Hypogenesis (hCC) and dysgenesis (dCC) of the corpus callosum (CC) are characterized by its smaller size or absence. The outcomes of these patients vary considerably and are unrelated to the size of the CC abnormality. The aim of the current study was to characterize the sulcal pattern in children with hCC and dCC and to explore its relation to clinical outcome. We used quantitative sulcal pattern analysis that measures deviation (similarity index, SI) of the composite or individual sulcal features (position, depth, area, and graph topology) compared to the control group. We calculated SI for each hemisphere and lobe in 11 children with CC disorder (hCC = 4, dCC = 7) and 15 controls. hCC and dCC had smaller hemispheric SI compared to controls. dCC subjects had smaller regional SI in the frontal and occipital lobes, which were driven by a smaller SI in a position or a graph topology. The significantly decreased SI gradient was found across groups only in the sulcal graph topology of the temporal lobes (controls > hCC > dCC) and was related to clinical outcome. Our results suggest that careful examination of sulcal pattern in hCC and dCC patients could be a useful biomarker of outcome.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P  0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.

Neurodevelopmental abnormalities are the most common noncardiac complications in patients with congenital heart disease (CHD). Prenatal brain abnormalities may be due to reduced oxygenation, genetic factors, or less commonly, teratogens. Understanding the contribution of these factors is essential to improve outcomes. Because primary sulcal patterns are prenatally determined and under strong genetic control, we hypothesized that they are influenced by genetic variants in CHD. In this study, we reveal significant alterations in sulcal patterns among subjects with single ventricle CHD (n = 115, 14.7 ± 2.9 years [mean ± standard deviation]) compared with controls (n = 45, 15.5 ± 2.4 years) using a graph-based pattern-analysis technique. Among patients with CHD, the left hemisphere demonstrated decreased sulcal pattern similarity to controls in the left temporal and parietal lobes, as well as the bilateral frontal lobes. Temporal and parietal lobes demonstrated an abnormally asymmetric left-right pattern of sulcal basin area in CHD subjects. Sulcal pattern similarity to control was positively correlated with working memory, processing speed, and executive function. Exome analysis identified damaging de novo variants only in CHD subjects with more atypical sulcal patterns. Together, these findings suggest that sulcal pattern analysis may be useful in characterizing genetically influenced, atypical early brain development and neurodevelopmental risk in subjects with CHD.

Copy number variants at the chromosomal locus 16p11.2 contribute to neurodevelopmental disorders such as autism spectrum disorders, epilepsy, schizophrenia, and language and articulation disorders. Here, we provide detailed findings on the disrupted structural brain connectivity in 16p11.2 deletion syndrome (patients: N = 21, age range: 8-16 years; typically developing (TD) controls: 18, 9-16 years) using structural and diffusion MRI. We performed global short-, middle-, long-range, and interhemispheric connectivity analysis in the whole brain using gyral topology-based cortical parcellation. Using region of interest analysis, we studied bilateral dorsal (3 segments of arcuate fasciculus (AF)) and ventral (inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF)) language pathways. Our results showed significantly increased axial (AD) and radial (RD) diffusivities in bilateral anterior AF, decreased volume for left long AF, increased mean diffusivity (MD) and RD for right long AF, and increased AD for bilateral UF in the 16p11.2 deletion group in the absence of significant abnormalities in the whole-brain gyral and interhemispheric connectivity. The selective involvement of the language networks may aid in understanding effects of altered white matter connectivity on neurodevelopmental outcomes in 16p11.2 deletion.

Spatial distribution and specific geometric and topological patterning of early sulcal folds have been hypothesized to be under stronger genetic control and are more associated with optimal organization of cortical functional areas and their white matter connections, compared to later developing sulci. Several previous studies of sulcal pit (putative first sulcal fold) distribution and sulcal pattern analyses using graph structures have provided evidence of the importance of sulcal pits and patterns as remarkable anatomical features closely related to human brain function, suggesting additional insights concerning the anatomical and functional development of the human brain. Recently, early sulcal folding patterns have been observed in healthy fetuses and fetuses with brain abnormalities such as polymicrogyria and agenesis of corpus callosum. Graph-based quantitative sulcal pattern analysis has shown high sensitivity in detecting emerging subtle abnormalities in cerebral cortical growth in early fetal stages that are difficult to detect via qualitative visual assessment or using traditional cortical measures such as gyrification index and curvature. It has proven effective for characterizing genetically influenced early cortical folding development. Future studies will be aimed at better understanding a comprehensive map of spatio-temporal dynamics of fetal cortical folding in a large longitudinal cohort in order to examine individual clinical fetal MRIs and predict postnatal neurodevelopmental outcomes from early fetal life.

Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.

