The parcellation of cingulate cortex in neonatal period based on resting-state functional MRI.

The human cingulate cortex (CC) is a complex region that is characterized by heterogeneous cytoarchitecture, connectivity, and function, and it is associated with various cognitive functions. The adult CC has been divided into various subregions, and this subdivision is highly consistent with its functional differentiation. However, only a few studies have focused on the function of neonatal CC. The aim of this study was to describe the cingulate segregation and the functional connectivity of each subdivision in full-term neonates (n = 60) based on resting-state functional magnetic resonance imaging. The neonatal CC was divided into three subregions, and each subregion showed specific connectivity patterns. The anterior cingulate cortex was mainly correlated with brain regions related to the salience (affected) network and default mode network (DMN), the midcingulate cortex was related to motor areas, and the posterior cingulate cortex was coupled with DMN. Moreover, we found that the cingulate subregions showed distinct functional profiles with major brain networks, which were defined using independent component analysis, and exhibited functional lateralization. This study provided new insights into the understanding of the functional specialization of neonatal CC, and these findings may have significant clinical implications, especially in predicting neurological disorder.

Altered cortical microstructure in preterm infants at term-equivalent age relative to term-born neonates.

Preterm (PT) birth is a potential factor for abnormal brain development. Although various alterations of cortical structure and functional connectivity in preterm infants have been reported, the underlying microstructural foundation is still undetected thoroughly in PT infants relative to full-term (FT) neonates. To detect the very early cortical microstructural alteration noninvasively with advanced neurite orientation dispersion and density imaging (NODDI) on a whole-brain basis, we used multi-shell diffusion MRI of healthy newborns selected from the Developing Human Connectome Project. 73 PT infants and 69 FT neonates scanned at term-equivalent age were included in this study. By extracting the core voxels of gray matter (GM) using GM-based spatial statistics (GBSS), we found that comparing to FT neonates, infants born preterm showed extensive lower neurite density in both primary and higher-order association cortices (FWE corrected, P < 0.025). Higher orientation dispersion was only found in very preterm subgroup in the orbitofrontal cortex, fronto-insular cortex, entorhinal cortex, a portion of posterior cingular gyrus, and medial parieto-occipital cortex. This study provided new insights into exploring structural MR for functional and behavioral variations in preterm population, and these findings may have marked clinical importance, particularly in the guidance of ameliorating the development of premature brain.

A comparative study of the superior longitudinal fasciculus subdivisions between neonates and young adults.

The superior longitudinal fasciculus (SLF) is a complex associative tract comprising three distinct subdivisions in the frontoparietal cortex, each of which has its own anatomical connectivity and functional roles. However, many studies on white matter development, hampered by limitations of data quality and tractography methods, treated the SLF as a single entity. The exact anatomical trajectory and developmental status of each sub-bundle of the human SLF in neonates remain poorly understood. Here, we compared the morphological and microstructural characteristics of each branch of the SLF at two ages using diffusion MRI data from 40 healthy neonates and 40 adults. A multi-shell multi-tissue constrained spherical deconvolution (MSMT-CSD) algorithm was used to ensure the successful separation of the three SLF branches (SLF I, SLF II and SLF III). Then, between-group differences in the diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics were investigated in all the SLF branches. Meanwhile, Mahalanobis distances based on all the diffusion metrics were computed to quantify the maturation of neonatal SLF branches, considering the adult brain as the reference. The SLF branches, excluding SLF II, had similar fibre morphology and connectivity between the neonatal and adult groups. The Mahalanobis distance values further supported the notion of heterogeneous maturation among SLF branches. The greatest Mahalanobis distance was observed in SLF II, possibly indicating that it was the least mature. Our findings provide a new anatomical basis for the early diagnosis and treatment of diseases caused by abnormal neonatal SLF development.

Morphological changes in the central sulcus of children with isolated growth hormone deficiency versus idiopathic short stature.

In this study, the morphological changes in the central sulcus between children with isolated growth hormone deficiency (IGHD) and those with idiopathic short stature (ISS) were analyzed. Thirty children with IGHD (peak growth hormone < 5 µg/L) and 30 children with ISS (peak growth hormone > 10.0 µg/L) were included. Morphological measurements of the central sulcus were obtained from T1-weighted MRIs using BrainVISA, including the average sulcal width, maximum depth, average depth, top length, bottom length, and depth position-based profiles (DPPs). The bilateral average width of the central sulci was significantly wider, while the left maximum depth and right average depth of the central sulcus were significantly smaller, in children with IGHD than in children with ISS. There were no significant differences in the right maximum depth, left average depth, or bilateral top length and bottom length of the central sulcus between groups. The DPPs of the middle part of both central sulci (corresponding to the hand motor activation area) and the inferior part of the right central sulcus (corresponding to the oral movement area) near the Sylvian fissure were significantly smaller in children with IGHD than in controls before false discovery rate (FDR) correction. However, all the above significant DPP sites disappeared after FDR correction. There were significant morphological changes in the three-dimensional structure of the central sulcus in children with IGHD, which were the outcome of other more essential cortical or subcortical changes, resulting in their relatively slower development in motor, cognitive, and linguistic functional performance.

