Faculty Bibliography

A population growth model that represents the growth trajectories of individual subjects is critical to study and understand neurodevelopment. This paper presents a framework for jointly estimating and modeling individual and population growth trajectories, and determining significant regional differences in growth pattern characteristics applied to longitudinal neuroimaging data. We use non-linear mixed effect modeling where temporal change is modeled by the Gompertz function. The Gompertz function uses intuitive parameters related to delay, rate of change, and expected asymptotic value; all descriptive measures which can answer clinical questions related to growth. Our proposed framework combines nonlinear modeling of individual trajectories, population analysis, and testing for regional differences. We apply this framework to the study of early maturation in white matter regions as measured with diffusion tensor imaging (DTI). Regional differences between anatomical regions of interest that are known to mature differently are analyzed and quantified. Experiments with image data from a large ongoing clinical study show that our framework provides descriptive, quantitative information on growth trajectories that can be directly interpreted by clinicians. To our knowledge, this is the first longitudinal analysis of growth functions to explain the trajectory of early brain maturation as it is represented in DTI.

Quantitative analysis of early brain development through imaging is critical for identifying pathological development, which may in turn affect treatment procedures. We propose a framework for analyzing spatiotemporal patterns of brain maturation by quantifying intensity changes in longitudinal MR images. We use a measure of divergence between a pair of intensity distributions to study the changes that occur within specific regions, as well as between a pair of anatomical regions, over time. The change within a specific region is measured as the contrast between white matter and gray matter tissue belonging to that region. The change between a pair of regions is measured as the divergence between regional image appearances, summed over all tissue classes. We use kernel regression to integrate the temporal information across different subjects in a consistent manner. We applied our method on multimodal MRI data with T1-weighted (T1W) and T2-weighted (T2W) scans of each subject at the approximate ages of 6 months, 12 months, and 24 months. The results demonstrate that brain maturation begins at posterior regions and that frontal regions develop later, which matches previously published histological, qualitative and morphometric studies. Our multimodal analysis also confirms that T1W and T2W modalities capture different properties of the maturation process, a phenomena referred to as T2 time lag compared to T1. The proposed method has potential for analyzing regional growth patterns across different populations and for isolating specific critical maturation phases in different MR modalities.

Longitudinal analysis of anatomical changes is a vital component in many personalized-medicine applications for predicting disease onset, determining growth/atrophy patterns, evaluating disease progression, and monitoring recovery. Estimating anatomical changes in longitudinal studies, especially through magnetic resonance (MR) images, is challenging because of temporal variability in shape (e.g. from growth/atrophy) and appearance (e.g. due to imaging parameters and tissue properties affecting intensity contrast, or from scanner calibration). This paper proposes a novel mathematical framework for constructing subject-specific longitudinal anatomical models. The proposed method solves a generalized problem of joint segmentation, registration, and subject-specific atlas building, which involves not just two images, but an entire longitudinal image sequence. The proposed framework describes a novel approach that integrates fundamental principles that underpin methods for image segmentation, image registration, and atlas construction. This paper presents evaluation on simulated longitudinal data and on clinical longitudinal brain MRI data. The results demonstrate that the proposed framework effectively integrates information from 4-D spatiotemporal data to generate spatiotemporal models that allow analysis of anatomical changes over time.

Although neuroimaging is essential for prompt and proper management of traumatic brain injury (TBI), there is a regrettable and acute lack of robust methods for the visualization and assessment of TBI pathophysiology, especially for of the purpose of improving clinical outcome metrics. Until now, the application of automatic segmentation algorithms to TBI in a clinical setting has remained an elusive goal because existing methods have, for the most part, been insufficiently robust to faithfully capture TBI-related changes in brain anatomy. This article introduces and illustrates the combined use of multimodal TBI segmentation and time point comparison using 3D Slicer, a widely-used software environment whose TBI data processing solutions are openly available. For three representative TBI cases, semi-automatic tissue classification and 3D model generation are performed to perform intra-patient time point comparison of TBI using multimodal volumetrics and clinical atrophy measures. Identification and quantitative assessment of extra- and intra-cortical bleeding, lesions, edema, and diffuse axonal injury are demonstrated. The proposed tools allow cross-correlation of multimodal metrics from structural imaging (e.g., structural volume, atrophy measurements) with clinical outcome variables and other potential factors predictive of recovery. In addition, the workflows described are suitable for TBI clinical practice and patient monitoring, particularly for assessing damage extent and for the measurement of neuroanatomical change over time. With knowledge of general location, extent, and degree of change, such metrics can be associated with clinical measures and subsequently used to suggest viable treatment options.

The aim of this paper is to present a functional analysis of a diffusion tensor tract statistics (FADTTS) pipeline for delineating the association between multiple diffusion properties along major white matter fiber bundles with a set of covariates of interest, such as age, diagnostic status and gender, and the structure of the variability of these white matter tract properties in various diffusion tensor imaging studies. The FADTTS integrates five statistical tools: (i) a multivariate varying coefficient model for allowing the varying coefficient functions in terms of arc length to characterize the varying associations between fiber bundle diffusion properties and a set of covariates, (ii) a weighted least squares estimation of the varying coefficient functions, (iii) a functional principal component analysis to delineate the structure of the variability in fiber bundle diffusion properties, (iv) a global test statistic to test hypotheses of interest, and (v) a simultaneous confidence band to quantify the uncertainty in the estimated coefficient functions. Simulated data are used to evaluate the finite sample performance of FADTTS. We apply FADTTS to investigate the development of white matter diffusivities along the splenium of the corpus callosum tract and the right internal capsule tract in a clinical study of neurodevelopment. FADTTS can be used to facilitate the understanding of normal brain development, the neural bases of neuropsychiatric disorders, and the joint effects of environmental and genetic factors on white matter fiber bundles. The advantages of FADTTS compared with the other existing approaches are that they are capable of modeling the structured inter-subject variability, testing the joint effects, and constructing their simultaneous confidence bands. However, FADTTS is not crucial for estimation and reduces to the functional analysis method for the single measure.

