Strengthening of alpha synchronization is a neural correlate of cognitive transfer.

Cognitive training can lead to improvements in both task-specific strategies and general capacities, such as visuo-spatial working memory (VSWM). The latter emerge slowly and linearly throughout training, in contrast to strategy where changes typically occur within the first days of training. Changes in strategy and capacity have not been separated in prior neuroimaging studies. Here, we used a within-participants design with dense temporal sampling to capture the time dynamics of neural mechanisms associated with change in capacity. In four participants, neural activity was recorded with magnetoencephalography on seven occasions over two months of visuo-spatial working memory training. During scanning, the participants performed a trained visuo-spatial working memory task, a transfer task, and a control task. First, we extracted an individual visuo-spatial working memory-load-dependent synchronization network for each participant. Next, we identified linear changes over time in the network, congruent with the temporal dynamics of capacity change. Three out of four participants showed a gradual strengthening of alpha synchronization. Strengthening of the same connections was also found in the transfer task but not in the control task. This suggests that cognitive transfer occurs through slow, gradual strengthening of alpha synchronization between cortical regions that are vital for both the trained task and the transfer task.

Effects of prenatal exposure to maternal diabetes mellitus on deep grey matter structures and attention deficit hyperactivity disorder symptoms in children.

AIM: The neuronal mechanism linking the association between maternal diabetes mellitus (DM) and risk of attention deficit hyperactivity disorder (ADHD) symptoms and working memory deficits in children was investigated. METHODS: A total of 6291 children (52% boys) born beyond 28 weeks of gestation were included and underwent brain magnetic resonance imaging scans at 9-10 years. Subcortical brain volumes were estimated from the T1-weighted images. ADHD symptoms were assessed using factorial analysis of the Child Behaviour Checklist completed by parents/caregivers. Working memory performance was assessed with the NIH Toolbox. RESULTS: Compared to unexposed children, those exposed to DM (n = 422) had smaller (ß = -0.15, p = 0.001) volumes of pooled deep grey matter (GM). Regional analysis revealed smaller volumes of the caudate nucleus, putamen, thalamus and cerebellum but not of hippocampus. They also had altered cortico-striatal white matter projection tracts. DM was not associated with working memory deficits or inattention, but with increased hyperactivity/impulsivity and Sluggish Cognitive Tempo symptoms in boys. This hyperactivity/impulsivity symptom in boys was partially mediated by smaller deep GM volume. CONCLUSION: Exposure to DM during pregnancy leads to altered deep GM development during late childhood in their offspring. This contributed to an increased risk of hyperactivity/impulsivity symptoms in boys.

Cognitive and brain development is independently influenced by socioeconomic status and polygenic scores for educational attainment.

Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational attainment (EduYears-PGS), as well as SES, in a longitudinal study of 551 adolescents to tease apart genetic and environmental associations with brain development and cognition. Subjects received a structural MRI scan at ages 14 and 19. At both time points, they performed three working memory (WM) tasks. SES and EduYears-PGS were correlated (r = 0.27) and had both common and independent associations with brain structure and cognition. Specifically, lower SES was related to less total cortical surface area and lower WM. EduYears-PGS was also related to total cortical surface area, but in addition had a regional association with surface area in the right parietal lobe, a region related to nonverbal cognitive functions, including mathematics, spatial cognition, and WM. SES, but not EduYears-PGS, was related to a change in total cortical surface area from age 14 to 19. This study demonstrates a regional association of EduYears-PGS and the independent prediction of SES with cognitive function and brain development. It suggests that the SES inequalities, in particular parental education, are related to global aspects of cortical development, and exert a persistent influence on brain development during adolescence.

The neuroscience of working memory capacity and training.

Working memory - the ability to maintain and manipulate information over a period of seconds - is a core component of higher cognitive functions. The storage capacity of working memory is limited but can be expanded by training, and evidence of the neural mechanisms underlying this effect is accumulating. Human imaging studies and neurophysiological recordings in non-human primates, together with computational modelling studies, reveal that training increases the activity of prefrontal neurons and the strength of connectivity in the prefrontal cortex and between the prefrontal and parietal cortex. Dopaminergic transmission could have a facilitatory role. These changes more generally inform us of the plasticity of higher cognitive functions.

Inter-Individual Differences in Striatal Connectivity Is Related to Executive Function Through Fronto-Parietal Connectivity.

