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There is robust evidence implicating inhibitory deficits as a fundamental behavioural phenotype in children with attention-deficit/hyperactivity disorder (ADHD). However, prior studies have not directly investigated the role in which white matter properties within the fronto-basal-ganglia circuit may play in the development of inhibitory control deficits in this group. Combining recent advancements in brain-behavioural modelling, we mapped the development of stop-signal task (SST) performance and fronto-basal-ganglia maturation in a longitudinal sample of children aged 9-14 with and without ADHD. In a large sample of 135 ADHD and 138 non-ADHD children, we found that the ADHD group had poorer inhibitory control (i.e., longer stop-signal reaction times) across age compared to non-ADHD controls. When applying the novel parametric race model, this group effect was driven by higher within-subject variability (sigma) and higher number of extreme responses (tau) on stop trials. The ADHD group also displayed higher within-subject variability on correct responses to go stimuli. Moreover, we observed the ADHD group committing more task-based failures such as responding on stop trials (trigger failures) and omissions on go trials (go failures) compared to non-ADHD controls, suggesting the contribution of attentional lapses to poorer response inhibition performance. In contrast, longitudinal modelling of fixel-based analysis measures revealed no significant group differences in the maturation of fronto-basal-ganglia fibre cross-section in a subsample (74 ADHD and 73 non-ADHD children). Finally, brain-behavioural models revealed that age-related changes in fronto-basal-ganglia morphology (fibre cross-section) were significantly associated with reductions in the variability of the correct go-trial responses (sigma.true) and skew of the stop-trial distribution (tauS). However, this effect did not differ between ADHD and typically developing children. Overall, our findings support the growing consensus suggesting that attentional deficits subserve ADHD-related inhibitory dysfunction. Furthermore, we show novel evidence suggesting that while children with ADHD are consistently performing worse on the SST than their non-affected peers, they appear to have comparable rates of neurocognitive maturation across this period., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The development and refinement of functional brain circuits crucial to human cognition is a continuous process that spans from childhood to adulthood. Research increasingly focuses on mapping these evolving configurations, with the aim to identify markers for functional impairments and atypical development. Among human cognitive systems, nonsymbolic magnitude representations serve as a foundational building block for future success in mathematical learning and achievement for individuals. Using task-based frontoparietal (FPN) and salience network (SN) features during nonsymbolic magnitude processing alongside machine learning algorithms, we developed a framework to construct brain age prediction models for participants aged 7-30. Our study revealed differential developmental profiles in the synchronization within and between FPN and SN networks. Specifically, we observed a linear increase in FPN connectivity, concomitant with a decline in SN connectivity across the age span. A nonlinear U-shaped trajectory in the connectivity between the FPN and SN was discerned, revealing reduced FPN-SN synchronization among adolescents compared to both pediatric and adult cohorts. Leveraging the Gradient Boosting machine learning algorithm and nested fivefold stratified cross-validation with independent training datasets, we demonstrated that functional connectivity measures of the FPN and SN nodes predict chronological age, with a correlation coefficient of .727 and a mean absolute error of 2.944 between actual and predicted ages. Notably, connectivity within the FPN emerged as the most contributing feature for age prediction. Critically, a more matured brain age estimate is associated with better arithmetic performance. Our findings shed light on the intricate developmental changes occurring in the neural networks supporting magnitude representations. We emphasize brain age estimation as a potent tool for understanding cognitive development and its relationship to mathematical abilities across the critical developmental period of youth. PRACTITIONER POINTS: This study investigated the prolonged changes in the brain's architecture across childhood, adolescence, and adulthood, with a focus on task-state frontoparietal and salience networks. Distinct developmental pathways were identified: frontoparietal synchronization strengthens consistently throughout development, while salience network connectivity diminishes with age. Furthermore, adolescents show a unique dip in connectivity between these networks. Leveraging advanced machine learning methods, we accurately predicted individuals' ages based on these brain circuits, with a more mature estimated brain age correlating with better math skills., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Neurodevelopmental delays and frontal lobe cortical dysmaturation are widespread among children with congenital heart disease (CHD). The subventricular zone (SVZ) is the largest pool of neural stem/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants., Methods: Three-week-old piglets (n = 29) were randomly assigned to control (no surgery), mild-CPB (34°C full flow for 60 minutes) and severe-CPB groups (25°C circulatory-arrest for 60 minutes). The SVZ and frontal lobe were analyzed with immunohistochemistry 3 days and 4 weeks postoperatively. MRI of the frontal lobe was used to assess cortical development., Results: SVZ neurogenic activity was reduced up to 4 weeks after both mild and severe CPB-induced insults. CPB also induced decreased migration of young neurons to the frontal lobe, demonstrating that CPB impairs postnatal neurogenesis. MRI 4 weeks after CPB displayed a decrease in gyrification index and cortical volume of the frontal lobe. Cortical fractional anisotropy was increased after severe CPB injury, indicating a prolonged deleterious impact of CPB on cortical maturation. Both CPB-induced insults displayed a significant change in densities of three major inhibitory neurons, suggesting excitatory-inhibitory imbalance in the frontal cortex. In addition, different CPB insults altered different subpopulations of inhibitory neurons., Interpretation: Our results provide novel insights into cellular mechanisms contributing to CHD-induced neurological impairments. Further refinement of CPB hardware and techniques is necessary to improve long-term frontal cortical dysmaturation observed in children with CHD. ANN NEUROL 2021;90:913-926., (© 2021 American Neurological Association.)

Across species, adolescence is a period of growing independence that is associated with the maturation of cognitive, social, and affective processing. Reorganization of neural circuits within the frontal cortex is believed to contribute to the emergence of adolescent changes in cognition and behavior. While puberty coincides with adolescence, relatively little is known about which aspects of frontal cortex maturation are driven by pubertal development and gonadal hormones. In this review, we highlight existing work that suggests puberty plays a role in the maturation of specific cell types in the medial prefrontal cortex (mPFC) of rodents, and highlight possible routes by which gonadal hormones influence frontal cortical circuit development., (Copyright © 2021. Published by Elsevier Ltd.)

