Cortical Maturation Research Articles

Altered cortical development in fetuses with isolated nonsevere ventriculomegaly assessed by neurosonography.

To perform a comprehensive assessment of cortical development in fetuses with isolated nonsevere ventriculomegaly (INSVM) by neurosonography. We prospectively included 40 fetuses with INSVM and 40 controls. INSVM was defined as atrial width between 10.0 and 14.9mm without associated malformation, infection, or chromosomal abnormality. Cortical development was assessed by neurosonography at 26 and 30weeks of gestation measuring depth of selected sulci and applying a maturation scale from 0 (no appearance) to 5 (maximally developed) of main sulci and areas. INSVM showed underdeveloped calcarine and parieto-occipital sulci. In addition, significant delayed maturation pattern was also observed in regions distant to ventricular system including Insula depth (controls 30.8mm [SD 1.7] vs INSVM 31.7mm [1.8]; P=.04), Sylvian fissure grading (>2 at 26weeks: controls 87.5% vs INSVM 50%, P=.01), mesial area grading (>2 at 30weeks: controls 95% vs INSVM 62.5%; P=.03), and cingulate sulcus grading (>2 at 30weeks: controls 100% vs INSVM 80.5%; P=.01). Fetuses with INSVM showed underdeveloped cortical maturation including also regions, where effect of ventricular dilatation is unlikely. These results suggest that in a proportion of fetuses with INSVM, ventricular dilation might be related with altered cortical architecture.

Network-based decoupling of local gyrification in obsessive-compulsive disorder.

Gyrification is associated with cortical maturation and closely linked to neurodevelopmental processes. Obsessive-compulsive disorder has previously been associated with neurodevelopmental risk factors. Using graph theoretical modeling we examined structural covariance patterns to assess potential disruptions in processes associated with neurodevelopment in OCD. In total 97 patients and 92 healthy controls underwent magnetic resonance imaging. Structural covariance networks based on local gyrification indices were constructed using an atlas-based parcellation scheme. Network properties were assessed using the network-based statistic as well as global and local graph theoretical measures. Correlations between gyrification and symptom severity as well as age of disease onset were examined. Network-based statistic analysis revealed one cluster with significantly decreased structural covariance in patients comprising mainly ventral brain regions (p=.041). Normalized characteristic path length was found to be impaired in patients (p=.051). On a nodal level, left middle frontal sulcus displayed a significantly decreased local clustering coefficient (p<.001). Finally, gyrification in several inferior frontal nodes significantly correlated with age of onset but not symptom severity. The decrease in a gyrification-based covariance network in OCD appears to be mostly confined to ventral areas in which gyrification starts the latest during development. This pattern may indicate that alterations taking place during development are potentially time locked to specific periods. Correlations between gyrification in inferio-frontal nodes and age of onset potentially indicate a structural trait rather than state marker for OCD. Finally, a trend in impaired global integration capabilities may point towards potentially widespread global alterations during neurodevelopment in patients.

Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons.

The degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD) contributes to cognitive impairment. Nerve growth factor (NGF) secreted in the cerebral cortex is necessary for the phenotypic maintenance of BFCNs. AD is associated with disturbances in NGF metabolism, leading to reduced mature NGF levels and to an accumulation of its precursor, proNGF. We previously described that, in rats, this neurotrophic imbalance is sufficient to induce a loss of cortical cholinergic synapses. In the present study, we investigated whether this neurotrophic imbalance can produce an AD-like retrograde degeneration of BFCNs. Using a combination of retrograde labeling and quantitative cell imaging, we could demonstrate that inhibiting cortical proNGF maturation results in an atrophy of BFCNs, a downregulation of the NGF receptors p75 neurotrophin receptor and tropomyosin receptor kinase A, and a reduction in choline acetyltransferase protein expression. The transient increase in sortilin levels and the sustained colocalization with p75 neurotrophin receptor suggest a participation of proNGF in this degenerative process. This study demonstrates that impairments in the extracellular maturation of proNGF are sufficient to cause a somatodendritic retrograde degeneration of the BFCNs.

