The Prenatal Morphomechanic Impact of Agenesis of the Corpus Callosum on Human Brain Structure and Asymmetry.

Genetic, molecular, and physical forces together impact brain morphogenesis. The early impact of deficient midline crossing in agenesis of the Corpus Callosum (ACC) on prenatal human brain development and architecture is widely unknown. Here we analyze the changes of brain structure in 46 fetuses with ACC in vivo to identify their deviations from normal development. Cases of complete ACC show an increase in the thickness of the cerebral wall in the frontomedial regions and a reduction in the temporal, insular, medial occipital and lateral parietal regions, already present at midgestation. ACC is associated with a more symmetric configuration of the temporal lobes and increased frequency of atypical asymmetry patterns, indicating an early morphomechanic effect of callosal growth on human brain development affecting the thickness of the pallium along a ventro-dorsal gradient. Altered prenatal brain architecture in ACC emphasizes the importance of conformational forces introduced by emerging interhemispheric connectivity on the establishment of polygenically determined brain asymmetries.

Anatomical correlates of face patches in macaque inferotemporal cortex.

Primate brains typically have regions within the ventral visual stream that are selectively responsive to faces. In macaques, these face patches are located in similar parts of inferotemporal cortex across individuals although correspondence with particular anatomical features has not been reported previously. Here, using high-resolution functional and anatomical imaging, we show that small "bumps," or buried gyri, along the lower bank of the superior temporal sulcus are predictive of the location of face-selective regions. Recordings from implanted multielectrode arrays verified that these bumps contain face-selective neurons. These bumps were present in monkeys raised without seeing faces and that lack face patches, indicating that these anatomical landmarks are predictive of, but not sufficient for, the presence of face selectivity. These bumps are found across primate species that span taxonomy lines, indicating common evolutionary developmental mechanisms. The bumps emerge during fetal development in macaques, indicating that they arise from general developmental mechanisms that result in the regularity of cortical folding of the entire brain.

Emerging Roles of Single-Cell Multi-Omics in Studying Developmental Temporal Patterning.

The complexity of brain structure and function is rooted in the precise spatial and temporal regulation of selective developmental events. During neurogenesis, both vertebrates and invertebrates generate a wide variety of specialized cell types through the expansion and specification of a restricted set of neuronal progenitors. Temporal patterning of neural progenitors rests on fine regulation between cell-intrinsic and cell-extrinsic mechanisms. The rapid emergence of high-throughput single-cell technologies combined with elaborate computational analysis has started to provide us with unprecedented biological insights related to temporal patterning in the developing central nervous system (CNS). Here, we present an overview of recent advances in Drosophila and vertebrates, focusing both on cell-intrinsic mechanisms and environmental influences. We then describe the various multi-omics approaches that have strongly contributed to our current understanding and discuss perspectives on the various -omics approaches that hold great potential for the future of temporal patterning research.

Sylvian fissure development is linked to differential genetic expression in the pre-folded brain.

The mechanisms by which the human cerebral cortex folds into its final form remain poorly understood. With most of the current models and evidence addressing secondary folds, we sought to focus on the global geometry of the mature brain by studying its most distinctive feature, the Sylvian fissure. A digital human fetal brain atlas was developed using previously obtained MRI imaging of 81 healthy fetuses between gestational ages 21 and 38 weeks. To account for the development of the Sylvian fissure, we compared the growth of the frontotemporal opercula over the insular cortex and compared the transcriptome of the developing cortices for both regions. Spatiotemporal mapping of the lateral hemispheric surface showed the highest rate of organized growth in regions bordering the Sylvian fissure of the frontal, parietal and temporal lobes. Volumetric changes were first observed in the posterior aspect of the fissure moving anteriorly to the frontal lobe and laterally in the direction of the temporal pole. The insular region, delineated by the limiting insular gyri, expanded to a much lesser degree. The gene expression profile, before folding begins in the maturing brain, was significantly different in the developing opercular cortex compared to the insula. The Sylvian fissure forms by the relative overgrowth of the frontal and temporal lobes over the insula, corresponding to domains of highly expressed transcription factors involved in neuroepithelial cell differentiation.