Formal education has a long-term impact on an individual's life. However, our knowledge of the effect of a specific lack of education, such as in mathematics, is currently poor but is highly relevant given the extant differences between countries in their educational curricula and the differences in opportunities to access education. Here we examined whether neurotransmitter concentrations in the adolescent brain could classify whether a student is lacking mathematical education. Decreased γ-aminobutyric acid (GABA) concentration within the middle frontal gyrus (MFG) successfully classified whether an adolescent studies math and was negatively associated with frontoparietal connectivity. In a second experiment, we uncovered that our findings were not due to preexisting differences before a mathematical education ceased. Furthermore, we showed that MFG GABA not only classifies whether an adolescent is studying math or not, but it also predicts the changes in mathematical reasoning ∼19 mo later. The present results extend previous work in animals that has emphasized the role of GABA neurotransmission in synaptic and network plasticity and highlight the effect of a specific lack of education on MFG GABA concentration and learning-dependent plasticity. Our findings reveal the reciprocal effect between brain development and education and demonstrate the negative consequences of a specific lack of education during adolescence on brain plasticity and cognitive functions., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Objectives: The primary objective of this study was to assess whether fetuses with congenital heart disease (CHD) have smaller frontal brain areas compared with normal controls. The secondary objective was to evaluate whether there are any differences in frontal brain area between cases with different types of CHD, grouped according to their impact on hemodynamics., Methods: This was a retrospective cross-sectional study, including 421 normal fetuses and 101 fetuses with isolated CHD evaluated between 20 and 39 gestational weeks at our fetal medicine and surgery unit in the period January 2016-December 2019. The study group was subdivided, according to the CHD hemodynamics, as follows: (1) hypoplastic left heart syndrome and other forms of functionally univentricular heart defect; (2) transposition of the great arteries; (3) conotruncal defects and other CHDs with large shunts; (4) right ventricular outflow tract obstruction, without a hypoplastic right ventricle; (5) left outflow tract obstruction; (6) others. The transventricular axial view of the fetal head was used as the reference view, on which the frontal lobe anteroposterior diameter (FAPD) and the occipitofrontal diameter (OFD) were measured, assuming the former to be representative of the area of the frontal lobes. The FAPD/OFD ratio was then calculated as FAPD/OFD × 100. These two variables (FAPD and FAPD/OFD ratio) were then evaluated and compared between the study and control groups. Adjustment for gestational age, both via multiple linear regression and by using a-posteriori matching based on the propensity score, was employed., Results: In normal fetuses, FAPD showed a linear positive correlation with gestational age. In fetuses with CHD, the FAPD was shorter than in normal fetuses from the 20 th  gestational week onwards, with the difference increasing after 30 gestational weeks. FAPD/OFD ratio was significantly smaller in fetuses with CHD than in normal fetuses (P < 0.0001) at all gestational ages, with no apparent differences among the various CHD categories, all of which had smaller FAPD/OFD ratio compared with controls., Conclusions: Fetuses with CHD have a shorter FAPD and a smaller FAPD/OFD ratio compared with normal fetuses. This impaired growth of the frontal area of the brain seems to occur in all types of CHD, regardless of their impact on hemodynamics. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Importance: Maturation of white matter fiber systems subserves cognitive, behavioral, emotional, and motor development during adolescence. Hazardous drinking during this active neurodevelopmental period may alter the trajectory of white matter microstructural development, potentially increasing risk for developing alcohol-related dysfunction and alcohol use disorder in adulthood., Objective: To identify disrupted adolescent microstructural brain development linked to drinking onset and to assess whether the disruption is more pronounced in younger rather than older adolescents., Design, Setting, and Participants: This case-control study, conducted from January 13, 2013, to January 15, 2019, consisted of an analysis of 451 participants from the National Consortium on Alcohol and Neurodevelopment in Adolescence cohort. Participants were aged 12 to 21 years at baseline and had at least 2 usable magnetic resonance diffusion tensor imaging (DTI) scans and up to 5 examination visits spanning 4 years. Participants with a youth-adjusted Cahalan score of 0 were labeled as no-to-low drinkers; those with a score of greater than 1 for at least 2 consecutive visits were labeled as heavy drinkers. Exploratory analysis was conducted between no-to-low and heavy drinkers. A between-group analysis was conducted between age- and sex-matched youths, and a within-participant analysis was performed before and after drinking., Exposures: Self-reported alcohol consumption in the past year summarized by categorical drinking levels., Main Outcomes and Measures: Diffusion tensor imaging measurement of fractional anisotropy (FA) in the whole brain and fiber systems quantifying the developmental change of each participant as a slope., Results: Analysis of whole-brain FA of 451 adolescents included 291 (64.5%) no-to-low drinkers and 160 (35.5%) heavy drinkers who indicated the potential for a deleterious association of alcohol with microstructural development. Among the no-to-low drinkers, 142 (48.4%) were boys with mean (SD) age of 16.5 (2.2) years and 149 (51.2%) were girls with mean (SD) age of 16.5 (2.1) years and 192 (66.0%) were White participants. Among the heavy drinkers, 86 (53.8%) were boys with mean (SD) age of 20.1 (1.5) years and 74 (46.3%) were girls with mean (SD) age of 20.5 (2.0) years and 142 (88.8%) were White participants. A group analysis revealed FA reduction in heavy-drinking youth compared with age- and sex-matched controls (t154 = -2.7, P = .008). The slope of this reduction correlated with log of days of drinking since the baseline visit (r156 = -0.21, 2-tailed P = .008). A within-participant analysis contrasting developmental trajectories of youths before and after they initiated heavy drinking supported the prediction that drinking onset was associated with and potentially preceded disrupted white matter integrity. Age-alcohol interactions (t152 = 3.0, P = .004) observed for the FA slopes indicated that the alcohol-associated disruption was greater in younger than older adolescents and was most pronounced in the genu and body of the corpus callosum, regions known to continue developing throughout adolescence., Conclusions and Relevance: This case-control study of adolescents found a deleterious association of alcohol use with white matter microstructural integrity. These findings support the concept of heightened vulnerability to environmental agents, including alcohol, associated with attenuated development of major white matter tracts in early adolescence.

Background: Vast increases in life expectancy over the last century have led to shifts in population demographics and the emergence of a largely aged population, globally. This has led to a need to understand neurobiological changes associated with healthy aging. Studies on age-related changes in functional connectivity networks have largely been cross-sectional and focused on the default mode network (DMN). The current study investigated longitudinal changes in functional connectivity in multiple resting-state networks over 4 years of aging in cognitively normal older adults. Methods: Resting-state functional magnetic resonance imaging scans from older adults ( n  = 16) who maintained "cognitive normal" status over 4 years were retrieved at baseline and follow-up from the Alzheimer's Disease Neuroimaging Initiative database. A seed-based approach was executed in Functional MRI of the Brain Software Library (FSL) to examine significant changes in functional connectivity within the DMN, frontoparietal network (FPN), and salience network (SN) within subjects over time. Results: Results indicated significantly ( p  < 0.05, corrected) reduced functional connectivity in the FPN and SN, but not in the DMN at year 4 compared with baseline in older adults who were cognitively stable. Conclusions: The current study highlights the importance of a longitudinal approach for understanding changes in functional connectivity. The findings also underscore the need to examine multiple networks within the same participants, given that changes were apparent in the FPN and SN but not in the DMN. Future studies should also examine changes in internetwork connectivity as well as shifts in structural connectivity over time. Impact statement Investigations of age-related changes in functional connectivity have largely been cross-sectional and focused on the default mode network (DMN). The current study examined the DMN as well as the frontoparietal network (FN) and salience network (SN), in a group of healthy aging adults over four years. The results revealed decreased functional connectivity over time, in the FN and SN, but not the DMN. These findings provide insights about the healthy aging brain. They also underscore the need to broaden the scope of functional connectivity analyses beyond the DMN and highlight the use of longitudinal methods.

We used functional magnetic resonance imaging (fMRI) to map the neural systems involved in reading Chinese in 125 participants 6-74 years old to examine two theoretical issues: how brain structure and function are related in the context of the lifetime neural development of human cognition and whether the neural network for reading is universal or different across languages. Our findings showed that a common network of left frontal and occipital regions typically involved in reading Chinese was recruited across all participants. Crucially, activation in left mid-inferior frontal regions, fusiform and striate-extrastriate sites, premotor cortex, right inferior frontal gyrus, bilateral insula, and supplementary motor area all showed linearly decreasing changes with age. These findings differ from previous findings on alphabetic reading development and suggest that early readers at age 6-7 are already using the same cortical network to process printed words as adults, though the connections among these regions are modulated by reading proficiency, and cortical regions for reading are tuned by experience toward reduced and more focused activation. This fMRI study has demonstrated, for the first time, the neurodevelopment of reading across the lifespan and suggests that learning experience, instead of pre-existing brain structures, determines reading acquisition., (© The Author(s) 2020. Published by Oxford University Press.)

