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Proper topographically organized neural connections between the thalamus and the cerebral cortex are mandatory for thalamus function. Thalamocortical (TC) fiber growth begins during the embryonic period and completes by the third trimester of gestation, so that human neonates at birth have a thalamus with a near-facsimile of adult functional parcellation. Whether congenital neocortical anomaly (e.g., lissencephaly) affects TC connection in humans is unknown. Here, via diffusion MRI fiber-tractography analysis of long-term formalin-fixed postmortem fetal brain diagnosed as lissencephaly in comparison with an age-matched normal one, we found similar topological patterns of thalamic subregions and of internal capsule parcellated by TC fibers. However, lissencephaly fetal brain showed white matter structural changes, including fewer/less organized TC fibers and optic radiations, and much less cortical plate invasion by TC fibers - particularly around the shallow central sulcus. Diffusion MRI fiber tractography of normal fetal brains at 15, 23, and 26 gestational weeks (GW) revealed dynamic volumetric change of each parcellated thalamic subregion, suggesting coupled developmental progress of the thalamus with the corresponding cortex. Moreover, from GW23 and GW26 normal fetal brains, TC endings in the cortical plate could be delineated to reflect cumulative progressive TC invasion of cortical plate. By contrast, lissencephaly brain showed a dramatic decrease in TC invasion of the cortical plate. Our study thus shows the feasibility of diffusion MRI fiber tractography in postmortem long-term formalin-fixed fetal brains to disclose the developmental progress of TC tracts coordinating with thalamic and neocortical growth both in normal and lissencephaly fetal brains at mid-gestational stage., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Genetic studies identified multiple mutations associated with malformations of cortical development (MCD) in humans. When analyzing the underlying mechanisms in non-human experimental models it became increasingly evident, that these mutations accumulate in genes, which functions evolutionary progressed from rodents to humans resulting in an incomplete reflection of the molecular and cellular alterations in these models. Human brain organoids derived from human pluripotent stem cells resemble early aspects of human brain development to a remarkable extent making them an attractive model to investigate MCD. Here we review how human brain organoids enable the generation of fundamental new insight about the underlying pathomechanisms of MCD. We show how phenotypic features of these diseases are reflected in human brain organoids and discuss challenges and future considerations but also limitations for the use of human brain organoids to model human brain development and associated disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Mota and Herculano-Houzel (Reports, 3 July 2015, p. 74) assign power functions to neuroanatomical data and present a model to account for evolutionary patterns of cortical folding in the mammalian brain. We detail how the model assumptions are in conflict with experimental and observational work and show that the model itself does not accurately fit the data., (Copyright © 2016, American Association for the Advancement of Science.)

The cerebrum of large mammals is convoluted, whereas that of small mammals is smooth. Mota and Herculano-Houzel (Reports, 3 July 2015, p. 74) inspired a model on an old theory that proposed a fractal geometry. I show that their model reduces to the product of gray-matter proportion times the folding index. This proportional relation describes the available data even better than the fractal model., (Copyright © 2016, American Association for the Advancement of Science.)

De Lussanet claims that our model that accounts for the degree of folding of the cerebral cortex based on the product of cortical surface area and the square root of cortical thickness is better reduced to the product of gray-matter proportion and folding index. Lewitus et al., in turn, claim that the assumptions of our model are in conflict with experimental data; that the model does not accurately fit the data; and that the ancestral mammalian brain was gyrencephalic. Here, we show that both claims are inappropriate., (Copyright © 2016, American Association for the Advancement of Science.)

Larger brains tend to have more folded cortices, but what makes the cortex fold has remained unknown. We show that the degree of cortical folding scales uniformly across lissencephalic and gyrencephalic species, across individuals, and within individual cortices as a function of the product of cortical surface area and the square root of cortical thickness. This relation is derived from the minimization of the effective free energy associated with cortical shape according to a simple physical model, based on known mechanisms of axonal elongation. This model also explains the scaling of the folding index of crumpled paper balls. We discuss the implications of this finding for the evolutionary and developmental origin of folding, including the newfound continuum between lissencephaly and gyrencephaly, and for pathologies such as human lissencephaly., (Copyright © 2015, American Association for the Advancement of Science.)

