Subcortical Brain Development in Autism and Fragile X Syndrome: Evidence for Dynamic, Age- and Disorder-Specific Trajectories in Infancy.

OBJECTIVE: Previous research has demonstrated that the amygdala is enlarged in children with autism spectrum disorder (ASD). However, the precise onset of this enlargement during infancy, how it relates to later diagnostic behaviors, whether the timing of enlargement in infancy is specific to the amygdala, and whether it is specific to ASD (or present in other neurodevelopmental disorders, such as fragile X syndrome) are all unknown. METHODS: Longitudinal MRIs were acquired at 6-24 months of age in 29 infants with fragile X syndrome, 58 infants at high likelihood for ASD who were later diagnosed with ASD, 212 high-likelihood infants not diagnosed with ASD, and 109 control infants (1,099 total scans). RESULTS: Infants who developed ASD had typically sized amygdala volumes at 6 months, but exhibited significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen's d=0.56) compared with all other groups. Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the infants were diagnosed with ASD. Infants with fragile X syndrome had a persistent and significantly enlarged caudate volume at all ages between 6 and 24 months (d=2.12), compared with all other groups, which was significantly associated with greater repetitive behaviors. CONCLUSIONS: This is the first MRI study comparing fragile X syndrome and ASD in infancy, demonstrating strikingly different patterns of brain and behavior development. Fragile X syndrome-related changes were present from 6 months of age, whereas ASD-related changes unfolded over the first 2 years of life, starting with no detectable group differences at 6 months. Increased amygdala growth rate between 6 and 12 months occurs prior to social deficits and well before diagnosis. This gradual onset of brain and behavior changes in ASD, but not fragile X syndrome, suggests an age- and disorder-specific pattern of cascading brain changes preceding autism diagnosis.

Development of cortical shape in the human brain from 6 to 24months of age via a novel measure of shape complexity.

The quantification of local surface morphology in the human cortex is important for examining population differences as well as developmental changes in neurodegenerative or neurodevelopmental disorders. We propose a novel cortical shape measure, referred to as the 'shape complexity index' (SCI), that represents localized shape complexity as the difference between the observed distributions of local surface topology, as quantified by the shape index (SI) measure, to its best fitting simple topological model within a given neighborhood. We apply a relatively small, adaptive geodesic kernel to calculate the SCI. Due to the small size of the kernel, the proposed SCI measure captures fine differences of cortical shape. With this novel cortical feature, we aim to capture comparatively small local surface changes that capture a) the widening versus deepening of sulcal and gyral regions, as well as b) the emergence and development of secondary and tertiary sulci. Current cortical shape measures, such as the gyrification index (GI) or intrinsic curvature measures, investigate the cortical surface at a different scale and are less well suited to capture these particular cortical surface changes. In our experiments, the proposed SCI demonstrates higher complexity in the gyral/sulcal wall regions, lower complexity in wider gyral ridges and lowest complexity in wider sulcal fundus regions. In early postnatal brain development, our experiments show that SCI reveals a pattern of increased cortical shape complexity with age, as well as sexual dimorphisms in the insula, middle cingulate, parieto-occipital sulcal and Broca's regions. Overall, sex differences were greatest at 6months of age and were reduced at 24months, with the difference pattern switching from higher complexity in males at 6months to higher complexity in females at 24months. This is the first study of longitudinal, cortical complexity maturation and sex differences, in the early postnatal period from 6 to 24months of age with fine scale, cortical shape measures. These results provide information that complement previous studies of gyrification index in early brain development.

Diffusion imaging quality control via entropy of principal direction distribution.

Diffusion MR imaging has received increasing attention in the neuroimaging community, as it yields new insights into the microstructural organization of white matter that are not available with conventional MRI techniques. While the technology has enormous potential, diffusion MRI suffers from a unique and complex set of image quality problems, limiting the sensitivity of studies and reducing the accuracy of findings. Furthermore, the acquisition time for diffusion MRI is longer than conventional MRI due to the need for multiple acquisitions to obtain directionally encoded Diffusion Weighted Images (DWI). This leads to increased motion artifacts, reduced signal-to-noise ratio (SNR), and increased proneness to a wide variety of artifacts, including eddy-current and motion artifacts, "venetian blind" artifacts, as well as slice-wise and gradient-wise inconsistencies. Such artifacts mandate stringent Quality Control (QC) schemes in the processing of diffusion MRI data. Most existing QC procedures are conducted in the DWI domain and/or on a voxel level, but our own experiments show that these methods often do not fully detect and eliminate certain types of artifacts, often only visible when investigating groups of DWI's or a derived diffusion model, such as the most-employed diffusion tensor imaging (DTI). Here, we propose a novel regional QC measure in the DTI domain that employs the entropy of the regional distribution of the principal directions (PD). The PD entropy quantifies the scattering and spread of the principal diffusion directions and is invariant to the patient's position in the scanner. High entropy value indicates that the PDs are distributed relatively uniformly, while low entropy value indicates the presence of clusters in the PD distribution. The novel QC measure is intended to complement the existing set of QC procedures by detecting and correcting residual artifacts. Such residual artifacts cause directional bias in the measured PD and here called dominant direction artifacts. Experiments show that our automatic method can reliably detect and potentially correct such artifacts, especially the ones caused by the vibrations of the scanner table during the scan. The results further indicate the usefulness of this method for general quality assessment in DTI studies.

Adaptive prior probability and spatial temporal intensity change estimation for segmentation of the one-year-old human brain.