Interleukin-6 (IL-6) is increased in maternal serum and amniotic fluid of children subsequently diagnosed with autism spectrum disorders. However, it is not clear how increased IL-6 alters brain development. Here, we show that IL-6 increases the prevalence of a specific platelet-derived growth factor (PDGF)-responsive multipotent progenitor, with opposite effects on neural stem cells and on subsets of bipotential glial progenitors. Acutely, increasing circulating IL-6 levels 2-fold above baseline in neonatal mice specifically stimulated the proliferation of a PDGF-responsive multipotential progenitor accompanied by increased phosphorylated STAT3, increased Fbxo15 expression, and decreased Dnmt1 and Tlx expression. Fate mapping studies using a Nestin-CreERT2 driver revealed decreased astrogliogenesis in the frontal cortex. IL-6-treated mice were hyposmic; however, olfactory bulb neuronogenesis was unaffected. Altogether, these studies provide important insights into how inflammation alters neural stem cells and progenitors and provide new insights into the molecular and cellular underpinnings of neurodevelopmental disorders associated with maternal infections., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent evidence suggests that relative to nonshy children, shy children exhibit a lower overall frontal EEG alpha/delta ratio (ADR) during middle childhood, possibly reflecting relatively less frontal brain maturation at this age. We examined this same ADR measure in relation to the stability of observed shyness and parent-reported child social anxiety measured across two laboratory visits separated by approximately 1 year during late childhood in 51 children (33% female, age range 10-16 years). We found that the overall frontal ADR score was significantly lower among children with high, stable observed shyness and parent-reported child social anxiety compared to children in the low, stable class. Findings provide convergent evidence suggesting that the stability of shyness in late childhood may be linked to relatively less overall frontal brain maturation at this age. We speculate on the adaptive function of delaying frontal brain maturation in the origins and maintenance of children's shyness., (© 2019 Wiley Periodicals, Inc.)

Importance: Alcohol abuse correlates with gray matter development in adolescents, but the directionality of this association remains unknown., Objective: To investigate the directionality of the association between gray matter development and increase in frequency of drunkenness among adolescents., Design, Setting, and Participants: This cohort study analyzed participants of IMAGEN, a multicenter brain imaging study of healthy adolescents in 8 European sites in Germany (Mannheim, Dresden, Berlin, and Hamburg), the United Kingdom (London and Nottingham), Ireland (Dublin), and France (Paris). Data from the second follow-up used in the present study were acquired from January 1, 2013, to December 31, 2016, and these data were analyzed from January 1, 2016, to March 31, 2018. Analyses were controlled for sex, site, socioeconomic status, family history of alcohol dependency, puberty score, negative life events, personality, cognition, and polygenic risk scores. Personality and frequency of drunkenness were assessed at age 14 years (baseline), 16 years (first follow-up), and 19 years (second follow-up). Structural brain imaging scans were acquired at baseline and second follow-up time points., Main Outcomes and Measures: Increases in drunkenness frequency were measured by latent growth modeling, a voxelwise hierarchical linear model was used to observe gray matter volume, and tensor-based morphometry was used for gray matter development. The hypotheses were formulated before the data analyses., Results: A total of 726 adolescents (mean [SD] age at baseline, 14.4 [0.38] years; 418 [58%] female) were included. The increase in drunkenness frequency was associated with accelerated gray matter atrophy in the left posterior temporal cortex (peak: t1,710 = -5.8; familywise error (FWE)-corrected P = 7.2 × 10-5; cluster: 6297 voxels; P = 2.7 × 10-5), right posterior temporal cortex (cluster: 2070 voxels; FWE-corrected P = .01), and left prefrontal cortex (peak: t1,710 = -5.2; FWE-corrected P = 2 × 10-3; cluster: 10 624 voxels; P = 1.9 × 10-7). According to causal bayesian network analyses, 73% of the networks showed directionality from gray matter development to drunkenness increase as confirmed by accelerated gray matter atrophy in late bingers compared with sober controls (n = 20 vs 60; β = 1.25; 95% CI, -2.15 to -0.46; t1,70 = 0.3; P = .004), the association of drunkenness increase with gray matter volume at age 14 years (β = 0.23; 95% CI, 0.01-0.46; t1,584 = 2; P = .04), the association between gray matter atrophy and alcohol drinking units (β = -0.0033; 95% CI, -6 × 10-3 to -5 × 10-4; t1,509 = -2.4; P = .02) and drunkenness frequency at age 23 years (β = -0.16; 95% CI, -0.28 to -0.03; t1,533 = -2.5; P = .01), and the linear exposure-response curve stratified by gray matter atrophy and not by increase in frequency of drunkenness., Conclusions and Relevance: This study found that gray matter development and impulsivity were associated with increased frequency of drunkenness by sex. These results suggest that neurotoxicity-related gray matter atrophy should be interpreted with caution.

Background: Cortical folding is essential for healthy brain development. Previous studies have found regional reductions in cortical folding in adult patients with psychotic illness. It is unknown whether these neuroanatomical markers are present in youth with subclinical psychotic symptoms., Methods: We collected MRIs and examined the local gyrification index in a sample of 110 youth (mean age ± standard deviation 14.0 ± 3.7 yr; range 9–25 yr) with a family history of severe mental illness: 48 with psychotic symptoms and 62 without. Images were processed using the Human Connectome Pipeline and FreeSurfer. We tested for group differences in local gyrification index using mixed-effects generalized linear models controlling for age, sex and familial clustering. Sensitivity analysis further controlled for intracranial volume, IQ, and stimulant and cannabis use., Results: Youth with psychotic symptoms displayed an overall trend toward lower cortical folding across all brain regions. After adjusting for multiple comparisons and confounders, regional reductions were localized to the frontal and occipital lobes. Specifically, the medial (B = –0.42, pFDR = 0.04) and lateral (B = –0.39, pFDR = 0.04) orbitofrontal cortices as well as the cuneus (B = –0.47, pFDR = 0.03) and the pericalcarine (B = –0.45, pFDR = 0.03) and lingual (B = –0.38, pFDR = 0.04) gyri., Limitations: Inference about developmental trajectories was limited by the cross-sectional data., Conclusion: Psychotic symptoms in youth are associated with cortical folding deficits, even in the absence of psychotic illness. The current study helps clarify the neurodevelopmental basis of psychosis at an early stage, before medication, drug use and other confounds have had a persistent effect on the brain., Competing Interests: None declared., (© 2020 Joule Inc. or its licensors)

Executive function (EF) refers as to a set of high-level cognitive abilities that are critical to many aspects of daily life. Despite its importance in human daily life, the neural networks responsible for the development of EF in childhood are not well understood. The present study thus aimed to examine the development of task-dependent brain network organization and its relationship to age-related improvements in EF. To address this issue, we recruited eighty-eight Chinese children ranging in age from 7 to 12 years old, and collected their functional magnetic resonance imaging (fMRI) data when they performed an EF task. By utilizing graph theory, we found that the task-dependent brain network modules became increasingly segregated with age. Specifically, the intra-module connections within the default-mode network (DMN), frontal-parietal network (FPN) and sensorimotor network (SMN) increased significantly with age. In contrast, the inter-module connections of the visual network to both the FPN/SMN decreased significantly with age. Most importantly, modular segregation of the FPN significantly mediated the relationship between age and EF performance. These findings add to our growing understanding of how development changes in task-dependent brain network organization support vast behavioral improvements in EF observed during childhood., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

