title: 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.
authors.affiliation: Department of Biomedical Engineering, Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland 21205-2195, USA. msmith@bme.jhu.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Brandt
authors.forename: R
authors.initials: R
authors.lastname: Shadmehr
mesh_terms: D017668:Age of Onset; D001132:Arm; D018450:Disease Progression; D020820:Dyskinesias; D005246:Feedback; D006580:Genetic Carrier Screening; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D016555:Matched-Pair Analysis; D009154:Mutation; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics; D011597:Psychomotor Performance
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins