Development Of Corpus Callosum Research Articles

ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an invitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.

Quantitative fetal MRI with diffusion tensor imaging in cases with 'short' corpus callosum.

It has been suggested previously that the presence of Probst bundles (PB) in cases with a short corpus callosum (SCC) on diffusion tensor imaging (DTI) may help to differentiate between corpus callosal (CC) dysplasia and a variant of normal CC development. The objectives of this study were to compare DTI parameters between cases of SCC vs normal CC and between cases of SCC with PB (SCC-PB+) vs SCC without PB (SCC-PB-). This was a retrospective study of patients referred to the Necker Hospital in Paris, France, for magnetic resonance imaging (MRI) evaluation of an apparently isolated SCC detected by sonography between November 2016 and December 2022 (IRB: 00011928). MRI was performed using a 1.5-Tesla Signa system. T2-weighted axial and sagittal sequences of the fetal brain were used to measure the length and thickness of the CC. 16-direction DTI axial brain sequences were performed to identify the presence of PB and to generate quantitative imaging parameters (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) of the entire CC, genu, body and splenium. Cases in which other associated brain abnormalities were detected on MRI were excluded. Cases were matched for fetal gender and gestational age with controls in a 1:3 ratio. Control cases were normal fetuses included in the LUMIERE on the FETUS trial (NCT04142606) that underwent the same DTI evaluation of the brain. Comparisons between SCC and normal CC cases, and between SCC-PB+ and SCC-PB- cases were performed using ANOVA and adjusted for potential confounders using ANCOVA. Twenty-two SCC cases were included and compared with 66 fetuses with a normal CC. In 10/22 (45.5%) cases of SCC, PB were identified. As expected, dimensions of the CC were significantly smaller in SCC compared with normal CC cases (all P < 0.01). In SCC-PB+ vs SCC-PB- cases, FA values were significantly lower in the entire CC (median, 0.21 (range, 0.19-0.24) vs 0.24 (range, 0.22-0.28); P < 0.01), genu (median, 0.21 (range, 0.15-0.29) vs 0.24 (range, 0.17-0.29); P = 0.04), body (median, 0.21 (range, 0.18-0.23) vs 0.23 (range, 0.21-0.27); P = 0.04) and splenium (median, 0.22 (range, 0.16-0.30) vs 0.25 (range, 0.20-0.29); P = 0.03). ADC values were significantly higher in the entire CC, genu and body in SCC-PB+ vs SCC-PB- cases (all P < 0.05). In SCC-PB+ cases, all FA values were significantly lower, and ADC values in the CC body were significantly higher compared with normal CC cases (all P < 0.05). In SCC-PB- cases, there was no significant difference in FA and ADC compared with normal CC cases (all P > 0.05). Fetal DTI evaluation of the CC showed that FA values were significantly lower and ADC values tended to be significantly higher in SCC-PB+ compared with normal CC cases. This may highlight alterations of the white matter microstructure in SCC-PB+. In contrast, isolated SCC-PB- did not demonstrate significant changes in DTI parameters, strengthening the possibility that this is a normal CC variant. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Molecular mechanisms of corpus callosum development: a four-step journey.

The Corpus Callosum (CC) is a bundle of axons connecting the cerebral hemispheres. It is the most recent structure to have appeared during evolution of placental mammals. Its development is controlled by a very complex interplay of many molecules. In humans it contains almost 80% of all commissural axons in the brain. The formation of the CC can be divided into four main stages, each controlled by numerous intracellular and extracellular molecular factors. First, a newborn neuron has to specify an axon, leave proliferative compartments, the Ventricular Zone (VZ) and Subventricular Zone (SVZ), migrate through the Intermediate Zone (IZ), and then settle at the Cortical Plate (CP). During the second stage, callosal axons navigate toward the midline within a compact bundle. Next stage is the midline crossing into contralateral hemisphere. The last step is targeting a defined area and synapse formation. This review provides an insight into these four phases of callosal axons development, as well as a description of the main molecular players involved.

