Structure of WM bundles constituting the working memory system in early multiple sclerosis: A quantitative DTI tractography study Bertrand Audoin, a,b Maxime Guye, a Françoise Reuter, a,b My-Van Au Duong, a Sylviane Confort-Gouny, a Irina Malikova, a,b Elisabeth Soulier, a Patrick Viout, a André Ali Chérif, b Patrick J. Cozzone, a Jean Pelletier, a,b and Jean-Philippe Ranjeva a, ⁎ a Centre de Résonance Magnétique Biologique et Médicale, UMR CNRS 6612, Faculté de Médecine, Université de la Méditerranée, 27 boulevard Jean Moulin, 13385 Marseille cedex 05, France b Service de Neurologie, Centre Hospitalier Universitaire Timone, 260 boulevard St Pierre, 13005 Marseille, France Received 21 November 2006; revised 12 April 2007; accepted 15 April 2007 Available online 27 April 2007 Working memory impairment is frequently observed in patients with early multiple sclerosis (MS). MRI and functional MRI studies have shown that working memory impairment is mostly due to diffuse white matter (WM) damage affecting the connectivity between distant cortical areas. However, working memory deficits in early MS patients can be either completely or partly masked by compensatory functional plasticity. It seems likely that concomitantly with the WM bundle injury resulting from pathological processes, the functional plasticity present in early MS patients may be accompanied by reactive structural WM plasticity. This structural plasticity may effectively compensate for connectivity disturbances and/or contribute to functional brain reorganization. The diffusion characteristics of WM bundles involved in working memory were assessed here by performing quantitative diffusion tensor imaging (DTI) tractography on 24 patients with early relapsing-remitting MS and 15 healthy control subjects. The DTI tractography findings showed that WM connections constituting the executive system of working memory were structurally impaired (the fractional anisotropy was lower than normal and the mean diffusivity, higher than normal). A significantly larger number of connections between the left and right thalami was concurrently observed in the MS patients than in the control subjects, which suggests that the WM is endowed with reactive structural plasticity. © 2007 Elsevier Inc. All rights reserved. Introduction Although multiple sclerosis (MS) is generally defined as a multifocal demyelinating disease, recent advances in the field of neuroimaging have shown that MS also involves the presence of diffuse white matter (WM) and grey matter (GM) injuries. Working memory impairment is frequently observed in patients with early multiple sclerosis (MS). MRI and functional MRI studies have shown that working memory impairment mostly results from diffuse WM injury, which alters the connectivity between distant cortical areas (Au Duong et al., 2005a,b). The working memory deficits observed in patients at the clinical onset of MS can be either completely or partly masked by compensatory functional processes occurring in regions involved in executive processing (the prefrontal cortices) (Audoin et al., 2005; Au Duong et al., 2005b; Forn et al., 2006). The structural substrates of working memory impairment and the exact nature of these compensatory functional processes still remain to be elucidated. The structural status of WM bundles belonging to a specific network can be assessed using diffusion tensor imaging (DTI) tractography, a powerful non-invasive technique which makes it possible to track WM bundles connecting distant cortical areas (Le Bihan, 2003). This technique was previously applied to MS in order to determine the extent of the lesions affecting the WM bundles involved in specific systems such as the motor system and to establish stronger relationships with clinical data (Pagani et al., 2005; Lowe et al., 2006). However, to our knowledge, the structural characteristics of complex systems such as the working memory network, which is known to be affected in early MS (Achiron and Barak, 2003; Deloire et al., 2005; Feuillet et al., 2007), have not yet been determined. In the present study, it was proposed to examine the extent of WM damage as well as the structural plasticity of the bundles involved in the working memory of patients at the clinical onset of MS, using quantitative DTI tractography methods. Methods Subjects Twenty-four patients presenting with a clinically isolated syndrome (CIS) corresponding to the clinical onset of MS were compared with 15 healthy age- and sex-matched control subjects (Table 1). All subjects (patients and controls) were right-handed (N 70% Olfield scale) native French speakers. Patients were recruited during a one-year inclusion period at the Department of Neurology www.elsevier.com/locate/ynimg NeuroImage 36 (2007) 1324 – 1330 ⁎ Corresponding author. E-mail address: jp.ranjeva@medecine.univ-mrs.fr (J.-P. Ranjeva). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2007.04.038