Statistical mapping analysis of lesion location and neurological disability in multiple sclerosis: application to 452 patient data sets Arnaud Charil, a Alex P. Zijdenbos, a Jonathan Taylor, b Cyrus Boelman, a Keith J. Worsley, a,b Alan C. Evans, a and Alain Dagher a, * a McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montre ´al, Canada b Department of Mathematics and Statistics, McGill University, Montre ´al, Canada Received 28 August 2002; accepted 14 February 2003 Abstract In multiple sclerosis (MS), the correlation between disability and the volume of white matter lesions on magnetic resonance imaging (MRI) is usually weak. This may be because lesion location also influences the extent and type of functional disability. We applied an automatic lesion-detection algorithm to 452 MRI scans of patients with relapsing-remitting MS to identify the regions preferentially responsible for different types of clinical deficits. Statistical parametric maps were generated by performing voxel-wise linear regressions between lesion probability and different clinical disability scores. There was a clear distinction between lesion locations causing physical and cognitive disability. Lesion likelihood correlated with the Expanded Disability Status Scale (EDSS) in the left internal capsule and in periventricular white matter mostly in the left hemisphere. Pyramidal deficits correlated with only one area in the left internal capsule that was also present in the EDSS correlation. Cognitive dysfunction correlated with lesion location at the grey-white junction of associative, limbic, and prefrontal cortex. Coordination impairment correlated with areas in interhemispheric and pyramidal periventricular white matter tracts, and in the inferior and superior longitudinal fascicles. Bowel and bladder scores correlated with lesions in the medial frontal lobes, cerebellum, insula, dorsal midbrain, and pons, areas known to be involved in the control of micturition. This study demonstrates for the first time a relationship between the site of lesions and the type of disability in large scale MRI data set in MS. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Multiple sclerosis; EDSS; Cognitive dysfunction; Disability; Magnetic resonance imaging Introduction The modern localization of brain function started in the 19th century when focal lesions identified at postmortem were related to specific neurological deficits. More recently positron emission tomography (PET) and functional mag- netic resonance imaging (MRI) have been used to map neurological function in living human subjects. The rela- tively low signal-to-noise ratios of these imaging techniques required averaging data from many individuals, which ne- cessitated two methodological developments, i.e., the reg- istration of different brains into a standard stereotaxic space, and the application of statistical tests to the resultant data to generate so-called statistical parametric maps. Here we ap- ply these computational methods to a lesional study in multiple sclerosis (MS). MRI is commonly used for the diagnosis of MS and for measuring disease severity in clinical trials (Miller et al., 1998; Rovaris and Filippi, 1999). Paradoxically, MRI-de- termined total lesion load in the brain correlates weakly with disability (Miki et al., 1999; Molyneux et al., 1998; Nijeholt et al., 1998) as assessed, for example, by Kurtzke’s Expanded Disability Status Scale (EDSS) (Kurtzke, 1983). There are several possible explanations for this poor corre- lation; i.e., the EDSS is nonlinear and heavily weighted toward ambulatory deficits (Willoughby and Paty, 1988); cortical reorganization could contribute to functional recov- ery (Lee et al., 2000; Reddy et al., 2000); conventional * Corresponding author. Montreal Neurological Institute, 3801 Univer- sity St., Montre ´al, Que ´bec H3A 2B4, Canada. Fax: +1-514-398-8948. E-mail address: alain@bic.mni.mcgill.ca (A. Dagher). NeuroImage 19 (2003) 532–544 www.elsevier.com/locate/ynimg 1053-8119/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1053-8119(03)00117-4