Journal Article

DZNE-2026-00439

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Fronto-cerebellar connectivity disruptions and functional reorganization in Friedreich's Ataxia: A structural and resting-state fMRI study.

Dadsena, R.Extern* ; Romanzetti, S. ; Lischewski, S. A. ; Jing, Y. ; Timmann, D. ; Faber, J.DZNE* ; Schulz, J. B. ; Reetz, K. ; Dogan, I. ; group, F. s. (Collaboration Author)

2026
Academic Press Orlando, Fla.

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Please use a persistent id in citations: doi:10.1016/j.neuroimage.2026.121872

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.

Keyword(s): Humans (MeSH) ; Friedreich Ataxia: physiopathology (MeSH) ; Friedreich Ataxia: pathology (MeSH) ; Friedreich Ataxia: diagnostic imaging (MeSH) ; Male (MeSH) ; Female (MeSH) ; Magnetic Resonance Imaging: methods (MeSH) ; Adult (MeSH) ; Cerebellum: physiopathology (MeSH) ; Cerebellum: pathology (MeSH) ; Cerebellum: diagnostic imaging (MeSH) ; Middle Aged (MeSH) ; Neural Pathways: physiopathology (MeSH) ; Neural Pathways: pathology (MeSH) ; Frontal Lobe: physiopathology (MeSH) ; Frontal Lobe: pathology (MeSH) ; Frontal Lobe: diagnostic imaging (MeSH) ; Young Adult (MeSH) ; Connectome: methods (MeSH) ; Nerve Net: physiopathology (MeSH) ; Nerve Net: pathology (MeSH) ; Brain connectivity ; Clinical correlations ; Cross-sectional study ; Friedreich's ataxia ; Neuroimaging ; Resting-state fMRI ; Structural MRI

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Contributing Institute(s):

1. Clinical Research Coordination (Clinical Research (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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