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Background: Malfunctioning of the default mode network (DMN) has been consistently related to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, evidence on differences in this network between MCI converters (MCI-c) and non-converters (MCI-nc), which could mark progression to AD, is still inconsistent. Objective: To multimodally investigate the DMN in the AD continuum. Methods: We measured gray matter (GM) volume, white matter (WM) integrity, and functional connectivity (FC) at rest in healthy elderly controls, MCI-c, MCI-nc, and AD patients, matched on sociodemographic variables. Results: Significant differences between AD patients and controls were found in the structure of most of the regions of the DMN. MCI-c only differed from MCI-nc in GM volume of the left parahippocampus and bilateral hippocampi and middle frontal gyri, as well as in WM integrity of the parahippocampal cingulum connecting the left hippocampus and precuneus. We found significant correlations between integrity in some of those regions and global neuropsychological status, as well as an excellent discrimination ability between converters and non-converters for the sum of GM volume of left parahippocampus, bilateral hippocampi, and middle frontal gyri, and WM integrity of left parahippocampal cingulum. However, we found no significant differences in FC. Conclusion: These results further support the relationship between abnormalities in the DMN and AD, and suggest that structural measures could be more accurate than resting-state estimates as markers of conversion from MCI to AD.

Introducción: Para determinar la malignidad del cáncer de próstata, es necesario un proceso de catalogación de imágenes histológicas de tejido prostático con el que se obtiene el grado de Gleason. Este proceso es llevado a cabo manualmente por patólogos expertos, lo que supone una gran carga de trabajo y un elevado nivel de subjetividad. A raíz de ello surge la necesidad de desarrollar un sistema de clasificación automático. Metodología: Se utilizó una arquitectura de red neuronal convolucional VGG16 para desarrollar un modelo que permitiera realizar la clasificación de las imágenes. En primer lugar, se utilizaron únicamente las imágenes anotadas por el experto, y posteriormente se añadió la anotación no experta al modelo, combinando la información experta y no experta con el fin de obtener una clasificación más precisa de las imágenes. Resultados: Ambos modelos se evaluaron utilizando el estadístico de kappa de Cohen. Se obtuvo como resultados un valor de 0,571 para el modelo que utilizaba entradas anotadas por el experto, y un valor de 0,685 al combinar estas entradas con las anotadas por el no experto mediante el modelo híbrido. Superando los valores de kappa de Cohen más elevados presentes en la literatura: 0,58. Conclusión: Tras analizar los resultados, se comprueba que la combinación de ambas anotaciones ayuda a mejorar la precisión del método considerablemente. Por ello, se plantea la aplicación de un modelo híbrido como una posible solución para ayudar a reducir la carga de trabajo de patólogos sin que la precisión del sistema se vea excesivamente afectada. Introduction: To determine the malignancy of prostate cancer, a process of cataloging histological samples of prostate tissue is necessary to obtain the Gleason grade. This process is carried out manually by expert pathologists, which involves a heavy workload and a high level of subjectivity. As a result, the need arose to develop an automatic grading system. Methodology: A VGG16 convolutional neural network architecture was used to develop a model for sample classification. First, only the images annotated by the expert were used, and then the non-expert annotation was added to the model, combining the expert and non-expert information in order to obtain a more accurate classification of the samples. Results: Both models were evaluated using Cohen’s kappa statistic. A value of 0.571 was obtained for the model using inputs annotated by the expert, and a value of 0.685 when combining these inputs with those annotated by the non-expert using the hybrid model. Exceeding the highest Cohen’s kappa values present in the literature: 0.58. Conclusion: After analyzing the results, it is found that the combination of both annotations helps to improve the accuracy of the method considerably. Therefore, the application of a hybrid model is proposed as a possible solution to help reduce the workload of pathologists without excessively affecting the accuracy of the system.

The present research used fMRI to longitudinally investigate the impact of learning new vocabulary on the activation pattern of the language control network by measuring BOLD signal changes during picture naming tasks with familiar pre-existing native words (old words) and new vocabulary. Nineteen healthy participants successfully learned new synonyms for already known Spanish words, and they performed a picture naming task using the old words and the new words immediately after learning and two weeks after learning. The results showed that naming with old words, compared to naming with newly learned words, produced activations in a cortical network involving frontal and parietal regions, whereas the opposite contrast showed activation in a broader cortical/subcortical network, including the SMA/ACC, the hippocampus, and the midbrain. These two networks are maintained two weeks after learning. These results suggest that the language control network can be separated into two functional circuits for diverse cognitive purposes.

