30055
Precision Sensorimotor Control and Neurophysiology in Aging FMR1 Premutation Carriers
FMR1 premutation carriers are at risk of developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), a neurodegenerative condition characterized by significant motor impairments as well as cognitive and psychiatric issues. It is unknown whether sensorimotor issues are present during aging in premutation carriers who are not yet reporting clinical signs of FXTAS. Studies examining sensorimotor control and associated neural processes in aging premutation carriers may provide important insights into degenerative processes associated with FMR1 premutations as well as neurobiological mechanisms associated with FXTAS.
Objectives:
We sought to (1) characterize precision motor behavior and (2) associated brain activation in aging FMR1 premutation carriers during task-based functional MRI (fMRI). We also quantified the relationships between sensorimotor behaviors and FMR1 premutation allele repeat count.
Methods:
27 FMR1 premutation carriers ages 44-77 years and 38 age-, sex-, and handedness-matched controls completed a visually guided precision gripping task. Participants pressed with their thumb and forefinger against two precision load cells while viewing two horizontal bars. Participants pressed to move the lower bar upwards to the height of the static target bar and maintained a constant force for 2- or 8- seconds. The target bar was set at 15%, 45%, or 85% of their maximum voluntary contraction (MVC). Approximate entropy (i.e., force time series complexity, or ApEn), force variability, force accuracy, and peak rate of force increase during initial responses were examined. Sixteen FMR1 premutation carriers and 20 controls repeated the 2-s version of the task during fMRI at 20% and 60% of their MVC.
Results:
Compared to controls, premutation carriers showed reduced MVCs. During the initial phase in which participants increased their force, premutation carriers showed a reduced rate of force increase compared to controls. When trying to maintain a constant level of force, premutation carriers showed reduced ApEn relative to controls, though there was no difference in force accuracy or force variability between groups. For premutation carriers, greater CGG repeat length was associated with reduced ApEn, increased force variability, and reduced force accuracy. During fMRI, premutation carriers demonstrated increased activation of left superior temporal gyrus (STG) and right superior parietal lobule during force relative to controls at 20% MVC only. At 60% MVC, premutation carriers demonstrated reduced force-related BOLD activation relative to controls in orbitofrontal cortex (fMRI FWE corrected p < .025).
Conclusions:
Our findings indicate that aging premutation carriers show deficits of precision sensorimotor behaviors that are associated with greater CGG repeat length. In the context of prior studies showing that greater CGG repeat length is associated with increased risk of FXTAS in aging premutation carriers, these findings suggest that reduced control of precision sensorimotor behaviors may provide important biobehavioral risk markers of disease. During fMRI, premutation carriers demonstrated increased activation in visual and multisensory processing cortical circuits, indicating that sensorimotor deficits may reflect deficits in processing sensory feedback information during behavior. Decreased OFC activation during sensorimotor behavior compared to rest may indicate that premutation carriers show a reduced ability to flexibly shift their behavior during rapid (2 sec) sensorimotor tasks.