Fetuses with congenital heart disease (CHD) have third trimester alterations in cortical development on brain magnetic resonance imaging (MRI). However, the intersulcal relationships contributing to global sulcal pattern remain unknown. This study applied a novel method for examining the geometric and topological relationships between sulci to fetal brain MRIs from 21-30 gestational weeks in CHD fetuses (n = 19) and typically developing (TD) fetuses (n = 17). Sulcal pattern similarity index (SI) to template fetal brain MRIs was determined for the position, area, and depth for corresponding sulcal basins and intersulcal relationships for each subject. CHD fetuses demonstrated altered global sulcal patterns in the left hemisphere compared with TD fetuses (TD [SI, mean ± SD]: 0.822 ± 0.023, CHD: 0.795 ± 0.030, P = 0.002). These differences were present in the earliest emerging sulci and were driven by differences in the position of corresponding sulcal basins (TD: 0.897 ± 0.024, CHD: 0.878 ± 0.019, P = 0.006) and intersulcal relationships (TD: 0.876 ± 0.031, CHD: 0.857 ± 0.018, P = 0.033). No differences in cortical gyrification index, mean curvature, or surface area were present. These data suggest our methods may be more sensitive than traditional measures for evaluating cortical developmental alterations early in gestation.

Despite extensive literature showing damages in the sensorimotor projection fibers of children with hemiplegic cerebral palsy (HCP), little is known about how these damages affect the global brain network. In this study, we assess the relationship between the structural integrity of sensorimotor projection fibers and the integrity of intergyral association white matter connections in children with HCP. Diffusion tensor imaging was performed in 10 children with HCP and 16 typically developing children. We estimated the regional and global white-matter connectivity using a region-of-interest (ROI)-based approach and a whole-brain gyrus-based parcellation method. Using the ROI-based approach, we tracked the spinothalamic (STh), thalamocortical (ThC), corticospinal (CST), and sensorimotor U- (SMU) fibers. Using the whole-brain parcellation method, we tracked the short-, middle-, and long-range association fibers. We observed for the more affected hemisphere of children with HCP: (i) an increase in axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) for the STh and ThC fibers; (ii) a decrease in fractional anisotropy (FA) and an increase in MD and RD for the CST and SMU fibers; in (iii) a decrease in FA and an increase in AD, MD, and RD for the middle- and long-range association fibers; and (iv) an association between the integrity of sensorimotor projection and intergyral association fibers. Our findings indicate that altered structural integrity of the sensorimotor projection fibers disorganizes the intergyral association white matter connections among local and distant regions in children with HCP.

The diffuse nature of mild traumatic brain injury (mTBI) impacts brain white-matter pathways with potentially long-term consequences, even after initial symptoms have resolved. To understand post-mTBI recovery in adolescents, longitudinal studies are needed to determine the interplay between highly individualised recovery trajectories and ongoing development. To capture the distributed nature of mTBI and recovery, we employ connectomes to probe the brain's structural organisation. We present a diffusion MRI study on adolescent mTBI subjects scanned one day, two weeks and one year after injury with controls. Longitudinal global network changes over time suggests an altered and more 'diffuse' network topology post-injury (specifically lower transitivity and global efficiency). Stratifying the connectome by its back-bone, known as the 'rich-club', these network changes were driven by the 'peripheral' local subnetwork by way of increased network density, fractional anisotropy and decreased diffusivities. This increased structural integrity of the local subnetwork may be to compensate for an injured network, or it may be robust to mTBI and is exhibiting a normal developmental trend. The rich-club also revealed lower diffusivities over time with controls, potentially indicative of longer-term structural ramifications. Our results show evolving, diffuse alterations in adolescent mTBI connectomes beginning acutely and continuing to one year.

Accurate parcellation and labeling of primary cortical sulci in the human fetal brain is useful for regional analysis of brain development. However, human fetal brains show large spatio-temporal changes in brain size, cortical folding patterns, and relative position/size of cortical regions, making accurate automatic sulcal labeling challenging. Here, we introduce a novel sulcal labeling method for the fetal brain using spatio-temporal gyrification information from multiple fetal templates. First, spatial probability maps of primary sulci are generated on the templates from 23 to 33 gestational weeks and registered to an individual brain. Second, temporal weights, which determine the level of contribution to the labeling for each template, are defined by similarity of gyrification between the individual and the template brains. We combine the weighted sulcal probability maps from the multiple templates and adopt sulcal basin-wise approach to assign sulcal labels to each basin. Our labeling method was applied to 25 fetuses (22.9-29.6 gestational weeks), and the labeling accuracy was compared to manually assigned sulcal labels using the Dice coefficient. Moreover, our multi-template basin-wise approach was compared to a single-template approach, which does not consider the temporal dynamics of gyrification, and a fully-vertex-wise approach. The mean accuracy of our approach was 0.958 across subjects, significantly higher than the accuracies of the other approaches. This novel approach shows highly accurate sulcal labeling and provides a reliable means to examine characteristics of cortical regions in the fetal brain.