Individual differences in pitch discrimination have been associated with the volume of both the bilateral Heschl’s gyrus and the right inferior frontal gyrus (IFG). However, most of these studies used samples composed of individuals with different amounts of musical training. Here, we investigated the relationship between pitch discrimination and individual differences in the gray matter (GM) volume of these brain structures in 32 adult musicians, 28 adult non-musicians, and 32 children without musical training. The results showed that (i) the individuals without musical training (whether children or adults) who were better at pitch discrimination had greater volume of auditory regions, whereas (ii) musicians with better pitch discrimination had greater volume of the IFG. These results suggest that the relationship between pitch discrimination and the volume of auditory regions is innately established early in life, and that musical training modulates the volume of the IFG, probably improving audio-motor connectivity. This is the first study to detect a relationship between pitch discrimination ability and GM volume before beginning any musical training in children and adults. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (PSI-2016-78805-R and PID2019-108198GB) to C.Á. Authors M-Á. P-G and A.M-P were supported by a postdoctoral graduate program grant (Jaume I University). Author M.H was supported by Ramón y Cajal Research Program of the Spanish Ministry of Science, Innovation, and Universities (RYC-2016-19477). Authors J.A-V and E.V-R were supported by a predoctoral graduate program grant (National FPU). Author V.C was supported by a postdoctoral grant (Juan de la Cierva).

This is a pre-print of an article published inBrain Structure and Function. The final authenticated version is available online at: https://doi.org/10.1007/s00429-019-02008-2 Brain functional connectivity is supposed to capture personal and lifetime learning experiences and contribute to generating individual differences in cognitive abilities. We tested this possibility using the visual search task as a measure of visual information processing and the functioning of the visual attention control system. Forty-two undergraduate students completed a functional MRI study with a resting-state session and a visual search task scan. The visual attention and control systems were studied by investigating the functional connectivity of the primary visual area, the posterior parietal cortex, the dorsolateral prefrontal cortex, and the dorsal anterior cingulate cortex because these areas have been closely related to the visual search task. A pairwise resting-state functional connectivity analysis was conducted between these regions, followed by a correlation analysis with the behavioral measures from the visual search task. Results showed that higher connectivity values between the posterior parietal cortex and the dorsal anterior cingulate cortex were positively correlated with faster response speed. The posterior parietal cortex has been related to the formation of priority maps and the integration of sensory and executive information. Inhibitory control, performance monitoring during top–down cognitive tasks, and target detection have been associated with the dorsal anterior cingulate cortex. In light of these results, we suggest that a priori enhanced connectivity between these regions defines individual differences in visual information processing and the ability to adapt to cognitive demands.

Previous investigations have used global graph theory measures in order to disentangle the complexity of the neural reorganizations occurring in cocaine use disorder (CUD). However, how these global topological alterations map into individual brain network areas remains unknown. In this study, we used resting state functional magnetic resonance imaging (fMRI) data to investigate node-level topological dysfunctions in CUD. The sample was composed of 32 individuals with CUD and 32 healthy controls, matched in age, years of education and intellectual functioning. Graph theory measures of optimal connectivity distance, node strength, nodal efficiency and clustering coefficient were estimated in each participant using voxel-wise functional connectivity connectomes. CUD individuals as compared with healthy controls showed higher optimal connectivity distances in ventral striatum, insula, cerebellum, temporal cortex, lateral orbitofrontal cortex, middle frontal cortex and left hippocampus. Furthermore, clinical measures quantifying severity of dependence were positively related with optimal connectivity distances in the right rolandic operculum and the right lateral orbitofrontal cortex, whereas length of abstinence was negatively associated with optimal connectivity distances in the right temporal pole and the left insula. Our results reveal a topological distancing of cognitive and affective related areas in addiction, suggesting an overall reduction in the communication capacity of these regions. Funding for open access charge: CRUE-Universitat Jaume I This research was supported by grant 040/2011 from Spanish National Drug Strategy, Ministerio de Sanidad y Consumo to ABL. JAV was supported by a predoctoral graduate programme grant (National FPU). MPG and AMP were supported by a postdoctoral graduate programme grant (postdoc-UJI). VC was supported by grant PID2019-105077RJ-I00 from Ministerio de Ciencia, Innovación y Universidades.

