Cortical Maturation Research Articles

Retained Primitive Reflexes and Potential for Intervention in Autistic Spectrum Disorders.

We provide evidence to support the contention that many aspects of Autistic Spectrum Disorder (ASD) are related to interregional brain functional disconnectivity associated with maturational delays in the development of brain networks. We think a delay in brain maturation in some networks may result in an increase in cortical maturation and development in other networks, leading to a developmental asynchrony and an unevenness of functional skills and symptoms. The paper supports the close relationship between retained primitive reflexes and cognitive and motor function in general and in ASD in particular provided to indicate that the inhibition of RPRs can effect positive change in ASD.

Altered Cerebral Curvature in Preterm Infants Is Associated with the Common Genetic Variation Related to Autism Spectrum Disorder and Lipid Metabolism.

Preterm births are often associated with neurodevelopmental impairment. In the critical developmental period of the fetal brain, preterm birth disrupts cortical maturation. Notably, preterm birth leads to alterations in the fronto-striatal and temporal lobes and the limbic region. Recent advances in MRI acquisition and analysis methods have revealed an integrated approach to the genetic influence on brain structure. Based on imaging studies, we hypothesized that the altered cortical structure observed after preterm birth is associated with common genetic variations. We found that the presence of the minor allele at rs1042778 in OXTR was associated with reduced curvature in the right medial orbitofrontal gyrus (p < 0.001). The presence of the minor allele at rs174576 in FADS2 (p < 0.001) or rs740603 in COMT (p < 0.001) was related to reduced curvature in the left posterior cingulate gyrus. This study provides biological insight into altered cortical curvature at term-equivalent age, suggesting that the common genetic variations related to autism spectrum disorder (ASD) and lipid metabolism may mediate vulnerability to early cortical dysmaturation in preterm infants.

Acute histologic chorioamnionitis independently and directly increases the risk for brain abnormalities seen on magnetic resonance imaging in very preterm infants

The independent risk for neurodevelopmental impairments attributed to chorioamnionitis in premature infants remains controversial. Delayed brain maturation or injury identified on magnetic resonance imaging at term-equivalent age can be used as a surrogate measure of neurodevelopmental impairments that is less confounded by postdelivery neonatal intensive care unit environmental factors to investigate this relationship more clearly. This study aimed to determine whether preterm infants born with moderate to severe acute histologic chorioamnionitis would have a higher magnetic resonance imaging-determined global brain abnormality score, independent of early premature birth, when compared with preterm infants with no or mild chorioamnionitis. This was a prospective, multicenter cohort study involving infants born very prematurely ≤32 weeks' gestational age with acute moderate to severe histologic chorioamnionitis, graded using standard histologic criteria. Brain abnormalities were diagnosed and scored using a well-characterized, standardized scoring system captured using a high-resolution 3 Tesla magnetic resonance imaging research magnet. In secondary analyses, total brain volume and 4 magnetic resonance imaging metrics of cortical maturation (cortical surface area, sulcal depth, gyral index, and inner cortical curvature) were calculated using an automated algorithm and correlated with chorioamnionitis. The association of funisitis (any grade) with brain abnormalities was also explored. We investigated if premature birth mediated the relationship between histologic chorioamnionitis and brain abnormality score using mediation analysis. Of 353 very preterm infants, 297 infants had mild or no chorioamnionitis (controls), and 56 were diagnosed with moderate to severe acute histologic chorioamnionitis. The primary outcome brain abnormality score was significantly higher in histologic chorioamnionitis-exposed infants than in the controls (median, 4 vs 7; P<.001). Infants with acute histologic chorioamnionitis had significantly lower brain tissue volume (P=.03) and sulcal depth (P=.04), whereas other morphometric indices did not differ statistically. In the multiple regression analysis, we observed persistent significant relationships between moderate to severe acute histologic chorioamnionitis and brain abnormality scores (β=2.84; 1.51-4.16; P<.001), total brain volume (P=.03), and sulcal depth (P=.02). Funisitis was also significantly associated with brain abnormality score after adjustment for clinical confounders (P=.005). Mediation analyses demonstrated that 50% of brain abnormalities was an indirect consequence of premature birth, and the remaining 50% was a direct effect of moderate to severe acute histologic chorioamnionitis when compared with preterm infants with no or mild chorioamnionitis exposure. Examining gestational age as a mediator, funisitis did not exert a significant direct effect on brain abnormalities after the significant indirect effects of preterm birth were accounted for. Acute histologic chorioamnionitis increases the risk for brain injury and delayed maturation, both directly and indirectly, by inducing premature birth.

Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function.

Impaired cortical maturation is a postulated mechanism in the etiology of neurodevelopmental disorders, including schizophrenia. In the sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. Whether thalamic activity also shapes prefrontal cortical maturation is unknown. We show that inhibiting the mediodorsal and midline thalamus in mice during adolescence leads to a long-lasting decrease in thalamo-prefrontal projection density and reduced excitatory drive to prefrontal neurons. It also caused prefrontal-dependent cognitive deficits during adulthood associated with disrupted prefrontal cross-correlations and task outcome encoding. Thalamic inhibition during adulthood had no long-lasting consequences. Exciting the thalamus in adulthood during a cognitive task rescued prefrontal cross-correlations, task outcome encoding and cognitive deficits. These data point to adolescence as a sensitive window of thalamocortical circuit maturation. Furthermore, by supporting prefrontal network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders.

The adolescent pattern of sleep spindle development revealed by HD-EEG.

Sleep spindles are developmentally relevant cortical oscillatory patterns; however, they have mostly been studied by considering the entire spindle frequency range (11-15 Hz) without a distinction between the functionally and topographically different slow and fast spindles, using relatively few electrodes and analysing wide age-ranges. Here, we employ high-density night sleep electroencephalography in three age-groups between 12 and 20 years of age (30 females and 30 males) and analyse the adolescent developmental pattern of the four major parameters of slow and fast sleep spindles. Most of our findings corroborate those very few previous studies that also make a distinction between slow and fast spindles in their developmental analysis. We find spindle frequency increasing with age. A spindle density change is not obvious in our study. We confirm the declining tendencies for amplitude and duration, although within narrower, more specific age-windows than previously determined. Spindle frequency seems to be higher in females in the oldest age-group. Based on the pattern of our findings, we suggest that high-density electroencephalography, specifically targeting slow and fast spindle ranges and relatively narrow age-ranges would advance the understanding of both adolescent cortical maturation and development and the functional relevance of sleep spindles in general.

Neural Epidermal Growth Factor-Like Like Protein 2 Is Expressed in Human Oligodendroglial Cell Types.

Neural epidermal growth factor-like like 2 (NELL2) is a cytoplasmic and secreted glycosylated protein with six epidermal growth factor-like domains. In animal models, NELL2 is predominantly expressed in neural tissues where it regulates neuronal differentiation, polarization, and axon guidance, but little is known about the role of NELL2 in human brain development. In this study, we show that rostral neural stem cells (rNSC) derived from human-induced pluripotent stem cell (hiPSC) exhibit particularly strong NELL2 expression and that NELL2 protein is enriched at the apical side of neural rosettes in hiPSC-derived brain organoids. Following differentiation of human rostral NSC into neurons, NELL2 remains robustly expressed but changes its subcellular localization from >20 small cytoplasmic foci in NSC to one–five large peri-nuclear puncta per neuron. Unexpectedly, we discovered that in human brain organoids, NELL2 is readily detectable in the oligodendroglia and that the number of NELL2 puncta increases as oligodendrocytes mature. Artificial intelligence-based machine learning further predicts a strong association of NELL2 with multiple human white matter diseases, suggesting that NELL2 may possess yet unexplored roles in regulating oligodendrogenesis and/or myelination during human cortical development and maturation.

Sleep Power Topography in Children with Attention Deficit Hyperactivity Disorder (ADHD).

