Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Testing the sensitivity of diagnosis-derived patterns in functional brain networks to symptom burden in a Norwegian youth sample.

Aberrant brain network development represents a putative aetiological component in mental disorders, which typically emerge during childhood and adolescence. Previous studies have identified resting-state functional connectivity (RSFC) patterns reflecting psychopathology, but the generalisability to other samples and politico-cultural contexts has not been established. We investigated whether a previously identified cross-diagnostic case-control and autism spectrum disorder (ASD)-specific pattern of RSFC (discovery sample; aged 5-21 from New York City, USA; n = 1666) could be validated in a Norwegian convenience-based youth sample (validation sample; aged 9-25 from Oslo, Norway; n = 531). As a test of generalisability, we investigated if these diagnosis-derived RSFC patterns were sensitive to levels of symptom burden in both samples, based on an independent measure of symptom burden. Both the cross-diagnostic and ASD-specific RSFC pattern were validated across samples. Connectivity patterns were significantly associated with thematically appropriate symptom dimensions in the discovery sample. In the validation sample, the ASD-specific RSFC pattern showed a weak, inverse relationship with symptoms of conduct problems, hyperactivity and prosociality, while the cross-diagnostic pattern was not significantly linked to symptoms. Diagnosis-derived connectivity patterns in a developmental clinical US sample were validated in a convenience sample of Norwegian youth, however, they were not associated with mental health symptoms.

Associations between everyday activities and arterial spin labeling-derived cerebral blood flow: A longitudinal study in community-dwelling elderly volunteers.

Cerebral blood flow (CBF) is critical for brain metabolism and function. Age-related changes in CBF are associated with increased risk of neurocognitive disorders and vascular events such as stroke. Identifying correlates and positive modifiers of age-related changes in CBF before the emergence of incipient clinical decline may inform public health advice and clinical practice. Former research has been inconclusive regarding the association between regular physical activity and CBF, and there is a lack of studies on the association between level of everyday activities and CBF, in older adults. To investigate these relationships, 118 healthy community-dwelling adults (65-89 years) underwent pseudo-continuous arterial spin labeling (ASL) MRI, neurocognitive, physical, and activity assessments at baseline. Eighty-six participants completed a follow-up ASL MRI, on average 506 (SD = 113) days after the baseline scan. Cross-sectional analysis revealed credible evidence for positive associations between time spent on low intensity physical activity and CBF in multiple cortical and subcortical regions, time spent on moderate to vigorous intensity physical activity and accumbens CBF, participation in social activity and CBF in multiple cortical regions, and between reading and thalamic CBF, indicating higher regional CBF in more active adults. Longitudinal analysis revealed anecdotal evidence for an interaction between time and baseline level of gardening on occipital and parietal CBF, and baseline reading on pallidum CBF, indicating more change in CBF in adults with lower level of activity. The findings support that malleable lifestyle factors contribute to healthy brain aging, with relevance for public health guidelines.

Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood.

Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74-96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.

Shared genetic architecture between mental health and the brain functional connectome in the UK Biobank.

Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30,701 participants aged 45-82 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular related to synaptic processes such as axonal growth (e.g. NGFR and RHOA). These findings provide further genetic evidence of an association between brain function and mental health traits in the population.

Patterns of sociocognitive stratification and perinatal risk in the child brain.

The expanding behavioral repertoire of the developing brain during childhood and adolescence is shaped by complex brain-environment interactions and flavored by unique life experiences. The transition into young adulthood offers opportunities for adaptation and growth but also increased susceptibility to environmental perturbations, such as the characteristics of social relationships, family environment, quality of schools and activities, financial security, urbanization and pollution, drugs, cultural practices, and values, that all act in concert with our genetic architecture and biology. Our multivariate brain-behavior mapping in 7,577 children aged 9 to 11 y across 585 brain imaging phenotypes and 617 cognitive, behavioral, psychosocial, and socioeconomic measures revealed three population modes of brain covariation, which were robust as assessed by cross-validation and permutation testing, taking into account siblings and twins, identified using genetic data. The first mode revealed traces of perinatal complications, including preterm and twin birth, eclampsia and toxemia, shorter period of breastfeeding, and lower cognitive scores, with higher cortical thickness and lower cortical areas and volumes. The second mode reflected a pattern of sociocognitive stratification, linking lower cognitive ability and socioeconomic status to lower cortical thickness, area, and volumes. The third mode captured a pattern related to urbanicity, with particulate matter pollution (PM25) inversely related to home value, walkability, and population density, associated with diffusion properties of white matter tracts. These results underscore the importance of a multidimensional and interdisciplinary understanding, integrating social, psychological, and biological sciences, to map the constituents of healthy development and to identify factors that may precede maladjustment and mental illness.