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.

Structural and functional neuroimaging studies have shown that brain areas associated with fear and anxiety (defensive system areas) are modulated by individual differences in sensitivity to punishment (SP). However, little is known about how SP is related to brain functional connectivity and the factors that modulate this relationship. In this study, we investigated whether a simple methodological manipulation, such as performing a resting state with eyes open or eyes closed, can modulate the manifestation of individual differences in SP. To this end, we performed an exploratory fMRI resting state study in which a group of participants (n = 88) performed a resting state with eyes closed and another group (n = 56) performed a resting state with eyes open. All participants completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Seed-based functional connectivity analyses were performed in the amygdala, hippocampus, and periaqueductal gray (PAG). Our results showed that the relationship between SP and left amygdala-precuneus and left hippocampus-precuneus functional connectivity was modulated by eye state. Moreover, in the eyes open group, SP was negatively related to the functional connectivity between the PAG and amygdala and between the PAG and left hippocampus, and it was positively related to the functional connectivity between the amygdala and hippocampus. Together, our results may suggest underlying differences in the connectivity between anxiety-related areas based on eye state, which in turn would affect the manifestation of individual differences in SP. This work was supported by grants from Generalitat Valenciana (PROMETEO/2017/109) and Ministerio de Economía y Competitividad (PSI2016-78805-R) to C.A. Also, it was supported by a grant from Jaume I University (UJI-B2016-21) to A.B-L. Additionally, this work was supported by a pre-doctoral graduate program grant (National FPU to J.A-V, L.M-M, E.V-R and N.A) and a post-doctoral graduate program grant (Juan de la Cierva to V.C and postdoc-UJI to A.M-P and M-Á.P-G). Author E.B was funded by a post-doctoral grant from the "Generalitat Valenciana (2018 APOSTD)" and the "European Social Fund (Investing in your future)"

Structural and functional neuroimaging studies have shown that brain areas associated with fear and anxiety (defensive system areas) are modulated by individual differences in sensitivity to punishment (SP). However, little is known about how SP is related to brain functional connectivity and the factors that modulate this relationship. In this study, we investigated whether a simple methodological manipulation, such as performing a resting state with eyes open or eyes closed, can modulate the manifestation of individual differences in SP. To this end, we performed an exploratory fMRI resting state study in which a group of participants (n = 88) performed a resting state with eyes closed and another group (n = 56) performed a resting state with eyes open. All participants completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Seed-based functional connectivity analyses were performed in the amygdala, hippocampus, and periaqueductal gray (PAG). Our results showed that the relationship between SP and left amygdala-precuneus and left hippocampus-precuneus functional connectivity was modulated by eye state. Moreover, in the eyes open group, SP was negatively related to the functional connectivity between the PAG and amygdala and between the PAG and left hippocampus, and it was positively related to the functional connectivity between the amygdala and hippocampus. Together, our results may suggest underlying differences in the connectivity between anxiety-related areas based on eye state, which in turn would affect the manifestation of individual differences in SP.

The adhesio interthalamica (AI) is a small midline brain structure that connects the left and right thalamus. According to in vivo data, between 2.3–22.3% of the general population lack the AI, and the question of whether this absence is more prevalent in males than in females is a matter of debate. Despite the existence of these demographic figures, it remains unclear how this distinctive feature affects healthy people, or what specific anatomic profile is related to the presence or absence of the AI. The aim of this study was to investigate whole brain gray matter (GM) volumetric differences depending on the presence or absence of the AI. A total of 240 healthy adult volunteers completed one MRI scanning session. After the AI assessment, the data from 110 participants were included in the final sample, of which 12.9% of the participants (n = 31) presented complete AI absence vs. 32.9% of participants (n = 79) who presented complete AI presence. Then, whole-brain group comparison analysis revealed that the absent AI brain, compared to the present AI brain, was associated with lower GM volume in the premotor cortex, inferior frontal gyrus, and anterior temporal cortex. Interestingly, neuroscience research has linked emotional and cognitive control brain processing to the latter two regions. The importance of these findings lies in providing a neuroanatomical profile for the absent AI brain in healthy human adults.