The degree of white matter (WM) myelination is rather inhomogeneous across the brain. White matter appears differently across the cortical lobes in MR images acquired during early postnatal development. Specifically at 1-year of age, the gray/white matter contrast of MR T1 and T2 weighted images in prefrontal and temporal lobes is reduced as compared to the rest of the brain, and thus, tissue segmentation results commonly show lower accuracy in these lobes. In this novel work, we propose the use of spatial intensity growth maps (IGM) for T1 and T2 weighted images to compensate for local appearance inhomogeneity. The IGM captures expected intensity changes from 1 to 2 years of age, as appearance homogeneity is greatly improved by the age of 24 months. The IGM was computed as the coefficient of a voxel-wise linear regression model between corresponding intensities at 1 and 2 years. The proposed IGM method revealed low regression values of 1-10% in GM and CSF regions, as well as in WM regions at maturation stage of myelination at 1 year. However, in the prefrontal and temporal lobes we observed regression values of 20-25%, indicating that the IGM appropriately captures the expected large intensity change in these lobes mainly due to myelination. The IGM is applied to cross-sectional MRI datasets of 1-year-old subjects via registration, correction and tissue segmentation of the IGM-corrected dataset. We validated our approach in a small leave-one-out study of images with known, manual 'ground truth' segmentations.

Asymmetric bias in user guided segmentations of brain structures.

Brain morphometric studies often incorporate comparative hemispheric asymmetry analyses of segmented brain structures. In this work, we present evidence that common user guided structural segmentation techniques exhibit strong left-right asymmetric biases and thus fundamentally influence any left-right asymmetry analyses. In this study, MRI scans from ten pediatric subjects were employed for studying segmentations of amygdala, globus pallidus, putamen, caudate, and lateral ventricle. Additionally, two pediatric and three adult scans were used for studying hippocampus segmentation. Segmentations of the sub-cortical structures were performed by skilled raters using standard manual and semi-automated methods. The left-right mirrored versions of each image were included in the data and segmented in a random order to assess potential left-right asymmetric bias. Using shape analysis we further assessed whether the asymmetric bias is consistent across subjects and raters with the focus on the hippocampus. The user guided segmentation techniques on the sub-cortical structures exhibited left-right asymmetric volume bias with the hippocampus displaying the most significant asymmetry values (p<<0.01). The hippocampal shape analysis revealed the bias to be strongest on the lateral side of the body and medial side of the head and tail. The origin of this asymmetric bias is considered to be based in laterality of visual perception; therefore segmentations with any degree of user interaction contain an asymmetric bias. The aim of our study is to raise awareness in the neuroimaging community regarding the presence of the asymmetric bias and its influence on any left-right hemispheric analyses. We also recommend reexamining previous research results in the light of this new finding.

Automatic corpus callosum segmentation using a deformable active Fourier contour model.

The corpus callosum (CC) is a structure of interest in many neuroimaging studies of neuro-developmental pathology such as autism. It plays an integral role in relaying sensory, motor and cognitive information from homologous regions in both hemispheres. We have developed a framework that allows automatic segmentation of the corpus callosum and its lobar subdivisions. Our approach employs constrained elastic deformation of flexible Fourier contour model, and is an extension of Szekely's 2D Fourier descriptor based Active Shape Model. The shape and appearance model, derived from a large mixed population of 150+ subjects, is described with complex Fourier descriptors in a principal component shape space. Using MNI space aligned T1w MRI data, the CC segmentation is initialized on the mid-sagittal plane using the tissue segmentation. A multi-step optimization strategy, with two constrained steps and a final unconstrained step, is then applied. If needed, interactive segmentation can be performed via contour repulsion points. Lobar connectivity based parcellation of the corpus callosum can finally be computed via the use of a probabilistic CC subdivision model. Our analysis framework has been integrated in an open-source, end-to-end application called CCSeg both with a command line and Qt-based graphical user interface (available on NITRC). A study has been performed to quantify the reliability of the semi-automatic segmentation on a small pediatric dataset. Using 5 subjects randomly segmented 3 times by two experts, the intra-class correlation coefficient showed a superb reliability (0.99). CCSeg is currently applied to a large longitudinal pediatric study of brain development in autism.

Reduced relationship to cortical white matter volume revealed by tractography-based segmentation of the corpus callosum in young children with developmental delay.

OBJECTIVE: The corpus callosum is the primary anatomical substrate for interhemispheric communication, which is important for a range of adaptive and cognitive behaviors in early development. Previous studies that have measured the corpus callosum in developmental populations have been limited by the use of rather arbitrary methods of subdividing the corpus callosum. The purpose of this study was to measure the corpus callosum in a clinical group of developmentally delayed children using a subdivision that more accurately reflected the anatomical properties of the corpus callosum. METHOD: The authors applied tractography to subdivide the corpus callosum into regions corresponding to the cortical regions to and from which its fibers travel in a clinical group of very young children with developmental delay, a precursor to general mental retardation, in comparison with typically developing children. RESULTS: The data demonstrate that the midsagittal area of the entire corpus callosum is reduced in children presenting with developmental delay, reflected in the smaller area of each of the fiber-based callosal subdivisions. In addition, while the area of each subdivision was strongly and significantly correlated with the corresponding cortical white matter volume in comparison subjects, this correlation was prominently absent in the developmentally delayed group. CONCLUSIONS: A fiber-based subdivision successfully separates lobar regions of the corpus callosum, and the areas of these regions distinguish a developmentally delayed clinical group from the comparison group. This distinction was evident both in the area measurements themselves and in their correlation to the white matter volumes of the corresponding cortical lobes.