Objective: Recent years saw an increasing interest towards sleep microstructure abnormalities in attention-deficit/hyperactivity disorder (ADHD). However, the existing literature on sleep electroencephalographic (EEG) power in ADHD is still controversial, often based on single electrode recordings, and mainly focused on slow wave activity (SWA) during NREM sleep. This study aimed to systematically investigate sleep power topography in all traditional frequency bands, in all sleep stages and across sleep cycles using high-density EEG (HD-EEG). Method: Thirty drug-naïve children with ADHD (10.5 ± 2.1 years, 21 male) and 23 typically developing (TD) control participants (mean age: 10.2 ± 1.6 years, 13 male) were included in the current analysis. Signal power topography was computed in classical frequency bands during sleep, contrasted between groups and sleep cycles, and correlated with measures of ADHD severity, cognitive functioning and estimated total sleep time. Results: Compared to TD subjects, patients with ADHD consistently displayed a widespread increase in low-frequency activity (between 3 and 10 Hz) during NREM sleep, but not during REM sleep and wake before sleep onset. Such a difference involved a wide centro-posterior cluster of channels in the upper SWA range, in Theta, and low-Alpha. Between-group difference was maximal in sleep stage N3 in the first sleep cycle, and positively correlated with average total sleep time. Conclusions: These results support the concept that children with ADHD, compared to TD peers, have a higher sleep pressure and altered sleep homeostasis, which possibly interfere with (and delay) cortical maturation.

P53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

SummaryProper gene regulation is critical for both neuronal development and maintenance as the brain matures. We previously demonstrated that Akirin2, an essential nuclear protein that interacts with transcription factors and chromatin remodeling complexes, is required for the embryonic formation of the cerebral cortex. Here we show that Akirin2 plays a mechanistically distinct role in maintaining healthy neurons during cortical maturation. Restricting Akirin2 loss to excitatory cortical neurons resulted in progressive neurodegeneration via necroptosis and severe cortical atrophy with age. Comparing transcriptomes from Akirin2-null postnatal neurons and cortical progenitors revealed that targets of the tumor suppressor p53, a regulator of both proliferation and cell death encoded by Trp53, were consistently upregulated. Reduction of Trp53 rescued neurodegeneration in Akirin2-null neurons. These data: (1) implicate Akirin2 as a critical neuronal maintenance protein, (2) identify p53 pathways as mediators of Akirin2 functions, and (3) suggest Akirin2 dysfunction may be relevant to neurodegenerative diseases.

Cortical auditory evoked potentials in 1-month-old infants predict language outcomes at 12months.

The neurophysiological assessment of infants in their first developmental year can provide important information about the functional changes of the brain and supports the study of behavioral and developmental characteristics. Infants' cortical auditory evoked potentials (CAEPs) reflect cortical maturation and appear to predict subsequent language abilities. This study aimed to identify CAEP components to two auditory stimulus intensities in 1-month-old infants and to understand how these are associated with social interactive and self-regulatory behaviors. In addition, it examined whether CAEPs predicted developmental outcomes when infants were assessed at 12months of age. At 1month, P2 and N2 components were present for both auditory stimulus intensities, with an increased P2 amplitude being observed for the higher-intensity stimuli. We also observed that an increased P2 amplitude in the lower intensity predicted receptive and expressive language competencies at 12months. These results are consistent with previous findings indicating an association between auditory processing and developmental outcomes in infants. This study suggests that specific auditory neurophysiological markers are associated with developmental outcomes in the first developmental year.

The Anti-Inflammatory Agent Bindarit Attenuates the Impairment of Neural Development through Suppression of Microglial Activation in a Neonatal Hydrocephalus Mouse Model.

Neonatal hydrocephalus presents with various degrees of neuroinflammation and long-term neurologic deficits in surgically treated patients, provoking a need for additional medical treatment. We previously reported elevated neuroinflammation and severe periventricular white matter damage in the progressive hydrocephalus (prh) mutant which contains a point mutation in the Ccdc39 gene, causing loss of cilia-mediated unidirectional CSF flow. In this study, we identified cortical neuropil maturation defects such as impaired excitatory synapse maturation and loss of homeostatic microglia, and swimming locomotor defects in early postnatal prh mutant mice. Strikingly, systemic application of the anti-inflammatory small molecule bindarit significantly supports healthy postnatal cerebral cortical development in the prh mutant. While bindarit only mildly reduced the ventricular volume, it significantly improved the edematous appearance and myelination of the corpus callosum. Moreover, the treatment attenuated thinning in cortical Layers II-IV, excitatory synapse formation, and interneuron morphogenesis, by supporting the ramified-shaped homeostatic microglia from excessive cell death. Also, the therapeutic effect led to the alleviation of a spastic locomotor phenotype of the mutant. We found that microglia, but not peripheral monocytes, contribute to amoeboid-shaped activated myeloid cells in prh mutants' corpus callosum and the proinflammatory cytokines expression. Bindarit blocks nuclear factor (NF)-kB activation and its downstream proinflammatory cytokines, including monocyte chemoattractant protein-1, in the prh mutant. Collectively, we revealed that amelioration of neuroinflammation is crucial for white matter and neuronal maturation in neonatal hydrocephalus. Future studies of bindarit treatment combined with CSF diversion surgery may provide long-term benefits supporting neuronal development in neonatal hydrocephalus.SIGNIFICANCE STATEMENT In neonatal hydrocephalus, little is known about the signaling cascades of neuroinflammation or the impact of such inflammatory insults on neural cell development within the perinatal cerebral cortex. Here, we report that proinflammatory activation of myeloid cells, the majority of which are derived from microglia, impairs periventricular myelination and cortical neuronal maturation using the mouse prh genetic model of neonatal hydrocephalus. Administration of bindarit, an anti-inflammatory small molecule that blocks nuclear factor (NF)-kB activation, restored the cortical thinning and synaptic maturation defects in the prh mutant brain through suppression of microglial activation. These data indicate the potential therapeutic use of anti-inflammatory reagents targeting neuroinflammation in the treatment of neonatal hydrocephalus.

