Jiangyang Zhang

YNIMG Journal 2025 Journal Article

Hippocampal subfields in aging: Sex-specific trajectories in structure and hemodynamics

• Jiaqi Wen
• Chenyang Li
• Zhe Sun
• Chao Wang
• Jiangyang Zhang
• Xiaojun Guan
• Xiaojun Xu
• Thomas Wisniewski

Sex differences in hippocampal aging have been increasingly recognized, with females showing greater vulnerability to neurodegeneration, particularly after menopause. However, the underlying neurobiological mechanisms remain unclear, especially at the level of hippocampal subfields. Leveraging high-resolution T1-, T2-weighted, and multi-delay arterial spin labeling MRI from 650 adults in the Human Connectome Project-Aging dataset, we examined sex-specific alterations in hippocampal subfield volume, arterial transit time (ATT), and cerebral blood flow (CBF) across the adult lifespan. All hippocampal subfields showed age-related atrophy and ATT prolongation. An age × sex interaction effect on ATT was observed in CA1 and CA2, indicating that age-related increases in ATT were more pronounced in females than in males in these subfields. Moreover, females exhibited more pronounced hippocampal subfields CBF reductions with aging and atrophy, while males showed relatively preserved CBF, with an increase in subiculum perfusion. Furthermore, CA1 showed the lowest perfusion and the strongest association with atrophy among hippocampal subfields. To investigate the potential impact of menopausal hormonal changes on sex-specific patterns, we explored the hypothalamic structure and hemodynamic alterations during aging and their effects on the hippocampus, given that hypothalamus regulates gonadal hormone secretion through the hypothalamic-pituitary-gonadal axis. We found significant hypothalamic atrophy during aging in both sexes, accompanied by ATT prolongation exclusively in females, which was associated with hippocampal atrophy and impaired hemodynamics. Our study highlights the intricate interplay between hippocampal structure and vascular function, revealing sex- and subfield-specific aging trajectories. These findings provide a normative quantitative imaging reference to age-related neurodegenerative diseases such as Alzheimer's Disease.

YNIMG Journal 2025 Journal Article

Motor-cognitive aging: The role of motor cortex and its pathways

• Jiaqi Wen
• Zifei Liang
• Chenyang Li
• Huize Pang
• Li Jiang
• Jiayi Li
• Xiaojun Guan
• Jiangyang Zhang

BACKGROUND: Motor and cognitive decline are hallmark features of aging. In the primary motor cortex (M1), pyramidal neurons project to the corticospinal tract (CST), a well-established motor pathway, and send collaterals to the ipsilateral striatum, forming the corticostriatal tract (CStrT). While the CST has been extensively studied, the role of the CStrT in motor and cognitive aging remains poorly understood. METHODS: We analyzed T1- and T2-weighted MRI, multi-delay arterial spin labeling, and multi-shell diffusion MRI data from 339 right-handed healthy adults (aged 36-90 years) in the Human Connectome Project-Aging dataset. Age-related trajectories of M1 structure and hemodynamics, as well as CST and CStrT microstructure, were assessed. Segment-wise along-tract analyses were conducted to identify localized tract degeneration. Mediation analyses were performed to examine whether tract integrity linked M1 atrophy to motor and cognitive performance. RESULTS: With age, M1 exhibited reduced volume and hemodynamics, altered T1/T2 ratio, and increased cortical curvature, reflecting structural and hemodynamic alterations. Along-tract analyses revealed localized microstructural degeneration in the CST adjacent to M1, whereas the CStrT showed more extensive degeneration along its trajectory. These tract changes were associated with structural and hemodynamic alterations in M1. Furthermore, integrity of the dominant (left) CST and CStrT mediated the relationship between ipsilateral M1 atrophy and motor decline. Notably, CStrT integrity also mediated the association between M1 atrophy and motor cognition decline. CONCLUSION: These findings establish age-related structural and functional degeneration of M1 and its pathways, highlighting the CStrT as a critical mediator between motor cortical atrophy and both motor and cognitive decline. These normative imaging markers of healthy aging may help inform the early detection of neurodegenerative diseases.

YNIMG Journal 2024 Journal Article

In vivo mapping of hippocampal venous vasculature and oxygenation using susceptibility imaging at 7T

• Chenyang Li
• Sagar Buch
• Zhe Sun
• Marco Muccio
• Li Jiang
• Yongsheng Chen
• E. Mark Haacke
• Jiangyang Zhang

Mapping the small venous vasculature of the hippocampus in vivo is crucial for understanding how functional changes of hippocampus evolve with age. Oxygen utilization in the hippocampus could serve as a sensitive biomarker for early degenerative changes, surpassing hippocampal tissue atrophy as the main source of information regarding tissue degeneration. Using an ultrahigh field (7T) susceptibility-weighted imaging (SWI) sequence, it is possible to capture oxygen-level dependent contrast of submillimeter-sized vessels. Moreover, the quantitative susceptibility mapping (QSM) results derived from SWI data allow for the simultaneous estimation of venous oxygenation levels, thereby enhancing the understanding of hippocampal function. In this study, we proposed two potential imaging markers in a cohort of 19 healthy volunteers aged between 20 and 74 years. These markers were: 1) hippocampal venous density on SWI images and 2) venous susceptibility ( Δ χ vein ) in the hippocampus-associated draining veins (the inferior ventricular veins (IVV) and the basal veins of Rosenthal (BVR) using QSM images). They were chosen specifically to help characterize the oxygen utilization of the human hippocampus and medial temporal lobe (MTL). As part of the analysis, we demonstrated the feasibility of measuring hippocampal venous density and Δ χ vein in the IVV and BVR at 7T with high spatial resolution (0. 25 × 0. 25 × 1 mm3). Our results demonstrated the in vivo reconstruction of the hippocampal venous system, providing initial evidence regarding the presence of the venous arch structure within the hippocampus. Furthermore, we evaluated the age effect of the two quantitative estimates and observed a significant increase in Δ χ vein for the IVV with age (p = 0. 006, r2 = 0. 369). This may suggest the potential application of Δ χ vein in IVV as a marker for assessing changes in atrophy-related hippocampal oxygen utilization in normal aging and neurodegenerative diseases such as AD and dementia.

