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Quantitative diffusion imaging techniques enable the characterization of tissue microstructural properties of the human brain "in vivo", and are widely used in neuroscientific and clinical contexts. In this review, we present the basic physical principles behind diffusion imaging and provide an overview of the current diffusion techniques, including standard and advanced techniques as well as their main clinical applications. Standard diffusion tensor imaging (DTI) offers sensitivity to changes in microstructure due to diseases and enables the characterization of single fiber distributions within a voxel as well as diffusion anisotropy. Nonetheless, its inability to represent complex intravoxel fiber topologies and the limited biological specificity of its metrics motivated the development of several advanced diffusion MRI techniques. For example, high-angular resolution diffusion imaging (HARDI) techniques enabled the characterization of fiber crossing areas and other complex fiber topologies in a single voxel and supported the development of higher-order signal representations aiming to decompose the diffusion MRI signal into distinct microstructure compartments. Biophysical models, often known by their acronym (e.g., CHARMED, WMTI, NODDI, DBSI, DIAMOND) contributed to capture the diffusion properties from each of such tissue compartments, enabling the computation of voxel-wise maps of axonal density and/or morphology that hold promise as clinically viable biomarkers in several neurological and neuroscientific applications; for example, to quantify tissue alterations due to disease or healthy processes. Current challenges and limitations of state-of-the-art models are discussed, including validation efforts. Finally, novel diffusion encoding approaches (e.g., b-tensor or double diffusion encoding) may increase the biological specificity of diffusion metrics towards intra-voxel diffusion heterogeneity in clinical settings, holding promise in neurological applications.

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER, "Otra manera de hacer Europa", "Investing in your future"); Red Española de Esclerosis Múltiple (REEM - RD16/0015/0002, RD16/0015/0003, RD12/0032/0002, RD12/0060/01-02); TEVA Spain; Fundación Merck Salud (Ayudas Merck de Investigación 2017); Proyecto Societat Catalana Neurologia 2017; CIBERNED program (Program 1, Alzheimer Disease and SIGNAL study); National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, R01AG061566;, Fundació La Marató de TV3 (20142030, 20141210); Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Lucas; Generalitat de Catalunya (SLT006/17/00119); Universitat de Barcelona (APIF Pre-doctoral grant); Hospital Clinic Emili Letang). The spatio-temporal characteristics of grey matter (GM) impairment in multiple sclerosis (MS) are poorly understood. We used a new surface-based diffusion MRI processing tool to investigate regional modifications of microstructure, and we quantified volume loss in GM in a cohort of patients with MS classified into three groups according to disease duration. Additionally, we investigated the relationship between GM changes with disease severity. We studied 54 healthy controls and 247 MS patients classified regarding disease duration: MS1 (less than 5 years, n = 67); MS2 (5-15 years, n = 107); and MS3 (more than15 years, n = 73). We compared GM mean diffusivity (MD), fractional anisotropy (FA) and volume between groups, and estimated their clinical associations. Regional modifications in diffusion measures (MD and FA) and volume did not overlap early in the disease, and became widespread in later phases. We found higher MD in MS1 group, mainly in the temporal cortex, and volume reduction in deep GM and left precuneus. Additional MD changes were evident in cingulate and occipital cortices in the MS2 group, coupled to volume reductions in deep GM and parietal and frontal poles. Changes in MD and volume extended to more than 80% of regions in MS3 group. Conversely, increments in FA, with very low effect size, were observed in the parietal cortex and thalamus in MS1 and MS2 groups, and extended to the frontal lobe in the later group. MD and GM changes were associated with white matter lesion load and with physical and cognitive disability. Microstructural integrity loss and atrophy present differential spatial predominance early in MS and accrual over time, probably due to distinct pathogenic mechanisms that underlie tissue damage.

