Intrinsic Activity Reductions and Cerebello‐Cortical Diaschisis‐Like Mechanism in Friedreich Ataxia: An fALFF Resting‐State fMRI Study

BACKGROUND: Friedreich ataxia (FA) is characterized by progressive degeneration of the cerebellum and its output pathways, particularly the dentato-thalamo-cortical system, leading to motor impairment and the cerebellar cognitive affective syndrome (CCAS). Resting-state fMRI studies in FA have focused on alterations of long-range functional connectivity, but little is known about how intrinsic regional neural activity is affected within cerebello-cortical networks. METHODS: Twenty-eight adults with genetically confirmed FA and 28 age- and sex-matched healthy controls underwent resting-state functional MRI. Intrinsic brain activity was quantified using the fractional amplitude of low-frequency fluctuations (fALFF). Whole-brain comparisons were performed between controls and patients, and between patients with definite CCAS (FA-Cog) and cognitively preserved patients (FA-NoCog). Within the FA group, voxelwise regressions assessed associations between fALFF, motor severity (Scale for the Assessment and Rating of Ataxia [SARA]), and cognitive performance (Cerebellar Cognitive Affective Syndrome Scale [CCAS-S]), adjusting for age, sex, head motion, and cerebellar gray matter volume. RESULTS: Compared with controls, patients exhibited reduced fALFF in medial and lateral prefrontal regions. Higher SARA scores were associated with lower fALFF in occipital, sensorimotor, posterior cingulate, and cerebellar regions, whereas higher CCAS-S scores correlated with higher fALFF in bilateral prefrontal and cerebellar cognitive networks. Compared with FA-NoCog, FA-Cog patients showed lower fALFF in bilateral frontal and insular regions. CONCLUSIONS: Resting-state fALFF reveals downstream dysfunction of distributed cerebello-cortical networks in FA. Associations with motor severity and cognition, together with additional fronto-insular dysfunction in patients with definite CCAS, support progressive cerebello-cortical disconnection consistent with a diaschisis-like mechanism.