Twin studies suggest that global and regional brain volumes are highly heritable. However, estimates of heritability vary across development. Given that all twin studies are open to the potential criticism of non-generalizability due to differences in intrauterine environment between twins and singletons, these age effects may reflect the influence of perinatal environmental factors, which are unique to twins and which may be especially evident early in life. To address this question, we compared brain volumes and the relationship of brain volumes to gestational age in 136 singletons (67 male, 69 female) and 154 twins (75 male, 79 female; 82 DZ, 72 MZ) who had received high resolution MRI scans of the brain in the first month of life. Intracranial volume, total white matter, and ventricle volumes did not differ between twins and singletons. However, cerebrospinal fluid and frontal white matter volume was greater in twins compared to singletons. While gray matter volumes at MRI did not differ between groups, the slope of the relationship between total and cortical gray matter and gestational age at the MRI scan was steeper in MZ twins compared to DZ twins. Post-hoc analyses suggested that gray matter development is delayed in MZ twins in utero and that they experience 'catch-up' growth in the first month of life. These differences should be taken into account when interpreting and designing studies in the early postnatal period.

CONTEXT: Brain enlargement has been observed in 2-year-old children with autism, but the underlying mechanisms are unknown. OBJECTIVE: To investigate early growth trajectories in brain volume and cortical thickness. DESIGN: Longitudinal magnetic resonance imaging study. SETTING: Academic medical centers. PARTICIPANTS: Fifty-nine children with autism spectrum disorder (ASD) and 38 control children. INTERVENTION: Children were examined at approximately 2 years of age. Magnetic resonance imaging was repeated approximately 24 months later (when aged 4-5 years; 38 children with ASD; 21 controls). MAIN OUTCOME MEASURES: Cerebral gray and white matter volumes and cortical thickness. RESULTS: We observed generalized cerebral cortical enlargement in individuals with ASD at both 2 and 4 to 5 years of age. Rate of cerebral cortical growth across multiple brain regions and tissue compartments in children with ASD was parallel to that seen in the controls, indicating that there was no increase in rate of cerebral cortical growth during this interval. No cerebellar differences were observed in children with ASD. After controlling for total brain volume, a disproportionate enlargement in temporal lobe white matter was observed in the ASD group. We found no significant differences in cortical thickness but observed an increase in an estimate of surface area in the ASD group compared with controls for all cortical regions measured (temporal, frontal, and parieto-occipital lobes). CONCLUSIONS: Our longitudinal magnetic resonance imaging study found generalized cerebral cortical enlargement in children with ASD, with a disproportionate enlargement in temporal lobe white matter. There was no significant difference from controls in the rate of brain growth for this age interval, indicating that brain enlargement in ASD results from an increased rate of brain growth before age 2 years. The presence of increased cortical volume, but not cortical thickness, suggests that early brain enlargement may be associated with increased cortical surface area. Cortical surface area overgrowth in ASD may underlie brain enlargement and implicates a distinct set of pathogenic mechanisms.

In recent years, diffusion tensor imaging (DTI) has become the modality of choice to investigate white matter pathology in the developing brain. To study neonate Krabbe disease with DTI, we evaluate the performance of linear and non-linear DTI registration algorithms for atlas based fiber tract analysis. The DTI scans of 10 age-matched neonates with infantile Krabbe disease are mapped into an atlas for the analysis of major fiber tracts - the genu and splenium of the corpus callosum, the internal capsules tracts and the uncinate fasciculi. The neonate atlas is based on 377 healthy control subjects, generated using an unbiased diffeomorphic atlas building method. To evaluate the performance of one linear and seven nonlinear commonly used registration algorithms for DTI we propose the use of two novel evaluation metrics: a regional matching quality criterion incorporating the local tensor orientation similarity, and a fiber property profile based metric using normative correlation. Our experimental results indicate that the whole tensor based registration method within the DTI-ToolKit (DTI-TK) shows the best performance for our application.

The acquisition of high-quality magnetic resonance (MR) images of neonatal brains is largely hampered by their characteristically small head size and insufficient tissue contrast. As a result, subsequent image processing and analysis, especially brain tissue segmentation, are often affected. To overcome this problem, a dedicated phased array neonatal head coil is utilized to improve MR image quality by augmenting signal-to-noise ratio and spatial resolution without lengthening data acquisition time. In addition, a specialized hybrid atlas-based tissue segmentation algorithm is developed for the delineation of fine structures in the acquired neonatal brain MR images. The proposed tissue segmentation method first enhances the sheet-like cortical gray matter (GM) structures in the to-be-segmented neonatal image with a Hessian filter for generation of a cortical GM confidence map. A neonatal population atlas is then generated by averaging the presegmented images of a population, weighted by their cortical GM similarity with respect to the to-be-segmented image. Finally, the neonatal population atlas is combined with the GM confidence map, and the resulting enhanced tissue probability maps for each tissue form a hybrid atlas is used for atlas-based segmentation. Various experiments are conducted to compare the segmentations of the proposed method with manual segmentation (on both images acquired with a dedicated phased array coil and a conventional volume coil), as well as with the segmentations of two population-atlas-based methods. Results show the proposed method is capable of segmenting the neonatal brain with the best accuracy, and also preserving the most structural details in the cortical regions.