Purpose: To develop an accelerated postprocessing pipeline for reproducible and efficient assessment of white matter lesions using quantitative magnetic resonance fingerprinting (MRF) and deep learning. Methods: MRF using echo-planar imaging (EPI) scans with varying repetition and echo times were acquired for whole brain quantification of (Formula presented.) and (Formula presented.) in 50 subjects with multiple sclerosis (MS) and 10 healthy volunteers along 2 centers. MRF (Formula presented.) and (Formula presented.) parametric maps were distortion corrected and denoised. A CNN was trained to reconstruct the (Formula presented.) and (Formula presented.) parametric maps, and the WM and GM probability maps. Results: Deep learning-based postprocessing reduced reconstruction and image processing times from hours to a few seconds while maintaining high accuracy, reliability, and precision. Mean absolute error performed the best for (Formula presented.) (deviations 5.6%) and the logarithmic hyperbolic cosinus loss the best for (Formula presented.) (deviations 6.0%). Conclusions: MRF is a fast and robust tool for quantitative (Formula presented.) and (Formula presented.) mapping. Its long reconstruction and several postprocessing steps can be facilitated and accelerated using deep learning.

Background:Prognostic markers are needed to guide multiple sclerosis (MS) management in the context of large availability of disease-modifying drugs (DMDs).Objective:To investigate the role of cerebrospinal fluid (CSF) markers to inform long-term MS outcomes.Methods:Demographic features, IgM index, oligoclonal IgM bands (OCMB), lipid-specific OCMB, CSF neurofilament light chain protein levels, expanded disability status scale (EDSS), relapses and DMD use over the study period and peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thicknesses in non-optic neuritis eyes (end of follow-up) were collected from relapsing MS (RMS) patients with CSF obtained ⩽2 years after MS onset prospectively followed at the Hospital Clinic of Barcelona. We assessed associations between CSF markers and MS outcomes using multivariable models.Results:A total of 89 patients (71 females; median 32.9 years of age) followed over a median of 9.6 years were included. OCMB were associated with a 33% increase in the annualized relapse rate (ARR; p = 0.06), higher odds for high-efficacy DMDs use (OR = 4.8; 95% CI = (1.5, 16.1)), thinner pRNFL (β = −4.4; 95% CI = (−8.6, −0.2)) and GCIPL (β = −2.9; 95% CI = (−5.9, +0.05)), and higher rates to EDSS ⩾ 3.0 (HR = 4.4; 95% CI = (1.6, 11.8)) and EDSS ⩾ 4.0 (HR = 5.4; 95% CI = (1.1, 27.1)). No overall associations were found for other CSF markers.Conclusion:The presence of OCMB was associated with unfavorable long-term outcomes. OCMB should be determined in RMS to inform long-term prognosis.

Brain structural network modifications in multiple sclerosis (MS) seem to be clinically relevant. The discriminative ability of those changes to identify MS patients or their cognitive status remains unknown. Therefore, this study aimed to investigate connectivity changes in MS patients related to their cognitive status, and to define an automatic classification method to classify subjects as patients and healthy volunteers (HV) or as cognitively preserved (CP) and impaired (CI) patients. We analysed structural brain connectivity in 45 HV and 188 MS patients (104 CP and 84 CI). A support vector machine with k-fold cross-validation was built using the graph metrics features that best differentiate the groups (p

The Expanded Disability Status Scale (EDSS) and Patient Determined Disease Steps (PDDS) are two of the most widely disability scales used in multiple sclerosis (MS). When physical visits are unavailable, remote evaluation through telephone interview may be helpful. We aimed to translate both scales into Spanish, and to 1) validate the telephone EDSS and PDDS, and 2) explore the association pattern between both telephone questionnaires.103 patients underwent a neurological examination to generate the EDSS and completed the PDDS questionnaire. Telephone questionnaires (EDSS, PDDS) were performed within 15 days. Feasibility and psychometric properties of both telephone questionnaires included internal consistency, acceptability, inter-rater agreement and validity. Test-retest reliability was evaluated in 36 patients.Both scales showed excellent internal consistency and test-retest reliability. The agreement between conventional and telephone assessments in ambulatory impaired patients (EDSS 4.0) was good for EDSS (kappa = 0.72) and excellent for PDDS (kappa = 0.93); fully ambulatory patients (EDSS ≤ 4.0) showed lower values (kappa = 0.24, and 0.54, respectively). Full agreement was higher for telephone PDDS than telephone EDSS (78% vs 44%). Overestimation of disability was more frequent in fully ambulatory patients. Strong correlation was found between telephone questionnaires (rho = 0.88; p 0.001). The pattern of association was not isomorphic, but a PDDS cut-off of 3 identified with high accuracy patients with ambulatory impairment.Telephone EDSS and PDDS questionnaires for Spanish patients are valid tools to assess disability status in MS and offer complementary information. Patients with ambulatory impairment are those who benefit the most from a remote assessment.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.