T1 white/gray contrast as a predictor of chronological age, and an index of cognitive performance

Knowing the maturational schedule of typical brain development is critical to our ability to identify deviations from it; such deviations have been related to cognitive performance and even developmental disorders. Chronological age can be predicted from brain images with considerable accuracy, but with limited spatial specificity, particularly in the case of the cerebral cortex. Methods using multi-modal data have shown the greatest accuracy, but have made limited use of cortical measures. Methods using complex measures derived from voxels throughout the brain have also shown great accuracy, but are difficult to interpret in terms of cortical development. Measures based on cortical surfaces have yielded less accurate predictions, suggesting that perhaps cortical maturation is less strongly related to chronological age than is maturation of deep white matter or subcortical structures. We question this suggestion. We show that a simple metric based on the white/gray contrast at the inner border of the cortex is a good predictor of chronological age. We demonstrate this in two large datasets: the NIH Pediatric Data, with 832 scans of typically developing children, adolescents, and young adults; and the Pediatric Imaging, Neurocognition, and Genetics data, with 760 scans of individuals in a similar age-range. Further, our usage of an elastic net penalized linear regression model reveals the brain regions which contribute most to age-prediction. Moreover, we show that the residuals of age-prediction based on this white/gray contrast metric are not merely random errors, but are strongly related to IQ, suggesting that this metric is sensitive to aspects of brain development that reflect cognitive performance.

Methylphenidate enhances neuronal differentiation and reduces proliferation concomitant to activation of Wnt signal transduction pathways

Methylphenidate (Ritalin) is the most commonly prescribed drug in the treatment of attention-deficit hyperactivity disorder. It is suggested that in vivo, methylphenidate treatment supports cortical maturation, however, the molecular and cellular mechanisms are not well understood. This study aimed to explore the potential effect of methylphenidate on cell proliferation and maturation in various cellular models, hypothesizing its interaction with the Wnt-signaling. The termination of cell proliferation concomitant to neuronal maturation following methylphenidate treatment was observed in all of the cell-models tested: murine neural stem-, rat PC12- and the human SH-SY5Y-cells. Inhibition of Wnt-signaling in SH-SY5Y cells with Dkk1 30 min before methylphenidate treatment suppressed neuronal differentiation but enhanced proliferation. The possible involvement of the dopamine-transporter in cell differentiation was discounted following the observation of opposing results after GBR-12909 treatment. Moreover, Wnt-activation via methylphenidate was confirmed in Wnt-luciferase-reporter assay. These findings reveal a new mechanism of action of methylphenidate that might explain long-term effects.

Ontogenetic development of sensitivity of the cerebral cortex to an antagonist of GABA(A) receptor bicuculline.

Local application of four concentrations of bicuculline methiodide (a specific antagonist of GABA(A) receptors) was used to study a sensitivity of somatosensory cortex in four age groups of immature rats with implanted electrodes. Presence and latencies of two epileptic phenomena (focal discharges and seizures) were evaluated. Focal discharges exhibited moderate tendency to a decrease of sensitivity to bicuculline methiodide with maturation. Concentration-effect relation of incidence of focal discharges was observed only in 7- and 12-day-old but not in older animals. Results with incidence and latencies of seizures did not show relations to age or concentration of bicuculline. Neither of the epileptic phenomena can be used as a reliable index of cortical maturation.

Maturation trajectories of cortical resting-state networks depend on the mediating frequency band

The functional significance of resting state networks and their abnormal manifestations in psychiatric disorders are firmly established, as is the importance of the cortical rhythms in mediating these networks. Resting state networks are known to undergo substantial reorganization from childhood to adulthood, but whether distinct cortical rhythms, which are generated by separable neural mechanisms and are often manifested abnormally in psychiatric conditions, mediate maturation differentially, remains unknown. Using magnetoencephalography (MEG) to map frequency band specific maturation of resting state networks from age 7 to 29 in 162 participants (31 independent), we found significant changes with age in networks mediated by the beta (13–30 Hz) and gamma (31–80 Hz) bands. More specifically, gamma band mediated networks followed an expected asymptotic trajectory, but beta band mediated networks followed a linear trajectory. Network integration increased with age in gamma band mediated networks, while local segregation increased with age in beta band mediated networks. Spatially, the hubs that changed in importance with age in the beta band mediated networks had relatively little overlap with those that showed the greatest changes in the gamma band mediated networks. These findings are relevant for our understanding of the neural mechanisms of cortical maturation, in both typical and atypical development.

Social, motor, and cognitive development through the lens of sleep network dynamics in infants and toddlers between 12 and 30 months of age.

