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Background: Working memory (WM) deficits are common in multiple sclerosis (MS) patients. Computerized cognitive training may enhance WM capabilities but its efficacy in MS patients has not been sufficiently explored. Methods: This study examines the effects of n-back training on cognitive performance and functional connectivity (FC) in 29 MS patients and 29 healthy controls (HC). Baseline (S1) performance on 2- and 3-back tasks and FC within the fronto-parietal network were assessed before randomly splitting the sample into four subgroups: trained MS (MSt, n = 15), trained HC (HCt, n = 14), untrained MS (MSu, n = 14), and untrained HC (HCu, n = 15). The trained subgroups underwent adaptive n-back training (60 min/day; 4 days) and n-back task performance and FC were reassessed in a second session (S2). Results: As revealed by mixed two-way ANOVAs, trained participants (MSt and HCt) exhibited a significant increase in the number of correct responses and significantly reduced reaction times in S2. These performance improvements were accompanied by an increase in FC in the fronto-parietal pathways and statistically significant correlations between both effects were found. Conclusions: Computerised WM training results in behavioural and neuroplasticity positive effects that may be useful when trying to prevent or attenuate cognitive decline in MS patients.

The present study aimed to investigate altered grey matter (GM) and functional connectivity (FC) in deep subcortical areas, like the thalamus and basal ganglia, and their relationship with cognitive impairment in multiple sclerosis (MS). Thirty-six patients were neuropsychologically assessed, classified as cognitive preserved (CP) and cognitive impairment (CI), and were compared with 18 healthy controls (HC). GM atrophy and FC were observed in 10 predefined functional areas of the thalamus and in six of basal ganglia. GM atrophy was prominent in the basal ganglia in CI patients compared to CP MS patients. Increased FC was observed between the right caudate and the bilateral orbitofrontal cortex in CI vs. CP patients. The discriminant and correlation analyses revealed that the enhanced FC observed between the right caudate and the orbitofrontal cortex was closely associated with cognitive impairment in MS patients. In conclusion, reduced GM volume and enhanced fronto-basal ganglia connectivity are related to cognition in MS patients.

Background/Objective. To explore the effectiveness of a specific working memory (WM) training program in MS patients and healthy controls (HC). Method. 29 MS patients and 29 matched HC were enrolled in the study. MS and HC were randomly split into two groups: nontraining groups (15HC/14 MS) and training groups (14 HC/15 MS). Training groups underwent adaptive n-back training (60 min/day; 4 days). Functional magnetic resonance imaging (fMRI) was used to monitor brain activity during n-back performance (conditions: 0-back, 2-back, and 3-back) at 3 time points: (1) baseline, (2) post-training (+7days), and (3) follow-up (+35days). Results. In post-training and follow-up fMRI sessions, trained groups (HC and MS patients) exhibited significant reaction time (RT) reductions and increases in Correct Responses (CRs) during 2-back and 3-back performance. This improvement of task performance was accompanied by a decrease in brain activation in the WM frontoparietal network. The two effects were significantly correlated. Conclusions. After WM training, both cognitively preserved MS patients and HC participants showed task performance improvement made possible by neuroplastic processes that enhanced neural efficiency.

Background and purpose: We explored the relationship between gray matter atrophy and reorganization of functional connectivity in multiple sclerosis patients during execution of the Paced Auditory Serial Addition Test (PASAT). Materials and methods: Seventeen patients and 15 healthy controls were selected for the study. Atrophy was determined using voxel-based morphometry, and atrophy-related connectivity changes were assessed using psychophysiological interaction analysis. Group differences, and correlations with PASAT performance and radiological variables were also examined. Results: Gray matter atrophy in MS patients was circumscribed to the bilateral posterior cingulate gyrus/precuneus. Compared with controls, patients showed stronger connectivity between the left posterior cingulate gyrus/precuneus, and the left middle temporal gyrus and left cerebellum. A regression analysis in controls showed a negative correlation between PASAT scores and functional connectivity between: (1) the left posterior cingulate gyrus/precuneus, and left pre/postcentral gyri and left occipital gyrus, and (2) the right posterior cingulate gyrus/precuneus, and bilateral cerebellum and left pre/postcentral gyri. Patients showed a negative correlation between brain parenchymal fraction and functional connectivity between the left posterior cingulate gyrus/precuneus and left cerebellum. Conclusion: Patients with early MS and little brain damage presented more connectivity during PASAT execution, which may be interpreted as compensatory processes that help preserve cognitive functions. This work was supported by the Brainglot project of the CONSOLIDER-INGENIO 2010 Program (grant number CSD2007-00012), a grant from MINECO (PSI2010-20168), a grant from Universitat Jaume I (P1 · 1B2011-09), and an edu- cational grant from Biogen Idec to CA.

Background and aims Minimal hepatic encephalopathy (MHE) is associated with cognitive alterations and changes in connectivity. We assessed the relationship of the abnormalities of resting-state functional connectivity (rs-FC) and gray matter (GM) volume with different cognitive alterations and biochemical parameters associated to MHE. Methods Thirty-nine cirrhotic patients (26 without and 13 with MHE) and 24 controls were widely cognitive assessed with a battery of psychometric tests. Atrophy was determined using Voxel-Based Morphometry and rs-FC was assessed by independent component analysis. Receiver operating characteristic (ROC) curves was performed to assess the diagnostic utility of rs-FC and GM reduction for the discrimination of patients with and without MHE. Blood ammonia, cGMP, and levels of pro-inflammatory interleukins were measured. Results MHE patients showed significant decrease of GM volume and lesser degree of rs-FC in different networks related to attention and executive functions as compared to controls and patients without MHE. There is a progressive reduction in rs-FC in the default mode network with the progression of cognitive impairment. MHE patients showed GM reduction in theright frontal lobe, right insula and right cerebellum compared to patients without MHE. Alterations in GM volume and rs-FC correlated with the scores of different cognitive tests. Conclusions Decreased cognitive performance is associated by reduced rs-FC and GM atrophy in MHE patients. These changes could have predictive value for detecting MHE.

Objective To evaluate the utility of an oral fMRI-adapted version of the Symbol Digit Modalities Test (SDMT) to assess information processing speed (IPS) using three different interstimulus intervals (ISI). Methods Nineteen right-handed healthy controls performed the adapted version of the SDMT, consisting of a block design that had a total of 6 control/activation block pairs with 3 different ISIs (1.5, 2 and 2.5 s) presented in two different runs: in ascending and descending orders. The brain activation patterns during different ISIs were assessed by effective functional connectivity analysis based on independent component analysis. Results As expected, all conditions yielded activations in the fronto-parietal networks (FPNs) related to attention processes. Shorter ISIs (1.5 and 2 s) not only yielded greater patterns of connectivity within fronto-parietal and occipital regions such as the FPN and fronto-occipital network (FON), but also recruited more functional networks overall. Task performance at the shortest ISI was negatively correlated with connectivity at the FPN and activity of the pre-supplementary motor area extending to the cingulate gyrus. Conclusion Increasing IPS demands due to shorter ISIs resulted in an increased level and number of functional networks required, increased connectivity within the FPN and FON, and enhancement of the prefrontal cortex. IPS does not arise from activity of a single b area but from affective information transfer among distant cortical regions of the frontal and parietal cortices. This adapted version of the SDMT may be useful for studying alterations of IPS in clinical and nonclinical populations.

Evidence suggests that sex/gender is an important factor for understanding multiple sclerosis (MS) and that some of its neuropathological consequences might manifest earlier in males. In the present study, we assessed gray matter (GM) volume and functional connectivity (FC) in a sample of female and male MS patients (MSp) and female and male healthy controls (HCs). As compared to female MSp, male MSp showed decreased GM volume in the bilateral frontal areas and increased FC between different brain regions. Because both sets of changes correlated significantly and no differences in cognitive performance were observed, we suggest that the FC increase observed in male MSp acts as a compensatory mechanism for their more extensive GM loss and that it promotes a functional convergence between male- and female-MSp. This research has been supported by grant P1-1B2014-15 provided to Cristina Forn by the Universitat Jaume I.

Background: Reduced information-processing speed (IPS) is a primary cognitive deficit of multiple sclerosis (MS) patients. The neural efficiency hypothesis describes an inverse relationship between cognitive performance in a task and the amount of cognitive resources devoted to it. Previous studies have shown that the neural efficiency hypothesis provides an appropriate framework to explore cognitive dysfunction in neurological patients. Objective: The aim of this study was to explore the neural efficiency hypothesis regarding IPS capabilities in cognitively preserved MS patients. Methods: 16 MS patients and 17 healthy controls (HCs) were enrolled and neuropsychologically assessed. All participants also performed a functional magnetic resonance imaging (fMRI)-adapted version of the Symbol Digit Modalities Test (SDMT) at different interstimulus intervals (ISI: 1.5, 2, and 2.5 s). Results: MS patients only displayed lower SDMT performance when the ISI was set at 1.5 s. However, MS patients´ normal SDMT performance at larger ISIs was achieved at the cost of increased brain activation, hence revealing that they were less cognitively efficient than the HCs. Regression analyses confirmed this conclusion by showing an opposite relationship between SDMT performance and the amount of neural resources recruited in the HC and MS groups. Thus, while a positive relationship between both variables was observed in MS patients, this correlation was negative for the HC group. Conclusions: MS patients require more cognitive resources than HCs to achieve a normal SDMT performance, then revealing that they are less efficient regarding IPS capabilities. Fil: Fittipaldi, María Sol. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universitat Jaume I; España Fil: Cruz Gómez, Álvaro Javier. Universitat Jaume I; España Fil: Sanchis Segura, Carla. Universitat Jaume I; España Fil: Belenguer, Antonio. Hospital General de Castellón; España Fil: Ávila, César. Universitat Jaume I; España Fil: Forn, Cristina. Universitat Jaume I; España

La Esclerosis Múltiple (EM) es una enfermedad en la que la memoria de trabajo (MT) se encuentra comúnmente afectada. Estudiar la eficacia de un programa de entrenamiento en MT en pacientes de EM. 29 pacientes de EM Remitente-Recurrente fueron seleccionados para el estudio: 15 realizaron el entrenamiento en MT y 14 fueron seleccionados como grupo control. Todos los participantes fueron valorados a nivel neuropsicológico y se adquirieron imágenes de Resonancia Magnética funcional (RMf) durante la realización de la tarea 2 y 3-back (basal y post tratamiento-7 días). Los pacientes entrenados mejoraron su ejecución en 2 y 3-back (p