ObjectiveTo investigate the incidence of coronavirus disease 2019 (COVID-19) in a single-center cohort of patients with MS and to explore the contribution of their comorbidities and therapies to the outcome.MethodsA cross-sectional mixed-method study was conducted involving an email-based, self-administered questionnaire sent on May 21, 2020, to 586 patients with MS followed at the MS Unit of Hospital Clinic, University of Barcelona, along with telephone interview, and review of electronic medical records until June 18, 2020. The cumulative incidence of confirmed COVID-19 (positive PCR or antibody test) and all COVID-19 cases (confirmed and suspected) from the start of the pandemic was compared with the population estimates for Barcelona.ResultsA total of 407 patients (69.5%) completed the survey. Most of the responders (67%) were female. The responders had a median age of 48 years (range 19–86), relapsing-remitting disease (84%), at least 1 comorbidity (45%), and were on disease-modifying therapy (DMT; 74.7%). COVID-19 was confirmed in 5 patients (1.2%) and suspected in 46 (11.3%). The cumulative incidence of confirmed COVID-19 cases was similar to that of the general population but was almost 2-fold higher when all cases were considered (p < 0.001). Six patients (11.7%) were hospitalized, of which 5 had good recovery and 1 died. Hospitalized patients were more frequently male, had diabetes and had progressive forms of MS (p < 0.05). DMT was not associated with the risk of infection or the outcome.ConclusionsIn the studied MS cohort, the incidence of COVID-19 was higher than that of the general population; however, most patients did not require hospitalization and had a good outcome despite the frequent presence of comorbidities and treatment with DMT.

Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium- enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p

1AbstractQuadrantanopia caused by inadvertent severing of Meyer’s Loop of the optic radiation is a well-recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer’s Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer’s Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT – a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust preprocessing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 694 scans of predominantly healthy participants (538 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer’s Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan-rescan error of this distance was 1mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer’s Loop with clinically accessible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post-processing methods.HighlightsWe propose a fully automated means of delineating the optic radiation using diffusion MRI from DICOM dataAnatomical measurements from tractography of over 500 brains align well with previous dissection studiesThe proposed pipeline works well with clinically accessible and advanced acquisitionsMedian scan-rescan error was 1mmPlausible tractography was generated when pathology was present

Patients with multiple sclerosis (MS) display reduced structural connectivity among brain regions, but the pathogenic mechanisms underlying network disruption are still unknown. We aimed to investigate the association between the loss of diffusion-based structural connectivity, measured with graph theory metrics, and magnetic resonance (MR) markers of microstructural damage. Moreover, we evaluated the cognitive consequences of connectivity changes. We analysed the frontoparietal network in 102 MS participants and 25 healthy volunteers (HV). MR measures included radial diffusivity (RD), as marker of demyelination, and ratios of myo-inositol, N-acetylaspartate and glutamate+glutamine with creatine in white (WM) and grey matter as markers of astrogliosis, neuroaxonal integrity and glutamatergic neurotoxicity. Patients showed decreased global and local efficiency, and increased assortativity (p, Highlights • The pathogenic mechanisms underlying structural network disruption in MS are unknown. • The microstructural damage of the white matter contributes to network impairment. • The worsening of global efficiency is associated with markers of neuroaxonal burden. • Local efficiency impairment is related to MR measures of demyelination. • The described network modifications contribute to cognitive dysfunction.

Aim To evaluate the reliability of synthetic magnetic resonance imaging (SyMRI) for detecting complications associated with subarachnoid haemorrhage (SAH), such as ischaemic lesions, hydrocephalus, or bleeding complications. Materials and methods Twenty patients with SAH, who underwent a conventional brain MRI and a SyMRI on a 3 T MRI machine. Comparable conventional and synthetic T2-weighted fluid attenuated inversion recovery (FLAIR) images were acquired. The presence of ischaemic lesions, hydrocephalus, extra-axial blood collections as well as the volumes of grey matter (GMv), white matter (WMv), and cerebrospinal (CSFv) were compared. The acquisition times of both sequences was also analysed. Results The concordance between the two techniques was excellent for the detection of ischaemic lesions and extra-axial collections (kappa = 0.80 and 0.88 respectively) and good for the detection of hydrocephalus (kappa = 0.69). No significant differences were detected in the number of ischaemic lesions (p=0.31) or in the Evans index (p=0.11). The WMv and CSFv measures were also similar (p=0.18 and p=0.94, respectively), as well as the volume of ischaemic lesions (p=0.79). Compared to conventional MRI, the SyMRI acquisition time was shorter regardless of the number of sections (32% and 6% time reduction for 4 or 3 mm section thickness, respectively). Conclusions SyMRI allows the detection of potential complications of SAH in a similar way to conventional MRI with a shorter acquisition time.