A randomized control trial was conducted to investigate the effects of skin-to-skin, chest-to-chest contact (kangaroo care, KC) in mother-infant dyads on patterns of infant brain activity and associated mother-infant neurohormone releases. 33 mother-infant dyads participated during pregnancy (29-38 weeks gestation), at neonatal and 3-month periods. Overall, analyses indicated that: 1) infants in the KC group showed left frontal brain activation patterns (asymmetry and coherence) associated with KC training; 2) KC produced moderate to large increases in oxytocin levels; and 3) KC yielded moderate decreases in cortisol reactivity. Findings suggest KC may garner favorable neuro-maturational and neurobiological outcomes for dyads., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Asymmetric patterns of frontal brain electrical activity reflect approach and avoidance tendencies, with stability of relative right activation associated with withdrawal emotions/motivation and left hemisphere activation linked with approach and positive affect. However, considerable shifts in approach/avoidance-related lateralization have been reported for children not targeted because of extreme temperament. In this study, dynamic effects of frontal electroencephalogram (EEG) power within and across hemispheres were examined throughout early childhood. Specifically, EEG indicators at 5, 10, 24, 36, 48, and 72 months-of-age (n = 410) were analyzed via a hybrid of difference score and panel design models, with baseline measures and subsequent time-to-time differences modeled as potentially influencing all subsequent amounts of time-to-time change (i.e., predictively saturated). Infant sex was considered as a moderator of dynamic developmental effects, with temperament attributes measured at 5 months examined as predictors of EEG hemisphere development. Overall, change in left and right frontal EEG power predicted declining subsequent change in the same hemisphere, with effects on the opposing neurobehavioral system enhancing later growth. Infant sex moderated the pattern of within and across-hemisphere effects, wherein for girls more prominent left hemisphere influences on the right hemisphere EEG changes were noted and right hemisphere effects were more salient for boys. Largely similar patterns of temperament prediction were observed for the left and the right EEG power changes, with limited sex differences in links between temperament and growth parameters. Results were interpreted in the context of comparable analyses using parietal power values, which provided evidence for unique frontal effects., (© 2019 John Wiley & Sons Ltd.)

Asymmetry of the human brain is a well-known phenomenon, but the nature and extent of these differences throughout postnatal development have not been examined. Accordingly, linear measurements of the brains of 121 infants, children, and adolescents were determined to ascertain cerebral hemispheric asymmetries. Using multiple statistical methods, the results showed that: 1) the frontal lobe is wider on the right, while the occipital lobe is wider on the left; 2) there are no side to side differences in cerebral hemispheric length or height; and 3) there are no major sex differences. Especially notable is the lack of any correlation between side to side differences in length, width, or height and increasing age, which was also the case for cerebral hemispheric area or volume with increasing age. Regarding petalias: 1) the right frontal petalia occurs in 61%, the left occipital in 60%, and both petalias in 36% of the cohort; 2) the right frontal and left occipital petalias are of similar lengths; 3) the distances of both petalias increase with advancing age but not when scaled to either cerebral hemispheric area or volume, indicating that petalias are equally prominent early in postnatal life compared to later development; and 4) there are no major sex differences in the frequency or magnitude of either petalia. These findings provide comprehensive new information regarding age and sex related cerebral hemispheric asymmetries during development., (Copyright © 2019 Elsevier B.V. All rights reserved.)

During healthy brain aging, different brain regions show anatomical or functional declines at different rates, and some regions may show compensatory increases in functional activity. However, few studies have explored interregional influences of brain activity during the aging process. We proposed a causality analysis framework combining high dimensionality independent component analysis (ICA), Granger causality, and least absolute shrinkage and selection operator regression on longitudinal brain metabolic activity data measured by Fludeoxyglucose positron emission tomography (FDG-PET). We analyzed FDG-PET images from healthy old subjects, who were scanned for at least five sessions with an averaged intersession interval of 1 year. The longitudinal data were concatenated across subjects to form a time series, and the first-order autoregressive model was used to measure interregional causality among the independent sources of metabolic activity identified using ICA. Several independent sources with reduced metabolic activity in aging, including the anterior temporal lobe and orbital frontal cortex, demonstrated causal influences over many widespread brain regions. On the other hand, the influenced regions were more distributed, and had smaller age-related declines or even relatively increased metabolic activity. The current data demonstrated interregional spreads of aging on metabolic activity at the scale of a year, and have identified key brain regions in the aging process that have strong influences over other regions., (© 2019 Wiley Periodicals, Inc.)

The cortex is organised into broadly hierarchical functional systems with distinct neuroanatomical characteristics reflected by macroscopic measures of cortical morphology. Diffusion-weighted magnetic resonance imaging allows the delineation of areal connectivity, changes to which reflect the ongoing maturation of white matter tracts. These developmental processes are intrinsically linked with timing coincident with the development of cognitive function. In this study, we use a data-driven multivariate approach, nonnegative matrix factorisation, to define cortical regions that co-vary together across a large paediatric cohort (n = 456) and are associated with specific subnetworks of cortical connectivity. We find that age between 3 and 21 years is associated with accelerated cortical thinning in frontoparietal regions, whereas relative thinning of primary motor and sensory regions is slower. Together, the subject-specific weights of the derived set of cortical components can be combined to predict chronological age. Structural connectivity networks reveal a relative increase in strength in connection within, as opposed to between hemispheres that vary in line with cortical changes. We confirm our findings in an independent sample., (© 2019 Wiley Periodicals, Inc.)