Relationship between Brain Function and Microstructural Brain Maturation in Preterm Infants

Introduction: Preterm infants are at risk for impairment in brain maturation at term equivalent age (TEA). Diffusion tensor imaging (DTI) is a powerful magnetic resonance imaging (MRI) technique, quantitatively reflecting microstructural brain development of white matter regions with parameters such as fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Amplitude-integrated electroencephalography (aEEG) assesses electrocortical activity and brain function. Methods: Aim of this study was to investigate a possible correlation between functional and microstructural brain maturation using neonatal aEEG and DTI-MRI at TEA. The study was conducted as a retrospective single-center study in 446 infants born below 32 gestational weeks. Spearman rank’s correlation coefficients were calculated between aEEG (total maturation score) and FA/ADC value. To compare aEEG and DTI-MRI to neurodevelopmental outcome at 24 months of corrected age, we performed a multivariate linear regression analysis. Results: Analysis showed an all-time significant correlation between total maturation score and FA/ADC values of the corpus callosum at TEA with the strongest correlation at day 2, day 3, week 3, and week 4. After including perinatal variables in the model, this correlation remained highly significant at day 2 and 3. When comparing the association of aEEG and DTI-MRI to outcome, both the total maturation score at day 2, day 3, and FA/ADC of the splenium of the corpus callosum showed a significant correlation. Conclusion: This study indicates that early monitoring of functional brain maturation may predict later assessment of microstructural brain development of corpus callosum in preterm infants with a relation to neurodevelopmental outcome.

3 Emotional Expression in Infants with Agenesis of the Corpus Callosum: The Role of Callosal Connectivity in Early Temperament

Objective:Accumulating evidence suggests that corpus callosum development is critically involved in the emergence of behavioral and cognitive skills during the first two years of life and that structural abnormalities of the corpus callosum are associated with a variety of neurodevelopmental disorders. Indeed by adulthood ∼30% of individuals with agenesis of the corpus callosum (ACC), a congenital condition resulting in a partial or fully absent corpus callosum, exhibit phenotypic features consistent with autism spectrum disorder (ASD). However, very little is known about developmental similarities and/or differences among infants with ACC and infants who develop ASD. This study describes temperament in infants with ACC during the first year of life in comparison with a neurotypical control group. Additionally, it examines the potential contribution of disrupted callosal connectivity to early expression of temperament in ASD through comparison to children with high familial likelihood of ASD.Participants and Methods:Longitudinal ratings of positive and negative emotionality were acquired at 6 and 12 months on the Infant Behavior Questionnaire-Revised across four groups of infants: isolated complete and partial ACC (n=104), high familial likelihood of ASD who do and do not have a confirmed ASD diagnosis (HL+ n=81, HL- n=282), and low-likelihood controls (LL- n=152).Results:Overall, the ACC group demonstrated blunted affect, with significantly lower positive and negative emotionality than LL controls at both timepoints. Specifically, the ACC group exhibited lower activity and approach dimensions of positive emotionality at both timepoints, with lower high-intensity pleasure at 6 months and lower vocal reactivity at 12 months. On negative emotionality subscales, the ACC group exhibited lower distress to limitations and sadness at both timepoints, as well as lower falling reactivity at 6 months. The ACC and HL groups did not differ significantly on positive emotionality at either timepoint. However, negative emotionality was lower in the ACC group than the HL- group at both timepoints and lower than the HL+ group at 12 months, with lower distress to limitations and sadness ratings than both HL groups at both timepoints.Conclusions:These findings highlight the importance of interhemispheric connections in facilitating active engagement and pursuit of pleasurable activities during the first year of life, as well as expression of sadness and distress to limitations. Notably, similarities between infants with ACC and infants at elevated familial risk of ASD suggest that disrupted callosal connectivity may specifically contribute to reductions in positive emotionality.

Neuronal miR-17-5p contributes to interhemispheric cortical connectivity defects induced by prenatal alcohol exposure

Structural and functional deficits in brain connectivity are reported in patients with fetal alcohol spectrum disorders (FASDs), but whether and how prenatal alcohol exposure (PAE) affects axonal development of neurons and disrupts wiring between brain regions is unknown. Here, we develop a mouse model of moderate alcohol exposure during prenatal brain wiring to study the effects of PAE on corpus callosum (CC) development. PAE induces aberrant navigation of interhemispheric CC axons that persists even after exposure ends, leading to ectopic termination in the contralateral cortex. The neuronal miR-17-5p and its target ephrin type A receptor 4 (EphA4) mediate the effect of alcohol on the contralateral targeting of CC axons. Thus, altered microRNA-mediated regulation of axonal guidance may have implications for interhemispheric cortical connectivity and associated behaviors in FASD.