Highlights • Macroscopic and microscopic diffusion properties discriminate between MS lesion types. • The number and volume of lesions with larger diffusion changes are associated with worse clinical outcomes. • Diffusion MRI provides useful information of the pathological heterogeneity in plaques., Diffusion magnetic resonance imaging can reveal quantitative information about the tissue changes in multiple sclerosis. The recently developed multi-compartment spherical mean technique can map different microscopic properties based only on local diffusion signals, and it may provide specific information on the underlying microstructural modifications that arise in multiple sclerosis. Given that the lesions in multiple sclerosis may reflect different degrees of damage, we hypothesized that quantitative diffusion maps may help characterize the severity of lesions “in vivo” and correlate these to an individual’s clinical profile. We evaluated this in a cohort of 59 multiple sclerosis patients (62% female, mean age 44.7 years), for whom demographic and disease information was obtained, and who underwent a comprehensive physical and cognitive evaluation. The magnetic resonance imaging protocol included conventional sequences to define focal lesions, and multi-shell diffusion imaging was used with b-values of 1000, 2000 and 3000 s/mm2 in 180 encoding directions. Quantitative diffusion properties on a macro- and micro-scale were used to discriminate distinct types of lesions through a k-means clustering algorithm, and the number and volume of those lesion types were correlated with parameters of the disease. The combination of diffusion tensor imaging metrics (fractional anisotropy and radial diffusivity) and multi-compartment spherical mean technique values (microscopic fractional anisotropy and intra-neurite volume fraction) differentiated two type of lesions, with a prediction strength of 0.931. The B-type lesions had larger diffusion changes compared to the A-type lesions, irrespective of their location (P

BACKGROUND: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. METHODS: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients =4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. FINDINGS: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p

Analysis of the structural connectomes can lead to powerful insights about the brain's organization and damage. However, the accuracy and reproducibility of constructing the structural connectome done with different acquisition and reconstruction techniques is not well defined. In this work, we evaluated the reproducibility of the structural connectome techniques by performing test-retest (same day) and longitudinal studies (after 1 month) as well as analyzing graph-based measures on the data acquired from 22 healthy volunteers (6 subjects were used for the longitudinal study). We compared connectivity matrices and tract reconstructions obtained with the most typical acquisition schemes used in clinical application: diffusion tensor imaging (DTI), high angular resolution diffusion imaging (HARDI), and diffusion spectrum imaging (DSI). We observed that all techniques showed high reproducibility in the test-retest analysis (correlation >.9). However, HARDI was the only technique with low variability (2%) in the longitudinal assessment (1-month interval). The intraclass coefficient analysis showed the highest reproducibility for the DTI connectome, however, with more sparse connections than HARDI and DSI. Qualitative (neuroanatomical) assessment of selected tracts confirmed the quantitative results showing that HARDI managed to detect most of the analyzed fiber groups and fanning fibers. In conclusion, we found that HARDI acquisition showed the most balanced trade-off between high reproducibility of the connectome, higher rate of path detection and of fanning fibers, and intermediate acquisition times (10-15 minutes), although at the cost of higher appearance of aberrant fibers.

