Does the Relationship between Age and Brain Structure Differ in Youth with Conduct Disorder?

Conduct disorder (CD) is characterised by persistent antisocial and aggressive behaviour and typically emerges in childhood or adolescence. Although several authors have proposed that CD is a neurodevelopmental disorder, very little evidence is available about brain development in this condition. Structural brain alterations have been observed in CD, and some indirect evidence for delayed brain maturation has been reported. However, no detailed analysis of age-related changes in brain structure in youth with CD has been conducted. Using cross-sectional MRI data, this study aimed to explore differences in brain maturation in youth with CD versus healthy controls to provide further understanding of the neurodevelopmental processes underlying CD. 291 CD cases (153 males) and 379 healthy controls (160 males) aged 9-18 years (Mage = 14.4) were selected from the European multisite FemNAT-CD study. Structural MRI scans were analysed using surface-based morphometry followed by application of the ENIGMA quality control protocols. An atlas-based approach was used to investigate group differences and test for group-by-age and group-by-age-by-sex interactions in cortical thickness, surface area and subcortical volumes. Relative to healthy controls, the CD group showed lower surface area across frontal, temporal and parietal regions as well as lower total surface area. No significant group-by-age or group-by-age-by-sex interactions were observed on any brain structure measure. These findings suggest that CD is associated with lower surface area across multiple cortical regions, but do not support the idea that CD is associated with delayed brain maturation, at least within the age bracket considered here.

The Role of Maternal Secretor Status and Human Milk Oligosaccharides on Early Childhood Development: A Systematic Review and Meta-Analysis.

Background: Breast milk is the gold standard of infant nutrition, delivering nutrients and bioactive molecules as needed to support optimal infant growth and cognitive development. Increasing evidence links human milk oligosaccharides (HMOs) to these early childhood development milestones. Aims: To summarize and synthesize the evidence relating to HMOs and infant brain development, physical growth, and cognitive development. In addition, HMO concentrations in secretor and nonsecretor mothers were compared via a meta-analysis. Study Design: A systematic review and meta-analysis were carried out in accordance with the PRISMA statement. This review used three databases (PubMed, Scopus, and Web of Science) and was limited to English-language articles published between 2000 and June 30, 2023. Results: The initial searches yielded 245 articles, 27 of which were included in the systematic review and 12 in the meta-analysis. The meta-analysis revealed a substantial between-study heterogeneity, I2 = 97.3%. The pooled effect was 0.21 (95% CI: -0.41 to 0.83; p = 0.484), indicating that secretors had higher HMO concentrations, although this difference was not statistically significant. At one month of age, 2'FL, 3FL, and 3'SL play an important role in brain maturation and thus play a critical role in cognitive development. Secretors produce higher concentrations of 2'FL and 3'SL, explaining the benefits to infants of secretor mothers. Growth velocity was correlated to fucosylated and sialylated HMO concentrations, with lower concentrations linked to stunting. Conclusions: According to evidence from the systematically reviewed articles, HMOs are essential for a child's early development, but the extent to which they have an impact depends on maternal secretor status.

Lifelong absence of microglia alters hippocampal glutamatergic networks but not synapse and spine density.

Microglia sculpt developing neural circuits by eliminating excess synapses in a process called synaptic pruning, by removing apoptotic neurons, and by promoting neuronal survival. To elucidate the role of microglia during embryonic and postnatal brain development, we used a mouse model deficient in microglia throughout life by deletion of the fms-intronic regulatory element (FIRE) in the Csf1r locus. Surprisingly, young adult Csf1rΔFIRE/ΔFIRE mice display no changes in excitatory and inhibitory synapse number and spine density of CA1 hippocampal neurons compared with Csf1r+/+ littermates. However, CA1 neurons are less excitable, receive less CA3 excitatory input and show altered synaptic properties, but this does not affect novel object recognition. Cytokine profiling indicates an anti-inflammatory state along with increases in ApoE levels and reactive astrocytes containing synaptic markers in Csf1rΔFIRE/ΔFIRE mice. Notably, these changes in Csf1rΔFIRE/ΔFIRE mice closely resemble the effects of acute microglial depletion in adult mice after normal development. Our findings suggest that microglia are not mandatory for synaptic pruning, and that in their absence pruning can be achieved by other mechanisms.

Origin of functional de novo genes in humans from "hopeful monsters".