Prenatal stress and the developing brain: Risks for neurodevelopmental disorders.

The prenatal period is increasingly considered as a crucial target for the primary prevention of neurodevelopmental and psychiatric disorders. Understanding their pathophysiological mechanisms remains a great challenge. Our review reveals new insights from prenatal brain development research, involving (epi)genetic research, neuroscience, recent imaging techniques, physical modeling, and computational simulation studies. Studies examining the effect of prenatal exposure to maternal distress on offspring brain development, using brain imaging techniques, reveal effects at birth and up into adulthood. Structural and functional changes are observed in several brain regions including the prefrontal, parietal, and temporal lobes, as well as the cerebellum, hippocampus, and amygdala. Furthermore, alterations are seen in functional connectivity of amygdalar-thalamus networks and in intrinsic brain networks, including default mode and attentional networks. The observed changes underlie offspring behavioral, cognitive, emotional development, and susceptibility to neurodevelopmental and psychiatric disorders. It is concluded that used brain measures have not yet been validated with regard to sensitivity, specificity, accuracy, or robustness in predicting neurodevelopmental and psychiatric disorders. Therefore, more prospective long-term longitudinal follow-up studies starting early in pregnancy should be carried out, in order to examine brain developmental measures as mediators in mediating the link between prenatal stress and offspring behavioral, cognitive, and emotional problems and susceptibility for disorders.

Prenatal neural origins of infant motor development: Associations between fetal brain and infant motor development.

Functional circuits of the human brain emerge and change dramatically over the second half of gestation. It is possible that variation in neural functional system connectivity in utero predicts individual differences in infant behavioral development, but this possibility has yet to be examined. The current study examines the association between fetal sensorimotor brain system functional connectivity and infant postnatal motor ability. Resting-state functional connectivity data was obtained in 96 healthy human fetuses during the second and third trimesters of pregnancy. Infant motor ability was measured 7 months after birth using the Bayley Scales of Infant Development. Increased connectivity between the emerging motor network and regions of the prefrontal cortex, temporal lobes, posterior cingulate, and supplementary motor regions was observed in infants that showed more mature motor functions. In addition, females demonstrated stronger fetal-brain to infant-behavior associations. These observations extend prior longitudinal research back into prenatal brain development and raise exciting new ideas about the advent of risk and the ontogeny of early sex differences.

Nestin-expressing cell types in the temporal lobe and hippocampus: Morphology, differentiation, and proliferative capacity.

Nestin is expressed in immature neuroepithelial and progenitor cell types and transiently upregulated in proliferative neuroglial cells responding to acute brain injury, including following seizures. In 36 temporal lobe (TLobe) specimens from patients with TLobe epilepsy (age range 8-60 years) we studied the number, distribution and morphology of nestin-expressing cells (NEC) in the pes, hippocampus body, parahippocampal gyrus, amygdala, temporal cortex and pole compared with post mortem control tissues from 26 cases (age range 12 gestational weeks to 76 years). The proliferative fraction of NEC was evaluated in selected regions, including recognized niches, using MCM2. Their differentiation was explored with neuronal (DCX, mushashi, ßIII tubulin, NeuN) and glial (GFAP, GFAPdelta, glutamine synthetase, aquaporin4, EAAT1) markers, both in sections or following culture. Findings were correlated with clinical parameters. A stereotypical pattern in the distribution and morphologies of NEC was observed, reminiscent of patterns in the developing brain, with increased densities in epilepsy than adult controls (p < .001). Findings included MCM2-positive radial glial-like cells in the periventricular white matter and rows of NEC in the hippocampal fimbria and sulcus. Nestin cells represented 29% of the hippocampal proliferative fraction in epilepsy cases; 20% co-expressed ßIII tubulin in culture compared with 28% with GFAP. Significant correlations were noted between age at surgery, memory deficits and nestin populations. TLobe NEC with ongoing proliferative capacity likely represent vestiges of developmental migratory streams and resident reactive cell populations of potential relevance to hippocampal epileptogenesis, TLobe pathology, and co-morbidities, including memory decline.

