Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Premutation carriers of the FMR1 gene are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS).
• FXTAS involves motor, cognitive, and psychiatric decline, with cerebellar and white matter pathology.
• Preclinical sensorimotor deficits are known, but their neural basis in premutation carriers is unclear.

Purpose of the Study:

• To investigate sensorimotor brain system alterations in FMR1 premutation carriers.
• To determine if these alterations represent early indicators of neurodegeneration.
• To examine functional connectivity (FC) during a visually guided gripping task.

Main Methods:

• fMRI was used to scan 16 FMR1 premutation carriers and 18 healthy controls during a precision gripping task.
• Participants performed a visually guided task requiring sustained force output.
• BOLD signal changes and task-based functional connectivity (FC) between brain regions were analyzed.

Main Results:

• Premutation carriers exhibited increased trial-to-trial force variability, especially younger carriers.
• Reduced extrastriate cortex activation was observed in carriers compared to controls.
• Reduced functional connectivity between cerebellar Crus I and extrastriate cortex correlated with increased force variability.

Conclusions:

• Reduced extrastriate activation and cerebellar-cortical FC suggest impaired visual feedback processing and motor command modulation.
• Altered cerebellar-cortical network connectivity during sensorimotor tasks may be a prodromal feature of FXTAS.
• These findings highlight potential early neural markers for atypical neurodegeneration in FMR1 premutation carriers.