Krüppel-like factor 7 deficiency disrupts corpus callosum development and neuronal migration in the developing mouse cerebral cortex.

Krüppel-like Factor 7 (KLF7) is a zinc finger transcription factor that has a critical role in cellular differentiation, tumorigenesis, and regeneration. Mutations in Klf7 are associated with autism spectrum disorder, which is characterized by neurodevelopmental delay and intellectual disability. Here we show that KLF7 regulates neurogenesis and neuronal migration during mouse cortical development. Conditional depletion of KLF7 in neural progenitor cells resulted in agenesis of the corpus callosum, defects in neurogenesis, and impaired neuronal migration in the neocortex. Transcriptomic profiling analysis indicated that KLF7 regulates a cohort of genes involved in neuronal differentiation and migration, including p21 and Rac3. These findings provide insights into our understanding of the potential mechanisms underlying neurological defects associated with Klf7 mutations.

Early Fetal Corpus Callosum: Demonstrating Normal Growth and Detecting Pathologies in Early Pregnancy.

A malformed corpus callosum carries a risk for abnormal neurodevelopment. The advent of high-frequency transducers offers the opportunity to assess corpus callosum development in early pregnancy. The aim of the study was to construct a reference chart of the fetal corpus callosum length on ultrasound between 13 and 19 weeks of gestation and to prospectively examine growth patterns in pathologic cases. We performed a prospective cross-sectional study between 2020 and 2022 in well-dated, low-risk, singleton pregnancies between 13 and 19 weeks of gestation. A standardized image was obtained in the midsagittal plane. Imaging criteria were used as a confirmation of the early corpus callosum. Measurements were taken by 4 trained sonographers. Intra- and interobserver variability was assessed. Corpus callosum length in centiles were calculated for each gestational week. One hundred eighty-seven fetuses were included in the study. All cases met inclusion criteria. At 13 weeks of gestation, the margins of the early corpus callosum were sufficiently clear to be measured in 80% (20/25) of fetuses. A cubic polynomial regression model best described the correlation between corpus length and gestational age. The correlation coefficient (r 2) was 0.929 (P < .001). Intra- and interobserver variability had high interclass correlation coefficients (>0.99). Presented is the earliest published case of agenesis of corpus callosum and a case of dysgenetic corpus callosum in Rubinstein-Taybi syndrome. Provided is a nomogram of the early fetal corpus callosum. Applying imaging criteria helped to identify a case of complete agenesis of the corpus callosum as early as 14 weeks.

Three dimensional development and asymmetry of the corpus callosum in the 0-18 age group: A retrospective magnetic resonance imaging study.

Most of the corpus callosum (CC) developmental studies are concerned with its two-dimensional structure. Linear and area measurements do not directly assess the CC size but estimate the overall structure from the cross-sectional image. This study investigated age- and sex-related changes in volumetric development and asymmetry of CC from birth to 18. For this retrospective study, we selected 696 patients (329 [47.27%] females) with both 3D-T1-weighted sequence and normal radiological anatomy from patients 0-18 years of age who had brain magnetic resonance imaging (MRI) between 2012 and 2020. The genu, body, splenium, and total volume of CC were calculated using MRICloud. The measurement results of 23 age groups were analyzed with SPSS (ver.28). Total CC volume was 18740.76 ± 4314.06 mm3 between 0 and 18 years of age, and its ratio to total brain volume (TBV) was 1.70% ± 0.23%. We observed that the total CC volume has six developmental periods 0 years, 1, 2-4, 5-9, 10-16, and 17-18 years. Genu and body grew in five developmental periods, while splenium in seven. There was intermittent sexual dimorphism in the CC volume in the first 4 years of life (p < 0.05). However, sex factor was insignificant in CC ratio to TBV. Total CC was right lateralized on average 1.81% (ranging -0.59% to 4.52%). Genu was 8.70% lateralized to the right, the body was 2.99% to the left, and the splenium was 1.41% to the right. The three-dimensional development of CC agreed with the two-dimensional developmental data of CC except for some differences.

