White matter signals in resting state blood oxygen level dependent functional magnetic resonance (BOLD-fMRI) have been largely discounted, yet there is growing evidence that these signals are indicative of brain activity. Understanding how these white matter signals capture function can provide insight into brain physiology. Moreover, functional signals could potentially be used as early markers for neurological changes, such as in Alzheimer’s Disease. To investigate white matter brain networks, we leveraged the OASIS-3 dataset to extract white matter signals from resting state BOLDFMRI data on 711 subjects. The imaging was longitudinal with a total of 2,026 images. Hierarchical clustering was performed to investigate clusters of voxel-level correlations on the timeseries data. The stability of clusters was measured with the average Dice coefficients on two different cross fold validations. The first validated the stability between scans, and the second validated the stability between subject populations. Functional clusters at hierarchical levels 4, 9, 13, 18, and 24 had local maximum stability, suggesting better clustered white matter. In comparison with JHU-DTI-SS Type-I Atlas defined regions, clusters at lower hierarchical levels identified well defined anatomical lobes. At higher hierarchical levels, functional clusters mapped motor and memory functional regions, identifying 50.00%, 20.00%, 27.27%, and 35.14% of the frontal, occipital, parietal, and temporal lobe regions respectively.
KEYWORDS: Functional magnetic resonance imaging, Matrices, Databases, White matter, Signal processing, Signal detection, Reliability, Quality control, Neuroimaging, Correlation coefficients
Recently, increasing evidence suggests that fMRI signals in white matter (WM), conventionally ignored as nuisance, are robustly detectable using appropriate processing methods and are related to neural activity, while changes in WM with aging and degeneration are also well documented. These findings suggest variations in patterns of BOLD signals in WM should be investigated. However, existing fMRI analysis tools, which were designed for processing gray matter signals, are not well suited for large-scale processing of WM signals in fMRI data. We developed an automatic pipeline for high-performance preprocessing of fMRI images with emphasis on quantifying changes in BOLD signals in WM in an aging population. At the image processing level, the pipeline integrated existing software modules with fine parameter tunings and modifications to better extract weaker WM signals. The preprocessing results primarily included whole-brain time courses, functional connectivity, maps and tissue masks in a common space. At the job execution level, this pipeline exploited a local XNAT to store datasets and results, while using DAX tool to automatic distribute batch jobs that run on high-performance computing clusters. Through the pipeline, 5,034 fMRI/T1 scans were preprocessed. The intraclass correlation coefficient (ICC) of test-retest experiment based on the preprocessed data is 0.52 - 0.86 (N=1000), indicating a high reliability of our pipeline, comparable to previously reported ICC in gray matter experiments. This preprocessing pipeline highly facilitates our future analyses on WM functional alterations in aging and may be of benefit to a larger community interested in WM fMRI studies.
Background: The dentate-rubro-thalamic-tract (DRTT) has recently been suggested as a new target in treatment of tremors for patients of essential tremor and Parkinson’s disease. Diffusion MRI (dMRI) tractography was reported to able to reconstruct DRTT non-invasively in human brain. However, the performance of dMRI tractography with different setups has not been rigorously evaluated, which serves as a necessary step to optimize the protocol of reconstruction. Purpose: In this study, we aim to assess the efficacy of the dMRI-based DRTT tractography by comparing with histological “ground truth” in the same brain. Method: A fixed squirrel monkey brain was scanned in 9.4T magnet with four shells (b=3000/6000/9000/12000s/mm2 ) and 100 diffusion gradient directions for each shell. Probabilistic tractography was implemented with a set of variables (i.e., b value, number of gradient directions, step length and binarization threshold), and the dMRI-derived DRTT volume was quantitatively compared with histological DRTT volume, which was obtained from Myelin stain of the same brain. Moreover, the primary orientations estimated by dMRI were compared with histological fiber orientations along the skeleton of histological DRTT. Result: The sensitivity of dMRI measure increases as the number of gradient directions increases and decreases as the binarization threshold increases. As b value increases, primary orientations estimated from dMRI agree more with histological ones along the skeleton of histological DRTT. Conclusion: Our work provides a valuable assessment of DRTT tractography, which serves as a guideline for optimization of protocol starting from image acquisition, orientation estimation to tractography.
