Precision Sensorimotor Control in Aging FMR1 Gene Premutation Carriers

Abstract

BackgroundIndividuals with premutation alleles of the FMR1 gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative condition affecting sensorimotor function. Information on quantitative symptom traits associated with aging in premutation carriers is needed to clarify neurodegenerative processes contributing to FXTAS.Materials and Methods26 FMR1 premutation carriers ages 44–77 years and 31 age-matched healthy controls completed rapid (2 s) and sustained (8 s) visually guided precision gripping tasks. Individuals pressed at multiple force levels to determine the impact of increasing the difficulty of sensorimotor actions on precision behavior. During initial pressing, reaction time, the rate at which individuals increased their force, the duration of pressing, and force accuracy were measured. During sustained gripping, the complexity of the force time series, force variability, and mean force were examined. During relaxation, the rate at which individuals decreased their force was measured. We also examined the relationships between visuomotor behavior and cytosine-guanine-guanine (CGG) repeat length and clinically rated FXTAS symptoms.ResultsRelative to controls, premutation carriers showed reduced rates of initial force generation during rapid motor actions and longer durations of their initial pressing with their dominant hand. During sustained force, premutation carriers demonstrated reduced force complexity, though this effect was specific to younger premutation carries during dominant hand pressing and was more severe for younger relative to older premutation carriers at low and medium force levels. Increased reaction time and lower sustained force complexity each were associated with greater CGG repeat length for premutation carriers. Increased reaction time and increased sustained force variability were associated with more severe clinically rated FXTAS symptoms.ConclusionOverall our findings suggest multiple sensorimotor processes are disrupted in aging premutation carriers, including initial force control guided by feedforward mechanisms and sustained sensorimotor behaviors guided by sensory feedback control processes. Results indicating that sensorimotor issues in aging premutation carriers relate to both greater CGG repeat length and clinically rated FXTAS symptoms suggest that quantitative tests of precision sensorimotor ability may serve as key targets for monitoring FXTAS risk and progression.

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

“…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.…”

“…In the context of our cross-sectional data, it is likely that these results highlight important differences between relatively younger and older asymptomatic premutation carriers in susceptibility to FXTAS degeneration. While FXTAS penetrance increases with age in premutation carriers, it is possible that the older premutation carriers in our sample possess background and behavioral characteristics that are protective against FXTAS as has been suggested previously ( Steyaert et al, 1994 , Goodrich-Hunsaker et al, 2011 , McKinney et al, 2019 ). This is consistent with survival biases frequently observed in cross-sectional studies, in which disease-related mortality leads to the recruitment of a preponderance of individuals who are at risk for a disease but who are at lower risk for disease-related mortality ( Anderson et al, 2011 ).…”

“…Procedures for processing and analyzing force data were similar to those previously reported ( McKinney et al, 2019 ). Force data were digitized at 125 Hz by an si425 Fiber Optic Interrogator (Micron Optics, Atlanta, GA) and converted to Newtons within MATLAB (National Instruments, Austin, TX).…”

“…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 ).…”