YNIMG Journal 2023 Journal Article

Towards reliable reconstruction of the mouse brain corticothalamic connectivity using diffusion MRI

• Tanzil Mahmud Arefin
• Choong Heon Lee
• Zifei Liang
• Harikrishna Rallapalli
• Youssef Z. Wadghiri
• Daniel H. Turnbull
• Jiangyang Zhang

Diffusion magnetic resonance imaging (dMRI) tractography has yielded intriguing insights into brain circuits and their relationship to behavior in response to gene mutations or neurological diseases across a number of species. Still, existing tractography approaches suffer from limited sensitivity and specificity, leading to uncertain interpretation of the reconstructed connections. Hence, in this study, we aimed to optimize the imaging and computational pipeline to achieve the best possible spatial overlaps between the tractography and tracer-based axonal projection maps within the mouse brain corticothalamic network. We developed a dMRI-based atlas of the mouse forebrain with structural labels imported from the Allen Mouse Brain Atlas (AMBA). Using the atlas and dMRI tractography, we first reconstructed detailed node-to-node mouse brain corticothalamic structural connectivity matrices using different imaging and tractography parameters. We then investigated the effects of each condition for accurate reconstruction of the corticothalamic projections by quantifying the similarities between the tractography and the tracer data from the Allen Mouse Brain Connectivity Atlas (AMBCA). Our results suggest that these parameters significantly affect tractography outcomes and our atlas can be used to investigate macroscopic structural connectivity in the mouse brain. Furthermore, tractography in mouse brain gray matter still face challenges and need improved imaging and tractography methods.

YNIMG Journal 2023 Journal Article

Using mesoscopic tract-tracing data to guide the estimation of fiber orientation distributions in the mouse brain from diffusion MRI

• Zifei Liang
• Tanzil Mahmud Arefin
• Choong H. Lee
• Jiangyang Zhang

Diffusion MRI (dMRI) tractography is the only tool for non-invasive mapping of macroscopic structural connectivity over the entire brain. Although it has been successfully used to reconstruct large white matter tracts in the human and animal brains, the sensitivity and specificity of dMRI tractography remained limited. In particular, the fiber orientation distributions (FODs) estimated from dMRI signals, key to tractography, may deviate from histologically measured fiber orientation in crossing fibers and gray matter regions. In this study, we demonstrated that a deep learning network, trained using mesoscopic tract-tracing data from the Allen Mouse Brain Connectivity Atlas, was able to improve the estimation of FODs from mouse brain dMRI data. Tractography results based on the network generated FODs showed improved specificity while maintaining sensitivity comparable to results based on FOD estimated using a conventional spherical deconvolution method. Our result is a proof-of-concept of how mesoscale tract-tracing data can guide dMRI tractography and enhance our ability to characterize brain connectivity.

YNIMG Journal 2020 Journal Article

Acceleration of three-dimensional diffusion magnetic resonance imaging using a kernel low-rank compressed sensing method

• Chaoyi Zhang
• Tanzil Mahmud Arefin
• Ukash Nakarmi
• Choong Heon Lee
• Hongyu Li
• Dong Liang
• Jiangyang Zhang
• Leslie Ying

Diffusion Magnetic Resonance Imaging (dMRI) has shown great potential in probing tissue microstructure and structural connectivity in the brain but is often limited by the lengthy scan time needed to sample the diffusion profile by acquiring multiple diffusion weighted images (DWIs). Although parallel imaging technique has improved the speed of dMRI acquisition, attaining high resolution three dimensional (3D) dMRI on preclinical MRI systems remained still time consuming. In this paper, kernel principal component analysis, a machine learning approach, was employed to estimate the correlation among DWIs. We demonstrated the feasibility of such correlation estimation from low-resolution training DWIs and used the correlation as a constraint to reconstruct high-resolution DWIs from highly under-sampled k-space data, which significantly reduced the scan time. Using full k-space 3D dMRI data of post-mortem mouse brains, we retrospectively compared the performance of the so-called kernel low rank (KLR) method with a conventional compressed sensing (CS) method in terms of image quality and ability to resolve complex fiber orientations and connectivity. The results demonstrated that the KLR-CS method outperformed the conventional CS method for acceleration factors up to 8 and was likely to enhance our ability to investigate brain microstructure and connectivity using high-resolution 3D dMRI.