Neurophysiology of the Developing Cerebral Cortex: What We Have Learned and What We Need to Know.

This review article aims to give a brief summary on the novel technologies, the challenges, our current understanding, and the open questions in the field of the neurophysiology of the developing cerebral cortex in rodents. In the past, in vitro electrophysiological and calcium imaging studies on single neurons provided important insights into the function of cellular and subcellular mechanism during early postnatal development. In the past decade, neuronal activity in large cortical networks was recorded in pre- and neonatal rodents in vivo by the use of novel high-density multi-electrode arrays and genetically encoded calcium indicators. These studies demonstrated a surprisingly rich repertoire of spontaneous cortical and subcortical activity patterns, which are currently not completely understood in their functional roles in early development and their impact on cortical maturation. Technological progress in targeted genetic manipulations, optogenetics, and chemogenetics now allow the experimental manipulation of specific neuronal cell types to elucidate the function of early (transient) cortical circuits and their role in the generation of spontaneous and sensory evoked cortical activity patterns. Large-scale interactions between different cortical areas and subcortical regions, characterization of developmental shifts from synchronized to desynchronized activity patterns, identification of transient circuits and hub neurons, role of electrical activity in the control of glial cell differentiation and function are future key tasks to gain further insights into the neurophysiology of the developing cerebral cortex.

Early alterations of the neuronal network processing whisker-related sensory signal during absence epileptogenesis.

Epileptogenesis is the particular process during which the epileptic network builds up progressively before the onset of the first seizures. Whether physiological functions are impacted by this development of epilepsy remains unclear. To explore this question, we used Genetic Absence Epilepsy Rats From Strasbourg (GAERS), in which spike-and-wave discharges are initiated in the whisker primary somatosensory cortex (wS1) and first occur during cortical maturation. We studied the development of both the epileptic and the physiological wS1 circuits during cortical maturation to understand the interactions between them and the consequences for the animals' behavior. In sedated and immobilized rat pups, we recorded in vivo epileptic and whisker sensory evoked activities across the wS1 and thalamus using multicontact electrodes. We compared sensory evoked potentials based on current source density analysis. We then analyzed the multiunit activities evoked by whisker stimulation in GAERS and control rats. Finally, we evaluated behavioral performance dependent on the functionality of the wS1 cortex using the gap-crossing task. We showed that the epileptic circuit changed during the epileptogenesis period in GAERS, by involving different cortical layers of wS1. Neuronal activities evoked by whisker stimulation were reduced in the wS1 cortex at P15 and P30 in GAERS but increased in the ventral posteromedial nucleus of the thalamus at P15 and in the posterior medial nucleus at P30, when compared to control rats. Finally, we observed lower performance in GAERS versus controls, at both P15 and P30, in a whisker-mediated behavioral task. Our data show that the functionality of wS1 cortex and thalamus is altered early during absence epileptogenesis in GAERS and then evolves before spike-and-wave discharges are fully expressed. They suggest that the development of the pathological circuit disturbs the physiological one and may be responsible for both the emergence of seizures and associated comorbidities.