Development of the corpus callosum and cognition after neonatal encephalopathy.

Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic-ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. Participants aged 6-8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. Adjusting for age, sex and intracranial volume, cases (N=40) compared to controls (N=39) demonstrated reduced whole corpus callosum area (β=-26.9, 95% confidence interval [CI]=-53.17, -0.58), volume (β=-138.5, 95% CI=-267.54, -9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II-V. In cases, segment V area (β=0.18, 95% CI=0.004, 0.35), volume (β=0.04, 95% CI=0.001, 0.079), whole corpus callosum fractional anisotropy (β=13.8 95% CI=0.6, 27.1) and radial diffusivity (β=-11.3, 95% CI=-22.22, -0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age.

Neuropathological hallmarks of antenatal mitochondrial diseases with a corpus callosum defect.

Corpus callosum defects are frequent congenital cerebral disorders caused by mutations in more than 300 genes. These include genes implicated in corpus callosum development or function, as well as genes essential for mitochondrial physiology. However, in utero corpus callosum anomalies rarely raise a suspicion of mitochondrial disease and are characterized by a very large clinical heterogeneity. Here, we report a detailed pathological and neuro-histopathological investigation of nine foetuses from four unrelated families with prenatal onset of corpus callosum anomalies, sometimes associated with other cerebral or extra-cerebral defects. Next generation sequencing allowed the identification of novel pathogenic variants in three different nuclear genes previously reported in mitochondrial diseases: TIMMDC1, encoding a Complex I assembly factor never involved before in corpus callosum defect; MRPS22, a protein of the small mitoribosomal subunit; and EARS2, the mitochondrial tRNA-glutamyl synthetase. The present report describes the antenatal histopathological findings in mitochondrial diseases and expands the genetic spectrum of antenatal corpus callosum anomalies establishing OXPHOS function as an important factor for corpus callosum biogenesis. We propose that, when observed, antenatal corpus callosum anomalies should raise suspicion of mitochondrial disease and prenatal genetic counselling should be considered.

Genetic heterogeneity in corpus callosum agenesis.

The corpus callosum is the largest white matter structure connecting the two cerebral hemispheres. Agenesis of the corpus callosum (ACC), complete or partial, is one of the most common cerebral malformations in humans with a reported incidence ranging between 1.8 per 10,000 livebirths to 230–600 per 10,000 in children and its presence is associated with neurodevelopmental disability. ACC may occur as an isolated anomaly or as a component of a complex disorder, caused by genetic changes, teratogenic exposures or vascular factors. Genetic causes are complex and include complete or partial chromosomal anomalies, autosomal dominant, autosomal recessive or X-linked monogenic disorders, which can be either de novo or inherited. The extreme genetic heterogeneity, illustrated by the large number of syndromes associated with ACC, highlight the underlying complexity of corpus callosum development. ACC is associated with a wide spectrum of clinical manifestations ranging from asymptomatic to neonatal death. The most common features are epilepsy, motor impairment and intellectual disability. The understanding of the genetic heterogeneity of ACC may be essential for the diagnosis, developing early intervention strategies, and informed family planning. This review summarizes our current understanding of the genetic heterogeneity in ACC and discusses latest discoveries.

Early life metal exposure is associated with reduced fractional anisotropy in the corpus callosum in children