Maternal smoking of conventional or vapor cigarettes during pregnancy, a form of developmental nicotine exposure (DNE), enhances the risk of neurodevelopmental disorders such as ADHD, autism, and schizophrenia in children. Modeling the multigenerational effects of smoking during pregnancy and nursing in the first- (F1) and second- (F2) generation adolescent offspring of oral nicotine-treated female C57BL/6J mice, we have previously reported that DNE precipitates intergenerational transmission of nicotine preference, hyperactivity and impulsivity-like behaviors, altered rhythmicity of home cage activity, corticostriatal nicotinic acetylcholine receptor and dopamine transporter dysfunction, and corticostriatal global DNA methylome deficits. In aggregate, these DNE-evoked behavioral, neuropharmacological, and epigenomic anomalies mirror fundamental etiological aspects of neurodevelopmental disorders including ADHD, autism, and schizophrenia. Expanding this line of research, the current study profiled the multigenerational neurotrophic and neuroendocrine consequences of DNE. Results reveal impaired proBDNF proteolysis as indicated by proBDNF-BDNF imbalance, downregulation of the proBDNF processing enzyme furin, atypical glucocorticoid receptor (GR) activity as implied by decreased relative nuclear GR localization, and deficient basal plasma corticosterone (CORT) levels in adolescent DNE offspring and grandoffspring. Collectively, these data recapitulate the BDNF deficits and HPA axis dysregulation characteristic of neurodevelopmental disorders such as ADHD, autism, and schizophrenia as well as the children of maternal smokers. Notably, as BDNF is a quintessential mediator of neurodevelopment, our prior findings of multigenerational DNE-induced behavioral and neuropharmacological abnormalities may stem from neurodevelopmental insults conferred by the proBDNF-BDNF imbalance detected in DNE mice. Similarly, our findings of multigenerational GR hypoactivity may contribute to the increased risk-taking behaviors and aberrant circadian rhythmicity of home cage activity that we previously documented in first- and second-generation DNE mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Children born preterm are at higher risk to develop language deficits. Auditory speech discrimination deficits may be early signs for language developmental problems. The present study used functional near-infrared spectroscopy to investigate neural speech discrimination in 15 preterm infants at term-equivalent age compared to 15 full term neonates. The full term group revealed a significantly greater hemodynamic response to forward compared to backward speech within the left hemisphere extending from superior temporal to inferior parietal and middle and inferior frontal areas. In contrast, the preterm group did not show differences in their hemodynamic responses during forward versus backward speech, thus, they did not discriminate speech from non-speech. Groups differed significantly in their responses to forward speech, whereas they did not differ in their responses to backward speech. The significant differences between groups point to an altered development of the functional network underlying language acquisition in preterm infants as early as in term-equivalent age., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Language development and the capacity for communication in infants are predominantly supported by their mothers, beginning when infants are still in utero. Although a mother's speech should thus have a significant impact on her neonate's brain, neurocognitive evidence for this hypothesis remains elusive. The present study examined 37 neonates using near-infrared spectroscopy and observed the interactions between multiple cortical regions while neonates heard speech spoken by their mothers or by strangers. We analyzed the functional connectivity between regions whose response-activation patterns differed between the two types of speakers. We found that when hearing their mothers' speech, functional connectivity was enhanced in both the neonatal left and right frontotemporal networks. On the left it was enhanced between the inferior/middle frontal gyrus and the temporal cortex, while on the right it was enhanced between the frontal pole and temporal cortex. In particular, the frontal pole was more strongly connected to the left supramarginal area when hearing speech from mothers. These enhanced frontotemporal networks connect areas that are associated with language (left) and voice processing (right) at later stages of development. We suggest that these roles are initially fostered by maternal speech., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is a growing need to understand the global impact of poverty on early brain and behavioural development, particularly with regard to key cognitive processes that emerge in early development. Although the impact of adversity on brain development can trap children in an intergenerational cycle of poverty, the massive potential for brain plasticity is also a source of hope: reliable, accessible, culturally agnostic methods to assess early brain development in low resource settings might be used to measure the impact of early adversity, identify infants for timely intervention and guide the development and monitor the effectiveness of early interventions. Visual working memory (VWM) is an early marker of cognitive capacity that has been assessed reliably in early infancy and is predictive of later academic achievement in Western countries. Here, we localized the functional brain networks that underlie VWM in early development in rural India using a portable neuroimaging system, and we assessed the impact of adversity on these brain networks. We recorded functional brain activity as young children aged 4-48 months performed a VWM task. Brain imaging results revealed localized activation in the frontal cortex, replicating findings from a Midwestern US sample. Critically, children from families with low maternal education and income showed weaker brain activity and poorer distractor suppression in canonical working memory areas in the left frontal cortex. Implications of this work are far-reaching: it is now cost-effective to localize functional brain networks in early development in low-resource settings, paving the way for novel intervention and assessment methods., (© 2019 The Authors. Developmental Science Published by John Wiley & Sons Ltd.)

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications ( DAAM1 and THBS3 ), or close to genes causing Mendelian brain-related diseases ( ZIC4 and FGFRL1 ). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes., Competing Interests: Competing interestsThe authors declare no competing interests.

When a listener hears a word, multiple lexical items may come to mind; for instance, /kæn/ may activate concepts with similar phonological onsets such as candy and candle. Acquisition of two lexicons may increase such linguistic competition. Using functional Near-Infrared Spectroscopy neuroimaging, we investigate whether bilingualism impacts word processing in the child's brain. Bilingual and monolingual children (N = 52; ages 7-10) completed a lexical selection task in English, where participants adjudicated phonological competitors (e.g., car/cat vs. car/pen). Children were less accurate and responded more slowly during competing than non-competing items. In doing so, children engaged top-down fronto-parietal regions associated with cognitive control. In comparison to bilinguals, monolinguals showed greater activity in left frontal regions, a difference possibly due to bilinguals' adaptation for dual-lexicons. These differences provide insight to theories aiming to explain the role of experience on children's emerging neural networks for lexical selection and language processing., (Published by Elsevier Inc.)

Early social interactions shape the development of social behavior, although the critical periods or the underlying neurodevelopmental processes are not completely understood. Here, we studied the developmental changes in neural pathways underlying visual social engagement in the translational rhesus monkey model. Changes in functional connectivity (FC) along the ventral object and motion pathways and the dorsal attention/visuo-spatial pathways were studied longitudinally using resting-state functional MRI in infant rhesus monkeys, from birth through early weaning (3 months), given the socioemotional changes experienced during this period. Our results revealed that (1) maturation along the visual pathways proceeds in a caudo-rostral progression with primary visual areas (V1-V3) showing strong FC as early as 2 weeks of age, whereas higher-order visual and attentional areas (e.g., MT-AST, LIP-FEF) show weak FC; (2) functional changes were pathway-specific (e.g., robust FC increases detected in the most anterior aspect of the object pathway (TE-AMY), but FC remained weak in the other pathways (e.g., AST-AMY)); (3) FC matures similarly in both right and left hemispheres. Our findings suggest that visual pathways in infant macaques undergo selective remodeling during the first 3 months of life, likely regulated by early social interactions and supporting the transition to independence from the mother., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The hippocampus formation, although prominently implicated in schizophrenia pathogenesis, has been overlooked in large-scale genomics efforts in the schizophrenic brain. We performed RNA-seq in hippocampi and dorsolateral prefrontal cortices (DLPFCs) from 551 individuals (286 with schizophrenia). We identified substantial regional differences in gene expression and found widespread developmental differences that were independent of cellular composition. We identified 48 and 245 differentially expressed genes (DEGs) associated with schizophrenia within the hippocampus and DLPFC, with little overlap between the brain regions. 124 of 163 (76.6%) of schizophrenia GWAS risk loci contained eQTLs in any region. Transcriptome-wide association studies in each region identified many novel schizophrenia risk features that were brain region-specific. Last, we identified potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia and offer new insights into potentially causative biology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Substance-naïve offspring from high-density alcohol use disorder (AUD) families exhibit altered subcortical brain volumes structurally and altered executive-functioning and emotion-processing functionally, compared with their peers. However, there is a dearth of literature exploring alterations of cortical thickness (CTh) in this population. T1-weighted structural brain MRI was acquired in 75 substance-naïve male offspring of treatment-seeking early onset (<25 years) AUD patients with high familial loading of AUDs (≥2 affected relatives) (FHP) and 65 age-matched substance-naïve male controls with negative family history from the community. Surface-based CTh reconstruction was done using FreeSurfer. Univariate general linear models were implemented at each vertex using SurfStat, controlling for age (linear and quadratic effects), and head size, to examine the main effect of familial AUD risk on CTh and its relationship with externalizing symptom score (ESS). A Johnson-Neyman procedure revealed that the main effect of familial AUD risk on CTh was seen during adolescence, where the FHP group had thicker cortices involving bilateral precentral gyri, left caudal middle frontal gyrus (MFG), bilateral temporo-parietal junction, left inferior-frontal gyrus and right inferior-temporal gyrus. Thicker cortices in left MFG and inferior-parietal lobule were also associated with greater ESS within both groups. More importantly, these group differences diminished with age by young adulthood. Familial AUD risk is associated with age-related differences in maturation of several higher order association cortices that are critical to ongoing development in executive function, emotion regulation and social cognition during adolescence. Early supportive intervention for a delay in alcohol initiation during this critical phase may be crucial for this at-risk population., (© 2018 Society for the Study of Addiction.)