Exploring the Early Organization and Maturation of Linguistic Pathways in the Human Infant Brain.

Linguistic processing is based on a close collaboration between temporal and frontal regions connected by two pathways: the "dorsal" and "ventral pathways" (assumed to support phonological and semantic processing, respectively, in adults). We investigated here the development of these pathways at the onset of language acquisition, during the first post-natal weeks, using cross-sectional diffusion imaging in 21 healthy infants (6-22 weeks of age) and 17 young adults. We compared the bundle organization and microstructure at these two ages using tractography and original clustering analyses of diffusion tensor imaging parameters. We observed structural similarities between both groups, especially concerning the dorsal/ventral pathway segregation and the arcuate fasciculus asymmetry. We further highlighted the developmental tempos of the linguistic bundles: The ventral pathway maturation was more advanced than the dorsal pathway maturation, but the latter catches up during the first post-natal months. Its fast development during this period might relate to the learning of speech cross-modal representations and to the first combinatorial analyses of the speech input.

Region-specific changes in brain diffusivity in fetal isolated mild ventriculomegaly.

OBJECTIVES: To evaluate the impact of symmetric and asymmetric isolated mild ventriculomegaly (IMVM, atrial width 10-15 mm) on apparent diffusion coefficient (ADC) values in fetal brain areas. METHODS: Sixty-seven sequential fetal head magnetic resonance imaging scans (feMRI) of VM cases performed between 2009 and 2014 were compared to 38 normal feMRI scans matched for gestational age (controls). Ultrasound- and MRI-proven IMVM cases were divided into asymmetrical (AVM, ≥2 mm difference in atrial width), symmetrical (SVM, <2 mm difference in atrial width), and asymmetrical IMVM with one normal-sized ventricle (AV1norm). RESULTS: ADC values were significantly elevated in the basal ganglia (BG) of the SVM and AV1norm groups compared to controls (p < 0.004 and p < 0.013, respectively). High diffusivity was constantly detected in the BG ipsilateral to the enlarged atria relative to the normal-sized atria in the AV1norm group (p < 0.03). Frontal lobe ADC values were significantly reduced in the AVM and SVM groups (p < 0.003 and p < 0.003 vs. controls). Temporal lobe ADC values were significantly reduced in the AVM group (p < 0.001 vs. controls). CONCLUSION: Isolated mild ventriculomegaly is associated with distinct ADC value changes in different brain regions. This phenomenon could reflect the pathophysiology associated with different IMVM patterns. KEY POINTS: Various ventriculomegaly patterns are associated with distinct diffusional changes. Frontal and temporal lobe ADC values are altered bilaterally, even in asymmetric ventriculomegaly. Basal ganglia ADC values are elevated ipsilateral to the enlarged ventricle.

Development of the fetal cerebral cortex in the second trimester: assessment with 7T postmortem MR imaging.

BACKGROUND AND PURPOSE: Few investigators have analyzed the fetal cerebral cortex with MR imaging of high magnetic strength. Our purpose was to document the sulcal development and obtain quantitative measurements of the fetal brain in the second trimester. MATERIALS AND METHODS: The brains of 69 fetal specimens, with GA 12-22 weeks, were first scanned on a 7T MR imaging scanner. Then the sequential development of the different fissures and sulci was analyzed, and quantitative measurements of the cerebral cortex were obtained. RESULTS: A new chronology of sulcal development during 12-22 weeks GA was summarized. Before 12 weeks, few sulci were present; by 16 weeks, many sulci were present. The 16th week could be considered the most intensive time point for sulcal emergence. Most sulci, except for the postcentral sulcus and intraparietal sulcus, were present by 22 weeks GA. Measurements of the fetal brains, each with different growth rates, linearly increased with GA, but no sexual dimorphisms or cerebral asymmetries were detected. CONCLUSIONS: The second trimester is the most important phase, during which most sulci are present and can be clearly shown on 7T postmortem MR imaging. It is apparent that the specific time during which neuropathologic features of sulci appear, previously thought to be well understood, should be redefined. Quantitative data provide assistance in the precise understanding of the immature brain. The present results are valuable in anatomic education, research, and assessment of normal brain development in the uterus.