Objective To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans-synaptic degeneration in multiple sclerosis (MS). Methods We performed a longitudinal evaluation on a cohort of 100 patients with MS, acquiring retinal optical coherence tomography to measure anterior visual pathway damage (peripapillary retinal nerve fiber layer [RNFL] thickness and macular volume) and 3T brain magnetic resonance imaging (MRI) for posterior visual pathway damage (volumetry and spectroscopy of visual cortex, lesion volume within optic radiations) at inclusion and after 1 year. Freesurfer and SPM8 software was used for MRI analysis. We evaluated the relationships between the damage in the anterior and posterior visual pathway by voxel-based morphometry (VBM), multiple linear regressions, and general linear models. Results VBM analysis showed that RNFL thinning was specifically associated with atrophy of the visual cortex and with lesions in optic radiations at study inclusion (p < 0.05). Visual cortex volume (β = +0.601, 95% confidence interval [CI] = +0.04 to +1.16), N-acetyl aspartate in visual cortex (β = +1.075, 95% CI = +0.190 to +1.961), and lesion volume within optic radiations (β = −2.551, 95% CI = −3.910 to −1.192) significantly influenced average RNFL thinning at study inclusion independently of other confounders, especially optic neuritis (ON). The model indicates that a decrease of 1cm3 in visual cortex volume predicts a reduction of 0.6μm in RNFL thickness. This association was also observed after 1 year of follow-up. Patients with severe prior ON (adjusted difference = −3.01, 95% CI = −5.08 to −0.95) and mild prior ON (adjusted difference = −1.03, 95% CI = −3.02 to +0.95) had a lower adjusted mean visual cortex volume than patients without ON. Interpretation Our results suggest the presence of trans-synaptic degeneration as a contributor to chronic axon damage in MS. ANN NEUROL 2014;75:98–107

IMPORTANCE: Before using brain volume loss (BVL) as a marker of therapeutic response in multiple sclerosis (MS), certain biological and methodological issues must be clarified. OBJECTIVES: To assess the dynamics of BVL as MS progresses and to evaluate the repeatability and exchangeability of BVL estimates with Jacobian Integration (JI) and Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) (specifically, the Structural Image Evaluation, Using Normalisation, of Atrophy–Cross-Sectional [SIENA-X] tool or FMRIB’s Integrated Registration and Segmentation Tool [FIRST]). DESIGN, SETTING, AND PARTICIPANTS: A cohort of patients who had either clinically isolated syndrome or MS was enrolled from February 2011 through October 2015. All underwent a series of annual magnetic resonance imaging (MRI) scans. Images from 2 cohorts of healthy volunteers were used to evaluate short-term repeatability of the MRI measurements (n = 34) and annual BVL (n = 20). Data analysis occurred from January to May 2017. MAIN OUTCOMES AND MEASURES: The goodness of fit of different models to the dynamics of BVL throughout the MS disease course was assessed. The short-term test-retest error was used as a measure of JI and FSL repeatability. The correlations (R(2)) of the changes quantified in the brain using JI and FSL, together with the accuracy of the annual BVL cutoffs to discriminate patients with MS from healthy volunteers, were used to measure compatibility of imaging methods. RESULTS: A total of 140 patients with clinically isolated syndrome or MS were enrolled, including 95 women (67.9%); the group had a median (interquartile range) age of 40.7 (33.6-48.1) years. Patients underwent 4 MRI scans with a median (interquartile range) interscan period of 364 (351-379) days. The 34 healthy volunteers (of whom 18 [53%] were women; median [IQR] age, 33.5 [26.2-42.5] years) and 20 healthy volunteers (of whom 10 [50%] were women; median [IQR] age, 33.0 [28.7-39.2] years) underwent 2 MRI scans within a median (IQR) of 24.5 (0.0-74.5) days and 384.5 (366.3-407.8) days for the short-term and long-term MRI follow-up, respectively. The BVL rates were higher in the first 5 years after MS onset (R(2) = 0.65 for whole-brain volume change and R(2) = 0.52 for gray matter volume change) with a direct association with steroids (β = 0.280; P = .02) and an inverse association with age at MS onset, particularly in the first 5 years (β = 0.015; P = .047). The reproducibility of FSL (SIENA) and JI was similar for whole-brain volume loss, while JI gave more precise, less biased estimates for specific brain regions than FSL (SIENA-X and FIRST). The correlation between whole-brain volume loss using JI and FSL was high (R(2) = 0.92), but the same correlations were poor for specific brain regions. The area under curve of the whole-brain volume change to discriminate between patients with MS and healthy volunteers was similar, although the thresholds and accuracy index were distinct for JI and FSL. CONCLUSIONS AND RELEVANCE: The proposed BVL threshold of less than 0.4% per year as a marker of therapeutic efficiency should be reconsidered because of the different dynamics of BVL as MS progresses and because of the limited reproducibility and variability of estimates using different imaging methods.