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS-EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS-EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high-density TMS-EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between-group differences in the topography of the TMS-evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS-EEG co-registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders., (© 2019 Wiley Periodicals, Inc.)

Behavioral and developmental studies have made a critical distinction between item and serial order processing components of verbal working memory (WM). This functional magnetic resonance imaging (fMRI) study determined the extent to which item and serial order WM components are characterized by specialized neural networks already in young children or whether this specialization emerges at a later developmental stage. Total of 59 children aged 7-12 years performed item and serial order short-term probe recognition tasks in an fMRI experiment. While a left frontoparietal network was recruited in both item and serial order WM conditions, the right intraparietal sulcus was selectively involved in the serial order WM condition. This neural segregation was modulated by age, with both networks becoming increasingly separated in older children. Our results indicate a progressive specialization of networks involved in item and order WM processes during cognitive development., (© 2018 Wiley Periodicals, Inc.)

Neuron-glial related cell adhesion molecule NrCAM is a newly identified negative regulator of spine density that genetically interacts with Semaphorin3F (Sema3F), and is implicated in autism spectrum disorders (ASD). To investigate a role for NrCAM in spine pruning during the critical adolescent period when networks are established, we generated novel conditional, inducible NrCAM mutant mice (Nex1Cre-ERT2: NrCAMflox/flox). We demonstrate that NrCAM functions cell autonomously during adolescence in pyramidal neurons to restrict spine density in the visual (V1) and medial frontal cortex (MFC). Guided by molecular modeling, we found that NrCAM promoted clustering of the Sema3F holoreceptor complex by interfacing with Neuropilin-2 (Npn2) and PDZ scaffold protein SAP102. NrCAM-induced receptor clustering stimulated the Rap-GAP activity of PlexinA3 (PlexA3) within the holoreceptor complex, which in turn, inhibited Rap1-GTPase and inactivated adhesive β1 integrins, essential for Sema3F-induced spine pruning. These results define a developmental function for NrCAM in Sema3F receptor signaling that limits dendritic spine density on cortical pyramidal neurons during adolescence.

Early numeracy provides the foundation of acquiring mathematical skills that is essential for future academic success. This study examined numerical functional networks in relation to counting and number relational skills in preschoolers at 4 and 6 years of age. The counting and number relational skills were assessed using school readiness test (SRT). Resting-state fMRI (rs-fMRI) was acquired in 123 4-year-olds and 146 6-year-olds. Among them, 61 were scanned twice over the course of 2 years. Meta-analysis on existing task-based numeracy fMRI studies identified the left parietal-dominant network for both counting and number relational skills and the right parietal-dominant network only for number relational skills in adults. We showed that the fronto-parietal numerical networks, observed in adults, already exist in 4-year and 6-year-olds. The counting skills were associated with the bilateral fronto-parietal network in 4-year-olds and with the right parietal-dominant network in 6-year-olds. Moreover, the number relational skills were related to the bilateral fronto-parietal and right parietal-dominant networks in 4-year-olds and had a trend of the significant relationship with the right parietal-dominant network in 6-year-olds. Our findings suggested that neural fine-tuning of the fronto-parietal numerical networks may subserve the maturation of numeracy in early childhood.

Development of the frontal lobe is critical to acquisition, execution, and control of a wide range of functions, from basic motor response to complex decision-making. These functions are influenced by contingency-based (e.g., reward and response-cost/punishment) feedback that is mediated through the adaptive integration of fronto-subcortical neural circuitry. The frontal lobe manages incoming information and chooses the appropriate action based on one's goals in a particular context. This aspect of frontal function, while only one component, is crucial to development and maintenance of approach and avoidance behavior central to all human (and animal) behavior. Furthermore, disruptions in fronto-subcortical circuitry governing motivated behavior appear to contribute to a range of developmental disorders, including attention-deficit/hyperactivity disorder (ADHD), and confer vulnerability for psychopathology more broadly. The particular deficits that manifest in altered behavior depend upon the specific circuitry that is compromised due to the functional specificity of distinct regions of the frontal lobe and its interconnections with subcortical structures. Neurobiologic models of motivated behavior provide a valuable framework for characterizing developmental disorders from a transdiagnostic dimensional systems perspective. Improved characterization of approach and avoidance motivation across neurodevelopmental disorders has the potential to inform the development of novel interventions and personalized medicine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Perinatal neurodevelopment involves extensive formation of neural connections and onset of activity-dependent gene expression for synaptic function and plasticity. Exposure to psychostimulants at this stage imposes significant risks for developing cognitive and affective disorders later in life. However, how developmental exposure to psychostimulants may induce long-lasting molecular changes relevant to neural circuit function remains incompletely understood. In this study, we investigated the impacts of psychostimulant amphetamine on the activity-dependent induction of synaptic adaptor molecule Arc in the frontal cortex of neonatal mice. We found that transient exposure to amphetamine not only amplifies activity-dependent Arc mRNA expression immediately, but also potentiates subsequent induction of Arc mRNA in the absence of amphetamine. This priming effect is associated with a rapid and persistent increase in histone mono-methylation (H3K4me1), a marker for transcriptionally permissive chromatin, at the Arc locus, but not any long-lasting change in the phosphorylation of upstream transcription factor CREB. Furthermore, the increase in H3K4me1 at the Arc locus requires dopamine receptor signaling, and the priming of Arc expression correlates with the dopaminergic innervation pattern in the frontal cortex. Together, our results demonstrate that developmental exposure to psychostimulant amphetamine induces long-lasting chromatin changes and primes activity-dependent Arc gene induction. These findings reveal the molecular targets of psychostimulant during perinatal development that may contribute to long-term psychiatric risks., (© Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Although research shows that working memory improves during early childhood, it remains unclear how the fronto-parietal network of cortical regions, known to support this ability in adults, relates to changes in young children. Measures of cortical thickness may be useful in investigating this association as they reflect age-related differences in gray matter and have been proposed to support age-related improvements in other cognitive abilities, but have only sparingly been tested empirically in early childhood. The present study sought to investigate relations between cortical thickness and performance on a digit span task in 200 4- to 8-year-old children using both a priori defined regions of interest related to working memory (superior frontal cortex, middle frontal cortex, anterior cingulate cortex, superior parietal cortex) and whole brain analyses. Results indicated a significant association between cortical thickness in each a priori defined fronto-parietal region and performance on digit span, such that those with a thinner cortex recalled more items than those with a thicker cortex. Similar regions emerged from the whole brain analyses, as did several other regions not typically included in the fronto-parietal network. Results of a mediation analysis indicated that age-related differences in behavior were partially explained by variations in thickness of anterior cingulate cortex, suggesting a potentially important role for this structure during early childhood. Overall, these results suggest that in children as young as 4 years of age there are associations between working memory abilities and thickness in cortical areas known to support working memory in adults., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Greater relative right- than left-frontal cortical activity has been frequently found in adults with major depression (MD). As the few studies in adolescents with MD have been inconclusive, the aim of this study was to assess frontal alpha asymmetry (FAA) in an adolescent sample with MD whilst taking into account possible confounding variables such as disease state and comorbid anxiety disorder., Methods: An 8-minute resting frontal EEG was assessed in 34 healthy controls (HCs), 16 adolescents with MD in remission without comorbid anxiety disorder (rMDa-), 22 adolescents with acute depression without comorbid anxiety disorder (MDa-), and 23 adolescents with acute depression and comorbid anxiety disorder (MDa+). Alpha power was analyzed over corresponding frontal Regions of Interests., Results: Compared to HCs, MDa+ adolescents demonstrated more left- than right-sided EEG alpha power, indicating greater right-than left-frontal cortical activity. No other group differences emerged., Conclusions: The results suggest that greater relative right-frontal cortical activity in adolescent MD is not a result of disease state but can be attributed to comorbid anxiety disorder., Significance: Results suggest that FAA is not linked to adolescent depression per se and highlight the importance of considering comorbid disorders when examining asymmetry patterns in adolescent MD., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