The striatum has long been associated with cognitive functions, but the mechanisms behind this are still unclear. Here we tested a new hypothesis that the striatum contributes to executive function (EF) by strengthening cortico-cortical connections. Striatal connectivity was evaluated by measuring the resting-state functional connectivity between ventral and dorsal striatum in 570 individuals, aged 3-20 years. Using structural equation modeling, we found that inter-individual differences in striatal connectivity had an indirect effect (via fronto-parietal functional connectivity) and a direct effect on a compound EF measure of working memory, inhibition, and set-shifting/flexibility. The effect of fronto-parietal connectivity on cognition did not depend on age: the influence was as strong in older as younger children. In contrast, striatal connectivity was closely related to changes in cognitive ability during childhood development, suggesting a specific role of the striatum in cognitive plasticity. These results support a new principle for striatal functioning, according to which striatum promotes cognitive development by strengthening of cortico-cortical connectivity.

Working Memory Training in Alcohol Use Disorder: A Randomized Controlled Trial.

BACKGROUND: Alcohol use disorder (AUD) is associated with cognitive deficits such as impaired executive functions, which are hypothesized to contribute to the progression of the disease and worsen treatment outcome. Training of working memory (WM) to improve cognitive functions and thereby reduce alcohol use has been proposed as a novel treatment strategy. METHODS: Patients with AUD (n = 50) who were recruited to an outpatient addiction clinic were randomized to receive 5 weeks of active WM training or control training. Participants had weekly follow-up visits, and all cognitive training sessions were done online at home. Primary outcomes were WM function and change in self-reported heavy drinking. Secondary outcomes were craving, other drinking outcomes, and performance on a range of neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery. RESULTS: The active training group demonstrated a significantly greater improvement in verbal WM compared with the control group. No statistically significant effect of training was found on the primary drinking outcome, but a trend was observed indicating that WM training reduces the number of drinks per drinking occasion. WM training had no statistically significant effect on any of the other neuropsychological tasks. CONCLUSIONS: Cognitive training can improve WM function in individuals with AUD, suggesting that such interventions are feasible to administer in this patient population. The results do not support an effect of WM training on heavy drinking or transfer effects to other cognitive domains. Future studies should evaluate WM training as an adjunct to evidence-based treatments for AUD to assess potential synergistic effects.

Functional differentiation between convergence and non-convergence zones of the striatum in children.

Most cortical areas send projections to the striatum. In some parts of the striatum, the connections converge from several cortical areas. It is unknown whether the convergence and non-convergence zones of the striatum differ functionally. Here, we used diffusion-weighted magnetic resonance imaging and probabilistic fiber tracking to parcellate the striatum based on its connections to dorsolateral prefrontal, parietal and orbitofrontal cortices in two different datasets (children aged 6-7 years and adults). In both samples, quantitative susceptibility mapping (QSM) values were significantly correlated with working memory (WM) in convergence zones, but not in non-convergence zones. In children, this was also true for mean diffusivity, MD. The association of MD to WM specifically in the convergent zone was replicated in the Pediatric Imaging, Neurocognition, and Genetics (PING) dataset for 135 children aged 6-9 years. QSM data was not available in the PING dataset, and the association to QSM still needs to be replicated. These results suggest that connectivity-based segments of the striatum exhibit functionally different characteristics. The association between convergence zones and WM performance might relate to a role in integrating and coordinating activity in different cortical areas.

Timing of White Matter Development Determines Cognitive Abilities at School Entry but Not in Late Adolescence.

The primary aim of this study was to investigate to what degree the age-related white matter development, here called "brain age", is associated with working memory (WM) and numeric abilities in 6-year-old children. We measured white matter development using diffusion tensor imaging to calculate fractional anisotropy (FA). A "brain age" model was created using multivariate statistics, which described association between FA and age in a sample of 6- to 20-year-old children. This age model was then applied to predict "brain age" in a second sample of 6-year-old children. The predicted brain age correlated with WM performance and numerical ability (NA) (P < 0.01, P < 0.05) in the 6-year-old children. More than 50% of the stable variance in WM performance was explained. We found that in children older than 13 years of age, this association between brain age and WM was no longer significant (P > 0.5). The results bear theoretical implications as they suggest that the variability in individual developmental timing strongly affects WM and NA at school start but badly predicts adolescent cognitive functioning. Furthermore, it bears practical implications as one may differentiate maturation lags from persistent low cognitive abilities in school children, complementing cognitive tests.

