Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Biomechanical Analysis of Normal Brain Development during the First Year of Life Using Finite Strain Theory

The first year of life is the most critical time period for structural and functional development of the human brain. Combining longitudinal MR imaging and finite strain theory, this study aimed to provide new insights into normal brain development through a biomechanical framework. Thirty-three normal infants were longitudinally imaged using MRI from 2 weeks to 1 year of age. Voxel-wise Jacobian determinant was estimated to elucidate volumetric changes while Lagrange strains (both normal and shear strains) were measured to reveal directional growth information every 3 months during the first year of life. Directional normal strain maps revealed that, during the first 6 months, the growth pattern of gray matter is anisotropic and spatially inhomogeneous with higher left-right stretch around the temporal lobe and interhemispheric fissure, anterior-posterior stretch in the frontal and occipital lobes, and superior-inferior stretch in right inferior occipital and right inferior temporal gyri. In contrast, anterior lateral ventricles and insula showed an isotropic stretch pattern. Volumetric and directional growth rates were linearly decreased with age for most of the cortical regions. Our results revealed anisotropic and inhomogeneous brain growth patterns of the human brain during the first year of life using longitudinal MRI and a biomechanical framework

Regional Brain Differences in Cortical Thickness, Surface Area and Subcortical Volume in Individuals with Williams Syndrome

Williams syndrome (WS) is a rare genetic neurodevelopmental disorder characterized by increased non-social anxiety, sensitivity to sounds and hypersociability. Previous studies have reported contradictory findings with regard to regional brain variation in WS, relying on only one type of morphological measure (usually volume) in each study. The present study aims to contribute to this body of literature and perhaps elucidate some of these discrepancies by examining concurrent measures of cortical thickness, surface area and subcortical volume between WS subjects and typically-developing (TD) controls. High resolution MRI scans were obtained on 31 WS subjects and 50 typically developing control subjects. We derived quantitative regional estimates of cortical thickness, cortical surface area, and subcortical volume using FreeSurfer software. We evaluated between-group ROI differences while controlling for total intracranial volume. In post-hoc exploratory analyses within the WS group, we tested for correlations between regional brain variation and Beck Anxiety Inventory scores. Consistent with our hypothesis, we detected complex patterns of between-group cortical variation, which included lower surface area in combination with greater thickness in the following cortical regions: post central gyrus, cuneus, lateral orbitofrontal cortex and lingual gyrus. Additional cortical regions showed between-group differences in one (but not both) morphological measures. Subcortical volume was lower in the basal ganglia and the hippocampus in WS versus TD controls. Exploratory correlations revealed that anxiety scores were negatively correlated with gray matter surface area in insula, OFC, rostral middle frontal, superior temporal and lingual gyrus. Our results were consistent with previous reports showing structural alterations in regions supporting the socio-affective and visuospatial impairments in WS. However, we also were able to effectively capture novel and complex patterns of cortical differences using both surface area and thickness. In addition, correlation results implicate specific brain regions in levels of anxiety in WS, consistent with previous reports investigating general anxiety disorders in the general population

X-linked disorders with cerebellar dysgenesis

X-linked disorders with cerebellar dysgenesis (XLCD) are a genetically heterogeneous and clinically variable group of disorders in which the hallmark is a cerebellar defect (hypoplasia, atrophy or dysplasia) visible on brain imaging, caused by gene mutations or genomic imbalances on the X-chromosome. The neurological features of XLCD include hypotonia, developmental delay, intellectual disability, ataxia and/or other cerebellar signs. Normal cognitive development has also been reported. Cerebellar dysgenesis may be isolated or associated with other brain malformations or multiorgan involvement. There are at least 15 genes on the X-chromosome that have been constantly or occasionally associated with a pathological cerebellar phenotype. 8 XLCD loci have been mapped and several families with X-linked inheritance have been reported. Recently, two recurrent duplication syndromes in Xq28 have been associated with cerebellar hypoplasia. Given the report of several forms of XLCD and the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiological and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance

Phenotypic And Electrophysiologic Characterization of a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. It is caused by a mutation in the fragile X mental retardation (FMR1) gene on the X chromosome. Many children with FXS exhibit autistic behaviors and deficits in motor coordination including speech articulation deficits. The development of the FMR1 knockout (Fmr1 KO) mouse, in which the Fmr1 gene is inactivated, has provided an animal model that can be used to investigate underlying neuro-physiological mechanisms associated with FXS as well as to evaluate potential therapeutic treatments. In this study, quantitative behavioral assays were used, such as long term fluid licking observations, measurements of ultrasonic vocalizations (USV), and 3D tracking of whisker movements to test Fmr1 KO mice for behavioral deficits compared to their Wild type (WT) littermates. Electrophysiological techniques were employed to evaluate the functional properties of the neocortex. Pyramidal neurons in the neocortex of human FXS patients and Fmr1 KO mice are characterized by abnormally long, thin and numerous dendritic spines. Multiple electrode recordings were used to study how loss of Fmr1 expression affects several aspects of the neocortical network activities in Fmr1 KO mice. Single and multi unit spike activities and local field potentials (LFPs) were recorded in the whisker barrel cortex of awake mice. Baseline spike activity was significantly lower in cortical neurons of Fmr1 KO mice. Synchronous activity at the LFP was strongly reduced in Fmr1 KO mice. Relative power in the delta range frequency band of LFP activity was significantly reduced in the neocortex of Fmr1 KO mice. Furthermore, relative power in the beta frequency band was significantly higher in Fmr1 KO compared to WT mice. Our behavioral assays identified several phenotypical differences between Fmr1 KO and WT mice. Orofacial behavioral deficits in fluid licking and USV may be comparable to speech deficits in fragile X patients. Severely impaired dynamics of neocortical network activity may be causally linked to the cognitive and sensorimotor impairments associated with fragile X syndrome

Distinct neuroanatomical and neuropsychological features of Down syndrome compared to related neurodevelopmental disorders: a systematic review

ObjectivesWe critically review research findings on the unique changes in brain structure and cognitive function characteristic of Down syndrome (DS) and summarize the similarities and differences with other neurodevelopmental disorders such as Williams syndrome, 22q11.2 deletion syndrome, and fragile X syndrome.MethodsWe conducted a meta-analysis and systematic literature review of 84 studies identified by searching PubMed, Google Scholar, and Web of Science from 1977 to October 2022. This review focuses on the following issues: (1) specific neuroanatomic and histopathological features of DS as revealed by autopsy and modern neuroimaging modalities, (2) language and memory deficits in DS, (3) the relationships between these neuroanatomical and neuropsychological features, and (4) neuroanatomic and neuropsychological differences between DS and related neurodevelopmental syndromes.ResultsNumerous post-mortem and morphometric neuroimaging investigations of individuals with DS have reported complex changes in regional brain volumes, most notably in the hippocampal formation, temporal lobe, frontal lobe, parietal lobe, and cerebellum. Moreover, neuropsychological assessments have revealed deficits in language development, emotional regulation, and memory that reflect these structural changes and are more severe than expected from general cognitive dysfunction. Individuals with DS also show relative preservation of multiple cognitive, linguistic, and social domains compared to normally developed controls and individuals with other neurodevelopmental disorders. However, all these neurodevelopment disorders exhibit substantial heterogeneity among individuals.ConclusionPeople with Down syndrome demonstrate unique neurodevelopmental abnormalities but cannot be regarded as a homogenous group. A comprehensive evaluation of individual intellectual skills is essential for all individuals with neurodevelopment disorders to develop personalized care programs

Magnetic resonance imaging In Alzheimer’s disease, mild cognitive impairment and normal aging : Multi-template tensor-based morphometry and visual rating