For a long time, it was believed that new genes arise only from modifications of preexisting genes, but the discovery of de novo protein-coding genes that originated from noncoding DNA regions demonstrates the existence of a "motherless" origination process for new genes. However, the features, distributions, expression profiles, and origin modes of these genes in humans seem to support the notion that their origin is not a purely "motherless" process; rather, these genes arise preferentially from genomic regions encoding preexisting precursors with gene-like features. In such a case, the gene loci are typically not brand new. In this short review, we will summarize the definition and features of human de novo genes and clarify their process of origination from ancestral non-coding genomic regions. In addition, we define the favored precursors, or "hopeful monsters," for the origin of de novo genes and present a discussion of the functional significance of these young genes in brain development and tumorigenesis in humans. This article is categorized under: RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution.

PRDM16 co-operates with LHX2 to shape the human brain.

PRDM16 is a dynamic transcriptional regulator of various stem cell niches, including adipocytic, hematopoietic, cardiac progenitors, and neural stem cells. PRDM16 has been suggested to contribute to 1p36 deletion syndrome, one of the most prevalent subtelomeric microdeletion syndromes. We report a patient with a de novo nonsense mutation in the PRDM16 coding sequence, accompanied by lissencephaly and microcephaly features. Human stem cells were genetically modified to mimic this mutation, generating cortical organoids that exhibited altered cell cycle dynamics. RNA sequencing of cortical organoids at day 32 unveiled changes in cell adhesion and WNT-signaling pathways. ChIP-seq of PRDM16 identified binding sites in postmortem human fetal cortex, indicating the conservation of PRDM16 binding to developmental genes in mice and humans, potentially at enhancer sites. A shared motif between PRDM16 and LHX2 was identified and further examined through comparison with LHX2 ChIP-seq data from mice. These results suggested a collaborative partnership between PRDM16 and LHX2 in regulating a common set of genes and pathways in cortical radial glia cells, possibly via their synergistic involvement in cortical development.

[Effects of antenatal corticosteroid therapy in pregnant women on the brain development of preterm infants as assessed by amplitude-integrated electroencephalography]. / æŒ¯å¹ æ•´åˆè„‘ç”µå›¾è¯„ä¼°å­•å¦‡äº§å‰ç³–çš®è´¨æ¿€ç´ æ²»ç–—å¯¹æ—©äº§å„¿è„‘å‘è‚²çš„å½±å“.

OBJECTIVES: To investigate the effects of antenatal corticosteroid (ACS) therapy in pregnant women on the brain development of preterm infants using amplitude-integrated electroencephalography (aEEG). METHODS: A retrospective analysis was conducted on 211 preterm infants with a gestational age of 28 to 34+6 weeks. The infants were divided into an ACS group (131 cases) and a control group (80 cases) based on whether antenatal dexamethasone was given for promoting fetal lung maturity. The first aEEG monitoring (referred to as aEEG1) was performed within 24 hours after birth, and the second aEEG monitoring (referred to as aEEG2) was performed between 5 to 7 days after birth. The aEEG results were compared between the two groups. RESULTS: In preterm infants with a gestational age of 28 to 31+6 weeks, the ACS group showed a more mature periodic pattern and higher lower amplitude boundary in aEEG1 compared to the control group (P<0.05). In preterm infants with a gestational age of 32 to 33+6 weeks and 34 to 34+6 weeks, the ACS group showed a higher proportion of continuous patterns, more mature periodic patterns and higher Burdjalov scores in aEEG1 (P<0.05). And the ACS group exhibited a higher proportion of continuous patterns, more mature periodic patterns, higher lower amplitude boundaries, narrower bandwidths, and higher Burdjalov scores in aEEG2 (P<0.05). CONCLUSIONS: ACS-treated preterm infants have more mature aEEG patterns compared to those not treated with ACS, suggesting a beneficial effect of ACS on the brain development of preterm infants.

Cortical specialization associated with native speech category acquisition in early infancy.

This study investigates neural processes in infant speech processing, with a focus on left frontal brain regions and hemispheric lateralization in Mandarin-speaking infants' acquisition of native tonal categories. We tested 2- to 6-month-old Mandarin learners to explore age-related improvements in tone discrimination, the role of inferior frontal regions in abstract speech category representation, and left hemisphere lateralization during tone processing. Using a block design, we presented four Mandarin tones via [ta] and measured oxygenated hemoglobin concentration with functional near-infrared spectroscopy. Results showed age-related improvements in tone discrimination, greater involvement of frontal regions in older infants indicating abstract tonal representation development and increased bilateral activation mirroring native adult Mandarin speakers. These findings contribute to our broader understanding of the relationship between native speech acquisition and infant brain development during the critical period of early language learning.