YNICL Journal 2018 Journal Article

Brain tumors disrupt the resting-state connectome

• Darian H. Hadjiabadi
• Leland Pung
• Jiangyang Zhang
• B.D. Ward
• Woo-Taek Lim
• Meghana Kalavar
• Nitish V. Thakor
• Bharat B. Biswal

Brain tumor patients often experience functional deficits that extend beyond the tumor site. While resting-state functional MRI (rsfMRI) has been used to map such functional connectivity changes in brain tumor patients, the interplay between abnormal tumor vasculature and the rsfMRI signal is still not well understood. Therefore, there is an exigent need for new tools to elucidate how the blood‑oxygenation-level-dependent (BOLD) rsfMRI signal is modulated in brain cancer. In this initial study, we explore the utility of a preclinical model for quantifying brain tumor-induced changes on the rsfMRI signal and resting-state brain connectivity. We demonstrate that brain tumors induce brain-wide alterations of resting-state networks that extend to the contralateral hemisphere, accompanied by global attenuation of the rsfMRI signal. Preliminary histology suggests that some of these alterations in brain connectivity may be attributable to tumor-related remodeling of the neurovasculature. Moreover, this work recapitulates clinical rsfMRI findings from brain tumor patients in terms of the effects of tumor size on the neurovascular microenvironment. Collectively, these results lay the foundation of a preclinical platform for exploring the usefulness of rsfMRI as a potential new biomarker in patients with brain cancer.

YNIMG Journal 2016 Journal Article

In vivo mapping of macroscopic neuronal projections in the mouse hippocampus using high-resolution diffusion MRI

• Dan Wu
• Jiangyang Zhang

Recent developments in diffusion magnetic resonance imaging (MRI) make it a promising tool for non-invasive mapping of the spatial organization of axonal and dendritic networks in gray matter regions of the brain. Given the complex cellular environments, in which these networks reside, evidence on the capability of diffusion MRI-based tractography to study these networks is still lacking. In this study, we used a localized diffusion MRI approach to acquire high spatial and angular resolution images of the live mouse hippocampus. The diffusion MRI and tractography results were compared with histology and the Allen mouse brain connectivity atlas using a multi-step image registration pipeline. The results demonstrated that in vivo diffusion MRI data at 0. 1mm isotropic resolution revealed the organization of axonal and dendritic networks in the hippocampus and the tractography results shared remarkable similarity with the viral tracer data in term of their spatial projection patterns. Quantitative analysis showed significant correlations between tractography- and tracer-based projection density measurements in the mouse hippocampus. These findings suggest that high-resolution diffusion MRI and tractography can reveal macroscopic neuronal projections in the mouse hippocampus and are important for future development of advanced tractography methods.

YNIMG Journal 2014 Journal Article

Evaluation of group-specific, whole-brain atlas generation using Volume-based Template Estimation (VTE): Application to normal and Alzheimer's populations

• Yajing Zhang
• Jiangyang Zhang
• Johnny Hsu
• Kenichi Oishi
• Andreia V. Faria
• Marilyn Albert
• Michael I. Miller
• Susumu Mori

MRI-based human brain atlases, which serve as a common coordinate system for image analysis, play an increasingly important role in our understanding of brain anatomy, image registration, and segmentation. Study-specific brain atlases are often obtained from one of the subjects in a study or by averaging the images of all participants after linear or non-linear registration. The latter approach has the advantage of providing an unbiased anatomical representation of the study population. But, the image contrast is influenced by both inherent MR contrasts and residual anatomical variability after the registration; in addition, the topology of the brain structures cannot reliably be preserved. In this study, we demonstrated a population-based template-creation approach, which is based on Bayesian template estimation on a diffeomorphic random orbit model. This approach attempts to define a population-representative template without the cross-subject intensity averaging; thus, the topology of the brain structures is preserved. It has been tested for segmented brain structures, such as the hippocampus, but its validity on whole-brain MR images has not been examined. This paper validates and evaluates this atlas generation approach, i. e. , Volume-based Template Estimation (VTE). Using datasets from normal subjects and Alzheimer's patients, quantitative measurements of sub-cortical structural volumes, metric distance, displacement vector, and Jacobian were examined to validate the group-averaged shape features of the VTE. In addition to the volume-based quantitative analysis, the preserved brain topology of the VTE allows surface-based analysis within the same atlas framework. This property was demonstrated by analyzing the registration accuracy of the pre- and post-central gyri. The proposed method achieved registration accuracy within 1mm for these population-preserved cortical structures in an elderly population.

YNIMG Journal 2014 Journal Article

Localized diffusion magnetic resonance micro-imaging of the live mouse brain

• Dan Wu
• Dominik Reisinger
• Jiadi Xu
• S. Ali Fatemi
• Peter C.M. van Zijl
• Susumu Mori
• Jiangyang Zhang

High-resolution diffusion MRI (dMRI) is useful for resolving complex microstructures in the mouse brain, but technically challenging for in vivo studies due to the long scan time. In this study, selective excitation and a three-dimensional fast imaging sequence were used to achieve in vivo high-resolution dMRI of the mouse brain at 11. 7Tesla. By reducing the field of view using spatially selective radio frequency pulses, we were able to focus on targeted brain structures and acquire high angular resolution diffusion imaging (HARDI) data at an isotropic resolution of 0. 1mm and 30 diffusion encoding directions in approximately 1h. We investigated the complex tissue microstructures of the mouse hippocampus, cerebellum, and several cortical areas using this localized dMRI approach, and compared the results with histological sections stained with several axonal and dendritic markers. In the mouse visual cortex, the results showed predominately radially arranged structures in an outer layer and tangentially arranged structures in an inner layer, similar to observations from postmortem human brain specimens.