Alzheimer's disease (AD) is the most common neurodegenerative disease preceded by a stage of mild cognitive impairment (MCI). The structural brain changes in AD can be detected more than 20 years before symptoms appear. If we are to reveal early brain changes in AD process, it is important to develop new diagnostic methods. Magnetic resonance imaging (MRI) is an imaging technique used in the diagnosis and monitoring of neurodegenerative diseases. Magnetic resonance imaging can detect the typical signs of brain atrophy of degenerative diseases, but similar changes can also be seen in normal aging. Visual rating methods (VRM) have been developed for visual evaluation of atrophy in dementia. A computer-based tensor-based morphometry (TBM) analysis is capable of assessing the brain volume changes typically encountered in AD. This study compared the VRM and TBM analysis in MCI and AD subjects by cross-sectional and longitudinal examination. The working hypothesis was that TBM analysis would be better than the visual methods in detecting atrophy in the brain. TBM was also used to analyze volume changes in the deep gray matter (DGM). Possible associations between TBM changes and neuropsychological tests performances were examined. This working hypothesis was that the structural DGM changes would be associated with impairments in cognitive functions. In the cross-sectional study, TBM distinguished the MCI from controls more sensitively than VRM, but the methods were equally effective in differentiating AD from MCI and controls. In the longitudinal study, both methods were equally good in the evaluation of atrophy in MCI, if the groups were sufficiently large and the disease progressed to AD. Volume changes were found in DGM structures, and the atrophy of DGM structures was related to cognitive impairment in AD. Based on these results, a TBM analysis is more sensitive in detecting brain changes in early AD as compared to VRM. In addition, the study produced information about the involvement of the deep gray matter in cognitive impairment in AD.Magneettikuvaus Alzheimerin taudissa, lievässä muistihäiriössä ja normaalissa ikääntymisessä: Tensoripohjainen muotoanalyysi ja visuaalinen arviointimenetelmä Alzheimerin tauti (AT) on yleisin dementoiva sairaus, jota edeltää yleensä lievä muistitoimintojen heikentyminen. AT:n aivomuutoksia voidaan todeta yli 20 vuotta ennen sairastumista. Jotta vielä varhaisempia AT:n aivomuutoksia voidaan todeta, on tärkeää kehittää uusia diagnostisia menetelmiä. Magneettikuvausta (MK) käytetään rappeuttavien aivosairauksien diagnostiikassa ja seurannassa. MK:lla voidaan havaita aivorappeumasairauksille tyypillistä kutistumista, mutta samanlaisia muutoksia voi esiintyä myös normaalissa ikääntymisessä. Aivorappeuman arviointiin on kehitetty silmämääräisiä arviointimenetelmiä. Tietokoneperusteinen tensoripohjainen muotoanalyysi (TPM) laskee esimerkiksi AT:lle tyypillisiä aivojen tilavuusmuutoksia. Tämä tutkimus vertaili silmämääräisiä arvioitimenetelmiä ja TPM:ä lievässä muistitoimintojen heikentymisessä ja AT:ssa poikittais- ja pitkittäistutkimuksella. TPM:n oletettiin olevan silmämääräisiä menetelmiä parempi tunnistamaan aivojen kutistumismuutoksia. Lisäksi TPM:llä tutkittiin AT:iin liittyviä aivojen syvän harmaan aiheen muutoksia, joita verrattiin neuropsykologisten testien tuloksiin. Syvän harmaan aineen kutistumisen oletettiin olevan yhteydessä tietojenkäsittelyn heikentymiseen. Tulosten perustella TPM tunnisti AT:iin liittyviä aivomuutoksia silmämääräistä menetelmää paremmin jo lievän muistitoimintojen heikentymisen vaiheessa. AT:iin liittyviä aivomuutoksia löytyi myös aivojen syvästä harmaasta aineesta ja ne olivat osittain yhteydessä neuropsykologisten testien tuloksiin. Tutkimuksen perusteella TPM voi parantaa AT:n varhaisdiagnostiikkaa verrattuna silmämääräisiin arviointimenetelmiin. Tutkimus antoi myös tietoa aivojen syvän harmaan aineen osallisuudesta ihmisen tietojenkäsittelyyn