This study aimed to explore the effects of postnatal low-concentration arsenic exposure on learning, social skills and frontal cortex neurogenesis in rats. Water-based arsenic exposure rat models were established on postnatal days 4-10 (P4-P10). The experimental animals were divided into four groups: the control group, a 15 μg/L As 2 O 3 water group, a 30 μg/L As 2 O 3 water group, and a 45 μg/L As 2 O 3 water group. Cognitive function was examined with the Morris water maze, anxiety-like behavior with the open field test and light-dark box test, and social skills with a social interaction test. The frontal cortices of pups from each experimental group were sectioned at various time points after arsenic exposure. The morphologies and neurogenesis of the neurons in the frontal cortices were observed by hematoxylin-eosin staining, Nissl staining, and doublecortin (DCX) immunostaining. Significant positive correlations between arsenic concentration and deficits in learning and social skills were found, and the arsenic exposure groups showed significant increases in anxiety-like behavior compared with the control group (all Ps<0.05). Abnormal morphologic changes in the external granular layer and external pyramidal layer were positively correlated with the water arsenic concentration in the acute phase of arsenic exposure. However, at five weeks after arsenic exposure, the frontal cortex morphology was restored. Moreover, immunohistochemistry revealed that compared to the control group, the groups that were exposed to arsenic exhibited significantly higher levels of DCX expression in the external granular and external pyramidal layers (all Ps<0.001). Furthermore, the 30 μg/L and 45 μg/L arsenic exposure groups still showed some DCX expression at five weeks after exposure. In conclusion, postnatal low-concentration arsenic exposure impaired learning and social skills and increased anxiety-like behaviors, and abnormal frontal cortex neurogenesis may be the mechanism underlying these effects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The perineuronal net (PN), a highly organized extracellular matrix structure, is believed to play an important role in synaptic function, including maturation and stabilization. In addition to its role in restricting plasticity, alterations in the PN are implicated in disorders such as epilepsy and schizophrenia. However, the time course of PN development is not known in humans. Therefore we set out to document the developmental timeline of the PN formation in humans in 14 frontal and hippocampal specimens from donors aged 27 days to 31 years old. Using immunohistochemistry and western blotting, we demonstrate that the PN begins to form as early as the second month of life but does not reach its robust, mature appearance until around 8 years of age, though aggrecan cleavage products are observed prior to this. A similar developmental time course was observed in specimens from epilepsy patients. Our data suggest that aggrecan is present early in development but the structured PN develops throughout early childhood, similar to what has been observed in rodents. This timeline provides information for future pathological studies on the role of the PN in disease and an additional parallel between human and rodent development., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

Cholinergic dysfunction, impaired brain-derived neurotrophic factor and cAMP response element binding protein (BDNF-CREB) signaling are one of the major pathological hallmarks of cognitive impairment. Therefore, improving cholinergic neurotransmission, and regulating the BDNF-CREB pathway by downregulating apoptosis genes is one strategy for inhibiting the etiology of dementia. This study evaluates the potential effects of Stachys sieboldii MIQ (SS) extract against cognitive dysfunction and its underlying mechanisms. SS supplementation for 33 days improved scopolamine-induced memory impairment symptoms in Morris water maze test and Y-maze test. SS reduced the acetylcholineesterase activity and significantly increase acetylcholine and cholineacetyltransferase activity in the brain. In the subsequent mechanism study, SS regulated the mRNA expression level of neuronal plasticity molecules such as (nerve growth factor) NGF, BDNF, CREB, and its downstream molecules such as Bcl-2 and Egr-1 by downregulating the neuronal apoptosis targets in both hippocampus and frontal cortex. Additionally, inward currents caused by SS in hippocampal CA1 neurons was partially blocked by the GABA receptor antagonist picrotoxin (50 μM), suggesting that SS acts on synaptic/extrasynaptic GABA A receptors. These findings indicate that SS may function in a way that is similar to nootropic drugs by inhibiting cholinergic abnormalities, and neuronal apoptosis targets and ultimately increasing the expression of BDNF-CREB.

Executive function (EF) is a key cognitive process that emerges in early childhood and facilitates children's ability to control their own behavior. Individual differences in EF skills early in life are predictive of quality-of-life outcomes 30 years later (Moffitt et al., 2011). What changes in the brain give rise to this critical cognitive ability? Traditionally, frontal cortex growth is thought to underlie changes in cognitive control (Bunge & Zelazo, 2006; Moriguchi & Hiraki, 2009). However, more recent data highlight the importance of long-range cortical interactions between frontal and posterior brain regions. Here, we test the hypothesis that developmental changes in EF skills reflect changes in how posterior and frontal brain regions work together. Results show that children who fail a "hard" version of an EF task and who are thought to have an immature frontal cortex, show robust frontal activity in an "easy" version of the task. We show how this effect can arise via posterior brain regions that provide on-the-job training for the frontal cortex, effectively teaching the frontal cortex adaptive patterns of brain activity on "easy" EF tasks. In this case, frontal cortex activation can be seen as both the cause and the consequence of rule switching. Results also show that older children have differential posterior cortical activation on "easy" and "hard" tasks that reflects continued refinement of brain networks even in skilled children. These data set the stage for new training programs to foster the development of EF skills in at-risk children., (© 2017 John Wiley & Sons Ltd.)

This study investigates multimodal structural MR imaging biomarkers of development trajectories in pediatric bipolar disorder. T1-weighted and diffusion-weighted MR imaging was conducted to investigate cross-sectional group differences with age between typically developing controls (N = 26) and youths diagnosed with bipolar disorder (N = 26). Region-based analysis was used to examine cortical thickness of gray matter and diffusion tensor parameters in superficial white matter, and tractography-based analysis was used to examine deep white matter fiber bundles. Patients and controls showed significantly different maturation trajectories across brain areas; however, the magnitude of differences varied by region. The rate of cortical thinning with age was greater in patients than controls in the left frontal pole. While controls showed increasing fractional anisotropy (FA) and axial diffusivity (AD) with age, patients showed an opposite trend of decreasing FA and AD with age in fronto-temporal-striatal regions located in both superficial and deep white matter. The findings support fronto-temporal-striatal alterations in the developmental trajectories of youths diagnosed with bipolar disorder, and further, show the value of multimodal computational techniques in the assessment of neuropsychiatric disorders. These preliminary results warrant further investigation into longitudinal changes and the effects of treatment in the brain areas identified in this study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Arithmetic processing in adults is known to rely on a frontal-parietal network. However, neurocognitive research focusing on the neural and behavioral correlates of arithmetic development has been scarce, even though the acquisition of arithmetic skills is accompanied by changes within the fronto-parietal network of the developing brain. Furthermore, experimental procedures are typically adjusted to constraints of functional magnetic resonance imaging, which may not reflect natural settings in which children and adolescents actually perform arithmetic. Therefore, we investigated the longitudinal neurocognitive development of processes involved in performing the four basic arithmetic operations in 19 adolescents. By using functional near-infrared spectroscopy, we were able to use an ecologically valid task, i.e., a written production paradigm., Results: A common pattern of activation in the bilateral fronto-parietal network for arithmetic processing was found for all basic arithmetic operations. Moreover, evidence was obtained for decreasing activation during subtraction over the course of 1 year in middle and inferior frontal gyri, and increased activation during addition and multiplication in angular and middle temporal gyri. In the self-paced block design, parietal activation in multiplication and left angular and temporal activation in addition were observed to be higher for simple than for complex blocks, reflecting an inverse effect of arithmetic complexity., Conclusions: In general, the findings suggest that the brain network for arithmetic processing is already established in 12-14 year-old adolescents, but still undergoes developmental changes.