Widespread change in behavior and the underlying brain network substrate is a hallmark of early development. Sleep plays a fundamental role in this process. Both slow waves and spindles are key features of nonrapid eye movement sleep (NREM) that exhibit pronounced developmental trajectories from infancy to adulthood. Yet, these prominent features of NREM sleep are poorly understood in infants and toddlers in the age range of 12 to 30 months. Moreover, it is unknown how network dynamics of NREM sleep are associated with outcomes of early development. Addressing this gap in our understanding of sleep during development will enable the subsequent study of pathological changes in neurodevelopmental disorders. The aim of the current study was to characterize the sleep topography with high-density electroencephalography in this age group. We found that δ, θ, and β oscillations and sleep spindles exhibited clear developmental changes. Low δ and high θ oscillations correlated with motor, language, and social skills, independent of age. These findings suggest an important role of network dynamics of NREM sleep in cortical maturation and the associated development of skills during this important developmental period.

Personality Traits Are Associated With Cortical Development Across Adolescence: A Longitudinal Structural MRI Study.

How personality traits relate to structural brain changes in development is an important but understudied question. In this study, cortical thickness (CT) and surface area (SA), estimated using magnetic resonance imaging (MRI), were investigated in 99 participants aged 8-19years. Follow-up MRI data were collected after on average 2.6years for 74 individuals. The Big Five personality traits were related to longitudinal regional CT or SA development, but limited cross-sectional relations were observed. Conscientiousness, emotional stability, and imagination were associated with more age-expected cortical thinning over time. The results suggest that the substantial individual variability observed in personality traits may partly be explained by cortical maturation across adolescence, implying a developmental origin for personality-brain relations observed in adults.

Neurodevelopmental perspectives on dance learning: Insights from early adolescence and young adulthood.

Studies investigating human motor learning and movement perception have shown that similar sensorimotor brain regions are engaged when we observe or perform action sequences. However, the way these networks enable translation of complex observed actions into motor commands-such as in the context of dance-remains poorly understood. Emerging evidence suggests that the ability to encode specific visuospatial and kinematic movement properties encountered via different routes of sensorimotor experience may be an integral component of action learning throughout development. Using a video game-based dance training paradigm, we demonstrate that patterns of voxel activity in visual and sensorimotor brain regions when perceiving movements following training are related to the sensory modalities through which these movements were encountered during whole-body dance training. Compared to adolescents, young adults in this study demonstrated more distinctive patterns of voxel activity in visual cortices in relation to different types of sensorimotor experience. This finding suggests that cortical maturity might influence the extent to which prior sensorimotor experiences shape brain activity when watching others in action, and potentially impact how we acquire new motor skills.

Differential Rates of Perinatal Maturation of Human Primary and Nonprimary Auditory Cortex.

Primary and nonprimary cerebral cortex mature along different timescales; however, the differences between the rates of maturation of primary and nonprimary cortex are unclear. Cortical maturation can be measured through changes in tissue microstructure detectable by diffusion magnetic resonance imaging (MRI). In this study, diffusion tensor imaging (DTI) was used to characterize the maturation of Heschl’s gyrus (HG), which contains both primary auditory cortex (pAC) and nonprimary auditory cortex (nAC), in 90 preterm infants between 26 and 42 weeks postmenstrual age (PMA). The preterm infants were in different acoustical environments during their hospitalization: 46 in open ward beds and 44 in single rooms. A control group consisted of 15 term-born infants. Diffusion parameters revealed that (1) changes in cortical microstructure that accompany cortical maturation had largely already occurred in pAC by 28 weeks PMA, and (2) rapid changes were taking place in nAC between 26 and 42 weeks PMA. At term equivalent PMA, diffusion parameters for auditory cortex were different between preterm infants and term control infants, reflecting either delayed maturation or injury. No effect of room type was observed. For the preterm group, disturbed maturation of nonprimary (but not primary) auditory cortex was associated with poorer language performance at age two years.