Morphological changes of the cerebral cortex between children with isolated growth hormone deficiency and idiopathic short stature.

The growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis plays an important role in normal brain development, and GH deficiency inevitably affects the growth of the cerebral cortex. This study was designed to analyze morphological differences in gray matter volume, cortical surface area, and gray matter thickness between children with isolated growth hormone deficiency (IGHD) and children with idiopathic short stature (ISS). Twenty-four children with IGHD (mean age 9.42 years, peak GH < 5 µg/l) and 24 controls with ISS (mean age 9.21 years, peak GH > 10 µg/l) were included. High-resolution three-dimensional T1-weighted MRIs were acquired at participants' first visit. Measurements of gray matter volume, cortical surface area and gray matter thickness were obtained using FreeSurfer. The total and regional differences between groups were statistically analyzed. Correlations between the FreeSurfer results and GH and IGF-I levels were also obtained. The gray matter volume, cortical surface area and gray matter thickness of the total brain and of the bilateral hemispheres of children with IGHD were significantly smaller than those of children with ISS (all P values < 0.05). All the measurements had similar cortical distributions between groups but varied across regions. Cortical regions with significant differences in the mean gray matter volume and surface area were mainly distributed around the bilateral central sulci and the lateral and basal parts of the temporal lobes (all P values < 0.05). There were negative correlations between gray matter volume, cortical surface area and GH levels, and the right hemispheric and total cortical surface area correlated significantly with GH levels (all P values < 0.05) in children with IGHD. There were significant positive correlations between gray matter volume, cortical surface area and IGF-I levels (all P values < 0.05) in both groups, except for in left hemispheric gray matter volume in children with ISS. Children with IGHD have significant morphological changes in the cerebral cortex, which were partially influenced by GH and IGF-I levels. These cortical changes may be related to deficits in their relatively slower development in intelligence, motor performance, and other functions.

Fetal ocular development in the second trimester of pregnancy documented by 7.0 T postmortem Magnetic Resonance Imaging.

Few investigators have analyzed fetal ocular growth with Magnetic Resonance Imaging (MRI) of high magnetic strength. Our purpose is to obtain normative biometrics for fetal ocular development in the second trimester of pregnancy. Sixty specimens with a gestational age (GA) of 12-23 weeks were scanned using a 7.0 T MRI scanner. The linear interocular and binocular distances (IOD and BOD, respectively), globe diameter (GD) and lens diameter (LD) were measured on the transverse section of the largest diameter of the eyeballs. The three dimensional (3D) visualization model of the eyeball was reconstructed with Amira software. Then, the globe and lens volumes (GV and LV, respectively) were obtained. All the measurements were plotted as a function of GA. The fetal ocular structures in the second trimester of pregnancy could be clearly delineated on 7.0 T postmortem MRI images. All the linear measurements logarithmically increased with GA, while, the volumetric measurements linearly increased with GA. Postmortem MRI of high magnetic strength can clearly document fetal ocular growth in the second trimester of pregnancy. These quantitative data may be a valuable reference for the assessment of normal fetal eyeball development in clinical settings and may be considered a supplement to anatomical investigations.

Population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space.

Animal models of the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate, have been irreplaceable in neurobiological studies. However, a population-averaged macaque brain diffusion tensor imaging (DTI) atlas, including comprehensive gray and white matter labeling as well as bony and facial landmarks guiding invasive experimental procedures, is not available. The macaque white matter tract pathways and microstructures have been rarely recorded. Here, we established a population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space incorporating bony and facial landmarks, and delineated microstructures and three-dimensional pathways of major white matter tracts in vivo MRI/DTI and ex vivo (postmortem) DTI of ten rhesus macaque brains were acquired. Single-subject macaque brain DTI template was obtained by transforming the postmortem high-resolution DTI data into in vivo space. Ex vivo DTI of ten macaque brains was then averaged in the in vivo single-subject template space to generate population-averaged macaque brain DTI atlas. The white matter tracts were traced with DTI-based tractography. One hundred and eighteen neural structures including all cortical gyri, white matter tracts and subcortical nuclei, were labeled manually on population-averaged DTI-derived maps. The in vivo microstructural metrics of fractional anisotropy, axial, radial and mean diffusivity of the traced white matter tracts were measured. Population-averaged digital atlas integrated into in vivo space can be used to label the experimental macaque brain automatically. Bony and facial landmarks will be available for guiding invasive procedures. The DTI metric measurements offer unique insights into heterogeneous microstructural profiles of different white matter tracts.