The large number of behavioral studies testing whether working memory training improves performance on an untrained task have yielded inconclusive results. Moreover, some studies have investigated the possible neural changes during the performance of untrained tasks after training. Here, we studied the transfer from n-back training to the Paced Auditory Serial Addition Test (PASAT), two different tasks that use the central executive system to maintain verbal stimuli. Participants completed fMRI sessions at baseline, immediately after one week of training, and at the five-week follow-up. Although behavioral transfer effects were not obtained, training was associated with decreased activation in the anterior dorsolateral prefrontal cortex (DLPFC; BA 9/46) while performing the PASAT that remained stable five weeks later. Consistent with our hypothesis, the changes in the anterior DLFPC largely overlapped with the n-back task fMRI activations. In conclusion, working memory training improves efficiency in brain areas involved in the trained task that may affect untrained tasks, specifically in brain areas responsible for the same cognitive processes.

Working memory training causes functional adaptations in the brain, which include changes in activation and functional connectivity that remain stable over time. Few studies have investigated gray matter (GM) changes after working memory training, and they have produced heterogeneous results without clarifying the stable effects of training. The present study was designed to test for sustained and transient anatomic changes after only 200 min of working memory training. The voxel-based morphometry technique was used in order to investigate the GM changes produced by a brief single n-back training, immediately and 5 weeks after finishing it. The sample was composed by 59 human participants who underwent MRI scanning and were assigned to either a training group or a passive control group. Results showed sustained GM volume enlargement in the right superior parietal cortex and a transient GM decrease in the right putamen. The brain adaptation in the right superior parietal cortex was stronger in individuals who showed greater improvements in performance. The results provide further evidence that a brief working memory training is able to produce brain plasticity in structures related to the trained task. This work was supported by grants from Universitat Jaume I (P1•1B2013-63) and Ministerio de Economia y Competitividad (PSI2013-47504-R and PSI2016-78805-R). Authors J. Adrián-Ventura, E. Villar-Rodriguez, L. Marin-Marin and N. Aguirre were supported by a pre-doctoral graduate program grant (National FPU to J.A-V, L.M-M, E.V-R and N.A). In addition, this work was supported by a post-doctoral graduate program grant to V. Costumero, M-Á. Palomar-García and A. Miró-Padilla (Juan de la Cierva to V.C and postdoc-UJI to M-Á.P-G and A.M.P). Author E. Bueichekú was funded by a postdoctoral grant from the "Generalitat Valenciana (2018 APOSTD)" and the "European Social Fund (Investing in your future)".

We investigated the neural correlates of accented speech processing (ASP) with an fMRI study that overcame prior limitations in this line of research: we preserved intelligibility by using two regional accents that differ in prosody but only mildly in phonetics (Latin American and Castilian Spanish), and we used independent component analysis to identify brain networks as opposed to isolated regions. ASP engaged a speech perception network composed primarily of structures related with the processing of prosody (cerebellum, putamen, and thalamus). This network also included anterior fronto-temporal areas associated with lexical-semantic processing and a portion of the inferior frontal gyrus linked to executive control. ASP also recruited domain-general executive control networks related with cognitive demands (dorsal attentional and default mode networks) and the processing of salient events (salience network). Finally, the reward network showed a preference for the native accent, presumably revealing people's sense of social belonging.

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.

This is a pre-print of an article published in [ Brain Imaging and Behavior. The final authenticated version is available online at: https://doi.org/10.1007/s11682-018-9993-y Brain plasticity occurs over the course of the human lifetime. Learning and training modify our neuronal synapses and adapt our brain activity, from priming effects in modal areas to higher-order changes in the association cortex. The current state of the art suggests that learning and training effects might induce large-scale brain connectivity changes. Here, we used task-fMRI data and graph-based approaches to study the immediate brain changes in functional connections associated with training on a visual search task, and the individual differences in learning were studied by means of brain-behavior correlations. In a previous work, we found that trained participants improved their response speed on a visual search task by 31%, whereas the control group hardly changed. In the present study, we showed that trained individuals changed regional connections (local links) in cortical areas devoted to the specific visual search processes and to areas that support information integration, and largely modified distributed connections (distant links) linking primary visual areas to specific attentional and cognitive control areas. In addition, we found that the individuals with the most enhanced connectivity in the dorsolateral prefrontal cortex performed the task faster after training. The observed behavioral and brain connectivity findings expand our understanding of large-scale dynamic readjustment of the human brain after learning experiences.

