Abstract
A steady progression of motor dysfunction takes place in Huntington's disease (HD). The origin of this disturbance with relation to the motor control process is not understood. Here we studied reaching movements in asymptomatic HD gene-carriers (AGCs) and subjects with manifest HD. We found that movement jerkiness, which characterizes the smoothness and efficiency of motion, was a sensitive indicator of presymptomatic HD progression. A large fraction of AGCs displayed elevated jerk even when more than seven years remained until predicted disease onset. Movement termination was disturbed much more than initiation and was highly variable from trial to trial. Analysis of this variability revealed that the sensitivity of end-movement jerk to subtle, self-generated early-movement errors was greater in HD subjects than in controls. Additionally, we found that HD corrective responses to externally-generated force pulses were greatly disturbed, indicating that HD subjects display aberrant responses to both external and self-generated errors. Because feedback corrections are driven by error and are delayed such that they predominantly affect movement termination, these findings suggest that a dysfunction in error correction characterizes the motor control deficit in early HD. This dysfunction may be observed years before clinical disease onset and grows worse as the disease progresses.
Highlights
Structural features of methyl-accepting taxis proteins conserved between archaebacteria and eubacteria revealed by antigenic cross-reation
All asymptomatic HD genecarriers (AGCs) have normal aiming biases of 3±78 and none has above-normal aiming variability. These results suggest that Huntington's disease1 (HD) movements often begin normally, but become jerky and irregular at some point during their course
Our analysis of the response to internal, self-generated errors suggested that error correction in general might be disturbed in HD
Summary
Subjects with manifest HD (P = 0.006) and AGCs (P = 0.04) display signi®cantly higher sensitivity in their response of end-movement jerk to early-movement error than do controls, as measured by slope in this relationship. The sensitivity of post-peak jerk to PSP displacement indicates the degree to which end-movement smoothness depends on early-movement error The increase in this sensitivity in HD subjects with and without clinically manifest symptoms suggests that an error-dependent control process is disturbed early in the disease course and further deteriorates with disease progression. Our analysis of the response to internal, self-generated errors suggested that error correction in general might be disturbed in HD To test this hypothesis we externally imposed errors upon movements of these subjects via an occasional brief (70 ms) force pulse shortly after movement initiation.
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