The effects of stimulus rate on ABR morphology and its relationship to P1 CAEP responses and auditory speech perception outcomes in children with auditory neuropathy spectrum disorder: evidence from case reports

Objective: Auditory neuropathy spectrum disorder (ANSD) affects approximately 5–15% of children with sensorineural hearing loss (SNHL). ANSD is characterized by the presence of otoacoustic emissions (OAE) and an absent or abnormal auditory brainstem response (ABR). The purpose of this study was to investigate the prognostic value of slow-rate ABR in predicting the auditory cortical development and auditory speech perception outcomes in case studies of children with ANSD.Design: ABR waveform characteristics were collected at slow stimulation rates (5.1 clicks/second) and a fast stimulation rates (>11–31.1 clicks/second, rates typically used in a clinical setting) in three case reports of children with ANSD. P1 CAEP responses and measures of auditory speech perception using the Infant Toddler Meaningful Auditory Integration Scale (IT-MAIS) were also collected in these children. Retrospective analysis was performed to evaluate the prognostic value of slow- versus fast-rate ABR in predicting P1 CAEP responses and auditory speech perception outcomes in these children.Study sample: Participants included case reports of three paediatric participants with a clinical diagnosis of ANSD.Results: Slow-rate ABR did not elicit significant improvements in waveform morphology compared to fast-rate ABR. P1 CAEP results were present in 2 out of 3 cases and were consistent with auditory speech perception outcomes.Conclusions: Even when ABR stimulation rates were slowed, ABR responses in these children with ANSD did not display any characteristic or replicable pattern, and ABR responses were not predictive of cortical auditory maturation or behavioural performance. In contrast, P1 CAEP responses provided valuable information regarding the maturational status of the auditory cortex and P1 CAEP responses were consistent with behavioural measures of auditory speech perception. Overall, results highlight the high prognostic value of P1 CAEP testing when used in conjunction with behavioural measures of auditory speech perception in children with ANSD.

Effects of the brain-derived neurotropic factor variant Val66Met on cortical structure in late childhood and early adolescence

BackgroundThe brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been associated with several neuropsychiatric disorders and regional structural brain changes in adults, but little is known about Val66Met's effect on brain morphology during typical or atypical neurodevelopment. Windows of vulnerability to psychopathology may be associated with the different alleles of the Val66Met polymorphism during childhood and adolescence. MethodologyWe investigated the effect of Val66Met on cortical thickness in MRI scans of 718 children and adolescents (6–12 years old) with typical development, and in those meeting DSM criteria for a psychiatric disorder. ResultsVal66Met had a significant effect on cortical thickness. Considering the typically developing group, Met-carriers presented thicker parietal and occipital lobes and prefrontal cortices compared to Val homozygotes. Met-carriers with psychiatric disorders presented thicker medial and lateral temporal cortices than Val homozygotes. Furthermore, a significant genotype × psychiatric diagnosis interaction was found: Met-carriers with a psychiatric diagnosis presented thinner bilateral prefrontal cortices than Val homozygotes. ConclusionThis study provides evidence that Val66Met is associated with cortical maturation in children and adolescents with and without psychiatric disorders.

Different maturational changes of fast and slow sleep spindles in the first four years of life

Objective/BackgroundMassive changes in brain morphology and function in the first years of life reveal a postero-anterior trajectory of cortical maturation accompanied by regional modifications of NREM sleep. One of the most sensible marker of this maturation process is represented by electroencephalographic (EEG) activity within the frequency range of sleep spindles. However, direct evidence that these changes actually reflect maturational modifications of fast and slow spindles still lacks.Our study aimed at answering the following questions:1. Do cortical changes at 11.50 Hz frequency correspond to slow spindles?2. Do fast and slow spindles show different age trajectories and different topographical distributions?3. Do changes in peak frequency explain age changes of slow and fast spindles? Patients/MethodsWe measured the antero-posterior changes of slow and fast spindles in the first 60 min of nightly sleep of 39 infants and children (0–48 mo.). ResultsWe found that (A) changes of slow spindles from birth to childhood mostly affect frontal areas (B) variations of fast and slow spindles across age groups go in opposite direction, the latter progressively increasing across ages; (C) this process is not merely reducible to changes of spindle frequency. ConclusionsAs a main finding, our cross-sectional study shows that the first form of mature spindle (i.e., corresponding to the adult phasic event of NREM sleep) is marked by the emergence of slow spindles on anterior regions around the age of 12 months.

Eye opening differentially modulates inhibitory synaptic transmission in the developing visual cortex.