Specialization of the Right Intraparietal Sulcus for Processing Mathematics During Development.

Mathematical ability, especially perception of numbers and performance of arithmetics, is known to rely on the activation of intraparietal sulcus (IPS). However, reasoning ability and working memory, 2 highly associated abilities also activate partly overlapping regions. Most studies aimed at localizing mathematical function have used group averages, where individual variability is averaged out, thus confounding the anatomical specificity when localizing cognitive functions. Here, we analyze the functional anatomy of the intraparietal cortex by using individual analysis of subregions of IPS based on how they are structurally connected to frontal, parietal, and occipital cortex. Analysis of cortical thickness showed that the right anterior IPS, defined by its connections to the frontal lobe, was associated with both visuospatial working memory, and mathematics in 6-year-old children. This region specialized during development to be specifically related to mathematics, but not visuospatial working memory in adolescents and adults. This could be an example of interactive specialization, where interacting with the environment in combination with interactions between cortical regions leads from a more general role of right anterior IPS in spatial processing, to a specialization of this region for mathematics.

Grit Is Associated with Structure of Nucleus Accumbens and Gains in Cognitive Training.

There is a long-standing interest in the determinants of successful learning in children. "Grit" is an individual trait, reflecting the ability to pursue long-term goals despite temporary setbacks. Although grit is known to be predictive of future success in real-world learning situations, an understanding of the underlying neural basis and mechanisms is still lacking. Here we show that grit in a sample of 6-year-old children (n = 55) predicts the working memory improvement during 8 weeks of training on working memory tasks (p = .009). In a separate neuroimaging analysis performed on a partially overlapping sample (n = 27), we show that interindividual differences in grit were associated with differences in the volume of nucleus accumbens (peak voxel p = .021, x = 12, y = 11, z = -11). This was also confirmed in a leave-one-out analysis of gray matter density in the nucleus accumbens (p = .018). The results can be related to previous animal research showing the role of the nucleus accumbens to search out rewards regardless of delays or obstacles. The results provide a putative neural basis for grit and could contribute a cross-disciplinary connection of animal neuroscience to child psychology.

Quantitative susceptibility mapping of striatum in children and adults, and its association with working memory performance.

Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging (MRI) technique in which the magnetic susceptibility characteristic of molecular and cellular components, including iron and myelin, is quantified. Rapid iron accumulation in subcortical nuclei and myelination of the white matter tracts are two important developmental processes that contribute to cognitive functions. Both also contribute to the magnetic susceptibility of the brain tissues. Here, we used the QSM as indirect measures of iron in subcortical nuclei and myelin in caudo-frontal white matter pathways. We included two groups of participants; 21 children aged 6-7years and 25 adults aged 21-40years. All subjects also performed tests estimating their visuo-spatial working memory capacity. Adults had higher magnetic susceptibility in all subcortical nuclei, compared to children. The magnetic susceptibility of these nuclei highly correlated with their previously reported iron content. Moreover, working memory performance correlated significantly with the magnetic susceptibility in caudate nucleus in both children and adults, while the correlation was not significant for gray matter density. QSM of white matter in the caudo-frontal tract also differed between children and adults, but did not correlate with working memory scores. These results indicate that QSM is a feasible technique to measure developmental aspects of changes in the striatum, possibly related to iron content that is relevant to cognition.

Neonatal MRI is associated with future cognition and academic achievement in preterm children.