[Fundamental embryology and anatomy of the lateral ventricle]. / Embryologie et anatomie fondamentale du ventricule latéral.

The lateral ventricles are the C-shaped cavities of the telencephalon. Embryology of theses cavities is recalled as well as the immediate relationship of the frontal horn, the body, the atrium and the temporal and occipital horns.

The prenatal origin of hemispheric asymmetry: an in utero neuroimaging study.

Anatomical and functional hemispheric lateralization originates from differential gene expression and leads to asymmetric structural brain development, which initially appears in the perisylvian regions by 26 gestational weeks (GWs). In this in vivo neuroimaging study, we demonstrated a predominant pattern of temporal lobe (TL) asymmetry in a large cohort of human fetuses between 18 and 37 GWs. Over two-thirds of fetuses showed a larger, left-sided TL, combined with the earlier appearance of the right superior temporal sulcus by 23 GWs (vs. 25 GWs on the left side), which was also deeper than its left counterpart in the majority of cases (94.2%). Shape analysis detected highly significant differences in the contour of the right and left TLs by 20 GWs. Thus, fetal hemispheric asymmetry can be detected in utero, opening new diagnostic possibilities for the assessment of diseases that are believed to be linked to atypical hemispheric lateralization.

Effect of cytomegalovirus infection on temporal lobe development in utero: quantitative MRI studies.

Several environmental factors, including viral infections during fetal development, are known to increase the risk of schizophrenia. Cytomegalovirus (CMV) is the main cause of viral congenital infection. Since changes in temporal lobe structures are a consistent finding in imaging studies of adult schizophrenics, we investigated possible derangement in temporal lobe development in CMV infected fetuses. Abdominal MRI (1.5 T) was performed using a single-shot fast spin echo T2-weighted sequence. MRI volumetry was employed to measure brain and temporal lobe size in 27 CMV infected fetuses and 52 gestational age matched controls in utero. The ratio of temporal lobe to whole brain was computed for each fetus and group comparisons were performed using Student's t-test or ANOVA. Temporal lobe volumes, normalized to whole brain and co-varied with gestational age; were significantly smaller in fetuses infected with CMV compared to uninfected fetuses. (Infected group mean ± SEM: 0.086 ± 0.006, controls: 0.113 ± 0.003, p<0.0001). Infection during the 1st and 2nd trimester had a more pronounced effect than infection during the 3rd trimester. Infected fetuses with no MRI findings had significantly lower temporal lobe/whole brain ratios than controls (0.092 ± 0.008, p<0.01, N=11) and the lowest ratios were observed in fetuses with overt findings such as cysts or gray matter heterotopy (0.067 ± 0.015). These results demonstrate the ability of quantitative fetal brain MRI to detect previously unreported, specific deficits in brain development in CMV infected fetuses, which, in conjunction with other genetic and environmental factors, may contribute to the risk of developing schizophrenia later in life.

Embryological development of the human insula and its implications for the spread and resection of insular gliomas.

The human insular cortex, or the lobus insularis, is considered the developmentally most primitive lobe of the telencephalon. Covered by an overlying cortical lid, the insula has functions that are distinct from yet related to those of the adjacent temporal lobe and deep limbic structures. In the first part of this paper the authors outline the development of the human insula, including the cellular heterogeneity comprising the various parts of the insular lobe. Using the understanding gained from the development of the insula they then address implications of insular development for cortical development and connection as well as for tumorigenesis and tumor spread from the insula to other cortical structures, most notably the temporal lobe. An understanding of cortico-insular development and interconnection allows for both a better understanding of insular pathology and also facilitates planning of resection of cortico-insular gliomas to avoid damage to eloquent structures.

An additional manifestation in acrocallosal syndrome: temporal lobe hypoplasia.

