title: Preclinical Huntington's disease: compensatory brain responses during learning.
abstract: Motor sequence learning is abnormal in presymptomatic Huntington's disease (p-HD). The neural substrates underlying this early manifestation of HD are poorly understood. To study the mechanism of this cognitive abnormality in p-HD, we used positron emission tomography to record brain activity during motor sequence learning in these subjects. Eleven p-HD subjects (age, 45.8 +/- 11.0 years; CAG repeat length, 41.6 +/- 1.8) and 11 age-matched control subjects (age, 45.3 +/- 13.4 years) underwent H(2) (15)O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks. Differences in regional brain activation responses between groups and conditions were assessed. In addition, we identified discrete regions in which learning-related activity correlated with performance. We found that sequence learning was impaired in p-HD subjects despite normal motor performance. In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47). Impaired learning performance in these subjects was associated with increased activation responses in the precuneus (BA 18/31). These data suggest that enhanced activation of thalamocortical pathways during motor learning can compensate for caudate degeneration in p-HD. Nonetheless, this mechanism may not be sufficient to sustain a normal level of task performance, even during the presymptomatic stage of the disease.
authors.affiliation: Center for Neurosciences, Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feigin
authors.forename: Maria-Felice
authors.initials: MF
authors.lastname: Ghilardi
authors.forename: Chaorui
authors.initials: C
authors.lastname: Huang
authors.forename: Yilong
authors.initials: Y
authors.lastname: Ma
authors.forename: Maren
authors.initials: M
authors.lastname: Carbon
authors.forename: Mark
authors.initials: M
authors.lastname: Guttman
authors.forename: Jane S
authors.initials: JS
authors.lastname: Paulsen
authors.forename: Claude P
authors.initials: CP
authors.lastname: Ghez
authors.forename: David
authors.initials: D
authors.lastname: Eidelberg
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007858:Learning / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology*; D049268:Positron-Emission Tomography; D011597:Psychomotor Performance / Q000502:physiology*