Neurobehavioral effects of cognitive training have become a popular research issue. Specifically, behavioral studies have demonstrated the long-term efficacy of cognitive training of working memory functions, but the neural basis for this training have been studied only at short-term. Using fMRI, we investigate the cerebral changes produced by brief single n-back training immediately and 5 weeks after finishing the training. We used the data from a sample of 52 participants who were assigned to either an experimental condition (training group) or a no-contact control condition. Both groups completed three fMRI sessions with the same n-back task. Behavioral and brain effects were studied, comparing the conditions and sessions in both groups. Our results showed that n-back training improved performance in terms of accuracy and response speed in the trained group compared to the control group. These behavioral changes in trained participants were associated with decreased activation in various brain areas related to working memory, specifically the frontal superior/middle cortex, inferior parietal cortex, anterior cingulate cortex, and middle temporal cortex. Five weeks after training, the behavioral and brain changes remained stable. We conclude that cognitive training was associated with an improvement in behavioral performance and decreased brain activation, suggesting better neural efficiency that persists over time.

There is some evidence that functional connectivity (FC) measures obtained at rest may reflect individual differences in cognitive capabilities. We tested this possibility by using the FAS test as a measure of phonemic fluency. Seed regions of the main brain areas involved in this task were extracted from meta-analysis results (Wagner et al., 2014) and used for pairwise resting-state FC analysis. Ninety-three undergraduates completed the FAS test outside the scanner. A correlation analysis was conducted between the F-A-S scores (behavioral testing) and the pairwise FC pattern of verbal fluency regions of interest. Results showed that the higher FC between the thalamus and the cerebellum, and the lower FCs between the left inferior frontal gyrus and the right insula and between the supplementary motor area and the right insula were associated with better performance on the FAS test. Regression analyses revealed that the first two FCs contributed independently to this better phonemic fluency, reflecting a more general attentional factor (FC between thalamus and cerebellum) and a more specific fluency factor (FC between the left inferior frontal gyrus and the right insula). The results support the Spontaneous Trait Reactivation hypothesis, which explains how resting-state derived measures may reflect individual differences in cognitive abilities. This research was supported by grants from the Spanish Department of Economy and Competitiveness (PSI2013-47504-R); and Jaume I University (P1·1B2013-63). Authors AMP, EB and MAP were supported by Pre-doctoral Graduate Program grants (Jaume I University FPI to AMP; National FPU to EB; and National FPI to MAPG).

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

Spatiotemporal activity that emerges spontaneously “at rest” has been proposed to reflect individual a priori biases in cognitive processing. This research focused on testing neurocognitive models of visual attention by studying the functional connectivity (FC) of the superior parietal lobule (SPL), given its central role in establishing priority maps during visual search tasks. Twenty-three human participants completed a functional magnetic resonance imaging session that featured a resting-state scan, followed by a visual search task based on the alphanumeric category effect. As expected, the behavioral results showed longer reaction times and more errors for the within-category (i.e., searching a target letter among letters) than the between-category search (i.e., searching a target letter among numbers). The within-category condition was related to greater activation of the superior and inferior parietal lobules, occipital cortex, inferior frontal cortex, dorsal anterior cingulate cortex, and the superior colliculus than the between-category search. The resting-state FC analysis of the SPL revealed a broad network that included connections with the inferotemporal cortex, dorsolateral prefrontal cortex, and dorsal frontal areas like the supplementary motor area and frontal eye field. Noteworthy, the regression analysis revealed that the more efficient participants in the visual search showed stronger FC between the SPL and areas of primary visual cortex (V1) related to the search task. We shed some light on how the SPL establishes a priority map of the environment during visual attention tasks and how FC is a valuable tool for assessing individual differences while performing cognitive tasks. This research was supported by grants from the Spanish Department of Economy and Competitiveness (PSI2013-47504-R); and Jaume I University (P1·1B2013-63). Authors E.B., MA.PG and A.MP. were supported by pre-doctoral graduate program grants (National FPU to E.B; National FPI to MA.PG; and Jaume I University FPI to A.MP)