Acrocallosal Syndrome is a rare genetic disorder which is characterized by moderate to severe mental retardation, agenesis or hypoplasia of the corpus callosum and polydactyly of fingers and toes. The spectrum of this syndrome is very variable. Prominent forehead, broad nasal bridge, short nose and mandible, hypertelorism, epicanthic folds, large anterior fontanelle and tapered fingers, omphalocele and inguinal hernia are some other common findings in this syndrome. Twenty percent of the patients have associated brain abnormalities such as cerebral atrophy, hypothalamic dysfunction, small cerebrum, micropolygyria, hypoplasia of pons, hypoplasia of cerebellar hemispheres, hypoplasia of medulla oblongata, agenesis or hypoplasia of cerebellar vermis and corpus callosum abnormalities. Here we present a 10-month-old female infant with clinical and radiological findings indicative of acrocallosal syndrome. She was noted to have craniofacial abnormalities suggestive of acrocallosal syndrome, optic atrophy and polydactyly. MRI revealed cerebral atrophy, corpus callosum agenesis, dilated lateral ventricules and unilateral right temporal lobe hypoplasia, the latter not previously reported in the spectrum of this syndrome. Based on this observation we conclude the importance of screening brain abnormalities and present temporal lobe hypoplasia as a new additional anomaly in this syndrome.

Exploring cortical subplate evolution using magnetic resonance imaging of the fetal brain.

The subplate is a transient structure essential for normal development of the cortex. We used magnetic resonance imaging of the fetal brain to assess cortical subplate evolution between 20 and 35 weeks gestation. Two-dimensional measures of diameter were obtained for the cortex, subplate and fetal white matter. The subplate was originally seen as a continuous band at early gestations measuring up to 4.5 mm. It became magnetic resonance invisible from approximately 28 weeks initially from the depths of the sulci and then from the tops of the gyri. The disappearance of the subplate was regional, involuting most rapidly in the parietal lobe and remaining prominent in the anterior temporal lobe up to 35 weeks. x

Dynamic and redundant regulation of LRRK2 and LRRK1 expression.

BACKGROUND: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene account for a significant proportion of autosomal-dominant and some late-onset sporadic Parkinson's disease. Elucidation of LRRK2 protein function in health and disease provides an opportunity for deciphering molecular pathways important in neurodegeneration. In mammals, LRRK1 and LRRK2 protein comprise a unique family encoding a GTPase domain that controls intrinsic kinase activity. The expression profiles of the murine LRRK proteins have not been fully described and insufficiently characterized antibodies have produced conflicting results in the literature. RESULTS: Herein, we comprehensively evaluate twenty-one commercially available antibodies to the LRRK2 protein using mouse LRRK2 and human LRRK2 expression vectors, wild-type and LRRK2-null mouse brain lysates and human brain lysates. Eleven antibodies detect over-expressed human LRRK2 while four antibodies detect endogenous human LRRK2. In contrast, two antibodies recognize over-expressed mouse LRRK2 and one antibody detected endogenous mouse LRRK2. LRRK2 protein resides in both soluble and detergent soluble protein fractions. LRRK2 and the related LRRK1 genes encode low levels of expressed mRNA species corresponding to low levels of protein both during development and in adulthood with largely redundant expression profiles. CONCLUSION: Despite previously published results, commercially available antibodies generally fail to recognize endogenous mouse LRRK2 protein; however, several antibodies retain the ability to detect over-expressed mouse LRRK2 protein. Over half of the commercially available antibodies tested detect over-expressed human LRRK2 protein and some have sufficient specificity to detect endogenous LRRK2 in human brain. The mammalian LRRK proteins are developmentally regulated in several tissues and coordinated expression suggest possible redundancy in the function between LRRK1 and LRRK2.

[Prenatal ontogenesis of the human brain cortex temporal area].

Prenatal ontogenesis of temporal areas of the human cortex was studied. In the fetal cortex at the gestational age of 16-18 weeks three zones can be distinguished: marginal zone (eI layer), cortex plate and subplate. At 20-26 weeks cortex plate is divided into following layers: eII, eIII, eIV, eV and eVI, with "efferent" complex of layers being wider than "associative" one. The subplate neurons are eliminated in the fetus at 27-33 weeks, when "associative" complex composes over 50 per cent of the cortex thickness. The subplate has been identified by positive correlation between layer eII and the upper subplate layer spu cell density.