The optic radiation (OR) is one of the major components of the visual system and a key structure at risk in white matter diseases such as multiple sclerosis (MS). However, it is challenging to perform track reconstruction of the OR using diffusion MRI due to a sharp change of direction in the Meyer's loop and the presence of kissing and crossing fibers along the pathway. As such, we aimed to provide a highly precise and reproducible framework for tracking the OR from thalamic and visual cortex masks. The framework combined the generation of probabilistic streamlines by high order fiber orientation distributions estimated with constrained spherical deconvolution and an automatic post-processing based on anatomical exclusion criteria (AEC) to compensate for the presence of anatomically implausible streamlines. Specifically, those ending in the contralateral hemisphere, cerebrospinal fluid or grey matter outside the visual cortex were automatically excluded. We applied the framework to two distinct high angular resolution diffusion-weighted imaging (HARDI) acquisition protocols on one cohort, comprised of ten healthy volunteers and five MS patients. The OR was successfully delineated in both HARDI acquisitions in the healthy volunteers and MS patients. Quantitative evaluation of the OR position was done by comparing the results with histological reference data. Compared with histological mask, the OR reconstruction into a template (OR-TCT) was highly precise (percentage of voxels within the OR-TCT correctly defined as OR), ranging from 0.71 to 0.83. The sensitivity (percentage of voxels in histological reference mask correctly defined as OR in OR-TCT) ranged from 0.65 to 0.81 and the accuracy (measured by F1 score) was 0.73 to 0.77 in healthy volunteers. When AEC was not applied the precision and accuracy decreased. The absolute agreement between both HARDI datasets measured by the intraclass correlation coefficient was 0.73. This improved framework allowed us to reconstruct the OR with high reliability and accuracy independently of the acquisition parameters. Moreover, the reconstruction was possible even in the presence of tissue damage due to MS. This framework could also be applied to other tracts with complex configuration.

OBJECTIVE: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study. METHODS: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×10(6) bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects. RESULTS: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients. CONCLUSION: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266.

Background: Colour vision assessment correlates with damage of the visual pathway and might be informative of overall brain damage in multiple sclerosis (MS). Objective: The objective of this paper is to investigate the association between impaired colour vision and disease severity. Methods: We performed neurological and ophthalmic examinations, as well as magnetic resonance imaging (MRI) and optical coherence tomography (OCT) analyses, on 108 MS patients, both at baseline and after a follow-up of one year. Colour vision was evaluated by Hardy, Rand and Rittler plates. Dyschromatopsia was defined if colour vision was impaired in either eye, except for participants with optic neuritis (ON), for whom only the unaffected eye was considered. We used general linear models adjusted for sex, age, disease duration and MS treatment for comparing presence of dyschromatopsia and disease severity. Results: Impaired colour vision in non-ON eyes was detected in 21 out of 108 patients at baseline. At baseline, patients with dyschromatopsia had lower Multiple Sclerosis Functional Composite (MSFC) scores and Brief Repeatable Battery-Neuropsychology executive function scores than those participants with normal colour vision. In addition, these patients had thinner retinal nerve fiber layer (RNFL), and smaller macular volume, normalized brain volume and normalized gray matter volume (NGMV) at baseline. Moreover, participants with incident dyschromatopsia after one-year follow-up had a greater disability measured by the Expanded Disability Status Scale and MSFC-20 and a greater decrease in NGMV than participants with normal colour vision. Conclusions: Colour vision impairment is associated with greater MS severity.