YNIMG Journal 2013 Journal Article

Feasibility of creating a high-resolution 3D diffusion tensor imaging based atlas of the human brainstem: A case study at 11.7T

• Manisha Aggarwal
• Jiangyang Zhang
• Olga Pletnikova
• Barbara Crain
• Juan Troncoso
• Susumu Mori

A three-dimensional stereotaxic atlas of the human brainstem based on high resolution ex vivo diffusion tensor imaging (DTI) is introduced. The atlas consists of high resolution (125–255μm isotropic) three-dimensional DT images of the formalin-fixed brainstem acquired at 11. 7T. The DTI data revealed microscopic neuroanatomical details, allowing three-dimensional visualization and reconstruction of fiber pathways including the decussation of the pyramidal tract fibers, and interdigitating fascicles of the corticospinal and transverse pontine fibers. Additionally, strong gray-white matter contrasts in the apparent diffusion coefficient (ADC) maps enabled precise delineation of gray matter nuclei in the brainstem, including the cranial nerve and the inferior olivary nuclei. Comparison with myelin-stained histology shows that at the level of resolution achieved in this study, the structural details resolved with DTI contrasts in the brainstem were comparable to anatomical delineation obtained with histological sectioning. Major neural structures delineated from DTI contrasts in the brainstem are segmented and three-dimensionally reconstructed. Further, the ex vivo DTI data are nonlinearly mapped to a widely-used in vivo human brain atlas, to construct a high-resolution atlas of the brainstem in the Montreal Neurological Institute (MNI) stereotaxic coordinate space. The results demonstrate the feasibility of developing a 3D DTI based atlas for detailed characterization of brainstem neuroanatomy with high resolution and contrasts, which will be a useful resource for research and clinical applications.

YNIMG Journal 2013 Journal Article

In vivo high-resolution diffusion tensor imaging of the mouse brain

• Dan Wu
• Jiadi Xu
• Michael T. McMahon
• Peter C.M. van Zijl
• Susumu Mori
• Frances J. Northington
• Jiangyang Zhang

Diffusion tensor imaging (DTI) of the laboratory mouse brain provides important macroscopic information for anatomical characterization of mouse models in basic research. Currently, in vivo DTI of the mouse brain is often limited by the available resolution. In this study, we demonstrate in vivo high-resolution DTI of the mouse brain using a cryogenic probe and a modified diffusion-weighted gradient and spin echo (GRASE) imaging sequence at 11. 7T. Three-dimensional (3D) DTI of the entire mouse brain at 0. 125mm isotropic resolution could be obtained in approximately 2h. The high spatial resolution, which was previously only available with ex vivo imaging, enabled non-invasive examination of small structures in the adult and neonatal mouse brains. Based on data acquired from eight adult mice, a group-averaged DTI atlas of the in vivo adult mouse brain with 60 structure segmentations was developed. Comparisons between in vivo and ex vivo mouse brain DTI data showed significant differences in brain morphology and tissue contrasts, which indicate the importance of the in vivo DTI-based mouse brain atlas.

YNIMG Journal 2012 Journal Article

Spatiotemporal mapping of brain atrophy in mouse models of Huntington's disease using longitudinal in vivo magnetic resonance imaging

• Manisha Aggarwal
• Wenzhen Duan
• Zhipeng Hou
• Neal Rakesh
• Qi Peng
• Christopher A. Ross
• Michael I. Miller
• Susumu Mori

Mouse models of Huntington's disease (HD) that recapitulate some of the phenotypic features of human HD, play a crucial role in investigating disease mechanisms and testing potential therapeutic approaches. Longitudinal studies of these models can yield valuable insights into the temporal course of disease progression and the effect of drug treatments on the progressive phenotypes. Atrophy of the brain, particularly the striatum, is a characteristic phenotype of human HD, is known to begin long before the onset of motor symptoms, and correlates strongly with clinical features. Elucidating the spatial and temporal patterns of atrophy in HD mouse models is important to characterize the phenotypes of these models, as well as evaluate the effects of neuroprotective treatments at specific time frames during disease progression. In this study, three dimensional in vivo magnetic resonance imaging (MRI) and automated longitudinal deformation-based morphological analysis was used to elucidate the spatial and temporal patterns of brain atrophy in the R6/2 and N171-82Q mouse models of HD. Using an established MRI-based brain atlas and mixed-effects modeling of deformation-based metrics, we report the rates of progression and region-specificity of brain atrophy in the two models. Further, the longitudinal analysis approach was used to evaluate the effects of sertraline and coenzyme Q10 (CoQ10) treatments on progressive atrophy in the N171-82Q model. Sertraline treatment resulted in significant slowing of atrophy, especially in the striatum and frontal cortex regions, while no significant effects of CoQ10 treatment were observed. Progressive cortical and striatal atrophy in the N171-82Q mice showed significant positive correlations with measured functional deficits. The findings of this report can be used for future testing and comparison of potential therapeutics in mouse models of HD.

