More than 80% of the variance in the effect on relapses between trials is explained by the variance in MRI effects. Smaller and shorter phase II studies based on MRI lesion end points may give indications also on the effect of the treatment on relapse end points.

Corpus callosum (CC) is involved in the performance of bimanual motor tasks. We asked whether its functional role could be investigated by combining a motor behavioral study on bimanual movements in multiple sclerosis (MS) patients with a quantitative magnetic resonance diffusion tensor imaging (DTI) analysis of CC, which is shown to be damaged in this disease. MS patients and normal subjects were asked to perform sequences of bimanual finger opposition movements at different metronome rates; then we explored the structural integrity of CC by means of DTI. Significant differences in motor performance, mainly referred to timing accuracy, were observed between MS patients and control subjects. Bimanual motor coordination was impaired in MS patients as shown by the larger values of the interhand interval observed at all the tested metronome rates with respect to controls. Furthermore, DTI revealed a significant reduction of fractional anisotropy (FA), indicative of microstructural tissue damage, in the CC of MS patients. By correlating the mean FA values with the different motor behavior parameters, we found that the degree of damage in the anterior callosal portions mainly influences the bimanual coordination and, in particular, the movement phase preceding the finger touch. Finally, the described approach, which correlates quantitative measures of tissue damage obtained by advanced magnetic resonance imaging tools with appropriate behavioral measurements, may help the exploration of different aspects of motor performance impairment attributable to the disease.

This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.

These findings support the use of commonly used surrogate markers of EDSS worsening as endpoints in multiple sclerosis clinical trials. Further research is warranted to validate surrogate endpoints at the individual level rather than at the trial level, to draw important conclusions in the management of the individual patient.

Fatigue, an overwhelming lack of physical or mental energy, is a common complaint in patients affected by multiple sclerosis (MS). Although different mechanisms have been proposed to explain MS-related fatigue, injury of distinct anatomical networks seems to be relevant in fatigue etiology. Particularly, theories point to fronto-striatal network pathological changes as a possible neural basis of fatigue. To investigate the role of fronto-striatal white matter structural alterations in fatigue perception we prospectively recruited 40 relapsing remitting patients with MS and 15 healthy controls. In patients with MS, fatigue was assessed using a validated measure, the Modified Fatigue Impact Scale (MFIS; Kos et al., 2005). Brain MRI scans were acquired for each subject enrolled with diffusion tensor imaging. Diffusion tensor data were correlated with MFIS scores using voxel-wise analysis of fractional anisotropy maps and fiber tractography algorithms. A significant cluster of voxels correlating with fatigue scores located in the deep left frontal white matter was identified. Fiber tractography revealed the cluster to be included in a complex fronto-frontal, fronto-striatal, fronto-occipital, and fronto-limbic network. Structural properties of the traced white matter fiber bundles correlated with fatigue perception and patients with clinically relevant fatigue were found to present reduced white matter integrity in the aforementioned tracts compared to those with lower levels of fatigue. Our observations show a significant involvement of different frontal networks in the pathophysiology of fatigue, thus accounting for the multifaceted nature of this disabling symptom.

Upper limb impairments can occur in patients with multiple sclerosis, affecting daily living activities; however there is at present no definite agreement on the best rehabilitation treatment strategy to pursue. Moreover, motor training has been shown to induce changes in white matter architecture in healthy subjects. This study aimed at evaluating the motor behavioral and white matter microstructural changes following a 2-month upper limb motor rehabilitation treatment based on task-oriented exercises in patients with multiple sclerosis. Thirty patients (18 females and 12 males; age=43.3 ± 8.7 years) in a stable phase of the disease presenting with mild or moderate upper limb sensorimotor deficits were randomized into two groups of 15 patients each. Both groups underwent twenty 1-hour treatment sessions, three times a week. The "treatment group" received an active motor rehabilitation treatment, based on voluntary exercises including task-oriented exercises, while the "control group" underwent passive mobilization of the shoulder, elbow, wrist and fingers. Before and after the rehabilitation protocols, motor performance was evaluated in all patients with standard tests. Additionally, finger motor performance accuracy was assessed by an engineered glove. In the same sessions, every patient underwent diffusion tensor imaging to obtain parametric maps of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. The mean value of each parameter was separately calculated within regions of interest including the fiber bundles connecting brain areas involved in voluntary movement control: the corpus callosum, the corticospinal tracts and the superior longitudinal fasciculi. The two rehabilitation protocols induced similar effects on unimanual motor performance, but the bimanual coordination task revealed that the residual coordination abilities were maintained in the treated patients while they significantly worsened in the control group (p=0.002). Further, in the treatment group white matter integrity in the corpus callosum and corticospinal tracts was preserved while a microstructural integrity worsening was found in the control group (fractional anisotropy of the corpus callosum and corticospinal tracts: p=0.033 and p=0.022; radial diffusivity of the corpus callosum and corticospinal tracts: p=0.004 and p=0.008). Conversely, a significant increase of radial diffusivity was observed in the superior longitudinal fasciculi in both groups (p=0.02), indicating lack of treatment effects on this structure, showing damage progression likely due to a demyelination process. All these findings indicate the importance of administering, when possible, a rehabilitation treatment consisting of voluntary movements. We also demonstrated that the beneficial effects of a rehabilitation treatment are task-dependent and selective in their target; this becomes crucial towards the implementation of tailored rehabilitative approaches.

We prospectively investigated pathological modifications in the corticospinal tract (CST), by diffusion tensor imaging (DTI) in 14 patients with sporadic amyotrophic lateral sclerosis (ALS) and 12 healthy volunteers. We used a validated automated method to accurately measure the in vivo thickness of the cerebral cortex. We found a reduction of precentral cortical ribbon thickness in ALS patients with respect to control subjects. DTI metrics demonstrated disorganization of the CST, as characterized by decreased fractional anisotropy (FA) and increased Apparent Diffusion Coefficient in ALS patients with respect to control subjects. Decreased mean FA values along the CST significantly correlated with clinical measures of pyramidal and bulbar impairment. Quantitative analysis of MR data shows that thinning of the motor cortex coexists with CST damage in ALS patients.

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