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Previous studies have shown that machine-learning (ML) algorithms can “predict” sex based on brain anatomical/ functional features. The high classification accuracy achieved by ML algorithms is often interpreted as revealing large differences between the brains of males and females and as confirming the existence of “male/female brains”. However, classification and estimation are quite different concepts, and using classification metrics as surrogate estimates of between-group differences results in major statistical and interpretative distortions. The present study illustrates these distortions and provides a novel and detailed assessment of multivariate sex differences in gray matter volume (GMVOL) that does not rely on classification metrics. Moreover, modeling and clustering techniques and analyses of similarities (ANOSIM) were used to identify the brain areas that contribute the most to these multivariate differences, and to empirically assess whether they assemble into two sex-typical profiles. Results revealed that multivariate sex differences in GMVOL: 1) are “large” if not adjusted for total intracranial volume (TIV) variation, but “small” when controlling for this variable; 2) differ in size between individuals and also depends on the ML algorithm used for their calculation 3) do not stem from two sex-typical profiles, and so describing them in terms of “male/female brains” is misleading.

Cognitive Reserve (CR) is considered a protective factor during the aging process. However, although CR is a multifactorial construct, it has been operationalized in a unitary way (years of formal education or IQ). In the present study, a validated measure to categorize CR holistically (Cognitive Reserve Index Questionnaire) was used to evaluate the resting-state functional connectivity in 77 cognitively unimpaired participants aged 50 years and over with high and low CR, and matched brain global atrophy levels. The connectivity of networks linked to attentional (Dorsal Attention Network -DAN-) and executive (Frontal-Parietal Control Network -FPCN-) processes were evaluated by the combination of Independent Component Analysis and seed-based approaches, since these networks have been proposed as candidates to underlie the protective effect of CR in the aging context. Participants with high CR showed an increase of the connectivity in the FPCN and a decrease in the DAN with respect to the low CR group, correlating with neuropsychological scores and supporting that high CR is related to a better neurocognitive preservation during aging This study was supported by grants from the Spanish Government, Ministerio de Ciencia e Innovación (PSI2017-89389-C2-R; PID2020-114521RB-C21/C22); the Galician Government (Xunta de Galicia), Axudas para a Consolidación e Estruturación de Unidades de Investigación Competitivas do Sistema Universitario de Galicia: GRC (GI-1807-USC); Ref: ED431-2017/27; ED431C-2021/04; all with ERDF/FEDER fund SI

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: 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.

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.

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.

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

Objective: The objective of this paper is to explore differences in resting-state functional connectivity between cognitively impaired and preserved multiple sclerosis (MS) patients. Methods: Sixty MS patients and 18 controls were assessed with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). A global Z score of the BRB-N was obtained and allowed us to classify MS patients as cognitively impaired and cognitively preserved ( n = 30 per group). Functional connectivity was assessed by independent component analysis of resting-state networks (RSNs) related to cognition: the default mode network, left and right frontoparietal and salience network. Between-group differences were evaluated and a regression analysis was performed to describe relationships among cognitive status, functional connectivity and radiological variables. Results: Compared to cognitively preserved patients and healthy controls, cognitively impaired patients showed a lesser degree of functional connectivity in all RSNs explored. Cognitively preserved patients presented less connectivity than the control group in the left frontoparietal network. Global Z scores were positively and negatively correlated with brain parenchymal fraction and lesion volume, respectively. Conclusion: Decreased cognitive performance is accompanied by reduced resting state functional connectivity and directly related to brain damage. These results support the use of connectivity as a powerful tool to monitor and predict cognitive impairment in MS patients.