Effect of 16P11.2 copy number variants on cognitive traits and brain structures

The 600kb 16p11.2 CNVs (breakpoints 4–5, 29.6-30.2 Mb-Hg19) are among the most frequent genetic risk factors for neurodevelopmental and psychiatric conditions: A 10-fold enrichment of deletions and duplications is observed in autism cohorts and a 10-fold enrichment of duplications in schizophrenia cohorts. Previous studies demonstrated “mirror” effects of both CNVs on body mass index and head circumference (deletion>control>duplication). However, the large global effect of brain size and the sample size of the two previous neuroimaging studies limited the interpretation of the analyses on regional brain structures, any estimate of the effect size, and the generalizability of the results across different ascertainments of the patients. In the first part of my Ph.D., I analyze structural magnetic resonance imaging (MRI) on 78 deletion carriers, 71 duplication carriers, and 212 controls. I show that both CNVs affect in a “mirror” way the volume and the cortical surface of the insula (Cohen’s d>1), whilst other brain regions are preferentially altered in either the deletion carriers (calcarine cortex and superior, middle, transverse temporal gyri, Cohen’s d>1) or the duplication carriers (caudate and hippocampus, Cohen’s d of 0.5 to 1). Results are generalizable across scanning sites, computational methods, age, sex, ascertainment for psychiatric disorders. They partially overlap with results of meta-analyses performed across psychiatric disorders. In the second part, I characterize the developmental trajectory of global brain metrics and regional brain structures in the 16p11.2 CNV carriers. I adapt a previously published longitudinal pipeline and normalizing method, derived from 339 typically developing individuals aged from 4.5 to 20 years old. From this population of reference, I Z-score our cross-sectional 16p11.2 dataset and show that all the brain alterations in the 16p11.2 carriers are already present at 4.5 years old and follow parallel trajectories to the controls. In summary, my results suggest that brain alterations, present in childhood and stable across adolescence and adulthood, are related to the risk conferred by the 16p11.2 CNVs, regardless of the carriers’ symptoms. Additional factors are therefore likely required for the development of psychiatric disorders. I highlight the relevance of studying genetic risk factors and mechanisms as a complement to groups defined by behavioral criteria. Further studies comparing multiple CNVs and monogenic conditions, from the earliest age, are required to understand the onset of neuroanatomical alterations and their overlap between different genetic risk factors for neurodevelopmental disorders. -- Les variations en nombre de copies (CNV), au locus 16p11.2 et d’une taille d’600kb (points de cassure 4–5, 29.6-30.2 Mb-Hg19) représentent un des facteurs de risque génétique les plus fréquents parmi les troubles psychiatriques : 10% d’enrichissement en délétion et duplication pour les troubles du spectre autistique, 10% d’enrichissement en duplication pour la schizophrénie. Les effets « miroirs » des deux CNVs sur l’indice de masse corporelle et le périmètre cranien ont déjà été démontrés (délétion>contrôle>duplication). Cependant, les différences en taille de cerveau et les échantillons des deux précédentes études de neuro- imagerie ont limité les analyses des régions cérébrales, l’estimation de la taille des effets, et la généralisation des résultats selon les modes de recrutement des patients. Dans cette thèse, j’analyse les images par résonance magnétique (IRM) de 78 porteurs de la délétion, 71 porteurs de la duplication et 212 participants contrôles. Je montre que les deux CNVs sont associées à des différences « en miroir » du volume et de la surface corticale de l’insula (Cohen’s d>1), tandis que le cortex calcarin, les gyri temporaux supérieur, moyen et transverse sont préférentiellement altérés par la délétion (Cohen’s d>1), les noyaux caudés et l’hippocampe sont préférentiellement altérés par la duplication (0.5<Cohen’s d<1). Les résultats sont généralisables à travers les differents sites d’IRM, les méthodes d’analyse computationnelle, les âges, les sexes et les divers diagnostiques psychiatriques des patients. Les résultats chevauchent partiellement ceux d’une méta-analyse sur plusieurs diagnostiques psychiatriques. Dans un second temps, je caractérise la trajectoire développementale de ces différences cérébrales. J’adapte un pipeline longitunal et une méthode de normalisation déjà publiés, construits à partir de 339 participants contrôles de 4.5 à 20 ans. Je calcule des Z-scores pour nos données transversales et montre que les différences cérébrales liées aux CNVs sont déjà présentes à 4.5 ans, avec les mêmes tailles d’effet et une trajectoire parallèle aux contrôles. En résumé, mes résultats suggèrent que les différences cérébrales, présentes dans la jeune enfance et stables à l’adolescence et l’âge adulte, sont liées au risque conféré par les CNVs en 16p11.2, quelque soient les symptômes. Des facteurs additionnels sont probablement nécessaires pour le développement de maladies psychiatriques. Je montre la pertinence d’étudier les facteurs de risque génétiques en complément des groupes de patients définis sur des critères comportementaux. Des études comparant diverses conditions génétiques, dès la naissance, sont nécessaires pour comprendre le début et le chevauchement des différences neuro-anatomiques observées pour différents facteurs de risque génétiques