Functional MRI Studies in Friedreich's Ataxia: A Systematic Review

Abstract

Friedreich's ataxia (FRDA) is an inherited neurodegenerative movement disorder with early onset, widespread cerebral and cerebellar pathology, and no cure still available. Functional MRI (fMRI) studies, although currently limited in number, have provided a better understanding of brain changes in people with FRDA. This systematic review aimed to provide a critical overview of the findings and methodologies of all fMRI studies conducted in genetically confirmed FRDA so far, and to offer recommendations for future study designs. About 12 cross-sectional and longitudinal fMRI studies, included 198 FRDA children and young adult patients and, 205 healthy controls (HCs), according to the inclusion criteria. Details regarding GAA triplet expansion and demographic and clinical severity measures were widely reported. fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining in vivo insights into FRDA pathology, but addressing that its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future.

Keywords: Friedreich's ataxia; clinical study; fMRI protocol; functional magnetic resonance imaging; study design; systematic review.

Figure 1

Flowchart of the search for eligible studies on the functional MRI (fMRI) findings in Friedreich's Ataxia (FRDA).

Figure 2

Cerebral and cerebellar areas reported as activated in the studies that performed a motor task fMRI. The colors of the nodes reflect activation in the respective groups as reported from each study: green [healthy controls (HCs)], red (FRDA), and blue (both groups). The panels on the left show the reported activated areas for each group or both groups, the panels on the right show the differential activation consistently reported when FRDA was compared to controls. The blue areas in the right panels are the areas in which the reports are conflicting. The size of the nodes reflects the number of papers reporting activation in a particular area, reported for each right and left hemisphere.