Purpose: Pachygyria/agyria are congenital brain malformations characterized by presence of a few broad, flat gyri with thickened cortex, resulting from arrest of neuronal migration in early gestation. We are hereby describing diffusion tensor imaging findings in different histological layers of lissencephaly cortex in two children., Method: DTI in addition to conventional MR imaging was performed in two children on a 3 T MRI and post-processed with vendor supplied software to generate the fractional anisotropy, mean diffusivity and trace maps. Tractography was also performed to identify presence of tracts in the thickened cortex., Results: DTI demonstrated the dysplastic multilayered cortex in cases of pachygyria/agyria; the thickened fourth layer and superficial layer demonstrated high anisotropy on diffusion tensor imaging., Conclusion: DTI is a useful tool for identifying gross histological features of pachygyria-agyria complex. Superficial layer and thickened fourth layer demonstrate high anisotropy. Identification of anisotropy in the superficial layer has not been described in previous reports.

The purpose of the study is to explore the causative role of TUBB2B gene mutations in patients with different malformations of cortical development. We collected and evaluated clinical and MRI data of a cohort of 128 consecutive patients (61 females and 67 males) in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, who were mutation-negative to other possible causative genes. Mutation analysis of the TUBB2B gene was performed. We identified three new TUBB2B mutations in three unrelated patients (3 out of 128; 2.3%) with a diffuse and rather symmetrical cortical abnormality, including diffuse polymicrogyria in two and bilateral regional pachygyria in one. One patient harbored a p.Asp417Asn amino-acid substitution in the C-terminal domain of the protein; one patient a p.Asn256Ser amino-acid substitution in the intermediate domain and one patient a p.Leu117Pro amino-acid substitution in the N-terminal domain. The localization of each mutation within the secondary structure of the β2-tubulin polypeptide suggests that these mutations might alter the proper functions of microtubules. The phenotypic spectrum associated with TUBB2B mutations is wider than previously reported and includes diffuse, symmetric malformations of cortical development.

Objective: To analyze the clinical manifestations and magnetic resonance imaging (MRI) features of lissencephaly of various types and provide clinical and imaging evidences for the clinical diagnosis of the disease., Methods: The clinical symptoms and signs and the findings in neurobehavioral evaluation, laboratory examination and magnetic resonance imaging (MRI) of 11 cases of lissencephaly were investigated retrospectively., Results: The 11 patients consisted of 4 with isolated lissencephaly sequence, 3 with Miller-Dieker syndrome, 3 with cobblestone lissencephaly, and 1 with lissencephaly with cerebellar hypoplasia. The main clinical manifestations included mental retardation, developmental delay, microcephaly, epilepsy, hearing abnormality and facial malformation. Cobblestone lissencephaly presented with congenital muscular dystrophy and eye malformation, and lissencephaly with cerebellar hypoplasia showed ataxia manifestations. In terms of MRI features, classical lissencephaly displayed absent or broad cerebral gyri, thickened cortex and reduced white matter, smooth border between the gray and white matter, and thin white matter. Cobblestone lissencephaly displayed thick cortex and gyri deficiency with cobblestone surface. Lissencephaly with cerebellar hypoplasia presented with pachygyria, cerebellar hypoplasia and hippocampal dysplasia., Conclusion: Lissencephaly is a developmental malformation of the brain with obvious heterogeneity, and the clinical manifestations and MRI features can be the evidences for a clinical diagnosis and classification of the disease.

Disrupted cortical cytoarchitecture in cerebellum is a typical pathology in reeler. Particularly interesting are structural problems at the cellular level: dendritic morphology has important functional implication in signal processing. Here we describe a combinatorial imaging method of synchrotron X-ray microtomography with Golgi staining, which can deliver 3-dimensional(3-D) micro-architectures of Purkinje cell(PC) dendrites, and give access to quantitative information in 3-D geometry. In reeler, we visualized in 3-D geometry the shape alterations of planar PC dendrites (i.e., abnormal 3-D arborization). Despite these alterations, the 3-D quantitative analysis of the branching patterns showed no significant changes of the 77 ± 8° branch angle, whereas the branch segment length strongly increased with large fluctuations, comparing to control. The 3-D fractal dimension of the PCs decreased from 1.723 to 1.254, indicating a significant reduction of dendritic complexity. This study provides insights into etiologies and further potential treatment options for lissencephaly and various neurodevelopmental disorders.