YNIMG Journal 2011 Journal Article

An MRI-based atlas and database of the developing mouse brain

• Nelson Chuang
• Susumu Mori
• Akira Yamamoto
• Hangyi Jiang
• Xin Ye
• Xin Xu
• Linda J. Richards
• Jeremy Nathans

The advent of mammalian gene engineering and genetically modified mouse models has led to renewed interest in developing resources for referencing and quantitative analysis of mouse brain anatomy. In this study, we used diffusion tensor imaging (DTI) for quantitative characterization of anatomical phenotypes in the developing mouse brain. As an anatomical reference for neuroscience research using mouse models, this paper presents DTI based atlases of ex vivo C57BL/6 mouse brains at several developmental stages. The atlas complements existing histology and MRI-based atlases by providing users access to three-dimensional, high-resolution images of the developing mouse brain, with distinct tissue contrasts and segmentations of major gray matter and white matter structures. The usefulness of the atlas and database was demonstrated by quantitative measurements of the development of major gray matter and white matter structures. Population average images of the mouse brain at several postnatal stages were created using large deformation diffeomorphic metric mapping and their anatomical variations were quantitatively characterized. The atlas and database enhance our ability to examine the neuroanatomy in normal or genetically engineered mouse strains and mouse models of neurological diseases.

YNIMG Journal 2011 Journal Article

Erratum to “Quantitative analysis of brain pathology based on MRI and brain atlases—Applications for cerebral palsy” [NeuroImage 54/3 (2011) 1854–1861]

• Andreia V. Faria
• Alexander Hoon
• Elaine Stashinko
• Xin Li
• Hangyi Jiang
• Ameneh Mashayekh
• Kazi Akhter
• John Hsu

YNIMG Journal 2011 Journal Article

Quantitative analysis of brain pathology based on MRI and brain atlases—Applications for cerebral palsy

• Andreia V. Faria
• Alexander Hoon
• Elaine Stashinko
• Xin Li
• Hangyi Jiang
• Ameneh Mashayekh
• Kazi Akhter
• John Hsu

We have developed a new method to provide a comprehensive quantitative analysis of brain anatomy in cerebral palsy patients, which makes use of two techniques: diffusion tensor imaging and automated 3D whole brain segmentation based on our brain atlas and a nonlinear normalization technique (large-deformation diffeomorphic metric mapping). This method was applied to 13 patients and normal controls. The reliability of the automated segmentation revealed close agreement with the manual segmentation. We illustrate some potential applications for individual characterization and group comparison. This technique also provides a framework for determining the impact of various neuroanatomic features on brain functions.

YNIMG Journal 2011 Journal Article

Structural MRI detects progressive regional brain atrophy and neuroprotective effects in N171-82Q Huntington's disease mouse model

• Yong Cheng
• Qi Peng
• Zhipeng Hou
• Manisha Aggarwal
• Jiangyang Zhang
• Susumu Mori
• Christopher A. Ross
• Wenzhen Duan

Huntington's disease (HD) displays progressive striatal atrophy that occurs long before the onset of clinical motor symptoms. As there is no treatment for the disease once overt symptoms appear, it has been suggested that neuroprotective therapy given during this presymptomatic period might slow progression of the disease. This requires biomarkers that can reliably detect early changes and are sensitive to treatment response. In mouse models of HD, structural MRI measures have been shown to detect disease onset. To determine whether such measures could also be suitable biomarkers for following responses to treatment, we used T2-weighted MR imaging combined with automated morphological analyses and characterized changes in regional brain volumes longitudinally in the N171-82Q HD mouse model in a preclinical trial. We report here that N171-82Q HD mice exhibit adult-onset and progressive brain atrophy in the striatum and neocortex as well as in whole brain; the progressive atrophy in striatum and neocortex is positively correlated with motor deficits. Most notably, MRI also detected neuroprotective effects of sertraline treatment, a neuroprotective agent confirmed in our previous studies. Our present studies provide the first evidence that longitudinal structural MRI measures can detect the therapeutic effect in HD mice, suggesting that such measures in brain could be valuable biomarkers in HD clinical trials.

YNIMG Journal 2010 Journal Article

Atlas-based analysis of neurodevelopment from infancy to adulthood using diffusion tensor imaging and applications for automated abnormality detection

• Andreia V. Faria
• Jiangyang Zhang
• Kenichi Oishi
• Xin Li
• Hangyi Jiang
• Kazi Akhter
• Laurent Hermoye
• Seung-Koo Lee

Quantification of normal brain maturation is a crucial step in understanding developmental abnormalities in brain anatomy and function. The aim of this study was to develop atlas-based tools for time-dependent quantitative image analysis, and to characterize the anatomical changes that occur from 2years of age to adulthood. We used large deformation diffeomorphic metric mapping to register diffusion tensor images of normal participants into the common coordinates and used a pre-segmented atlas to segment the entire brain into 176 structures. Both voxel- and atlas-based analyses reported a structure that showed distinctive changes in terms of its volume and diffusivity measures. In the white matter, fractional anisotropy (FA) linearly increased with age in logarithmic scale, while diffusivity indices, such as apparent diffusion coefficient (ADC), and axial and radial diffusivity, decreased at a different rate in several regions. The average, variability, and the time course of each measured parameter are incorporated into the atlas, which can be used for automated detection of developmental abnormalities. As a demonstration of future application studies, the brainstem anatomy of cerebral palsy patients was evaluated and the altered anatomy was delineated.

