Frontoparietal and salience network synchronizations during nonsymbolic magnitude processing predict brain age and mathematical performance in youth.

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.

Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation.

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.

The impact of a lack of mathematical education on brain development and future attainment.

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.

Coming of age in the frontal cortex: The role of puberty in cortical maturation.

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.

Frontal lobe growth is impaired in fetuses with congenital heart disease.

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 20th 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.

Association of Heavy Drinking With Deviant Fiber Tract Development in Frontal Brain Systems in Adolescents.

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.

A Longitudinal Study of Changes in Resting-State Functional Magnetic Resonance Imaging Functional Connectivity Networks During Healthy Aging.

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.

Developmental IL-6 Exposure Favors Production of PDGF-Responsive Multipotential Progenitors at the Expense of Neural Stem Cells and Other Progenitors.

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.

A Lifespan fMRI Study of Neurodevelopment Associated with Reading Chinese.

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.

Parent-Training with Kangaroo Care Impacts Infant Neurophysiological Development & Mother-Infant Neuroendocrine Activity.

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.

Psychotic symptoms are associated with lower cortical folding in youth at risk for mental illness

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 9­25 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.

Modular segregation of task-dependent brain networks contributes to the development of executive function in children.

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.

Association of Gray Matter and Personality Development With Increased Drunkenness Frequency During Adolescence.

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; ß = 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 (ß = 0.23; 95% CI, 0.01-0.46; t1,584 = 2; P = .04), the association between gray matter atrophy and alcohol drinking units (ß = -0.0033; 95% CI, -6 × 10-3 to -5 × 10-4; t1,509 = -2.4; P = .02) and drunkenness frequency at age 23 years (ß = -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.

Modeling development of frontal electroencephalogram (EEG) asymmetry: Sex differences and links with temperament.

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.

Frontal brain maturation and the stability of children's shyness.

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.

Development of the frontal lobe.

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.

Cerebral asymmetry during development using linear measures from MRI.

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.

Maternal speech shapes the cerebral frontotemporal network in neonates: A hemodynamic functional connectivity study.

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.

Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice.

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.

A genome-wide association study identifies genetic loci associated with specific lobar brain volumes.

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.