Inhibitory control (IC) is a core executive function that enables humans to resist habits, temptations, or distractions. IC efficiency in childhood is a strong predictor of academic and professional success later in life. Based on analysis of the sulcal pattern, a qualitative feature of cortex anatomy determined during fetal life and stable during development, we searched for evidence that interindividual differences in IC partly trace back to prenatal processes. Using anatomical magnetic resonance imaging (MRI), we analyzed the sulcal pattern of two key regions of the IC neural network, the dorsal anterior cingulate cortex (ACC) and the inferior frontal cortex (IFC), which limits the inferior frontal gyrus. We found that the sulcal pattern asymmetry of both the ACC and IFC contributes to IC (Stroop score) in children and adults: participants with asymmetrical ACC or IFC sulcal patterns had better IC efficiency than participants with symmetrical ACC or IFC sulcal patterns. Such additive effects of IFC and ACC sulcal patterns on IC efficiency suggest that distinct early neurodevelopmental mechanisms targeting different brain regions likely contribute to IC efficiency. This view shares some analogies with the "common variant-small effect" model in genetics, which states that frequent genetic polymorphisms have small effects but collectively account for a large portion of the variance. Similarly, each sulcal polymorphism has a small but additive effect: IFC and ACC sulcal patterns, respectively, explained 3% and 14% of the variance of the Stroop interference scores.

Atomic force microscopy (AFM) is emerging as an innovative tool to phenotype the brain. This study demonstrates the utility of AFM to determine nanomechanical and nanostructural features of the murine dorsolateral frontal cortex from weaning to adulthood. We found an increase in tissue stiffness of the primary somatosensory cortex with age, along with an increased cortical mechanical heterogeneity. To characterize the features potentially responsible for this heterogeneity, we applied AFM scan mode to directly image the topography of thin sections of the primary somatosensory cortical layers II/III, IV and V/VI. Topographical mapping of the cortical layers at successive ages showed progressive smoothing of the surface. Topographical images were also compared with histochemically derived morphological information, which demonstrated the deposition of perineuronal nets, important extracellular components and markers of maturity. Our work demonstrates that high-resolution AFM images can be used to determine the nanostructural properties of cortical maturation, well beyond embryonic and postnatal development. Furthermore, it may offer a new method for brain phenotyping and screening to uncover topographical changes in early stages of neurodegenerative diseases.

The event-related P3 potential, as elicited in auditory signal detection tasks, originates from neural activity of multiple cortical structures and presumably reflects an overlap of several cognitive processes. The fact that the P3 is affected by aging makes it a potential metric for age-related cognitive change. The P3 in older participants is thought to encompass frontal compensatory activity in addition to task-related processes. The current study investigates this by decomposing the P3 using group independent component analysis (ICA). Independent components (IC) of young and old participants were compared in order to investigate the effects of aging. Exact low-resolution tomography analysis (eLORETA) was used to compare current source densities between young and old participants for the P3-ICs to localize differences in cortical source activity for every IC. One of the P3-related ICs reflected a different constellation of cortical generators in older participants compared to younger participants, suggesting that this P3-IC reflects shifts in neural activations and compensatory processes with aging. This P3-IC was localized to the orbitofrontal/temporal, and the medio-parietal regions. For this IC, older participants showed more frontal activation and less parietal activation as measured on the scalp. The differences in cortical sources were localized in the precentral gyrus and the parahippocampal gyrus. This finding might reflect compensatory activity recruited from these cortical sources during a signal detection task.

Motivated by prior data on local cortical shrinkage and intracortical myelination, we predicted age-related changes in topological organization of cortical structural networks during adolescence. We estimated structural correlation from magnetic resonance imaging measures of cortical thickness at 308 regions in a sample of N = 297 healthy participants, aged 14-24 years. We used a novel sliding-window analysis to measure age-related changes in network attributes globally, locally and in the context of several community partitions of the network. We found that the strength of structural correlation generally decreased as a function of age. Association cortical regions demonstrated a sharp decrease in nodal degree (hubness) from 14 years, reaching a minimum at approximately 19 years, and then levelling off or even slightly increasing until 24 years. Greater and more prolonged age-related changes in degree of cortical regions within the brain network were associated with faster rates of adolescent cortical myelination and shrinkage. The brain regions that demonstrated the greatest age-related changes were concentrated within prefrontal modules. We conclude that human adolescence is associated with biologically plausible changes in structural imaging markers of brain network organization, consistent with the concept of tuning or consolidating anatomical connectivity between frontal cortex and the rest of the connectome., (© The Author 2017. Published by Oxford University Press.)

Smoking rates are particularly high during adolescence and young adulthood, when the brain is still undergoing significant developmental changes. Cross-sectional studies have revealed altered brain structure in smokers, such as thinner frontal cortical areas. Attention-deficit/hyperactivity disorder (ADHD) increases the risk of becoming nicotine-dependent, and has also been associated with abnormalities in frontal gray matter structure. The present study examines the relationships between smoking, cortical thickness and ADHD symptoms in a longitudinal design that compares adolescent and young adult smokers (n=44; 35 ADHD-affected) and non-smokers (n=45; 32 ADHD-affected) on frontal cortical thickness. Average frontal cortical thickness was estimated through structural magnetic resonance imaging (MRI) at two time points (mean ages 17.7 and 21.1 years), on average 3.4 years apart. Smokers had a 2.6% thinner frontal cortex than non-smokers and this difference was not explained by ADHD or other confounding factors. The rate of cortical thinning across the 3.4-year MRI measurement interval was similar in the total group of smokers compared to non-smokers. However, speeded thinning did occur in smokers who had started regular smoking more recently, in between the two measurements. These novel regular smokers did not differ significantly from the non-smokers at baseline. This suggests that the thinner frontal cortex was not a predisposing factor but rather a consequence of smoking. Although smokers had more ADHD symptoms overall, smoking did not influence the developmental course of ADHD symptoms., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Adolescence has traditionally been viewed as a period of vulnerability to increased risk-taking and adverse outcomes, which have been linked to neurobiological maturation of the frontostriatal reward system. However, growing research on the role of developmental changes in the adolescent frontostriatal system in facilitating learning will provide a more nuanced view of adolescence. In this review, we discuss the implications of existing research on this topic for learning during adolescence, and suggest that the very neural changes that render adolescents vulnerable to social pressure and risky decision making may also stand to play a role in scaffolding the ability to learn from rewards and from performance-related feedback., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)