Associations between brain imaging and polygenic scores of mental health and educational attainment in children aged 9-11.

Psychiatric disorders are highly heritable and polygenic, and many have their peak onset in late childhood and adolescence, a period of tremendous changes. Although the neurodevelopmental antecedents of mental illness are widely acknowledged, research in youth population cohorts is still scarce, preventing our progress towards the early characterization of these disorders. We included 7,124 children (9-11 years old) from the Adolescent Brain and Cognitive Development Study to map the associations of structural and diffusion brain imaging with common genetic variants and polygenic scores for psychiatric disorders and educational attainment. We used principal component analysis to derive imaging components, and calculated their heritability. We then assessed the relationship of imaging components with genetic and clinical psychiatric risk with univariate models and Canonical correlation analysis (CCA). Most imaging components had moderate heritability. Univariate models showed limited evidence and small associations of polygenic scores with brain structure at this age. CCA revealed two significant modes of covariation. The first mode linked higher polygenic scores for educational attainment with less externalizing problems and larger surface area. The second mode related higher polygenic scores for schizophrenia, bipolar disorder, and autism spectrum disorder to higher global cortical thickness, smaller white matter volumes of the fornix and cingulum, larger medial occipital surface area and smaller surface area of lateral and medial temporal regions. While cross-validation suggested limited generalizability, our results highlight the potential of multivariate models to better understand the transdiagnostic and distributed relationships between mental health and brain structure in late childhood.

Mind the gap: Performance metric evaluation in brain-age prediction.

Estimating age based on neuroimaging-derived data has become a popular approach to developing markers for brain integrity and health. While a variety of machine-learning algorithms can provide accurate predictions of age based on brain characteristics, there is significant variation in model accuracy reported across studies. We predicted age in two population-based datasets, and assessed the effects of age range, sample size and age-bias correction on the model performance metrics Pearson's correlation coefficient (r), the coefficient of determination (R2 ), Root Mean Squared Error (RMSE) and Mean Absolute Error (MAE). The results showed that these metrics vary considerably depending on cohort age range; r and R2 values are lower when measured in samples with a narrower age range. RMSE and MAE are also lower in samples with a narrower age range due to smaller errors/brain age delta values when predictions are closer to the mean age of the group. Across subsets with different age ranges, performance metrics improve with increasing sample size. Performance metrics further vary depending on prediction variance as well as mean age difference between training and test sets, and age-bias corrected metrics indicate high accuracy-also for models showing poor initial performance. In conclusion, performance metrics used for evaluating age prediction models depend on cohort and study-specific data characteristics, and cannot be directly compared across different studies. Since age-bias corrected metrics generally indicate high accuracy, even for poorly performing models, inspection of uncorrected model results provides important information about underlying model attributes such as prediction variance.

Cardiometabolic risk factors associated with brain age and accelerate brain ageing.

The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.

A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group.

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.

Greater male than female variability in regional brain structure across the lifespan.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Genetic control of variability in subcortical and intracranial volumes.

Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8-89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

Functional connectivity in multiple sclerosis modelled as connectome stability: A 5-year follow-up study.