School-age children born preterm are particularly at risk for low mathematical achievement, associated with reduced working memory and number skills. Early identification of preterm children at risk for future impairments using brain markers might assist in referral for early intervention. This study aimed to examine the use of neonatal magnetic resonance imaging measures derived from automated methods (Jacobian maps from deformation-based morphometry; fractional anisotropy maps from diffusion tensor images) to predict skills important for mathematical achievement (working memory, early mathematical skills) at 5 and 7 years in a cohort of preterm children using both univariable (general linear model) and multivariable models (support vector regression). Participants were preterm children born <30 weeks' gestational age and healthy control children born ≥37 weeks' gestational age at the Royal Women's Hospital in Melbourne, Australia between July 2001 and December 2003 and recruited into a prospective longitudinal cohort study. At term-equivalent age ( ±2 weeks) 224 preterm and 46 control infants were recruited for magnetic resonance imaging. Working memory and early mathematics skills were assessed at 5 years (n = 195 preterm; n = 40 controls) and 7 years (n = 197 preterm; n = 43 controls). In the preterm group, results identified localized regions around the insula and putamen in the neonatal Jacobian map that were positively associated with early mathematics at 5 and 7 years (both P < 0.05), even after covarying for important perinatal clinical factors using general linear model but not support vector regression. The neonatal Jacobian map showed the same trend for association with working memory at 7 years (models ranging from P = 0.07 to P = 0.05). Neonatal fractional anisotropy was positively associated with working memory and early mathematics at 5 years (both P < 0.001) even after covarying for clinical factors using support vector regression but not general linear model. These significant relationships were not observed in the control group. In summary, we identified, in the preterm brain, regions around the insula and putamen using neonatal deformation-based morphometry, and brain microstructural organization using neonatal diffusion tensor imaging, associated with skills important for childhood mathematical achievement. Results contribute to the growing evidence for the clinical utility of neonatal magnetic resonance imaging for early identification of preterm infants at risk for childhood cognitive and academic impairment.

The role of fronto-parietal and fronto-striatal networks in the development of working memory: a longitudinal study.

The increase in working memory (WM) capacity is an important part of cognitive development during childhood and adolescence. Cross-sectional analyses have associated this development with higher activity, thinner cortex, and white matter maturation in fronto-parietal networks. However, there is still a lack of longitudinal data showing the dynamics of this development and the role of subcortical structures. We included 89 individuals, aged 6-25 years, who were scanned 1-3 times at 2-year intervals. Functional magnetic resonance imaging (fMRI) was used to identify activated areas in superior frontal, intraparietal cortices, and caudate nucleus during performance on a visuo-spatial WM task. Probabilistic tractography determined the anatomical pathways between these regions. In the cross-sectional analysis, WM capacity correlated with activity in frontal and parietal regions, cortical thickness in parietal cortex, and white matter structure [both fractional anisotropy (FA) and white matter volume] of fronto-parietal and fronto-striatal tracts. However, in the longitudinal analysis, FA in white matter tracts and activity in caudate predicted future WM capacity. The results show a dynamic of neural networks underlying WM development in which cortical activity and structure relate to current capacity, while white matter tracts and caudate activity predict future WM capacity.

CTNND2-a candidate gene for reading problems and mild intellectual disability.

BACKGROUND: Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders. METHODS AND RESULTS: Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon. CONCLUSIONS: Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.

Structural maturation and brain activity predict future working memory capacity during childhood development.

Human working memory capacity develops during childhood and is a strong predictor of future academic performance, in particular, achievements in mathematics and reading. Predicting working memory development is important for the early identification of children at risk for poor cognitive and academic development. Here we show that structural and functional magnetic resonance imaging data explain variance in children's working memory capacity 2 years later, which was unique variance in addition to that predicted using cognitive tests. While current working memory capacity correlated with frontoparietal cortical activity, the future capacity could be inferred from structure and activity in basal ganglia and thalamus. This gives a novel insight into the neural mechanisms of childhood development and supports the idea that neuroimaging can have a unique role in predicting children's cognitive development.

DCDC2 polymorphism is associated with left temporoparietal gray and white matter structures during development.

Three genes, DYX1C1, DCDC2, and KIAA0319, have been previously associated with dyslexia, neuronal migration, and ciliary function. Three polymorphisms within these genes, rs3743204 (DYX1C1), rs793842 (DCDC2), and rs6935076 (KIAA0319) have also been linked to normal variability of left temporoparietal white matter volume connecting the middle temporal cortex to the angular and supramarginal gyri. Here, we assessed whether these polymorphisms are also related to the cortical thickness of the associated regions during childhood development using a longitudinal dataset of 76 randomly selected children and young adults who were scanned up to three times each, 2 years apart. rs793842 in DCDC2 was significantly associated with the thickness of left angular and supramarginal gyri as well as the left lateral occipital cortex. The cortex was significantly thicker for T-allele carriers, who also had lower white matter volume and lower reading comprehension scores. There was a negative correlation between white matter volume and cortical thickness, but only white matter volume predicted reading comprehension 2 years after scanning. These results show how normal variability in reading comprehension is related to gene, white matter volume, and cortical thickness in the inferior parietal lobe. Possibly, the variability of gray and white matter structures could both be related to the role of DCDC2 in ciliary function, which affects both neuronal migration and axonal outgrowth.

Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family.

Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated.

Trade-off between capacity and precision in visuospatial working memory.

Limitations in the performance of working memory (WM) tasks have been characterized in terms of the number of items retained (capacity) and in terms of the precision with which the information is retained. The neural mechanisms behind these limitations are still unclear. Here we used a biological constrained computational model to study the capacity and precision of visuospatial WM. The model consists of two connected networks of spiking neurons. One network is responsible for storage of information. The other provides a nonselective excitatory input to the storage network. Simulations showed that this excitation boost could temporarily increase storage capacity but also predicted that this would be associated with a decrease in precision of the memory. This prediction was subsequently tested in a behavioral (38 participants) and fMRI (22 participants) experiment. The behavioral results confirmed the trade-off effect, and the fMRI results suggest that a frontal region might be engaged in the trial-by-trial control of WM performance. The average effects were small, but individuals differed in the amount of trade-off, and these differences correlated with the frontal activation. These results support a two-module model of WM where performance is determined both by storage capacity and by top-down influence, which can vary on a trial-by-trial basis, affecting both the capacity and precision of WM.

Polymorphisms in the dopamine receptor 2 gene region influence improvements during working memory training in children and adolescents.

Studying the effects of cognitive training can lead to finding better treatments, but it can also be a tool for investigating factors important for brain plasticity and acquisition of cognitive skills. In this study, we investigated how single-nucleotide polymorphisms (SNPs) and ratings of intrinsic motivation were associated to interindividual differences in improvement during working memory training. The study included 256 children aged 7-19 years who were genotyped for 13 SNPs within or near eight candidate genes previously implicated in learning: COMT, SLC6A3 (DAT1), DRD4, DRD2, PPP1R1B (DARPP32), MAOA, LMX1A, and BDNF. Ratings on the intrinsic motivation inventory were also available for 156 of these children. All participants performed at least 20 sessions of working memory training, and performance during the training was logged and used as the outcome variable. We found that two SNPs, rs1800497 and rs2283265, located near and within the dopamine receptor 2 (DRD2) gene, respectively, were significantly associated with improvements during training (p < .003 and p < .0004, respectively). Scores from a questionnaire regarding intrinsic motivation did not correlate with training outcome. However, we observed both the main effect of genotype at those two loci as well as the interaction between genotypes and ratings of intrinsic motivation (perceived competence). Both SNPs have previously been shown to affect DRD2 receptor density primarily in the BG. Our results suggest that genetic variation is accounting for some interindividual differences in how children acquire cognitive skills and that part of this effect is also seen on intrinsic motivation. Moreover, they suggest that dopamine D2 transmission in the BG is a key factor for cognitive plasticity.

Effect of working memory training on working memory, arithmetic and following instructions.

Mathematical ability is dependent on specific mathematical training but also associated with a range of cognitive factors, including working memory (WM) capacity. Previous studies have shown that WM training leads to improvement in non-trained WM tasks, but the results regarding transfer to mathematics are inconclusive. In the present study, 176 children with WM deficits, aged 7-15 years performed 5 weeks of WM training. During the training period, they were assessed five times with a test of complex WM (the Odd One Out), a test of remembering and following instructions and a test of arithmetic. The improvements were compared to the performance of a control group of 304 typically developing children aged 7-15 years who performed the same transfer tasks at the same time intervals, but without training. The training group improved significantly more than the control group on all three transfer tests (all p < 0.0001), after correction for baseline performance, age and sex. The effect size for mathematics was small and the effect sizes for the WM tasks were moderate to large. The transfer increased linearly with the amount of training time and correlated with the amount of improvement on the trained tasks. These results confirm previous findings of training-induced improvements in non-trained WM tasks including the ability to follow instructions, but extend previous findings by showing improvements also for arithmetic. This is encouraging regarding the potential role of cognitive training for education, but it is desirable to find paradigms that would enhance the effect of the training on mathematics. One of the future challenges for studying training effects is combining large sample sizes with high quality and compliance, to detect relevant but smaller effects of cognitive training.