Annals of Neurology: Volume 90, Number 6, December 2021

A diffusion tensor imaging MRI scan showing fractional anisotropy of the prefrontal cortex of a 7 week old pig, used to study the effect of cardiopulmonary bypass on developing brains. Increased cortical fractional anisotropy after severe injury due to cardiopulmonary bypass served as a measure of the impact on cortical maturation. See paper by Dhari and colleagues in this issue (pp. 913‐926).

Assessment of normal fetal cortical sulcus development

The aim of our study was to investigate the normal cortical sulcus development in fetuses without central nervous system abnormality with transabdominal ultrasonography. Our study was planned as a cross-sectional study in our clinic between November 2011 and October 2012. The study group was selected among pregnant women who applied to our hospital for routine antenatal follow-up. Singleton pregnancies, between 15th and 32nd gestational weeks, were included in the study. During the routine fetal ultrasonographic examination of these pregnant women, sylvian sulcus, parietooccipital sulcus, calcarine sulcus, and cingulate sulcus length measurements were taken and the correlation of these values with gestational week was evaluated. Three hundred and thirty-two patients were included in the study. Sylvian sulcus length, parietooccipital sulcus length, calcarine sulcus length, and cingulate sulcus length could be first measured respectively, at 15th, 17th, 17th and 25th gestational week. We found a positive correlation between gestational age and sylvian sulcus, parietooccipital sulcus, calcarine sulcus, and cingulate sulcus length measurements (p < 0.001). Sulcal development and cortical maturation can be evaluated prenatally with transabdominal ultrasonography of the central nervous system.

Delayed maturation of P2 flash visual evoked potential (VEP) latency in newborns of gestational diabetic mothers

The prevalence of gestational diabetes mellitus (GDM) has rapidly increased, yet few prior studies have investigated parameters of early brain development in infants born to gestational diabetic mothers. The present study assessed visual evoked potentials (VEPs) in healthy infants born to gestational diabetic mothers and matched controls. After exclusions, in this prospective study we examined VEPs in 73 neonates between 37weeks and 41weeks gestation at birth (n=37 infants of gestational diabetic mothers). Stroboscopic flashes were presented through closed eyelids during passive electroencephalography (EEG) recording to derive VEP waveforms during natural sleep. There was a statistically significant moderate correlation between gestational age at birth and P2 latency of the flash VEP where P2 latency significantly decreased with increasing gestational age (Pearson's R(73)=-0.32, p<.01). There was also a significant moderate correlation between postnatal age (hours of life) and P2 latency of the flash VEP where P2 latency significantly decreased with increasing postnatal age (Pearson's R(73)=-0.23, p<.05). When controlling for gestational age at birth, postnatal age, and sex, there was a significant effect of group (GDM-exposed vs. control) on P2 latency of the flash VEP (p<.05). Infants of gestational diabetic mothers had a significantly longer P2 latency (M: 215.29±SD: 2.58ms) than controls (M: 206.41±SD: 2.62ms). Our findings suggest P2 flash VEP latency is a potential measure of cortical maturation and marker of immature development in infants of gestational diabetic mothers.

Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation.

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. 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. 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. 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.

VP53.02: Clinical characteristics and outcome of fetal partial agenesis of septum pellucidum

Agenesis of septum pellucidum (ASP) has an excellent prognosis when is isolated. Available series in ASP include few cases of the partial ASP (pASP) subgroup, probably because it is a very uncommon and misdiagnosed condition. Thus, our objective was to describe clinical characteristics and outcomes of pSAP. Retrospective study including fetuses diagnosed of pASP in our neurosonography unit from January 2019 to December 2020. Cases secondary to destructive origin were excluded. We collected data from advanced neurosonography and magnetic resonance including gestational age (GA) at diagnose, the evaluation of the optic nerves and chiasma, the presence of associated CNS and non-CNS anomalies and the presence of the pituitary gland. All cases have genetic study with array-CGH. pASP was considered as isolated when no other prenatal findings were detected. Postnatal data included MRI after delivery, evaluation of the visual system, endocrine tests and clinical neurologic follow-up. Seven patients with a prenatal diagnosis of pASP were included. Mean GA at diagnose was 27.2 weeks (range 24.1-30.7). pASP was considered isolated in 4 fetuses and all are developing normally at 13 months (range 8-16). From the three fetuses considered non-isolated, one with other CNS findings (mild ventriculomegaly, cortical maturation delay in operculum area and cerebellar growth in the lower limit) presents delay in language acquisition at 17 months; one with other CNS and non-CNS findings (column fornix fusion, dilatation of anterior horns, short corpus callosum, ARSA and low implantation ears) is considered as SOD spectrum at 12 months; and one with non-CNS findings (unilateral cleft lip and palate) is developing normal at 18 months. pASP has a good prognosis when isolated and the presence of associated findings increases the risk of abnormal neurodevelopment. pASP is an underdiagnosed condition and further research is warranted to explore its incidence and specific prognosis.