Sex differences in normal fetal regional brain apparent diffusion coefficient changes assessed by in utero DWI.

Objective: There are differences in the vulnerability of male and female fetal brains to adverse intrauterine exposure, preterm birth, and associated perinatal brain injury. The main objective of this study was to identify any statistically significant difference in the change of apparent diffusion coefficient (ADC) in the intracranial regions of male and female fetuses in the second and third trimesters. Methods: Diffusion-weighted imaging (DWI) was performed in 200 fetuses between 20 and 37 gestational ages (GA) with normal results or suspicious results on sonography followed by structural MRI. Pairwise ADC values of the regions of interest (ROIs) were manually delineated on either side of the cerebral white matter: frontal white matter (FWM), parietal white matter (PWM), occipital white matter (OWM), temporal white matter (TWM), basal ganglia (BG), thalamus (THA), cerebellar hemisphere (CBM), and a single measurement in the pons. The changes in these values were studied over the gestational range, along with potential sex differences and asymmetries of the cerebral hemispheres. Results: During the third trimester, ADC values in OWM, TWM, and CBM were significantly higher in male fetuses than those in female fetuses (p < 0.05). After the correction of false-discovery rates (FDR), the difference in CBM was the only statistically significant (p = 0.0032). However, the decreased rate of ADC values in male fetuses in CWM (except for FWM), BG, THA, CBM, and pons was higher than that in female fetuses during the second and third trimesters. Conclusions: We have shown some differences in the intracranial regional ADC changes between male and female fetuses using in utero DWI during the second and third trimesters.

Role of miRNAs in Brain Development.

Non-coding RNAs that are small in size, called microRNAs (miRNAs), exert a conse-quence in neutralizing gene activity after transcription. The nervous system is a massively ex-pressed organ, and an expanding body of research reveals the vital functions that miRNAs play in the brain's growth and neural activity. The significant benefit of miRNAs on the development of the central nervous system is currently shown through new scientific methods that concentrate on targeting and eradicating vital miRNA biogenesis pathways the elements involving Dicer and DGCR8. Modulation of miRNA has been associated with numerous essential cellular processes on neural progenitors, like differentiation, proliferation, and destiny determination. Current re-search discoveries that emphasize the significance of miRNAs in the complex process of brain development are included in this book. The miRNA pathway plays a major role in brain devel-opment, its operational dynamics, and even diseases. Recent studies on miRNA-mediated gene regulation within neural discrepancy, the circadian period and synaptic remodeling are signs of this. We also discussed how these discoveries may affect our comprehension of the fundamental processes behind brain diseases, highlighting the novel therapeutic opportunities miRNAs pro-vide for treating various human illnesses.

Single-cell approaches define two groups of mammalian oligodendrocyte precursor cells and their evolution over developmental time.

Here, we used single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq), and single-cell spatial transcriptomics to characterize murine cortical OPCs throughout postnatal life. During development, we identified two groups of differentially localized PDGFRα+ OPCs that are transcriptionally and epigenetically distinct. One group (active, or actOPCs) is metabolically active and enriched in white matter. The second (homeostatic, or hOPCs) is less active, enriched in gray matter, and predicted to derive from actOPCs. In adulthood, these two groups are transcriptionally but not epigenetically distinct, and relative to developing OPCs are less active metabolically and have less open chromatin. When adult oligodendrogenesis is enhanced during experimentally induced remyelination, adult OPCs do not reacquire a developmental open chromatin state, and the oligodendrogenesis trajectory is distinct from that seen neonatally. These data suggest that there are two OPC groups subserving distinct postnatal functions and that neonatal and adult OPC-mediated oligodendrogenesis are fundamentally different.

Brain volumes, behavioral inhibition, and anxiety disorders in children: results from the adolescent brain cognitive development study.