Background: The corpus callosum (CC) is the largest white matter structure in the brain, connecting the left and right hemispheres into functional networks subserving cognition and behavior. Neuroimaging studies demonstrate rapid CC development during the first years of life. During these early-life critical windows, the CC is vulnerable to perturbation by neurotoxicants including heavy metals. Most environmental studies consider single neurotoxicant exposures at a single time point, potentially missing the effects of joint exposure across a developmental stage. Here, we investigated associations between early life metal mixture exposure and CC white matter microstructure integrity in children. Methods: In a preliminary analysis of 47 children (8-13 years; 22 females) enrolled in a neuroimaging substudy within the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly exposure (22nd-week gestation through 43rd week postnatal) to manganese (Mn), zinc (Zn), and lead (Pb) using laser ablation-inductively coupled plasma-mass spectrometry of teeth. We estimated CC white matter microstructure integrity using fractional anisotropy (FA) from diffusion tensor imaging (DTI) acquired in a 3T Siemens scanner. We used lagged weighted quantile sum (lWQS) regression to estimate the time-varying mixture effect on FA in the CC. Results: A higher metal mixture index in the 24th-43rd postnatal weeks was associated with decreased FA in the CC genu, body, and splenium (maximum β = -0.65 [95% CI -0.25, -1.07]), driven mainly by Zn and Pb. Conclusion: The CC may demonstrate a postnatal critical window to metals, with higher exposure to Zn and Pb associated with reduced FA. These results may help understand the role of exposure timing in driving neurodevelopmental outcomes, pointing to future optimal and timely public health interventions.

Association of Corpus Callosum Development With Fetal Growth Restriction and Maternal Preeclampsia or Gestational Hypertension

It remains unknown whether neurodevelopmental impairments are directly associated with the structural development of the brain in offspring with fetal growth restriction (FGR) and mothers with preeclampsia (PE) or gestational hypertension (GH). To assess whether fetal corpus callosum (CC) development differed among pregnancies with PE or GH with FGR, pregnancies with PE or GH without FGR, and normotensive pregnancies, particularly the severity of maternal disease and FGR, and to identify the association between adverse perinatal outcomes and structural development of the CC in fetuses with FGR in pregnancies with PE or GH. This retrospective matched case-control study was conducted between January 1, 2014, and January 31, 2021, at Women's Hospital, Zhejiang University School of Medicine in Hangzhou, China. The participant group included cases of singleton pregnancies with PE or GH with FGR; the control groups included cases with PG or GH without FGR and cases with paired normotensive pregnancy. Maternal PE or GH and FGR. The length, thickness, total area, subdivision areas, and apparent diffusion coefficient (ADC) values of fetal CC were measured on magnetic resonance imaging (MRI) and analyzed. The association between adverse perinatal outcomes and structural development of CC was further investigated. A total of 56 pregnant individuals with singleton pregnancies and PE or GH and fetuses with FGR were enrolled (maternal median [IQR] age, 29.0 [26.0-34.0] years; mean [SD] gestational age at MRI, 33.6 [2.5] weeks). Significant patterns of decreased median (IQR) fetal CC length (0.4284 [0.4079-0.4470] mm vs 0.4614 [0.4461-0.4944] mm, P < .001, vs 0.4591 [0.4310-0.4927] mm, P < .001) and mean (SD) CC total area (1.0779 [0.1931] mm2 vs 1.1896 [0.1803] mm2, P = .001, vs 1.1438 [0.1935] mm2, P = .02), adjusted for the cephalic index, was observed in cases of PE or GH with FGR compared with cases without FGR and cases with normotensive pregnancy. The splenium region of fetal CC also exhibited the distinct alterations in macrostructural development (with FGR: 0.3149 [0.0697] mm2 vs without FGR: 0.3727 [0.0698] mm2, P < .001, vs normotensive pregnancies: 0.3565 [0.0763] mm2, P < .001) and microstructural development (median [IQR] ADC values: 1.47 [1.38-1.57] × 10-3 mm2/s vs 1.57 [1.53-1.63] × 10-3 mm2/s, P = .009, vs 1.63 [1.50-1.70] × 10-3 mm2/s, P < .001) in all groups. Furthermore, significant associations were found between structural abnormality of the splenium region and adverse perinatal outcomes in the PE or GH with FGR group (mean [SD] ADC value: 1.40 [0.07] × 10-3 mm2/s; P = .04). Results of this study suggest that, in fetuses with FGR in pregnancies with PE or GH, decreased structural development of the CC, predominantly the splenium region, may be significantly associated with a higher risk of adverse perinatal outcomes and may be regarded as an MRI-based biomarker for better prenatal counseling and early management decisions.

Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling

Transmembrane of coiled-coil domains 1 (TMCO1) plays an important role in maintaining homeostasis of calcium (Ca2+) stores in the endoplasmic reticulum (ER). TMCO1-defect syndrome shares multiple features with human cerebro-facio-thoracic (CFT) dysplasia, including abnormal corpus callosum (CC). Here, we report that TMCO1 is required for the normal development of CC through sustaining Ca2+ homeostasis. Tmco1−/− mice exhibit severe agenesis of CC with stalled white matter fiber bundles failing to pass across the midline. Mechanistically, the excessive Ca2+ signals caused by TMCO1 deficiency result in upregulation of FGFs and over-activation of ERK, leading to an excess of glial cell migration and overpopulated midline glia cells in the indusium griseum which secretes Slit2 to repulse extension of the neural fiber bundles before crossing the midline. Supportingly, using the clinical MEK inhibitors to attenuate the over-activated FGF/ERK signaling can significantly improve the CC formation in Tmco1−/− brains. Our findings not only unravel the underlying mechanism of abnormal CC in TMCO1 defect syndrome, but also offer an attractive prevention strategy to relieve the related agenesis of CC in patients.

C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south Indian child

Open reading frame variants which lack stop codons such as C12orf57 variants are known to cause Temtamy syndrome, an extremely rare disorder characterized by intellectual disability, seizures, facial dysmorphism and agenesis of corpus callosum. C12orf57 was initially reported to be required for human corpus callosum development. We report the first child who is of Indian origin with developmental and epileptic encephalopathy (DEE) with a unique phenotypic evolution as focal onset reflex seizures. We performed whole exome sequencing of genomic DNA isolated from peripheral blood samples of proband and his parents. Two pathogenic compound heterozygous variants, a start loss variant (Chr12:7053285:c.1A>G) and a premature stop gain variant (Chr12:7053327:c.43C>T), involving the C12orf57 gene were identified in the proband. Our case report which details genotyping in this rare syndromic developmental encephalopathy, with no prior cases reported from India, expands the ethnic spectrum of patients.

TrkB-dependent EphrinA reverse signaling regulates callosal axon fasciculate growth downstream of Neurod2/6.

Abnormal development of corpus callosum is relatively common and causes a broad spectrum of cognitive impairments in humans. We use acallosal Neurod2/6-deficient mice to study callosal axon guidance within the ipsilateral cerebral cortex. Initial callosal tracts form but fail to traverse the ipsilateral cingulum and are not attracted towards the midline in the absence of Neurod2/6. We show that the restoration of Ephrin-A4 (EfnA4) expression in the embryonic neocortex of Neurod2/6-deficient embryos is sufficient to partially rescue targeted callosal axon growth towards the midline. EfnA4 cannot directly mediate reverse signaling within outgrowing axons, but it forms co-receptor complexes with TrkB (Ntrk2). The ability of EfnA4 to rescue the guided growth of a subset of callosal axons in Neurod2/6-deficient mice is abolished by the co-expression of dominant negative TrkBK571N (kinase-dead) or TrkBY515F (SHC-binding deficient) variants, but not by TrkBY816F (PLCγ1-binding deficient). Additionally, EphA4 is repulsive to EfnA4-positive medially projecting axons in organotypic brain slice culture. Collectively, we suggest that EfnA4-mediated reverse signaling acts via TrkB-SHC and is required for ipsilateral callosal axon growth accuracy towards the midline downstream of Neurod family factors.

Individual variability in the nonlinear development of the corpus callosum during infancy and toddlerhood: a longitudinal MRI analysis.

The human brain spends several years bootstrapping itself through intrinsic and extrinsic modulation, thus gradually developing both spatial organization and functions. Based on previous studies on developmental patterns and inter-individual variability of the corpus callosum (CC), we hypothesized that inherent variations of CC shape among infants emerge, depending on the position within the CC, along the developmental timeline. Here we used longitudinal magnetic resonance imaging data from infancy to toddlerhood and investigated the area, thickness, and shape of the midsagittal plane of the CC by applying multilevel modeling. The shape characteristics were extracted using the Procrustes method. We found nonlinearity, region-dependency, and inter-individual variability, as well as intra-individual consistencies, in CC development. Overall, the growth rate is faster in the first year than in the second year, and the trajectory differs between infants; the direction of CC formation in individual infants was determined within six months and maintained to two years. The anterior and posterior subregions increase in area and thickness faster than other subregions. Moreover, we clarified that the growth rate of the middle part of the CC is faster in the second year than in the first year in some individuals. Since the division of regions exhibiting different tendencies coincides with previously reported divisions based on the diameter of axons that make up the region, our results suggest that subregion-dependent individual variability occurs due to the increase in the diameter of the axon caliber, myelination partly due to experience and axon elimination during the early developmental period.