Phenotypic and Genetic Correlations Between the Lobar Segments of the Inferior Fronto-occipital Fasciculus and Attention.

Attention deficits may present dysfunctions in any one or two components of attention (alerting, orienting, and executive control (EC)). However, these various forms of attention deficits generally have abnormal microstructure integrity of inferior fronto-occipital fasciculus (IFOF). In this work, we aim to deeply explore: (1) associations between microstructure integrities of IFOF (including frontal, parietal, temporal, occipital, and insular segments) and attention by means of structural equation models and multiple regression analyses; (2) genetic/environmental effects on IFOF, attention, and their correlations using bivariate genetic analysis. EC function was attributed to the fractional anisotropy (FA) of left (correlation was driven by genetic and environmental factors) and right IFOF (correlation was driven by environmental factors), especially to left frontal part and right occipital part (correlation was driven by genetic factors). Alerting was associated with FA in parietal and insular parts of left IFOF. No significant correlation was found between orienting and IFOF. This study revealed the advantages of lobar-segmental analysis in structure-function correlation study and provided the anatomical basis for kinds of attention deficits. The common genetic/environmental factors implicated in the certain correlations suggested the common physiological mechanisms for two traits, which should promote the discovery of single-nucleotide polymorphisms affecting IFOF and attention.

Structural Development of Human Fetal and Preterm Brain Cortical Plate Based on Population-Averaged Templates.

We hypothesized that the distinct maturational processes take place across different cortical areas from middle fetal stage to normal time of birth and these maturational processes are altered in late third trimester. Fractional anisotropies (FA) from diffusion tensor imaging (DTI) infer the microstructures of the early developing cortical plate. High-resolution DTI of 11 fetal brain specimens at postmenstrual age of 20 weeks (or simplified as 20 weeks), 19 in vivo brains at 35 weeks, and 17 in vivo brains at normal time of birth at term (40 weeks) were acquired. Population-averaged age-specific DTI templates were established with large deformation diffeomorphic metric mapping for subject groups at 20, 35, and 40 weeks. To alleviate partial volume effects, skeletonized FA values were used for mapping averaged cortical FA to the cortical surface and measuring FA at 12 functionally distinctive cortical regions. Significant and heterogeneous FA decreases take place in distinct cortical areas from 20 to 35 weeks and from 35 to 40 weeks, suggesting differentiated cortical development patterns. Temporally nonuniform FA decrease patterns during 35-40 weeks compared with those during 20-35 weeks were observed in higher-order association cortex. Measured skeletonized FA suggested dissociated changes between cerebral cortex and white matter during 35-40 weeks.

Development of the human fetal hippocampal formation during early second trimester.

Development of the fetal hippocampal formation has been difficult to fully describe because of rapid changes in its shape during the fetal period. The aims of this study were to: (1) segment the fetal hippocampal formation using 7.0 T MR images from 41 specimens with gestational ages ranging from 14 to 22 weeks and (2) reveal the developmental course of the fetal hippocampal formation using volume and shape analyses. Differences in hemispheric volume were observed, with the right hippocampi being larger than the left. Absolute volume changes showed a linear increase, while relative volume changes demonstrated an inverted-U shape trend during this period. Together these exhibited a variable developmental rate among different regions of the fetal brain. Different sub-regional growth of the fetal hippocampal formation was specifically observed using shape analysis. The fetal hippocampal formation possessed a prominent medial-lateral bidirectional shape growth pattern during its rotation process. Our results provide additional insight into 3D hippocampal morphology in the assessment of fetal brain development and can be used as a reference for future hippocampal studies.

Clinicopathological significance and potential drug targeting of CDH1 in lung cancer: a meta-analysis and literature review.

BACKGROUND: CDH1 is a protein encoded by the CDH1 gene in humans. Mutations in this gene are linked with several types of cancer. Loss of CDH1 function contributes to the progression of cancer by increasing proliferation, invasion, and/or metastasis. However, the association between and clinicopathological significance of CDH1 promoter methylation and lung cancer remains unclear. In this study, we systematically reviewed the studies of CDH1 promoter methylation and lung cancer, and evaluated the association between CDH1 promoter methylation and lung cancer using meta-analysis methods. METHODS: A comprehensive search of the PubMed and Embase databases was performed up to July 2014. The methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized. RESULTS: Finally, an analysis of 866 patients with non-small cell lung cancer from 13 eligible studies was performed. The CDH1 methylation level in the cancer group was significantly higher than in the controls (OR 3.89, 95% confidence interval [CI] 2.87-5.27, P<0.00001). However, there were no correlations between CDH1 promoter methylation and clinicopathological characteristics (sex status, OR 0.78, 95% CI 0.41-1.50, P=0.46; smoking history, OR 0.97, 95% CI 0.53-1.79, P=0.93; pathological type, OR 0.97, 95% CI 0.59-1.60, P=0.91; clinical staging, OR 1.48, 95% CI 0.81-2.68, P=0.2; lymph node metastasis, OR 0.68, 95% CI 0.13-3.63, P=0.65; or differentiation degree, OR 1.01, 95% CI 0.34-3.02, P=0.99). CONCLUSION: The results of this meta-analysis suggest that CDH1 methylation is associated with an increased risk of lung cancer. CDH1 hypermethylation, which induces inactivation of the CDH1 gene, plays an important role in carcinogenesis and may serve as a potential drug target in lung cancer. However, CDH1 methylation does not correlate with other factors, such as smoking history, clinical stage, pathological type, sex status, lymph node metastasis, or degree of differentiation.