Eye opening, a natural and timed event during animal development, influences cortical circuit assembly and maturation; yet, little is known about its precise effect on inhibitory synaptic connections. Here, we show that coinciding with eye opening, the strength of unitary inhibitory postsynaptic currents (uIPSCs) from somatostatin-expressing interneurons (Sst-INs) to nearby excitatory neurons, but not interneurons, sharply decreases in layer 2/3 of the mouse visual cortex. In contrast, the strength of uIPSCs from fast-spiking interneurons (FS-INs) to excitatory neurons significantly increases during eye opening. More importantly, these developmental changes can be prevented by dark rearing or binocular lid suture, and reproduced by the artificial opening of sutured lids. Mechanistically, this differential maturation of synaptic transmission is accompanied by a significant change in the postsynaptic quantal size. Together, our study reveals a differential regulation in GABAergic circuits in the cortex driven by eye opening may be crucial for cortical maturation and function.

Sleep and cortical maturation: slow and fast sleep spindles in the first 4 years of life

Sleep and cortical maturation: slow and fast sleep spindles in the first 4 years of life

Developmental Connectivity and Molecular Phenotypes of Unique Cortical Projection Neurons that Express a Synapse-Associated Receptor Tyrosine Kinase.

The complex circuitry and cell-type diversity of the cerebral cortex are required for its high-level functions. The mechanisms underlying the diversification of cortical neurons during prenatal development have received substantial attention, but understanding of neuronal heterogeneity is more limited during later periods of cortical circuit maturation. To address this knowledge gap, connectivity analysis and molecular phenotyping of cortical neuron subtypes that express the developing synapse-enriched MET receptor tyrosine kinase were performed. Experiments used a MetGFP transgenic mouse line, combined with coexpression analysis of class-specific molecular markers and retrograde connectivity mapping. The results reveal that MET is expressed by a minor subset of subcerebral and a larger number of intratelencephalic projection neurons. Remarkably, MET is excluded from most layer 6 corticothalamic neurons. These findings are particularly relevant for understanding the maturation of discrete cortical circuits, given converging evidence that MET influences dendritic elaboration and glutamatergic synapse maturation. The data suggest that classically defined cortical projection classes can be further subdivided based on molecular characteristics that likely influence synaptic maturation and circuit wiring. Additionally, given that MET is classified as a high confidence autism risk gene, the data suggest that projection neuron subpopulations may be differentially vulnerable to disorder-associated genetic variation.

Childhood Music Training Induces Change in Micro and Macroscopic Brain Structure: Results from a Longitudinal Study.

Several studies comparing adult musicians and nonmusicians have shown that music training is associated with structural brain differences. It is not been established, however, whether such differences result from pre-existing biological traits, lengthy musical training, or an interaction of the two factors, or if comparable changes can be found in children undergoing music training. As part of an ongoing longitudinal study, we investigated the effects of music training on the developmental trajectory of children's brain structure, over two years, beginning at age 6. We compared these children with children of the same socio-economic background but either involved in sports training or not involved in any systematic after school training. We established at the onset that there were no pre-existing structural differences among the groups. Two years later we observed that children in the music group showed (1) a different rate of cortical thickness maturation between the right and left posterior superior temporal gyrus, and (2) higher fractional anisotropy in the corpus callosum, specifically in the crossing pathways connecting superior frontal, sensory, and motor segments. We conclude that music training induces macro and microstructural brain changes in school-age children, and that those changes are not attributable to pre-existing biological traits.

Cerebral organoids reveal early cortical maldevelopment in schizophrenia\u2014computational anatomy and genomics, role of FGFR1

Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia.

Local changes in computational non-rapid eye movement sleep depth in infants

ObjectiveDeep NREM sleep and its hallmark EEG phenomenon slow wave activity (SWA) are under homeostatic control in adults. SWA is also locally regulated as it increases in the brain areas that have been used intensively. Moreover, in children, SWA is a marker of cortical maturation. In the present study the local properties of NREM sleep depth were evaluated using the quantitative mean frequency method. We aimed to study if age is related to NREM sleep depth in young infants. In addition, we studied if young infants have local differences in their NREM sleep. MethodsAmbulatory over-night polysomnographies were recorded in 59 healthy and full-term infants at the age of one month. The infants were divided into two age groups (<44 weeks and ≥44 weeks) to allow maturational evaluations. ResultsThe quantitative sleep depth analysis showed differences between the age groups. In addition, there were local sleep depth differences within the age groups. ConclusionsThe sleep depth change with age is most likely related to cortical maturation, whereas the local sleep depth gradients might also reflect the use-dependent properties of SWA. SignificanceThe results support the idea that young infants have frontal cortical processing.