

   Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen 45147, Essen, Germany

6. Jennifer Faber

   University Hospital Bonn · German Center for Neurodegenerative Diseases

   Affiliation as printed

   German Center for Neurodegenerative Diseases (DZNE) 53127, Bonn, Germany; Department of Neurology, University Hospital Bonn 53127, Bonn, Germany

7. Jörg B. Schulz Aachen Department of Neurology JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

   RWTH Aachen University · Jülich Aachen Research Alliance

   Affiliation as printed

   Department of Neurology, RWTH Aachen University 52074, Aachen, Germany; JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11), Research Centre Jülich and RWTH Aachen University 52056, Aachen, Germany

8. Kathrin Reetz corresponding Aachen Department of Neurology JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

   RWTH Aachen University · Jülich Aachen Research Alliance

   Affiliation as printed

   Department of Neurology, RWTH Aachen University 52074, Aachen, Germany; JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11), Research Centre Jülich and RWTH Aachen University 52056, Aachen, Germany. Electronic address: kreetz@ukaachen.de

9. Imis Dogan Aachen Department of Neurology JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

   RWTH Aachen University · Jülich Aachen Research Alliance

   Affiliation as printed

   Department of Neurology, RWTH Aachen University 52074, Aachen, Germany; JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11), Research Centre Jülich and RWTH Aachen University 52056, Aachen, Germany