BACKGROUND: Magnetic resonance imaging (MRI) studies have identified brain changes associated with anxiety disorders (ADs), but the results remain mixed, particularly at a younger age. One key predictor of ADs is behavioral inhibition (BI), a childhood tendency for high avoidance of novel stimuli. This study aimed to evaluate the relationships between candidate brain regions, BI, and ADs among children using baseline data from the Adolescent Brain Cognitive Development (ABCD) study. METHODS: We analyzed global and regional brain volumes of 9,353 children (9-10 years old) in relation to BI and current ADs, using linear mixed models accounting for family clustering and important demographic and socioeconomic covariates. We further investigated whether and how past anxiety was related to brain volumes. RESULTS: Among included participants, 249 (2.66%) had a current AD. Larger total white matter (Beta = -0.152; 95% CI [-0.281, -0.023]), thalamus (Beta = -0.168; 95% CI [-0.291, -0.044]), and smaller hippocampus volumes (Beta = 0.094; 95% CI [-0.008, 0.196]) were associated with lower BI scores. Amygdala volume was not related to BI. Larger total cortical (OR = 0.751; 95% CI [0.580;0.970]), amygdala (OR = 0.798; 95%CI [0.666;0.956]), and precentral gyrus (OR = 0.802; 95% CI [0.661;0.973]) volumes were associated with lower odds of currently having ADs. Children with past ADs had smaller total white matter and amygdala volumes. CONCLUSIONS: The results show associations between brain volumes and both BI and ADs at an early age. Importantly, results suggest that ADs and BI have different neurobiological correlates and that earlier occurrences of ADs may influence brain structures related to BI and ADs, motivating research that can better delineate the similarities and divergence in the neurobiological underpinnings and building blocks of BI and ADs across their development in early life.

Evaluation of apparently healthy Egyptian infants and toddlers on the bayley-III scales according to age and sex.

BACKGROUND: Child development is shaped throughout the first years of life through the interaction of genetics and the environment. Bayley-III is valuably used to determine early developmental delay (DD). The aim of this study was to detect the differences in performance of a sample of apparently healthy Egyptian infants and toddlers on the Bayley-III scales in relation to their age and gender. METHODS: This was a cross-sectional study. Bayley scales were applied to 270 of the 300 recruited children following the inclusion criteria; to avoid potential risk factors affecting development. Assessment included cognitive, language and motor skills. Engaged children aged 18-42 months were divided into 4 age groups with six-month intervals. RESULTS: Approximately 78.4%, 76.2%, and 72% of the participants had average and above average scores in the cognitive, motor, and language domains, respectively. The language domain was characteristically impacted. The oldest age group (36-42 months) scored the highest means composite scores, while the 2nd group aged 24 - <30 months, scored the lowest means in the three evaluated domains. In general, girls had non-significantly higher composite scores than boys, with a small effect size (d = 0.2-0.4). In the language domain, girls aged 30 to < 36 months scored significantly higher composite scores than boys (p < 0.05), with a medium effect size (d = 0.73). CONCLUSION: The study indicates that the performance of apparently healthy Egyptian children on the Bayley III evaluation differs in relation to age and sex. The most vulnerable age group at potential risk of DD was children aged 24-30 months. Efforts must be directed to investigate the nutritional, physical, psychological and safety needs of this group. Attention must be paid to early childhood intervention programs that stimulate development, especially language development, and they must be tailored on the basis of age and gender. Gender-specific norms may be needed in the evaluation of language development.

Cockayne Syndrome Patient iPSC-Derived Brain Organoids and Neurospheres Show Early Transcriptional Dysregulation of Biological Processes Associated with Brain Development and Metabolism.

Cockayne syndrome (CS) is a rare hereditary autosomal recessive disorder primarily caused by mutations in Cockayne syndrome protein A (CSA) or B (CSB). While many of the functions of CSB have been at least partially elucidated, little is known about the actual developmental dysregulation in this devasting disorder. Of particular interest is the regulation of cerebral development as the most debilitating symptoms are of neurological nature. We generated neurospheres and cerebral organoids utilizing Cockayne syndrome B protein (CSB)-deficient induced pluripotent stem cells derived from two patients with distinct severity levels of CS and healthy controls. The transcriptome of both developmental timepoints was explored using RNA-Seq and bioinformatic analysis to identify dysregulated biological processes common to both patients with CS in comparison to the control. CSB-deficient neurospheres displayed upregulation of the VEGFA-VEGFR2 signalling pathway, vesicle-mediated transport and head development. CSB-deficient cerebral organoids exhibited downregulation of brain development, neuron projection development and synaptic signalling. We further identified the upregulation of steroid biosynthesis as common to both timepoints, in particular the upregulation of the cholesterol biosynthesis branch. Our results provide insights into the neurodevelopmental dysregulation in patients with CS and strengthen the theory that CS is not only a neurodegenerative but also a neurodevelopmental disorder.

Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease.

