Brain Advance Access published online on April 15, 2009
Brain, doi:10.1093/brain/awp081
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Functional compensation of motor function in pre-symptomatic Huntington's disease
1 Department of Neurology, Neurozentrum and Freiburg Brain Imaging, University Clinic Freiburg, Freiburg, Germany 2 Department of Psychiatry and Psychotherapy, University Clinic Freiburg, Freiburg, Germany 3 Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London, UK 4 Danish Research Centre for Magnetic Resonance, Hvidore University Hospital, Hvidore, Denmark 5 Department of Clinical Neurology, Institute of Neurology, UCL, London, UK 6 Service de neurologie, CHUV, 1005 - Lausanne, Switzerland 7 Laboratory of Neuroimaging, IRCCS Santa Lucia, Roma, Italy
Correspondence to:
Stefan Klöppel MD, Department of Psychiatry und Psychotherapy, Hauptstrasse 5, 79104 Freiburg, Germany E-mail: stefan.kloeppel{at}uniklinik-freiburg.de
Involuntary choreiform movements are a clinical hallmark of Huntington's disease. Studies in clinically affected patients suggest a shift of motor activations to parietal cortices in response to progressive neurodegeneration. Here, we studied pre-symptomatic gene carriers to examine the compensatory mechanisms that underlie the phenomenon of retained motor function in the presence of degenerative change. Fifteen pre-symptomatic gene carriers and 12 matched controls performed button presses paced by a metronome at either 0.5 or 2 Hz with four fingers of the right hand whilst being scanned with functional magnetic resonance imaging. Subjects pressed buttons either in the order of a previously learnt 10-item finger sequence, from left to right, or kept still. Error rates ranged from 2% to 7% in the pre-symptomatic gene carriers and from 0.5% to 4% in controls, depending on the condition. No significant difference in task performance was found between groups for any of the conditions. Activations in the supplementary motor area (SMA) and superior parietal lobe differed with gene status. Compared with healthy controls, gene carriers showed greater activations of left caudal SMA with all movement conditions. Activations correlated with increasing speed of movement were greater the closer the gene carriers were to estimated clinical diagnosis, defined by the onset of unequivocal motor signs. Activations associated with increased movement complexity (i.e. with the pre-learnt 10-item sequence) decreased in the rostral SMA with nearing diagnostic onset. The left superior parietal lobe showed reduced activation with increased movement complexity in gene carriers compared with controls, and in the right superior parietal lobe showed greater activations with all but the most demanding movements. We identified a complex pattern of motor compensation in pre-symptomatic gene carriers. The results show that preclinical compensation goes beyond a simple shift of activity from premotor to parietal regions involving multiple compensatory mechanisms in executive and cognitive motor areas. Critically, the pattern of motor compensation is flexible depending on the actual task demands on motor control.
Key Words: pre-symptomatic Huntington's disease; fMRI; motor control
Abbreviations: fMRI, functional MRI; M1, primary sensorimotor cortex; PET, positron emission tomography; PMd, dorsal premotor cortex; ROIs, regions of interests; rTMS, repetitive transcranial magnetic stimulation; SMA, supplementary motor area; SPL, superior parietal lobe; UHDRS, Unified Huntington's Disease Rating Scale
Received November 18, 2008. Revised January 25, 2009. Accepted February 23, 2009.