Functional motor control deficits in older FMR1 premutation carriers

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

“…Deficits in the rapid execution of precision manual motor actions may reflect multiple issues including delayed information processing or action execution at peripheral or central levels ( Soontarapornchai et al, 2008 ). This is consistent with our prior findings of reduced motor unit discharge rate ( Park et al, 2019 ). Efficient processing of sensory information and the transmission of motor commands to initiate movement also rely on intact white matter structural networks which may be affected in premutation carriers, as indicated by prior findings of reduced structural connectivity of white matter motor fiber tracts in FXTAS patients as well as findings of associations between molecular and genetic markers and reduced structural connectivity in asymptomatic premutation carriers ( Wang et al, 2013 ).…”

“…We document that aging premutation carriers show increased precision force variability relative to controls, though only during the younger ages studied here, implicating deficient sensory feedback processing of error information and alterations of motor control processes involved in dynamically adjusting output in response to error information. These results are consistent with our prior findings of increased force variability during sustained motor action in premutation carriers ( Park et al, 2019 ). Our finding that elevated force variability is specific to younger premutation carriers reflects an age-associated improvement in motor control (i.e., lower force accuracy variability) in premutation carriers that contrasts age-associated declines seen in our control sample and documented previously in healthy aging ( Laidlaw et al, 2000 , Vaillancourt et al, 2003a , Vaillancourt and Newell, 2003 ).…”

“…In the present fMRI study, we examined cerebellar-cortical function and connectivity in aging FMR1 gene premutation carriers performing a test of visually guided precision grip force. Consistent with our prior studies ( McKinney et al, 2019 , Park et al, 2019 ), we expected FMR1 premutation carriers to show reduced force accuracy and greater force variability across trials relative to controls. We also hypothesized atypical sensory cortical and cerebellar activation and reduced cerebellar-cortical functional connectivity in premutation carriers.…”

“…Reduced complexity of postural sway also has been demonstrated and is associated with increased CGG repeat length in asymptomatic premutation carriers, indicating quantitative sensorimotor measurements may track with disease risk ( O'Keeffe et al, 2019 , Wang et al, 2019 ). Similarly, using tests of precision manual force, we recently documented increased motor variability in aging premutation carriers (between 44 and 77 years of age; Park et al, 2019 ) and reduced motor complexity associated with more severe clinical motor issues and increased CGG repeats ( McKinney et al, 2019 ). Findings that deficits of precision manual motor control are associated with both molecular and clinical indicators of FXTAS in premutation carriers with subclinical presentations suggest that quantifiable differences in manual motor behavior may represent prodromal features of the disease.…”

“…FXTAS symptom presentation and timing are variable, and several studies have suggested that a “prodromal” phase, characterized by structural brain changes and subclinical social-emotional, cognitive, and motor issues may be detectable prior to clinically-observable symptoms ( Wang et al, 2012 , Loesch et al, 2015 , Gossett et al, 2016 , Wang et al, 2017 , McKinney et al, 2019 , Park et al, 2019 ). Quantitative markers of core sensorimotor and brain system differences representing prodromal FXTAS are needed to better understand disease course, identify degenerative processes during early stages, and to track and eventually mitigate disease progression, as has been done in other neurological disorders ( Rowe et al, 2010 , González-Garcia et al, 2011 , Trujillo et al, 2015 ).…”