Objectives: To assess the association of primary retinal inflammation, namely retinal periphlebitis (RP) and microcystic macular edema, with clinical, brain, and retinal imaging biomarkers of multiple sclerosis (MS) severity. Methods: One hundred patients with MS underwent a neurologic and ophthalmic examination, MRI, and optical coherence tomography. Disability was assessed using the Expanded Disability Status Scale at baseline and after a 1-year follow-up. The normalized brain volume, the normal-appearing gray matter volume, and T1 lesion volume were assessed at baseline as radiologic biomarkers of disease severity. Retinal nerve fiber layer thickness and macular volume at baseline were used as surrogate markers of axonal damage. We used general linear models adjusted for sex, age, disease duration, and MS treatment to compared adjusted means of these parameters among patients with RP and patients without primary retinal inflammation. Results: Five patients showed RP, 2 showed microcystic macular edema, and the retina was normal in the remaining 93. Patients with RP had a tendency toward a higher adjusted-mean Expanded Disability Status Scale score at baseline and disability progression after a 1-year follow-up compared with patients without primary retinal inflammation. These patients also had a higher adjusted-mean T1 lesion volume (adjusted differences: 10.4, 95% confidence interval [CI]: 0.6 to 20.2; p = 0.038) and lower T1 brain volume (adjusted differences: −68, 95% CI: −139 to 2; p = 0.059). Patients with RP had a lower adjusted-mean retinal nerve fiber layer thickness (adjusted differences: −13.4, 95% CI: −24.4 to −2.3; p = 0.018) and a trend toward lower macular volume. Conclusions: These results support the role of RP as a biomarker of MS severity.

s of Oral Presentations / Clinical Neurophysiology 125, Supplement 1 (2014) S1–S339 S41 catheters were placed at T3, T6, T11 and L1. The spinal cord was severed at the T8 level. At the T12-T13 and at the T4-T5 level, progressive compression of the spinal cord was performed with a precise compression device using a pair of parallel sticks sequentially shortening their distances 0.5 mm every 2 minutes. Cord-to-cord evoked potentials (EP), D-wave and epidural somatosensory evoked potentials (SEPs) were obtained with each mean of compression. Results: In all the cases cord-to-cord EPs were obtained, in both cranial and caudal segments. Spinal cord compression causes the loss of the cordto-cord EP with a 5mm compression cranial to the lesion, and with a3 mm compression caudal to the lesion. D-wave was capable of detecting injuries above the acute lesion, while epidural SEPs detected the injuries below the lesion. Conclusion: It is possible to perform IOM using appropriate electrophysiologic techniques in patients with acute spinal cord injuries, both above and below the lesion. The spinal cord segments caudal to the lesion are more sensitive to new injuries than those cranial to the lesion. Pathophysiology and genetics of mirror movements O40 Interand intrahemispheric inhibition and their role in mirror movements pathophysiology A. Kulaga, M. Ostrowska, A. Szczudlik University Hospital, Neurology, Cracow, Poland Question: Mirror movements (MM) are unintendend and unaware movements of the limb, which remains at rest, during performing intentional movements with the contralateral one. The fibers running through corpus callosum play an important role in inhibition of contralateral hemisphere during performing unilateral motor tasks. MM occur with higher frequency in patients with pathology of corpus callosum. The aim of this study was to determinate the role of corpus callosum in MM’s generation in patients with central nervous system disorders with involment of pyramidal tract. Methods: Clinical evaluation of MM was performed in patients with motor neuron disease (n=36), multiple sclerosis (n=25), acute ischemic stroke (n=17) and control group (n=31). Then all the studied groups were subjected to transcranial magnetic stimulation (TMS) in order to assess the excitatory and inhibitory functions of motor cortex. Results: The frequency of MM was higher in patients with multiple sclerosis, patients with motor neuron disease and in stroke patients (in limbs without paresis), compared to control group. The duration of ipsilateral silent period (iSP), which reflects the function of corpus callosum, was significantly shorter in patients with motor neuron disease and in damaged hemisphere in stroke patients compared to control group. The lack of iSP in one hemisphere in all patient groups occurred in conjunction with shorter duration of contralateral silent period (cSP), which reflects the intrahemispheric inhibition. Conclusion: The fibers of corpus callosum play an important, but probably not exclusive role in MM’s pathophysiology. An additional shortening of intrahemispheric inhibition contralateral to pathological interhemispheric inhibition may facilitate MM occurance. O41 Mirror movements in multiple sclerosis C. Cabib1, S. Llufriu2, E. Martinez-Heras2, A. Saiz2, J. Valls-Sole3 1Clinic Hospital of Barcelona, EMG Unit, Barcelona, Spain; 2Clinic Hospital of Barcelona and Centre d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Center for Neuroinmunology, Neurology Service., Barcelona, Spain; 3Clinic Hospital of Barcelona, EMG Unit, Department of Neurology, Barcelona

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. FINDINGS: The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway. DISCUSSION: The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients.