Lipid and smooth muscle architectural pathology in the rabbit atherosclerotic vessel wall using Q-space cardiovascular magnetic resonance.

BACKGROUND: Atherosclerosis is an arterial vessel wall disease characterized by slow, progressive lipid accumulation, smooth muscle disorganization, and inflammatory infiltration. Atherosclerosis often remains subclinical until extensive inflammatory injury promotes vulnerability of the atherosclerotic plaque to rupture with luminal thrombosis, which can cause the acute event of myocardial infarction or stroke. Current bioimaging techniques are unable to capture the pathognomonic distribution of cellular elements of the plaque and thus cannot accurately define its structural disorganization. METHODS: We applied cardiovascular magnetic resonance spectroscopy (CMRS) and diffusion weighted CMR (DWI) with generalized Q-space imaging (GQI) analysis to architecturally define features of atheroma and correlated these to the microscopic distribution of vascular smooth muscle cells (SMC), immune cells, extracellular matrix (ECM) fibers, thrombus, and cholesteryl esters (CE). We compared rabbits with normal chow diet and cholesterol-fed rabbits with endothelial balloon injury, which accelerates atherosclerosis and produces advanced rupture-prone plaques, in a well-validated rabbit model of human atherosclerosis. RESULTS: Our methods revealed new structural properties of advanced atherosclerosis incorporating SMC and lipid distributions. GQI with tractography portrayed the locations of these components across the atherosclerotic vessel wall and differentiated multi-level organization of normal, pro-inflammatory cellular phenotypes, or thrombus. Moreover, the locations of CE were differentiated from cellular constituents by their higher restrictive diffusion properties, which permitted chemical confirmation of CE by high field voxel-guided CMRS. CONCLUSIONS: GQI with tractography is a new method for atherosclerosis imaging that defines a pathological architectural signature for the atheromatous plaque composed of distributed SMC, ECM, inflammatory cells, and thrombus and lipid. This provides a detailed transmural map of normal and inflamed vessel walls in the setting of atherosclerosis that has not been previously achieved using traditional CMR techniques. Although this is an ex-vivo study, detection of micro and mesoscale level vascular destabilization as enabled by GQI with tractography could increase the accuracy of diagnosis and assessment of treatment outcomes in individuals with atherosclerosis.

Measuring Strain in Diffusion-Weighted Data Using Tagged Magnetic Resonance Imaging.

Accurate strain measurement in a deforming organ has been essential in motion analysis using medical images. In recent years, internal tissue's in vivo motion and strain computation has been mostly achieved through dynamic magnetic resonance (MR) imaging. However, such data lack information on tissue's intrinsic fiber directions, preventing computed strain tensors from being projected onto a direction of interest. Although diffusion-weighted MR imaging excels at providing fiber tractography, it yields static images unmatched with dynamic MR data. This work reports an algorithm workflow that estimates strain values in the diffusion MR space by matching corresponding tagged dynamic MR images. We focus on processing a dataset of various human tongue deformations in speech. The geometry of tongue muscle fibers is provided by diffusion tractography, while spatiotemporal motion fields are provided by tagged MR analysis. The tongue's deforming shapes are determined by segmenting a synthetic cine dynamic MR sequence generated from tagged data using a deep neural network. Estimated motion fields are transformed into the diffusion MR space using diffeomorphic registration, eventually leading to strain values computed in the direction of muscle fibers. The method was tested on 78 time volumes acquired during three sets of specific tongue deformations including both speech and protrusion motion. Strain in the line of action of seven internal tongue muscles was extracted and compared both intra- and inter-subject. Resulting compression and stretching patterns of individual muscles revealed the unique behavior of individual muscles and their potential activation pattern.

A deep joint sparse non-negative matrix factorization framework for identifying the common and subject-specific functional units of tongue motion during speech.

Intelligible speech is produced by creating varying internal local muscle groupings-i.e., functional units-that are generated in a systematic and coordinated manner. There are two major challenges in characterizing and analyzing functional units. First, due to the complex and convoluted nature of tongue structure and function, it is of great importance to develop a method that can accurately decode complex muscle coordination patterns during speech. Second, it is challenging to keep identified functional units across subjects comparable due to their substantial variability. In this work, to address these challenges, we develop a new deep learning framework to identify common and subject-specific functional units of tongue motion during speech. Our framework hinges on joint deep graph-regularized sparse non-negative matrix factorization (NMF) using motion quantities derived from displacements by tagged Magnetic Resonance Imaging. More specifically, we transform NMF with sparse and graph regularizations into modular architectures akin to deep neural networks by means of unfolding the Iterative Shrinkage-Thresholding Algorithm to learn interpretable building blocks and associated weighting map. We then apply spectral clustering to common and subject-specific weighting maps from which we jointly determine the common and subject-specific functional units. Experiments carried out with simulated datasets show that the proposed method achieved on par or better clustering performance over the comparison methods.Experiments carried out with in vivo tongue motion data show that the proposed method can determine the common and subject-specific functional units with increased interpretability and decreased size variability.

Longitudinal predictive modeling of tau progression along the structural connectome.

Tau neurofibrillary tangles, a pathophysiological hallmark of Alzheimer's disease (AD), exhibit a stereotypical spatiotemporal trajectory that is strongly correlated with disease progression and cognitive decline. Personalized prediction of tau progression is, therefore, vital for the early diagnosis and prognosis of AD. Evidence from both animal and human studies is suggestive of tau transmission along the brains preexisting neural connectivity conduits. We present here an analytic graph diffusion framework for individualized predictive modeling of tau progression along the structural connectome. To account for physiological processes that lead to active generation and clearance of tau alongside passive diffusion, our model uses an inhomogenous graph diffusion equation with a source term and provides closed-form solutions to this equation for linear and exponential source functionals. Longitudinal imaging data from two cohorts, the Harvard Aging Brain Study (HABS) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), were used to validate the model. The clinical data used for developing and validating the model include regional tau measures extracted from longitudinal positron emission tomography (PET) scans based on the 18F-Flortaucipir radiotracer and individual structural connectivity maps computed from diffusion tensor imaging (DTI) by means of tractography and streamline counting. Two-timepoint tau PET scans were used to assess the goodness of model fit. Three-timepoint tau PET scans were used to assess predictive accuracy via comparison of predicted and observed tau measures at the third timepoint. Our results show high consistency between predicted and observed tau and differential tau from region-based analysis. While the prognostic value of this approach needs to be validated in a larger cohort, our preliminary results suggest that our longitudinal predictive model, which offers an in vivo macroscopic perspective on tau progression in the brain, is potentially promising as a personalizable predictive framework for AD.

Diffusion interactions between crossing fibers of the brain.

PURPOSE: Recent observations of several preferred orientations of diffusion in deep white matter may indicate either (a) that axons in different directions are independently bundled in thick sheets and function noninteractively, or more interestingly, (b) that the axons are closely interwoven and would exhibit branching and sharp turns. This study aims to investigate whether the dependence of dMRI Q-ball signal on the interpulse time Δ can decode the smaller-than-voxel-size brain structure, in particular, to distinguish scenarios (a) and (b). METHODS: High-resolution Q-ball images of a healthy brain taken with b=8000  s/mm2 for 3 different values of Δ were analyzed. The exchange of water molecules between crossing fibers was characterized by the fourth Fourier coefficient f4(Δ) of the signal profile in the plane of crossing. To interpret the empirical results, a model consisting of differently oriented parallel sheets of cylinders was developed. Diffusion of water molecules inside and outside cylinders was simulated by the Monte Carlo method. RESULTS: Simulations predict that f4(Δ) , agreeing with the empirical results, must increase with Δ for large b-values, but may peak at a typical Δ that depends on the thickness of the cylinder sheets for intermediate b-values. Thus, the thickness of axon layers in voxels with 2 predominant orientations can be detected from empirical f4(Δ) taken at smaller b-values. CONCLUSION: Based on the simulation results, recommendations are made on how to design a dMRI experiment with optimal b-value and range of Δ in order to measure the thickness of axon sheets in the white matter, hence to distinguish (a) and (b).

A physics-informed geometric learning model for pathological tau spread in Alzheimer's disease.

Tau tangles are a pathophysiological hallmark of Alzheimer's disease (AD) and exhibit a stereotypical pattern of spatiotemporal spread which has strong links to disease progression and cognitive decline. Preclinical evidence suggests that tau spread depends on neuronal connectivity rather than physical proximity between different brain regions. Here, we present a novel physics-informed geometric learning model for predicting tau buildup and spread that learns patterns directly from longitudinal tau imaging data while receiving guidance from governing physical principles. Implemented as a graph neural network with physics-based regularization in latent space, the model enables effective training with smaller data sizes. For training and validation of the model, we used longitudinal tau measures from positron emission tomography (PET) and structural connectivity graphs from diffusion tensor imaging (DTI) from the Harvard Aging Brain Study. The model led to higher peak signal-to-noise ratio and lower mean squared error levels than both an unregularized graph neural network and a differential equation solver. The method was validated using both two-timepoint and three-timepoint tau PET measures. The effectiveness of the approach was further confirmed by a cross-validation study.

Identifying the Common and Subject-specific Functional Units of Speech Movements via a Joint Sparse Non-negative Matrix Factorization Framework.

The tongue is capable of producing intelligible speech because of successful orchestration of muscle groupings-i.e., functional units-of the highly complex muscles over time. Due to the different motions that tongues produce, functional units are transitional structures which transform muscle activity to surface tongue geometry and they vary significantly from one subject to another. In order to compare and contrast the location and size of functional units in the presence of such substantial inter-person variability, it is essential to study both common and subject-specific functional units in a group of people carrying out the same speech task. In this work, a new normalization technique is presented to simultaneously identify the common and subject-specific functional units defined in the tongue when tracked by tagged magnetic resonance imaging. To achieve our goal, a joint sparse non-negative matrix factorization framework is used, which learns a set of building blocks and subject-specific as well as common weighting matrices from motion quantities extracted from displacements. A spectral clustering technique is then applied to the subject-specific and common weighting matrices to determine the subject-specific functional units for each subject and the common functional units across subjects. Our experimental results using in vivo tongue motion data show that our approach is able to identify the common and subject-specific functional units with reduced size variability of tongue motion during speech.

Speech Map: A Statistical Multimodal Atlas of 4D Tongue Motion During Speech from Tagged and Cine MR Images.

Quantitative measurement of functional and anatomical traits of 4D tongue motion in the course of speech or other lingual behaviors remains a major challenge in scientific research and clinical applications. Here, we introduce a statistical multimodal atlas of 4D tongue motion using healthy subjects, which enables a combined quantitative characterization of tongue motion in a reference anatomical configuration. This atlas framework, termed Speech Map, combines cine- and tagged-MRI in order to provide both the anatomic reference and motion information during speech. Our approach involves a series of steps including (1) construction of a common reference anatomical configuration from cine-MRI, (2) motion estimation from tagged-MRI, (3) transformation of the motion estimations to the reference anatomical configuration, and (4) computation of motion quantities such as Lagrangian strain. Using this framework, the anatomic configuration of the tongue appears motionless, while the motion fields and associated strain measurements change over the time course of speech. In addition, to form a succinct representation of the high-dimensional and complex motion fields, principal component analysis is carried out to characterize the central tendencies and variations of motion fields of our speech tasks. Our proposed method provides a platform to quantitatively and objectively explain the differences and variability of tongue motion by illuminating internal motion and strain that have so far been intractable. The findings are used to understand how tongue function for speech is limited by abnormal internal motion and strain in glossectomy patients.

Differentiating post-cancer from healthy tongue muscle coordination patterns during speech using deep learning.

The ability to differentiate post-cancer from healthy tongue muscle coordination patterns is necessary for the advancement of speech motor control theories and for the development of therapeutic and rehabilitative strategies. A deep learning approach is presented to classify two groups using muscle coordination patterns from magnetic resonance imaging (MRI). The proposed method uses tagged-MRI to track the tongue's internal tissue points and atlas-driven non-negative matrix factorization to reduce the dimensionality of the deformation fields. A convolutional neural network is applied to the classification task yielding an accuracy of 96.90%, offering the potential to the development of therapeutic or rehabilitative strategies in speech-related disorders.

A Sparse Non-Negative Matrix Factorization Framework for Identifying Functional Units of Tongue Behavior From MRI.

Muscle coordination patterns of lingual behaviors are synergies generated by deforming local muscle groups in a variety of ways. Functional units are functional muscle groups of local structural elements within the tongue that compress, expand, and move in a cohesive and consistent manner. Identifying the functional units using tagged-magnetic resonance imaging (MRI) sheds light on the mechanisms of normal and pathological muscle coordination patterns, yielding improvement in surgical planning, treatment, or rehabilitation procedures. In this paper, to mine this information, we propose a matrix factorization and probabilistic graphical model framework to produce building blocks and their associated weighting map using motion quantities extracted from tagged-MRI. Our tagged-MRI imaging and accurate voxel-level tracking provide previously unavailable internal tongue motion patterns, thus revealing the inner workings of the tongue during speech or other lingual behaviors. We then employ spectral clustering on the weighting map to identify the cohesive regions defined by the tongue motion that may involve multiple or undocumented regions. To evaluate our method, we perform a series of experiments. We first use two-dimensional images and synthetic data to demonstrate the accuracy of our method. We then use three-dimensional synthetic and in vivo tongue motion data using protrusion and simple speech tasks to identify subject-specific and data-driven functional units of the tongue in localized regions.

Strain Map of the Tongue in Normal and ALS Speech Patterns from Tagged and Diffusion MRI.

Amyotrophic Lateral Sclerosis (ALS) is a neurological disease that causes death of neurons controlling muscle movements. Loss of speech and swallowing functions is a major impact due to degeneration of the tongue muscles. In speech studies using magnetic resonance (MR) techniques, diffusion tensor imaging (DTI) is used to capture internal tongue muscle fiber structures in three-dimensions (3D) in a non-invasive manner. Tagged magnetic resonance images (tMRI) are used to record tongue motion during speech. In this work, we aim to combine information obtained with both MR imaging techniques to compare the functionality characteristics of the tongue between normal and ALS subjects. We first extracted 3D motion of the tongue using tMRI from fourteen normal subjects in speech. The estimated motion sequences were then warped using diffeomorphic registration into the b0 spaces of the DTI data of two normal subjects and an ALS patient. We then constructed motion atlases by averaging all warped motion fields in each b0 space, and computed strain in the line of action along the muscle fiber directions provided by tractography. Strain in line with the fiber directions provides a quantitative map of the potential active region of the tongue during speech. Comparison between normal and ALS subjects explores the changing volume of compressing tongue tissues in speech facing the situation of muscle degradation. The proposed framework provides for the first time a dynamic map of contracting fibers in ALS speech patterns, and has the potential to provide more insight into the detrimental effects of ALS on speech.

Magnetic resonance imaging based anatomical assessment of tongue impairment due to amyotrophic lateral sclerosis: A preliminary study.

Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder, which impairs tongue function for speech and swallowing. A widely used Diffusion Tensor Imaging (DTI) analysis pipeline is employed for quantifying differences in tongue fiber myoarchitecture between controls and ALS patients. This pipeline uses both high-resolution magnetic resonance imaging (hMRI) and DTI. hMRI is used to delineate tongue muscles, while DTI provides indices to reveal fiber connectivity within and between muscles. The preliminary results using five controls and two patients show quantitative differences between the groups. This work has the potential to provide insights into the detrimental effects of ALS on speech and swallowing.

Geometric Navigation of Axons in a Cerebral Pathway: Comparing dMRI with Tract Tracing and Immunohistochemistry.

Brain fiber pathways are presumed to follow smooth curves but recent high angular resolution diffusion MRI (dMRI) suggests that instead they follow 3 primary axes often nearly orthogonal. To investigate this, we analyzed axon pathways under monkey primary motor cortex with (1) dMRI tractography, (2) axon tract tracing, and (3) axon immunohistochemistry. dMRI tractography shows the predicted crossings of axons in mediolateral and dorsoventral orientations and does not show axon turns in this region. Axons labeled with tract tracer in the motor cortex dispersed in the centrum semiovale by microscopically sharp axonal turns and/or branches (radii ≤15 µm) into 2 sharply defined orientations, mediolateral and dorsoventral. Nearby sections processed with SMI-32 antibody to label projection axons and SMI-312 antibody to label all axons revealed axon distributions parallel to the tracer axons. All 3 histological methods confirmed preponderant axon distributions parallel with dMRI axes with few axons (<20%) following smooth curves or diagonal orientations. These findings indicate that axons navigate deep white matter via microscopic sharp turns and branches between primary axes. They support dMRI observations of primary fiber axes, as well as the prediction that fiber crossings include navigational events not yet directly resolved by dMRI. New methods will be needed to incorporate coherent microscopic navigation into dMRI of connectivity.

A Four-dimensional Motion Field Atlas of the Tongue from Tagged and Cine Magnetic Resonance Imaging.

Representation of human tongue motion using three-dimensional vector fields over time can be used to better understand tongue function during speech, swallowing, and other lingual behaviors. To characterize the inter-subject variability of the tongue's shape and motion of a population carrying out one of these functions it is desirable to build a statistical model of the four-dimensional (4D) tongue. In this paper, we propose a method to construct a spatio-temporal atlas of tongue motion using magnetic resonance (MR) images acquired from fourteen healthy human subjects. First, cine MR images revealing the anatomical features of the tongue are used to construct a 4D intensity image atlas. Second, tagged MR images acquired to capture internal motion are used to compute a dense motion field at each time frame using a phase-based motion tracking method. Third, motion fields from each subject are pulled back to the cine atlas space using the deformation fields computed during the cine atlas construction. Finally, a spatio-temporal motion field atlas is created to show a sequence of mean motion fields and their inter-subject variation. The quality of the atlas was evaluated by deforming cine images in the atlas space. Comparison between deformed and original cine images showed high correspondence. The proposed method provides a quantitative representation to observe the commonality and variability of the tongue motion field for the first time, and shows potential in evaluation of common properties such as strains and other tensors based on motion fields.

HIgh b-value and high Resolution Integrated Diffusion (HIBRID) imaging.

The parameter selection for diffusion MRI experiments is dominated by the "k-q tradeoff" whereby the Signal to Noise Ratio (SNR) of the images is traded for either high spatial resolution (determined by the maximum k-value collected) or high diffusion sensitivity (effected by b-value or the q vector) but usually not both. Furthermore, different brain regions (such as gray matter and white matter) likely require different tradeoffs between these parameters due to the size of the structures to be visualized or the length-scale of the microstructure being probed. In this case, it might be advantageous to combine information from two scans - a scan with high q but low k (high angular resolution in diffusion but low spatial resolution in the image domain) to provide maximal information about white matter fiber crossing, and one low q but high k (low angular resolution but high spatial resolution) for probing the cortex. In this study, we propose a method, termed HIgh b-value and high Resolution Integrated Diffusion (HIBRID) imaging, for acquiring and combining the information from these two complementary types of scan with the goal of studying diffusion in the cortex without compromising white matter fiber information. The white-gray boundary and pial surface obtained from anatomical scans are incorporated as prior information to guide the fusion. We study the complementary advantages of the fused datasets, and assess the quality of the HIBRID data compared to either alone.

MGH-USC Human Connectome Project datasets with ultra-high b-value diffusion MRI.

The MGH-USC CONNECTOM MRI scanner housed at the Massachusetts General Hospital (MGH) is a major hardware innovation of the Human Connectome Project (HCP). The 3T CONNECTOM scanner is capable of producing a magnetic field gradient of up to 300 mT/m strength for in vivo human brain imaging, which greatly shortens the time spent on diffusion encoding, and decreases the signal loss due to T2 decay. To demonstrate the capability of the novel gradient system, data of healthy adult participants were acquired for this MGH-USC Adult Diffusion Dataset (N=35), minimally preprocessed, and shared through the Laboratory of Neuro Imaging Image Data Archive (LONI IDA) and the WU-Minn Connectome Database (ConnectomeDB). Another purpose of sharing the data is to facilitate methodological studies of diffusion MRI (dMRI) analyses utilizing high diffusion contrast, which perhaps is not easily feasible with standard MR gradient system. In addition, acquisition of the MGH-Harvard-USC Lifespan Dataset is currently underway to include 120 healthy participants ranging from 8 to 90 years old, which will also be shared through LONI IDA and ConnectomeDB. Here we describe the efforts of the MGH-USC HCP consortium in acquiring and sharing the ultra-high b-value diffusion MRI data and provide a report on data preprocessing and access. We conclude with a demonstration of the example data, along with results of standard diffusion analyses, including q-ball Orientation Distribution Function (ODF) reconstruction and tractography.

Simple, Scalable Proteomic Imaging for High-Dimensional Profiling of Intact Systems.

Combined measurement of diverse molecular and anatomical traits that span multiple levels remains a major challenge in biology. Here, we introduce a simple method that enables proteomic imaging for scalable, integrated, high-dimensional phenotyping of both animal tissues and human clinical samples. This method, termed SWITCH, uniformly secures tissue architecture, native biomolecules, and antigenicity across an entire system by synchronizing the tissue preservation reaction. The heat- and chemical-resistant nature of the resulting framework permits multiple rounds (>20) of relabeling. We have performed 22 rounds of labeling of a single tissue with precise co-registration of multiple datasets. Furthermore, SWITCH synchronizes labeling reactions to improve probe penetration depth and uniformity of staining. With SWITCH, we performed combinatorial protein expression profiling of the human cortex and also interrogated the geometric structure of the fiber pathways in mouse brains. Such integrated high-dimensional information may accelerate our understanding of biological systems at multiple levels.

Optical coherence tomography visualizes neurons in human entorhinal cortex.

The cytoarchitecture of the human brain is of great interest in diverse fields: neuroanatomy, neurology, neuroscience, and neuropathology. Traditional histology is a method that has been historically used to assess cell and fiber content in the ex vivo human brain. However, this technique suffers from significant distortions. We used a previously demonstrated optical coherence microscopy technique to image individual neurons in several square millimeters of en-face tissue blocks from layer II of the human entorhinal cortex, over 50 µm in depth. The same slices were then sectioned and stained for Nissl substance. We registered the optical coherence tomography (OCT) images with the corresponding Nissl stained slices using a nonlinear transformation. The neurons were then segmented in both images and we quantified the overlap. We show that OCT images contain information about neurons that is comparable to what can be obtained from Nissl staining, and thus can be used to assess the cytoarchitecture of the ex vivo human brain with minimal distortion. With the future integration of a vibratome into the OCT imaging rig, this technique can be scaled up to obtain undistorted volumetric data of centimeter cube tissue blocks in the near term, and entire human hemispheres in the future.

Probing dynamic myocardial microstructure with cardiac magnetic resonance diffusion tensor imaging.

This article is an invited editorial comment on the paper entitled "In vivo cardiovascular magnetic resonance diffusion tensor imaging shows evidence of abnormal myocardial laminar orientations and mobility in hypertrophic cardiomyopathy" by Ferreira et al., and published as Journal of Cardiovascular Magnetic Resonance 2014; 16:87.

Investigating the capability to resolve complex white matter structures with high b-value diffusion magnetic resonance imaging on the MGH-USC Connectom scanner.

One of the major goals of the NIH Blueprint Human Connectome Project was to map and quantify the white matter connections in the brain using diffusion tractography. Given the prevalence of complex white matter structures, the capability of resolving local white matter geometries with multiple crossings in the diffusion magnetic resonance imaging (dMRI) data is critical. Increasing b-value has been suggested for delineation of the finer details of the orientation distribution function (ODF). Although increased gradient strength and duration increase sensitivity to highly restricted intra-axonal water, gradient strength limitations require longer echo times (TE) to accommodate the increased diffusion encoding times needed to achieve a higher b-value, exponentially lowering the signal-to-noise ratio of the acquisition. To mitigate this effect, the MGH-USC Connectom scanner was built with 300 mT/m gradients, which can significantly reduce the TE of high b-value diffusion imaging. Here we report comparisons performed across b-values based on q-ball ODF metrics to investigate whether high b-value diffusion imaging on the Connectom scanner can improve resolving complex white matter structures. The q-ball ODF features became sharper as the b-value increased, with increased power fraction in higher order spherical harmonic series of the ODF and increased peak heights relative to the overall size of the ODF. Crossing structures were detected in an increasingly larger fraction of white matter voxels and the spatial distribution of two-way and three-way crossing structures was largely consistent with known anatomy. Results indicate that dMRI with high diffusion encoding on the Connectom system is a promising tool to better characterize, and ultimately understand, the underlying structural organization and motifs in the human brain.