BACKGROUND: In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa. METHODS: Levodopa/carbidopa (4:1) was started at age 11 to 13 months, aiming at escalating to 5 to 6 mg/kg levodopa per day. Follow-up focused on dystonia severity and whether self-injury occurred. In addition, the literature was reviewed to delineate the age at onset of self-injury for all reported cases to date. RESULTS: During long-term follow-up, self-injury appears to have been prevented in two patients (now aged 14 and 15.5 years), as their HPRT1 gene mutations had been invariably associated with self-injury before. Future self-injury is unlikely, as only 1.1% of 264 published cases had self-injury onset later in life than these patients' current ages. The third patient started self-injury at age 1.5 years, while on a substantially lower levodopa dose. A clear effect of levodopa on dystonia could not be determined. CONCLUSIONS: Our observations suggest that levodopa, given early enough and sufficiently dosed, might be able to prevent self-injury in LND. Therefore, levodopa could be considered in patients with LND as early as possible, at least before the self-injury appears. Further research is needed to establish very early levodopa as an effective treatment strategy in LND, and to optimize timing and dosing.

Mimicking bacterial infection in male mice changes sperm small RNA profiles and multigenerationally alters offspring behavior and physiology.

Paternal pre-conceptual exposures, including stress, diet, substance abuse, parasite infection, and viral immune activation via Poly I:C, have been reported to influence the brains and behavior of offspring through sperm epigenetic changes. However, the effects of paternal (F0) pre-conceptual exposure to bacterial-induced immune activation on the behavior and physiology of F1 and F2 generations remain unexplored. We examined this using C57BL/6J mice. Eight-week-old males (F0) received a single intraperitoneal injection of the bacterial mimetic lipopolysaccharide (LPS: 5 mg/kg) or 0.9 % saline (vehicle control) before mating with naïve females at four weeks post-injection. Comprehensive behavioral assessments were conducted to investigate anxiety, social behaviors, depressive-like behaviors and cognition in both the F1 and F2 generations within the age range of 8 to 14 weeks. Results demonstrated that only female offspring of LPS-exposed fathers exhibited reduced anxiety levels in the light/dark box, large open field, and novelty-suppressed feeding test. These F1 female offspring also exhibited heightened sociability in the 3-chambered social interaction test and a reduced preference for saccharin in the saccharin preference test. Additionally, the F1 male offspring of LPS-challenged males demonstrated an increased total distance traveled in the light/dark box and a longer distance covered in the light zone. They also exhibited diminished preference for social novelty in the 3-chambered social interaction test and an elevated novel arm preference index in the Y-maze. In the F2 generation, male descendants of LPS-treated fathers showed reduced latency to feed in the novelty-suppressed feeding test. Additionally, the F2 generation of LPS challenged fathers, but not the F1 generation, displayed enhanced immune response in both sexes after an acute LPS immune challenge (5 mg/kg). Analysis of sperm small noncoding RNA profiles from LPS-treated F0 mice revealed significant changes at 4 weeks after administration of LPS. These changes included three microRNAs, eight PIWI-interacting RNAs, and two transfer RNAs, exhibiting significant upregulation (mmu-miR-146a-5p, mmu-piR-27082 and mmu-piR-29102) or downregulation (mmu-miR-5110, mmu-miR-467e-3p, mmu-piR-22583, mmu-piR-23548, mmu-piR-36341, mmu-piR-50293, mmu-piR-16583, mmu-piR-36507, Mus_musculus_tRNA-Ile-AAT-2-1 and Mus_musculus_tRNA-Tyr-GTA-1-1). Additionally, we detected 52 upregulated small noncoding RNAs (including 9 miRNAs, 41 piRNAs, and 2 tRNAs) and 7 downregulated small noncoding RNAs (3 miRNAs, 3 piRNAs, and 1 tRNA) in the sperm of F1 offspring from LPS-treated males. These findings provide compelling evidence for the involvement of epigenetic mechanisms in the modulation of brain function and immunity, and associated behavioral and immunological traits, across generations, in response to bacterial infection.

[Congenital brain malformations]. / Angeborene Hirnfehlbildungen.

