Alterations in voluntary movement execution in Huntington's disease are related to the dominant motor system — Evidence from event-related potentials Christian Beste a,b, ⁎, Carsten Konrad c , Carsten Saft d , Tim Ukas c , Jürgen Andrich d , Bettina Pfleiderer e , Markus Hausmann f , Michael Falkenstein a a Leibniz Research Centre for Working Environment and Human Factors, WHO Collaborating Centre for Occupational Health, Ardeystr. 67, D-44139, Dortmund, Germany b Institute for Cognitive Neuroscience, Biopsychology, Ruhr-University Bochum, Germany c Department of Psychiatry and Psychotherapy, Interdisciplinary Center for Clinical Research (IZKF), University of Münster, Germany d Department of Neurology, Huntington Centre NRW, St. Josef-Hospital, Ruhr-University Bochum, Germany e Department of Clinical Radiology, University of Münster, Germany f Department of Psychology, Durham University, Durham, UK abstract article info Article history: Received 29 October 2008 Revised 19 November 2008 Accepted 20 November 2008 Available online 10 December 2008 Keywords: Huntington's disease Voluntary movements Event-related potential (ERP) Huntington's disease is an autosomal dominant neurogenetic disorder leading to striatal atrophy, characterized by involuntary movements. Voluntary movements also deteriorate, but the neurophysiological mechanisms are less understood. We investigated voluntary movement execution and its neural correlates by means of movement-related potentials (MRPs) in symptomatic HD (HD), presymptomatic HD (pHD) and controls. Reaction times (RTs) revealed hand differences in controls and HD, but not in pHDs. Response-locked MRPs above the contralateral primary motor area (M1) were similar across all groups. Yet, the HD-group showed, selectively for the right hand, a second contralateral (left) activation after the response, followed by similar activation over the ipsilateral (right) motor area, which is normally inhibited. Similarly parietal processes were reversed for right hand movements. In strong contrast, pHDs showed an increased inhibition of the ipsilateral hemisphere. The results suggest modulations of inhibitory processes in HD dependent on disease stage. Importantly, these modulations occur after the response and are restricted to right-hand responses, or the dominant motor system (left hemisphere). Since also cognitive processes preceding the MRPs changed, the results suggest a cognitive contribution to the emergence of voluntary movement dysfunction. The pattern in the pHD-group, namely an increased inhibition of the ipsilateral hemisphere and similar RTs between the hands suggest compensatory mechanisms in presymptomatic stages of the disease. Despite neurophysiological alterations originating in the dominant left hemisphere in HDs, they also affect the right hemisphere, probably due to a dysfunction in interhemispheric inhibition in HD. © 2008 Elsevier Inc. All rights reserved. Introduction Huntington's disease (HD) is an autosomal dominant neurological disorder. The causative mutation is an expansion of the CAG trinucleotide repeat in the HD gene (IT 15) on chromosome 4 (Beal and Ferrante, 2004). The most prominent sign of HD is chorea (Van Vugt et al., 1996; Penney et al., 1990). These motor symptoms are probably related to striatal pathology (e.g. Aylward et al., 2004; Kassubek et al., 2005; Thieben et al., 2002; rev. Rosas et al., 2004). The striatum can be seen as the main focus of pathology and is found to be more pronounced in the left hemisphere (Finke et al., 2006). Degeneration begins in the medium spiny neurons (MSN) (Cepeda et al., 2007) that provide inhibitory synaptic connections (Bevan et al., 2002) to pallidal structures. MSNs play an important role regulating the striatal output to pallidal structures (Gurney et al., 2004; Wickens and Wilson, 1998). Pallidal structures in turn project to the VA/VL complex of the thalamus, which in turn project to the primary motor cortex (Purves, 2004). Striatal and pallidal basal ganglia structures are influenced by the substantia nigra and the nucleus subthalamicus, respectively. Thalamic structures are also affected in HD (Beste et al., 2008; Kassubek et al., 2005) and hence an important structure mediating voluntary movement is dysfunctional, too. Indeed, it has been shown that voluntary movements are affected in HD (Kremer, 2002), which greatly impairs everyday living (Van Vugt et al., 2004). Since the precise nature of this motor impairment in HD is unknown (Kremer, 2002) we try to elucidate these processes on a neurophysiological level by using event-related potentials (ERPs). The most frequently used movement-related ERP component, the lateralized readiness Experimental Neurology 216 (2009) 148–157 ⁎ Corresponding author. Leibniz Research Centre for Working Environment and Human Factors, WHO Collaborating Centre for Occupational Health and Human Factors, Ardeystr. 67, D-44139 Dortmund, Germany. Fax: +49 231 1084 401. E-mail address: beste@ifado.de (C. Beste). 0014-4886/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2008.11.018 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr