Mapping microvasculature with acoustic angiography yields quantifiable differences between healthy and tumor-bearing tissue volumes in a rodent model.

PURPOSE: To determine if the morphologies of microvessels could be extracted from contrast material-enhanced acoustic angiographic ultrasonographic (US) images and used as a quantitative basis for distinguishing healthy from diseased tissue. MATERIALS AND METHODS: All studies were institutional animal care and use committee approved. Three-dimensional contrast-enhanced acoustic angiographic images were acquired in both healthy (n = 7) and tumor-bearing (n = 10) rats. High-spatial-resolution and high signal-to-noise acquisition was enabled by using a prototype dual-frequency US transducer (transmit at 4 MHz, receive at 30 MHz). A segmentation algorithm was utilized to extract microvessel structure from image data, and the distance metric (DM) and the sum of angles metric (SOAM), designed to distinguish different types of tortuosity, were applied to image data. The vessel populations extracted from tumor-bearing tissue volumes were compared against vessels extracted from tissue volumes in the same anatomic location within healthy control animals by using the two-sided Student t test. RESULTS: Metrics of microvascular tortuosity were significantly higher in the tumor population. The average DM of the tumor population (1.34 ± 0.40 [standard deviation]) was 23.76% higher than that of the control population (1.08 ± 0.08) (P < .0001), while the average SOAM (22.53 ± 7.82) was 50.73% higher than that of the control population (14.95 ± 4.83) (P < .0001). The DM and SOAM metrics for the control and tumor populations were significantly different when all vessels were pooled between the two animal populations. In addition, each animal in the tumor population had significantly different DM and SOAM metrics relative to the control population (P < .05 for all; P value ranges for DM, 3.89 × 10(-)(7) to 5.63 × 10(-)(3); and those for SOAM, 2.42 × 10(-)(12) to 1.57 × 10(-)(3)). CONCLUSION: Vascular network quantification by using high-spatial-resolution acoustic angiographic images is feasible. Data suggest that the angiogenic processes associated with tumor development in the models studied result in higher instances of vessel tortuosity near the tumor site.

A Feature-based Affine Registration Method for Capturing Background Lung Tissue Deformation for Ground Glass Nodule Tracking.

Lung nodule tracking assessment relies on cross-sectional measurements of the largest lesion profile depicted in initial and follow-up computed tomography (CT) images. However, apparent changes in nodule size assessed via simple image-based measurements may also be compromised by the effect of the background lung tissue deformation on the GGN between the initial and follow-up images, leading to erroneous conclusions about nodule changes due to disease. To compensate for the lung deformation and enable consistent nodule tracking, here we propose a feature-based affine registration method and study its performance vis-a-vis several other registration methods. We implement and test each registration method using both a lung- and a lesion-centered region of interest on ten patient CT datasets featuring twelve nodules, including both benign and malignant GGO lesions containing pure GGNs, part-solid, or solid nodules. We evaluate each registration method according to the target registration error (TRE) computed across 30 - 50 homologous fiducial landmarks surrounding the lesions and selected by expert radiologists in both the initial and follow-up patient CT images. Our results show that the proposed feature-based affine lesion-centered registration yielded a 1.1 ± 1.2 mm TRE, while a Symmetric Normalization deformable registration yielded a 1.2 ± 1.2 mm TRE, and a least-square fit registration of the 30-50 validation fiducial landmark set yielded a 1.5 ± 1.2 mm TRE. Although the deformable registration yielded a slightly higher registration accuracy than the feature-based affine registration, it is significantly more computationally efficient, eliminates the need for ambiguous segmentation of GGNs featuring ill-defined borders, and reduces the susceptibility of artificial deformations introduced by the deformable registration, which may lead to increased similarity between the registered initial and follow-up images, over-compensating for the background lung tissue deformation, and, in turn, compromising the true disease-induced nodule change assessment. We also assessed the registration qualitatively, by visual inspection of the subtraction images, and conducted a pilot pre-clinical study that showed the proposed feature-based lesion-centered affine registration effectively compensates for the background lung tissue deformation between the initial and follow-up images and also serves as a reliable baseline registration method prior to assessing lung nodule changes due to disease.

Perfusion Imaging: An Advection Diffusion Approach.

Perfusion imaging is of great clinical importance and is used to assess a wide range of diseases including strokes and brain tumors. Commonly used approaches for the quantitative analysis of perfusion images are based on measuring the effect of a contrast agent moving through blood vessels and into tissue. Contrast-agent free approaches, for example, based on intravoxel incoherent motion and arterial spin labeling, also exist, but are so far not routinely used clinically. Existing contrast-agent-dependent methods typically rely on the estimation of the arterial input function (AIF) to approximately model tissue perfusion. These approaches neglect spatial dependencies. Further, as reliably estimating the AIF is non-trivial, different AIF estimates may lead to different perfusion measures. In this work we therefore propose PIANO, an approach that provides additional insights into the perfusion process. PIANO estimates the velocity and diffusion fields of an advection-diffusion model best explaining the contrast dynamics without using an AIF. PIANO accounts for spatial dependencies and neither requires estimating the AIF nor relies on a particular contrast agent bolus shape. Specifically, we propose a convenient parameterization of the estimation problem, a numerical estimation approach, and extensively evaluate PIANO. Simulation experiments show the robustness and effectiveness of PIANO, along with its ability to distinguish between advection and diffusion. We further apply PIANO on a public brain magnetic resonance (MR) perfusion dataset of acute stroke patients, and demonstrate that PIANO can successfully resolve velocity and diffusion field ambiguities and results in sensitive measures for the assessment of stroke, comparing favorably to conventional measures of perfusion.

Automatic Spine Ultrasound Segmentation for Scoliosis Visualization and Measurement.

OBJECTIVE: Integrate tracked ultrasound and AI methods to provide a safer and more accessible alternative to X-ray for scoliosis measurement. We propose automatic ultrasound segmentation for 3-dimensional spine visualization and scoliosis measurement to address difficulties in using ultrasound for spine imaging. METHODS: We trained a convolutional neural network for spine segmentation on ultrasound scans using data from eight healthy adult volunteers. We tested the trained network on eight pediatric patients. We evaluated image segmentation and 3-dimensional volume reconstruction for scoliosis measurement. RESULTS: As expected, fuzzy segmentation metrics reduced when trained networks were translated from healthy volunteers to patients. Recall decreased from 0.72 to 0.64 (8.2% decrease), and precision from 0.31 to 0.27 (3.7% decrease). However, after finding optimal thresholds for prediction maps, binary segmentation metrics performed better on patient data. Recall decreased from 0.98 to 0.97 (1.6% decrease), and precision from 0.10 to 0.06 (4.5% decrease). Segmentation prediction maps were reconstructed to 3-dimensional volumes and scoliosis was measured in all patients. Measurement in these reconstructions took less than 1 minute and had a maximum error of 2.2° compared to X-ray. CONCLUSION: automatic spine segmentation makes scoliosis measurement both efficient and accurate in tracked ultrasound scans. SIGNIFICANCE: Automatic segmentation may overcome the limitations of tracked ultrasound that so far prevented its use as an alternative of X-ray in scoliosis measurement.

Computerized assessment of vessel morphological changes during treatment of glioblastoma multiforme: report of a case imaged serially by MRA over four years.

A patient with glioblastoma multiforme underwent serial computerized analysis of tumor-associated vasculature defined from magnetic resonance angiographic (MRA) scans obtained over almost a four year period. The clinical course included tumor resection with subsequent radiation therapy, a long symptom-free interval, emergence of a new malignant focus, resection of that focus, a stroke, and treatment with chemotherapy and anti-angiogenic therapy. Image analysis methods included segmentation of vessels from each MRA and statistical comparison of vessel morphology over 4 regions of interest (the initial tumor site, the second tumor site, a distant control region, and the entire brain) to the same 4 regions of interest in 50 healthy volunteers (26 females and 24 males; mean age 39 years). Results suggested that following completion of focal radiation therapy (RT) vessel shape abnormalities, if elevated at the time of RT completion, may progressively normalize for months in focal regions, that progressively severe vessel shape abnormalities can precede the emergence of a gadolinium enhancing lesion by months, that lesion resection can produce a dramatic but highly transient drop in abnormal vessel tortuosity both focally and globally, and that treatment with anti-angiogenic agents does not necessarily normalize vessel shape. Quantitative measurements of vessel morphology as defined from MRA may provide useful insights into tumor development and response to therapy.

Image-Based Methods for Phase Estimation, Gating, and Temporal Superresolution of Cardiac Ultrasound.

OBJECTIVE: Ultrasound is an effective tool for rapid noninvasive assessment of cardiac structure and function. Determining the cardiorespiratory phases of each frame in the ultrasound video and capturing the cardiac function at a much higher temporal resolution are essential in many applications. Fulfilling these requirements is particularly challenging in preclinical studies involving small animals with high cardiorespiratory rates, requiring cumbersome and expensive specialized hardware. METHODS: We present a novel method for the retrospective estimation of cardiorespiratory phases directly from the ultrasound videos. It transforms the videos into a univariate time series preserving the evidence of periodic cardiorespiratory motion, decouples the signatures of cardiorespiratory motion with a trend extraction technique, and estimates the cardiorespiratory phases using a Hilbert transform approach. We also present a robust nonparametric regression technique for respiratory gating and a novel kernel-regression model for reconstructing images at any cardiac phase facilitating temporal superresolution. RESULTS: We validated our methods using two-dimensional echocardiography videos and electrocardiogram (ECG) recordings of six mice. Our cardiac phase estimation method provides accurate phase estimates with a mean-phase-error range of 3%-6% against ECG derived phase and outperforms three previously published methods in locating ECGs R-wave peak frames with a mean-frame-error range of 0.73-1.36. Our kernel-regression model accurately reconstructs images at any cardiac phase with a mean-normalized-correlation range of 0.81-0.85 over 50 leave-one-out-cross-validation rounds. CONCLUSION AND SIGNIFICANCE: Our methods can enable tracking of cardiorespiratory phases without additional hardware and reconstruction of respiration-free single cardiac-cycle videos at a much higher temporal resolution.

A new preclinical ultrasound platform for widefield 3D imaging of rodents.

Noninvasive in vivo imaging technologies enable researchers and clinicians to detect the presence of disease and longitudinally study its progression. By revealing anatomical, functional, or molecular changes, imaging tools can provide a near real-time assessment of important biological events. At the preclinical research level, imaging plays an important role by allowing disease mechanisms and potential therapies to be evaluated noninvasively. Because functional and molecular changes often precede gross anatomical changes, there has been a significant amount of research exploring the ability of different imaging modalities to track these aspects of various diseases. Herein, we present a novel robotic preclinical contrast-enhanced ultrasound system and demonstrate its use in evaluating tumors in a rodent model. By leveraging recent advances in ultrasound, this system favorably compares with other modalities, as it can perform anatomical, functional, and molecular imaging and is cost-effective, portable, and high throughput, without using ionizing radiation. Furthermore, this system circumvents many of the limitations of conventional preclinical ultrasound systems, including a limited field-of-view, low throughput, and large user variability.

The effects of gray scale image processing on digital mammography interpretation performance.

RATIONALE AND OBJECTIVES: To determine the effects of three image-processing algorithms on diagnostic accuracy of digital mammography in comparison with conventional screen-film mammography. MATERIALS AND METHODS: A total of 201 cases consisting of nonprocessed soft copy versions of the digital mammograms acquired from GE, Fischer, and Trex digital mammography systems (1997-1999) and conventional screen-film mammograms of the same patients were interpreted by nine radiologists. The raw digital data were processed with each of three different image-processing algorithms creating three presentations-manufacturer's default (applied and laser printed to film by each of the manufacturers), MUSICA, and PLAHE-were presented in soft copy display. There were three radiologists per presentation. RESULTS: Area under the receiver operating characteristic curve for GE digital mass cases was worse than screen-film for all digital presentations. The area under the receiver operating characteristic for Trex digital mass cases was better, but only with images processed with the manufacturer's default algorithm. Sensitivity for GE digital mass cases was worse than screen film for all digital presentations. Specificity for Fischer digital calcifications cases was worse than screen film for images processed in default and PLAHE algorithms. Specificity for Trex digital calcifications cases was worse than screen film for images processed with MUSICA. CONCLUSION: Specific image-processing algorithms may be necessary for optimal presentation for interpretation based on machine and lesion type.

Quantification of Microvascular Tortuosity during Tumor Evolution Using Acoustic Angiography.

The recent design of ultra-broadband, multifrequency ultrasound transducers has enabled high-sensitivity, high-resolution contrast imaging, with very efficient suppression of tissue background using a technique called acoustic angiography. Here we perform the first application of acoustic angiography to evolving tumors in mice predisposed to develop mammary carcinoma, with the intent of visualizing and quantifying angiogenesis progression associated with tumor growth. Metrics compared include vascular density and two measures of vessel tortuosity quantified from segmentations of vessels traversing and surrounding 24 tumors and abdominal vessels from control mice. Quantitative morphologic analysis of tumor vessels revealed significantly increased vascular tortuosity abnormalities associated with tumor growth, with the distance metric elevated approximately 14% and the sum of angles metric increased 60% in tumor vessels versus controls. Future applications of this imaging approach may provide clinicians with a new tool in tumor detection, differentiation or evaluation, though with limited depth of penetration using the current configuration.

Neuroimaging in human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) is associated with central nervous system (CNS) changes that may affect cerebral blood flow (CBF), metabolism, structure, and diffusion. Each of the available neuroimaging techniques offers unique insight into the neural mechanisms underlying HIV, as well as a potential means of monitoring disease progression and treatment response. The purpose of the article is to provide a review of experimental studies evaluating changes related to HIV with imaging techniques, including single-photon emission computed tomography (SPECT), positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and perfusion MRI (pMRI).

Initialization, noise, singularities, and scale in height ridge traversal for tubular object centerline extraction.

The extraction of the centerlines of tubular objects in two and three-dimensional images is a part of many clinical image analysis tasks. One common approach to tubular object centerline extraction is based on intensity ridge traversal. In this paper, we evaluate the effects of initialization, noise, and singularities on intensity ridge traversal and present multiscale heuristics and optimal-scale measures that minimize these effects. Monte Carlo experiments using simulated and clinical data are used to quantify how these "dynamic-scale" enhancements address clinical needs regarding speed, accuracy, and automation. In particular, we show that dynamic-scale ridge traversal is insensitive to its initial parameter settings, operates with little additional computational overhead, tracks centerlines with subvoxel accuracy, passes branch points, and handles significant image noise. We also illustrate the capabilities of the method for medical applications involving a variety of tubular structures in clinical data from different organs, patients, and imaging modalities.

Volume rendering of segmented image objects.

This paper describes a new method of combining ray-casting with segmentation. Volume rendering is performed at interactive rates on personal computers, and visualizations include both "superficial" ray-casting through a shell at each object's surface and "deep" ray-casting through the confines of each object. A feature of the approach is the option to smoothly and interactively dilate segmentation boundaries along all axes. This ability, when combined with selective "turning off" of extraneous image objects, can help clinicians detect and evaluate segmentation errors that may affect surgical planning. We describe both a method optimized for displaying tubular objects and a more general method applicable to objects of arbitrary geometry. In both cases, select three-dimensional points are projected onto a modified z buffer that records additional information about the projected objects. A subsequent step selectively volume renders only through the object volumes indicated by the z buffer. We describe how our approach differs from other reported methods for combining segmentation with ray-casting, and illustrate how our method can be useful in helping to detect segmentation errors.

Measuring tortuosity of the intracerebral vasculature from MRA images.

The clinical recognition of abnormal vascular tortuosity, or excessive bending, twisting, and winding, is important to the diagnosis of many diseases. Automated detection and quantitation of abnormal vascular tortuosity from three-dimensional (3-D) medical image data would, therefore, be of value. However, previous research has centered primarily upon two-dimensional (2-D) analysis of the special subset of vessels whose paths are normally close to straight. This report provides the first 3-D tortuosity analysis of clusters of vessels within the normally tortuous intracerebral circulation. We define three different clinical patterns of abnormal tortuosity. We extend into 3-D two tortuosity metrics previously reported as useful in analyzing 2-D images and describe a new metric that incorporates counts of minima of total curvature. We extract vessels from MRA data, map corresponding anatomical regions between sets of normal patients and patients with known pathology, and evaluate the three tortuosity metrics for ability to detect each type of abnormality within the region of interest. We conclude that the new tortuosity metric appears to be the most effective in detecting several types of abnormalities. However, one of the other metrics, based on a sum of curvature magnitudes, may be more effective in recognizing tightly coiled, "corkscrew" vessels associated with malignant tumors.

A locally adaptive regularization based on anisotropic diffusion for deformable image registration of sliding organs.

We propose a deformable image registration algorithm that uses anisotropic smoothing for regularization to find correspondences between images of sliding organs. In particular, we apply the method for respiratory motion estimation in longitudinal thoracic and abdominal computed tomography scans. The algorithm uses locally adaptive diffusion tensors to determine the direction and magnitude with which to smooth the components of the displacement field that are normal and tangential to an expected sliding boundary. Validation was performed using synthetic, phantom, and 14 clinical datasets, including the publicly available DIR-Lab dataset. We show that motion discontinuities caused by sliding can be effectively recovered, unlike conventional regularizations that enforce globally smooth motion. In the clinical datasets, target registration error showed improved accuracy for lung landmarks compared to the diffusive regularization. We also present a generalization of our algorithm to other sliding geometries, including sliding tubes (e.g., needles sliding through tissue, or contrast agent flowing through a vessel). Potential clinical applications of this method include longitudinal change detection and radiotherapy for lung or abdominal tumours, especially those near the chest or abdominal wall.

Functional ultrasound imaging for assessment of extracellular matrix scaffolds used for liver organoid formation.

A method of 3D functional ultrasound imaging has been developed to enable non-destructive assessment of extracellular matrix scaffolds that have been prepared by decellularization protocols and are intended for recellularization to create organoids. A major challenge in organ decellularization is retaining patent micro-vascular structures crucial for nutrient access and functionality of organoids. The imaging method described here provides statistical distributions of flow rates throughout the tissue volumes, 3D vessel network architecture visualization, characterization of microvessel volumes and sizes, and delineation of matrix from vascular circuits. The imaging protocol was tested on matrix scaffolds that are tissue-specific, but not species-specific, matrix extracts, prepared by a process that preserved >98% of the collagens, collagen-associated matrix components, and matrix-bound growth factors and cytokines. Image-derived data are discussed with respect to assessment of scaffolds followed by proof-of-concept studies in organoid establishment using Hep3B, a human hepatoblast-like cell line. Histology showed that the cells attached to scaffolds with patent vasculature within minutes, achieved engraftment at near 100%, expressed liver-specific functions within 24 h, and yielded evidence of proliferation and increasing differentiation of cells throughout the two weeks of culture studies. This imaging method should prove valuable in analyses of such matrix scaffolds.

3D of Brain Shape and Volume After Cranial Vault Remodeling Surgery for Craniosynostosis Correction in Infants.

The skull of young children is made up of bony plates that enable growth. Craniosynostosis is a birth defect that causes one or more sutures on an infant's skull to close prematurely. Corrective surgery focuses on cranial and orbital rim shaping to return the skull to a more normal shape. Functional problems caused by craniosynostosis such as speech and motor delay can improve after surgical correction, but a post-surgical analysis of brain development in comparison with age-matched healthy controls is necessary to assess surgical outcome. Full brain segmentations obtained from pre- and post-operative computed tomography (CT) scans of 8 patients with single suture sagittal (n=5) and metopic (n=3), non-syndromic craniosynostosis from 41 to 452 days-of-age were included in this study. Age-matched controls obtained via 4D acceleration-based regression of a cohort of 402 full brain segmentations from healthy controls magnetic resonance images (MRI) were also used for comparison (ages 38 to 825 days). 3D point-based models of patient and control cohorts were obtained using SPHARM-PDM shape analysis tool. From a full dataset of regressed shapes, 240 healthy regressed shapes between 30 and 588 days-of-age (time step = 2.34 days) were selected. Volumes and shape metrics were obtained for craniosynostosis and healthy age-matched subjects. Volumes and shape metrics in single suture craniosynostosis patients were larger than age-matched controls for pre- and post-surgery. The use of 3D shape and volumetric measurements show that brain growth is not normal in patients with single suture craniosynostosis.