YNIMG Journal 2010 Journal Article

Atlas-guided tract reconstruction for automated and comprehensive examination of the white matter anatomy

• Yajing Zhang
• Jiangyang Zhang
• Kenichi Oishi
• Andreia V. Faria
• Hangyi Jiang
• Xin Li
• Kazi Akhter
• Pedro Rosa-Neto

Tractography based on diffusion tensor imaging (DTI) is widely used to quantitatively analyze the status of the white matter anatomy in a tract-specific manner in many types of diseases. This approach, however, involves subjective judgment in the tract-editing process to extract only the tracts of interest. This process, usually performed by manual delineation of regions of interest, is also time-consuming, and certain tracts, especially the short cortico-cortical association fibers, are difficult to reconstruct. In this paper, we propose an automated approach for reconstruction of a large number of white matter tracts. In this approach, existing anatomical knowledge about tract trajectories (called the Template ROI Set or TRS) were stored in our DTI-based brain atlas with 130 three-dimensional anatomical segmentations, which were warped non-linearly to individual DTI data. We examined the degree of matching with manual results for selected fibers. We established 30 TRSs to reconstruct 30 prominent and previously well-described fibers. In addition, TRSs were developed to delineate 29 short association fibers that were found in all normal subjects examined in this paper (N=20). Probabilistic maps of the 59 tract trajectories were created from the normal subjects and were incorporated into our image analysis tool for automated tract-specific quantification.

YNIMG Journal 2010 Journal Article

Longitudinal characterization of brain atrophy of a Huntington's disease mouse model by automated morphological analyses of magnetic resonance images

• Jiangyang Zhang
• Qi Peng
• Qing Li
• Neda Jahanshad
• Zhipeng Hou
• Mali Jiang
• Naoki Masuda
• Douglas R. Langbehn

Mouse models of human diseases play crucial roles in understanding disease mechanisms and developing therapeutic measures. Huntington's disease (HD) is characterized by striatal atrophy that begins long before the onset of motor symptoms. In symptomatic HD, striatal volumes decline predictably with disease course. Thus, imaging based volumetric measures have been proposed as outcomes for presymptomatic as well as symptomatic clinical trials of HD. Magnetic resonance imaging of the mouse brain structures is becoming widely available and has been proposed as one of the biomarkers of disease progression and drug efficacy testing. However, three-dimensional and quantitative morphological analyses of the brains are not straightforward. In this paper, we describe a tool for automated segmentation and voxel-based morphological analyses of the mouse brains. This tool was applied to a well-established mouse model of Huntington's disease, the R6/2 transgenic mouse strain. Comparison between the automated and manual segmentation results showed excellent agreement in most brain regions. The automated method was able to sensitively detect atrophy as early as 4 weeks of age and accurately follow disease progression. Comparison between ex vivo and in vivo MRI suggests that the ex vivo end-point measurement of brain morphology is also a valid approach except for the morphology of the ventricles. This is the first report of longitudinal characterization of brain atrophy in a mouse model of Huntington's disease by using automatic morphological analysis.

YNIMG Journal 2009 Journal Article

Atlas-based whole brain white matter analysis using large deformation diffeomorphic metric mapping: Application to normal elderly and Alzheimer's disease participants

• Kenichi Oishi
• Andreia Faria
• Hangyi Jiang
• Xin Li
• Kazi Akhter
• Jiangyang Zhang
• John T. Hsu
• Michael I. Miller

The purpose of this paper is to establish single-participant white matter atlases based on diffusion tensor imaging. As one of the applications of the atlas, automated brain segmentation was performed and the accuracy was measured using Large Deformation Diffeomorphic Metric Mapping (LDDMM). High-quality diffusion tensor imaging (DTI) data from a single-participant were B0-distortion-corrected and transformed to the ICBM-152 atlas or to Talairach coordinates. The deep white matter structures, which have been previously well documented and clearly identified by DTI, were manually segmented. The superficial white matter areas beneath the cortex were defined, based on a population-averaged white matter probability map. The white matter was parcellated into 176 regions based on the anatomical labeling in the ICBM-DTI-81 atlas. The automated parcellation was achieved by warping this parcellation map to normal controls and to Alzheimer's disease patients with severe anatomical atrophy. The parcellation accuracy was measured by a kappa analysis between the automated and manual parcellation at 11 anatomical regions. The kappa values were 0. 70 for both normal controls and patients while the inter-rater reproducibility was 0. 81 (controls) and 0. 82 (patients), suggesting “almost perfect” agreement. A power analysis suggested that the proposed method is suitable for detecting FA and size abnormalities of the white matter in clinical studies.

YNIMG Journal 2009 Journal Article

Landmark-referenced voxel-based analysis of diffusion tensor images of the brainstem white matter tracts

• Weihong Zhang
• Xin Li
• Jiangyang Zhang
• Andreas Luft
• Daniel F. Hanley
• Peter van Zijl
• Michael I. Miller
• Laurent Younes

Although DTI can provide detailed information about white matter anatomy, it is not yet straightforward enough to quantify the anatomical information it visualizes. In this study, we developed and tested a new tool to perform brain normalization and voxel-based analysis of DTI data. For the normalization part, manually placed landmarks ensured that the visualized white matter tracts were well-registered among the populations. A standard landmark set in ICBM-152 space and an interface to remap them to subject data were integrated in the procedure. After landmark placement, highly elastic non-linear Large Deformation Diffeomorphic Metric Mapping (LDDMM) was driven by the landmarks to normalize the brainstem anatomy of normal subjects. The approach was then applied to delineate brainstem tract abnormalities in patients with left chronic middle cerebral artery (MCA) stroke. The voxel-based comparison between control and patient groups identified abnormalities in the ipsilesional corticospinal tract and contralesional cerebellar peduncles. We believe that this tool is useful for regional brain normalization of patients with severe anatomical alterations, such as stroke, brain tumor, and lobectomy, for whom standard automated normalization tools may not work properly.

