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Measures of atrophy in the whole brain can be used to reliably assess treatment effect in clinical trials of patients with multiple sclerosis (MS). Trials assessing the effect of treatment on grey matter (GM) and white matter (WM) atrophy are very informative, but hindered by technical limitations. This study aimed to measure GM and WM volume changes, using a robust longitudinal method, in patients with relapsing MS randomized to cladribine tablets 3.5 mg/kg or placebo in the CLARITY study.We analysed T1-weighted magnetic resonance sequences using SIENA-XL, from 0 to 6 months (cladribine, n = 267; placebo, n = 265) and 6 to 24 months (cladribine, n = 184; placebo, n = 186). Mean percentage GM and WM volume changes (PGMVC and PWMVC) were compared using a mixed-effect model.More GM and WM volume loss was found in patients taking cladribine versus those taking placebo in the first 6 months of treatment (PGMVC: cladribine: -0.53 vs. placebo: -0.25 [p = 0.045]; PWMVC: cladribine: -0.49 vs. placebo: -0.34 [p = 0.137]), probably due to pseudoatrophy. However, over the period 6 to 24 months, GM volume loss was significantly lower in patients on cladribine than in those on placebo (PGMVC: cladribine: -0.90 vs. placebo: -1.27 [p = 0.026]). In this period, volume changes in WM were similar in the two treatment arms (p = 0.52).After a short period of pseudoatrophy, treatment with cladribine 3.5 mg/kg significantly reduced GM atrophy in comparison with placebo. This supports the relevance of GM damage in MS and may have important implications for physical and cognitive disability progression.

Objective To assess the dynamics of “pseudo‐atrophy,” the accelerated brain volume loss observed after initiation of anti‐inflammatory therapies, in patients with multiple sclerosis (MS). Methods Monthly magnetic resonance imaging (MRI) data of patients from the IMPROVE clinical study (NCT00441103) comparing relapsing‐remitting MS patients treated with interferon beta‐1a (IFNβ‐1a) for 40 weeks versus those receiving placebo (16 weeks) and then IFNβ‐1a (24 weeks) were used to assess percentage of gray (PGMVC) and white matter (PWMVC) volume changes. Comparisons of PGMVC and PWMVC slopes were performed with a mixed effect linear model. In the IFNβ‐1a‐treated arm, a quadratic term was included in the model to evaluate the plateauing effect over 40 weeks. Results Up to week 16, PGMVC was −0.14% per month in the placebo and −0.27% per month in treated patients (P

Important work has been done to measure legislative effectiveness in the U.S. Congress and to explain the individual characteristics that drive it. Much less attention, however, has been devoted to study the extent to which legislative effectiveness depends on the legislators' social connections. We address this issue with a new model of legislative effectiveness that formalizes the role of social connections, and we test its predictions using the network of cosponsorship links in the 109th–113th Congresses. We propose a new empirical strategy that addresses network endogeneity by implementing a two‐step Heckman correction based on an original instrument: the legislators' alumni connections. We find that social connections are a significant determinant of legislative effectiveness. We also study the influence of legislators' characteristics in shaping the network effects. In doing so, we provide new insights into how social connectedness interacts with factors such as seniority, partisanship, and legislative leadership in determining legislators' effectiveness.

In this article, SIENA-XL, a new segmentation-based longitudinal pipeline is introduced, for: (i) increasing the precision of longitudinal volume change estimation for white (WM) and gray (GM) matter separately, compared with cross-sectional segmentation methods such as SIENAX; and (ii) avoiding potential biases in registration-based methods when Jacobians are used, with a smoothing extent larger than spatial scale between tissue-interfaces, which is where atrophy usually occurs. SIENA-XL implements a new brain extraction procedure and a multi-time-point intensity equalization step before performing the final segmentation that also includes separate segmentation of deep GM structures by using FMRIB's Integrated Registration and Segmentation Tool. The detection of GM and WM volume changes with SIENA-XL was evaluated using different healthy control (HC) and multiple sclerosis (MS) MRI datasets and compared with the traditional SIENAX and two Jacobian-based approaches, SPM12 and SIENAX-JI (a version of SIENAX including Jacobian integration - JI). In scan-rescan data from HCs, SIENA-XL showed: (i) a significant decrease in error, of 50-70% when compared with SIENAX; (ii) no significant differences in error when compared with SIENAX-JI and SPM12 in a scan-rescan HC dataset that included repositioning. When tested in a HC dataset with scan-rescan both at baseline and after 1 year of follow-up, SIENA-XL showed: (i) significantly higher precision (P < 0.01) than SIENAX; (ii) no significant differences to SIENAX-JI and SPM12. Finally, in a dataset of 79 MS patients with a 2 years follow-up, SIENA-XL showed a substantial reduction of sample size, by comparison with SIENAX, SIENAX-JI, and SPM12, for detecting treatment effects of 25, 30, and 50%. Hum Brain Mapp 39:1063-1077, 2018. © 2017 Wiley Periodicals, Inc.

Key points A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders. Abstract It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

Background Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS. Methods Patients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11C]PiB and magnetic resonance imaging. Voxel-wise maps of [11C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination. Results At baseline, there was a progressive reduction in [11C]PiB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta-coefficient = –0.67 with the Expanded Disability Status Scale; p = 0.003 and beta-coefficient = –0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index. Interpretation [11C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726–738

Purpose To propose and evaluate a new automated method for the identification of new/enlarging multiple sclerosis (MS) lesions on subtracted images (SI). The subtraction of serially acquired images has shown great potential in assessing new/enlarging brain magnetic resonance imaging (MRI) lesions in MS patients. However, this approach relies on the manual definition of lesions, which is labor-intensive and subject to operator-dependent variability. Materials and Methods An overestimated mask of candidate SI lesions was created and then these hyperintense voxel clusters were filtered using specific constraints for extent, shape, and intensity. The method was tested on normal and pathological MRI datasets. Results The automated method did not detect hyperintense voxels on SI of healthy controls. SI lesions were identified manually and automatically in a multicenter MS dataset of 19 patients with paired MRI over 36 weeks. Sensitivity of the method was high (0.91) and in agreement with the results of manually defined SI lesions (Cohen's k = 0.82, 95% confidence interval [CI]: 0.77–0.87). On a second multicenter MS dataset of 103 patients with paired MRI over 76 weeks, the number of SI lesions detected automatically correlated with the number of gadolinium-enhancing lesions (r = 0.74). Conclusion The proposed method is robust, accurate, and sensitive and may be used with confidence in Phase II MS trials. J. Magn. Reson. Imaging 2014;39:1543–1549. © 2013 Wiley Periodicals, Inc.