Neuroimaging of structural pathology and connectomics in traumatic brain injury: Toward personalized outcome prediction.

Recent contributions to the body of knowledge on traumatic brain injury (TBI) favor the view that multimodal neuroimaging using structural and functional magnetic resonance imaging (MRI and fMRI, respectively) as well as diffusion tensor imaging (DTI) has excellent potential to identify novel biomarkers and predictors of TBI outcome. This is particularly the case when such methods are appropriately combined with volumetric/morphometric analysis of brain structures and with the exploration of TBI-related changes in brain network properties at the level of the connectome. In this context, our present review summarizes recent developments on the roles of these two techniques in the search for novel structural neuroimaging biomarkers that have TBI outcome prognostication value. The themes being explored cover notable trends in this area of research, including (1) the role of advanced MRI processing methods in the analysis of structural pathology, (2) the use of brain connectomics and network analysis to identify outcome biomarkers, and (3) the application of multivariate statistics to predict outcome using neuroimaging metrics. The goal of the review is to draw the community's attention to these recent advances on TBI outcome prediction methods and to encourage the development of new methodologies whereby structural neuroimaging can be used to identify biomarkers of TBI outcome.

Deformable Image Registration of Sliding Organs Using Anisotropic Diffusive Regularization.

Traditional deformable image registration imposes a uniform smoothness constraint on the deformation field. This is not appropriate when registering images visualizing organs that slide relative to each other, and therefore leads to registration inaccuracies. In this paper, we present a deformation field regularization term that is based on anisotropic diffusion and accommodates the deformation field discontinuities that are expected when considering sliding motion. The registration algorithm was assessed first using artificial images of geometric objects. In a second validation, monomodal chest images depicting both respiratory and cardiac motion were generated using an anatomically-realistic software phantom and then registered. Registration accuracy was assessed based on the distances between corresponding segmented organ surfaces. Compared to an established diffusive regularization approach, the anisotropic diffusive regularization gave deformation fields that represented more plausible image correspondences, while giving rise to similar transformed moving images and comparable registration accuracy.

Approach-specific multi-grid anatomical modeling for neurosurgery simulation with public-domain and open-source software.

We present on-going work on multi-resolution sulcal-separable meshing for approach-specific neurosurgery simulation, in conjunction multi-grid and Total Lagrangian Explicit Dynamics finite elements. Conflicting requirements of interactive nonlinear finite elements and small structures lead to a multi-grid framework. Implications for meshing are explicit control over resolution, and prior knowledge of the intended neurosurgical approach and intended path. This information is used to define a subvolume of clinical interest, within some distance of the path and the target pathology. Restricted to this subvolume are a tetrahedralization of finer resolution, the representation of critical tissues, and sulcal separability constraint for all mesh levels.

Geometric metamorphosis.

Standard image registration methods do not account for changes in image appearance. Hence, metamorphosis approaches have been developed which jointly estimate a space deformation and a change in image appearance to construct a spatio-temporal trajectory smoothly transforming a source to a target image. For standard metamorphosis, geometric changes are not explicitly modeled. We propose a geometric metamorphosis formulation, which explains changes in image appearance by a global deformation, a deformation of a geometric model, and an image composition model. This work is motivated by the clinical challenge of predicting the long-term effects of traumatic brain injuries based on time-series images. This work is also applicable to the quantification of tumor progression (e.g., estimating its infiltrating and displacing components) and predicting chronic blood perfusion changes after stroke. We demonstrate the utility of the method using simulated data as well as scans from a clinical traumatic brain injury patient.