YNIMG Journal 2008 Journal Article

Human brain white matter atlas: Identification and assignment of common anatomical structures in superficial white matter

• Kenichi Oishi
• Karl Zilles
• Katrin Amunts
• Andreia Faria
• Hangyi Jiang
• Xin Li
• Kazi Akhter
• Kegang Hua

Structural delineation and assignment are the fundamental steps in understanding the anatomy of the human brain. The white matter has been structurally defined in the past only at its core regions (deep white matter). However, the most peripheral white matter areas, which are interleaved between the cortex and the deep white matter, have lacked clear anatomical definitions and parcellations. We used axonal fiber alignment information from diffusion tensor imaging (DTI) to delineate the peripheral white matter, and investigated its relationship with the cortex and the deep white matter. Using DTI data from 81 healthy subjects, we identified nine common, blade-like anatomical regions, which were further parcellated into 21 subregions based on the cortical anatomy. Four short association fiber tracts connecting adjacent gyri (U-fibers) were also identified reproducibly among the healthy population. We anticipate that this atlas will be useful resource for atlas-based white matter anatomical studies.

YNIMG Journal 2008 Journal Article

Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template

• Susumu Mori
• Kenichi Oishi
• Hangyi Jiang
• Li Jiang
• Xin Li
• Kazi Akhter
• Kegang Hua
• Andreia V. Faria

Brain registration to a stereotaxic atlas is an effective way to report anatomic locations of interest and to perform anatomic quantification. However, existing stereotaxic atlases lack comprehensive coordinate information about white matter structures. In this paper, white matter-specific atlases in stereotaxic coordinates are introduced. As a reference template, the widely used ICBM-152 was used. The atlas contains fiber orientation maps and hand-segmented white matter parcellation maps based on diffusion tensor imaging (DTI). Registration accuracy by linear and non-linear transformation was measured, and automated template-based white matter parcellation was tested. The results showed a high correlation between the manual ROI-based and the automated approaches for normal adult populations. The atlases are freely available and believed to be a useful resource as a target template and for automated parcellation methods.

YNIMG Journal 2008 Journal Article

Tract probability maps in stereotaxic spaces: Analyses of white matter anatomy and tract-specific quantification

• Kegang Hua
• Jiangyang Zhang
• Setsu Wakana
• Hangyi Jiang
• Xin Li
• Daniel S. Reich
• Peter A. Calabresi
• James J. Pekar

Diffusion tensor imaging (DTI) is an exciting new MRI modality that can reveal detailed anatomy of the white matter. DTI also allows us to approximate the 3D trajectories of major white matter bundles. By combining the identified tract coordinates with various types of MR parameter maps, such as T2 and diffusion properties, we can perform tract-specific analysis of these parameters. Unfortunately, 3D tract reconstruction is marred by noise, partial volume effects, and complicated axonal structures. Furthermore, changes in diffusion anisotropy under pathological conditions could alter the results of 3D tract reconstruction. In this study, we created a white matter parcellation atlas based on probabilistic maps of 11 major white matter tracts derived from the DTI data from 28 normal subjects. Using these probabilistic maps, automated tract-specific quantification of fractional anisotropy and mean diffusivity were performed. Excellent correlation was found between the automated and the individual tractography-based results. This tool allows efficient initial screening of the status of multiple white matter tracts.

YNIMG Journal 2007 Journal Article

Evidence of slow maturation of the superior longitudinal fasciculus in early childhood by diffusion tensor imaging

• Jiangyang Zhang
• Alan Evans
• Laurent Hermoye
• Seung-Koo Lee
• Setsu Wakana
• Weihong Zhang
• Pamela Donohue
• Michael I. Miller

While the majority of axonal organization is established by birth in mammalian brains, axonal wiring and pruning processes, as well as myelination, are known to extend to the postnatal periods, where environmental stimuli often play a major role. Normal axonal and myelin development of individual white matter tracts of human in this period is poorly understood and may have a major role in cognitive development of human. In this study, we applied diffusion tensor imaging and normalization-based population analyses to 44 preteen children and 30 adult images. We observed highly significant changes of fiber orientations at regions that correspond to the superior longitudinal fasciculus during the first 5 years. The result is attributed to slow axonal and/or myelin maturation of this tract, which is believed to be involved in language functions.

YNIMG Journal 2007 Journal Article

Reproducibility of quantitative tractography methods applied to cerebral white matter

• Setsu Wakana
• Arvind Caprihan
• Martina M. Panzenboeck
• James H. Fallon
• Michele Perry
• Randy L. Gollub
• Kegang Hua
• Jiangyang Zhang

Tractography based on diffusion tensor imaging (DTI) allows visualization of white matter tracts. In this study, protocols to reconstruct eleven major white matter tracts are described. The protocols were refined by several iterations of intra- and inter-rater measurements and identification of sources of variability. Reproducibility of the established protocols was then tested by raters who did not have previous experience in tractography. The protocols were applied to a DTI database of adult normal subjects to study size, fractional anisotropy (FA), and T 2 of individual white matter tracts. Distinctive features in FA and T 2 were found for the corticospinal tract and callosal fibers. Hemispheric asymmetry was observed for the size of white matter tracts projecting to the temporal lobe. This protocol provides guidelines for reproducible DTI-based tract-specific quantification.

