Motor disorder in Huntington's disease begins as a dysfunction in error feedback control

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.

Figure 1

Hand paths from selected subjects after 200 practice trials (movements 201-300). a, The two most regular movements in each direction. b, The two least regular movements each direction. Movement regularity was determined by the correlation coefficient of the velocity profile with the velocity profile of that subject’s typical movement. The typical movement was defined as the movement in each direction with the highest average correlation to other movements. Hand paths are plotted from the center out relative to their starting positions. Points are spaced 30ms apart in time. The distance between consecutive points is proportional to the movement speed during that interval. Top row: subjects with manifest HD. Second row: asymptomatic gene-carriers. Third row: controls who have a parent with HD but who are mutation negative. Bottom row: controls age matched to the asymptomatic gene-carriers. The letter that labels each subject identifies him or her in figure 2.

Figure 2

Quantification of movement properties. Red: subjects with manifest HD. Orange: asymptomatic gene-carriers. Blue: age matched controls. Green: gene-negative individuals having a parent with HD. Note that a-c are plotted on a logarithmic scale for clarity. The blue dotted lines show the 95% confidence intervals for the control distribution (mean +/- 1.96 standard deviations). The black diagonal line in a represents the axis of equality (y=x). a, The mean of the normalized total squared jerk for all subjects in the first 100 movements and in movements 201-300. All symptomatic subjects and a subset of asymptomatic gene-carriers have higher than normal jerk. b, The mean of normalized jerk (in movements 201-300) before and after the peak in the movement speed. The pre-peak segment, which reflects movement initiation, appears much less disturbed in HD than post-peak segment, which reflects movement completion. c, Aiming bias and aiming variability. We refer to aiming as the direction of travel with respect to the initial target direction, during the pre-peak movement segment. Like pre-peak jerk, aiming reflects the quality of movement. d,e, Group-wise comparisons of normalized pre-peak and post-peak jerk, respectively. Asterisks indicate significantly worse performance than control subjects. * p<0.05. ** p<0.01. *** p<0.001. **** p<0.0001. HD7+: Subjects with manifest HD for more than 7 years. HD7-: Subjects with manifest HD for less than 7 years. GPA7-: Gene-carriers less than 7 years from predicted onset. GPA7-11: Gene-carriers 7 to 11 years from predicted onset. GPA11+: Gene-carriers more than 11 years from predicted onset. Age>32: controls more than 32 years old. Age<32: controls less than 32 years old.

Figure 3

Squared jerk profiles for different movement speeds. Average raw squared jerk ± standard error is plotted on a logarithmic scale as function of time since movement onset for movements in each speed range, in different subject groups. For reference, the second peak in the squared jerk profile approximately corresponds to the peak in the speed profile. Note that at all speed ranges the separate groups have quite similar jerk profiles until 300ms, but HD subjects have very different profiles after this point.

Figure 4

Errors that occur early in the movement, before the hand reaches its peak speed, predict jerk that occurs later. a,c,e, The two-dimensional probability densities of peak speed positions (PSPs), for each group during movements 301-400. This is the likelihood of the peak speed occurring at each position. The x-axes are in the target direction, and the y-axes are in the direction perpendicular to the target. PSPs are clustered near the movement midway point. g, Summary of a,c,e: the average probability density at a given displacement between the PSP and movement midway point (50%, 0%). Large values for the distance from midway point to peak speed position indicate large early-movement errors, which are uncommon. The similarity of these distributions indicates that there are not large differences in the pattern of error recorded from the three subject groups early in the movement. b,d,f, End-movement jerk as a function of peak speed position. When large early movement errors occur, as indicated by large PSP displacements (near the image boundaries), the post-peak jerk is increased for all groups, but the increase is greater for asymptomatic and symptomatic HD subjects than controls. White color on images indicates no data. h, Summary of b,d,f: the average end-movement jerk at a given displacement between the PSP and movement midway point. i, average PSP displacement for each group. j, sensitivity of end movement jerk to PSP, measured as the slope of the relationship between them. Asterisks indicate significantly worse performance than control subjects. * p<0.05. ** p<0.01. *** p<0.001.