A histological survey of avian post-natal skeletal ontogeny.

Bone histology of crown-group birds is a research topic of great interest, permitting insight into the evolution of remarkably high growth rates in this clade and variation across the altricial-precocial spectrum. In this study, we describe microanatomical characteristics of the humerus and femur in partial growth series from 14 crown group birds representing ten major clades (Struthioniformes, Galliformes, Apodiformes, Columbiformes, Charadriiformes, Accipitriformes, Strigiformes, Psittaciformes, Falconiformes, and Passeriformes). Our goals were to: (1) describe the microanatomy of each individual; (2) make inter-and intra-taxonomic comparisons; (3) assess patterns that correspond with developmental mode; and (4) to further parse out phylogenetic, developmental, and functional constraints on avian osteological development. Across taxa, the femoral and humeral tissue of neonates can be broadly characterized as highly-vascularized, disorganized woven bone with great variation in cortical thickness (inter-and intrataxonomically, within an individual specimen, and within a single section). The tissue of precocial chicks is relatively more mature at hatching than in altricial, but other categories along the developmental spectrum were less easy to distinguish, thus we were unable to identify a definitive histological proxy for developmental mode. We did not find evidence to support hypotheses that precocial chicks exclusively have thicker cortices and more mature bone in the femur than the humerus at time of hatching; instead, this is a characteristic of nearly all taxa (regardless of developmental mode), suggesting deep evolutionary origins and the effects of developmental channeling. Bone tissue in adults exhibited unexpected variation, corresponding to differences in body size. Large-bodied birds have cortices of fibrolamellar bone, but organization of tissue increases and vascularity decreases with diminishing body size. The outer circumferential layer (OCL) also appears at earlier growth stages in small-bodied taxa. Thus, while the OCL is indicative of a cessation of appositional growth it is not always indicative of cortical maturity (that is, maximum organization of bony tissue for a given taxon). Small size is achieved by truncating the period of fast growth; manipulation of the timing of offset of bone growth is therefore an important factor in changing growth trajectories to alter adult body size.

Serial neurosonography in fetuses with congenital heart defects shows mild delays in cortical development.

IntroductionNeurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri‐operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development.MethodsCerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0–5) by blinded examiners using a cortical maturation scheme.ResultsCortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: −0.12 grade, 95% CI (−0.23; −0.01) p = 0.05, cingulate fissure: −0.24 grade, 95% CI (−0.38; −0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses.ConclusionSmall differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third‐trimester delay. The clinical implications of the small differences however, remain unknown.

Disrupted Timing of MET Signaling Derails the Developmental Maturation of Cortical Circuits and Leads to Altered Behavior in Mice.

The molecular regulation of the temporal dynamics of circuit maturation is a key contributor to the emergence of normal structure-function relations. Developmental control of cortical MET receptor tyrosine kinase, expressed early postnatally in subpopulations of excitatory neurons, has a pronounced impact on the timing of glutamatergic synapse maturation and critical period plasticity. Here, we show that using a controllable overexpression (cto-Met) transgenic mouse, extending the duration of MET signaling after endogenous Met is switched off leads to altered molecular constitution of synaptic proteins, persistent activation of small GTPases Cdc42 and Rac1, and sustained inhibitory phosphorylation of cofilin. These molecular changes are accompanied by an increase in the density of immature dendritic spines, impaired cortical circuit maturation of prefrontal cortex layer 5 projection neurons, and altered laminar excitatory connectivity. Two photon in vivo imaging of dendritic spines reveals that cto-Met enhances de novo spine formation while inhibiting spine elimination. Extending MET signaling for two weeks in developing cortical circuits leads to pronounced repetitive activity and impaired social interactions in adult mice. Collectively, our data revealed that temporally controlled MET signaling as a critical mechanism for controlling cortical circuit development and emergence of normal behavior.