Brain predicted age difference, or BrainPAD, compares chronological age to an age estimate derived by applying machine learning (ML) to MRI brain data. BrainPAD studies in youth have been relatively limited, often using only a single MRI modality or a single ML algorithm. Here, we use multimodal MRI with a stacked ensemble ML approach that iteratively applies several ML algorithms (AutoML). Eligible participants in the Healthy Brain Network (N = 489) were split into training and test sets. Morphometry estimates, white matter connectomes, or both were entered into AutoML to develop BrainPAD models. The best model was then applied to a held‐out evaluation dataset, and associations with psychometrics were estimated. Models using morphometry and connectomes together had a mean absolute error of 1.18 years, outperforming models using a single MRI modality. Lower BrainPAD values were associated with more symptoms on the CBCL (pcorr = .012) and lower functioning on the Children's Global Assessment Scale (pcorr = .012). Higher BrainPAD values were associated with better performance on the Flanker task (pcorr = .008). Brain age prediction was more accurate using ComBat‐harmonized brain data (MAE = 0.26). Associations with psychometric measures remained consistent after ComBat harmonization, though only the association with CGAS reached statistical significance in the reduced sample. Our findings suggest that BrainPAD scores derived from unharmonized multimodal MRI data using an ensemble ML approach may offer a clinically relevant indicator of psychiatric and cognitive functioning in youth.

ObjectivePost-stroke cognitive impairment (PSCI) is resistant to treatment. Recent studies have widely applied repetitive transcranial magnetic stimulation (rTMS) to treat various brain dysfunctions, such as post-stroke syndromes. Nonetheless, a protocol for PSCI has not been established. Therefore, this study is aimed to evaluate the therapeutic effect of our high-frequency rTMS protocol for PSCI during the chronic phase of stroke.MethodsIn this prospective study, ten patients with PSCI were enrolled and received high-frequency rTMS on the ipsilesional dorsolateral prefrontal cortex (DLPFC) for 10 sessions (5 days per week for 2 weeks). Cognitive and affective abilities were assessed at baseline and 2 and 14 weeks after rTMS initiation. To investigate the therapeutic mechanism of rTMS, the mRNA levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-1β, transforming growth factor beta [TGF-β], and tumor necrosis factor alpha [TNF-α]) in peripheral blood samples were quantified using reverse transcription polymerase chain reaction, and cognitive functional magnetic resonance imaging (fMRI) was conducted at baseline and 14 weeks in two randomly selected patients after rTMS treatment.ResultsThe scores of several cognitive evaluations, i.e., the Intelligence Quotient (IQ) of Wechsler Adult Intelligence Scale, auditory verbal learning test (AVLT), and complex figure copy test (CFT), were increased after completion of the rTMS session. After 3 months, these improvements were sustained, and scores on the Mini-Mental Status Examination and Montreal Cognitive Assessment (MoCA) were also increased (p < 0.05). While the Geriatric Depression Scale (GeDS) did not show change among all patients, those with moderate-to-severe depression showed amelioration of the score, with marginal significance. Expression of pro-inflammatory cytokines was decreased immediately after the ten treatment sessions, among which, IL-1β remained at a lower level after 3 months. Furthermore, strong correlations between the decrease in IL-6 and increments in AVLT (r = 0.928) and CFT (r = 0.886) were found immediately after the rTMS treatment (p < 0.05). Follow-up fMRI revealed significant activation in several brain regions, such as the medial frontal lobe, hippocampus, and angular area.ConclusionsHigh-frequency rTMS on the ipsilesional DLPFC may exert immediate efficacy on cognition with the anti-inflammatory response and changes in brain network in PSCI, lasting at least 3 months.

Sex impacts the development of the brain and cognition differently across individuals. However, the literature on brain sex dimorphism in humans is mixed. We aim to investigate the biological underpinnings of the individual variability of sexual dimorphism in the brain and its impact on cognitive performance. To this end, we tested whether the individual difference in brain sex would be linked to that in cognitive performance that is influenced by genetic factors in prepubertal children (N = 9,658, ages 9-10 years old; the Adolescent Brain Cognitive Development study). To capture the interindividual variability of the brain, we estimated the probability of being male or female based on the brain morphometry and connectivity features using machine learning (herein called a brain sex score). The models accurately classified the biological sex with a test ROC-AUC of 93.32%. As a result, a greater brain sex score correlated significantly with greater intelligence (p fdr < .001, η 2 p = .011-.034; adjusted for covariates) and higher cognitive genome-wide polygenic scores (GPSs) (p fdr < .001, η 2 p < .005). Structural equation models revealed that the GPS-intelligence association was significantly modulated by the brain sex score, such that a brain with a higher maleness score (or a lower femaleness score) mediated a positive GPS effect on intelligence (indirect effects = .006-.009; p = .002-.022; sex-stratified analysis). The finding of the sex modulatory effect on the gene-brain-cognition relationship presents a likely biological pathway to the individual and sex differences in the brain and cognitive performance in preadolescence.

Early life stress (ELS), such as abuse, neglect, and maltreatment, is a well-known risk factor for mental illness. However, it is unclear how ELS affects the brain and cognitive development. Identifying specific relationships of ELS with the genetic and brain-related underpinnings of cognitive development may reveal biological mechanisms responsible for the negative impact of ELS and those that lead to individual differences in sensitivity (or resilience) to ELS. In this study, to investigate the interlinked processes of cognitive development, we analyzed the multimodal data of DNA genotypes, brain imaging (MRI), and neuropsychological assessment (NIH Toolbox) outcomes of 4,276 children (ages 9 to 10 years, European ancestry) from the Adolescent Brain Cognitive Development (ABCD) study. We estimated the genetic influence on cognitive capacity using genome-wide polygenic scores (GPSs). Our regression and mediation analyses revealed significant causal relationships for the gene-brain-cognition pathway: Brain structural development significantly mediated the genetic influence on cognitive development (partial mediation effect = 0.016, PFWE<0.001). Interestingly, within the triangular relationship, we found a significant moderation effect of abuse only on the gene-to-brain pathway (Index of Moderated Mediation = -0.007; 95% CI= -0.012 ~ -0.002; PFWE<0.05). These findings indicate the negative modulatory effects of ELS on the genetic influence on brain structural development that lead to disadvantageous neurocognitive development in prepubertal children.

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