Language lateralization in very preterm children: associating dichotic listening to interhemispheric connectivity and language performance.

Language difficulties of very preterm (VPT) children might be related to weaker cerebral hemispheric lateralization of language. Language lateralization refers to the development of an expert region for language processing in the left hemisphere during the first years of life. Children born VPT might not develop such a dominant left hemisphere for language processing. A dichotic listening task may be a functional task to show the dominance of the left hemisphere during language processing. During this task, different acoustic events are simultaneously presented to both ears. Due to crossing fibers in the brain, right ear stimuli are transferred directly to the left hemisphere, and left ear stimuli are transferred first to the right hemisphere and then, through the corpus callosum (CC), to the left hemisphere. Dichotic listening typically shows a right ear advantage, assuming to reflect left hemispherical language dominance. The CC, in particular the splenium, is associated with auditory processing and is considered important for language lateralization. The objective of this work was to explore whether dichotic listening performance in school-aged VPT children are associated with language performance and interhemispheric connectivity. This is a cross-sectional study of 58 VPT children and 30 full term controls at age 10 years. Language performance and dichotic digit test (DDT) were assessed. In 44 VPT children, additionally diffusion weighted imaging (DWI) was performed using a 3 T MRI scanner. Fractional anisotropy (FA) and mean diffusivity (MD) values of the splenium of the CC were extracted. Poorer right ear DDT scores were associated with poorer language performance in VPT children only (p = 0.015). Association between right ear DDT scores and MD of the splenium approached the level of significance (p = 0.051). These results support the hypothesis that poor language performance in VPT children may be a consequence of weaker lateralized language organization, due to a poorly developed splenium of the CC. Dichotic listening may reflect the level of language lateralization in VPT children. Poor language performance in VPT children may be a consequence of weaker lateralized language organization, due to a poorly developed splenium of the CC. Dichotic listening performance may reflect the level of language lateralization in VPT children and right ear scores of a dichotic listening task are associated with both the splenium of the corpus callosum and language performance. If our results could be validated in future research, it suggests that poor CC development may indicate VPT children at risk for long-term language problems.

Fetal thick corpus callosum: new insights from neuroimaging and neuropathology in two cases and literature review.

To describe the correlation between fetal imaging (in vivo and ex vivo) and neuropathology in two fetuses at early gestational age (GA) with isolated thick corpus callosum (CC), a rare finding whose pathological significance and neuropathology data are scarce. Two fetuses at 21-week GA underwent fetal MRI (fMRI) for suspected callosal anomalies at ultrasound (US). After fMRI results, termination of pregnancy (TOP) was carried out and post-mortem MRI (pmMRI) was performed. Neuropathology correlation consisted in macro and microscopic evaluation with sections prepared for hematoxylin-eosin and immunohistochemistry staining. Fetal imaging confirmed in both cases the presence of a shorter and thicker CC with respect to the reference standard at the same GA, without a clear distinction between its different parts. Moreover, on pmMRI, an abnormal slightly T2-weighted hyperintense layer along the superior and inferior surface of CC was noted in both cases. At histopathology, these findings corresponded to an increased amount of white matter tracts but also to an abnormal representation of embryological structures that contribute to CC development, naming induseum griseum (IG) and the glioepithelial layer (GL) of the "callosal sling." After reviewing the literature data, we confirmed the recent embryological theory regarding the CC development and provide new insights into the pathophysiology of the abnormal cases. An abnormally thick CC at the early fetal period could be associated to an abnormal representation of the midline glia structures, so to result in potential disturbance of the axon guidance mechanism of callosal formation and eventually in CC dysgenesis.