Background: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder, in which pathological alterations are seen in both gray matter (GM) and white matter (WM). To date functional MRI (fMRI) studies of AD have been exclusively focused on GM, since blood oxygenation level dependent (BOLD) signals in WM are relatively weak and thus ignored in practice. Our recent work provides compelling evidence that BOLD fluctuations in brain WM are reliably detectable and reflect neural activities, offering the potential of investigating the functional connectivity in WM. Purpose: In this study, we aim to apply our fMRI analysis method to the investigation of functional alterations in WM during the progression of AD. Method: Raw resting state fMRI data of normal subjects and patients (total n=290, 5 diagnostic groups) were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. Each fMRI image was parcellated into 82 GM regions and 48 WM bundles. Temporal correlation between each pair of GM and WM was calculated and the correlations of all pairs constituted a functional correlation matrix (FCM) for each subject. The FCMs were averaged within each diagnostic group, and differences in the averaged FCMs between the normal group and each disease group were sought. Result: Differences in functional correlations progressively enlarge as the disease evolves, and fornix and ventral entorhinal cortices exhibited most pronounced differences between the normal and disease groups. Conclusion: Functional connectivity in WM may serve as a novel neuroimaging biomarker for the progression of AD.
Diffusion weighted magnetic resonance imaging (DW-MRI) is interpreted as a quantitative method that is sensitive to tissue microarchitecture at a millimeter scale. However, the sensitization is dependent on acquisition sequences (e.g., diffusion time, gradient strength, etc.) and susceptible to imaging artifacts. Hence, comparison of quantitative DW-MRI biomarkers across field strengths (including different scanners, hardware performance, and sequence design considerations) is a challenging area of research. We propose a novel method to estimate microstructure using DW-MRI that is robust to scanner difference between 1.5T and 3T imaging. We propose to use a null space deep network (NSDN) architecture to model DW-MRI signal as fiber orientation distributions (FOD) to represent tissue microstructure. The NSDN approach is consistent with histologically observed microstructure (on previously acquired ex vivo squirrel monkey dataset) and scan-rescan data. The contribution of this work is that we incorporate identical dual networks (IDN) to minimize the influence of scanner effects via scan-rescan data. Briefly, our estimator is trained on two datasets. First, a histology dataset was acquired on three squirrel monkeys with corresponding DW-MRI and confocal histology (512 independent voxels). Second, 37 control subjects from the Baltimore Longitudinal Study of Aging (67-95 y/o) were identified who had been scanned at 1.5T and 3T scanners (b-value of 700 s/mm2 , voxel resolution at 2.2mm, 30-32 gradient volumes) with an average interval of 4 years (standard deviation 1.3 years). After image registration, we used paired white matter (WM) voxels for 17 subjects and 440 histology voxels for training and 20 subjects and 72 histology voxels for testing. We compare the proposed estimator with super-resolved constrained spherical deconvolution (CSD) and a previously presented regression deep neural network (DNN). NSDN outperformed CSD and DNN in angular correlation coefficient (ACC) 0.81 versus 0.28 and 0.46, mean squared error (MSE) 0.001 versus 0.003 and 0.03, and general fractional anisotropy (GFA) 0.05 versus 0.05 and 0.09. Further validation and evaluation with contemporaneous imaging are necessary, but the NSDN is promising avenue for building understanding of microarchitecture in a consistent and deviceindependent manner.
Background: Clustering thalamic nuclei is important for both research and clinical purposes. For example, ventral intermediate nuclei in thalami serve as targets in both deep brain stimulation neurosurgery and radiosurgery for treating patients suffering from movement disorders (e.g., Parkinson's disease and essential tremor). Diffusion magnetic resonance imaging (dMRI) is able to reflect tissue microstructure in the central nervous system via fitting different models, such as, the diffusion tensor (DT), constrained spherical deconvolution (CSD), neurite orientation dispersion and density imaging (NODDI), diffusion kurtosis imaging (DKI) and the spherical mean technique (SMT). Purpose: To test which of the above-mentioned dMRI models is better for thalamic parcellation, we proposed a framework of k-means clustering, implemented it on each model, and evaluated the agreement with histology. Method: An ex vivo monkey brain was scanned in a 9.4T MRI scanner at 0.3mm resolution with b values of 3000, 6000, 9000 and 12000 s/mm2. K-means clustering on each thalamus was implemented using maps of dMRI models fitted to the same data. Meanwhile, histological nuclei were identified by AChE and Nissl stains of the same brain. Overall agreement rate and agreement rate for each nucleus were calculated between clustering and histology. Sixteen thalamic nuclei on each hemisphere were included. Results: Clustering with the DKI model has slightly higher overall agreement rate but clustering with other dMRI models result in higher agreement rate in some nuclei. Conclusion: dMRl models should be carefully selected to better parcellate the thalamus, depending on the specific purpose of the parcellation.