CLINICAL ISSUE: Malformations of the central nervous system belong to the most common developmental disorders in humans. The clinical presentation of brain malformations is nonspecific including developmental delay, hypotonia, and/or epilepsy. The great heterogeneity concerning etiology, mechanisms of development and morphology is challenging for diagnosis and classification of brain malformations. Thereby recognizing specific malformations is essential for optimal patient management and prognostic evaluation. The aim of this article is to give an overview of several clinically relevant brain malformations occurring from different disrupted developmental processes in brain formation. STANDARD RADIOLOGICAL METHODS: Several brain malformations are already diagnosed during routine ultrasound in pregnancy. However pre- and postnatal magnetic resonance imaging remains the gold standard in detecting the partially subtle changes and to classify the malformations. METHODICAL INNOVATIONS: Advances in pre- and postnatal neuroimaging techniques and increasing investigation of genetic mechanisms underlying brain formation and its abnormalities have led to a better understanding of embryologic development and pathogeneses of brain malformations. CONCLUSION: Besides patient's history and clinical phenotype, neuroimaging plays a key role in diagnosis. Not always a specific diagnosis can be made, but neuroimaging patterns often enable a focused genetic testing and therefore are revolutionary for etiologic and prognostic assignment. Basic knowledge of brain development facilitates understanding and classifying of structural brain abnormalities.

Neurodevelopmental trajectories of cerebellar grey matter associated with verbal abilities in males with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with structural cerebellar abnormalities. Whether cerebellar grey matter volumes (GMV) are linked to verbal impairments remains controversial. Here, the association between cerebellar GMV and verbal abilities in ASD was examined across the lifespan. Lobular segmentation of the cerebellum was performed on structural MRI scans from the ABIDE I dataset in male individuals with ASD (N=144, age: 8.5-64.0 years) and neurotypical controls (N=188; age: 8.0-56.2 years). Stepwise linear mixed effects modeling including group (ASD vs. neurotypical controls), lobule-wise GMV, and age was performed to identify cerebellar lobules which best predicted verbal abilities as measured by verbal IQ (VIQ). An age-specific association between VIQ and GMV of bilateral Crus II was found in ASD relative to neurotypical controls. In children with ASD, higher VIQ was associated with larger GMV of left Crus II but smaller GMV of right Crus II. By contrast, in adults with ASD, higher VIQ was associated with smaller GMV of left Crus II and larger GMV of right Crus II. These findings indicate that relative to the contralateral hemisphere, an initial reliance on the language-nonspecific left cerebellar hemisphere is offset by more typical right-lateralization in adulthood.

The effect of prenatal maternal distress on offspring brain development: A systematic review.

BACKGROUND: Prenatal maternal distress can negatively affect pregnancy outcomes, yet its impact on the offspring's brain structure and function remains unclear. This systematic review summarizes the available literature on the relationship between prenatal maternal distress and brain development in fetuses and infants up to 12 months of age. METHODS: We searched Central, Embase, MEDLINE, PsycINFO, and PSYNDEXplus for studies published between database inception and December 2023. Studies were included if prenatal maternal anxiety, stress, and/or depression was assessed, neuroimaging was used to examine the offspring, and the offspring's brain was imaged within the first year of life. The quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-II. RESULTS: Out of the 1516 studies retrieved, 71 met our inclusion criteria. Although the studies varied greatly in their methodology, the results generally pointed to structural and functional aberrations in the limbic system, prefrontal cortex, and insula in fetuses and infants prenatally exposed to maternal distress. CONCLUSIONS: The hippocampus, amygdala, and prefrontal cortex have a high density of glucocorticoid receptors, which play a key role in adapting to stressors and maintaining stress-related homeostasis. We thus conclude that in utero exposure to maternal distress prompts these brain regions to adapt by undergoing structural and functional changes, with the consequence that these alterations increase the risk for developing a neuropsychiatric illness later on. Future research should investigate the effect of providing psychological support for pregnant women on the offspring's early brain development.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality.

BACKGROUND: High levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite Orientation Dispersion and Density Imaging (NODDI) estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. METHODS: We modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n=61) and at 9 months (n=50), using multivariable and subsequent bivariate regression models. RESULTS: The most robust statistically-significant findings were positive associations among 3-month rACC ODI and cACC NDI and concurrent NE, and 3-month lOFC ODI and prospective NE; and a negative association between 3-month dlPFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, and infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. CONCLUSIONS: Greater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rACC), decision-making (lOFC), action selection (cACC), and attentional processes (dlPFC) might result in greater integration of these subregions with other neural networks, greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.

Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy.

Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we found the emergence of the cortical hierarchy revealed by highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increased in a biphasic pattern with initial rapid and sequentially slower rate, with break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices were associated with enhanced language and motor skills, and frontoparietal association cortices for cognitive skills. The study discovered emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy, and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning.