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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.

Sex differences in 116 local gray matter volumes (GMVOL) were assessed in 444 males and 444 females without correcting for total intracranial volume (TIV) or after adjusting the data with the scaling, proportions, power-corrected proportions (PCP), and residuals methods. The results confirmed that only the residuals and PCP methods completely eliminate TIV-variation and result in sex-differences that are “small” (∣d∣ $$\approx $$ ≈ 93%) than scaling and proportions adjusted-data $$( \approx $$ ( ≈ 68%) or raw data ($$\approx $$ ≈ 45%). The replicated effects were meta-analyzed together and confirmed that, when TIV-variation is adequately controlled, volumetric sex differences become “small” (∣d∣ VOL features in predicting individuals’ sex with 12 different machine learning classifiers. Sex could be reliably predicted (> 80%) when using raw local GMVOL, but also when using scaling or proportions adjusted-data or TIV as a single predictor. Conversely, after properly controlling TIV variation with the PCP and residuals’ methods, prediction accuracy dropped to $$\approx $$ ≈ 60%. It is concluded that gross morphological differences account for most of the univariate and multivariate sex differences in GMVOL

Background: Previous studies have suggested a relationship between neuroanatomical and neurofunctional hippocampal alterations and episodic memory impairments in multiple sclerosis (MS) patients. Objective: We examined hippocampus volume and functional connectivity (FC) changes in MS patients with different episodic memory capabilities. Methods: Hippocampal subfield volume and FC changes were compared in two subgroups of MS patients with and without episodic memory impairment (multiple sclerosis impaired (MSi) and multiple sclerosis preserved (MSp), respectively) and healthy controls (HC). A discriminant function (DF) analysis was used to identify which of these neuroanatomical and neurofunctional parameters were the most relevant components of the mnemonic profiles of HC, MSp, and MSi. Results: MSi showed reduced volume in several hippocampal subfields compared to MSp and HC. Ordinal gradation (MSi > MSp > HC) was also observed for FC between the posterior hippocampus and several cortical areas. DF-based analyses revealed that reduced right fimbria volume and enhanced FC at the right posterior hippocampus were the main neural signatures of the episodic memory impairments observed in the MSi group. Conclusion: Before any sign of episodic memory alterations (MSp), FC increased on several pathways that connect the hippocampus with cortical areas. These changes further increased when the several hippocampal volumes reduced and memory deficits appeared (MSi).

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.

Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with alterations in attentional and executive networks. There are no studies evaluating the relationship between memory in MHE and structural and functional connectivity (FC) changes in the hippocampal system. This study aimed to evaluate verbal learning and long-term memory in cirrhotic patients with (C-MHE) and without MHE (C-NMHE) and healthy controls. We assessed the relationship between alterations in memory and the structural integrity and FC of the hippocampal system. C-MHE patients showed impairments in learning, long-term memory, and recognition, compared to C-NMHE patients and controls. Cirrhotic patients showed reduced fimbria volume compared to controls. Larger volumes in hippocampus subfields were related to better memory performance in C-NMHE patients and controls. C-MHE patients presented lower FC between the L-presubiculum and L-precuneus than C-NMHE patients. Compared to controls, C-MHE patients had reduced FC between L-presubiculum and subiculum seeds and bilateral precuneus, which correlated with cognitive impairment and memory performance. Alterations in the FC of the hippocampal system could contribute to learning and long-term memory impairments in C-MHE patients. This study demonstrates the association between alterations in learning and long-term memory and structural and FC disturbances in hippocampal structures in cirrhotic patients.

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.

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

Introducción. Una de las alteraciones cognitivas más prevalentes en los pacientes con esclerosis múltiple son los proble- mas de codificación de la información (tanto verbal como visual), proceso relacionado con el hipocampo. Objetivo. Estudiar la relación entre los procesos de aprendizaje y retención de la información a largo plazo con el volumen hipocampal y la conectividad funcional (CF) en pacientes con esclerosis múltiple comparados con un grupo control. Sujetos y métodos. Ambos grupos fueron evaluados con la batería neuropsicológica breve, que incluye pruebas de me- moria verbal y visual. Se realizó el estudio de volumetría de la sustancia gris mediante la técnica de morfometría basada en el vóxel y un estudio de CF de vóxel de semilla centrado en la zona de interés (hipocampo). Se realizaron análisis de asociación entre rendimiento en memoria y cambios volumétricos y de CF. Resultados. Los resultados mostraron atrofia en la sustancia gris en el hipocampo izquierdo y una menor CF entre el hipo- campo izquierdo y el troncoencéfalo, el cerebelo, el giro fusiforme y el giro temporal superior en los pacientes respecto al grupo control. En el grupo de pacientes se observa una correlación positiva entre la sustancia gris en ambos hipocampos y el rendimiento en memoria verbal, así como una correlación positiva entre el rendimiento en memoria visual y la CF entre el hipocampo izquierdo y diversas regiones temporales. Conclusiones. Los resultados muestran una relación entre el rendimiento de memoria verbal y visual, y cambios estructu- rales y funcionales en el hipocampo en pacientes con esclerosis múltiple. Introduction. One of the most prevalent cognitive deficits in multiple sclerosis (MS) patients relates to (both verbal and visual) information encoding, a process related the hippocampus. Aim. To assess the relationship between information learning and long-term retention processes and hippocampal volume and functional connectivity (FC) in MS patients. Subjects and methods. MS patients and a control group of healthy volunteers were assessed using the brief neuro- psychological battery, which includes tests of verbal and visual memory. Gray matter volume was assessed through the voxel based morphometry technique, and a study of seed-based FC focused on the region of interest (hippocampus) was also conducted. Results. Results revealed that, as compared to the control group, MS patients display gray matter atrophy at the left hippocampus gray matter and smaller FC between left hippocampus and brainstem, cerebellum, fusiform gyrus and superior temporal gyrus. Association analyses were performed between memory tests performance and both volumetric and FC changes. Results showed a positive correlation between gray matter hippocampal (bilateral) volume and verbal memory performance of the MS group. Further, in MS patients, a positive correlation between visual memory performance and FC between the left hippocampus and several temporal regions was also found. Conclusions. The results of the present study reveal a relationship between structural and functional changes in the hippocampus of MS patients and their performance on verbal and visual memory tests. Subvención concedida por la Universitat Jaume I (P1.1B2014-05).