YNIMG Journal 2006 Journal Article

White and gray matter development in human fetal, newborn and pediatric brains

• Hao Huang
• Jiangyang Zhang
• Setsu Wakana
• Weihong Zhang
• Tianbo Ren
• Linda J. Richards
• Paul Yarowsky
• Pamela Donohue

Brain anatomy is characterized by dramatic growth from the end of the second trimester through the neonatal stage. The characterization of normal axonal growth of the white matter tracts has not been well-documented to date and could provide important clues to understanding the extensive inhomogeneity of white matter injuries in cerebral palsy (CP) patients. However, anatomical studies of human brain development during this period are surprisingly scarce and histology-based atlases have become available only recently. Diffusion tensor magnetic resonance imaging (DTMRI) can reveal detailed anatomy of white matter. We acquired diffusion tensor images (DTI) of postmortem fetal brain samples and in vivo neonates and children. Neural structures were annotated in two-dimensional (2D) slices, segmented, measured, and reconstructed three-dimensionally (3D). The growth status of various white matter tracts was evaluated on cross-sections at 19–20 gestational weeks, and compared with 0-month-old neonates and 5- to 6-year-old children. Limbic, commissural, association, and projection white matter tracts and gray matter structures were illustrated in 3D and quantitatively characterized to assess their dynamic changes. The overall pattern of the time courses for the development of different white matter is that limbic fibers develop first and association fibers last and commissural and projection fibers are forming from anterior to posterior part of the brain. The resultant DTMRI-based 3D human brain data will be a valuable resource for human brain developmental study and will provide reference standards for diagnostic radiology of premature newborns.

YNIMG Journal 2005 Journal Article

DTI tractography based parcellation of white matter: Application to the mid-sagittal morphology of corpus callosum

• Hao Huang
• Jiangyang Zhang
• Hangyi Jiang
• Setsu Wakana
• Lidia Poetscher
• Michael I. Miller
• Peter CM. van Zijl
• Argye E. Hillis

Morphology of the corpus callosum (CC) at the mid-sagittal level has been a target of extensive studies. However, the lack of internal structures and its polymorphism make it a challenging task to quantitatively analyze shape differences among subjects. In this paper, diffusion tensor Imaging (DTI) and tract tracing technique were applied to incorporate cortical connectivity information to the morphological study. The CC was parcellated into six major subdivisions based on trajectories to different cortical areas. This subdivision was performed for eight normal subjects and one stroke patient. The parcellated CCs of the normal subjects were normalized for morphological analysis. When comparing the stroke patient to the normal population, we detected significant atrophy in the motor and sensory areas of the patient CC, in line with the clinical deficits. This approach provides a new tool to investigate callosal morphology and functional relationships.

YNIMG Journal 2005 Journal Article

Mapping postnatal mouse brain development with diffusion tensor microimaging

• Jiangyang Zhang
• Michael I. Miller
• Celine Plachez
• Linda J. Richards
• Paul Yarowsky
• Peter van Zijl
• Susumu Mori

While mouse brain development has been extensively studied using histology, quantitative characterization of morphological changes is still a challenging task. This paper presents how developing brain structures can be quantitatively characterized with magnetic resonance diffusion tensor microimaging coupled with techniques of computational anatomy. High resolution diffusion tensor images of ex vivo postnatal mouse brains provide excellent contrasts to reveal the evolutions of mouse forebrain structures. Using anatomical landmarks defined on diffusion tensor images, tissue level growth patterns of mouse brains were quantified. The results demonstrate the use of these techniques to three-dimensionally and quantitatively characterize brain growth.

YNIMG Journal 2003 Journal Article

Three-dimensional anatomical characterization of the developing mouse brain by diffusion tensor microimaging

• Jiangyang Zhang
• Linda J Richards
• Paul Yarowsky
• Hao Huang
• Peter C.M van Zijl
• Susumu Mori

Investigation of three-dimensional (3D) morphometry of developing brains has been hindered by a lack of imaging modalities that can monitor the 3D evolution of various anatomical structures without sectioning and staining processes. In this study, we combined magnetic resonance microimaging and diffusion tensor imaging techniques to accomplish such visualization. The application of this approach to developing mouse embryos revealed that it could clearly delineate early critical structures such as neuroepithelium, cortical plate, and various axonal structures, and follow their developmental evolution. The technique was applied to the study of the Netrin-1 mutant, allowing verification of its anatomical phenotype.

YNIMG Journal 2002 Journal Article

Three-Dimensional Diffusion Tensor Magnetic Resonance Microimaging of Adult Mouse Brain and Hippocampus

• Jiangyang Zhang
• Peter C.M. van Zijl
• Susumu Mori

The use of diffusion tensor information as an additional contrast in MR microimaging was investigated in ex vivo mouse brain and isolated hippocampus. Diffusion Tensor Imaging (DTI) provided unique contrast to identify many internal structures of the gray matter such as hippocampus, thalamus, and cortex. In hippocampus, stratum granulosum and stratum pyramidale could be identified using the isotropic water diffusion constant. Stratum moleculare and stratum radiatum were identified from their characteristic fiber architecture revealed by color-coded DTI. Identification of these structures allowed reconstruction of their 3-D volume. Thus, high-resolution DTI has excellent potential as a tool for 3-D characterization of murine brains.