Lissencephaly has been long maintained a malformation involving only the brain. Classic lissencephaly includes agyria and pachygyria and it is the most severe form of malformations derived from abnormal neuronal migration. It is defined as a smooth or nearly smooth cerebral surface with absence of normal sulci and gyria. It encompasses a group of syndromes which show many different clinical conditions. Four groups are actually distinguished: classic lissencephaly variants, other lissencephalies including forms with unknown pathogenesis, microlissencephaly spectrum and Cobblestone cortical malformations. Several genes and proteins are involved in this syndromic spectrum and each year new molecular data are reported in the literature: classifications in this sense are always in progress. Lissencephaly now is recognised to involve not only the brain but also several other organs and districts including eyes, face, muscles, genital organs, heart and bones. Mental retardation and different form of epilepsies usually drug-resistant are the main clinical signs. The Authors in this topic discuss on this subject, underlying the different forms of lissencephaly their wide heterogeneity and the complex involvement of several organs.

Objectives: To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities., Methods: MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal-Wallis and chi(2) McNemar tests., Results: There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p = 0.0029)., Conclusion: Our study focused on posterior fossa anomalies, which are an integral part of cobblestone complex lissencephalies but previously have not been well categorized for other lissencephalies. According to our results and the review of the literature, we propose a new classification of human lissencephalies.

Objective: Adult-onset schizophrenia has repeatedly been associated with disturbances in the temporal lobes and alterations in cortical folding, which are thought to reflect neurodevelopmental impairment. Early-onset schizophrenia (EOS; onset before 18 years) is considered to involve even more pronounced neurodevelopmental deviance across a wide range of brain structural measures. We hypothesized that overall alteration of cortical folding also applies to EOS, and EOS involves prominent structural aberrations in superior temporal and collateral sulci., Method: Magnetic resonance T1 images of 51 patients with EOS and 59 healthy participants were investigated. A fully automated method was applied to the images to extract, label, and measure the sulcus area in the whole cortex. Cortical folding was assessed by computing global sulcal indices (the ratio between total sulcal area and total outer cortex area) for each hemisphere and local sulcal indices (the ratio between the area of labeled sulcus and total outer cortex area in the corresponding hemisphere) for superior temporal and collateral sulci., Results: Relative to healthy individuals, patients with EOS had significantly lower global sulcal indices in both hemispheres and a lower local sulcal index in the left collateral sulcus., Conclusions: Reduced hemispheric sulcation appears to be a feature of schizophrenia, irrespective of age at onset. Structural aberration involving the left collateral sulcus may contribute to neurobiological substrate of EOS.

Reelin is an extracellular protein that directs the organization of cortical structures of the brain through the activation of two receptors, the very low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (ApoER2), and the phosphorylation of Disabled-1 (Dab1). Lis1, the product of the Pafah1b1 gene, is a component of the brain platelet-activating factor acetylhydrolase 1b (Pafah1b) complex, and binds to phosphorylated Dab1 in response to Reelin. Here we investigated the involvement of the whole Pafah1b complex in Reelin signaling and cortical layer formation and found that catalytic subunits of the Pafah1b complex, Pafah1b2 and Pafah1b3, specifically bind to the NPxYL sequence of VLDLR, but not to ApoER2. Compound Pafah1b1(+/-);Apoer2(-/-) mutant mice exhibit a reeler-like phenotype in the forebrain consisting of the inversion of cortical layers and hippocampal disorganization, whereas double Pafah1b1(+/-);Vldlr(-/-) mutants do not. These results suggest that a cross-talk between the Pafah1b complex and Reelin occurs downstream of the VLDLR receptor.