Modern magnetic resonance imaging (MRI) brain atlases are high quality 3-D volumes with specific structures labeled in the volume. Atlases are essential in providing a common space for interpretation of results across studies, for anatomical education, and providing quantitative image-based navigation. Extensive work has been devoted to atlas construction for humans, macaque, and several non-primate species (e.g., rat). One notable gap in the literature is the common squirrel monkey – for which the primary published atlases date from the 1960’s. The common squirrel monkey has been used extensively as surrogate for humans in biomedical studies, given its anatomical neuro-system similarities and practical considerations. This work describes the continued development of a multi-modal MRI atlas for the common squirrel monkey, for which a structural imaging space and gray matter parcels have been previously constructed. This study adds white matter tracts to the atlas. The new atlas includes 49 white matter (WM) tracts, defined using diffusion tensor imaging (DTI) in three animals and combines these data to define the anatomical locations of these tracks in a standardized coordinate system compatible with previous development. An anatomist reviewed the resulting tracts and the inter-animal reproducibility (i.e., the Dice index of each WM parcel across animals in common space) was assessed. The Dice indices range from 0.05 to 0.80 due to differences of local registration quality and the variation of WM tract position across individuals. However, the combined WM labels from the 3 animals represent the general locations of WM parcels, adding basic connectivity information to the atlas.
A revised version of this paper, published originally on 17 March 2015, was published on 2 July 2015, replacing the original paper. The text of the first paragraph of Section 2.2.2 has been revised and two additional references have been added. The text of the first paragraph of Section 2.3 has also been revised. The revised paper is available at http://dx.doi.org/10.1117/12.2081443.
This effort is a continuation of development of a digital brain atlas of the common squirrel monkey, Saimiri sciureus, a New World monkey with functional and microstructural organization of central nervous system similar to that of humans. Here, we present the integration of histology with multi-modal magnetic resonance imaging (MRI) atlas constructed from the brain of an adult female squirrel monkey. The central concept of this work is to use block face photography to establish an intermediate common space in coordinate system which preserves the high resolution in-plane resolution of histology while enabling 3-D correspondence with MRI. In vivo MRI acquisitions include high resolution T2 structural imaging (300 μm isotropic) and low resolution diffusion tensor imaging (600 um isotropic). Ex vivo MRI acquisitions include high resolution T2 structural imaging and high resolution diffusion tensor imaging (both 300 μm isotropic). Cortical regions were manually annotated on the co-registered volumes based on published histological sections in-plane. We describe mapping of histology and MRI based data of the common squirrel monkey and construction of a viewing tool that enable online viewing of these datasets. The previously descried atlas MRI is used for its deformation to provide accurate conformation to the MRI, thus adding information at the histological level to the MRI volume. This paper presents the mapping of single 2D image slice in block face as a proof of concept and this can be extended to map the atlas space in 3D coordinate system as part of the future work and can be loaded to an XNAT system for further use.
KEYWORDS: Brain, Magnetic resonance imaging, In vivo imaging, Neuroimaging, Diffusion tensor imaging, Diffusion, Image resolution, Data acquisition, Tissues, Structural imaging
The common squirrel monkey, Saimiri sciureus, is a New World monkey with functional and microstructural organization of central nervous system similar to that of humans. It is one of the most commonly used South American primates in biomedical research. Unlike its Old World macaque cousins, no digital atlases have described the organization of the squirrel monkey brain. Here, we present a multi-modal magnetic resonance imaging (MRI) atlas constructed from the brain of an adult female squirrel monkey. In vivo MRI acquisitions include high resolution T2 structural imaging and low resolution diffusion tensor imaging. Ex vivo MRI acquisitions include high resolution T2 structural imaging and high resolution diffusion tensor imaging. Cortical regions were manually annotated on the co-registered volumes based on published histological sections.
Yurui Gao, Scott Burns, Carolyn Lauzon, Andrew Fong, Terry James, Joel Lubar, Robert Thatcher, David Twillie, Michael Wirt, Marc Zola, Bret Logan, Adam Anderson, Bennett Landman
Traumatic brain injury (TBI) is an increasingly important public health concern. While there are several promising avenues of intervention, clinical assessments are relatively coarse and comparative quantitative analysis is an emerging field. Imaging data provide potentially useful information for evaluating TBI across functional, structural, and microstructural phenotypes. Integration and management of disparate data types are major obstacles. In a multi-institution collaboration, we are collecting electroencephalogy (EEG), structural MRI, diffusion tensor MRI (DTI), and single photon emission computed tomography (SPECT) from a large cohort of US Army service members exposed to mild or moderate TBI who are undergoing experimental treatment. We have constructed a robust informatics backbone for this project centered on the DICOM standard and eXtensible Neuroimaging Archive Toolkit (XNAT) server. Herein, we discuss (1) optimization of data transmission, validation and storage, (2) quality assurance and workflow management, and (3) integration of high performance computing with research software.
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