BACKGROUND: Brain functional connectivity (FC) in multiple sclerosis (MS) is abnormal compared to healthy controls (HCs). More longitudinal studies in MS are needed to evaluate whether FC stability is clinically relevant. OBJECTIVE: To compare functional magnetic resonance imaging (fMRI)-based FC between MS and HC, and to determine the relationship between longitudinal FC changes and structural brain damage, cognitive performance and physical disability. METHODS: T1-weighted MPRAGE and resting-state fMRI (1.5T) were acquired from 70 relapsing-remitting MS patients and 94 matched HC at baseline (mean months since diagnosis 14.0 ± 11) and from 60 MS patients after 5 years. Independent component analysis and network modelling were used to measure longitudinal FC stability and cross-sectional comparisons with HC. Linear mixed models, adjusted for age and sex, were used to calculate correlations. RESULTS: At baseline, patients with MS showed FC abnormalities both within networks and in single connections compared to HC. Longitudinal analyses revealed functional stability and no significant relationships with clinical disability, cognitive performance, lesion or brain volume. CONCLUSION: FC abnormalities occur already at the first decade of MS, yet we found no relevant clinical correlations for these network deviations. Future large-scale longitudinal fMRI studies across a range of MS subtypes and outcomes are required.

Population-based neuroimaging reveals traces of childbirth in the maternal brain.

Maternal brain adaptations have been found across pregnancy and postpartum, but little is known about the long-term effects of parity on the maternal brain. Using neuroimaging and machine learning, we investigated structural brain characteristics in 12,021 middle-aged women from the UK Biobank, demonstrating that parous women showed less evidence of brain aging compared to their nulliparous peers. The relationship between childbirths and a "younger-looking" brain could not be explained by common genetic variation or relevant confounders. Although prospective longitudinal studies are needed, the results suggest that parity may involve neural changes that could influence women's brain aging later in life.

Replicating extensive brain structural heterogeneity in individuals with schizophrenia and bipolar disorder.

Identifying brain processes involved in the risk and development of mental disorders is a major aim. We recently reported substantial interindividual heterogeneity in brain structural aberrations among patients with schizophrenia and bipolar disorder. Estimating the normative range of voxel-based morphometry (VBM) data among healthy individuals using a Gaussian process regression (GPR) enables us to map individual deviations from the healthy range in unseen datasets. Here, we aim to replicate our previous results in two independent samples of patients with schizophrenia (n1 = 94; n2 = 105), bipolar disorder (n1 = 116; n2 = 61), and healthy individuals (n1 = 400; n2 = 312). In line with previous findings with exception of the cerebellum our results revealed robust group level differences between patients and healthy individuals, yet only a small proportion of patients with schizophrenia or bipolar disorder exhibited extreme negative deviations from normality in the same brain regions. These direct replications support that group level-differences in brain structure disguise considerable individual differences in brain aberrations, with important implications for the interpretation and generalization of group-level brain imaging findings to the individual with a mental disorder.

Reliability, sensitivity, and predictive value of fMRI during multiple object tracking as a marker of cognitive training gain in combination with tDCS in stroke survivors.

Computerized cognitive training (CCT) combined with transcranial direct current stimulation (tDCS) has showed some promise in alleviating cognitive impairments in patients with brain disorders, but the robustness and possible mechanisms are unclear. In this prospective double-blind randomized clinical trial, we investigated the feasibility and effectiveness of combining CCT and tDCS, and tested the predictive value of and training-related changes in fMRI-based brain activation during attentive performance (multiple object tracking) obtained at inclusion, before initiating training, and after the three-weeks intervention in chronic stroke patients (>6 months since hospital admission). Patients were randomized to one of two groups, receiving CCT and either (a) tDCS targeting left dorsolateral prefrontal cortex (1 mA), or (b) sham tDCS, with 40s active stimulation (1 mA) before fade out of the current. Of note, 77 patients were enrolled in the study, 54 completed the cognitive training, and 48 completed all training and MRI sessions. We found significant improvement in performance across all trained tasks, but no additional gain of tDCS. fMRI-based brain activation showed high reliability, and higher cognitive performance was associated with increased tracking-related activation in the dorsal attention network and default mode network as well as anterior cingulate after compared to before the intervention. We found no significant associations between cognitive gain and brain activation measured before training or in the difference in activation after intervention. Combined, these results show significant training effects on trained cognitive tasks in stroke survivors, with no clear evidence of additional gain of concurrent tDCS.