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      DTI and VBM reveal white matter changes without associated gray matter changes in patients with idiopathic restless legs syndrome

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          Background and Purpose

          We evaluated cerebral white and gray matter changes in patients with iRLS in order to shed light on the pathophysiology of this disease.


          Twelve patients with iRLS were compared to 12 age- and sex-matched controls using whole-head diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) techniques. Evaluation of the DTI scans included the voxelwise analysis of the fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD).


          Diffusion tensor imaging revealed areas of altered FA in subcortical white matter bilaterally, mainly in temporal regions as well as in the right internal capsule, the pons, and the right cerebellum. These changes overlapped with changes in RD. Voxel-based morphometry did not reveal any gray matter alterations.


          We showed altered diffusion properties in several white matter regions in patients with iRLS. White matter changes could mainly be attributed to changes in RD, a parameter thought to reflect altered myelination. Areas with altered white matter microstructure included areas in the internal capsule which include the corticospinal tract to the lower limbs, thereby supporting studies that suggest changes in sensorimotor pathways associated with RLS.

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          Most cited references 58

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          Advances in functional and structural MR image analysis and implementation as FSL.

          The techniques available for the interrogation and analysis of neuroimaging data have a large influence in determining the flexibility, sensitivity, and scope of neuroimaging experiments. The development of such methodologies has allowed investigators to address scientific questions that could not previously be answered and, as such, has become an important research area in its own right. In this paper, we present a review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data. The majority of the research laid out in this paper has been implemented as freely available software tools within FMRIB's Software Library (FSL).
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            A voxel-based morphometric study of ageing in 465 normal adult human brains.

            Voxel-based-morphometry (VBM) is a whole-brain, unbiased technique for characterizing regional cerebral volume and tissue concentration differences in structural magnetic resonance images. We describe an optimized method of VBM to examine the effects of age on grey and white matter and CSF in 465 normal adults. Global grey matter volume decreased linearly with age, with a significantly steeper decline in males. Local areas of accelerated loss were observed bilaterally in the insula, superior parietal gyri, central sulci, and cingulate sulci. Areas exhibiting little or no age effect (relative preservation) were noted in the amygdala, hippocampi, and entorhinal cortex. Global white matter did not decline with age, but local areas of relative accelerated loss and preservation were seen. There was no interaction of age with sex for regionally specific effects. These results corroborate previous reports and indicate that VBM is a useful technique for studying structural brain correlates of ageing through life in humans.
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              Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water.

              Myelin loss and axonal damage are both observed in white matter injuries. Each may have significant impact on the long-term disability of patients. Currently, there does not exist a noninvasive biological marker that enables differentiation between myelin and axonal injury. We describe herein the use of magnetic resonance diffusion tensor imaging (DTI) to quantify the effect of dysmyelination on water directional diffusivities in brains of shiverer mice in vivo. The principal diffusion eigenvalues of eight axonal fiber tracts that can be identified with certainty on DTI maps were measured. The water diffusivity perpendicular to axonal fiber tracts, lambda(perpendicular), was significantly higher in shiverer mice compared with age-matched controls, reflecting the lack of myelin and the increased freedom of cross-fiber diffusion in white matter. The water diffusivity parallel to axonal fiber tracts, lambda(parallel), was not different, which is consistent with the presence of intact axons. It is clear that dysmyelination alone does not impact lambda(parallel). The presence of intact axons in the setting of incomplete myelination was confirmed by electron microscopy. Although further validation is still needed, our finding suggests that changes in lambda(perpendicular) and lambda(parallel) may potentially be used to differentiate myelin loss versus axonal injury.

                Author and article information

                Brain Behav
                Brain Behav
                Brain and Behavior
                John Wiley & Sons, Ltd (Chichester, UK )
                September 2015
                30 July 2015
                : 5
                : 9
                [1 ]Department of Neurology, Philipps-University Marburg Baldingerstrasse, Marburg, 35043, Germany
                [2 ]Department of Diagnostic Radiology, Philipps-University Marburg Baldingerstrasse, Marburg, 35043, Germany
                [3 ]Epilepsy Center Franfurt Rhein-Main, Department of Neurology, Johann Wolfgang Goethe University Frankfurt am Main, Germany
                [4 ]Somnomar, Institute for Medical Research and Sleep Medicine Marburg Marburger Strasse 9a, Marburg, 35043, Germany
                Author notes
                Correspondence Susanne Knake, Center of Brain Imaging, Philipps-University Marburg, Department of Neurology, Baldingerstrasse, 35043 Marburg, Germany. Tel: 0049 6421 5865200; Fax: 0049 6421 5865208; E-mail: knake@

                Funding Information No funding information provided.


                Equal contribution

                © 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Original Research


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