Structural development of human brain white matter from mid-fetal to perinatal stage.

The structures of developing human brain white matter (WM) tracts can be effectively quantified by DTI-derived metrics, including fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD and RD). However, dynamics of WM microstructure during very early developmental period from mid-fetal to perinatal stage is unknown. It is difficult to accurately measure microstructural properties of these WM tracts due to severe contamination from cerebrospinal fluid (CSF). In this study, high resolution DTI of fetal brains at mid-fetal stage (20 weeks of gestation or 20wg), 19 brains in the middle of 3rd trimester (35wg) and 17 brains around term (40wg) were acquired. We established first population-averaged DTI templates at these three time points and extracted WM skeleton. 16 major WM tracts in limbic, projection, commissural and association tract groups were traced with DTI tractography in native space. The WM skeleton in the template space was inversely transformed back to the native space for measuring core WM microstructures of each individual tract. Continuous microstructural enhancement and volumetric increase of WM tracts were found from 20wg to 40wg. The microstructural enhancement from FA measurement is decelerated in late 3rd trimester compared to mid-fetal to middle 3rd trimester, while volumetric increase of prefrontal WM tracts is accelerated. The microstructural enhancement from 35wg to 40wg is heterogeneous among different tract groups with microstructures of association tracts undergoing most dramatic change. Besides decreases of RD indicating active myelination, the decrease of AD for most WM tracts during late 3rd trimester suggests axonal packing process.

Microstructure, length, and connection of limbic tracts in normal human brain development.

The cingulum and fornix play an important role in memory, attention, spatial orientation, and feeling functions. Both microstructure and length of these limbic tracts can be affected by mental disorders such as Alzheimer's disease, depression, autism, anxiety, and schizophrenia. To date, there has been little systematic characterization of their microstructure, length, and functional connectivity in normally developing brains. In this study, diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) data from 65 normally developing right-handed subjects from birth to young adulthood was acquired. After cingulate gyrus part of the cingulum (cgc), hippocampal part of the cingulum (cgh) and fornix (fx) were traced with DTI tractography, absolute and normalized tract lengths and DTI-derived metrics including fractional anisotropy, mean, axial, and radial diffusivity were measured for traced limbic tracts. Free water elimination (FWE) algorithm was adopted to improve accuracy of the measurements of DTI-derived metrics. The role of these limbic tracts in the functional network at birth and adulthood was explored. We found a logarithmic age-dependent trajectory for FWE-corrected DTI metric changes with fast increase of microstructural integrity from birth to 2 years old followed by a slow increase to 25 years old. Normalized tract length of cgc increases with age, while no significant relationship with age was found for normalized tract lengths of cgh and fx. Stronger microstructural integrity on the left side compared to that of the right side was found. With integrated DTI and rs-fMRI, the key connectional role of cgc and cgh in the default mode network was confirmed as early as birth. Systematic characterization of length and DTI metrics after FWE correction of limbic tracts offers insight into their morphological and microstructural developmental trajectories. These trajectories may serve as a normal reference for pediatric patients with mental disorders.

Increasing breadth of the frontal lobe but decreasing height of the human brain between two Chinese samples from a Neolithic site and from living humans.

Morphological observation and measurements of endocasts have played a vital role in research on the evolution of the human brain. However, endocasts have never been used to investigate how the human brain has evolved since the Neolithic period. We investigated the evolution of the human brain during the Holocene by comparing virtual endocasts from Beiqian site (a Neolithic Chinese site) and a sample of Chinese modern-day humans. Standardized measurements and indices were taken to provide quantification of the overall endocast shape, including the length, breadth, height, frontal breadth, and the ratio of frontal breadth to breadth, as well as the cranial capacity. We found that the height of the endocasts and cranial capacity have decreased between our two samples, whereas the frontal breadth and sexual dimorphism have increased. We argue that these changes can be caused by random genetic mutation and epigenetic change in response to changes in the environment.